Hypermetabolism in ALS is associated with greater functional decline and shorter survival.

PubMed

Steyn, Frederik J; Ioannides, Zara A; van Eijk, Ruben P A; Heggie, Susan; Thorpe, Kathryn A; Ceslis, Amelia; Heshmat, Saman; Henders, Anjali K; Wray, Naomi R; van den Berg, Leonard H; Henderson, Robert D; McCombe, Pamela A; Ngo, Shyuan T

2018-04-29

To determine the prevalence of hypermetabolism, relative to body composition, in amyotrophic lateral sclerosis (ALS) and its relationship with clinical features of disease and survival. Fifty-eight patients with clinically definite or probable ALS as defined by El Escorial criteria, and 58 age and sex-matched control participants underwent assessment of energy expenditure. Our primary outcome was the prevalence of hypermetabolism in cases and controls. Longitudinal changes in clinical parameters between hypermetabolic and normometabolic patients with ALS were determined for up to 12 months following metabolic assessment. Survival was monitored over a 30-month period following metabolic assessment. Hypermetabolism was more prevalent in patients with ALS than controls (41% vs 12%, adjusted OR=5.4; p<0.01). Change in body weight, body mass index and fat mass (%) was similar between normometabolic and hypermetabolic patients with ALS. Mean lower motor neuron score (SD) was greater in hypermetabolic patients when compared with normometabolic patients (4 (0.3) vs 3 (0.7); p=0.04). In the 12 months following metabolic assessment, there was a greater change in Revised ALS Functional Rating Scale score in hypermetabolic patients when compared with normometabolic patients (-0.68 points/month vs -0.39 points/month; p=0.01). Hypermetabolism was inversely associated with survival. Overall, hypermetabolism increased the risk of death during follow-up to 220% (HR 3.2, 95% CI 1.1 to 9.4, p=0.03). Hypermetabolic patients with ALS have a greater level of lower motor neuron involvement, faster rate of functional decline and shorter survival. The metabolic index could be important for informing prognosis in ALS. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Dysregulation of chemokine receptor expression and function in leukocytes from ALS patients.

PubMed

Perner, Caroline; Perner, Florian; Stubendorff, Beatrice; Förster, Martin; Witte, Otto W; Heidel, Florian H; Prell, Tino; Grosskreutz, Julian

2018-03-28

Amyotrophic lateral sclerosis (ALS) is rapidly progressive adult-onset motor neuron disease characterized by the neurodegeneration of both upper and lower motor neurons in the cortex and the spinal cord; the majority of patients succumb to respiratory failure. Although the etiology is not yet fully understood, there is compelling evidence that ALS is a multi-systemic disorder, with peripheral inflammation critically contributing to the disease process. However, the full extent and nature of this immunological dysregulation remains to be established, particularly within circulating blood cells. Therefore, the aim of the present study was to identify dysregulated inflammatory molecules in peripheral blood cells of ALS patients and analyze for functional consequences of the observed findings. To this end, we employed flow cytometry-based screening to quantify the surface expression of major chemokine receptors and integrins. A significantly increased expression of CXCR3, CXCR4, CCL2, and CCL5 was observed on T cells in ALS patients compared to healthy controls. Intriguingly, the expression was even more pronounced in patients with a slow progressive phenotype. To further investigate the functional consequences of this altered surface expression, we used a modified Boyden chamber assay to measure chemotaxis in ALS patient-derived lymphocytes. Interestingly, chemoattraction with the CXCR3-Ligand IP10 led to upregulated migratory behavior of ALS lymphocytes compared to healthy controls. Taken together, our data provides evidence for a functional dysregulation of IP10-directed chemotaxis in peripheral blood cells in ALS patients. However, whether the chemokine itself or its receptor CXCR3, or both, could serve as potential therapeutic targets in ALS requires further investigations.

A Retrospective Study of the Characteristics and Clinical Significance of A-Waves in Amyotrophic Lateral Sclerosis.

PubMed

Fang, Jia; Cui, Liying; Liu, Mingsheng; Guan, Yuzhou; Ding, Qingyun; Shen, Dongchao; Li, Dawei; Tai, Hongfei

2017-01-01

A-wave was observed in patients with motor neuron disease (1). However, data on the characteristics and clinical significance of A-waves in patients with amyotrophic lateral sclerosis (ALS) have been scarce. The F-wave studies of 83 patients with ALS and 63 normal participants which were conducted previously at the Department of Neurology in Peking Union Medical College Hospital were retrospectively reviewed to determine the occurrence of A-waves in ALS. A-waves occurred more frequently in ALS patients than in normal controls. For the median and peroneal nerves, the frequencies of nerves with A-waves and frequencies of patients with A-waves were comparable between the ALS patients and normal controls. For the ulnar and tibial nerves, the frequencies of nerves with A-waves and frequencies of patients with A-waves were significantly increased in the ALS patients compared with those of the normal participants. Disease progression rate was slower in the ALS patients with A-waves (0.73 ± 0.99) than that in the ALS patients without A-waves (0.87 ± 0.55, P  = 0.007). No correlations were found between the amplitudes of F-waves with A-waves and those of A-waves in the ulnar nerves ( r  = 0.423, P  = 0.149). No correlations were found between the persistence of F-waves with A-waves and the persistence of A-waves in the ulnar nerves as well ( r  = 0.219, P  = 0.473). The occurrence of A-waves may indicate dysfunction of lower motor neurons and possibly imply a relatively slower degenerative process.

A Retrospective Study of the Characteristics and Clinical Significance of A-Waves in Amyotrophic Lateral Sclerosis

PubMed Central

Fang, Jia; Cui, Liying; Liu, Mingsheng; Guan, Yuzhou; Ding, Qingyun; Shen, Dongchao; Li, Dawei; Tai, Hongfei

2017-01-01

A-wave was observed in patients with motor neuron disease (1). However, data on the characteristics and clinical significance of A-waves in patients with amyotrophic lateral sclerosis (ALS) have been scarce. The F-wave studies of 83 patients with ALS and 63 normal participants which were conducted previously at the Department of Neurology in Peking Union Medical College Hospital were retrospectively reviewed to determine the occurrence of A-waves in ALS. A-waves occurred more frequently in ALS patients than in normal controls. For the median and peroneal nerves, the frequencies of nerves with A-waves and frequencies of patients with A-waves were comparable between the ALS patients and normal controls. For the ulnar and tibial nerves, the frequencies of nerves with A-waves and frequencies of patients with A-waves were significantly increased in the ALS patients compared with those of the normal participants. Disease progression rate was slower in the ALS patients with A-waves (0.73 ± 0.99) than that in the ALS patients without A-waves (0.87 ± 0.55, P = 0.007). No correlations were found between the amplitudes of F-waves with A-waves and those of A-waves in the ulnar nerves (r = 0.423, P = 0.149). No correlations were found between the persistence of F-waves with A-waves and the persistence of A-waves in the ulnar nerves as well (r = 0.219, P = 0.473). The occurrence of A-waves may indicate dysfunction of lower motor neurons and possibly imply a relatively slower degenerative process. PMID:29033889

Assessing behavioural changes in ALS: cross-validation of ALS-specific measures.

PubMed

Pinto-Grau, Marta; Costello, Emmet; O'Connor, Sarah; Elamin, Marwa; Burke, Tom; Heverin, Mark; Pender, Niall; Hardiman, Orla

2017-07-01

The Beaumont Behavioural Inventory (BBI) is a behavioural proxy report for the assessment of behavioural changes in ALS. This tool has been validated against the FrSBe, a non-ALS-specific behavioural assessment, and further comparison of the BBI against a disease-specific tool was considered. This study cross-validates the BBI against the ALS-FTD-Q. Sixty ALS patients, 8% also meeting criteria for FTD, were recruited. All patients were evaluated using the BBI and the ALS-FTD-Q, completed by a carer. Correlational analysis was performed to assess construct validity. Precision, sensitivity, specificity, and overall accuracy of the BBI when compared to the ALS-FTD-Q, were obtained. The mean score of the whole sample on the BBI was 11.45 ± 13.06. ALS-FTD patients scored significantly higher than non-demented ALS patients (31.6 ± 14.64, 9.62 ± 11.38; p < 0.0001). A significant large positive correlation between the BBI and the ALS-FTD-Q was observed (r = 0.807, p < 0.0001), and no significant correlations between the BBI and other clinical/demographic characteristics indicate good convergent and discriminant validity, respectively. 72% of overall concordance was observed. Precision, sensitivity, and specificity for the classification of severely impaired patients were adequate. However, lower concordance in the classification of mild behavioural changes was observed, with higher sensitivity using the BBI, most likely secondary to BBI items which endorsed behavioural aspects not measured by the ALS-FTD-Q. Good construct validity has been further confirmed when the BBI is compared to an ALS-specific tool. Furthermore, the BBI is a more comprehensive behavioural assessment for ALS, as it measures the whole behavioural spectrum in this condition.

Prevalence and predictors of thyroid functional abnormalities in newly diagnosed AL amyloidosis.

PubMed

Muchtar, E; Dean, D S; Dispenzieri, A; Dingli, D; Buadi, F K; Lacy, M Q; Hayman, S R; Kapoor, P; Leung, N; Russell, S; Lust, J A; Lin, Yi; Warsame, R; Gonsalves, W; Kourelis, T V; Go, R S; Chakraborty, R; Zeldenrust, S; Kyle, R A; Rajkumar, S Vincent; Kumar, S K; Gertz, M A

2017-06-01

Data on the effect of systemic immunoglobulin light chain amyloidosis (AL amyloidosis) on thyroid function are limited. To assess the prevalence of hypothyroidism in AL amyloidosis patients and determine its predictors. 1142 newly diagnosed AL amyloidosis patients were grouped based on the thyroid-stimulating hormone (TSH) measurement at diagnosis: hypothyroid group (TSH above upper normal reference; >5 mIU L -1 ; n = 217, 19% of study participants) and euthyroid group (n = 925, 81%). Predictors for hypothyroidism were assessed in a binary multivariate model. Survival between groups was compared using the log-rank test and a multivariate analysis. Patients with hypothyroidism were older, more likely to present with renal and hepatic involvement and had a higher light chain burden compared to patients in the euthyroid group. Higher proteinuria in patients with renal involvement and lower albumin in patients with hepatic involvement were associated with hypothyroidism. In a binary logistic regression model, age ≥65 years, female sex, renal involvement, hepatic involvement, kappa light chain restriction and amiodarone use were independently associated with hypothyroidism. Ninety-three per cent of patients in the hypothyroid group with free thyroxine measurement had normal values, consistent with subclinical hypothyroidism. Patients in the hypothyroid group had a shorter survival compared to patients in the euthyroid group (4-year survival 36% vs 43%; P = 0.008), a difference that was maintained in a multivariate analysis. A significant proportion of patients with AL amyloidosis present with hypothyroidism, predominantly subclinical, which carries a survival disadvantage. Routine assessment of TSH in these patients is warranted. © 2017 The Association for the Publication of the Journal of Internal Medicine.

Outcomes after out-of-hospital cardiac arrest treated by basic vs advanced life support.

PubMed

Sanghavi, Prachi; Jena, Anupam B; Newhouse, Joseph P; Zaslavsky, Alan M

2015-02-01

Most out-of-hospital cardiac arrests receiving emergency medical services in the United States are treated by ambulance service providers trained in advanced life support (ALS), but supporting evidence for the use of ALS over basic life support (BLS) is limited. To compare the effects of BLS and ALS on outcomes after out-of-hospital cardiac arrest. Observational cohort study of a nationally representative sample of traditional Medicare beneficiaries from nonrural counties who experienced out-of-hospital cardiac arrest between January 1, 2009, and October 2, 2011, and for whom ALS or BLS ambulance services were billed to Medicare (31,292 ALS cases and 1643 BLS cases). Propensity score methods were used to compare the effects of ALS and BLS on patient survival, neurological performance, and medical spending after cardiac arrest. Survival to hospital discharge, to 30 days, and to 90 days; neurological performance; and incremental medical spending per additional survivor to 1 year. Survival to hospital discharge was greater among patients receiving BLS (13.1% vs 9.2% for ALS; 4.0 [95% CI, 2.3-5.7] percentage point difference), as was survival to 90 days (8.0% vs 5.4% for ALS; 2.6 [95% CI, 1.2-4.0] percentage point difference). Basic life support was associated with better neurological functioning among hospitalized patients (21.8% vs 44.8% with poor neurological functioning for ALS; 23.0 [95% CI, 18.6-27.4] percentage point difference). Incremental medical spending per additional survivor to 1 year for BLS relative to ALS was $154,333. Patients with out-of-hospital cardiac arrest who received BLS had higher survival at hospital discharge and at 90 days compared with those who received ALS and were less likely to experience poor neurological functioning.

Death with dignity in Washington patients with amyotrophic lateral sclerosis

PubMed Central

Elliott, Michael A.; Jung Henson, Lily; Gerena-Maldonado, Elba; Strom, Susan; Downing, Sharon; Vetrovs, Jennifer; Kayihan, Paige; Paul, Piper; Kennedy, Kate; Benditt, Joshua O.; Weiss, Michael D.

2016-01-01

Objectives: To describe the amyotrophic lateral sclerosis (ALS) patients who sought medication under the Washington State Death with Dignity (DWD) Act since its inception in 2009. Methods: Chart review at 3 tertiary medical centers in the Seattle/Puget Sound region and comparison to publicly available data of ALS and all-cause DWD cohorts from Washington and Oregon. Results: In Washington State, 39 patients with ALS requested DWD from the University of Washington, Virginia Mason, and Swedish Medical Centers beginning in 2009. The median age at death was 65 years (range 46–86). Seventy-seven percent of the patients used the prescriptions. All of the patients who used the medications passed away without complications. The major reasons for patients to request DWD as reported by participating physicians were loss of autonomy and dignity and decrease in enjoyable activities. Inadequate pain control, financial cost, and loss of bodily control were less commonly indicated. These findings were similar to those of the 92 patients who sought DWD in Oregon. In Washington and Oregon, the percentage of patients with ALS seeking DWD is higher compared to the cancer DWD cohort. Furthermore, compared to the all-cause DWD cohort, patients with ALS are more likely to be non-Hispanic white, married, educated, enrolled in hospice, and to have died at home. Conclusions: Although a small number, ALS represents the disease with the highest proportion of patients seeking to participate in DWD. Patients with ALS who choose DWD are well-educated and have access to palliative or life-prolonging care. The use of the medications appears to be able to achieve the patients' goals without complications. PMID:27770068

Death with dignity in Washington patients with amyotrophic lateral sclerosis.

PubMed

Wang, Leo H; Elliott, Michael A; Jung Henson, Lily; Gerena-Maldonado, Elba; Strom, Susan; Downing, Sharon; Vetrovs, Jennifer; Kayihan, Paige; Paul, Piper; Kennedy, Kate; Benditt, Joshua O; Weiss, Michael D

2016-11-15

To describe the amyotrophic lateral sclerosis (ALS) patients who sought medication under the Washington State Death with Dignity (DWD) Act since its inception in 2009. Chart review at 3 tertiary medical centers in the Seattle/Puget Sound region and comparison to publicly available data of ALS and all-cause DWD cohorts from Washington and Oregon. In Washington State, 39 patients with ALS requested DWD from the University of Washington, Virginia Mason, and Swedish Medical Centers beginning in 2009. The median age at death was 65 years (range 46-86). Seventy-seven percent of the patients used the prescriptions. All of the patients who used the medications passed away without complications. The major reasons for patients to request DWD as reported by participating physicians were loss of autonomy and dignity and decrease in enjoyable activities. Inadequate pain control, financial cost, and loss of bodily control were less commonly indicated. These findings were similar to those of the 92 patients who sought DWD in Oregon. In Washington and Oregon, the percentage of patients with ALS seeking DWD is higher compared to the cancer DWD cohort. Furthermore, compared to the all-cause DWD cohort, patients with ALS are more likely to be non-Hispanic white, married, educated, enrolled in hospice, and to have died at home. Although a small number, ALS represents the disease with the highest proportion of patients seeking to participate in DWD. Patients with ALS who choose DWD are well-educated and have access to palliative or life-prolonging care. The use of the medications appears to be able to achieve the patients' goals without complications. © 2016 American Academy of Neurology.

Small airway dysfunction in smokers with stable ischemic heart disease.

PubMed

Llontop, Claudia; Garcia-Quero, Cristina; Castro, Almudena; Dalmau, Regina; Casitas, Raquel; Galera, Raúl; Iglesias, Alberto; Martinez-Ceron, Elisabet; Soriano, Joan B; García-Río, Francisco

2017-01-01

A higher prevalence of airflow limitation (AL) has been described in patients with ischemic heart disease (IHD). Although small airway dysfunction (SAD) is an early feature of AL, there is little information about its occurrence in IHD patients. Our objective was to describe the prevalence of SAD in IHD patients, while comparing patient-related outcomes and future health risk among IHD patients with AL, SAD and normal lung function. In 118 consecutive smoking patients with stable IHD, comorbidities, utilization of healthcare resources, current treatment, blood biochemistry and health status were recorded. SAD was evaluated by impulse oscillometry, and pre- and post-bronchodilator spirometry was performed. The prevalence of AL and SAD were 20.3 (95% CI, 13.1-27.6%) and 26.3% (95% CI, 18.3-34.2%), respectively. Compared to the normal lung function group, patients with SAD and without AL had lower spirometric values, poorer quality of life and higher levels of C-reactive protein (CRP), as well as increased cardiovascular risk and more vascular age. In patients with normal spirometry, the presence of SAD was independently associated with pack-years, HDL-cholesterol and CRP levels. In patients with IHD, the presence of SAD is common and that it is associated with reduced health status and increased future cardiac risk.

Small airway dysfunction in smokers with stable ischemic heart disease

PubMed Central

Llontop, Claudia; Garcia-Quero, Cristina; Castro, Almudena; Dalmau, Regina; Casitas, Raquel; Galera, Raúl; Iglesias, Alberto; Martinez-Ceron, Elisabet; Soriano, Joan B.; García-Río, Francisco

2017-01-01

Background A higher prevalence of airflow limitation (AL) has been described in patients with ischemic heart disease (IHD). Although small airway dysfunction (SAD) is an early feature of AL, there is little information about its occurrence in IHD patients. Our objective was to describe the prevalence of SAD in IHD patients, while comparing patient-related outcomes and future health risk among IHD patients with AL, SAD and normal lung function. Methods In 118 consecutive smoking patients with stable IHD, comorbidities, utilization of healthcare resources, current treatment, blood biochemistry and health status were recorded. SAD was evaluated by impulse oscillometry, and pre- and post-bronchodilator spirometry was performed. Results The prevalence of AL and SAD were 20.3 (95% CI, 13.1–27.6%) and 26.3% (95% CI, 18.3–34.2%), respectively. Compared to the normal lung function group, patients with SAD and without AL had lower spirometric values, poorer quality of life and higher levels of C-reactive protein (CRP), as well as increased cardiovascular risk and more vascular age. In patients with normal spirometry, the presence of SAD was independently associated with pack-years, HDL-cholesterol and CRP levels. Conclusion In patients with IHD, the presence of SAD is common and that it is associated with reduced health status and increased future cardiac risk. PMID:28846677

"ALS reversals": demographics, disease characteristics, treatments, and co-morbidities.

PubMed

Harrison, Daniel; Mehta, Paul; van Es, Michael A; Stommel, Elijah; Drory, Vivian E; Nefussy, Beatrice; van den Berg, Leonard H; Crayle, Jesse; Bedlack, Richard

2018-04-02

To identify differences in demographics, disease characteristics, treatments, and co-morbidities between patients with "amyotrophic lateral sclerosis (ALS) reversals" and those with typically progressive ALS. Cases of possible ALS reversals were found in prior publications, in the Duke ALS clinic, through self-referral or referral from other Neurologists, and on the internet. Of 89 possible reversals identified, 36 cases were included because chart or literature review confirmed their diagnosis and a robust, sustained improvement in at least one objective measure. Controls were participants in the Pooled Resource Open-Access ALS Clinical Trials database and the National ALS Registry. Cases and controls were compared using descriptive statistics. ALS reversals were more likely to be male, have limb onset disease, and initially progress faster. The prevalences of myasthenia gravis (MG) and purely lower motor neuron disease in cases were higher than estimates of these prevalences in the general population. The odds of taking curcumin, luteolin, cannabidiol, azathioprine, copper, glutathione, vitamin D, and fish oil were greater for cases than controls. When compared to patients with typically progressive ALS, patients with reversals differed in their demographics, disease characteristics, and treatments. While some of these patients may have had a rare antibody-mediated ALS mimicker, such as atypical myasthenia gravis, details of their exams, EMGs and family histories argue that this was unlikely. Instead, our data suggest that ALS reversals warrant evaluation for mechanisms of disease resistance and that treatments associated with multiple ALS reversals deserve further study.

Longitudinal course of cortical thickness decline in amyotrophic lateral sclerosis.

PubMed

Schuster, Christina; Kasper, Elisabeth; Machts, Judith; Bittner, Daniel; Kaufmann, Jörn; Benecke, Reiner; Teipel, Stefan; Vielhaber, Stefan; Prudlo, Johannes

2014-10-01

To determine longitudinal rates of cortical atrophy in classical Amyotrophic lateral sclerosis (ALS) and ALS variants. Rates of cortical thinning were determined between 2 scans, 3-15 months apart, in 77 ALS patients: 51 classical, 12 upper motor neuron (UMN), and 14 lower motor neuron (LMN) ALS variants. Cortical thickness at the first assessment was compared with 60 healthy controls matched by age and gender. Atrophy rates were compared between patient sub-groups and correlated with disease duration, progression, and severity. Using a cross-sectional analysis, we found a significant difference in cortical thickness between ALS patients and controls in the motor and extra-motor areas (left medial orbito frontal gyrus, left inferior parietal gyrus, bilateral insular cortex, right fusiform gyrus, bilateral precuneus). Using a longitudinal analysis, we found a significant decline of cortical thickness in frontal, temporal, and parietal regions over the course of the study in ALS patients. Effects were independent of the clinical subtype, with exception of the precentral gyrus (p < 0.001). The LMN ALS variants demonstrated the highest rates of cortical thinning in the precentral gyrus, the UMN-dominant subjects exhibited intermediate rates of atrophy, and the classical ALS patients exhibited no such change. Atrophy of the precentral gyrus in classical ALS indicates a floor effect at the first assessment, resulting in a lack of further atrophy over time. Structural loss of the precentral gyrus appears to be an early sign of classical ALS. Over time, patterns of cortical thinning in extra-motor areas can be identified in ALS, regardless of the phenotype.

Plasma Aluminum Concentrations in Pediatric Patients Receiving Long-Term Parenteral Nutrition.

PubMed

Courtney-Martin, Glenda; Kosar, Christina; Campbell, Alison; Avitzur, Yaron; Wales, Paul W; Steinberg, Karen; Harrison, Debra; Chambers, Kathryn

2015-07-01

Patients receiving long-term parenteral nutrition (PN) are at increased risk of aluminium (Al) toxicity because of bypass of the gastrointestinal tract during PN infusion. Complications of Al toxicity include metabolic bone disease (MBD), Al-associated encephalopathy in adults, and impaired neurological development in preterm infants. Unlike the United States, there are no regulations regarding Al content of large- and small-volume parenterals in Canada. We, therefore, aimed to present our data on plasma Al concentration and Al intake from our cohort of pediatric patients receiving long-term PN. Plasma Al concentration was retrospectively gathered from the patient charts of all 27 patients with intestinal failure (IF) receiving long-term PN at The Hospital for Sick Children, Toronto, Canada, and compared with age- and sex-matched controls recruited for comparison. In addition, Al concentration was measured in PN samples collected from 10 randomly selected patients with IF and used to determine their Al intake. The plasma Al concentration of patients with IF receiving long-term PN was significantly higher than that of control participants (1195 ± 710 vs 142 ± 63 nmol/L; P < .0001). In the subgroup of 10 patients for whom Al intake from their PN solution was determined, mean ± SD Al intake from PN was 15.4 ± 15 µg/kg, 3 times the Food and Drug Administration upper recommended intake level, and Al intake was significantly related to plasma Al concentration (P = .02, r (2) = 0.52). Pediatric patients receiving long-term PN for IF in Canada are at risk for Al toxicity. © 2014 American Society for Parenteral and Enteral Nutrition.

Elevated levels of ferritin in the cerebrospinal fluid of amyotrophic lateral sclerosis patients.

PubMed

Zheng, Y; Gao, L; Wang, D; Zang, D

2017-08-01

The aim of the study was to detect changes in the levels of ferritin heavy chain (FHC), ferritin light chain (FLC), and transferrin in the cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients and to analyze the correlations between the levels of these proteins and various clinical parameters. Cerebrospinal fluid and serum samples were obtained from 54 ALS patients and 46 non-inflammatory neurological disease control (non-INDC) patients. CSF and serum FHC, FLC, and transferring levels were measured via the enzyme-linked immunosorbent method using a commercial ELISA kit, and the times from onset (durations), ALS functional rating scale-revised (ALSFRS-r) scores, and disease progression rates (DPRs) were analyzed by registered neurologists. Statistical analysis was performed via Prism software. Compared with controls, ALS patients exhibited significantly increased FHC and FLC levels in CSF, which were positively correlated with DPR and negatively correlated with duration. Serum transferrin levels were significantly increased in ALS patients but were not correlated with disease progression. FHC and FLC in CSF rapidly increased as the disease worsened. This study demonstrated that the clinical measurement of FHC and FLC in CSF may be beneficial for disease differentiation and evaluating progression in patients with ALS. Compared with levels in serum, the levels of FHC and FLC in CSF might be more reliable for diagnosing and assessing the progression of ALS. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Defining SOD1 ALS natural history to guide therapeutic clinical trial design.

PubMed

Bali, Taha; Self, Wade; Liu, Jingxia; Siddique, Teepu; Wang, Leo H; Bird, Thomas D; Ratti, Elena; Atassi, Nazem; Boylan, Kevin B; Glass, Jonathan D; Maragakis, Nicholas J; Caress, James B; McCluskey, Leo F; Appel, Stanley H; Wymer, James P; Gibson, Summer; Zinman, Lorne; Mozaffar, Tahseen; Callaghan, Brian; McVey, April L; Jockel-Balsarotti, Jennifer; Allred, Peggy; Fisher, Elena R; Lopate, Glenn; Pestronk, Alan; Cudkowicz, Merit E; Miller, Timothy M

2017-02-01

Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALS SOD1 ) will provide key information for optimising clinical trials in this patient population. To establish an updated natural history of ALS SOD1 . Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000. Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1 A4V ), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1 non-A4V ) for analysis. Mean age of disease onset was 49.7±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1 A4V and SOD1 non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1 A4V . SOD1 A4V survival probability (median survival 1.2 years) was significantly decreased compared with SOD1 non-A4V (median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1 A4V compared with SOD1 non-A4V participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1 A4V compared with SOD1 non-A4V (p=0.02). SOD1 A4V is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALS SOD1 patient population. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Value of 18fluorodeoxyglucose-positron-emission tomography in amyotrophic lateral sclerosis: a prospective study.

PubMed

Van Laere, Koen; Vanhee, Annelies; Verschueren, Jolien; De Coster, Liesbeth; Driesen, An; Dupont, Patrick; Robberecht, Wim; Van Damme, Philip

2014-05-01

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder primarily affecting the motor system, with extramotor involvement to a variable extent. Biomarkers for early differential diagnosis and prognosis are needed. An autosomal dominant hexanucleotide (GGGGCC) expansion in the noncoding region of the chromosome 9 open reading frame 72 (C9orf72) gene is the most frequent genetic cause of ALS, but its metabolic pattern has not been studied systematically. To evaluate the use of 18fluorodeoxyglucose-positron-emission tomography as a marker of ALS pathology and investigate whether a specific metabolic signature is present in patients with C9orf72 mutations. In total, 81 patients with a suspected diagnosis of ALS at University Hospital Leuven were prospectively investigated. All underwent detailed neurological examination and electrodiagnostic and genetic testing for the major known genetic causes of ALS (C9orf72, SOD1, TARDBP, and FUS). A diagnosis of ALS was made in 70 of 81 patients. Of these, 11 were C9orf72 positive and 59 were C9orf72 negative. In 7 patients, the diagnosis of primary lateral sclerosis was made; 4 patients had progressive muscular atrophy. A screened healthy control population was used for comparison. Positron-emission tomographic data were spatially normalized and analyzed using a predefined volume of interest and a voxel-based analysis (SPM8). Discriminant analysis was done both volume of interest based and voxel based using a support vector machine approach. Compared with control participants, 18fluorodeoxyglucose-positron-emission tomography showed perirolandic and variable prefrontal hypometabolism in most patients. Patients with primary lateral sclerosis showed a similar pattern. Patients with C9orf72-positive ALS had discrete relative hypometabolism in the thalamus and posterior cingulate compared with those with C9orf72-negative ALS. A posteriori-corrected discriminant analysis was able to correctly classify 95% of ALS cases and 71% of primary lateral sclerosis cases. Prefrontal hypometabolism was associated with reduced clinical functioning (ALS Functional Rating Scale). Extensive hypometabolism in the prefrontal or anterior temporal areas was present in 10% of patients and associated with significantly shorter survival as an independent factor (n = 63, P < .001). Patients who were C9orf72 positive did not differ in survival compared with those who were C9orf72 negative. 18Fluorodeoxyglucose-positron-emission tomography is a useful early diagnostic and prognostic marker for ALS. Amyotrophic lateral sclerosis that is positive for C9orf72 is characterized by only mild cerebral metabolic differences that show no prognostic difference.

Comparative feasibility of implementing rapid diagnostic test and microscopy for parasitological diagnosis of malaria in Uganda.

PubMed

Batwala, Vincent; Magnussen, Pascal; Nuwaha, Fred

2011-12-19

In Uganda, parasite-based diagnosis is recommended for every patient suspected to have malaria before prescribing anti-malarials. However, the majority of patients are still treated presumptively especially in low-level health units. The feasibility of implementing parasite-based diagnosis for uncomplicated malaria in rural health centres (HCs) was investigated with a view to recommending measures for scaling up the policy. Thirty HCs were randomized to implement parasite-based diagnosis based on rapid diagnostic tests [RDTs] (n = 10), blood microscopy (n = 10) and presumptive diagnosis (control arm) (n = 10). Feasibility was assessed by comparing the proportion of patients who received parasite-based diagnosis; with a positive malaria parasite-based diagnosis who received artemether-lumefantrine (AL); with a negative malaria parasite-based diagnosis who received AL; and patient waiting time. Clinicaltrials.gov: NCT00565071. 102, 087 outpatients were enrolled. Patients were more likely to be tested in the RDT 44, 565 (96.6%) than in microscopy arm 19, 545 (60.9%) [RR: 1.59]. RDTs reduced patient waiting time compared to microscopy and were more convenient to health workers and patients. Majority 23, 804 (99.7%) in presumptive arm were prescribed AL. All (100%) of patients who tested positive for malaria in RDT and microscopy arms were prescribed anti-malarials. Parasitological-based diagnosis significantly reduced AL prescription in RDT arm [RR: 0.62] and microscopy arm [RR: 0.72] compared to presumptive treatment. Among patients not tested in the two intervention arms, 12, 044 (96.1%) in microscopy and 965 (61.6%) in RDT arm were treated with AL [RR: 1.56]. Overall 10, 558 (29.4%) with negative results [5, 110 (23.4%) in RDT and 5, 448 (39.0%) in microscopy arms] were prescribed AL. It was more feasible to implement parasite-based diagnosis for malaria using RDT than with microscopy. A high proportion of patients with negative malaria results are still prescribed anti-malarials. There is need to increase access to parasite-based diagnosis where microscopy is used. In order to fully harness the benefits of parasitological confirmation of malaria, it is necessary to reduce the prescription of anti-malarials in negative patients.

High frequency of C9orf72 hexanucleotide repeat expansion in amyotrophic lateral sclerosis patients from two founder populations sharing the same risk haplotype.

PubMed

Goldstein, Orly; Gana-Weisz, Mali; Nefussy, Beatrice; Vainer, Batel; Nayshool, Omri; Bar-Shira, Anat; Traynor, Bryan J; Drory, Vivian E; Orr-Urtreger, Avi

2018-04-01

We characterized the C9orf72 hexanucleotide repeat expansion (RE) mutation in amyotrophic lateral sclerosis (ALS) patients of 2 distinct origins, Ashkenazi and North Africa Jews (AJ, NAJ), its frequency, and genotype-phenotype correlations. In AJ, 80% of familial ALS (fALS) and 11% of sporadic ALS carried the RE, a total of 12.9% of all AJ-ALS compared to 0.3% in AJ controls (odds ratio [OR] = 44.3, p < 0.0001). In NAJ, 10% of fALS and 9% of sporadic ALS carried the RE, a total of 9.1% of all NAJ-ALS compared to 1% in controls (OR = 9.9, p = 0.0006). We identified a risk haplotype shared among all ALS patients, although an association with age at disease onset, fALS, and dementia were observed only in AJ. Variations were identified downstream the repeats. The risk haplotype and these polymorphisms were at high frequencies in alleles with 8 repeats or more, suggesting sequence instability. The different genotype-phenotype correlations and OR, together with the large range in age at onset, suggest that other modifiers and risk factors may affect penetrance and phenotype in ALS. Copyright © 2017 Elsevier Inc. All rights reserved.

Increased oxidative stress in patients with amyotrophic lateral sclerosis and the effect of edaravone administration.

PubMed

Nagase, Midori; Yamamoto, Yorihiro; Miyazaki, Yusuke; Yoshino, Hiide

2016-05-01

Compared to age-matched healthy controls (n = 55), patients with amyotrophic lateral sclerosis (ALS) (n = 26) showed increased oxidative stress as indicated by a significantly increased percentage of oxidized coenzyme Q10 (%CoQ10) in total plasma coenzyme Q10, a significantly decreased level of plasma uric acid, and a significantly decreased percentage of polyunsaturated fatty acids in total plasma free fatty acids (FFA). Therefore, the efficacy of edaravone, a radical scavenger, in these ALS patients was examined. Among 26 ALS patients, 17 received edaravone (30 mg/day, one to four times a week) for at least 3 months, and 13 continued for 6 months. Changes in revised ALS functional rating scale (ALSFRS-R) were significantly smaller in these patients than in edaravone-untreated ALS patients (n = 19). Edaravone administration significantly reduced excursions of more than one standard deviation from the mean for plasma FFA levels and the contents of palmitoleic and oleic acids, plasma markers of tissue oxidative damage, in the satisfactory progress group (ΔALSFRS-R ≥ 0) as compared to the ingravescent group (ΔALSFRS-R < -5). Edaravone treatment increased plasma uric acid, suggesting that it is an effective scavenger of peroxynitrite. However, edaravone administration did not decrease %CoQ10. Therefore, combined treatment with agents such as coenzyme Q10 may further reduce oxidative stress in ALS patients.

Comparison of Fixed-dose Combinations of Amlodipine/Losartan Potassium/Chlorthalidone and Amlodipine/Losartan Potassium in Patients With Stage 2 Hypertension Inadequately Controlled With Amlodipine/Losartan Potassium: A Randomized, Double-blind, Multicenter, Phase III Study.

PubMed

Hong, Soon Jun; Jeong, Han Saem; Han, Seung Hwan; Chang, Ki Yuk; Hong, Bum Kee; Lee, Bong Ki; Chae, Shung Chull; Kim, Woo Shik; Park, Chang Gyu; Heo, Jung Ho; Lee, Seung Uk; Kim, Young Dae; Kim, Kee Sik; Choi, Jung Hyun; Kang, Hyun Jae; Kim, Jae Joong; Kang, Seok Min; Choi, Young Jin; Shin, Joon Han; Chun, Kook Jin; Shin, Dong Gu; Park, Seong Hoon; Kwan, Jun; Choi, Yu Jeong; Jeong, Myung Ho; Chae, Jei Keon; Kim, Dong Woon; Cho, Jung Rae; Han, Kyoo Rok; Won, Kyung Heon; Park, Sang Ho; Lee, Sang Kon; Kim, Sang Hoon; Jung, Jina; Kim, Cheol Ho

2017-10-01

The goal of this study was to compare the efficacy and safety of fixed-dose combinations of amlodipine/losartan potassium/chlorthalidone (A/L/C) and A/L in Korean patients with stage 2 hypertension inadequately controlled by A/L. This study was an 8-week, randomized double-blind, multicenter, phase III clinical trial. Three hundred forty volunteer patients with stage 2 hypertension were randomized to receive A/L/C or A/L. The primary end point was a change in sitting systolic blood pressure (SitSBP) after 8 weeks of treatment. As secondary end points, the change in SitSBP after 2 weeks of treatment and the change in sitting diastolic blood pressure (SitDBP) were compared between treatment groups. All patients were assessed for adverse events, clinical laboratory data, and vital signs. Of 330 patients from 33 medical centers, 328 patients who had available efficacy data were analyzed. After 8 weeks of double-blind treatment, the mean (SD) changes in SitSBP at 8 weeks were -16.4 (0.9) mm Hg and -6.9 (1.0) mm Hg in the A/L/C and A/L groups, respectively. A/L/C had a statistically superior blood pressure-lowering effect compared with that of A/L (mean [SD] difference, 9.5 [1.3] mm Hg; P < 0.001). The mean (SD) change in SitDBP at 8 weeks was significantly greater with A/L/C (-8.0 [0.6] mm Hg) than with A/L (-3.6 [0.6] mm Hg) (P < .001). In terms of the mean (SD) change in SitDBP at 2 weeks compared with baseline, A/L/C (-5.9 [0.5] mm Hg) was statistically different from A/L (-2.9 [0.5] mm Hg) (P < .001). Mean (SD) SitSBP change from baseline to week 2 was -13.2 (0.9) and -5.5 (0.9) in the A/L/C and A/L groups, respectively, with a statistically significant blood pressure-lowering effect (P < 0.001). The number of participants who achieved target blood pressure at week 8 was significantly higher in the A/L/C group (93 patients [55.7%]) than in the A/L group (48 [29.8%]) (P < 0.001). Adverse drug reactions were observed in 23 patients (7.0%), and the incidence of dizziness was significantly higher in the A/L/C group than in the A/L group (4.8% vs 0.6%, P = 0.037) There were no serious adverse events associated with the study drugs. The results of this study suggest that A/L/C had a significantly increased blood pressure-lowering efficacy compared with that of A/L and had a good safety profile. ClinicalTrials.gov identifier: NCT02916602. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Differential involvement of corticospinal tract (CST) fibers in UMN-predominant ALS patients with or without CST hyperintensity: A diffusion tensor tractography study.

PubMed

Rajagopalan, Venkateswaran; Pioro, Erik P

2017-01-01

Diagnosis of amyotrophic lateral sclerosis (ALS) depends on clinical evidence of combined upper motor neuron (UMN) and lower motor neuron (LMN) degeneration, although ALS patients can present with features predominantly of one or the other. Some UMN-predominant patients show hyperintense signal along the intracranial corticospinal tract (CST) on T2- and proton density (PD)-weighted images (ALS-CST +), and appear to have faster disease progression when compared to those without CST hyperintensity (ALS-CST -). The reason for this is unknown. We hypothesized that diffusion tensor tractography (DTT) would reveal differences in DTI abnormalities along the intracranial CST between these two patient subgroups. Clinical DTI scans were obtained at 1.5T in 14 neurologic controls and 45 ALS patients categorized into two UMN phenotypes based on clinical measures and MRI. DTT was used to quantitatively assess the CST in control and ALS groups. DTT revealed subcortical loss ('truncation') of virtual motor CST fibers (presumably) projecting from the precentral gyrus (PrG) in ALS patients but not in controls; in contrast, virtual fibers (presumably) projecting to the adjacent postcentral gyrus (PoG) were spared. No significant differences in virtual CST fiber length were observed between controls and ALS patients. However, the frequency of CST truncation was significantly higher in the ALS-CST + subgroup (9 of 21) than in the ALS-CST - subgroup (4 of 24; p  = 0.049), suggesting this finding could differentiate these ALS subgroups. Also, because virtual CST truncation occurred only in the ALS patient group and not in the control group ( p  = 0.018), this DTT finding could prove to be a diagnostic biomarker of ALS. Significantly shorter disease duration and faster disease progression rate were observed in ALS patients with CST fiber truncation than in those without ( p  < 0.05). DTI metrics of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were also determined in four regions of interest (ROIs) along the CST, namely: cerebral peduncle (CP), posterior limb of internal capsule (PLIC), centrum semiovale at top of lateral ventricle (CSoLV) and subcortical to primary motor cortex (subPMC). Of note, FA values along the left hemisphere virtual CST tract were significantly different between controls and ALS-CST + patients ( p  < 0.05) only at the PLIC level, but not at the CSoLV or subPMC level. Also, no significant differences in FA values were observed between ALS subgroups or between control and ALS-CST - groups ( p  > 0.05) in any of the ROIs. In addition, comparing FA values between ALS patients with CST truncation and those without in the aforementioned four ROIs, revealed no significant differences in either hemisphere. However, visual evaluation of DTT was able to identify UMN degeneration in patients with ALS, particularly in those with a more aggressive clinical disease course and possibly different pathologic processes.

Hyaluronic acid is increased in the skin and urine in patients with amyotrophic lateral sclerosis

NASA Technical Reports Server (NTRS)

Ono, S.; Imai, T.; Yamauchi, M.; Nagao, K.

1996-01-01

We performed morphological studies of skin and measured glycosaminoglycans in the urine from patients with sporadic amyotrophic lateral sclerosis (ALS) and control subjects. The wide spaces separating collagen bundles reacted strongly with alcian blue stain in ALS patients and stained more markedly as ALS progressed. Staining with alcian blue was virtually eliminated by Streptomyces hyaluronidase. The urinary excretion of hyaluronic acid (HA) (mg/day) was significantly increased (P < 0.01) in ALS patients compared with that of control subjects, and there was a significant positive correlation between the excreted amount of HA and the duration of illness in advanced ALS patients with a duration of more than 2 years from clinical onset (r = 0.72, P < 0.02). We suggest that sporadic ALS includes a metabolic disorder of HA in which an accumulation of HA in the skin is linked to an increased urinary excretion of HA.

Defining SOD1 ALS natural history to guide therapeutic clinical trial design

PubMed Central

Bali, Taha; Self, Wade; Liu, Jingxia; Siddique, Teepu; Wang, Leo H; Bird, Thomas D; Ratti, Elena; Atassi, Nazem; Boylan, Kevin B; Glass, Jonathan D; Maragakis, Nicholas J; Caress, James B; McCluskey, Leo F; Appel, Stanley H; Wymer, James P; Gibson, Summer; Zinman, Lorne; Mozaffar, Tahseen; Callaghan, Brian; McVey, April L; Jockel-Balsarotti, Jennifer; Allred, Peggy; Fisher, Elena R; Lopate, Glenn; Pestronk, Alan; Cudkowicz, Merit E; Miller, Timothy M

2016-01-01

Importance Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALSSOD1) will provide key information for optimising clinical trials in this patient population. Objective To establish an updated natural history of ALSSOD1. Design, setting and participants Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000. Main outcomes and measures Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1A4V), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1non-A4V) for analysis. Results Mean age of disease onset was 49.7 ±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1A4V and SOD1non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1A4V. SOD1A4V survival probability (median survival 1.2 years) was significantly decreased compared with SOD1non-A4V (median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1A4V compared with SOD1non-A4V participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1A4V compared with SOD1non-A4V (p=0.02). Conclusions and relevance SOD1A4V is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALSSOD1 patient population. PMID:27261500

Clinical features and psychiatric comorbidities of borderline personality disorder patients with versus without a history of suicide attempt.

PubMed

Sher, Leo; Fisher, Amanda M; Kelliher, Caitlin H; Penner, Justin D; Goodman, Marianne; Koenigsberg, Harold W; New, Antonia S; Siever, Larry J; Hazlett, Erin A

2016-12-30

Patients with borderline personality disorder (BPD) are at high risk for suicidal behavior. However, many BPD patients do not engage in suicidal behavior. In this study, we compared clinical features of BPD patients with or without a history of suicide attempts and healthy volunteers. Compared with healthy volunteers, both BPD groups had higher Affective Lability Scale (ALS), ALS - Depression-Anxiety Subscale, Barratt Impulsivity Scale (BIS), and Lifetime History of Aggression (LHA) scores and were more likely to have a history of temper tantrums. BPD suicide attempters had higher ALS, ALS - Depression-Anxiety Subscale and LHA scores and were more likely to have a history of non-suicidal self-injury or temper tantrums compared to BPD non-attempters. Also, BPD suicide attempters were more likely to have a history of comorbid major depressive disorder and less likely to have comorbid narcissistic personality disorder (NPD) in comparison to BPD non-attempters. About 50% of study participants in each BPD group had a history of comorbid substance use disorder (SUD). Our study indicates that BPD patients with a history of suicide attempt are more aggressive, affectively dysregulated and less narcissistic than BPD suicide non-attempters. Published by Elsevier Ireland Ltd.

An assessment of treatment guidelines, clinical practices, demographics, and progression of disease among patients with amyotrophic lateral sclerosis in Japan, the United States, and Europe.

PubMed

Takei, Koji; Tsuda, Kikumi; Takahashi, Fumihiro; Hirai, Manabu; Palumbo, Joseph

2017-10-01

There is an increasing clinical research focus on neuroprotective agents in amyotrophic lateral sclerosis (ALS). However, it is unclear how generalisable clinical study trial results are between different countries and regions. To assess similarities and differences in clinical practice and treatment guidelines for ALS, and also to compare the demographics and rate of progression of disease in patients with ALS enrolled in clinical trials in Japan, the US, and Europe. We performed a review of clinical studies published since 2000 to compare the demographics and characteristics of patients with ALS. Progression of ALS disease was assessed in patients receiving placebo. The changes per month in ALSFRS-R score were calculated and compared between the studies. Overall, diagnostic criteria, recognition of ALS symptoms, comorbidities, use of riluzole, and nutritional, and respiratory support were similar. Regarding demographics and characteristics, there were no clear differences in the incidence of sporadic ALS (range 91-98%), bulbar onset (range 11-41%), and median time from onset to diagnosis (range 9-14 months) among the populations despite the difference in race between regions. However, use of tracheostomy-based invasive respiratory support was higher in Japan (29-38%) than in the US (4%) and Europe (1-31%). Rate of progression of disease was similar between the US and Europe study populations (range -0.89 to -1.60 points/month), and the Japanese study populations (range -1.03 to -1.21 points/month). There is evidence to support the generalisability of data from the Japanese ALS trial experience to the US and Europe populations in early to mid-stage of ALS.

The cognitive profile of behavioural variant FTD and its similarities with ALS: a systematic review and meta-analysis.

PubMed

Beeldman, Emma; Raaphorst, Joost; Klein Twennaar, Michelle; Govaarts, Rosanne; Pijnenburg, Yolande A L; de Haan, Rob J; de Visser, Marianne; Schmand, Ben A

2018-02-09

Approximately 30% of patients with amyotrophic lateral sclerosis (ALS) have cognitive impairment and 8%-14% fulfil the criteria for behavioural variant frontotemporal dementia (bv-FTD). The cognitive profiles of ALS and bv-FTD have been reported to be comparable, but this has never been systematically investigated. We aimed to determine the cognitive profile of bv-FTD and examine its similarities with that of ALS, to provide evidence for the existence of a cognitive disease continuum encompassing bv-FTD and ALS. We therefore systematically reviewed neuropsychological studies on bv-FTD patients and healthy volunteers. Neuropsychological tests were divided in 10 cognitive domains and effect sizes were calculated for all domains and compared with the cognitive profile of ALS by means of a visual comparison and a Pearson's r correlation coefficient. We included 120 studies, totalling 2425 bv-FTD patients and 2798 healthy controls. All cognitive domains showed substantial effect sizes, indicating cognitive impairment in bv-FTD patients compared to healthy controls. The cognitive domains with the largest effect sizes were social cognition, verbal memory and fluency (1.77-1.53). The cognitive profiles of bv-FTD and ALS (10 cognitive domains, 1287 patients) showed similarities on visual comparison and a moderate correlation 0.58 (p=0.13). When social cognition, verbal memory, fluency, executive functions, language and visuoperception were considered, i.e. the cognitive profile of ALS, Pearson's r was 0.73 (p=0.09), which raised to 0.92 (p=0.03), when language was excluded in this systematic analysis of patients with a non-language subtype of FTD. The cognitive profile of bv-FTD consists of deficits in social cognition, verbal memory, fluency and executive functions and shows similarities with the cognitive profile of ALS. These findings support a cognitive continuum encompassing ALS and bv-FTD. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

The UCSF screening exam effectively screens cognitive and behavioral impairment in patients with ALS.

PubMed

Murphy, Jennifer; Ahmed, Fizaa; Lomen-Hoerth, Catherine

2015-03-01

The University of California San Francisco (UCSF) Screening Battery provides clinicians with a uniquely tailored tool to measure ALS patients' cognitive and behavioral changes, adjusting for dysarthria and hand weakness. The battery consists of the ALS-CBS ( 1 ), Written Fluency Test ( 2 ), and a new revision of the Frontal Behavior Inventory (FBI-ALS) ( 3 ). The validity of each component was tested by comparing results with a gold standard neuropsychological exam (GNE). Consensus criteria-based GNE diagnoses ( 4 ) were assigned (n = 24) and concurrent validity was tested for each screening exam component. Results showed that each of the four cognitive and behavioral screening test components were significantly associated with diagnoses confirmed by GNE. GNE diagnoses were significantly associated with FBI-ALS negative score, written S-words score, and ALS-CBS cognitive score. The total FBI-ALS score and C-words tests were less predictive of GNE-diagnosed impairment. In conclusion, the UCSF Cognitive Screening Battery demonstrates good external validity compared with GNE in this modest sample, encouraging its use in larger investigations. These data suggest that this battery may provide an effective screen to identify ALS patients who will then benefit from a full examination to confirm their diagnosis.

Open Randomized Clinical Trial on JWSJZ Decoction for the Treatment of ALS Patients

PubMed Central

Su, Xiaojing; Bao, Jie; Wang, Jun; Zhu, Jin; Cai, Dingfang; Yu, Li; Zhou, Hua

2013-01-01

Objective. To investigate the efficacy and safety of the traditional Chinese medicine Jiawei Sijunzi (JWSJZ) decoction for the treatment of patients with amyotrophic lateral sclerosis (ALS). Methods. Forty-eight patients with ALS were divided into a JWSJZ group (n = 24) and a control group (n = 24) using a randomized number method. Together with the basic treatment for ALS, JWSJZ decoction was added to the treatment regimen of patients in the JWSJZ group or Riluzole was administered to the control group for 6 months. Neurologists evaluated the treated and control patients using the ALS functional rating scale (ALSFRS) before, 3 and 6 months after starting the additional treatments. Results. The ALSFRS scores in both groups were lower 3 and 6 months after treatment than before. There was a significant difference at 6 months after treatment between the subgroups of patients with ALS whose limbs were the initial site of attack. No serious adverse effects were observed in the JWSJZ group. Conclusion. JWSJZ decoction may be a safe treatment for ALS, and may have delayed the development of ALS, especially in the subgroup of patients in whom the limbs were attacked first when compared with Riluzole treatment. PMID:24093046

Comparative Analysis of VOCs in Exhaled Breath of Amyotrophic Lateral Sclerosis and Cervical Spondylotic Myelopathy Patients.

PubMed

Wang, Changsong; Li, Mingjuan; Jiang, Hongquan; Tong, Hongshuang; Feng, Yue; Wang, Yue; Pi, Xin; Guo, Lei; Nie, Maomao; Feng, Honglin; Li, Enyou

2016-05-23

Amyotrophic lateral sclerosis (ALS) is an incurable neurological degenerative disease. It can cause irreversible neurological damage to motor neurons; typical symptoms include muscle weakness and atrophy, bulbar paralysis and pyramidal tract signs. The ALS-mimicking disease cervical spondylotic myelopathy (CSM) presents similar symptoms, but analysis of breath volatile organic compounds (VOCs) can potentially be used to distinguish ALS from CSM. In this study, breath samples were collected from 28 ALS and 13 CSM patients. Subsequently, gas chromatography/mass spectrometry (GCMS) was used to analyze breath VOCs. Principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLSDA) were the statistical methods used to process the final data. We identified 4 compounds with significantly decreased levels in ALS patients compared with CSM controls: (1) carbamic acid, monoammonium salt; (2) 1-alanine ethylamide, (S)-; (3) guanidine, N,N-dimethyl-; and (4) phosphonic acid, (p-hydroxyphenyl)-. Currently, the metabolic origin of the VOCs remains unclear; however, several pathways might explain the decreasing trends observed. The results of this study demonstrate that there are specific VOC profiles associated with ALS and CSM patients that can be used to differentiate between the two. In addition, these metabolites could contribute to a better understanding of the underlying pathophysiological mechanisms of ALS.

Functional reorganization during cognitive function tasks in patients with amyotrophic lateral sclerosis.

PubMed

Keller, Jürgen; Böhm, Sarah; Aho-Özhan, Helena E A; Loose, Markus; Gorges, Martin; Kassubek, Jan; Uttner, Ingo; Abrahams, Sharon; Ludolph, Albert C; Lulé, Dorothée

2018-06-01

Cognitive deficits, especially in the domains of social cognition and executive function including verbal fluency, are common in amyotrophic lateral sclerosis (ALS) patients. There is yet sparse understanding of pathogenesis of the underlying, possibly adaptive, cortical patterns. To address this issue, 65 patients with ALS and 33 age-, gender- and education-matched healthy controls were tested on cognitive and behavioral deficits with the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Using functional magnetic resonance imaging (fMRI), cortical activity during social cognition and executive function tasks (theory of mind, verbal fluency, alternation) adapted from the ECAS was determined in a 3 Tesla scanner. Compared to healthy controls, ALS patients performed worse in the ECAS overall (p < 0.001) and in all of its subdomains (p < 0.02), except memory. Imaging revealed altered cortical activation during all tasks, with patients consistently showing a hyperactivation in relevant brain areas compared to healthy controls. Additionally, cognitively high performing ALS patients consistently exhibited more activation in frontal brain areas than low performing patients and behaviorally unimpaired patients presented with more neuronal activity in orbitofrontal areas than behaviorally impaired patients. In conclusion, hyperactivation in fMRI cognitive tasks seems to represent an early adaptive process to overcome neuronal cell loss in relevant brain areas. The hereby presented cortical pattern change might suggest that, once this loss passes a critical threshold and no cortical buffering is possible, clinical representation of cognitive and behavioral impairment evolves. Future studies might shed light on the pattern of cortical pattern change in the course of ALS.

Prefrontal involvement related to cognitive impairment in progressive muscular atrophy.

PubMed

Raaphorst, Joost; van Tol, Marie-José; Groot, Paul F C; Altena, Ellemarije; van der Werf, Ysbrand D; Majoie, Charles B; van der Kooi, Anneke J; van den Berg, Leonard H; Schmand, Ben; de Visser, Marianne; Veltman, Dick J

2014-08-26

To examine brain activation patterns during verbal fluency performance in patients with progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS). fMRI was used to examine the blood oxygen level-dependent response during letter and category fluency performance in 18 patients with PMA, 21 patients with ALS, and 17 healthy control subjects, matched for age and education. fMRI results are reported at p<0.05, family-wise error (FWE)-corrected for multiple comparisons. We analyzed effects of performance, age-related white matter changes (ARWMC), and regional brain volumes; all participants underwent neuropsychological investigation. Disease duration of patients with PMA (mean 26.0 months, SD 13.6) and ALS (22.2 months, SD 11.4) was comparable. Patients with PMA and ALS had mild to moderate disease severity and showed impaired letter fluency compared with controls. Between-group analysis showed a main effect of group in the left inferior frontal gyrus (IFG, Brodmann area 45) during letter fluency, which was unaffected by performance, ARWMC, and IFG volume: patients with PMA showed lower activation than controls but higher than that of patients with ALS (ALS

ALS patients' regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity.

PubMed

Beers, David R; Zhao, Weihua; Wang, Jinghong; Zhang, Xiujun; Wen, Shixiang; Neal, Dan; Thonhoff, Jason R; Alsuliman, Abdullah S; Shpall, Elizabeth J; Rezvani, Katy; Appel, Stanley H

2017-03-09

Neuroinflammation is a pathological hallmark of ALS in both transgenic rodent models and patients, and is characterized by proinflammatory T lymphocytes and activated macrophages/microglia. In ALS mouse models, decreased regulatory T lymphocytes (Tregs) exacerbate the neuroinflammatory process, leading to accelerated motoneuron death and shortened survival; passive transfer of Tregs suppresses the neuroinflammation and prolongs survival. Treg numbers and FOXP3 expression are also decreased in rapidly progressing ALS patients. A key question is whether the marked neuroinflammation in ALS can be attributed to the impaired suppressive function of ALS Tregs in addition to their decreased numbers. To address this question, T lymphocyte proliferation assays were performed. Compared with control Tregs, ALS Tregs were less effective in suppressing responder T lymphocyte proliferation. Although both slowly and rapidly progressing ALS patients had dysfunctional Tregs, the greater the clinically assessed disease burden or the more rapidly progressing the patient, the greater the Treg dysfunction. Epigenetically, the percentage methylation of the Treg-specific demethylated region was greater in ALS Tregs. After in vitro expansion, ALS Tregs regained suppressive abilities to the levels of control Tregs, suggesting that autologous passive transfer of expanded Tregs might offer a novel cellular therapy to slow disease progression.

Elevation of cardiac troponin T in patients with amyotrophic lateral sclerosis.

PubMed

Mach, Lukas; Konecny, Tomas; Helanova, Katerina; Jaffe, Allan S; Sorenson, Eric J; Somers, Virend K; Reeder, Guy S

2016-12-01

Limited evidence suggests that specificity of cardiac troponin T (cTnT), a highly sensitive biomarker of myocardial injury, is reduced in patients with skeletal myopathies. Whether amyotrophic lateral sclerosis (ALS)-the most common motor neuron disease-could be also associated with abnormal plasma or serum cTnT levels remains unclear. Our objective was to assess cTnT levels in patients with ALS without known cTnT elevating conditions. Among ALS patients seen at our institution until 2012 we identified those who had their cTnT measured. Patients who suffered from conditions known to elevate cTnT were excluded. A case-control analysis comparing cTnT levels of these ALS patients to matched non-ALS controls fulfilling the same inclusion criteria was performed. We included 40 ALS patients of whom 27 (68 %) patients had a positive cTnT. In the control group (n = 40), 2 (5 %) tested as cTnT positive (p < 0.001). Among the ALS patients who underwent cTnT evaluation on more occasions (n = 7; median follow-up = 1.08 years), 2 (29 %) patients tested positive during the initial measurement while 6 (86 %) of them had positive cTnT at the subsequent evaluations. ALS patients with increased cTnT had been diagnosed with ALS significantly earlier than those without the elevation. Our findings raise the possibility that ALS may cause cTnT elevations. Further studies are needed to confirm these findings, clarify the pathophysiological mechanism, and establish the significance of cTnT elevations in patients with ALS.

Production of verbs related to body movement in amyotrophic lateral sclerosis (ALS) and Parkinson's Disease (PD).

PubMed

Cousins, Katheryn A Q; Ash, Sharon; Grossman, Murray

2018-03-01

Theories of grounded cognition propose that action verb knowledge relies in part on motor processing regions, including premotor cortex. Accordingly, impaired action verb knowledge in patients with amyotrophic lateral sclerosis (ALS) and Parkinson's Disease (PD) is thought to be due to motor system degeneration. Upper motor neuron disease in ALS degrades the motor cortex and related pyramidal motor system, while disease in PD is centered in the basal ganglia and can spread to frontostriatal areas that are important to language functioning. These anatomical distinctions in disease may yield subtle differences in the action verb impairment between patient groups. Here we compare verbs where the body is the agent of the action to verbs where the body is the theme. To examine the role of motor functioning in body verb production, we split patient groups into patients with high motor impairment (HMI) and those with low motor impairment (LMI), using disease-specific measures of motor impairment. Regression analyses assessed how verb production in ALS and PD was related to motor system atrophy. We find a dissociation between agent- and theme-body verbs in ALS: ALS HMI were impaired for agent body verbs but not theme verbs, compared to ALS LMI. This dissociation was not present in PD patients, who instead show depressed production for all body verbs. Although patients with cognitive impairment were excluded from this study, cognitive performance significantly correlated with the production of theme verbs in ALS and cognitive/stative verbs in PD. Finally, regression analyses related the agent-theme dissociation in ALS to grey matter atrophy of premotor cortex. These findings support the view that motor dysfunction and disease in premotor cortex contributes to the agent body verb deficit in ALS, and begin to identify some distinct characteristics of impairment for verbs in ALS and PD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Studies of Environmental Risk Factors in Amyotrophic Lateral Sclerosis (ALS) and a Phase I Clinical Trial of L-Serine.

PubMed

Bradley, Walter G; Miller, R X; Levine, T D; Stommel, E W; Cox, P A

2018-01-01

β-N-Methylamino-L-alanine (BMAA) has been linked to Guam ALS/PDC and shown to produce neurodegeneration in vitro and in vivo (Drosophila, mice, rats, primates). BMAA misincorporation into neuroproteins produces protein misfolding and is inhibited by L-serine. Case-control studies in Northern New England indicate that living near to water-bodies with cyanobacterial blooms increases the risk of developing amyotrophic lateral sclerosis (ALS). The distribution of addresses of ALS cases in New Hampshire, Vermont, and Florida was compared to that of controls. Areas of statistically significantly increased numbers of ALS cases were examined for sources of environmental toxins. A phase I trial of oral L-serine was performed in 20 ALS patients (0.5 to 15 g twice daily). Safety and tolerability were assessed by comparing the rate of deterioration with 430 matched placebo controls. The distribution of residential addresses of ALS cases in New England and Florida revealed many areas where the age- and gender-adjusted frequency of ALS was greater than expected (P < 0.01). GIS studies of these "hot spots" in relation to sources of environmental pollutants, like cyanobacterial blooms, Superfund and Brownfield sites, and landfills, are ongoing. In the phase I trial of L-serine, two patients withdrew from because of gastrointestinal side effects. Three patients died during the study, which was about the expected number. The ALSFRS-R in the L-serine-treated patients showed a dose-related decrease in the rate of progression (34% reduction in slope, P = 0.044). The non-random distribution of addresses of ALS patients suggests that residential exposure to environmental pollutants may play an important role in the etiology of ALS. L-Serine in doses up to 15 g twice daily appears to be safe in patients with ALS. Exploratory studies of efficacy suggested that L-serine might slow disease progression. A phase II trial is planned.

Trends and determinants of end-of-life practices in ALS in the Netherlands.

PubMed

Maessen, M; Veldink, Jan H; Onwuteaka-Philipsen, B D; de Vries, J M; Wokke, J H J; van der Wal, G; van den Berg, L H

2009-09-22

In the Netherlands, the proportion of patients with amyotrophic lateral sclerosis (ALS) who choose the option of euthanasia or physician-assisted suicide (PAS) is relatively high (20%). The objective of this study was to determine which factors influence end-of-life practices in ALS and whether rates are changing over time. In a cohort survey, 204 physicians and 198 informal caregivers (response rates 75% and 80%) of patients with ALS who died between 2000 and 2005 filled out questionnaires of the end-of-life circumstances of the patient. Results were compared with those of a similar study performed during the period 1994-1998. In 2000-2005, 16.8% of the patients decided on euthanasia or PAS compared to 20.2% in 1994-1998. Thirty-one (14.8%) patients died during continuous deep sedation (CDS) in 2000-2005. Euthanasia or PAS, but not CDS, were significantly associated with religion not being important to the patient, being more educated, and dying at home. Euthanasia or PAS were not associated with quality of care items or symptoms of depression. Loss of function was similar in both groups. Informal caregivers of patients who died after euthanasia or PAS more frequently reported fear of choking (p = 0.003), no chance of improvement (p = 0.001), loss of dignity (p = 0.02), being dependent on others (p = 0.002), and fatigue (p = 0.018) as reasons for shortening life. Hopelessness was associated with euthanasia or PAS, as with CDS. The frequency of euthanasia or physician-assisted suicide (PAS) in amyotrophic lateral sclerosis (ALS) appeared stable over time and 1 in 7 patients died during CDS. CDS is relatively common in ALS, but appears to have other determinants than euthanasia or PAS. Subjective factors may be important in explaining euthanasia or PAS in ALS.

END STAGE CARDIAC AMYLOIDOSIS: PREDICTORS OF SURVIVAL TO CARDIAC TRANSPLANTATION AND LONG TERM OUTCOMES

PubMed Central

Gilstrap, Lauren Gray; Niehaus, Emily; Malhotra, Rajeev; Ton, Van-Khue; Watts, James; Seldin, David C.; Madsen, Joren C.; Semigran, Marc J.

2013-01-01

Background Orthotopic heart transplant (OHT) followed by myeloablative chemotherapy and autologous stem cell transplant (ASCT) has been successful in the treatment of light chain (AL) cardiac amyloidosis. The purpose of this study is to identify predictors of survival to OHT in patients with end stage heart failure due to AL amyloidosis, and compare post-OHT survival of cardiac amyloid patients to that of other cardiomyopathy patients undergoing OHT. Methods From January 2000 to June 2011, 31 patients with end stage heart failure secondary to AL amyloidosis were listed for OHT at Massachusetts General Hospital (MGH). Univariate and multivariate regression analyses identified predictors of survival to OHT. Kaplan-Meier analysis compared survival between MGH amyloidosis patients and the Scientific Registry of Transplant Recipients (SRTR) non-amyloid cardiomyopathy patients. Results Low body mass index (BMI) was the only predictor of survival to OHT in patients with end stage heart failure due to cardiac amyloidosis. Survival of cardiac amyloid patients who died prior to receiving a donor heart was only 63 ± 45 days after listing. Patients who survived to OHT received a donor organ at 53 ± 48 days after listing. Survival of AL amyloidosis patients on the waitlist was less than patients waitlisted for all other non-amyloid diagnoses. The long-term survival of transplanted amyloid patients was no different than the survival of non-amyloid, restrictive (p=0.34), non-amyloid dilated (p=0.34) or all non-amyloid cardiomyopathy patients (p=0.22) in the SRTR database. Conclusions Those that survive to OHT followed by ASCT have a survival rate similar to other cardiomyopathy patients undergoing OHT. However, more than one third of the patients died awaiting OHT. The only predictor of survival to OHT in AL amyloidosis patients was low BMI, which correlated with shorter waitlist time. To optimize the survival of these patients, access to donor organs must be improved. In light chain (AL) amyloidosis, amyloid fibrils derived from clonal lambda or kappa immunoglobulin light chains deposit abnormally in organs. Cardiac involvement is apparent echocardiographically in 60% of AL amyloidosis patients at the time of diagnosis, with clinical evidence of heart failure in 69% of patients.1 The median survival of AL amyloidosis patients presenting with any heart failure symptom is 8.5 months2 and even less for end-stage heart failure pateints. PMID:24200511

Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: A phase II open label clinical trial

PubMed Central

STOMMEL, ELIJAH W.; COHEN, JEFFREY A.; FADUL, CAMILO E.; COGBILL, CHRISTOPHER H.; GRABER, DAVID J.; KINGMAN, LINDA; MACKENZIE, TODD; SMITH, JACQUELINE Y. CHANNON; HARRIS, BRENT T.

2013-01-01

Neuroinflammation through the cytokine, tumor necrosis factor-alpha (TNF-α) is thought to play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We conducted a preliminary phase II trial of thalidomide, which reduces levels of TNF-α pre-transcriptionally and post-transcriptionally in vivo and has been shown to prolong disease duration and extend the lifespan of transgenic animal models of ALS. Patients who met diagnostic criteria for ALS received thalidomide at escalating doses to a target dose of 400 mg/day. The primary endpoints in the trial were the ALS Functional Rating Scale (ALSFRS) and pulmonary function testing (PFT) curves after nine months of thalidomide treatment that were compared to historical controls. Secondary endpoints were: survival stratified for newly diagnosed and progressive disease, toxicity, quality of life, and serum cytokine measurements. Twenty-three patients were enrolled, but only 18 were evaluable for the primary outcome. There was no improvement in the ALSFRS or PFT compared to historical controls. Thalidomide had several side-effects in our ALS patients. There was no significant shift in cytokine profile after treatment compared to baseline. In conclusion, treatment of ALS with the TNF-α inhibitor, thalidomide, does not appear to effectively modulate disease progression and can cause adverse effects. PMID:19922130

Role of CTGF in White Matter Development in Tuberous Sclerosis

DTIC Science & Technology

2016-04-01

lungs(Crino et al., 2006). TSC patients present with epilepsy (~90%), intellectual disability and autism (~50%), and other disorders including sleep...with TSC that have autism compared to TSC patients without autism (Lewis et al., 2013; Peters et al., 2013). To uncover the underlying molecular...intellectual disability and autism (~50%), and other disorders including sleep disruption, attention-deficit hyperactivity disorder, and anxiety(Han

ALS-Plus Syndrome: Non-Pyramidal Features in a Large ALS Cohort

PubMed Central

McCluskey, Leo; Vandriel, Shannon; Elman, Lauren; Van Deerlin, Vivianna M.; Powers, John; Boller, Ashley; Wood, Elisabeth McCarty; Woo, John; McMillan, Corey T.; Rascovsky, Katya; Grossman, Murray

2014-01-01

Objective Autopsy studies show widespread pathology in amyotrophic lateral sclerosis (ALS), but clinical surveys of multisystem disease in ALS are rare. We investigated ALS-Plus syndrome, an understudied group of patients with clinical features extending beyond pyramidal and neuromuscular systems with or without cognitive/behavioral deficits. Methods In a large, consecutively-ascertained cohort of 550 patients with ALS, we documented atypical clinical manifestations. Genetic screening for C9orf72 hexanucleotide expansions was performed in 343 patients, and SOD1, TARDBP, and VCP were tested in the subgroup of patients with a family history of ALS. Gray matter and white matter imaging was available in a subgroup of 30 patients. Results Seventy-five (13.6%) patients were identified with ALS-Plus syndrome. We found disorders of ocular motility, cerebellar, extrapyramidal and autonomic functioning. Relative to those without ALS-Plus, cognitive impairment (8.0% vs 2.9%, p=0.029), bulbar-onset (49.3% vs 23.2%, p<0.001), and pathogenic mutations (20.0% vs 8.4%, p=0.015) were more than twice as common in ALS-Plus. Survival was significantly shorter in ALS-Plus (29.66 months vs 42.50 months, p=0.02), regardless of bulbar-onset or mutation status. Imaging revealed significantly greater cerebellar and cerebral disease in ALS-Plus compared to those without ALS-Plus. Conclusions ALS-Plus syndrome is not uncommon, and the presence of these atypical features is consistent with neuropathological observations that ALS is a multisystem disorder. ALS-Plus syndrome is associated with increased risk for poor survival and the presence of a pathogenic mutation. PMID:25086858

Interference with daily activities and major adverse events during esophageal pH monitoring with bravo wireless capsule versus conventional intranasal catheter: a systematic review of randomized controlled trials.

PubMed

Iluyomade, A; Olowoyeye, A; Fadahunsi, O; Thomas, L; Libend, C N; Ragunathan, K; Fenster, J; Vignesh, S

2017-02-01

For three decades, ambulatory 24-hour intranasal pH monitoring has been the established gold standard for detecting acid reflux in patients with refractory gastroesophageal reflux disease. However, device-associated adverse events and unpleasant experiences, reported by patients during pH monitoring have led to the invention of more convenient pH monitors such as Bravo wireless capsule. To compare the interference with daily activities and major adverse events during pH monitoring with Bravo wireless capsule (Bravo) versus conventional intranasal catheter (catheter), PubMed, Cochrane Library, Clinical Trials.gov, and Google Scholar were searched up to March 20, 2015. Only randomized controlled trials in adult patients that compared the interference with routine daily activities and adverse events between Bravo and catheter pH monitors were included. After screening 574 articles, three unique studies with 167 patients met our inclusion criteria. The average age of patients enrolled in these studies was 51 years. Interference with normal daily activities was more in the catheter than Bravo group: 75 ± 5 versus 92 ± 2, P < 0.001 (Andrews et al, findings were reported as100 mm, mean visual analogue scale (VAS) ± standard error of the mean, 100 = completely normal); Wong et al. (mean ± standard error of the mean): 1.3 ± 0.2 versus 0.32 ± 0.1, P = 0.001 and Wenner et al. using 10 cm median VAS (Interquartile range),10 been the worst is 5.7 (2.3-8.0) compared to 0.7 (0.2-3.4), P < 0.0001, respectively. Overall adverse events were more in the catheter group than Bravo (39 ± 4 vs. 26 ± 4, P = 0.012 for Andrews et al. (100 been the worst) and 5.1 (2.0-6.6) vs. 2.1 (0.5-4.6), P < 0.001 for Wenner et al.). No overall adverse events recorded for Wong et al. Most patients in catheter group complained of nasal and throat symptoms. Significantly, runny nose in 24 out of 25 patients (96%) catheter versus 13 out of 25 (52%) Bravo, P = 0.001 and nose pain 15 out 25 (60%) versus 8 out of 25 patients (32%), P = 0.047, respectively for Wong et al. Andrews and Wenner et al also showed profound nasal discomforts in catheter group compared to Bravo (39 ± 3 vs. 10 ± 3, P < 0.001 and 6.5 (1.5-8.0) versus 0.2 (0.0-1.9), P < 0.0001, respectively. Throat symptoms reported in Wong et al. were mainly throat discomfort in catheter group 23 out of 25 patients (92%) versus Bravo 12 out of 25 (48%), P = 0.001 and throat pain catheter (12 out of 25 patients (48%) vs. Bravo 4 out of 25 (16%)), P = 0.032. This trend was also observed in Andrews et al. with profound throat discomfort in the catheter group 43 ± 4 compared to Bravo 19 ± 4, P < 0.001. Majority of the patients randomized to Bravo group reportedly perceived chest pain higher than those in catheter group; 9 out of 25 patients (36%) versus 2 out of 25 (8%), P = 0.037 in Wong et al. 29 ± 4 versus 14 ± 3, P = 0.001 for Andrews et al., 2.4 (0.3-5.9) versus 1.1 (0.3-2.9), P = 0.084 in Wenner et al. respectively (though not statistically significant). Bravo wireless capsule pH monitor interfered less with daily activities and adverse events were minimal compared to conventional intranasal catheter. © 2016 International Society for Diseases of the Esophagus.

Memory deficits in amyotrophic lateral sclerosis are not exclusively caused by executive dysfunction: a comparative neuropsychological study of amnestic mild cognitive impairment.

PubMed

Machts, Judith; Bittner, Verena; Kasper, Elisabeth; Schuster, Christina; Prudlo, Johannes; Abdulla, Susanne; Kollewe, Katja; Petri, Susanne; Dengler, Reinhard; Heinze, Hans-Jochen; Vielhaber, Stefan; Schoenfeld, Mircea A; Bittner, Daniel M

2014-06-30

Recent work suggests that ALS and frontotemporal dementia can occur together and share at least in part the same underlying pathophysiology. However, it is unclear at present whether memory deficits in ALS stem from a temporal lobe dysfunction, or are rather driven by frontal executive dysfunction. In this study we sought to investigate the nature of memory deficits by analyzing the neuropsychological performance of 40 ALS patients in comparison to 39 amnestic mild cognitive impairment (aMCI) patients and 40 healthy controls (HC). The neuropsychological battery tested for impairment in executive functions, as well as memory and visuo-spatial skills, the results of which were compared across study groups. In addition, we calculated composite scores for memory (learning, recall, recognition) and executive functions (verbal fluency, cognitive flexibility, working memory). We hypothesized that the nature of memory impairment in ALS will be different from those exhibited by aMCI patients. Patient groups exhibited significant differences in their type of memory deficit, with the ALS group showing impairment only in recognition, whereas aMCI patients showed short and delayed recall performance deficits as well as reduced short-term capacity. Regression analysis revealed a significant impact of executive function on memory performance exclusively for the ALS group, accounting for one fifth of their memory performance. Interestingly, merging all sub scores into a single memory and an executive function score obscured these differences. The presented results indicate that the interpretation of neuropsychological scores needs to take the distinct cognitive profiles in ALS and aMCI into consideration. Importantly, the observed memory deficits in ALS were distinctly different from those observed in aMCI and can be explained only to some extent in the context of comorbid (coexisting) executive dysfunction. These findings highlight the qualitative differences in temporal lobe dysfunction between ALS and aMCI patients, and support temporal lobe dysfunction as a mechanism underlying the distinct cognitive impairments observed in ALS.

Brain White Matter Shape Changes in Amyotrophic Lateral Sclerosis (ALS): A Fractal Dimension Study

PubMed Central

Allexandre, Didier; Zhang, Luduan; Wang, Xiao-Feng; Pioro, Erik P.; Yue, Guang H.

2013-01-01

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder. Current diagnosis time is about 12-months due to lack of objective methods. Previous brain white matter voxel based morphometry (VBM) studies in ALS reported inconsistent results. Fractal dimension (FD) has successfully been used to quantify brain WM shape complexity in various neurological disorders and aging, but not yet studied in ALS. Therefore, we investigated WM morphometric changes using FD analyses in ALS patients with different clinical phenotypes. We hypothesized that FD would better capture clinical features of the WM morphometry in different ALS phenotypes than VBM analysis. High resolution MRI T1-weighted images were acquired in controls (n = 11), and ALS patients (n = 89). ALS patients were assigned into four subgroups based on their clinical phenotypes.VBM analysis was carried out using SPM8. FD values were estimated for brain WM skeleton, surface and general structure in both controls and ALS patients using our previously published algorithm. No significant VBM WM changes were observed between controls and ALS patients and among the ALS subgroups. In contrast, significant (p<0.05) FD reductions in skeleton and general structure were observed between ALS with dementia and other ALS subgroups. No significant differences in any of the FD measures were observed between control and ALS patients. FD correlated significantly with revised ALS functional rating scale (ALSFRS-R) score a clinical measure of function. Results suggest that brain WM shape complexity is more sensitive to ALS disease process when compared to volumetric VBM analysis and FD changes are dependent on the ALS phenotype. Correlation between FD and clinical measures suggests that FD could potentially serve as a biomarker of ALS pathophysiology, especially after confirmation by longitudinal studies. PMID:24040000

Functional studies of the parotid and pancreas glands in amyotrophic lateral sclerosis

PubMed Central

Charchaflie, R. J.; Fernandez, L. Bustos; Perec, C. J.; Gonzalez, E.; Marzi, A.

1974-01-01

Functional studies of the pancreas and parotid glands are reported in 17 patients with amyotrophic lateral sclerosis (ALS). The exocrine function of the pancreas was studied by measuring amylase concentration after stimulation with the endogenous secretin-pancreozymine test (ESP). Under these conditions, the pancreatic amylase concentration in ALS patients was found to be markedly decreased by about 45% when compared with those of healthy control subjects. Different conclusions in the literature about a possible impairment of the exocrine pancreas in ALS patients induced us to study the function of the parotid gland, which has close structural, functional, and physiopathological relationship with the pancreas. Flow rate and bicarbonate concentration of parotid saliva were measured after indirect stimulation (intraoral citric acid) and direct stimulation (pilocarpine). After indirect stimulation, both parotid flow rate and bicarbonate concentration from ALS patients were found to be decreased by about 66% and 70% respectively, when compared with controls. On the other hand, direct stimulation with pilocarpine in ALS patients elicited normal responses in both flow rate and bicarbonate concentration of saliva. It is concluded that the pancreatic and parotid deficiencies observed in ALS patients do not indicate primary disease of these exocrine glands. This interpretation is further emphasized by the results obtained by a sweat test, plasma osmolarity, and sialographic studies. The possibility that the gland impairments observed might be due to modifications of the neuroendocrine mechanisms regulating their secretory activity is suggested. PMID:4852110

White matter pathology in ALS and lower motor neuron ALS variants: a diffusion tensor imaging study using tract-based spatial statistics.

PubMed

Prudlo, Johannes; Bißbort, Charlotte; Glass, Aenne; Grossmann, Annette; Hauenstein, Karlheinz; Benecke, Reiner; Teipel, Stefan J

2012-09-01

The aim of this work was to investigate white-matter microstructural changes within and outside the corticospinal tract in classical amyotrophic lateral sclerosis (ALS) and in lower motor neuron (LMN) ALS variants by means of diffusion tensor imaging (DTI). We investigated 22 ALS patients and 21 age-matched controls utilizing a whole-brain approach with a 1.5-T scanner for DTI. The patient group was comprised of 15 classical ALS- and seven LMN ALS-variant patients (progressive muscular atrophy, flail arm and flail leg syndrome). Disease severity was measured by the revised version of the functional rating scale. White matter fractional anisotropy (FA) was assessed using tract-based spatial statistics (TBSS) and a region of interest (ROI) approach. We found significant FA reductions in motor and extra-motor cerebral fiber tracts in classical ALS and in the LMN ALS-variant patients compared to controls. The voxel-based TBSS results were confirmed by the ROI findings. The white matter damage correlated with the disease severity in the patient group and was found in a similar distribution, but to a lesser extent, among the LMN ALS-variant subgroup. ALS and LMN ALS variants are multisystem degenerations. DTI shows the potential to determine an earlier diagnosis, particularly in LMN ALS variants. The statistically identical findings of white matter lesions in classical ALS and LMN variants as ascertained by DTI further underline that these variants should be regarded as part of the ALS spectrum.

Phosphoneurofilament heavy chain and N-glycomics from the cerebrospinal fluid in amyotrophic lateral sclerosis.

PubMed

Gonçalves, Margarida; Tillack, Linda; de Carvalho, Mamede; Pinto, Susana; Conradt, Harald S; Costa, Júlia

2015-01-01

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease of the motor neuron for which no clinically validated biomarkers have been identified. We have quantified by ELISA the biomarker phosphoneurofilament heavy chain (pNFH) in the cerebrospinal fluid (CSF) of ALS patients (n=29) and age-matched control patients with other diseases (n=19) by ELISA. Furthermore, we compared protein N-glycosylation of the CSF in ALS patients and controls, by applying a glycomics approach based on liquid chromatography and mass spectrometry. pNFH levels were significantly higher in ALS patients in comparison with controls (P<0.0001) in particular in fast progressors. The N-glycans found in the CSF were predominantly complex diantennary with sialic acid in α2,3- and α2,6-linkage, and bisecting N-acetylglucosamine-containing structures as well as peripherally fucosylated structures were found. As compared with controls the ALS group had a significant increase of a peak composed of the monosialylated diantennary glycans A2G2S(6)1 and FA2G2S(3)1 (P=0.0348). Our results underscore the value of pNFH as a biomarker in ALS. In addition, we identified a variation of the N-glycosylation pattern in ALS, suggesting that this change should be explored in future studies as potential biomarker. Copyright © 2014 Elsevier B.V. All rights reserved.

Zinc Supplementation Alters Plasma Aluminum and Selenium Status of Patients Undergoing Dialysis: A Pilot Study

PubMed Central

Guo, Chih-Hung; Chen, Pei-Chung; Hsu, Guoo-Shyng W.; Wang, Chia-Liang

2013-01-01

End stage renal disease patients undergoing long-term dialysis are at risk for abnormal concentrations of certain essential and non-essential trace metals and high oxidative stress. We evaluated the effects of zinc (Zn) supplementation on plasma aluminum (Al) and selenium (Se) concentrations and oxidative stress in chronic dialysis patients. Zn-deficient patients receiving continuous ambulatory peritoneal dialysis or hemodialysis were divided into two groups according to plasma Al concentrations (HA group, Al > 50 μg/L; and MA group, Al > 30 to ≤ 50 μg/L). All patients received daily oral Zn supplements for two months. Age- and gender-matched healthy individuals did not receive Zn supplement. Clinical variables were assessed before, at one month, and after the supplementation period. Compared with healthy subjects, patients had significantly lower baseline plasma Se concentrations and higher oxidative stress status. After two-month Zn treatment, these patients had higher plasma Zn and Se concentrations, reduced plasma Al concentrations and oxidative stress. Furthermore, increased plasma Zn concentrations were related to the concentrations of Al, Se, oxidative product malondialdehyde (MDA), and antioxidant enzyme superoxide dismutase activities. In conclusion, Zn supplementation ameliorates abnormally high plasma Al concentrations and oxidative stress and improves Se status in long-term dialysis patients. PMID:23609777

NEK1 genetic variability in a Belgian cohort of ALS and ALS-FTD patients.

PubMed

Nguyen, Hung Phuoc; Van Mossevelde, Sara; Dillen, Lubina; De Bleecker, Jan L; Moisse, Matthieu; Van Damme, Philip; Van Broeckhoven, Christine; van der Zee, Julie

2018-01-01

We evaluated the genetic impact of the amyotrophic lateral sclerosis (ALS) risk gene never in mitosis gene a-related kinase 1 (NEK1) in a Belgian cohort of 278 patients with ALS (n = 245) or ALS with frontotemporal dementia (ALS-FTD, n = 33) and 609 control individuals. We identified 2 ALS patients carrying a loss-of-function (LOF) mutation, p.Leu854Tyrfs*2 and p.Tyr871Valfs*17, that was absent in the control group. A third LOF variant p.Ser1036* was present in 2 sibs with familial ALS but also in an unrelated control person. Missense variants were common in both patients (3.6%) and controls (3.0%). The missense variant, p.Arg261His, which was previously associated with ALS risk, was detected with a minor allele frequency of 0.90% in patients compared to 0.33% in controls. Taken together, NEK1 LOF variants accounted for 1.1% of patients, although interpretation of pathogenicity and penetrance is complicated by the observation of occasional LOF variants in unaffected individuals (0.16%). Furthermore, enrichment of additional ALS gene mutations was observed in NEK1 carriers, suggestive of a "second hit" model were NEK1 variants may modify disease presentation of driving mutations. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Transcultural validation of the ALS-CBS Cognitive Section for the Brazilian population.

PubMed

Branco, Lucas M T; Zanao, Tamires; De Rezende, Thiago J; Casseb, Raphael F; Balthazar, Marcio F; Woolley, Susan C; França, Marcondes C

2017-02-01

Cognitive decline (CD) is common but often under-recognized in ALS due to the scarcity of adequate cognitive screening methods. In this scenario, the Amyotrophic Lateral Sclerosis Cognitive Behavioural Screen (ALS-CBS) is the most investigated instrument and presents high sensitivity to identify CD. Currently, there are no validated cognitive screening tools for ALS patients in the Brazilian population and little is known about the frequency of ALS related CD in the country. We assessed the accuracy of the Brazilian Portuguese version of ALS-CBS Cognitive Section (ALS-CBS-Br) for classifying the cognitive status of Brazilian patients compared to a standard neuropsychological battery, and estimated the prevalence of CD in the Brazilian ALS population. Among 73 initially recruited ALS patients, 49 were included. Twenty-four patients were excluded due to severe motor disability, FTD diagnosis or non-acceptance. Ten healthy controls were also included. Ten ALS patients (20%) were diagnosed with executive dysfunction (ALSci) based on the battery results. ALS-CBS-Br scores were significantly lower in the ALSci group (p < 0.001). The scale accuracy in detecting executive dysfunction was 0.906. Optimal cut-off score was 10/20 (specificity 0.872 and sensitivity 0.900). In conclusion, the ALS-CBS-Br may facilitate the recognition of CD in routine clinical care and complement future studies in our population.

Amorphous material of the skin in amyotrophic lateral sclerosis: a morphologic and biochemical study

NASA Technical Reports Server (NTRS)

Ono, S.; Nagao, K.; Yamauchi, M.

1994-01-01

We performed morphologic studies on skin from seven patients with ALS and seven control subjects. By light microscopy, the wide spaces that separated collagen bundles reacted strongly with colloidal iron and alcian blue in ALS patients. Electron microscopy revealed markedly increased amorphous material that was positive for ruthenium red in the ground substance. These findings were not present in controls. Quantitative amino acid analysis showed that the amount of total amino acids (nmoles per mg dry weight) was significantly decreased (p < 0.01) in ALS patients compared with that of controls, and there was a significant negative correlation between skin amino acid content and duration of illness in ALS patients (r = -0.83, p < 0.001). These morphologic findings and biochemical data indicate that the amorphous material, which is markedly increased in ALS skin, includes glycosaminoglycans.

Lack of association between nuclear factor erythroid-derived 2-like 2 promoter gene polymorphisms and oxidative stress biomarkers in amyotrophic lateral sclerosis patients.

PubMed

LoGerfo, Annalisa; Chico, Lucia; Borgia, Loredana; Petrozzi, Lucia; Rocchi, Anna; D'Amelio, Antonia; Carlesi, Cecilia; Caldarazzo Ienco, Elena; Mancuso, Michelangelo; Siciliano, Gabriele

2014-01-01

Oxidative stress involvement has been strongly hypothesized among the possible pathogenic mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The intracellular redox balance is finely modulated by numerous complex mechanisms critical for cellular functions, among which the nuclear factor erythroid-derived 2-like 2 (NFE2L2/Nrf2) pathways. We genotyped, in a cohort of ALS patients (n = 145) and healthy controls (n = 168), three SNPs in Nrf2 gene promoter: -653 A/G, -651 G/A, and -617 C/A and evaluated, in a subset (n = 73) of patients, advanced oxidation protein products (AOPP), iron-reducing ability of plasma (FRAP), and plasma thiols (-SH) as oxidative damage peripheral biomarkers. Nrf2 polymorphisms were not different among patients and controls. Increased levels of AOPP (P < 0.05) and decreased levels of FRAP (P < 0.001) have been observed in ALS patients compared with controls, but no difference in -SH values was found. Furthermore, no association was found between biochemical markers of redox balance and Nrf2 polymorphisms. These data confirm an altered redox balance in ALS and indicate that, while being abnormally modified compared to controls, the oxidative stress biomarkers assessed in this study are independent from the -653 A/G, -651 G/A, and -617 C/A Nrf2 SNPs in ALS patients.

Choroidal Thickness Analysis in Patients with Usher Syndrome Type 2 Using EDI OCT.

PubMed

Colombo, L; Sala, B; Montesano, G; Pierrottet, C; De Cillà, S; Maltese, P; Bertelli, M; Rossetti, L

2015-01-01

To portray Usher Syndrome type 2, analyzing choroidal thickness and comparing data reported in published literature on RP and healthy subjects. Methods. 20 eyes of 10 patients with clinical signs and genetic diagnosis of Usher Syndrome type 2. Each patient underwent a complete ophthalmologic examination including Best Corrected Visual Acuity (BCVA), intraocular pressure (IOP), axial length (AL), automated visual field (VF), and EDI OCT. Both retinal and choroidal measures were measured. Statistical analysis was performed to correlate choroidal thickness with age, BCVA, IOP, AL, VF, and RT. Comparison with data about healthy people and nonsyndromic RP patients was performed. Results. Mean subfoveal choroidal thickness (SFCT) was 248.21 ± 79.88 microns. SFCT was statistically significant correlated with age (correlation coefficient -0.7248179, p < 0.01). No statistically significant correlation was found between SFCT and BCVA, IOP, AL, VF, and RT. SFCT was reduced if compared to healthy subjects (p < 0.01). No difference was found when compared to choroidal thickness from nonsyndromic RP patients (p = 0.2138). Conclusions. Our study demonstrated in vivo choroidal thickness reduction in patients with Usher Syndrome type 2. These data are important for the comprehension of mechanisms of disease and for the evaluation of therapeutic approaches.

Signs of impaired selective attention in patients with amyotrophic lateral sclerosis.

PubMed

Pinkhardt, Elmar H; Jürgens, Reinhart; Becker, Wolfgang; Mölle, Matthias; Born, Jan; Ludolph, Albert C; Schreiber, Herbert

2008-04-01

The evidence for involvement of extramotor cortical areas in non-demented patients with amyotrophic lateral sclerosis (ALS) has been provided by recent neuropsychological and functional brain imaging studies. The aim of this study was to investigate possible alterations in selective attention, as an important constituent part of frontal brain function in ALS patients. A classical dichotic listening task paradigm was employed to assess event-related EEG potential (ERPs) indicators of selective attention as well as preattentive processing of mismatch, without interference by motor impairment.A total of 20 patients with sporadic ALS according to the revised El Escorial criteria and 20 healthy controls were studied. Additionally a neuropsychological test battery of frontotemporal functions was applied. Compared with the controls, the ALS patients showed a distinct decrease of the fronto-precentral negative difference wave (Nd), i.e., the main ERP indicator of selective attention. Analysis of the P3 component of the ERPs indicated an increased processing of non-relevant stimuli in ALS patients confirming a reduced focus of attention. We conclude impaired selective attention reflects a subtle variant of frontotemporal dementia frequently observed in ALS patients at a relatively early stage of the disease.

DIRAE study: seasonal allergic rhinitis distribution in Spain.

PubMed

Roger, A; Quilez, E; Depreux, N; Farre, M

2013-01-01

National epidemiological study to observe if among patients with pollinic seasonal allergic rhinitis (SAR), there are differences between those visited by primary care physicians (GPs) or allergists (ALs). 758 and 739 adults were recruited respectively by GPs and ALs. The physicians filled in a questionnaire: ARIA classification, prescribed treatment, and asthma incidence. The patient completed a visual analogical scale (VAS) to evaluate the severity of the rhinitis. Rhinitis control (controlled, partially controlled, and not controlled) was assessed by physician and patient. No significant differences were found among patients visited by GPs or ALs concerning the ARIA classification and rhinitis severity. Treatment with oral antihistamines was 92.3% and 89.3% for GPs and ALs, respectively. The use of nasal corticosteroids was 76.7% and 60.4% for GP and AL patients, respectively. 31.9% of the patients visited by the ALs were treated with immunotherapy. The use of alternative medicine was 10.9% and 7.6% in GP and AL patients, respectively. The perception of "controlled" rhinitis was similar among patients (40.0%) and doctors (40.1%), although patients referred differences depending if they were visited by GP (44.8%) or AL (34.9%). Asthma prevalence was higher in those who suffered persistent as compared to intermittent rhinitis (OR=1.81, 95% CI: 1.39-2.36, p<0.001), and moderate/severe vs. mild rhinitis (OR=1.68, 95% CI: 1.05-2.68, p=0.029). The patients with pollinic SAR visited by GPs or ALs show no differences in severity. Less than half of the patients can be considered as "controlled". Copyright © 2011 SEICAP. Published by Elsevier Espana. All rights reserved.

Characteristics and Prognosis of Oldest Old Subjects with Amyotrophic Lateral Sclerosis.

PubMed

Dandaba, Meira; Couratier, Philippe; Labrunie, Anaïs; Nicol, Marie; Hamidou, Bello; Raymondeau, Marie; Logroscino, Giancarlo; Preux, Pierre Marie; Marin, Benoît

2017-01-01

Amyotrophic Lateral Sclerosis (ALS) is an age-related neurodegenerative disease with unclear characteristics and prognosis in the oldest old (80 years and over). The aim of this study was to compare the oldest old and younger ALS patients in terms of clinical and socio-demographic characteristics, and prognosis. ALS incident cases from the register of ALS in Limousin (FRALim), diagnosed between January 2000 and July 2013, were included. Descriptive and comparative analyses by age group were carried out. For time to event univariate analysis, Kaplan-Meier estimator and log rank test were used. Univariate and multivariate survival analyses were carried out with Cox's proportional hazard model. Out of 322 patients, 50 (15.5%) were aged 80 or over ("oldest old" ALS) at the time of diagnosis. Among them, the male:female gender-ratio was 1.27, and 32.6% had a bulbar onset (not different from subjects aged less than 80 years). With increasing age, there was a worsening of the clinical state of the patients at time of diagnosis in terms of weight loss, forced vital capacity, ALSFRS-R and manual muscular testing. Access to ALS referral centres decreased with age, and the use of riluzole tended to be lower in the oldest old group. The median survival of oldest old patients appeared to be 10 months shorter than that of subjects aged less than 80 years (7.4 vs. 17.4 months). The survival of oldest old ALS patients is particularly short. It relates to prognostic features at baseline and to an independent effect of advanced age. © 2017 S. Karger AG, Basel.

Immunoreactivity of valosin-containing protein in sporadic amyotrophic lateral sclerosis and in a case of its novel mutant.

PubMed

Ayaki, Takashi; Ito, Hidefumi; Fukushima, Hiroko; Inoue, Takeshi; Kondo, Takayuki; Ikemoto, Akito; Asano, Takeshi; Shodai, Akemi; Fujita, Takuji; Fukui, Satoshi; Morino, Hiroyuki; Nakano, Satoshi; Kusaka, Hirofumi; Yamashita, Hirofumi; Ihara, Masafumi; Matsumoto, Riki; Kawamata, Jun; Urushitani, Makoto; Kawakami, Hideshi; Takahashi, Ryosuke

2014-12-10

Mutations in the valosin-containing protein (VCP) gene were first found to cause inclusion- body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD). Mutations in the VCP gene were later reported to occur in familial amyotrophic lateral sclerosis (ALS). But the role of VCP in the neurodegenerative processes that occur in ALS remains unknown. The purpose of the present study was to elucidate the role of VCP in the neurodegeneration seen in sporadic and VCP mutant ALS. Immunohistochemistry demonstrated that the frequency of distinct VCP-positive nuclei of spinal motor neurons of patients with sporadic ALS (SALS) and the ALS with VCP novel mutation (ALS-VCP, M158V) was increased, compared with that of the control cases. No VCP-positive inclusion bodies were observed in SALS patients, a ALS-VCP patient or in control subjects. Neuropathologic examination of the ALS-VCP case showed loss of motor neurons, the presence of Bunina bodies, and degeneration of the corticospinal tracts. Bunina bodies detected in this case were confirmed to show immunohistochemical and ultrastructural features similar to those previously described. Furthermore, neuronal intracytoplasmic inclusions immunopositive for TAR DNA-binding protein 43 kDa (TDP-43), phosphorylated TDP-43, ubiquitin (Ub), p62, and optineurin were identified in the spinal and medullary motoneurons, but not in the neocortex. Gene analysis of this ALS-VCP patient confirmed the de novo mutation of M158V, which was not found in control cases; and bioinformatics using several in silico analyses showed possible damage to the structure of VCP. Immunocytochemical study of cultured cells showed increased cytoplasmic translocation of TDP-43 in cells transfected with several mutant VCP including our patient's compared with wild-type VCP. These findings support the idea that VCP is associated with the pathomechanism of SALS and familial ALS with a VCP mutation, presumably acting through a dominant-negative mechanism.

Effects of non-invasive ventilation and posture on chest wall volumes and motion in patients with amyotrophic lateral sclerosis: a case series

PubMed Central

Magalhães, Cristiana M.; Fregonezi, Guilherme A.; Vidigal-Lopes, Mauro; Vieira, Bruna S. P. P.; Vieira, Danielle S. R.; Parreira, Verônica F.

2016-01-01

ABSTRACT Background The effects of non-invasive ventilation (NIV) on the breathing pattern and thoracoabdominal motion of patients with amyotrophic lateral sclerosis (ALS) are unknown. Objectives 1) To analyze the influence of NIV on chest wall volumes and motion assessed by optoelectronic plethysmography in ALS patients and 2) to compare these parameters in the supine and sitting positions to those of healthy individuals (without NIV). Method Nine ALS patients were evaluated in the supine position using NIV. In addition, the ALS patients and nine healthy individuals were evaluated in both sitting and supine positions. Statistical analysis was performed using the paired Student t-test or Wilcoxon test and the Student t-test for independent samples or Mann-Whitney U test. Results Chest wall volume increased significantly with NIV, mean volume=0.43 (SD=0.16)L versus 0.57 (SD=0.19)L (p=0.04). No significant changes were observed for the pulmonary rib cage, abdominal rib cage, or abdominal contribution. The index of the shortening velocity of the diaphragmatic muscle, mean=0.15 (SD=0.05)L/s versus 0.21 (SD=0.05)L/s (p<0.01), and abdominal muscles, mean=0.09 (SD=0.02)L/s versus 0.14 (SD=0.06)L/s (p<0.01), increased during NIV. Comparisons between the supine and sitting positions showed similar changes in chest wall motion in both groups. However, the ALS patients presented a significantly lower contribution of the abdomen in the supine position compared with the controls, mean=56 (SD=13) versus 69 (SD=10) (p=0.02). Conclusions NIV improved chest wall volumes without changing the contribution of the chest wall compartment in ALS patients. In the supine position, ALS patients had a lower contribution of the abdomen, which may indicate early diaphragmatic dysfunction. PMID:27556390

Effects of non-invasive ventilation and posture on chest wall volumes and motion in patients with amyotrophic lateral sclerosis: a case series.

PubMed

Magalhães, Cristiana M; Fregonezi, Guilherme A; Vidigal-Lopes, Mauro; Vieira, Bruna S P P; Vieira, Danielle S R; Parreira, Verônica F

2016-01-01

The effects of non-invasive ventilation (NIV) on the breathing pattern and thoracoabdominal motion of patients with amyotrophic lateral sclerosis (ALS) are unknown. 1) To analyze the influence of NIV on chest wall volumes and motion assessed by optoelectronic plethysmography in ALS patients and 2) to compare these parameters in the supine and sitting positions to those of healthy individuals (without NIV). Nine ALS patients were evaluated in the supine position using NIV. In addition, the ALS patients and nine healthy individuals were evaluated in both sitting and supine positions. Statistical analysis was performed using the paired Student t-test or Wilcoxon test and the Student t-test for independent samples or Mann-Whitney U test. Chest wall volume increased significantly with NIV, mean volume=0.43 (SD=0.16)L versus 0.57 (SD=0.19)L (p=0.04). No significant changes were observed for the pulmonary rib cage, abdominal rib cage, or abdominal contribution. The index of the shortening velocity of the diaphragmatic muscle, mean=0.15 (SD=0.05)L/s versus 0.21 (SD=0.05)L/s (p<0.01), and abdominal muscles, mean=0.09 (SD=0.02)L/s versus 0.14 (SD=0.06)L/s (p<0.01), increased during NIV. Comparisons between the supine and sitting positions showed similar changes in chest wall motion in both groups. However, the ALS patients presented a significantly lower contribution of the abdomen in the supine position compared with the controls, mean=56 (SD=13) versus 69 (SD=10) (p=0.02). NIV improved chest wall volumes without changing the contribution of the chest wall compartment in ALS patients. In the supine position, ALS patients had a lower contribution of the abdomen, which may indicate early diaphragmatic dysfunction.

Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype.

PubMed

Cooper-Knock, Johnathan; Robins, Henry; Niedermoser, Isabell; Wyles, Matthew; Heath, Paul R; Higginbottom, Adrian; Walsh, Theresa; Kazoka, Mbombe; Ince, Paul G; Hautbergue, Guillaume M; McDermott, Christopher J; Kirby, Janine; Shaw, Pamela J

2017-01-01

Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72 . We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes ( n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72 . We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies ( p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression ( t -test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course ( t -test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development.

Very Early Colorectal Anastomotic Leakage within 5 Post-operative Days: a More Severe Subtype Needs Relaparatomy

PubMed Central

Li, Yi-Wei; Lian, Peng; Huang, Ben; Zheng, Hong-Tu; Wang, Ming-He; Gu, Wei-Lie; Li, Xin-Xiang; Xu, Ye; Cai, San-Jun

2017-01-01

Early anastomotic leakage (AL), usually defined as leakage within 30 post-operative days, represents a severe entity. However, mounting evidence has indicated that majorities of leakage occur within one week after surgery, making late AL rarity. Here we analyzed 101 consecutive colorectal AL, all of which occurred within 30 post-operative days, during Jan 2013 and Dec 2015 in cancer hospital of Fudan University. AL occurring within 5 post-operative days was defined as very early AL (vE-AL). We evaluated risk factors of vE-AL compared with non-vEAL and correlated with post-leakage peritonitis and need of relaparatomy. We found that AL occurred at median time of 7 days after surgery. 23 cases were vE-AL. Reconstruction of post-peritoneum for mid-low rectal carcinoma significantly reduced incidence of vE-AL compared with non-vE-AL (p = 0.042). Patients with vE-AL was associated with presence of peritonitis (p = 0.031), the latter significantly correlated with increased re-operation rate (p = 6.8E-13). Besides, patients with vE-AL trended to correlate with increased re-operation rate after leakage (p = 0.088). In concludsion, vE-AL occurring within 5 post-operative days represents a severe subtype associated with general peritonitis and need of relaparatomy. PMID:28084305

Neurofilament Subunit L Levels in the Cerebrospinal Fluid and Serum of Patients with Amyotrophic Lateral Sclerosis.

PubMed

Gong, Zhong-Ying; Lv, Gao-Peng; Gao, Li-Na; Lu, Yi; Guo, Jie; Zang, Da-Wei

2018-06-13

There are no reliable biomarkers that could evaluate the disease burden in amyotrophic lateral sclerosis (ALS). The aim of our study is to evaluate the changes in cerebrospinal fluid (CSF) and serum neurofilament subunit L (NF-L) in patients with ALS and to analyze the correlations between the levels of NF-L and clinical parameters. CSF and serum samples were obtained from 80 ALS patients and 40 controls. The levels of NF-L in CSF and serum were assessed, and disease progression parameters including duration, revised ALS Functional Rating Scale (ALSFRS-r) score, disease progression rate (DPR), upper motor neuron (UMN) score, and survival were analyzed by registered neurologists. All samples were measured using a commercial enzyme-linked immunosorbent assay. Statistical analyses were performed using Prism software. Compared to the controls, the ALS patients displayed significantly increased levels of NF-L; these values were negatively correlated with the ALSFRS-r score and positively correlated with the decrease in ALSFRS-r score, DPR, and UMN score. There was no correlation between levels of NF-L and duration. In addition, the cumulative survival rate in ALS patients with a low level of NF-L was higher than in patients with a high level of NF-L. NF-L levels increased in CSF and serum of patients with ALS. NF-L may thus be a neurodegenerative biomarker for predicting ALS severity and progression, and the survival of patients with this disease. © 2018 S. Karger AG, Basel.

Short- and long-term outcomes of AL amyloidosis patients admitted into intensive care units.

PubMed

Guinault, Damien; Canet, Emmanuel; Huart, Antoine; Jaccard, Arnaud; Ribes, David; Lavayssiere, Laurence; Venot, Marion; Cointault, Olivier; Roussel, Murielle; Nogier, Marie-Béatrice; Pichereau, Claire; Lemiale, Virginie; Arnulf, Bertrand; Attal, Michel; Chauveau, Dominique; Azoulay, Elie; Faguer, Stanislas

2016-09-01

Amyloidosis is a rare and threatening condition that may require intensive care because of amyloid deposit-related organ dysfunction or therapy-related adverse events. Although new multiple myeloma drugs have dramatically improved outcomes in AL amyloidosis, the outcomes of AL patients admitted into intensive care units (ICUs) remain largely unknown. Admission has been often restricted to patients with low Mayo Clinic staging and/or with a complete or very good immunological response at admission. In a retrospective multicentre cohort of 66 adult AL (n = 52) or AA (n = 14) amyloidosis patients, with similar causes of admission to an ICU, the 28-d and 6-month survival rates of AA patients were significantly higher compared to AL patients (93% vs. 60%, P = 0·03; 71% vs. 45%, P = 0·02, respectively). In AL patients, the simplified Index of Gravity Score (IGS2) was the only independent predictive factor for death by day 28, whereas the Mayo-Clinic classification stage had no influence. In Cox's multivariate regression model, only cardiac arrest and on-going chemotherapy at ICU admission significantly predicted death at 6 months. Short-term outcomes of AL patients admitted into an ICU were mainly related to the severity of the acute medical condition, whereas on-going chemotherapy for active amyloidosis impacted on long-term outcomes. © 2016 John Wiley & Sons Ltd.

Humoral immunity response to human endogenous retroviruses K/W differentiates between amyotrophic lateral sclerosis and other neurological diseases.

PubMed

Arru, G; Mameli, G; Deiana, G A; Rassu, A L; Piredda, R; Sechi, E; Caggiu, E; Bo, M; Nako, E; Urso, D; Mariotto, S; Ferrari, S; Zanusso, G; Monaco, S; Sechi, G; Sechi, L A

2018-03-31

Human endogenous retroviruses (HERV) K/W seem to play a role in fostering and exacerbation of some neurological diseases, including amyotrophic lateral sclerosis (ALS). Given these findings, the immunity response against HERV-K and HERV-W envelope surface (env-su) glycoprotein antigens in serum and cerebrospinal fluid (CSF) was investigated for ALS, multiple sclerosis (MS) and Alzheimer's disease patients and in healthy controls. Four antigenic peptides derived respectively from HERV-K and HERV-W env-su proteins were studied in 21 definite or probable ALS patients, 26 possible or definite relapsing-remitting MS patients, 18 patients with Alzheimer's disease and 39 healthy controls. An indirect enzyme-linked immunosorbent assay was set up to detect specific antibodies (Abs) against env-su peptides. Amongst the measured levels of Abs against the four different HERV-K peptide fragments, only HERV-K env-su 19-37 was significantly elevated in ALS compared to other groups, both in serum and CSF. Instead, amongst the Abs levels directed against the four different HERV-W peptide fragments, only HERV-W env-su 93-108 and HERV-W env-su 248-262 were significantly elevated, in the serum and CSF of the MS group compared to other groups. In ALS patients, the HERV-K env-su 19-37 Abs levels were significantly correlated with clinical measures of disease severity, both in serum and CSF. Increased circulating levels of Abs directed against the HERV-W env-su 93-108 and HERV-W env-su 248-262 peptide fragments could serve as possible biomarkers in patients with MS. Similarly, increased circulating levels of Abs directed against the HERV-K env-su 19-37 peptide fragment could serve as a possible early novel biomarker in patients with ALS. © 2018 EAN.

Genetic and Pathological Assessment of hnRNPA1, hnRNPA2/B1, and hnRNPA3 in Familial and Sporadic Amyotrophic Lateral Sclerosis.

PubMed

Fifita, Jennifer A; Zhang, Katharine Y; Galper, Jasmin; Williams, Kelly L; McCann, Emily P; Hogan, Alison L; Saunders, Neil; Bauer, Denis; Tarr, Ingrid S; Pamphlett, Roger; Nicholson, Garth A; Rowe, Dominic; Yang, Shu; Blair, Ian P

2017-01-01

Mutations in the genes encoding the heterogeneous nuclear ribonucleoproteins hnRNPA1 and hnRNPA2/B1 have been reported in a multisystem proteinopathy that includes amyotrophic lateral sclerosis (ALS) and inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia. Mutations were also described in the prion-like domain of hnRNPA1 in patients with classic ALS. Another hnRNP protein, hnRNPA3, has been found to be associated with the ALS/frontotemporal dementia protein C9orf72. To further assess their role in ALS, we examined these hnRNPs in spinal cord tissue from sporadic (SALS) and familial ALS (FALS) patients, including C9orf72 repeat expansion-positive patients, and controls. We also sought to determine the prevalence of HNRNPA1, HNRNPA2B1, and HNRNPA3 mutations in Australian ALS patients. Immunostaining was used to assess hnRNPs in ALS patient spinal cords. Mutation analysis of the HNRNPA1, HNRNPA2B1, and HNRNPA3 genes was performed in FALS and of their prion-like domains in SALS patients. Immunostaining of spinal motor neurons of ALS patients with the C9orf72 repeat expansion showed significant mislocalisation of hnRNPA3, and no differences in hnRNPA1 or A2/B1 localisation, compared to controls. No novel or known mutations were identified in HNRNPA1, HNRNPA2B1, or HNRNPA3 in Australian ALS patients. hnRNPA3 pathology was identified in motor neurons of ALS patients with C9orf72 repeat expansions, implicating hnRNPA3 in the pathogenesis of C9orf72-linked ALS. hnRNPA3 warrants further investigation into the pathogenesis of ALS linked to C9orf72. This study also determined that HNRNP mutations are not a common cause of FALS and SALS in Australia. © 2017 S. Karger AG, Basel.

Risk factors for anastomotic leakage and leak-related mortality after colonic cancer surgery in a nationwide audit.

PubMed

Bakker, I S; Grossmann, I; Henneman, D; Havenga, K; Wiggers, T

2014-03-01

Surgical resection with restoration of bowel continuity is the cornerstone of treatment for patients with colonic cancer. The aim of this study was to identify risk factors for anastomotic leakage (AL) and subsequent death after colonic cancer surgery. Data were retrieved from the Dutch Surgical Colorectal Audit. Patients undergoing colonic cancer resection with creation of an anastomosis between January 2009 to December 2011 were included. Outcomes were AL requiring reintervention and postoperative mortality following AL. AL occurred in 7·5 per cent of 15 667 patients. Multivariable analyses identified male sex, high American Society of Anesthesiologists (ASA) fitness grade, extensive tumour resection, emergency surgery, and surgical resection types such as transverse resection, left colectomy and subtotal colectomy as independent risk factors for AL. A defunctioning stoma was created in a small group of patients, leading to a lower risk of leakage. The mortality rate was 4·1 per cent overall, and was significantly higher in patients with AL than in those without leakage (16·4 versus 3·1 per cent; P < 0·001). Multivariable analyses identified older age, high ASA grade, high Charlson score and emergency surgery as independent risk factors for death after AL. The adjusted risk of death after AL was twice as high following right compared with left colectomy. The elderly and patients with co-morbidity have a higher risk of death after AL. Accurate preoperative patient selection, intensive postoperative surveillance for AL, and early and aggressive treatment of suspected leakage is important, especially in patients undergoing right colectomy. © 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.

Executive dysfunction predicts social cognition impairment in amyotrophic lateral sclerosis.

PubMed

Watermeyer, Tamlyn J; Brown, Richard G; Sidle, Katie C L; Oliver, David J; Allen, Christopher; Karlsson, Joanna; Ellis, Catherine M; Shaw, Christopher E; Al-Chalabi, Ammar; Goldstein, Laura H

2015-07-01

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of the motor system with recognised extra-motor and cognitive involvement. This cross-sectional study examined ALS patients' performance on measures requiring social inference, and determined the relationship between such changes and variations in mood, behaviour, personality, empathy and executive function. Fifty-five ALS patients and 49 healthy controls were compared on tasks measuring social cognition and executive function. ALS patients also completed measures examining mood, behaviour and personality. Regression analyses explored the contribution of executive function, mood, behaviour and personality to social cognition scores within the ALS sample. A between-group MANOVA revealed that, the ALS group was impaired relative to controls on two composite scores for social cognition and executive function. Patients also performed worse on individual tests of executive function measuring cognitive flexibility, response inhibition and concept formation, and on individual aspects of social cognition assessing the attribution of emotional and mental states. Regression analyses indicated that ALS-related executive dysfunction was the main predictor of social cognition performance, above and beyond demographic variables, behaviour, mood and personality. On at least some aspects of social cognition, impaired performance in ALS appears to be secondary to executive dysfunction. The profile of cognitive impairment in ALS supports a cognitive continuum between ALS and frontotemporal dementia.

ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity

PubMed Central

Beers, David R.; Zhao, Weihua; Wang, Jinghong; Zhang, Xiujun; Wen, Shixiang; Neal, Dan; Thonhoff, Jason R.; Alsuliman, Abdullah S.; Shpall, Elizabeth J.; Rezvani, Katy

2017-01-01

Neuroinflammation is a pathological hallmark of ALS in both transgenic rodent models and patients, and is characterized by proinflammatory T lymphocytes and activated macrophages/microglia. In ALS mouse models, decreased regulatory T lymphocytes (Tregs) exacerbate the neuroinflammatory process, leading to accelerated motoneuron death and shortened survival; passive transfer of Tregs suppresses the neuroinflammation and prolongs survival. Treg numbers and FOXP3 expression are also decreased in rapidly progressing ALS patients. A key question is whether the marked neuroinflammation in ALS can be attributed to the impaired suppressive function of ALS Tregs in addition to their decreased numbers. To address this question, T lymphocyte proliferation assays were performed. Compared with control Tregs, ALS Tregs were less effective in suppressing responder T lymphocyte proliferation. Although both slowly and rapidly progressing ALS patients had dysfunctional Tregs, the greater the clinically assessed disease burden or the more rapidly progressing the patient, the greater the Treg dysfunction. Epigenetically, the percentage methylation of the Treg-specific demethylated region was greater in ALS Tregs. After in vitro expansion, ALS Tregs regained suppressive abilities to the levels of control Tregs, suggesting that autologous passive transfer of expanded Tregs might offer a novel cellular therapy to slow disease progression. PMID:28289705

Advanced vs. Basic Life Support in the Treatment of Out-of-Hospital Cardiopulmonary Arrest in the Resuscitation Outcomes Consortium.

PubMed

Kurz, Michael Christopher; Schmicker, Robert H; Leroux, Brian; Nichol, Graham; Aufderheide, Tom P; Cheskes, Sheldon; Grunau, Brian; Jasti, Jamie; Kudenchuk, Peter; Vilke, Gary M; Buick, Jason; Wittwer, Lynn; Sahni, Ritu; Straight, Ronald; Wang, Henry E

2018-04-30

Prior observational studies suggest no additional benefit from advanced life support (ALS) when compared with providing basic life support (BLS) for patients with out-of-hospital cardiac arrest (OHCA). We compared the association of ALS care with OHCA outcomes using prospective clinical data from the Resuscitation Outcomes Consortium (ROC). Included were consecutive adults OHCA treated by participating emergency medical services (EMS) agencies between June 1, 2011, and June 30, 2015. We defined BLS as receipt of cardiopulmonary resuscitation (CPR) and/or automated defibrillation and ALS as receipt of an advanced airway, manual defibrillation, or intravenous drug therapy. We compared outcomes among patients receiving: 1) BLS-only; 2) BLS + late ALS; 3) BLS + early ALS; and 4) ALS-first care. Using multivariable logistic regression, we evaluated the associations between level of care and return of spontaneous circulation (ROSC), survival to hospital discharge, and survival with good functional status, adjusting for age, sex, witnessed arrest, bystander CPR, shockable initial rhythm, public location, EMS response time, CPR quality, and ROC site. Among 35,065 patients with OHCA, characteristics were median age 68 years (IQR 56-80), male 63.9%, witnessed arrest 43.8%, bystander CPR 50.6%, and shockable initial rhythm 24.2%. Care delivered was: 4.0% BLS-only, 31.5% BLS + late ALS, 17.2% BLS + early ALS, and 47.3% ALS-first. ALS care with or without initial BLS care was independently associated with increased adjusted ROSC and survival to hospital discharge unless delivered greater than 6 min after BLS arrival (BLS + late ALS). Regardless of when it was delivered, ALS care was not associated with significantly greater functional outcome. ALS care was associated with survival to hospital discharge when provided initially or within six minutes of BLS arrival. ALS care, with or without initial BLS care, was associated with increased ROSC, however it was not associated with functional outcome. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

No association between gluten sensitivity and amyotrophic lateral sclerosis.

PubMed

Visser, Anne E; Pazoki, Raha; Pulit, Sara L; van Rheenen, Wouter; Raaphorst, Joost; van der Kooi, Anneke J; Ricaño-Ponce, Isis; Wijmenga, Cisca; Otten, Henny G; Veldink, Jan H; van den Berg, Leonard H

2017-04-01

To examine evidence for a role of gluten sensitivity (GS) or celiac disease (CD) in ALS etiology, we included participants from a population-based case-control study in The Netherlands between January 2006 and December 2015. We compared levels and seroprevalence of IgA antibodies to tissue transglutaminase 6 (TG6) in 359 ALS patients and 359 controls, and to transglutaminase 2 (TG2) and endomysium (EMA) in 199 ALS patients and 199 controls. Questionnaire data on 1829 ALS patients and 3920 controls were examined for CD or gluten-free diets (GFD). Genetic correlation and HLA allele frequencies were analyzed using two genome-wide association studies: one on ALS (12,577 cases, 23,475 controls), and one on CD (4533 cases, 10,750 controls). We found one patient with TG6, TG2 and EMA antibodies who had typical ALS and no symptoms of GS. TG6 antibody concentrations and positivity, CD prevalence and adherence to a GFD were similar in patients and controls (p > 0.66) and in these patients disease progression was compatible with typical ALS. CD and ALS were not found to be genetically correlated (p > 0.37). CD-associated HLA allele frequencies were similar in patients and controls (p > 0.28). In conclusion, we found no serological evidence for involvement of gluten-related antibodies in ALS etiology nor did we observe an association between CD and ALS in medical history or genetic data, indicating that there is no evidence in our data for an association between the two diseases. Hence, a role for a GFD in the ALS treatment seems unlikely.

[Cytomorphology of acute mixed leukemia].

PubMed

Sucić, Mirna; Batinić, Drago; Zadro, Renata; Mrsić, Sanja; Labar, Boris

2008-10-01

Biphenotypic acute leukemias (AL) with blasts expressing both myeloid and lymphoid antigens are grouped with undifferentiated AL and bilineal AL in the group of AL of ambiguous lineage. Not all AL with myeloid and lymphoid antigens (ALMy+Ly) are true biphenotypic AL. According to EGIL scoring system, true biphenotypic ALMy+Ly are those with a sum of antigens 2 or more points for both myeloid and lymphoid lineage or for B and T lineage. The aim of this study was to compare cytomorphology and immunophenotype of AL to better understand the relation of certain AL morphology, immunophenotype, cytogenetics and molecular biology of biphenotypic AL. The study included a group of 169 AL patients treated from 1985 till 1991, and a group of 102 AL patients treated from 1993 till 1996 at Zagreb University Hospital Center. Bone marrow and peripheral blood of the two groups of AL patients were analyzed according to Pappenheim (May-Grunwald-Giemsa), cytochemical and alkaline phosphatase-anti-alkaline phosphatase (APAAP) immunocytochemical staining. Flow cytometry immunophenotyping of bone marrow was also done in both patient groups. In the group of 169 adult AL patients, 116 were cytomorphologically classified as acute myeloblastic leukemias (AML), 35 as acute lymphoblastic leukemias (ALL) and 18 as acute undifferentiated leukemias (ANLM). In 6 (3.4%) of 169 AL patients, blasts expressed both myeloid and lymphoid antigens. In the group of 102 AL patients there were 19 (18.6%) ALMy+Ly. In 64 patients cytomorphologically classified into AML subgroup out of 102 AL patients, there were 15 (14.7%/102; 23.4%/64) AML with lymphoid antigens (AMLLy+). In 35 patients cytomorphologically diagnosed as ALL and 3 as ANLM out of 102 AL, there were 4 (3.9%/102; 10.5%/38) ALL with myeloid antigens (ALLMy+). The incidence of mixed AL in 102 AL was more consistent with other studies, pointing to the necessity of myeloperoxidase (MPO), CD7 and TdT determination as part of standard immunophenotyping for better recognition of mixed AL. In both groups of 169 and 102 AL patients, the majority of AL cases were cytomorphologically classified as AML. In the group of 169 patients there were 5 AMLLy+ and in the group of 102 patients there were 15 AMLLy+. In one ANLM,My+ out of 169 AL and also one ANLM,My+ out of 102 AL, blasts were cytomorphologically undifferentiated; in 3 ALLMy+ of 102 AL blasts expressed lymphoid morphology. According to EGIL scoring system, among 15 AMLLy+ of 102 AL there were 4 true biphenotypic ALMy+Ly (1 M1, 2 M3, 1 M4), and in 4 ALMy+Ly with undifferentiated and lymphoid morphology there were 2 true biphenotypic AL (1 L2; 1 ANLM). In 3 ALLB+T out of 35 ALL, one was interlineal biphenotypic AL. These observations are consistent with other studies and WHO determinations indicating that the majority of true biphenotypic leukemias are associated with immature monoblastic or myeloid cytomorphology or with lymphoid or undifferentiated characteristics, but may also express any AML cytomorphology type. Thus, there is no direct correlation of leukemic cell cytomorphology and biphenotypic AL immunophenotype.

Lack of Association between Nuclear Factor Erythroid-Derived 2-Like 2 Promoter Gene Polymorphisms and Oxidative Stress Biomarkers in Amyotrophic Lateral Sclerosis Patients

PubMed Central

Chico, Lucia; Borgia, Loredana; Rocchi, Anna; D'Amelio, Antonia; Carlesi, Cecilia; Mancuso, Michelangelo; Siciliano, Gabriele

2014-01-01

Oxidative stress involvement has been strongly hypothesized among the possible pathogenic mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The intracellular redox balance is finely modulated by numerous complex mechanisms critical for cellular functions, among which the nuclear factor erythroid-derived 2-like 2 (NFE2L2/Nrf2) pathways. We genotyped, in a cohort of ALS patients (n = 145) and healthy controls (n = 168), three SNPs in Nrf2 gene promoter: −653 A/G, −651 G/A, and −617 C/A and evaluated, in a subset (n = 73) of patients, advanced oxidation protein products (AOPP), iron-reducing ability of plasma (FRAP), and plasma thiols (-SH) as oxidative damage peripheral biomarkers. Nrf2 polymorphisms were not different among patients and controls. Increased levels of AOPP (P < 0.05) and decreased levels of FRAP (P < 0.001) have been observed in ALS patients compared with controls, but no difference in -SH values was found. Furthermore, no association was found between biochemical markers of redox balance and Nrf2 polymorphisms. These data confirm an altered redox balance in ALS and indicate that, while being abnormally modified compared to controls, the oxidative stress biomarkers assessed in this study are independent from the −653 A/G, −651 G/A, and −617 C/A Nrf2 SNPs in ALS patients. PMID:24672634

Matrix Metalloproteinases and their Tissue Inhibitors in Cardiac Amyloidosis: Relationship to Structural, Functional Myocardial Changes and to Light Chain Amyloid Deposition

PubMed Central

Biolo, Andreia; Ramamurthy, Sujata; Connors, Lawreen H.; O'Hara, Carl J.; Meier-Ewert, Hans K.; Hoo, Pamela T. Soo; Sawyer, Douglas B.; Seldin, David S.; Sam, Flora

2009-01-01

Background Cardiac amyloidosis is characterized by amyloid infiltration resulting in extracellular matrix (ECM) disruption. Amyloid cardiomyopathy due to immunoglobulin light chain protein (AL-CMP) deposition, has an accelerated clinical course and a worse prognosis compared to non-light chain cardiac amyloidoses i.e., forms associated with wild-type or mutated transthyretin (TTR). We therefore tested the hypothesis that determinants of proteolytic activity of the ECM, the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), would have distinct patterns and contribute to the pathogenesis of AL-CMP vs. TTR. Methods / Results We studied 40 patients with systemic amyloidosis: 10 AL-CMP patients, 20 patients with TTR-associated forms of cardiac amyloidosis, i.e. senile systemic amyloidois (SSA, involving wild-type TTR) or mutant TTR (ATTR), and 10 patients with AL amyloidosis without cardiac involvement. Serum MMP-2 and −9, TIMP-1, −2 and −4, brain natriuretic peptide (BNP) values and echocardiography were determined. AL-CMP and SSA-ATTR groups had similar degrees of increased left ventricular wall thickness (LVWT). However, BNP, MMP-9 and TIMP-1 levels were distinctly elevated accompanied by marked diastolic dysfunction in the AL-CMP group vs. no or minimal increases in the SSA-ATTR group. BNP, MMPs and TIMPs were not correlated with the degree of LVWT but were correlated to each other and to measures of diastolic dysfunction. Immunostaining of human endomyocardial biopsies showed diffuse expression of MMP-9 and TIMP-1 in AL-CMP and limited expression in SSA or ATTR hearts. Conclusions Despite comparable LVWT with TTR-related cardiac amyloidosis, AL-CMP patients have higher BNP, MMPs and TIMPs, which correlated with diastolic dysfunction. These findings suggest a relationship between light chains and ECM proteolytic activation that may play an important role in the functional and clinical manifestations of AL-CMP, distinct from the other non-light chain cardiac amyloidoses. PMID:19808299

Familial Aggregation of Amyotrophic Lateral Sclerosis

PubMed Central

Kamel, Freya; Lichtenstein, Paul; Bellocco, Rino; Sparén, Pär; Sandler, Dale P; Ye, Weimin

2009-01-01

Objective To assess the relative risk of amyotrophic lateral sclerosis (ALS) in families of ALS patients. Methods We conducted a cohort study based on the Swedish Multi-Generation Register (MGR) in 1961-2005. Among 6,671 probands (first ALS case in the family), 1,909 full siblings, 13,947 children, and 5,405 spouses were identified (exposed group). Other persons in MGR, who were siblings, children, or spouses to persons without ALS, served as the reference group. Relative risks of ALS among the exposed group, compared to the reference group, were calculated from Poisson regression models. Concurrence of ALS within twins was assessed in 86,441 twin pairs registered in the Swedish Twin Register. Results Nine cases of ALS were noted among the siblings and 37 cases among the children of the probands, giving a 17-fold risk among the siblings (95% confidence interval [CI], 8.1-30.4) and a 9-fold risk among the children (95% CI, 6.2-12.0), compared to the reference group. Siblings and children had a higher excess risk if the proband was diagnosed at younger age, and the excess risks decreased with increasing age at diagnosis of the proband (p < 0.001). Spouses had no significantly increased risk (p = 0.27). Two cases were identified among the co-twins of ALS probands, giving a relative risk of 32 (95% CI, 5.2-102.6). Interpretation The siblings and children of ALS patients have an around 10-fold risk of ALS compared to the reference group. The excess risks vary with both age and kinship, indicating a major genetic role in familial ALS. PMID:19670447

Integrated MRI and [11 C]-PBR28 PET Imaging in Amyotrophic Lateral sclerosis.

PubMed

Alshikho, Mohamad J; Zürcher, Nicole R; Loggia, Marco L; Cernasov, Paul; Reynolds, Beverly; Pijanowski, Olivia; Chonde, Daniel B; Izquierdo Garcia, David; Mainero, Caterina; Catana, Ciprian; Chan, James; Babu, Suma; Paganoni, Sabrina; Hooker, Jacob M; Atassi, Nazem

2018-05-08

To characterize [ 11 C]-PBR28 brain uptake using positron emission tomography (PET) in people with amyotrophic lateral sclerosis (ALS), and primary lateral sclerosis (PLS). We have previously shown increased [ 11 C]-PBR28 uptake in the precentral gyrus in a small group of ALS patients. Herein, we confirm our initial finding, study the longitudinal changes, and characterize the gray vs. white matter distribution of [ 11 C]-PBR28 uptake in a larger cohort of patients with ALS and PLS. Eighty-five participants including 53 ALS, 11 PLS and 21 healthy controls underwent integrated [ 11 C]-PBR28 PET-MR brain imaging. Patients were clinically assessed using the upper motor neuron burden (UMNB), and the revised ALS functional rating scale (ALSFRS-R). [ 11 C]-PBR28 uptake was quantified as standardized uptake value ratio (SUVR), and compared between groups. Cortical thickness, and fractional anisotropy were compared between groups and correlated with SUVR and the clinical data. [ 11 C]-PBR28 uptake and ALSFRS-R were compared longitudinally over six-month in ten ALS individuals. Whole brain voxel-wise, surface-based and region of interest analyses revealed increased [ 11 C]-PBR28 uptake in the precentral and paracentral gyri in ALS, and in the sub-cortical white matter for the same regions in PLS, compared to controls. The increase in [ 11 C]-PBR28 uptake co-localized and correlated with cortical thinning, reduced fractional anisotropy, increased mean diffusivity, and correlated with higher UMNB score. No significant changes were detected in [ 11 C]-PBR28 uptake over six-month despite clinical progression. Glial activation measured by in vivo [ 11 C]-PBR28 PET is increased in pathologically relevant regions in people with ALS and correlates with clinical measures. This article is protected by copyright. All rights reserved. © 2018 American Neurological Association.

Essential trace elements in amyotrophic lateral sclerosis (ALS): Results in a population of a risk area of Italy.

PubMed

Forte, Giovanni; Bocca, Beatrice; Oggiano, Riccardo; Clemente, Simonetta; Asara, Yolande; Sotgiu, Maria Alessandra; Farace, Cristiano; Montella, Andrea; Fois, Alessandro Giuseppe; Malaguarnera, Michele; Pirina, Pietro; Madeddu, Roberto

2017-09-01

Sardinian (Italy) island population has a uniquely high incidence of amyotrophic lateral sclerosis (ALS). Essential trace element levels in blood, hair, and urine of ALS Sardinian patients were investigated in search of valid biomarkers to recognize and predict ALS. Six elements (Ca, Cu, Fe, Mg, Se, and Zn) were measured in 34 patients compared to 30 age- and sex-matched healthy controls by a validated method. Levels of Ca and Cu in blood and of Se and Zn in hair were significantly higher in ALS than in controls, while urinary excretion of Mg and Se was significantly decreased. The selected cut-off concentrations for these biomarkers may distinguish patients with or without ALS with sufficient sensitivity and specificity. Many positive (as Se-Cu and Se-Zn) and negative associations (as Ca-Mg and Ca-Zn) between elements suggested that multiple metals involved in multiple mechanisms have a role in the ALS degeneration.

Effect of vernal keratoconjunctivitis on vitreous depth in patients with keratoconus.

PubMed

Cingü, Abdullah Kürşat; Kaya, Savaş; Çınar, Yasin; Şahin, Muhammed; Türkçü, Fatih Mehmet; Yüksel, Harun; Murat, Mehmet; Çaça, İhsan

2015-05-01

The aim of this study was to comparatively evaluate the vitreous depth (VD) of keratoconic eyes in patients with or without vernal keratoconjunctivitis (VKC). Eighty eyes of 80 consecutive keratoconus (KC) patients and 40 emmetropic control subjects were enrolled. KC patients were divided into two groups according to accompanying VKC (VKC-KC group and KC group). Mean outcome measures were best-corrected visual acuity (BCVA), spherical equivalent (SE), mean keratometry (Km), intraocular pressure (IOP), and axial length (AL) and its components. The eyes with the highest Km were selected for statistical analysis for each participant. There were 50, 30, and 40 patients in the VKC-KC group, KC group, and control group respectively. The KC group and VKC-KC group were similar in BCVA, SE, Km, CCT, ACD, LT, and IOP (p>0.05). The mean ACD was significantly lower in the control group when compared with the KC group and VKC-KC group. The mean AL and VD were significantly higher in VKC-KC group than those of KC group and the control group, whereas similar in KC and control groups (p>0.05). In the current study we showed that VKC-associated KC patients have significantly longer AL and VD when compared with KC patients without VKC. Posterior segment elongation in VKC-KC group may be associated with the type IV collagen destruction due to chronic longstanding inflammation in VKC patients.

Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death.

PubMed

Muchtar, Eli; Gertz, Morie A; Kumar, Shaji K; Lacy, Martha Q; Dingli, David; Buadi, Francis K; Grogan, Martha; Hayman, Suzanne R; Kapoor, Prashant; Leung, Nelson; Fonder, Amie; Hobbs, Miriam; Hwa, Yi Lisa; Gonsalves, Wilson; Warsame, Rahma; Kourelis, Taxiarchis V; Russell, Stephen; Lust, John A; Lin, Yi; Go, Ronald S; Zeldenrust, Steven; Kyle, Robert A; Rajkumar, S Vincent; Dispenzieri, Angela

2017-04-13

In light of major advances in immunoglobulin light chain (AL) amyloidosis, we evaluated the trends in presentation, management, and outcome among 1551 newly diagnosed AL amyloidosis patients seen in our institution from 2000 to 2014. As compared with the 2 intervals 2000-2004 and 2005-2009, patients diagnosed in 2010-2014 were less likely to have >2 involved organs. Utilization of autologous stem cell transplant (ASCT) was similar across all periods, about one-third of patients, but there was an increase in the use of pre-ASCT bortezomib induction and of unattenuated melphalan conditioning in 2010-2014 compared with earlier periods. Non-ASCT first-line regimen changed with 65% of patients in 2010-2014 received bortezomib-based therapy, 79% of patients in 2005-2009 received melphalan-dexamethasone, and 64% of patients in 2000-2004 received melphalan-prednisone. The rate of better than very good partial response (VGPR) was higher in more recent periods (66% vs 58% vs 51%; P = .001), a change largely driven by improved VGPR rates in the non-ASCT population. Overall survival (OS) has improved, with inflection points for improvement differing for the ASCT and non-ASCT groups. In the ASCT population, the greatest gains were after 2010 (4-year OS, 91% compared with 73% and 65%). In the non-ASCT group, greatest gains were after 2005 (4-year OS, 38%, 32%, and 16%). Fewer patients died within 6 months of diagnosis in the 2 later periods (24% vs 25% vs 37%; P < .001). Overall, outcomes among patients with AL amyloidosis have improved with earlier diagnosis, higher rates of VGPR, lower early mortality, and improved OS. © 2017 by The American Society of Hematology.

Weight loss, dysphagia and supplement intake in patients with amyotrophic lateral sclerosis (ALS): impact on quality of life and therapeutic options

PubMed Central

2013-01-01

Background Weight loss is a frequent feature in the motor neuron disease Amyotrophic lateral sclerosis (ALS). In this study we investigated possible causes of weight loss in ALS, its impact on mood/quality of life (QOL) and the benefit of high calorie nutritional/other dietary supplements and percutaneous endoscopic gastrostomy (PEG). Methods 121 ALS patients were interviewed and answered standardized questionnaires (Beck depression inventory - II, SF36 Health Survey questionnaire, revised ALS functional rating scale). Two years after the initial survey we performed a follow-up interview. Results In our ALS-cohort, 56.3% of the patients suffered from weight loss. Weight loss had a negative impact on QOL and was associated with a shorter survival. Patients who took high calorie nutritional supplements respectively had a PEG stated a great benefit regarding weight stabilization and/or QOL. 38.2% of our patients had significant weight loss without suffering from dysphagia. To clarify the reasons for weight loss in these patients, we compared them with patients without weight loss. The two groups did not differ regarding severity of disease, depression, frontotemporal dementia or fasciculations, but patients with weight loss declared more often increased respiratory work. Conclusions Weight loss is a serious issue in ALS and cannot always be attributed to dysphagia. Symptomatic treatment of weight loss (high calorie nutritional supplements and/ or PEG) should be offered more frequently. PMID:23848967

Imaging Findings Associated with Cognitive Performance in Primary Lateral Sclerosis and Amyotrophic Lateral Sclerosis

PubMed Central

Meoded, Avner; Kwan, Justin Y.; Peters, Tracy L.; Huey, Edward D.; Danielian, Laura E.; Wiggs, Edythe; Morrissette, Arthur; Wu, Tianxia; Russell, James W.; Bayat, Elham; Grafman, Jordan; Floeter, Mary Kay

2013-01-01

Introduction Executive dysfunction occurs in many patients with amyotrophic lateral sclerosis (ALS), but it has not been well studied in primary lateral sclerosis (PLS). The aims of this study were to (1) compare cognitive function in PLS to that in ALS patients, (2) explore the relationship between performance on specific cognitive tests and diffusion tensor imaging (DTI) metrics of white matter tracts and gray matter volumes, and (3) compare DTI metrics in patients with and without cognitive and behavioral changes. Methods The Delis-Kaplan Executive Function System (D-KEFS), the Mattis Dementia Rating Scale (DRS-2), and other behavior and mood scales were administered to 25 ALS patients and 25 PLS patients. Seventeen of the PLS patients, 13 of the ALS patients, and 17 healthy controls underwent structural magnetic resonance imaging (MRI) and DTI. Atlas-based analysis using MRI Studio software was used to measure fractional anisotropy, and axial and radial diffusivity of selected white matter tracts. Voxel-based morphometry was used to assess gray matter volumes. The relationship between diffusion properties of selected association and commissural white matter and performance on executive function and memory tests was explored using a linear regression model. Results More ALS than PLS patients had abnormal scores on the DRS-2. DRS-2 and D-KEFS scores were related to DTI metrics in several long association tracts and the callosum. Reduced gray matter volumes in motor and perirolandic areas were not associated with cognitive scores. Conclusion The changes in diffusion metrics of white matter long association tracts suggest that the loss of integrity of the networks connecting fronto-temporal areas to parietal and occipital areas contributes to cognitive impairment. PMID:24052798

Evaluation of the Microbial Diversity in Amyotrophic Lateral Sclerosis Using High-Throughput Sequencing.

PubMed

Fang, Xin; Wang, Xin; Yang, Shaoguo; Meng, Fanjing; Wang, Xiaolei; Wei, Hua; Chen, Tingtao

2016-01-01

More and more evidences indicate that diseases of the central nervous system have been seriously affected by fecal microbes. However, little work is done to explore interaction between amyotrophic lateral sclerosis (ALS) and fecal microbes. In the present study, high-throughput sequencing method was used to compare the intestinal microbial diversity of healthy people and ALS patients. The principal coordinate analysis, Venn and unweighted pair-group method using arithmetic averages (UPGMA) showed an obvious microbial changes between healthy people (group H) and ALS patients (group A), and the average ratios of Bacteroides , Faecalibacterium , Anaerostipes , Prevotella , Escherichia , and Lachnospira at genus level between ALS patients and healthy people were 0.78, 2.18, 3.41, 0.35, 0.79, and 13.07. Furthermore, the decreased Firmicutes/Bacteroidetes ratio at phylum level using LEfSE (LDA > 4.0), together with the significant increased genus Dorea (harmful microorganisms) and significant reduced genus Oscillibacter , Anaerostipes , Lachnospiraceae (beneficial microorganisms) in ALS patients, indicated that the imbalance in intestinal microflora constitution had a strong association with the pathogenesis of ALS.

The Relationship between Anterior Chamber Depth, Axial Length and Intraocular Lens Power among Candidates for Cataract Surgery.

PubMed

Sedaghat, Mohammad Reza; Azimi, Ali; Arasteh, Peyman; Tehranian, Naghmeh; Bamdad, Shahram

2016-10-01

Basic anatomical parameters in ophthalmology are variable in different countries according to ethnic groups, genetics and some environmental factors. The aim of this study was to determine the relationship between axial length (AL), anterior chamber depth (ACD) and intraocular lens power (IOL) in a referral center from eastern Iran among patients who had cataract surgery, in comparison to studies from other regions of the world. In a cross-sectional retrospective study from 2011 to 2013, the records of 698 cataract patients referring to Khatam Al Anbia general hospital in Mashhad, Iran were evaluated. We divided patients, based on their AL and ACD, into three separate groups and compared their results. The SPSS software was used for data analysis. The Chi-Square test and the Independent-samples t-test were used to compare qualitative and quantitative data between two groups, respectively. The Kendall and the Pearson product-moment correlation tests were used to assess the relationship between AL and ACD. The linear Regression model was used to obtain a mathematical model to estimate ACD, using AL, age and sex. Among individuals who had normal AL (between 22-24.5mm), there was a positive correlation between AL and ACD (p<0.001, r=0.17), however, among individuals with short (AL<22mm) or long sightedness (AL>24.5mm), no significant correlation was detected. We also found that older people have shorter AL (p=0.001 and r=-0.287). Men have an average longer AL (23.7±2.4mm vs. 22.9±2.1mm; p<0.001) and deeper ACD compared to women (2.93±0.45mm vs. 2.82±0.42mm, p=0.002). Our findings were mostly similar to previous literature from other regions of the world and although some anatomical variations may exist regarding ophthalmic anatomy, factors like race and geographical area have little effect on the relationship between ACD, AL and IOL power calculation, furthermore our results support the use of third and fourth generation formulas for IOL power calculation.

Classification of Airflow Limitation Based on z-Score Underestimates Mortality in Patients with Chronic Obstructive Pulmonary Disease.

PubMed

Tejero, Elena; Prats, Eva; Casitas, Raquel; Galera, Raúl; Pardo, Paloma; Gavilán, Adelaida; Martínez-Cerón, Elisabet; Cubillos-Zapata, Carolina; Del Peso, Luis; García-Río, Francisco

2017-08-01

Global Lung Function Initiative recommends reporting lung function measures as z-score, and a classification of airflow limitation (AL) based on this parameter has recently been proposed. To evaluate the prognostic capacity of the AL classifications based on z-score or percentage predicted of FEV 1 in patients with chronic obstructive pulmonary disease (COPD). A cohort of 2,614 patients with COPD recruited outside the hospital setting was examined after a mean (± SD) of 57 ± 13 months of follow-up, totaling 10,322 person-years. All-cause mortality was analyzed, evaluating the predictive capacity of several AL staging systems. Based on Global Initiative for Chronic Obstructive Lung Disease guidelines, 461 patients (17.6%) had mild, 1,452 (55.5%) moderate, 590 (22.6%) severe, and 111 (4.2%) very severe AL. According to z-score classification, 66.3% of patients remained with the same severity, whereas 23.7% worsened and 10.0% improved. Unlike other staging systems, patients with severe AL according to z-score had higher mortality than those with very severe AL (increase of risk by 5.2 and 3.9 times compared with mild AL, respectively). The predictive capacity for 5-year survival was slightly higher for FEV 1 expressed as percentage of predicted than as z-score (area under the curve: 0.714-0.760 vs. 0.649-0.708, respectively). A severity-dependent relationship between AL grades by z-score and mortality was only detected in patients younger than age 60 years. In patients with COPD, the AL classification based on z-score predicts worse mortality than those based on percentage of predicted. It is possible that the z-score underestimates AL severity in patients older than 60 years of age with severe functional impairment.

Epidemiology of Amyotrophic Lateral Sclerosis: A Population-Based Study in Israel.

PubMed

Weil, Clara; Zach, Neta; Rishoni, Shay; Shalev, Varda; Chodick, Gabriel

2016-01-01

Globally, the annual incidence and prevalence of amyotrophic lateral sclerosis (ALS) are estimated at 1.9 and 4.5 per 100,000 population, respectively. This study is aimed at describing the epidemiology of ALS in Israel in a real-world setting. A retrospective study was performed using the databases of Maccabi Healthcare Services (MHS), a 2-million-member health maintenance organization in Israel. The study included all MHS adults diagnosed with ALS between 1997 and 2013. In 2013, characteristics of ALS patients were compared to those of age-sex-matched patients without ALS. Survival after ALS diagnosis was assessed until death and until tracheostomy or death (follow-up through 2014). In 2013 (n = 158), the prevalence of ALS was 8.1 per 100,000 population in MHS. In 1997-2013, a total of 375 ALS patients were diagnosed, corresponding to an average annual incidence of 1.8 per 100,000 population in MHS. The median survival from diagnosis to death was 3.5 years (95% CI 2.9-4.1), with approximately 28% surviving at least 10 years. Median tracheostomy-free survival was 2.5 years (95% CI 2.1-2.9). Results suggest that there is a relatively high prevalence of ALS in Israel. Further research is needed to investigate factors that may contribute to the survival of patients with ALS in Israel. © 2016 S. Karger AG, Basel.

Phenotypic differences of amyotrophic lateral sclerosis (ALS) in China and Germany.

PubMed

Rosenbohm, Angela; Liu, Mingsheng; Nagel, Gabriele; Peter, Raphael S; Cui, Bo; Li, Xiaoguang; Kassubek, Jan; Rothenbacher, Dietrich; Lulé, Dorothée; Cui, Liying; Ludolph, Albert C

2018-04-01

The aim of this study is to explore phenotypical differences of amyotrophic lateral sclerosis (ALS) between two cohorts from Germany and China. Registry-based studies of ALS were conducted in South-West Germany from 2010 to 2014 and an ALS clinic in Beijing from 2013 to 2016, respectively. Demographic and clinical features of 663 German and 276 Chinese ALS patients were collected and compared. Mean age-at-onset was higher in German than in Chinese ALS patients [66.6 years (95% CI 65.7, 67.5) vs. 53.2 years (95% CI 52.0, 54.5)]. Age distribution of ALS patients peaked around 70-74 years in Germany and 50-54 years in China. Bulbar onset was more prevalent among German than among Chinese patients (35.9 vs. 22.8%). Diagnostic delay was higher in the Chinese than in the German study sample (12 vs. 5 months). Cognitive deficits were more pronounced in the Chinese cohort. Both cohorts differed in smoking habits, prevalence of diabetes and in body mass index (BMI). The apparent discrepancies between German and Chinese ALS patients (age at onset, gender distribution, bulbar forms, cognitive dysfunction, risk factors) reveal a quite different clinical phenotype in China, maybe due to socioeconomic status, environmental factors or genetic background. The observed differences in phenotype need to be pursued by further epidemiological studies on environmental and genetic risk factors.

Laser and somatosensory evoked potentials in amyotrophic lateral sclerosis.

PubMed

Isak, Baris; Tankisi, Hatice; Johnsen, Birger; Pugdahl, Kirsten; Finnerup, Nanna Brix; Fuglsang-Frederiksen, Anders

2016-10-01

Mild involvement of sensory nerves has been reported in previous studies in ALS patients. In this study, we assessed sensory pathways in ALS patients using laser evoked potentials (LEPs) and somatosensory evoked potentials (SSEPs). We recruited 18 ALS patients and 31 healthy subjects. Neodymium-doped yttrium aluminium perovskite (Nd:YAP)-laser was used to evoke LEPs in upper (UE) and lower (LE) extremities. N1 and N2P2 potentials were obtained from contralateral insular cortex (T3 or T4) and vertex (Cz), respectively. Median SSEPs were recorded from C3' or C4' and tibial SSEPs from Cz'. Compared to controls, ALS patients had longer N2 and P2 latencies, and smaller N2P2 amplitudes in both UE- and LE-LEPs (p<0.05), and longer latencies for median and tibial SSEPs (p<0.05). LEPs and SSEPs were abnormal in 72.2% and 56.6% patients, respectively. Cortical potentials showed that A-beta or A-delta sensory fibres, or both, were impaired in more than half of the ALS patients. The findings support that ALS is a multi-systemic disorder involving, although to a lesser degree, other systems than the motor. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Is survival improved by the use of NIV and PEG in amyotrophic lateral sclerosis (ALS)? A post-mortem study of 80 ALS patients.

PubMed

Burkhardt, Christian; Neuwirth, Christoph; Sommacal, Andreas; Andersen, Peter M; Weber, Markus

2017-01-01

Non-invasive ventilation (NIV) and percutaneous gastrostomy (PEG) are guideline-recommended interventions for symptom management in amyotrophic lateral sclerosis (ALS). Their effect on survival is controversial and the impact on causes of death is unknown. To investigate the effect of NIV and PEG on survival and causes of death in ALS patients. Eighty deceased ALS patients underwent a complete post mortem analysis for causes of death between 2003 and 2015. Forty-two of these patients consented for genetic testing. Effects of NIV and PEG on survival and causes of death were analyzed in a multivariable Cox proportional hazard regression. Six patients, who requested assisted suicide causing drug-induced hypoxia, were excluded from final analysis. Respiratory failure was the main cause of death in 72 out of 74 patients. Fifteen out of 74 died of aspiration pneumonia 23/74 of bronchopneumonia and 8/74 of a combination of aspiration pneumonia and bronchopneumonia. Twenty died of hypoxia without concomitant infection, and six patients had pulmonary embolism alone or in combination with pneumonia. NIV (p = 0.01) and PEG (p<0.01) had a significant impact on survival. In patients using NIV bronchopneumonia was significantly more frequent (p <0.04) compared to non-NIV patients. This effect was even more pronounced in limb onset patients (p<0.002). Patients with C9orf72 hexanucleotide repeat expansions showed faster disease progression and shorter survival (p = 0.01). The use of NIV and PEG prolongs survival in ALS. This study supports current AAN and EFNS guidelines which recommend NIV and PEG as a treatment option in ALS. The risk of bronchopneumonia as cause of death may be increased by NIV.

Prognostic significance of B-cell lymphoma 2 expression in acute leukemia: A systematic review and meta-analysis.

PubMed

Liu, Yanfeng; He, Pengcheng; Liu, Feng; Shi, Lili; Zhu, Huachao; Cheng, Xiaoyan; Zhao, Jing; Wang, Yuan; Zhang, Mei

2014-05-01

A number of studies have provided estimates of the correlation between B-cell lymphoma 2 (Bcl-2) expression and its clinical significance in acute leukemia (AL); however, the results have been heterogeneous. In order to clarify the prognostic significance of Bcl-2 status in patients with AL, a systematic review and meta-analysis of 5 published studies including a total of 665 subjects was performed. The reported frequency of Bcl-2 expression was 0-99.00%. Bcl-2-positive patients had a higher median white blood cell count compared to Bcl-2-negative patients. Additionally, Bcl-2-negative patients had >2-fold higher odds of achieving complete remission (CR) compared to Bcl-2-positive patients. The summary hazard ratio of Bcl-2 negativity/positivity for CR was 0.62 [95% confidence interval: 0.53-0.81, P<0.001]. Although this meta-analysis was based on data abstracted from observational studies, our results may justify the use of risk-adapted therapeutic strategies for AL according to the Bcl-2 expression status.

The evolving genetic risk for sporadic ALS.

PubMed

Gibson, Summer B; Downie, Jonathan M; Tsetsou, Spyridoula; Feusier, Julie E; Figueroa, Karla P; Bromberg, Mark B; Jorde, Lynn B; Pulst, Stefan M

2017-07-18

To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)-associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity. Whole exome sequencing and repeat expansion PCR of C9orf72 and ATXN2 were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM. The percentage of patients with SALS with a rare and deleterious variant or repeat expansion in an ALS-associated gene was calculated. An odds ratio analysis was performed comparing the burden of ALS-associated genes in patients with SALS vs 324 normal controls. Nineteen rare nonsynonymous variants in an ALS-associated gene, 2 of which were found in 2 different individuals, were identified in 21 patients with SALS. Further, 5 deleterious C9orf72 and 2 ATXN2 repeat expansions were identified. A total of 17.2% of patients with SALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene. The genetic burden of ALS-associated genes in patients with SALS as predicted by MetaSVM was significantly higher than in normal controls. Previous analyses have identified SALS-predisposing variants only in terms of their rarity in normal control populations. By incorporating variant pathogenicity as well as variant frequency, we demonstrated that the genetic risk contributed by these genes for SALS is substantially lower than previous estimates. © 2017 American Academy of Neurology.

Microstructural White Matter Changes Underlying Cognitive and Behavioural Impairment in ALS – An In Vivo Study Using DTI

PubMed Central

Kasper, Elisabeth; Schuster, Christina; Machts, Judith; Kaufmann, Joern; Bittner, Daniel; Vielhaber, Stefan; Benecke, Reiner; Teipel, Stefan; Prudlo, Johannes

2014-01-01

Background A relevant fraction of patients with amyotrophic lateral sclerosis (ALS) exhibit a fronto-temporal pattern of cognitive and behavioural disturbances with pronounced deficits in executive functioning and cognitive control of behaviour. Structural imaging shows a decline in fronto-temporal brain areas, but most brain imaging studies did not evaluate cognitive status. We investigated microstructural white matter changes underlying cognitive impairment using diffusion tensor imaging (DTI) in a large cohort of ALS patients. Methods We assessed 72 non-demented ALS patients and 65 matched healthy control subjects using a comprehensive neuropsychological test battery and DTI. We compared DTI measures of fiber tract integrity using tract-based spatial statistics among ALS patients with and without cognitive impairment and healthy controls. Neuropsychological performance and behavioural measures were correlated with DTI measures. Results Patients without cognitive impairment demonstrated white matter changes predominantly in motor tracts, including the corticospinal tract and the body of corpus callosum. Those with impairments (ca. 30%) additionally presented significant white matter alterations in extra-motor regions, particularly the frontal lobe. Executive and memory performance and behavioural measures were correlated with fiber tract integrity in large association tracts. Conclusion In non-demented cognitively impaired ALS patients, white matter changes measured by DTI are related to disturbances of executive and memory functions, including prefrontal and temporal regions. In a group comparison, DTI is able to observe differences between cognitively unimpaired and impaired ALS patients. PMID:25501028

Non-invasive ventilation effectiveness and the effect of ventilatory mode on survival in ALS patients.

PubMed

Sancho, Jesus; Servera, Emilio; Morelot-Panzini, Capucine; Salachas, François; Similowski, Thomas; Gonzalez-Bermejo, Jesus

2014-03-01

Non-invasive ventilation (NIV) prolongs survival in amyotrophic lateral sclerosis (ALS), but there are no data with which to compare the effectiveness of the different ventilator modes - volume (Vol-NIV) or pressure-cycled (Pres-NIV) ventilation - in ALS. We aimed to determine whether the ventilatory mode has an effect on ventilation effectiveness and survival of ALS patients using NIV. We used a retrospective study that included all ALS patients for whom NIV was indicated in two referral units: one using Vol-NIV and the other using Pres-NIV. Demographic, functional and nocturnal gas exchange parameters at NIV initiation were recorded. Eighty-two ALS patients ventilated using Pres-NIV and 62 using Vol-NIV were included. No differences were found in survival from NIV initiation between Vol-NIV (median 15.00 (7.48-22.41) months) and Pres-NIV (median 15.00 (10.25-19.75) months, p = 0.533) patients. Effective NIV was achieved in 72.41% Vol-NIV patients and in 48.78% Pres-NIV patients (p < 0.001). Ventilator mode (OR 12.066 (4.251-32.270), p < 0.001) and severity of bulbar dysfunction (OR 1.07 (1.011-1.133), p = 0.02) were the variables correlated with effective NIV. In conclusion, although Vol-NIV provides more effective ventilation, Vol-NIV and Pres-NIV present similar survival in ALS. Effectiveness of NIV is related to the severity of bulbar dysfunction.

The agreement between abnormal venous lactate and arterial lactate in the ED: a retrospective chart review.

PubMed

Bloom, B; Pott, J; Freund, Y; Grundlingh, J; Harris, T

2014-06-01

The evidence for prognostication using lactate is often based on arterial lactate (AL). Arterial sampling is painful and difficult, and carries risks. Studies comparing peripheral venous lactate (PVL) with AL showed little difference but predominantly included patients with normal lactate. The objective of this study was to measure agreement between PVL and AL in patients with elevated venous lactate. This is a retrospective cross-sectional study. ED patients age≥16, attending from October 2010 to June 2011 inclusive, with PVL≥2.0 mmol/L and AL taken within 1 hour. intravenous fluid prior to or between initial venous and arterial sampling. Primary endpoint: agreement between PVL and AL defined as mean difference±95% limits of agreement (LOA). The misclassification rate was assessed. N=232. VL median 3.50 mmol/L, range 2.00 to 15.00 mmol/L. AL median 2.45 mmol/L, range 1.0 to 13.2 mmol/L. The mean difference±SD between PVL and AL for all patients was 1.06±1.30 mmol/L (95%LOA -1.53 to 3.66 mmol/L). Using a cut-off of 2 mmol/L and 4 mmol/L, 36.2% and 17.9% of patients respectively were incorrectly classified as having elevated lactate. We report greater bias between VL and AL with broader LOA than previously documented. This may partly be due to the fact that we studied only patients with abnormal venous values, for whom close agreement would confer greatest clinical significance. The agreement between abnormal PVL and AL is poor and the high rate of misclassification may suggest that PVL is not a good substitute for AL if the venous lactate is abnormal. Copyright © 2014 Elsevier Inc. All rights reserved.

Multiparametric Analysis of Sniff Nasal Inspiratory Pressure Test in Middle Stage Amyotrophic Lateral Sclerosis.

PubMed

Sarmento, Antonio; Aliverti, Andrea; Marques, Layana; Pennati, Francesca; Dourado-Júnior, Mario Emílio; Fregonezi, Guilherme; Resqueti, Vanessa

2018-01-01

The relaxation rates and contractile properties of inspiratory muscles are altered with inspiratory muscle weakness and fatigue. This fact plays an important role in neuromuscular disorders patients and had never been extensively studied in amyotrophic lateral sclerosis (ALS). In this cross-sectional study, these parameters were investigated non-invasively through nasal inspiratory sniff pressure test (SNIP) in 39 middle stage spinal onset ALS subjects and compared with 39 healthy controls. ALS patients were also divided into three subgroups according to a decline in their percentage of predicted forced vital capacity (FVC %pred ) as well as a decline in the ALS functional rating scale score and its respiratory subscore (R-subscore) in order to determine the best parameter linked to early respiratory muscle weakness. When compared with healthy subjects, middle stage ALS subjects exhibited a significantly lower ( p  < 0.0001) maximum relaxation rate and maximum rate of pressure development (MRPD), as well as a significantly higher ( p  < 0.0001) tau (τ), contraction time, and half-relaxation time. The results from receiver operating characteristic curves showed that MRPD (AUC 0.735, p  < 0.001) and FVC %pred (AUC 0.749, p  = 0.009) were the best discriminator parameters between ALS patients with ≤30 and >30 points in the ALS functional rating scale. In addition, 1/2RT (AUC 0.720, p  = 0.01), FVC %pred (AUC 0.700, p  = 0.03), τ (AUC 0.824, p  < 0.0001), and MRPD (AUC 0.721, p  = 0.01) were the parameters more sensitive in detecting a fall of three points in the R-subscore. On the other hand, MRPD (AUC 0.781, p  < 0.001), τ (AUC 0.794, p  = 0.0001), and percentage of predicted of SNIP (AUC 0.769, p  = 0.002) were the parameters able to detect a fall in 30% of the FVC %pred in middle stage ALS patients. The contractile properties and relaxation rates of the diaphragm are altered in middle stage spinal onset ALS when compared with healthy subjects. These parameters are able to discriminate between those middle stage ALS subjects with early decline in inspiratory muscle function and those who not.

A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: Possible mitochondrial biomarker target engagement

PubMed Central

Macchi, Zachary; Wang, Yunxia; Moore, Dan; Katz, Jonathan; Saperstein, David; Walk, David; Simpson, Ericka; Genge, Angela; Bertorini, Tulio; Fernandes, J Americo; Swenson, Andrea; Elman, Lauren; Dimachkie, Mazen; Herbelin, Laura; Miller, Joann; Lu, Jianghua; Wilkins, Heather; Swerdlow, Russell H; Statland, Jeffrey; Barohn, Richard

2015-01-01

OBJECTIVE Rasagiline, a monoamine oxidase B inhibitor, slowed disease progression in the SOD1 mouse, and in a case series of patients with amyotrophic lateral sclerosis (ALS). Here we determine whether rasagiline is safe and effective in ALS compared to historical placebo controls, and whether it alters mitochondrial biomarkers. METHODS We performed a prospective open-label, multicenter screening trial of 36 ALS patients treated with 2mg oral rasagiline daily for 12 months. Outcomes included the slope of deterioration of the revised ALS Functional Rating Scale (ALSFRS-R), adverse event monitoring, time to treatment failure, and exploratory biomarkers. RESULTS Participants experienced no serious drug-related adverse events, and the most common adverse event was nausea (11.1%). Rasagiline did not improve the rate of decline in the ALSFRS-R; however, differences in symptom duration compared to historical placebo controls differentially affected ALSFRS-R slope estimates. Rasagiline changed biomarkers over 12 months, such that the mitochondrial membrane potential increased (JC-1 red/green fluorescent ratio 1.92, P=0.0001) and apoptosis markers decreased (Bcl-2/Bax ratio 0.24, P<0.0001). CONCLUSION Engagement of exploratory biomarkers and questions about comparability of baseline characteristics lead us to recommend a further placebo-controlled trial. PMID:25832828

Metal concentrations in cerebrospinal fluid and blood plasma from patients with amyotrophic lateral sclerosis.

PubMed

Roos, Per M; Vesterberg, Olof; Syversen, Tore; Flaten, Trond Peder; Nordberg, Monica

2013-02-01

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal degenerative disorder of motor neurons. The cause of this degeneration is unknown, and different causal hypotheses include genetic, viral, traumatic and environmental mechanisms. In this study, we have analyzed metal concentrations in cerebrospinal fluid (CSF) and blood plasma in a well-defined cohort (n = 17) of ALS patients diagnosed with quantitative electromyography. Metal analyses were performed with high-resolution inductively coupled plasma mass spectrometry. Statistically significant higher concentrations of manganese, aluminium, cadmium, cobalt, copper, zinc, lead, vanadium and uranium were found in ALS CSF compared to control CSF. We also report higher concentrations of these metals in ALS CSF than in ALS blood plasma, which indicate mechanisms of accumulation, e.g. inward directed transport. A pattern of multiple toxic metals is seen in ALS CSF. The results support the hypothesis that metals with neurotoxic effects are involved in the pathogenesis of ALS.

Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse.

PubMed

Ikeda, Ken; Iwasaki, Yasuo

2015-01-01

Edaravone, a free radical scavenger is used widely in Japanese patients with acute cerebral infarction. This antioxidant could have therapeutic potentials for other neurological diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the upper and the lower motor neuron, leading to death within 3-5 years after onset. A phase III clinical trial of edaravone suggested no significant effects in ALS patients. However, recent 2nd double-blind trial has demonstrated therapeutic benefits of edaravone in definite patients diagnosed by revised El Escorial diagnostic criteria of ALS. Two previous studies showed that edaravone attenuated motor symptoms or motor neuron degeneration in mutant superoxide dismutase 1-transgenic mice or rats, animal models of familial ALS. Herein we examined whether this radical scavenger can retard progression of motor dysfunction and neuropathological changes in wobbler mice, sporadic ALS-like model. After diagnosis of the disease onset at the postnatal age of 3-4 weeks, wobbler mice received edaravone (1 or 10 mg/kg, n = 10/group) or vehicle (n = 10), daily for 4 weeks by intraperitoneal administration. Motor symptoms and neuropathological changes were compared among three groups. Higher dose (10 mg/kg) of edaravone treatment significantly attenuated muscle weakness and contracture in the forelimbs, and suppressed denervation atrophy in the biceps muscle and degeneration in the cervical motor neurons compared to vehicle. Previous and the present studies indicated neuroprotective effects of edaravone in three rodent ALS-like models. This drug seems to be worth performing the clinical trial in ALS patients in the United States of American and Europe, in addition to Japan.

Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse

PubMed Central

2015-01-01

Edaravone, a free radical scavenger is used widely in Japanese patients with acute cerebral infarction. This antioxidant could have therapeutic potentials for other neurological diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the upper and the lower motor neuron, leading to death within 3–5 years after onset. A phase III clinical trial of edaravone suggested no significant effects in ALS patients. However, recent 2nd double-blind trial has demonstrated therapeutic benefits of edaravone in definite patients diagnosed by revised El Escorial diagnostic criteria of ALS. Two previous studies showed that edaravone attenuated motor symptoms or motor neuron degeneration in mutant superoxide dismutase 1-transgenic mice or rats, animal models of familial ALS. Herein we examined whether this radical scavenger can retard progression of motor dysfunction and neuropathological changes in wobbler mice, sporadic ALS-like model. After diagnosis of the disease onset at the postnatal age of 3–4 weeks, wobbler mice received edaravone (1 or 10 mg/kg, n = 10/group) or vehicle (n = 10), daily for 4 weeks by intraperitoneal administration. Motor symptoms and neuropathological changes were compared among three groups. Higher dose (10 mg/kg) of edaravone treatment significantly attenuated muscle weakness and contracture in the forelimbs, and suppressed denervation atrophy in the biceps muscle and degeneration in the cervical motor neurons compared to vehicle. Previous and the present studies indicated neuroprotective effects of edaravone in three rodent ALS-like models. This drug seems to be worth performing the clinical trial in ALS patients in the United States of American and Europe, in addition to Japan. PMID:26469273

A comparison of maximal inspiratory pressure and forced vital capacity as potential criteria for initiating non-invasive ventilation in amyotrophic lateral sclerosis.

PubMed

Mendoza, Michelle; Gelinas, Deborah F; Moore, Dan H; Miller, Robert G

2007-04-01

Using a retrospective analysis of 161 patients with amyotrophic lateral sclerosis (ALS) from the Western ALS study group (WALS) database, the sensitivity of maximal inspiratory pressure (MIP)< -60 cm H(2)O and forced vital capacity (FVC)< 50% as US Medicare thresholds for initiating non-invasive ventilation (NIV) were compared. Sixty-five per cent of patients at enrollment met the MIP criterion, compared with only 8% of patients who met the FVC criterion. There were no cases in which FVC< 50% antedated MIP< -60 cm H(2)O. The longitudinal data showed that patients reached the MIP criterion 4 to 6.5 months earlier than the FVC criterion. For patients with clinical signs and symptoms needing treatment with NIV, a MIP< -60 cm H(2)O allows US clinicians to obtain non-invasive ventilatory support for patients earlier than if using the FVC criterion alone.

Hydration measured by doubly labeled water in ALS and its effects on survival.

PubMed

Scagnelli, Connor N; Howard, Diantha B; Bromberg, Mark B; Kasarskis, Edward J; Matthews, Dwight E; Mitsumoto, Hiroshi M; Simmons, Zachary; Tandan, Rup

2018-05-01

We present a study of hydration in ALS patients and its effects on survival. This was a multicenter study over 48 weeks in 80 ALS patients who underwent 250 individual measurements using doubly labeled water (DLW). Total body water (TBW) and water turnover (a surrogate for water intake) were 3.4% and 8.6% lower, respectively, in patients compared to age- and gender-matched healthy controls, and both significantly decreased over study duration. In 20% of patients, water turnover measured over 10 d was 2 standard deviations below the mean value in healthy controls. In a separate clinic cohort of 208 patients, water intake estimated from a de novo equation created from common clinical endpoints was a prognostic indicator of survival. Regardless of nutritional state assessed by BMI, survival was two-fold longer in the group above the median for estimated water intake, suggesting that hydration may be a more important predictor of survival than malnutrition. Risk factors for poor hydration were identified. Water intake equations recommended by US Centers for Medicare and Medicaid Services in healthy elderly were inaccurate for use in ALS patients. We developed equations to estimate TBW and water intake in ALS patients for use in clinics to accurately estimate hydration and improve clinical care.

Investigating the neuroanatomical substrate of pathological laughing and crying in amyotrophic lateral sclerosis with multimodal neuroimaging techniques.

PubMed

Christidi, Foteini; Karavasilis, Efstratios; Ferentinos, Panagiotis; Xirou, Sophia; Velonakis, Georgios; Rentzos, Michalis; Zouvelou, Vasiliki; Zalonis, Ioannis; Efstathopoulos, Efstathios; Kelekis, Nikolaos; Evdokimidis, Ioannis

2018-02-01

Pathological laughing and crying (PLC) is common in several neurological and psychiatric diseases and is associated with a distributed network involving the frontal cortex, the brainstem and cortico-pontine-cerebellar circuits. By applying multimodal neuroimaging approach, we examined the neuroanatomical substrate of PLC in a sample of patients with amyotrophic lateral sclerosis (ALS). We studied 56 non-demented ALS patients and 25 healthy controls (HC). PLC was measured in ALS using the Center of Neurologic Study Lability Scale (CNS-LS; cutoff score: 13). All participants underwent 3D-T1-weighted and 30-directional diffusion-weighted imaging at 3T. Voxel-based morphometry and tract-based spatial-statistics analysis was used to examine gray matter (GM) and white matter (WM) differences between ALS patients with and without PLC (ALS-PLC and ALS-nonPLC, respectively). Comparisons were restricted to regions with detected differences between ALS and HC, controlling for age, gender, total intracranial volume and depressive symptoms. In regions with significant differences between ALS and HC, ALS-PLC patients showed decreased GM volume in left orbitofrontal cortex, frontal operculum, and putamen and bilateral frontal poles, compared to ALS-nonPLC. They also had decreased fractional anisotropy in left cingulum bundle and posterior corona radiata. WM abnormalities were additionally detected in WM associative and ponto-cerebellar tracts (using a more liberal threshold). PLC in ALS is driven by both GM and WM abnormalities which highlight the role of circuits rather than isolated centers in the emergence of this condition. ALS is suggested as a useful natural experimental model to study PLC.

The terminal latency of the phrenic nerve correlates with respiratory symptoms in amyotrophic lateral sclerosis.

PubMed

Park, Jin-Sung; Park, Donghwi

2017-09-01

The aim of the study was to investigate the electrophysiological parameters in phrenic nerve conduction studies (NCS) that sensitively reflect latent respiratory insufficiency present in amyotrophic lateral sclerosis (ALS). Forty-nine patients with ALS were examined, and after exclusion, 21 patients with ALS and their phrenic NCS results were reviewed. The patients were divided into two groups according to their respiratory sub-score in the ALS functional rating scale - revised (Group A, sub-score 12vs. Group B, sub-score 11). We compared the parameters of phrenic NCS between the two groups. There were no significant differences in the clinical characteristics between the two groups. Using a multivariate model, we found that the terminal latency of the phrenic nerve was the only parameter that was associated with early symptoms of respiratory insufficiency (p<0.05). The optimal cutoff value for the terminal latency of the phrenic nerve was 7.65ms (sensitivity 80%, specificity 68.2%). The significantly prolonged terminal latency of the phrenic nerve in our study may reflect a profound distal motor axonal dysfunction of the phrenic nerve in patients with ALS in the early stage of respiratory insufficiency that can be used as a sensitive electrophysiological marker reflecting respiratory symptoms in ALS. The terminal latency of the phrenic nerve is useful for early detection of respiratory insufficiency in patients with ALS. Copyright © 2017. Published by Elsevier B.V.

The influence of nevirapine and efavirenz-based anti-retroviral therapy on the pharmacokinetics of lumefantrine and anti-malarial dose recommendation in HIV-malaria co-treatment.

PubMed

Maganda, Betty A; Ngaimisi, Eliford; Kamuhabwa, Appolinary A R; Aklillu, Eleni; Minzi, Omary M S

2015-04-25

HIV-malaria co-infected patients in most parts of sub-Saharan Africa are treated with both artemether-lumefantrine (AL) and efavirenz (EFV) or nevirapine (NVP)-based antiretroviral therapy (ART). EFV, NVP, artemether and lumefantrine are substrates, inhibitors or inducers of CYP3A4 and CYP2B6, creating a potential for drug-drug interactions. The effect of EFV and/or NVP on lumefantrine pharmacokinetic profile among HIV-malaria co-infected patients on ART and treated with AL was investigated. Optimal lumefantrine dosage regimen for patients on EFV-based ART was determined by population pharmacokinetics and simulation. This was a non-randomized, open label, parallel, prospective cohort study in which 128, 66 and 75 HIV-malaria co-infected patients on NVP-based ART (NVP-arm), EFV-based ART (EFV-arm) and ART naïve (control-am) were enrolled, respectively. Patients were treated with AL and contributed sparse venous plasma samples. Pharmacokinetic analysis of lumefantrine was done using non-linear mixed effect modelling. Of the evaluated models, a two-compartment pharmacokinetic model with first order absorption and lag-time described well lumefantrine plasma concentrations time profile. Patients in the EFV-arm but not in the NVP-arm had significantly lower lumefantrine bioavailability compared to that in the control-arm. Equally, 32% of patients in the EFV-arm had day-7 lumefantrine plasma concentrations below 280 ng/ml compared to only 4% in the control-arm and 3% in the NVP-arm. Upon post hoc simulation of lumefantrine exposure, patients in the EFV-arm had lower exposure (median (IQR)) compared to that in the control-arm; AUC0-inf; was 303,130 (211,080-431,962) versus 784,830 (547,405-1,116,250); day-7 lumefantrine plasma concentrations was: 335.5 (215.8-519.5) versus 858.7 (562.3-1,333.8), respectively. The predictive model through simulation of lumefantrine exposure at different dosage regimen scenarios for patients on EFV-based ART, suggest that AL taken twice daily for five days using the current dose could improve lumefantrine exposure and consequently malaria treatment outcomes. Co-treatment of AL with EFV-based ART but not NVP-based ART significantly reduces lumefantrine bioavailability and consequently total exposure. To ensure adequate lumefantrine exposure and malaria treatment success in HIV-malaria co-infected patients on EFV-based ART, an extension of the duration of AL treatment to five days using the current dose is proposed.

The role of exercise in amyotrophic lateral sclerosis.

PubMed

Chen, Amy; Montes, Jacqueline; Mitsumoto, Hiroshi

2008-08-01

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor nervous system. It causes progressive and cumulative physical disabilities in patients, and leads to eventual death due to respiratory muscle failure. The disease is diverse in its presentation, course, and progression. We do not yet fully understand the cause or causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating this disease. Currently, we rely on a multidisciplinary approach to symptomatically manage and care for patients who have ALS. In this article, the authors review the literature on the role of exercise in patients who have ALS, and briefly compare what is known about exercise in other neuromuscular diseases.

Antioxidant capacity and protein oxidation in cerebrospinal fluid of amyotrophic lateral sclerosis.

PubMed

Siciliano, G; Piazza, S; Carlesi, C; Del Corona, A; Franzini, M; Pompella, A; Malvaldi, G; Mancuso, M; Paolicchi, A; Murri, L

2007-05-01

The causes of Amyotrophic Lateral Sclerosis (ALS) are unknown. A bulk of evidence supports the hypothesis that oxidative stress and mitochondrial dysfunction can be implicated in ALS pathogenesis. METHODS =: We assessed, in cerebrospinal fluid (CSF) and in plasma of 49 ALS patients and 8 controls, the amount of oxidized proteins (AOPP, advanced oxidation protein products), the total antioxidant capacity (FRA, the ferric reducing ability), and, in CSF, two oxidation products, the 4-hydroxynonenal and the sum of nitrites plus nitrates. The FRA was decreased (p = 0.003) in CSF, and AOPP were increased in both CSF (p = 0.0039) and plasma (p = 0.001) of ALS patients. The content of AOPP was differently represented in CSF of ALS clinical subsets, resulting in increase in the common and pseudopolyneuropathic forms (p < 0.001) and nearly undetectable in the bulbar form, as in controls. The sum of nitrites plus nitrates and 4-hydroxynonenal were unchanged in ALS patients compared with controls. Our results, while confirming the occurrence of oxidative stress in ALS, indicate how its effects can be stratified and therefore implicated differently in the pathogenesis of different clinical forms of ALS.

Impact of craving on alcohol relapse during, and 12 months following, outpatient treatment.

PubMed

Bottlender, Miriam; Soyka, Michael

2004-01-01

This study investigated the relationship between craving in abstinent alcohol-dependent patients measured by the Obsessive Compulsive Craving Scale (OCDS) (Anton et al., 1995) and relapse during and after completion of an intensive outpatient treatment programme. In a prospective study, participants were interviewed at entry to, and end of, an outpatient treatment programme, and 12 months after the end of the programme. To measuring craving the OCDS total score by Anton et al. (1995) and the three-factor model by Kranzler et al. (1999) were used. OCDS was administered at the beginning of treatment (when all patients were abstinent), and at the end of treatment in those who were abstinent and had completed the programme. Of 103 alcohol-dependent patients, 74 completed the treatment programme and at follow-up after 12 months 97% of these patients were personally re-interviewed. Thirty-two patients (31%) relapsed during the treatment phase. They had significantly higher craving measured by the total OCDS score and a significantly higher score on the subscales 'obsessions' and 'drinking control and consequences' compared to abstinent patients. Of the 74 patients who completed the programme 16% had a major relapse in the next 12 months. Major relapse was predicted by the total OCDS score and the subscale 'obsessions'. OCDS total score predicts relapse in outpatient treatment. Treatment and aftercare of patients with high craving should be intensified. In our study design, the subscales of the three-factor model by Kranzler et al. (1999) provided only little information gain compared to the OCDS total score.

The use of serum free light chain dimerization patterns assist in the diagnosis of AL amyloidosis.

PubMed

Gatt, Moshe E; Kaplan, Batia; Yogev, Dean; Slyusarevsky, Elana; Pogrebijski, Galina; Golderman, Sizilia; Kukuy, Olga; Livneh, Avi

2018-05-16

The discrimination between benign and malignant forms of plasma cell dyscrasia (PCD) is often difficult. Free light chain monomer-dimer pattern analysis (FLC-MDPA) may assist in solving this dilemma and distinguish between AL amyloidosis and benign PCD. Serum samples of patients with AL amyloidosis and benign PCD were analysed in a blinded manner. Quantitative Western blotting was performed to estimate dimerization and clonality indices, and thereby determine the source of the tested samples, as derived either from benign or malignant PCD. The findings obtained by the FLC-MDPA were compared with the actual diagnosis. Of 37 samples from patients with active AL amyloidosis, 34 (91·9%) fulfilled dimerization criteria for diagnosis of AL amyloidosis. Of the 45 samples from patients with benign PCD, 10 (21·2%) tested falsely positive or gave an inconclusive result. Thus, the sensitivity of the analysis was 92·5% with a remarkable negative predictive value of 91·9%. In addition, of 20 patients who were in complete or very good partial remission, only one tested positive. By multivariate analysis, FLC-MDPA was the best independent marker predicting AL amyloidosis (odds ratio of 84). The FLC-MDPA offers a highly effective tool in the diagnostic assessment of patients with PCD. © 2018 John Wiley & Sons Ltd.

IGF-1, IGFBP-3 and ALS in adult patients with chronic kidney disease.

PubMed

Lepenies, Julia; Wu, Zida; Stewart, Paul M; Strasburger, Christian J; Quinkler, Marcus

2010-04-01

Insulin-like growth factor I (IGF-1) is for the most part bound in a ternary complex with IGF-binding protein-3 (IGFBP-3) and acid-labile subunit (ALS). This ternary complex is a storage form of IGF-1 in blood and passes not through the renal glomerulus. Little information is available in regard to the components of the ternary complex in adult renal disease. To investigate levels of serum IGF-1, IGFBP-3 and ALS in relation to renal function and extent of proteinuria. We measured IGF-1, IGFBP-3 and ALS concentrations in 137 patients who were investigated due to proteinuria and/or haematuria and/or renal impairment. The patients received renal biopsies and the histological diagnosis was documented. Urinary albumin excretion and relevant clinical parameter were evaluated. IGF-1 showed a highly positive correlation to IGFBP-3 and ALS, and the latter to IGFBP-3. IGF-1, IGFBP-3 and ALS decreased with increasing age. IGF-1 and IGFBP-3 showed no significant change depending on the creatinine clearance. However, ALS decreased with decreasing renal function. In patients with heavy proteinuria ALS levels, but not IGF-1 and IGFBP-3 levels, decreased significantly. Patients with chronic ischaemic renal damage and diabetic glomerulopathy showed higher IGF-1 and IGFBP-3 levels compared to patients with thin glomerular basement membrane disease despite their older age. IGF-1 and IGFBP-3 levels seem to be independent of renal function and severity of proteinuria. However, ALS levels are altered in renal failure and nephrotic syndrome, which may be due to increased renal loss or diminished hepatic production or both. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

Life course body mass index and risk and prognosis of amyotrophic lateral sclerosis: results from the ALS registry Swabia.

PubMed

Peter, Raphael Simon; Rosenbohm, Angela; Dupuis, Luc; Brehme, Torben; Kassubek, Jan; Rothenbacher, Dietrich; Nagel, Gabriele; Ludolph, Albert Christian

2017-10-01

Weight loss appears as a strong predictor of survival of patients with amyotrophic lateral sclerosis, yet no data are currently available to describe the life course history of pre-diagnostic body mass index (BMI) in these patients. 393 ALS cases (mean age: 65.8 years, 57.3% men) and 791 controls matched by age and sex from a population-based case-control study of the ALS Registry Swabia were analyzed. Differences of BMI change in cases and controls over time were modeled using a multilevel additive model. In addition, survival in ALS cases by BMI change was modeled using an accelerated failure time model adjusted for prognostic factors. In ALS cases, BMI was consistently higher than in controls in the 20-70 years before the interview. Conditional logistic regression revealed an odds ratio of 1.05 (95% confidence interval (CI) 1.00-1.11, p = 0.041) per 1 kg/m 2 higher BMI 35-45 years before interview. However, a sharp decrease was evident in the BMI of ALS cases about 10 years before disease onset. Moreover, weight loss was strongly associated with shorter survival in ALS patients. Illustrating this, patients with stable weight showed a median survival time of 22.1 (95%-CI 19.2-25.0) months, as compared to 13.4 (95%-CI 10.5-16.3) months for patients with weight loss of 2.5 kg/m 2 over the last 3 months before the interview. Thus, alterations in body weight are present in ALS patients already decades before clinical manifestation of ALS, while weight loss precedes motor symptoms of several years and is associated with poor prognosis.

High serum lactate as an adjunct in the early prediction of anastomotic leak following oesophagectomy.

PubMed

Ip, B; Ng, K T; Packer, S; Paterson-Brown, S; Couper, G W

2017-10-01

Anastomotic leak (AL) following oesophagectomy carries a high mortality and morbidity. Early detection and intervention is required for a successful outcome. We have examined the role of a high postoperative serum lactate in predicting which patients are at risk of developing an anastomotic leak(AL). All patients who underwent transthoracic oesophagectomy over a 3-year period were identified from a prospectively collected database. Medical records were reviewed to identify the highest serum lactate recorded from blood gas analysis over each 24hr post-operative period. Patients who underwent transhiatal and left thoraco-abdominal oesophagectomies were excluded. Patients who developed a chyle leak were excluded. Of a total of 136 oesophagectomies included for analysis, 18 developed an AL (13.2%). Of these patients, 10 underwent thoracoscopic oesophageal mobilization with cervical anastomosis and the rest an Ivor Lewis procedure. Predictive factors for AL included neoadjuvant chemotherapy (15/18 83.3% vs 55/118 46.6% p = 0.0046) and number of positive lymph nodes (mean 4.2 vs control mean 2.3 p = 0.045). Overall net fluid balance was comparable between the 2 groups, although AL patients received slightly more fluid on Day 3. High lactate levels on days 1-3 were associated with an AL. Using a Day 2 lactate of 1.7 mmol/L, the sensitivity of predicting AL was 72% and specificity 88%. The mean lag time using existing diagnostic modalities was 7.9 days. A serum lactate of >1.7 mmol/l on day 2 should raise the possibility of a potential AL. Such patients should be selected for more intensive monitoring, optimization and selective gastroscopy. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Pathology of callosal damage in ALS: An ex-vivo, 7 T diffusion tensor MRI study.

PubMed

Cardenas, Agustin M; Sarlls, Joelle E; Kwan, Justin Y; Bageac, Devin; Gala, Zachary S; Danielian, Laura E; Ray-Chaudhury, Abhik; Wang, Hao-Wei; Miller, Karla L; Foxley, Sean; Jbabdi, Saad; Welsh, Robert C; Floeter, Mary Kay

2017-01-01

The goal of this study was to better understand the changes in tissue microstructure that underlie white matter diffusion changes in ALS patients. Diffusion tensor imaging was carried out in postmortem brains of 4 ALS patients and two subjects without neurological disease on a 7 T MRI scanner using steady-state free precession sequences. Fractional anisotropy (FA) was measured in the genu, body, and splenium of the corpus callosum in formalin-fixed hemispheres. FA of the body and genu was expressed as ratio to FA of the splenium, a region unaffected in ALS. After imaging, tissue sections of the same segments of the callosum were stained for markers of different tissue components. Coded image fields were rated for pathological changes by blinded raters. The FA body/FA splenium ratio was reduced in ALS patients compared to controls. Patchy areas of myelin pallor and cells immunostained for CD68, a microglial-macrophage marker, were only observed in the body of the callosum of ALS patients. Blinded ratings showed increased CD68 + microglial cells in the body of the corpus callosum in ALS patients, especially those with C9orf72 mutations, and increased reactive astrocytes throughout the callosum. Reduced FA of the corpus callosum in ALS results from complex changes in tissue microstructure. Callosal segments with reduced FA had large numbers of microglia-macrophages in addition to loss of myelinated axons and astrogliosis. Microglial inflammation contributed to reduced FA in ALS, and may contribute to a pro-inflammatory state, but further work is needed to determine their role.

Anastomotic leakage after side-to-end anastomosis for rectal cancer: does leakage location matter?

PubMed

Hain, Elisabeth; Maggiori, Léon; Zappa, Magaly; Prost À la Denise, Justine; Panis, Yves

2018-01-06

To assess outcome according to location of anastomotic leakage (AL) after side-to-end stapler or manual low colorectal or coloanal anastomosis following laparoscopic total mesorectal excision (TME) for rectal cancer. All patients presenting with symptomatic or asymptomatic AL after TME and side-to-end low anastomosis for rectal cancer performed from 2005 to 2014 were identified from our prospective database. CT-scans with contrast enema were reviewed to assess location of AL origin. Among 279 patients who underwent TME with side-to-end anastomosis from 2005 to 2014, 70 patients presented with AL and were included: 43 (61%) patients with AL on the circular anastomosis (CAL) were compared to 27 (39%) with AL on the transverse stapling line of the colonic stump (TAL). CAL and TAL were associated with similar rates of symptomatic AL (63% versus 48%, respectively; p=0.339), severe postoperative morbidity rate (33% versus 18%; p=0.313), and long-term outcomes, including definitive stoma rate (10 versus 11%; p=0.622), and major low anterior resection syndrome rate (56% vs 57%; p=0.961). Our study showed that whatever the location of AL on a side-to-end low colorectal or coloanal anastomosis after TME for cancer, both short and long-term outcomes are similar. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Episodic and working memory deficits in alcoholic Korsakoff patients: the continuity theory revisited.

PubMed

Pitel, Anne Lise; Beaunieux, Hélène; Witkowski, Thomas; Vabret, François; de la Sayette, Vincent; Viader, Fausto; Desgranges, Béatrice; Eustache, Francis

2008-07-01

The exact nature of episodic and working memory impairments in alcoholic Korsakoff patients (KS) remains unclear, as does the specificity of these neuropsychological deficits compared with those of non-Korsakoff alcoholics (AL). The goals of the present study were therefore to (1) specify the nature of episodic and working memory impairments in KS, (2) determine the specificity of the KS neuropsychological profile compared with the AL profile, and (3) observe the distribution of individual performances within the 2 patient groups. We investigated episodic memory (encoding and retrieval abilities, contextual memory and state of consciousness associated with memories), the slave systems of working memory (phonological loop, visuospatial sketchpad and episodic buffer) and executive functions (inhibition, flexibility, updating and integration abilities) in 14 strictly selected KS, 40 AL and 55 control subjects (CS). Compared with CS, KS displayed impairments of episodic memory encoding and retrieval, contextual memory, recollection, the slave systems of working memory and executive functions. Although episodic memory was more severely impaired in KS than in AL, the single specificity of the KS profile was a disproportionately large encoding deficit. Apart from organizational and updating abilities, the slave systems of working memory and inhibition, flexibility and integration abilities were impaired to the same extent in both alcoholic groups. However, some KS were unable to complete the most difficult executive tasks. There was only a partial overlap of individual performances by KS and AL for episodic memory and a total mixture of the 2 groups for working memory. Korsakoff's syndrome encompasses impairments of the different episodic and working memory components. AL and KS displayed similar profiles of episodic and working memory deficits, in accordance with neuroimaging investigations showing similar patterns of brain damage in both alcoholic groups.

Oligoclonal bands in the cerebrospinal fluid of amyotrophic lateral sclerosis patients with disease-associated mutations.

PubMed

Ticozzi, Nicola; Tiloca, Cinzia; Mencacci, Niccolò E; Morelli, Claudia; Doretti, Alberto; Rusconi, Daniela; Colombrita, Claudia; Sangalli, Davide; Verde, Federico; Finelli, Palma; Messina, Stefano; Ratti, Antonia; Silani, Vincenzo

2013-01-01

In amyotrophic lateral sclerosis (ALS) cerebrospinal fluid (CSF) analysis is usually performed to exclude inflammatory processes of the central nervous system. Although in a small subset of patients an intrathecal synthesis of IgG is detectable, usually there is no clear explanation for this evidence. This study investigates the occurrence of oligoclonal bands (OCBs) in the CSF of a large series of ALS patients, attempting a correlation with genotype data. CSF was collected from 259 ALS patients. CSF parameters were measured according to standard procedures, and detection of OCBs performed by isoelectric focusing. The patients were screened for mutations in SOD1, FUS, TARDBP, ANG, OPTN, and C9ORF72. We observed the presence of OCBs in the CSF of 9/259 ALS patients (3.5 %), and of disease-associated mutations in 12 cases. OCBs were significantly more frequent in mutation carriers compared to the remaining cohort (3/12 vs 6/247; p < 0.01). Among patients with OCBs, two patients had the TARDBP p.A382T mutation (one of which in homozygous state), and one the ANG p.P-4S variant. Both patients carrying the p.A382T mutation had an atypical phenotype, one of them manifesting signs suggestive of a cerebellar involvement, and the other presenting neuroradiological findings suggestive of an inflammatory disorder of the central nervous system. Our results suggest that ALS patients with OCBs may harbor mutations in disease-causing genes. We speculate that mutations in both TARDBP and ANG genes may disrupt the blood-brain barrier (BBB), promoting local immune responses and neuroinflammation. The role of mutant TARDBP and ANG genes on BBB integrity of ALS patients warrants further investigation.

Reduction in STEMI transfer times utilizing a municipal "911" ambulance service.

PubMed

Tennyson, Joseph C; Quale, Mark R

2014-02-01

The time interval from diagnosis to reperfusion therapy for patients experiencing ST-segment elevation myocardial infarction (STEMI) has a significant impact on morbidity and mortality. It is hypothesized that the time required for interfacility patient transfers from a community hospital to a regional percutaneous coronary intervention (PCI) center using an Advanced Life Support (ALS) transfer ambulance service is no different than utilizing the "911" ALS ambulance. Quality assurance data collected by a tertiary care center cardiac catheterization program were reviewed retrospectively. Data were collected on all patients with STEMI requiring interfacility transfer from a local community hospital to the tertiary care center's PCI suite, approximately 16 miles away by ground, 12 miles by air. In 2009, transfers of patients with STEMI were redirected to the municipal ALS ambulance service, instead of the hospital's contracted ALS transfer service. Data were collected from January 2007 through May 2013. Temporal data were compared between transports initiated through the contracted ALS ambulance service and the municipal ALS service. Data points included time of initial transport request and time of ambulance arrival to the sending facility and the receiving PCI suite. During the 4-year study period, 63 patients diagnosed with STEMI and transferred to the receiving hospital's PCI suite were included in this study. Mean times from the transport request to arrival of the ambulance at the sending hospital's emergency department were six minutes (95% CI, 4-7 minutes) via municipal ALS and 13 minutes (95% CI, 9-16 minutes) for the ALS transfer service. The mean times from the ground transport request to arrival at the receiving hospital's PCI suite when utilizing the municipal ALS ambulance and hospital contracted ALS ambulance services were 48 minutes (95% CI, 33-64 minutes) and 56 minutes (95% CI 52-59 minutes), respectively. This eight-minute period represented a 14% (P = .001) reduction in the mean transfer time to the PCI suite for patients transported via the municipal ALS ambulance. In the appropriate setting, the use of the municipal "911" ALS ambulance service for the interfacility transport of patients with STEMI appears advantageous in reducing door-to-catheterization times.

Amyloid in bone marrow smears in systemic light-chain amyloidosis.

PubMed

Kimmich, Christoph; Schönland, Stefan; Kräker, Sandra; Andrulis, Mindaugas; Ho, Anthony D; Mayer, Gudrun; Dittrich, Tobias; Hundemer, Michael; Hegenbart, Ute

2017-03-01

We performed a prospective sensitivity analysis to detect amyloid in bone marrow (BM) smears stained with Congo red (CR) and according to Pappenheim of patients with systemic light-chain (AL) amyloidosis. Results were directly compared to routine BM histology and fat aspiration. We analysed 198 BM smears from patients with the diagnosis or suspicion of systemic AL amyloidosis. Ultimately, the diagnosis could be established for 168 patients. Amyloid was detected on BM smears with CR in 33% (56/168). All patients suspicious for amyloid on Pappenheim staining (n = 39) showed substantial amyloid infiltration on CR. No patient without systemic AL amyloidosis stained positive. Sensitivity for routine BM histology was 57% (74/129) and for fat aspiration 96% (134/140). Patients with amyloid on BM smears had significantly more hepatic (42 vs. 9%, p < .001), renal (78 vs. 43%, p < .001) and gastrointestinal involvement (40 vs. 22%, p < .01) and less commonly cardiac involvement (58 vs. 76%, p < .03) and consecutively no adverse prognosis. CR staining of BM smears cannot be recommended as a primary screening tool for systemic AL as its overall sensitivity is far inferior to BM histology and fat aspiration. However, we recommend using the technique when suspecting amyloid on Pappenheim staining to establish the diagnosis of systemic AL amyloidosis.

Basic and Advanced EMS Providers Are Equally Effective in Naloxone Administration for Opioid Overdose in Northern New England.

PubMed

Gulec, Nazey; Lahey, Joseph; Suozzi, James C; Sholl, Matthew; MacLean, Charles D; Wolfson, Daniel L

2018-01-01

Overdose mortality from illicit and prescription opioids has reached epidemic proportions in the United States, especially in rural areas. Naloxone is a safe and effective agent that has been shown to successfully reverse the effects of opioid overdose in the prehospital setting. The National EMS Scope of Practice Model currently only recommends advanced life support (ALS) providers to administer naloxone; however, some individual states have expanded this scope of practice to include intranasal (IN) administration of naloxone by basic life support (BLS) providers, including the Northern New England states. This study compares the effectiveness and appropriateness of naloxone administration between BLS and ALS providers. All Vermont, New Hampshire, and Maine EMS patient encounters between April 1, 2014 and December 31, 2016 where naloxone was administered were examined and 3,219 patients were identified. The proportion of successful reversals of opioid overdose, based on improvement in the Glasgow Coma Scale (GCS), respiratory rate (RR), and provider global assessment (GA) of response to medication was compared between BLS and ALS providers using a Chi-Squared statistic, Fisher's exact or Wilcoxon rank-sum test. There was no significant difference in the percent improvement in GCS between BLS and ALS (64% and 64% P = 0.94). There was no significant difference in the percentage of improvement in RR between BLS and ALS (45% and 48% P = 0.43). There was a significant difference in the percentage of improvement of GA between BLS and ALS (80% and 67% P < 0.001). There was no significant difference in determining appropriate cases to administer naloxone where RR < 12 and GCS < 15 between BLS and ALS (42% and 43% P = 0.94). BLS providers were as effective as ALS providers in improving patient outcome measures after naloxone administration and in identifying patients for whom administration of naloxone is appropriate. These findings support expanding the National EMS Scope of Practice Model to include BLS administration of intranasal naloxone for suspected opioid overdoses.

Voxel-based mapping of grey matter volume and glucose metabolism profiles in amyotrophic lateral sclerosis.

PubMed

Buhour, M-S; Doidy, F; Mondou, A; Pélerin, A; Carluer, L; Eustache, F; Viader, F; Desgranges, B

2017-12-01

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease of the nervous system involving both upper and lower motor neurons. The patterns of structural and metabolic brain alterations are still unclear. Several studies using anatomical MRI yielded a number of discrepancies in their results, and a few PET studies investigated the effect of ALS on cerebral glucose metabolism. The aim of this study was threefold: to highlight the patterns of grey matter (GM) atrophy, hypometabolism and hypermetabolism in patients with ALS, then to understand the neurobehavioral significance of hypermetabolism and, finally, to investigate the regional differences between the morphologic and functional changes in ALS patients, using a specially designed voxel-based method. Thirty-seven patients with ALS and 37 age- and sex-matched healthy individuals underwent both structural MRI and 18 [F]-fluorodeoxyglucose (FDG) PET examinations. PET data were corrected for partial volume effects. Structural and metabolic abnormalities were examined in ALS patients compared with control subjects using two-sample t tests in statistical parametric mapping (SPM). Then, we extracted the metabolic values of clusters presenting hypermetabolism to correlate with selected cognitive scores. Finally, GM atrophy and hypometabolism patterns were directly compared with a one-paired t test in SPM. We found GM atrophy as well as hypometabolism in motor and extra motor regions and hypermetabolism in medial temporal lobe and cerebellum. We observed negative correlations between the metabolism of the right and left parahippocampal gyri and episodic memory and between the metabolism of right temporal pole and cognitive theory of mind. GM atrophy predominated in the temporal pole, left hippocampus and right thalamus, while hypometabolism predominated in a single cluster in the left frontal superior medial cortex. Our findings provide direct evidence of regional variations in the hierarchy and relationships between GM atrophy and hypometabolism in ALS. Moreover, the 18 FDG-PET investigation suggests that cerebral hypermetabolism is deleterious to cognitive function in ALS.

A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study.

PubMed

Gijselinck, Ilse; Van Langenhove, Tim; van der Zee, Julie; Sleegers, Kristel; Philtjens, Stéphanie; Kleinberger, Gernot; Janssens, Jonathan; Bettens, Karolien; Van Cauwenberghe, Caroline; Pereson, Sandra; Engelborghs, Sebastiaan; Sieben, Anne; De Jonghe, Peter; Vandenberghe, Rik; Santens, Patrick; De Bleecker, Jan; Maes, Githa; Bäumer, Veerle; Dillen, Lubina; Joris, Geert; Cuijt, Ivy; Corsmit, Ellen; Elinck, Ellen; Van Dongen, Jasper; Vermeulen, Steven; Van den Broeck, Marleen; Vaerenberg, Carolien; Mattheijssens, Maria; Peeters, Karin; Robberecht, Wim; Cras, Patrick; Martin, Jean-Jacques; De Deyn, Peter P; Cruts, Marc; Van Broeckhoven, Christine

2012-01-01

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are extremes of a clinically, pathologically, and genetically overlapping disease spectrum. A locus on chromosome 9p21 has been associated with both disorders, and we aimed to identify the causal gene within this region. We studied 305 patients with FTLD, 137 with ALS, and 23 with concomitant FTLD and ALS (FTLD-ALS) and 856 controls from Flanders (Belgium); patients were identified from a hospital-based cohort and were negative for mutations in known FTLD and ALS genes. We also examined the family of one patient with FTLD-ALS previously linked to 9p21 (family DR14). We analysed 130 kbp at 9p21 in association and segregation studies, genomic sequencing, repeat genotyping, and expression studies to identify the causal mutation. We compared genotype-phenotype correlations between mutation carriers and non-carriers. In the patient-control cohort, the single-nucleotide polymorphism rs28140707 within the 130 kbp region of 9p21 was associated with disease (odds ratio [OR] 2·6, 95% CI 1·5-4·7; p=0·001). A GGGGCC repeat expansion in C9orf72 completely co-segregated with disease in family DR14. The association of rs28140707 with disease in the patient-control cohort was abolished when we excluded GGGGCC repeat expansion carriers. In patients with familial disease, six (86%) of seven with FTLD-ALS, seven (47%) of 15 with ALS, and 12 (16%) of 75 with FTLD had the repeat expansion. In patients without known familial disease, one (6%) of 16 with FTLD-ALS, six (5%) of 122 with ALS, and nine (4%) of 230 with FTLD had the repeat expansion. Mutation carriers primarily presented with classic ALS (10 of 11 individuals) or behavioural variant FTLD (14 of 15 individuals). Mean age at onset of FTLD was 55·3 years (SD 8·4) in 21 mutation carriers and 63·2 years (9·6) in 284 non-carriers (p=0·001); mean age at onset of ALS was 54·5 years (9·9) in 13 carriers and 60·4 years (11·4) in 124 non-carriers. Postmortem neuropathological analysis of the brains of three mutation carriers with FTLD showed a notably low TDP-43 load. In brain at postmortem, C9orf72 expression was reduced by nearly 50% in two carriers compared with nine controls (p=0·034). In familial patients, 14% of FTLD-ALS, 50% of ALS, and 62% of FTLD was not accounted for by known disease genes. We identified a pathogenic GGGGCC repeat expansion in C9orf72 on chromosome 9p21, as recently also reported in two other studies. The GGGGCC repeat expansion is highly penetrant, explaining all of the contribution of chromosome 9p21 to FTLD and ALS in the Flanders-Belgian cohort. Decreased expression of C9orf72 in brain suggests haploinsufficiency as an underlying disease mechanism. Unidentified genes probably also contribute to the FTLD-ALS disease spectrum. Full funding sources listed at end of paper (see Acknowledgments). Copyright © 2012 Elsevier Ltd. All rights reserved.

Gene polymorphisms and febrile neutropenia in acute leukemia--no association with IL-4, CCR-5, IL-1RA, but the MBL-2, ACE, and TLR-4 are associated with the disease in Turkish patients: a preliminary study.

PubMed

Pehlivan, Mustafa; Sahin, Handan Haydaroğlu; Ozdilli, Kurşat; Onay, Hüseyin; Ozcan, Ali; Ozkinay, Ferda; Pehlivan, Sacide

2014-07-01

The aim of this study was to investigate the mannose-binding lectin 2 (MBL-2), interleukin (IL)-4, Toll-like receptor 4 (TLR-4), angiotensin converting enzyme (ACE), chemokine receptor 5 (CCR-5), and IL-1 receptor antagonist (RA) gene polymorphisms (GPs) in acute leukemias (ALs) and to evaluate their roles in febrile neutropenia (FN) resulting from chemotherapy. The study included 60 AL patients hospitalized between the period of July 2001 and August 2006. Polymorphisms for the genes ACE(I/D), CCR-5, IL-1RA, MBL-2, TLR-4, and IL-4 were typed by polymerase chain reaction (PCR) and/or PCR-restriction fragment length polymerase. Genotype frequencies for these genes were compared in the patient and control groups. The relationships between the genotypes and the body distribution of infections, pathogens, the duration of neutropenia, and febrile episodes in AL patients were evaluated. No significant differences in either the genotype distribution or the allelic frequencies of TLR-4, IL-4, CCR-5, IL-1RN GPs were observed between patients and healthy controls. The AB/BB genotype (53.3%) in the MBL-2 gene was found to be significantly higher in the AL patients compared with control groups. There were correlations between the presence of MBL-2, TLR-4, and ACE polymorphisms and clinical parameters due to FN. Overall, bacteremia was more common in MBL BB and ACE DD. Gram-positive bacteremia was more common in ACE for ID versus DD genotype. Gram-negative bacteremia was more common for both the MBL-2 AB/BB genotype and TLR-4 AG genotype. Median durations of febrile episodes were significantly shorter in ACE DD and MBL AB/BB. Although TLR-4, ACE, and MBL-2 GPs have been extensively investigated in different clinical pictures, this is the first study to evaluate the role of these polymorphisms in the genetic etiopathogenesis of FN in patients with ALs. As a conclusion, TLR-4, ACE, and MBL-2 genes might play roles in the genetic etiopathogenesis of FN in patients with ALs.

Diagnostic value of serial measurement of C-reactive protein in serum and matrix metalloproteinase-9 in drainage fluid in the detection of infectious complications and anastomotic leakage in patients with colorectal resection.

PubMed

Kostić, Zoran; Panišić, Marina; Milev, Boško; Mijušković, Zoran; Slavković, Damjan; Ignjatović, Mile

2015-10-01

Postoperative infectious complications are one of the most important problems in surgical treatment of colorectal cancer (CRC), being present in up to 40% of patients. The aim of this paper was to establish the significance of serial measurement of C-reactive protein (CRP) in serum and matrix metalloproteinase-9 (MMP-9) in drainage fluid for the detection of infectious complications and anastomotic leakage (AL) in patients with colorectal resection. CRP and MMP-9 values in serum and drainage fluid, respectively, were measured on the first, third, fifth, and seventh postoperative day (POD) in 150 patients with colorectal resection and primary anastomosis. The values obtained were compared between the patients without complicatons and those with surgical site and remote infections and AL. Surgical site infections (SSIs) were observed in 41 (27.3%), and remote infections in 10 (6.7%) patients. Clinically evident AL was observed in 15 (10/6) patients. In 82% of the patients with SSIs, serum CRP value on POD 5 exceeded 82 mg/L, with 81% specificity. AL was reported in 85% and 92% of the patients on PODs 5 and 7, respectively, with CRP values of 77 mg/L and 90 mg/L, respectively. The specificity was 77% for POD 5 and 88% for POD 7. All the patients with CRP values exceeding 139 mg/L on POD 5 had some of SSIs and/or AL. The mean values of MMP-9 were not statistically different between the group without complications (n = 99) and the group with AL (n = 15). Serial measurement of CRP is recommended for screening of infectious complications of colorectal resection. Patients with CRP values above 139 mg/L on POD 5 cannot be discharged from hospital, and require an intensive search for infectious complications, particularly AL. MMP-9 measurement in drainage fluid is not relevant in the detection of AL in patients with colorectal resection.

Supported treadmill ambulation for amyotrophic lateral sclerosis: a pilot study.

PubMed

Sanjak, Mohammed; Bravver, Elena; Bockenek, William L; Norton, H James; Brooks, Benjamin R

2010-12-01

To determine the feasibility, tolerability, safety, and exercise treatment-effect size of repetitive rhythmic exercise mediated by supported treadmill ambulation training (STAT) for patients with amyotrophic lateral sclerosis (ALS). Interventional with repeated-measures design. Multidisciplinary ALS clinic at academic medical center. Convenience sample of patients with ALS (N=9) who were ambulatory with assistive devices (Sinaki-Mulder stages II-III). Repetitive rhythmic exercise-STAT (30min total; 5min of exercise intercalated with 5min of rest) performed 3 times a week for 8 weeks. ALS Functional Rating Scale-Revised (ALSFRS-R), percentage of predicted vital capacity (VC), total lower-extremities manual muscle test (MMT), rate of perceived exertion (RPE), Fatigue Severity Scale (FSS), and maximum voluntary isometric contraction (MVIC) in 10 lower and 10 upper extremities. Gait performance, which included walking distance, speed, steps, and stride length, was evaluated during treadmill and ground 6-minute walk tests (6MWTs) and 25-foot walk test (25FWT). Feasibility issues decreased screened participants by 4 patients (31%). Nine patients were enrolled, but 6 patients (67%) completed the study and 3 (23% of original cohort; 33% of enrolled cohort) could not complete the exercise intervention because of non-ALS-related medical problems. Tolerability of the intervention measures during the treadmill 6MWT showed improvement in RPE (P≤.05) and FSS score (P≥.05). Safety measures (ALSFRS-R, VC, MMT) showed no decrease and showed statistical improvement in ALSFRS-R score (P≤.05) during the study interval. Exercise treatment-effect size showed variable improvements. Gait speed, distance, and stride length during the treadmill 6MWT improved significantly (P≤.05) after 4 weeks and improvements were maintained after 8 weeks compared with baseline. Walking distance during the ground 6MWT increased significantly after 4 weeks and was maintained after 8 weeks compared with baseline (P≤.05). Walking speed during the 25FWT and lower-extremity MVIC improved, but were not statistically significant. Repetitive rhythmic exercise-STAT is feasible, tolerated, and safe for patients with ALS. Repetitive rhythmic exercise-STAT treatment-effect size across a number of ALS-related measures was consistent with improved work capacity and gait function in patients with ALS who are dependent on assistive devices for ambulation. Repetitive rhythmic exercise-STAT should be evaluated further in larger studies to determine the stability of this improved function in relation to the rate of progression of the underlying ALS. Copyright © 2010 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Respiratory insufficiency with preserved diaphragmatic function in amyotrophic lateral sclerosis.

PubMed

Yamauchi, Rika; Imai, Tomihiro; Tsuda, Emiko; Hozuki, Takayoshi; Yamamoto, Daisuke; Shimohama, Shun

2014-01-01

We performed a longitudinal study to elucidate the correlation between respiratory insufficiency and respiratory biomarkers, including diaphragmatic compound muscle action potential (DCMAP), at the initiation of noninvasive ventilation (NIV) in patients with amyotrophic lateral sclerosis (ALS). The patients were assessed at least every six months. Additional assessments were performed at the start of respiratory therapy when the patients met the criteria for the initiation of NIV. Each assessment consisted of a full neurological examination, a phrenic nerve conduction study, respiratory function tests, and nocturnal pulsed oximetry. We enrolled 43 patients with either definite or probable ALS as defined by the revised El Escorial criteria. The patients were divided into two groups according to the timing of the initiation of respiratory therapy. Seventeen patients (group A) met the criteria for NIV initiation when their DCMAP remained normal. Twenty-six patients (group B) met the criteria when their DCMAP decreased below normal limits. Although respiratory function parameters were significantly worse in group B compared with group A at NIV initiation, more than 80% of the patients in both groups developed nocturnal desaturation during sleep. DCMAP is not always a reliable indicator for determining the optimal timing for NIV initiation during the progression of respiratory insufficiency in ALS. Physicians should be aware of the risk of respiratory insufficiency during sleep in patients with ALS.

Factors predicting survival in ALS: a multicenter Italian study.

PubMed

Calvo, Andrea; Moglia, Cristina; Lunetta, Christian; Marinou, Kalliopi; Ticozzi, Nicola; Ferrante, Gianluca Drago; Scialo, Carlo; Sorarù, Gianni; Trojsi, Francesca; Conte, Amelia; Falzone, Yuri M; Tortelli, Rosanna; Russo, Massimo; Chiò, Adriano; Sansone, Valeria Ada; Mora, Gabriele; Silani, Vincenzo; Volanti, Paolo; Caponnetto, Claudia; Querin, Giorgia; Monsurrò, Maria Rosaria; Sabatelli, Mario; Riva, Nilo; Logroscino, Giancarlo; Messina, Sonia; Fini, Nicola; Mandrioli, Jessica

2017-01-01

The aim of this multicenter, retrospective study is to investigate the role of clinical characteristics and therapeutic intervention on ALS prognosis. The study included patients diagnosed from January 1, 2009 to December 31, 2013 in 13 Italian referral centers for ALS located in 10 Italian regions. Caring neurologists collected a detailed phenotypic profile and follow-up data until death into an electronic database. One center collected also data from a population-based registry for ALS. 2648 incident cases were collected. The median survival time from onset to death/tracheostomy was 44 months (SE 1.18, CI 42-46). According to univariate analysis, factors related to survival from onset to death/tracheostomy were: age at onset, diagnostic delay, site of onset, phenotype, degree of certainty at diagnosis according to revised El Escorial criteria (R-EEC), presence/absence of dementia, BMI at diagnosis, patients' provenance. In the multivariate analysis, age at onset, diagnostic delay, phenotypes but not site of onset, presence/absence of dementia, BMI, riluzole use, R-EEC criteria were independent prognostic factors of survival in ALS. We compared patients from an ALS Registry with patients from tertiary centers; the latter ones were younger, less frequently bulbar, but more frequently familial and definite at diagnosis. Our large, multicenter study demonstrated the role of some clinical and demographic factors on ALS survival, and showed some interesting differences between referral centers' patients and the general ALS population. These results can be helpful for clinical practice, in clinical trial design and to validate new tools to predict disease progression.

The burden of amyloid light chain amyloidosis on health-related quality of life.

PubMed

Bayliss, Martha; McCausland, Kristen L; Guthrie, Spencer D; White, Michelle K

2017-01-19

Light chain (AL) amyloidosis is a rare disease characterized by misfolded amyloid protein deposits in tissues and vital organs, and little is known about the burden of AL amyloidosis on health-related quality of life. This study aimed to quantify the burden of AL amyloidosis in terms of health-related quality of life in a diverse, community-based sample of AL amyloidosis patients. The SF-36v2® Health Survey (SF-36v2), a widely used generic measure of health-related quality of life (using physical and mental summary scales and subscales assessing eight aspects of functioning and well-being), was administered as an online survey of AL amyloidosis patients with AL amyloidosis (ClinicalTrials.gov, NCT02574676 ; n = 341). Compared with adjusted general population sample norms, health-related quality of life of AL amyloidosis patients was significantly worse across all SF-36v2 scales and summary measures based on analysis of variance (p < 0.05 for all). The largest decrement in AL amyloidosis patients was related to General Health (Δ = 9.7; p < 0.001). With the exception of Bodily Pain and Mental Health, differences were also clinically meaningful based on established clinically minimal important differences. The burden of AL amyloidosis overall and in key subgroups tended to be greater on physical health than on mental health. Stratified analyses indicated additional burden among patients with recently diagnosed disease and those with cardiac involvement than among their respective counterparts. Understanding the burden of AL amyloidosis highlights the unmet need for treatment, helps physicians identify ancillary treatments and services geared towards improving patients' functioning, well-being, and overall health-related quality of life. These findings also help to support the use of health-related quality of life end points as important outcome measures in current and future treatment studies. ClinicalTrials.gov, NCT02574676 . Registered October 5, 2015.

Macroscopic Localized Subicular Thinning as a Potential Indicator of Amyotrophic Lateral Sclerosis.

PubMed

Yamada, Hiroki; Takeda, Takahiro; Uchihara, Toshiki; Sato, Shizuko; Kirimura, Susumu; Hirota, Yuka; Kodama, Makoto; Kitagawa, Masanobu; Hirokawa, Katsuiku; Yokota, Takanori; Toru, Shuta

2018-03-23

Subicular degeneration occurs in amyotrophic lateral sclerosis (ALS) patients. However, it was unknown whether microscopic subicular degeneration could be observed as macroscopic changes and whether these changes were associated with the transactive-response DNA binding protein 43 kDa (TDP-43) pathology. Topographic differences between subicular degeneration caused by ALS and Alzheimer disease (AD) had also not been characterized. Here we investigated the subiculum and related areas in autopsied brains from 3 ALS and 3 AD patients. Macroscopic subicular thinning and corresponding astrocytosis were pronounced in ALS compared to AD. This thinning was frequently accompanied by TDP-43 pathology in the transentorhinal cortex and nucleus accumbens. The preferential susceptibility of the perforant pathway to TDP-43 deposition may be an underlying cause of subicular thinning in ALS. © 2018 S. Karger AG, Basel.

White matter structural network abnormalities underlie executive dysfunction in amyotrophic lateral sclerosis.

PubMed

Dimond, Dennis; Ishaque, Abdullah; Chenji, Sneha; Mah, Dennell; Chen, Zhang; Seres, Peter; Beaulieu, Christian; Kalra, Sanjay

2017-03-01

Research in amyotrophic lateral sclerosis (ALS) suggests that executive dysfunction, a prevalent cognitive feature of the disease, is associated with abnormal structural connectivity and white matter integrity. In this exploratory study, we investigated the white matter constructs of executive dysfunction, and attempted to detect structural abnormalities specific to cognitively impaired ALS patients. Eighteen ALS patients and 22 age and education matched healthy controls underwent magnetic resonance imaging on a 4.7 Tesla scanner and completed neuropsychometric testing. ALS patients were categorized into ALS cognitively impaired (ALSci, n = 9) and ALS cognitively competent (ALScc, n = 5) groups. Tract-based spatial statistics and connectomics were used to compare white matter integrity and structural connectivity of ALSci and ALScc patients. Executive function performance was correlated with white matter FA and network metrics within the ALS group. Executive function performance in the ALS group correlated with global and local network properties, as well as FA, in regions throughout the brain, with a high predilection for the frontal lobe. ALSci patients displayed altered local connectivity and structural integrity in these same frontal regions that correlated with executive dysfunction. Our results suggest that executive dysfunction in ALS is related to frontal network disconnectivity, which potentially mediates domain-specific, or generalized cognitive impairment, depending on the degree of global network disruption. Furthermore, reported co-localization of decreased network connectivity and diminished white matter integrity suggests white matter pathology underlies this topological disruption. We conclude that executive dysfunction in ALSci is associated with frontal and global network disconnectivity, underlined by diminished white matter integrity. Hum Brain Mapp 38:1249-1268, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Altered Brain Network in Amyotrophic Lateral Sclerosis: A Resting Graph Theory-Based Network Study at Voxel-Wise Level.

PubMed

Zhou, Chaoyang; Hu, Xiaofei; Hu, Jun; Liang, Minglong; Yin, Xuntao; Chen, Lin; Zhang, Jiuquan; Wang, Jian

2016-01-01

Amyotrophic lateral sclerosis (ALS) is a rare degenerative disorder characterized by loss of upper and lower motor neurons. Neuroimaging has provided noticeable evidence that ALS is a complex disease, and shown that anatomical and functional lesions extend beyond precentral cortices and corticospinal tracts, to include the corpus callosum; frontal, sensory, and premotor cortices; thalamus; and midbrain. The aim of this study is to investigate graph theory-based functional network abnormalities at voxel-wise level in ALS patients on a whole brain scale. Forty-three ALS patients and 44 age- and sex-matched healthy volunteers were enrolled. The voxel-wise network degree centrality (DC), a commonly employed graph-based measure of network organization, was used to characterize the alteration of whole brain functional network. Compared with the controls, the ALS patients showed significant increase of DC in the left cerebellum posterior lobes, bilateral cerebellum crus, bilateral occipital poles, right orbital frontal lobe, and bilateral prefrontal lobes; significant decrease of DC in the bilateral primary motor cortex, bilateral sensory motor region, right prefrontal lobe, left bilateral precuneus, bilateral lateral temporal lobes, left cingulate cortex, and bilateral visual processing cortex. The DC's z-scores of right inferior occipital gyrus were significant negative correlated with the ALSFRS-r scores. Our findings confirm that the regions with abnormal network DC in ALS patients were located in multiple brain regions including primary motor, somatosensory and extra-motor areas, supporting the concept that ALS is a multisystem disorder. Specifically, our study found that DC in the visual areas was altered and ALS patients with higher DC in right inferior occipital gyrus have more severity of disease. The result demonstrated that the altered DC value in this region can probably be used to assess severity of ALS.

Depression in amyotrophic lateral sclerosis

PubMed Central

ATASSI, NAZEM; COOK, AMANDA; PINEDA, CRISTIANA M. E.; YERRAMILLI-RAO, PADMAJA; PULLEY, DARLENE; CUDKOWICZ, MERIT

2011-01-01

Depression is an under-recognized comorbidity associated with amyotrophic lateral sclerosis (ALS). The goals of this study were to prospectively estimate the prevalence of depression and other ALS related symptoms and to study the impact of depression on enrollment in research studies. One hundred and twenty-seven people with ALS completed the ALS Depression Inventory (ADI-12) and answered questions about ALS related symptoms and research study enrollment preferences. Demographics, ALS symptoms, medications, functional status, and research enrollment were compared between depressed and non-depressed patients. Results showed that the prevalence of mild and severe depression was 29% and 6%, respectively. More than one-third of our ALS patients were receiving anti-depressants to treat depression, sialorrhea, and pseudobulbar affect. Depression prevalence was not correlated with disease duration or progression. Except for anxiety, none of the ALS related symptoms predicted depression. The presence of depression did not have an effect on the decision to enroll in research studies. In conclusion, major depression is less common in our ALS cohort than in the general population. The diagnosis of depression can be masked by some ALS related symptoms and it has no impact on enrollment in ALS clinical trials. PMID:21091399

Risk Group Systems for Penile Cancer Management: A Study of 203 Patients With Invasive Squamous Cell Carcinoma.

PubMed

Chaux, Alcides

2015-10-01

To evaluate the accuracy of previously published risk group systems for predicting inguinal nodal metastases in patients with penile carcinoma. Two hundred three cases of invasive penile squamous cell carcinomas (SCC) were stratified using the following systems: Solsona et al (J Urol 2001;165:1509), Hungerhuber et al (Urology 2006;68:621), and the system proposed by the European Association of Urology (EAU; Eur Urol 2004;46:1). Receiver operating characteristic (ROC) analysis was carried out to compare accuracy in predicting final nodal status and cancer-related death. Most of cases were pT2/pT3 high-grade tumors with a small percentage of low-grade pT1 carcinomas. The metastatic rates for the Solsona et al, EAU, and Hungerhuber et al systems in the high-risk category were 15 of 73 (21%), 16 of 103 (16%), and 10 of 35 (29%) in patients with clinically negative inguinal lymph nodes and 52 of 75 (69%), 55 of 93 (59%), and 34 of 47 (72%) in patients with palpable inguinal lymph nodes, respectively. Performance by ROC analysis showed a low accuracy for all stratification systems although the Solsona et al and the Hungerhuber et al systems performed better than the EAU system. Patients in intermediate-risk categories and with clinically palpable inguinal lymph nodes were more likely to have nodal metastasis than patients with clinically negative lymph nodes in the same category. These stratification systems may be useful for patients with low-grade superficial tumors and less accurate for evaluating patients with high-grade locally advanced penile carcinomas. These data may be useful for therapeutic planning of patients with penile SCC. Copyright © 2015 Elsevier Inc. All rights reserved.

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

PubMed

Nicolas, Aude; Kenna, Kevin P; Renton, Alan E; Ticozzi, Nicola; Faghri, Faraz; Chia, Ruth; Dominov, Janice A; Kenna, Brendan J; Nalls, Mike A; Keagle, Pamela; Rivera, Alberto M; van Rheenen, Wouter; Murphy, Natalie A; van Vugt, Joke J F A; Geiger, Joshua T; Van der Spek, Rick A; Pliner, Hannah A; Shankaracharya; Smith, Bradley N; Marangi, Giuseppe; Topp, Simon D; Abramzon, Yevgeniya; Gkazi, Athina Soragia; Eicher, John D; Kenna, Aoife; Mora, Gabriele; Calvo, Andrea; Mazzini, Letizia; Riva, Nilo; Mandrioli, Jessica; Caponnetto, Claudia; Battistini, Stefania; Volanti, Paolo; La Bella, Vincenzo; Conforti, Francesca L; Borghero, Giuseppe; Messina, Sonia; Simone, Isabella L; Trojsi, Francesca; Salvi, Fabrizio; Logullo, Francesco O; D'Alfonso, Sandra; Corrado, Lucia; Capasso, Margherita; Ferrucci, Luigi; Moreno, Cristiane de Araujo Martins; Kamalakaran, Sitharthan; Goldstein, David B; Gitler, Aaron D; Harris, Tim; Myers, Richard M; Phatnani, Hemali; Musunuri, Rajeeva Lochan; Evani, Uday Shankar; Abhyankar, Avinash; Zody, Michael C; Kaye, Julia; Finkbeiner, Steven; Wyman, Stacia K; LeNail, Alex; Lima, Leandro; Fraenkel, Ernest; Svendsen, Clive N; Thompson, Leslie M; Van Eyk, Jennifer E; Berry, James D; Miller, Timothy M; Kolb, Stephen J; Cudkowicz, Merit; Baxi, Emily; Benatar, Michael; Taylor, J Paul; Rampersaud, Evadnie; Wu, Gang; Wuu, Joanne; Lauria, Giuseppe; Verde, Federico; Fogh, Isabella; Tiloca, Cinzia; Comi, Giacomo P; Sorarù, Gianni; Cereda, Cristina; Corcia, Philippe; Laaksovirta, Hannu; Myllykangas, Liisa; Jansson, Lilja; Valori, Miko; Ealing, John; Hamdalla, Hisham; Rollinson, Sara; Pickering-Brown, Stuart; Orrell, Richard W; Sidle, Katie C; Malaspina, Andrea; Hardy, John; Singleton, Andrew B; Johnson, Janel O; Arepalli, Sampath; Sapp, Peter C; McKenna-Yasek, Diane; Polak, Meraida; Asress, Seneshaw; Al-Sarraj, Safa; King, Andrew; Troakes, Claire; Vance, Caroline; de Belleroche, Jacqueline; Baas, Frank; Ten Asbroek, Anneloor L M A; Muñoz-Blanco, José Luis; Hernandez, Dena G; Ding, Jinhui; Gibbs, J Raphael; Scholz, Sonja W; Floeter, Mary Kay; Campbell, Roy H; Landi, Francesco; Bowser, Robert; Pulst, Stefan M; Ravits, John M; MacGowan, Daniel J L; Kirby, Janine; Pioro, Erik P; Pamphlett, Roger; Broach, James; Gerhard, Glenn; Dunckley, Travis L; Brady, Christopher B; Kowall, Neil W; Troncoso, Juan C; Le Ber, Isabelle; Mouzat, Kevin; Lumbroso, Serge; Heiman-Patterson, Terry D; Kamel, Freya; Van Den Bosch, Ludo; Baloh, Robert H; Strom, Tim M; Meitinger, Thomas; Shatunov, Aleksey; Van Eijk, Kristel R; de Carvalho, Mamede; Kooyman, Maarten; Middelkoop, Bas; Moisse, Matthieu; McLaughlin, Russell L; Van Es, Michael A; Weber, Markus; Boylan, Kevin B; Van Blitterswijk, Marka; Rademakers, Rosa; Morrison, Karen E; Basak, A Nazli; Mora, Jesús S; Drory, Vivian E; Shaw, Pamela J; Turner, Martin R; Talbot, Kevin; Hardiman, Orla; Williams, Kelly L; Fifita, Jennifer A; Nicholson, Garth A; Blair, Ian P; Rouleau, Guy A; Esteban-Pérez, Jesús; García-Redondo, Alberto; Al-Chalabi, Ammar; Rogaeva, Ekaterina; Zinman, Lorne; Ostrow, Lyle W; Maragakis, Nicholas J; Rothstein, Jeffrey D; Simmons, Zachary; Cooper-Knock, Johnathan; Brice, Alexis; Goutman, Stephen A; Feldman, Eva L; Gibson, Summer B; Taroni, Franco; Ratti, Antonia; Gellera, Cinzia; Van Damme, Philip; Robberecht, Wim; Fratta, Pietro; Sabatelli, Mario; Lunetta, Christian; Ludolph, Albert C; Andersen, Peter M; Weishaupt, Jochen H; Camu, William; Trojanowski, John Q; Van Deerlin, Vivianna M; Brown, Robert H; van den Berg, Leonard H; Veldink, Jan H; Harms, Matthew B; Glass, Jonathan D; Stone, David J; Tienari, Pentti; Silani, Vincenzo; Chiò, Adriano; Shaw, Christopher E; Traynor, Bryan J; Landers, John E

2018-03-21

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Copyright © 2018 Elsevier Inc. All rights reserved.

Altered patterns of cortical activation in ALS patients during attention and cognitive response inhibition tasks.

PubMed

Goldstein, L H; Newsom-Davis, I C; Bryant, V; Brammer, M; Leigh, P N; Simmons, A

2011-12-01

Since amyotrophic lateral sclerosis (ALS) can be accompanied by executive dysfunction, it is hypothesised that ALS patients will have impaired performance on tests of cognitive inhibition. We predicted that ALS patients would show patterns of abnormal activation in extramotor regions when performing tests requiring the inhibition of prepotent responses (the Stroop effect) and the inhibition of prior negatively primed responses (the negative priming effect) when compared to healthy controls. Functional magnetic resonance imaging was used to measure activation during a sparse sequence block design paradigm investigating the Stroop and negative priming effects in 14 ALS patients and 8 healthy age- and IQ-matched controls. Behavioural measures of performance were collected. Both groups' reaction times (RTs) reflected the Stroop effect during scanning. The ALS and control groups did not differ significantly for any of the behavioural measures but did show significant differences in cerebral activation during both tasks. The ALS group showed increased activation predominantly in the left middle temporal gyrus (BA 20/21), left superior temporal gyrus (BA 22) and left anterior cingulate gyrus (BA 32). Neither group's RT data showed clear evidence of a negative priming effect. However the ALS group showed decreased activation, relative to controls, particularly in the left cingulate gyrus (BA 23/24), left precentral gyrus (BA 4/6) and left medial frontal gyrus (BA 6). Greater cerebral activation in the ALS group accompanying the performance of the Stroop effect and areas of decreased activation during the negative priming comparison suggest altered inhibitory processing in ALS, consistent with other evidence of executive dysfunction in ALS. The current findings require further exploration in a larger study.

Repetitive element transcripts are elevated in the brain of C9orf72 ALS/FTLD patients.

PubMed

Prudencio, Mercedes; Gonzales, Patrick K; Cook, Casey N; Gendron, Tania F; Daughrity, Lillian M; Song, Yuping; Ebbert, Mark T W; van Blitterswijk, Marka; Zhang, Yong-Jie; Jansen-West, Karen; Baker, Matthew C; DeTure, Michael; Rademakers, Rosa; Boylan, Kevin B; Dickson, Dennis W; Petrucelli, Leonard; Link, Christopher D

2017-09-01

Significant transcriptome alterations are detected in the brain of patients with amyotrophic lateral sclerosis (ALS), including carriers of the C9orf72 repeat expansion and C9orf72-negative sporadic cases. Recently, the expression of repetitive element transcripts has been associated with toxicity and, while increased repetitive element expression has been observed in several neurodegenerative diseases, little is known about their contribution to ALS. To assess whether aberrant expression of repetitive element sequences are observed in ALS, we analysed RNA sequencing data from C9orf72-positive and sporadic ALS cases, as well as healthy controls. Transcripts from multiple classes and subclasses of repetitive elements (LINEs, endogenous retroviruses, DNA transposons, simple repeats, etc.) were significantly increased in the frontal cortex of C9orf72 ALS patients. A large collection of patient samples, representing both C9orf72 positive and negative ALS, ALS/FTLD, and FTLD cases, was used to validate the levels of several repetitive element transcripts. These analyses confirmed that repetitive element expression was significantly increased in C9orf72-positive compared to C9orf72-negative or control cases. While previous studies suggest an important link between TDP-43 and repetitive element biology, our data indicate that TDP-43 pathology alone is insufficient to account for the observed changes in repetitive elements in ALS/FTLD. Instead, we found that repetitive element expression positively correlated with RNA polymerase II activity in postmortem brain, and pharmacologic modulation of RNA polymerase II activity altered repetitive element expression in vitro. We conclude that increased RNA polymerase II activity in ALS/FTLD may lead to increased repetitive element transcript expression, a novel pathological feature of ALS/FTLD. © The Author 2017. Published by Oxford University Press.

Role of diffusion tensor imaging or magnetic resonance spectroscopy in the diagnosis and disability assessment of amyotrophic lateral sclerosis.

PubMed

Liu, Chanchan; Jiang, Rifeng; Yi, Xiyan; Zhu, Wenzhen; Bu, Bitao

2015-01-15

To compare the results of magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS) patients. Nineteen ALS patients and thirteen age-matched healthy controls underwent MRS and DTI between October 2013 and July 2014. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) were collected as the quantitative results of the imaging study. The ALS functional rating scale-revised (ALSFRS-R) and disease progression rate were evaluated to assess patients' disability. The imaging study results were compared between ALS patients and healthy controls. The relationship between disability assessment and imaging study results was analyzed. NAA/Cr in the motor cortex and FA in the corticospinal tract (CST) of both sides were significantly lower in patients than controls. There was no significant difference between the two groups in Cho/Cr, tract length, tract volume, ADC or NAA. No relationship was found between ALSFRS-R and FA (r=0.243, p=0.316) in the right CST; NAA (r=0.095, p=0.699) or NAA/Cr (r=0.172, p=0.481) in the left motor cortex; or NAA (r=0.320, p=0.182) or NAA/Cr (r=0.193, p=0.492) in the right motor cortex. There was no relationship between the disease progression rate and FA, NAA, or NAA/Cr on either side. NAA/Cr and FA can help diagnose ALS. Regional brain NAA/Cr and FA values could not assess the ALSFRS-R or disease progression rate. Copyright © 2014 Elsevier B.V. All rights reserved.

Diagnostic interest of acid-labile subunit measurement in relationship to other components of the IGF system in pediatric patients with growth or eating disorders.

PubMed

Barrios, V; Argente, J; Muñoz, M T; Pozo, J; Chowen, J A; Hernández, M

2001-03-01

To analyze the possible utility of measuring acid-labile subunit (ALS) in some types of pathologies in which the IGF system is altered and to compare it with the clinical implications of measurements of other components of this axis. We studied serum ALS concentrations in 20 children with normal variants of short stature (NVSS) at diagnosis and 24 with growth hormone deficiency (GHD), 18 obese patients and 18 girls with anorexia nervosa at diagnosis and during a follow-up period. In patients with GHD and anorexia nervosa, mean ALS concentrations were significantly reduced, but there was a high percentage of overlap with control values. At diagnosis, ALS concentrations were normal in obese patients and children with NVSS. During follow-up, these values normalized in children with GHD who were treated with GH, tended to normalize in those with anorexia nervosa who showed weight gain, and did not change in obese children upon weight loss. However, ALS measurement was less accurate than that of IGF-I or IGF binding protein (IGFBP)-3 in diagnosis of GHD. The correlations found between ALS and some IGF system components at diagnosis either decreased or were non-significant during follow-up of these clinical conditions. ALS adds little information to that obtained with IGF-I and IGFBP-3 determinations.

Design and Analysis of an Enhanced Patient-Server Mutual Authentication Protocol for Telecare Medical Information System.

PubMed

Amin, Ruhul; Islam, S K Hafizul; Biswas, G P; Khan, Muhammad Khurram; Obaidat, Mohammad S

2015-11-01

In order to access remote medical server, generally the patients utilize smart card to login to the server. It has been observed that most of the user (patient) authentication protocols suffer from smart card stolen attack that means the attacker can mount several common attacks after extracting smart card information. Recently, Lu et al.'s proposes a session key agreement protocol between the patient and remote medical server and claims that the same protocol is secure against relevant security attacks. However, this paper presents several security attacks on Lu et al.'s protocol such as identity trace attack, new smart card issue attack, patient impersonation attack and medical server impersonation attack. In order to fix the mentioned security pitfalls including smart card stolen attack, this paper proposes an efficient remote mutual authentication protocol using smart card. We have then simulated the proposed protocol using widely-accepted AVISPA simulation tool whose results make certain that the same protocol is secure against active and passive attacks including replay and man-in-the-middle attacks. Moreover, the rigorous security analysis proves that the proposed protocol provides strong security protection on the relevant security attacks including smart card stolen attack. We compare the proposed scheme with several related schemes in terms of computation cost and communication cost as well as security functionalities. It has been observed that the proposed scheme is comparatively better than related existing schemes.

ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS): study methodology, recruitment, and baseline demographic and disease characteristics.

PubMed

Mitsumoto, Hiroshi; Factor-Litvak, Pam; Andrews, Howard; Goetz, Raymond R; Andrews, Leslie; Rabkin, Judith G; McElhiney, Martin; Nieves, Jeri; Santella, Regina M; Murphy, Jennifer; Hupf, Jonathan; Singleton, Jess; Merle, David; Kilty, Mary; Heitzman, Daragh; Bedlack, Richard S; Miller, Robert G; Katz, Jonathan S; Forshew, Dallas; Barohn, Richard J; Sorenson, Eric J; Oskarsson, Bjorn; Fernandes Filho, J Americo M; Kasarskis, Edward J; Lomen-Hoerth, Catherine; Mozaffar, Tahseen; Rollins, Yvonne D; Nations, Sharon P; Swenson, Andrea J; Shefner, Jeremy M; Andrews, Jinsy A; Koczon-Jaremko, Boguslawa A

2014-06-01

Abstract In a multicenter study of newly diagnosed ALS patients without a reported family history of ALS, we are prospectively investigating whether markers of oxidative stress (OS) are associated with disease progression. Methods utilize an extensive structured telephone interview ascertaining environmental, lifestyle, dietary and psychological risk factors associated with OS. Detailed assessments were performed at baseline and at 3-6 month intervals during the ensuing 30 months. Our biorepository includes DNA, plasma, urine, and skin. Three hundred and fifty-five patients were recruited. Subjects were enrolled over a 36-month period at 16 sites. To meet the target number of subjects, the recruitment period was prolonged and additional sites were included. Results showed that demographic and disease characteristics were similar between 477 eligible/non-enrolled and enrolled patients, the only difference being type of health insurance among enrolled patients. Sites were divided into three groups by the number of enrolled subjects. Comparing these three groups, the Columbia site had fewer 'definite ALS' diagnoses. This is the first prospective, interdisciplinary, in-depth, multicenter epidemiological investigation of OS related to ALS progression and has been accomplished by an aggressive recruitment process. The baseline demographic and disease features of the study sample are now fully characterized.

Methodological Challenges in Studies Comparing Prehospital Advanced Life Support with Basic Life Support.

PubMed

Li, Timmy; Jones, Courtney M C; Shah, Manish N; Cushman, Jeremy T; Jusko, Todd A

2017-08-01

Determining the most appropriate level of care for patients in the prehospital setting during medical emergencies is essential. A large body of literature suggests that, compared with Basic Life Support (BLS) care, Advanced Life Support (ALS) care is not associated with increased patient survival or decreased mortality. The purpose of this special report is to synthesize the literature to identify common study design and analytic challenges in research studies that examine the effect of ALS, compared to BLS, on patient outcomes. The challenges discussed in this report include: (1) choice of outcome measure; (2) logistic regression modeling of common outcomes; (3) baseline differences between study groups (confounding); (4) inappropriate statistical adjustment; and (5) inclusion of patients who are no longer at risk for the outcome. These challenges may affect the results of studies, and thus, conclusions of studies regarding the effect of level of prehospital care on patient outcomes should require cautious interpretation. Specific alternatives for avoiding these challenges are presented. Li T , Jones CMC , Shah MN , Cushman JT , Jusko TA . Methodological challenges in studies comparing prehospital Advanced Life Support with Basic Life Support. Prehosp Disaster Med. 2017;32(4):444-450.

Elevated Levels of Selenium Species in Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients with Disease-Associated Gene Mutations.

PubMed

Mandrioli, Jessica; Michalke, Bernhard; Solovyev, Nikolay; Grill, Peter; Violi, Federica; Lunetta, Christian; Conte, Amelia; Sansone, Valeria Ada; Sabatelli, Mario; Vinceti, Marco

2017-01-01

Although an increasing role of genetic susceptibility has been recognized, the role of environmental risk factors in amyotrophic lateral sclerosis (ALS) etiology is largely uncertain; among neurotoxic chemicals, epidemiological and biological plausibility has been provided for pesticides, the heavy metal lead, the metalloid selenium, and other persistent organic pollutants. Selenium involvement in ALS has been suggested on the basis of epidemiological studies, in vitro investigations, and veterinary studies in which selenium induced a selective toxicity against motor neurons. Hypothesizing a multistep pathogenic mechanism (genetic susceptibility and environmental exposure), we aimed to study selenium species in ALS patients carrying disease-associated gene mutations as compared to a series of hospital controls. Using advanced analytical techniques, we determined selenium species in cerebrospinal fluid sampled at diagnosis in 9 ALS patients carrying different gene mutations (C9ORF72, SOD1, FUS, TARDBP, ATXN2, and TUBA4A) compared to 42 controls. In a patient with the tubulin-related TUBA4A mutation, we found highly elevated levels (in μg/L) of glutathione-peroxidase-bound selenium (32.8 vs. 1.0) as well as increased levels of selenoprotein-P-bound selenium (2.4 vs. 0.8), selenite (1.8 vs. 0.1), and selenate (0.9 vs. 0.1). In the remaining ALS patients, we detected elevated selenomethionine-bound selenium levels (0.38 vs. 0.06). Selenium compounds can impair tubulin synthesis and the cytoskeleton structure, as do tubulin-related gene mutations. The elevated selenium species levels in the TUBA4A patient may have a genetic etiology and/or represent a pathogenic pathway through which this mutation favors disease onset, though unmeasured confounding cannot be excluded. The elevated selenomethionine levels in the other patients are also of interest due to the toxicity of this nonphysiological selenium species. Our study is the first to assess selenium exposure in genetic ALS, suggesting an interaction between this environmental factor and genetics in triggering disease onset. © 2017 S. Karger AG, Basel.

The impact of physical impairment on emotional well-being in ALS.

PubMed

Abdulla, Susanne; Vielhaber, Stefan; Kollewe, Katja; Machts, Judith; Heinze, Hans-Jochen; Dengler, Reinhard; Petri, Susanne

2014-09-01

There has been evidence that subjective quality of life in patients with amyotrophic lateral sclerosis (ALS) is comparatively good, unrelated to the state of physical functioning, so called 'disability paradox'. Other studies show weak to moderate correlations between disease severity and emotional well-being. Our aim was to analyse the impact of physical impairment on emotional well-being when assessed disease-specifically and seen through the patient's eyes with additional clinical evaluation. In 121 patients emotional functioning was evaluated by the ALS Assessment Questionnaire (ALSAQ-40). Physical status was assessed by the ALS Functional Rating Scale-Extension (ALSFRS-EX) and Borg dyspnoea scales and by clinical examination (muscle strength and pulmonary function). Multiple regression and correlation analyses were performed. Results showed that physical impairment and progression rate of physical deterioration had a significant impact and explained some variance in emotional well-being (adjusted R(2) = 0.22). Pulmonary function and the sense of dyspnoea correlated significantly on a weak to moderate level with emotional well-being. In conclusion, disease-specific patient- reported outcome measurement instruments revealed a moderate but distinct impact of physical impairment on emotional well-being. This study challenges the 'disability paradox' and has relevant findings that can support the timely delivery of care for ALS patients.

Data mining: comparing the empiric CFS to the Canadian ME/CFS case definition.

PubMed

Jason, Leonard A; Skendrovic, Beth; Furst, Jacob; Brown, Abigail; Weng, Angela; Bronikowski, Christine

2012-01-01

This article contrasts two case definitions for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We compared the empiric CFS case definition (Reeves et al., 2005) and the Canadian ME/CFS clinical case definition (Carruthers et al., 2003) with a sample of individuals with CFS versus those without. Data mining with decision trees was used to identify the best items to identify patients with CFS. Data mining is a statistical technique that was used to help determine which of the survey questions were most effective for accurately classifying cases. The empiric criteria identified about 79% of patients with CFS and the Canadian criteria identified 87% of patients. Items identified by the Canadian criteria had more construct validity. The implications of these findings are discussed. © 2011 Wiley Periodicals, Inc.

Observation of c.260A > G mutation in superoxide dismutase 1 that causes p.Asn86Ser in Iranian amyotrophic lateral sclerosis patient and absence of genotype/phenotype correlation.

PubMed

Khani, Marzieh; Alavi, Afagh; Nafissi, Shahriar; Elahi, Elahe

2015-07-06

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder in European populations. ALS can be sporadic ALS (SALS) or familial ALS (FALS). Among 20 known ALS genes, mutations in C9orf72 and superoxide dismutase 1 (SOD1) are the most common genetic causes of the disease. Whereas C9orf72 mutations are more common in Western populations, the contribution of SOD1 to ALS in Iran is more than C9orf72. At present, a clear genotype/phenotype correlation for ALS has not been identified. We aimed to perform mutation screening of SOD1 in a newly identified Iranian FALS patient and to assess whether a genotype/phenotype correlation for the identified mutation exists. The five exons of SOD1 and flanking intronic sequences of a FALS proband were screened for mutations by direct sequencing. The clinical features of the proband were assessed by a neuromuscular specialist (SN). The phenotypic presentations were compared to previously reported patients with the same mutation. Heterozygous c.260A > G mutation in SOD1 that causes Asn86Ser was identified in the proband. Age at onset was 34 years and site of the first presentation was in the lower extremities. Comparisons of clinical features of different ALS patients with the same mutation evidenced variable presentations. The c.260A > G mutation in SOD1 that causes Asn86Ser appears to cause ALS with variable clinical presentations.

Impaired corticopontocerebellar tracts underlie pseudobulbar affect in motor neuron disorders

PubMed Central

Katipally, Rohan; Kim, Meredith P.; Schanz, Olivia; Stephen, Matthew; Danielian, Laura; Wu, Tianxia; Huey, Edward D.; Meoded, Avner

2014-01-01

Objective: The objectives of the study were (1) to determine the prevalence and characteristics of pseudobulbar affect (PBA) in patients with primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS) in an outpatient clinic population, and (2) to test the hypothesis that damage of inputs to the cerebellum, leading to cerebellar dysmodulation, is associated with PBA. Methods: Chart review of all patients with PLS and ALS seen between 2000 and 2013. The examining neurologist documented the presence or absence of PBA in 87 patients. Forty-seven patients also had diffusion tensor imaging (DTI) studies. Tract-based spatial statistics were used to compare DTI of patients with and without PBA to identify altered white matter tracts associated with PBA. Results: Thirty-one of 50 patients with PLS and 12 of 37 patients with ALS had PBA. Psychiatric/emotional assessment found congruence between mood and affect during episodes, but excessive magnitude of the response. DTI studies of 25 PLS and 22 ALS patient brains showed reduced fractional anisotropy of the corticospinal and callosal white matter tracts in all patients. Patients with PBA additionally had increased mean diffusivity of white matter tracts underlying the frontotemporal cortex, the transverse pontine fibers, and the middle cerebellar peduncle. Conclusions: PBA is common in PLS. Imaging findings showing disruption of corticopontocerebellar pathways support the hypothesis that PBA can be viewed as a “dysmetria” of emotional expression resulting from cerebellar dysmodulation. PMID:25008395

Impaired corticopontocerebellar tracts underlie pseudobulbar affect in motor neuron disorders.

PubMed

Floeter, Mary Kay; Katipally, Rohan; Kim, Meredith P; Schanz, Olivia; Stephen, Matthew; Danielian, Laura; Wu, Tianxia; Huey, Edward D; Meoded, Avner

2014-08-12

The objectives of the study were (1) to determine the prevalence and characteristics of pseudobulbar affect (PBA) in patients with primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS) in an outpatient clinic population, and (2) to test the hypothesis that damage of inputs to the cerebellum, leading to cerebellar dysmodulation, is associated with PBA. Chart review of all patients with PLS and ALS seen between 2000 and 2013. The examining neurologist documented the presence or absence of PBA in 87 patients. Forty-seven patients also had diffusion tensor imaging (DTI) studies. Tract-based spatial statistics were used to compare DTI of patients with and without PBA to identify altered white matter tracts associated with PBA. Thirty-one of 50 patients with PLS and 12 of 37 patients with ALS had PBA. Psychiatric/emotional assessment found congruence between mood and affect during episodes, but excessive magnitude of the response. DTI studies of 25 PLS and 22 ALS patient brains showed reduced fractional anisotropy of the corticospinal and callosal white matter tracts in all patients. Patients with PBA additionally had increased mean diffusivity of white matter tracts underlying the frontotemporal cortex, the transverse pontine fibers, and the middle cerebellar peduncle. PBA is common in PLS. Imaging findings showing disruption of corticopontocerebellar pathways support the hypothesis that PBA can be viewed as a "dysmetria" of emotional expression resulting from cerebellar dysmodulation. © 2014 American Academy of Neurology.

Sensory cortex hyperexcitability predicts short survival in amyotrophic lateral sclerosis.

PubMed

Shimizu, Toshio; Bokuda, Kota; Kimura, Hideki; Kamiyama, Tsutomu; Nakayama, Yuki; Kawata, Akihiro; Isozaki, Eiji; Ugawa, Yoshikazu

2018-05-01

To investigate somatosensory cortex excitability and its relationship to survival prognosis in patients with amyotrophic lateral sclerosis (ALS). A total of 145 patients with sporadic ALS and 73 healthy control participants were studied. We recorded compound muscle action potential and sensory nerve action potential of the median nerve and the median nerve somatosensory evoked potential (SEP), and we measured parameters, including onset-to-peak amplitude of N13 and N20 and peak-to-peak amplitude between N20 and P25 (N20p-P25p). Clinical prognostic factors, including ALS Functional Rating Scale-Revised, were evaluated. We followed up patients until the endpoints (death or tracheostomy) and analyzed factors associated with survival using multivariate analysis in the Cox proportional hazard model. Compared to controls, patients with ALS showed a larger amplitude of N20p-P25p in the median nerve SEP. Median survival time after examination was shorter in patients with N20p-P25p ≥8 μV (0.82 years) than in those with N20p-P25p <8 μV (1.68 years, p = 0.0002, log-rank test). Multivariate analysis identified a larger N20p-P25p amplitude as a factor that was independently associated with shorter survival ( p = 0.002). Sensory cortex hyperexcitability predicts short survival in patients with ALS. © 2018 American Academy of Neurology.

Outcomes of Basic Versus Advanced Life Support for Out-of-Hospital Medical Emergencies.

PubMed

Sanghavi, Prachi; Jena, Anupam B; Newhouse, Joseph P; Zaslavsky, Alan M

2015-11-03

Most Medicare patients seeking emergency medical transport are treated by ambulance providers trained in advanced life support (ALS). Evidence supporting the superiority of ALS over basic life support (BLS) is limited, but some studies suggest ALS may harm patients. To compare outcomes after ALS and BLS in out-of-hospital medical emergencies. Observational study with adjustment for propensity score weights and instrumental variable analyses based on county-level variations in ALS use. Traditional Medicare. 20% random sample of Medicare beneficiaries from nonrural counties between 2006 and 2011 with major trauma, stroke, acute myocardial infarction (AMI), or respiratory failure. Neurologic functioning and survival to 30 days, 90 days, 1 year, and 2 years. Except in cases of AMI, patients showed superior unadjusted outcomes with BLS despite being older and having more comorbidities. In propensity score analyses, survival to 90 days among patients with trauma, stroke, and respiratory failure was higher with BLS than ALS (6.1 percentage points [95% CI, 5.4 to 6.8 percentage points] for trauma; 7.0 percentage points [CI, 6.2 to 7.7 percentage points] for stroke; and 3.7 percentage points [CI, 2.5 to 4.8 percentage points] for respiratory failure). Patients with AMI did not exhibit differences in survival at 30 days but had better survival at 90 days with ALS (1.0 percentage point [CI, 0.1 to 1.9 percentage points]). Neurologic functioning favored BLS for all diagnoses. Results from instrumental variable analyses were broadly consistent with propensity score analyses for trauma and stroke, showed no survival differences between BLS and ALS for respiratory failure, and showed better survival at all time points with BLS than ALS for patients with AMI. Only Medicare beneficiaries from nonrural counties were studied. Advanced life support is associated with substantially higher mortality for several acute medical emergencies than BLS. National Science Foundation, Agency for Healthcare Research and Quality, and National Institutes of Health.

Frontotemporal white matter changes in amyotrophic lateral sclerosis.

PubMed

Abrahams, Sharon; Goldstein, Laura H; Suckling, John; Ng, Virginia; Simmons, Andy; Chitnis, Xavier; Atkins, Louise; Williams, Steve C R; Leigh, P N

2005-03-01

Cognitive dysfunction can occur in some patients with amyotrophic lateral sclerosis (ALS) who are not suffering from dementia. The most striking and consistent cognitive deficit has been found using tests of verbal fluency. ALS patients with verbal fluency deficits have shown functional imaging abnormalities predominantly in frontotemporal regions using positron emission tomography (PET). This study used automated volumetric voxel-based analysis of grey and white matter densities of structural magnetic resonance imaging (MRI) scans to explore the underlying pattern of structural cerebral change in nondemented ALS patients with verbal fluency deficits. Two groups of ALS patients, defined by the presence or absence of cognitive impairment on the basis of the Written Verbal Fluency Test (ALSi, cognitively impaired, n=11; ALSu, cognitively unimpaired n=12) were compared with healthy age matched controls (n=12). A comparison of the ALSi group with controls revealed significantly (p<0.002) reduced white matter volume in extensive motor and non-motor regions, including regions corresponding to frontotemporal association fibres. These patients demonstrated a corresponding cognitive profile of executive and memory dysfunction. Less extensive white matter reductions were revealed in the comparison of the ALSu and control groups in regions corresponding to frontal association fibres. White matter volumes were also found to correlate with performance on memory tests. There were no significant reductions in grey matter volume in the comparison of either patient group with controls. The structural white matter abnormalities in frontal and temporal regions revealed here may underlie the cognitive and functional imaging abnormalities previously reported in non-demented ALS patients. The results also suggest that extra-motor structural abnormalities may be present in ALS patients with no evidence of cognitive change. The findings support the hypothesis of a continuum of extra-motor cerebral and cognitive change in this disorder.

Profiling Speech and Pausing in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)

PubMed Central

Yunusova, Yana; Graham, Naida L.; Shellikeri, Sanjana; Phuong, Kent; Kulkarni, Madhura; Rochon, Elizabeth; Tang-Wai, David F.; Chow, Tiffany W.; Black, Sandra E.; Zinman, Lorne H.; Green, Jordan R.

2016-01-01

Objective This study examines reading aloud in patients with amyotrophic lateral sclerosis (ALS) and those with frontotemporal dementia (FTD) in order to determine whether differences in patterns of speaking and pausing exist between patients with primary motor vs. primary cognitive-linguistic deficits, and in contrast to healthy controls. Design 136 participants were included in the study: 33 controls, 85 patients with ALS, and 18 patients with either the behavioural variant of FTD (FTD-BV) or progressive nonfluent aphasia (FTD-PNFA). Participants with ALS were further divided into 4 non-overlapping subgroups—mild, respiratory, bulbar (with oral-motor deficit) and bulbar-respiratory—based on the presence and severity of motor bulbar or respiratory signs. All participants read a passage aloud. Custom-made software was used to perform speech and pause analyses, and this provided measures of speaking and articulatory rates, duration of speech, and number and duration of pauses. These measures were statistically compared in different subgroups of patients. Results The results revealed clear differences between patient groups and healthy controls on the passage reading task. A speech-based motor function measure (i.e., articulatory rate) was able to distinguish patients with bulbar ALS or FTD-PNFA from those with respiratory ALS or FTD-BV. Distinguishing the disordered groups proved challenging based on the pausing measures. Conclusions and Relevance This study demonstrated the use of speech measures in the identification of those with an oral-motor deficit, and showed the usefulness of performing a relatively simple reading test to assess speech versus pause behaviors across the ALS—FTD disease continuum. The findings also suggest that motor speech assessment should be performed as part of the diagnostic workup for patients with FTD. PMID:26789001

Characterization of Gene Expression Phenotype in Amyotrophic Lateral Sclerosis Monocytes

PubMed Central

Zhao, Weihua; Beers, David R.; Hooten, Kristopher G.; Sieglaff, Douglas H.; Zhang, Aijun; Kalyana-Sundaram, Shanker; Traini, Christopher M.; Halsey, Wendy S.; Hughes, Ashley M.; Sathe, Ganesh M.; Livi, George P.; Fan, Guo-Huang

2017-01-01

Importance Amyotrophic lateral sclerosis (ALS) is a common adult-onset neurodegenerative disease characterized by selective loss of upper and lower motor neurons. Patients with ALS have persistent peripheral and central inflammatory responses including abnormally functioning T cells and activated microglia. However, much less is known about the inflammatory gene profile of circulating innate immune monocytes in these patients. Objective To characterize the transcriptomics of peripheral monocytes in patients with ALS. Design, Setting, and Participants Monocytes were isolated from peripheral blood of 43 patients with ALS and 22 healthy control individuals. Total RNA was extracted from the monocytes and subjected to deep RNA sequencing, and these results were validated by quantitative reverse transcription polymerase chain reaction. Main Outcomes and Measures The differential expressed gene signatures of these monocytes were identified using unbiased RNA sequencing strategy for gene expression profiling. Results The demographics between the patients with ALS (mean [SD] age, 58.8 [1.57] years; 55.8% were men and 44.2% were women; 90.7% were white, 4.65% were Hispanic, 2.33% were black, and 2.33% were Asian) and control individuals were similar (mean [SD] age, 57.6 [2.15] years; 50.0% were men and 50.0% were women; 90.9% were white, none were Hispanic, none were black, and 9.09% were Asian). RNA sequencing data from negative selected monocytes revealed 233 differential expressed genes in ALS monocytes compared with healthy control monocytes. Notably, ALS monocytes demonstrated a unique inflammation-related gene expression profile, the most prominent of which, including IL1B, IL8, FOSB, CXCL1, and CXCL2, were confirmed by quantitative reverse transcription polymerase chain reaction (IL8, mean [SE], 1.00 [0.18]; P = .002; FOSB, 1.00 [0.21]; P = .009; CXCL1, 1.00 [0.14]; P = .002; and CXCL2, 1.00 [0.11]; P = .01). Amyotrophic lateral sclerosis monocytes from rapidly progressing patients had more proinflammatory DEGs than monocytes from slowly progressing patients. Conclusions and Relevance Our data indicate that ALS monocytes are skewed toward a proinflammatory state in the peripheral circulation and may play a role in ALS disease progression, especially in rapidly progressing patients. This increased inflammatory response of peripheral immune cells may provide a potential target for disease-modifying therapy in patients with ALS. PMID:28437540

Plasma hepatocyte growth factor is a novel marker of AL cardiac amyloidosis.

PubMed

Swiger, Kristopher J; Friedman, Eitan A; Brittain, Evan L; Tomasek, Kelsey A; Huang, Shi; Su, Yan R; Sawyer, Douglas B; Lenihan, Daniel J

2016-12-01

Cardiac amyloidosis is an infiltrative cardiomyopathy that is challenging to diagnose. We hypothesized that the novel biomarkers hepatocyte growth factor (HGF), galectin-3 (GAL-3), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) would be elevated in cardiac amyloidosis and may be able to discriminate from non-cardiac systemic amyloidosis or other cardiomyopathies with similar clinical or morphologic characteristics. Patients were selected from the Vanderbilt Main Heart Registry according to the following groups: (1) amyloid light-chain (AL) cardiac amyloidosis (n = 26); (2) transthyretin (ATTR) cardiac amyloidosis (n = 7); (3) left ventricular hypertrophy (LVH) (n = 45); (4) systolic heart failure (n = 42); and (5) non-cardiac systemic amyloidosis (n = 7). Biomarkers were measured in stored plasma samples. Biomarkers' discrimination performance in predicting AL cardiac amyloidosis (i.e., Concordance index) was reported. A survival analysis was used to explore the relationship between HGF levels and mortality among AL cardiac amyloidosis patients. HGF levels were markedly elevated in patients with AL cardiac amyloidosis (median = 622, interquartile range (IQR): 299-1228 pg/mL) compared with the other groups, including those with non-cardiac systemic amyloidosis (median = 134, IQR: 94-163 pg/mL, p < 0.001). HGF was not a specific marker for ATTR amyloidosis. Gal-3 was elevated in all groups with amyloidosis but could not differentiate between those with and without cardiac involvement. There was no difference in IL-6 or VEGF between those with AL cardiac amyloidosis compared to other groups (p = 0.13 and 0.057, respectively). HGF may be a specific marker that distinguishes AL cardiac amyloidosis from other cardiomyopathies with similar clinical or morphologic characteristics. Further studies are necessary to determine whether HGF levels predict the likelihood of survival.

Topographic distribution of brain iron deposition and small cerebrovascular lesions in amyotrophic lateral sclerosis and in frontotemporal lobar degeneration: a post-mortem 7.0-tesla magnetic resonance imaging study with neuropathological correlates.

PubMed

De Reuck, Jacques; Devos, David; Moreau, Caroline; Auger, Florent; Durieux, Nicolas; Deramecourt, Vincent; Pasquier, Florence; Maurage, Claude-Alain; Cordonnier, Charlotte; Leys, Didier; Bordet, Regis

2017-12-01

Amyotrophic lateral sclerosis (ALS) is associated with frontotemporal lobar degeneration (FTLD) in 15% of the cases. A neuropathological continuity between ALS and FTLD-TDP is suspected. The present post-mortem 7.0-tesla magnetic resonance imaging (MRI) study compares the topographic distribution of iron (Fe) deposition and the incidence of small cerebrovascular lesions in ALS and in FTLD brains. Seventy-eight post-mortem brains underwent 7.0-tesla MRI. The patients consisted of 12 with ALS, 38 with FTLD, and 28 controls. Three ALS brains had minor FTLD features. Three coronal sections of a cerebral hemisphere were submitted to T2 and T2* MRI sequences. The amount of Fe deposition in the deep brain structures and the number of small cerebrovascular lesions was determined in ALS and the subtypes of FTLD compared to control brains, with neuropathological correlates. A significant increase of Fe deposition was observed in the claustrum, caudate nucleus, globus pallidus, thalamus, and subthalamic nucleus of the FTLD-FUS and FTLD-TDP groups, while in the ALS one, the Fe increase was only observed in the caudate and the subthalamic nuclei. White matter changes were only significantly more severe in the FTLD compared to those in ALS and in controls brains. Cortical micro-bleeds were increased in the frontal and temporal lobes of FTLD as well as of ALS brains compared to controls. Cortical micro-infarcts were, on the other hand, more frequent in the control compared to the ALS and FTLD groups. The present study supports the assumption of a neuropathological continuity between ALS and FTLD and illustrates the favourable vascular risk profile in these diseases.

Comparative Efficacy of the New Optical Biometer on Intraocular Lens Power Calculation (AL-Scan versus IOLMaster).

PubMed

Ha, Ahnul; Wee, Won Ryang; Kim, Mee Kum

2018-05-15

To evaluate the agreement in axial length (AL), keratometry, and anterior chamber depth measurements between AL-Scan and IOLMaster biometers and to compare the efficacy of the AL-Scan on intraocular lens (IOL) power calculations and refractive outcomes with those obtained by the IOLMaster. Medical records of 48 eyes from 48 patients who underwent uneventful phacoemulsification and IOL insertion were retrospectively reviewed. One of the two types of monofocal aspheric IOLs were implanted (Tecnis ZCB00 [Tecnis, n = 34] or CT Asphina 509M [Asphina, n = 14]). Two different partial coherence interferometers measured and compared AL, keratometry (2.4 mm), anterior chamber depth, and IOL power calculations with SRK/T, Hoffer Q, Holladay2, and Haigis formulas. The difference between expected and actual final refractive error was compared as refractive mean error (ME), refractive mean absolute error (MAE), and median absolute error (MedAE). AL measured by the AL-Scan was shorter than that measured by the IOLMaster (p = 0.029). The IOL power of Tecnis did not differ between the four formulas; however, the Asphina measurement calculated using Hoffer Q for the AL-Scan was lower (0.28 diopters, p = 0.015) than that calculated by the IOLMaster. There were no statistically significant differences between the calculations by MAE and MedAE for the four formulas in either IOL. In SRK/T, ME in Tecnis-inserted eyes measured by AL-Scan showed a tendency toward myopia (p = 0.032). Measurement by AL-Scan provides reliable biometry data and power calculations compared to the IOLMaster; however, refractive outcomes of Tecnis-inserted eyes by AL-Scan calculated using SRK/T can show a slight myopic tendency. © 2018 The Korean Ophthalmological Society.

Cachexia in cancer: what is in the definition?

PubMed Central

Vanhoutte, Greetje; van de Wiel, Mick; Wouters, Kristin; Sels, Michaël; Bartolomeeussen, Linda; De Keersmaecker, Sven; Verschueren, Caroline; De Vroey, Veronique; De Wilde, Annemieke; Smits, Elke; Cheung, Kin Jip; De Clerck, Liesbeth; Aerts, Petra; Baert, Didier; Vandoninck, Caroline; Kindt, Sofie; Schelfhaut, Sofie; Vankerkhoven, Marc; Troch, Annelies; Ceulemans, Lore; Vandenbergh, Hanne; Leys, Sven; Rondou, Tim; Dewitte, Elke; Maes, Kristel; Pauwels, Patrick; De Winter, Benedicte; Van Gaal, Luc; Ysebaert, Dirk; Peeters, Marc

2016-01-01

Objective This study aimed to provide evidence-based results on differences in overall survival (OS) rate to guide the diagnosis of cancer cachexia. Design Data collection and clinical assessment was performed every 3 months (5 visits): baseline data, muscle strength, nutritional and psychosocial status. 2 definitions on cachexia using different diagnostic criteria were applied for the same patient population. Fearon et al's definition is based on weight loss, body mass index (BMI) and sarcopenia. Evans et al nuances the contribution of sarcopenia and attaches additional attention to abnormal biochemistry parameters, fatigue and anorexia. The mean OS rates were compared between patients with and without cachexia for both definitions. Results Based on the population of 167 patients who enrolled, 70% developed cachexia according to Fearon et al's definition and 40% according to Evans et al's definition. The OS in the cachectic population is 0.97 and 0.55 years, respectively. The difference in OS between patients with and without cachexia is more significant using the diagnostic criteria of Evans et al. The focus of Fearon et al on weight loss and sarcopenia over-rates the assignment of patients to the cachectic group and OS rates have less prognostic value. Conclusion This study presents a correlation with prognosis in favour of Evans et al’ definition as a tool for cachexia diagnosis. This means that weight loss and BMI decline are both key factors in patients with cancer leading to cachexia but less decisive as stated by Fearon et al. Instead, extra factors gain importance in order to predict survival, such as chronic inflammation, anaemia, protein depletion, reduced food intake, fatigue, decreased muscle strength and lean tissue depletion. Trial registration number B300201112334. PMID:27843571

Increased Expressions of Plasma Galectin-3 in Patients with Amyotrophic Lateral Sclerosis

PubMed Central

Yan, Jun; Xu, Yun; Zhang, Li; Zhao, Hui; Jin, Ling; Liu, Wei-Guo; Weng, Lei-Hua; Li, Zuo-Han; Chen, Ling

2016-01-01

Background: High expressions of galectin-3 were identified recently in the end stage of amyotrophic lateral sclerosis (ALS) patients, which suggested that immune reactivity and inflammatory mechanisms might play an important role in the pathogenesis of ALS. The purpose of this study was to investigate plasma galectin-3 levels in different groups and stages of ALS patients and the association with related clinical characteristics. Methods: A total of 51 patients with ALS and 60 normal controls (NCs) were recruited in this study. Plasma galectin-3 levels were determined using the enzyme-linked immunosorbent assay. Patients with ALS were divided into several groups according to their clinical characteristics: gender, type of disease onset, duration of disease, and clinical conditions of disease. Statistical analyses of the differences of galectin-3 levels between groups and the association with the clinical characteristics of disease were performed. Results: As compared with the NCs (201.64 [22.35–401.63] ng/ml), plasma galectin-3 levels were significantly elevated in the patients with duration >12 months (341.17 [69.12–859.22] ng/ml, P < 0.05), and the patients with limb onset of disease (254.14 [69.12–859.22] ng/ml, P < 0.05); however, no difference was found in the patients with duration ≤12 months (250.62 [109.77–334.92] ng/ml, P > 0.05), and the patients with bulbar onset of disease (251.79 [109.20–404.76] ng/ml, P > 0.05). In addition, galectin-3 levels were significantly increased in the female patients (263.27 [123.32–859.22] ng/ml, P < 0.05) while no difference was found in the male patients (220.39 [69.12–748.73] ng/ml, P > 0.05). The further statistical analyses showed that plasma galectin-3 levels were positively correlated with the duration of disease (r = 0.293, P = 0.037). Conclusions: Plasma galectin-3 levels were significantly increased in ALS patients with limb onset of disease, especially in ALS female patients, and positively correlated with the duration of disease, which suggested that plasma galectin-3 might be an interesting and useful factor associated with ALS. PMID:27900991

EEG functional network topology is associated with disability in patients with amyotrophic lateral sclerosis

NASA Astrophysics Data System (ADS)

Fraschini, Matteo; Demuru, Matteo; Hillebrand, Arjan; Cuccu, Lorenza; Porcu, Silvia; di Stefano, Francesca; Puligheddu, Monica; Floris, Gianluca; Borghero, Giuseppe; Marrosu, Francesco

2016-12-01

Amyotrophic Lateral Sclerosis (ALS) is one of the most severe neurodegenerative diseases, which is known to affect upper and lower motor neurons. In contrast to the classical tenet that ALS represents the outcome of extensive and progressive impairment of a fixed set of motor connections, recent neuroimaging findings suggest that the disease spreads along vast non-motor connections. Here, we hypothesised that functional network topology is perturbed in ALS, and that this reorganization is associated with disability. We tested this hypothesis in 21 patients affected by ALS at several stages of impairment using resting-state electroencephalography (EEG) and compared the results to 16 age-matched healthy controls. We estimated functional connectivity using the Phase Lag Index (PLI), and characterized the network topology using the minimum spanning tree (MST). We found a significant difference between groups in terms of MST dissimilarity and MST leaf fraction in the beta band. Moreover, some MST parameters (leaf, hierarchy and kappa) significantly correlated with disability. These findings suggest that the topology of resting-state functional networks in ALS is affected by the disease in relation to disability. EEG network analysis may be of help in monitoring and evaluating the clinical status of ALS patients.

Bioassay of procoagulant albumin in human plasma.

PubMed

Grosset, A; Liu, L; Parker, C J; Rodgers, G M

1994-09-01

Procoagulant albumin (P-Al) is present in normal human plasma and increases monocyte and endothelial cell expression of tissue factor activity. To develop a bioassay for P-Al, we partially purified plasma from healthy volunteers and several patient groups using BaCl2 and (NH4)2SO4 precipitation. The samples were assayed for tissue factor (TF) inducing activity, expressed as a percentage increase compared to a serum-free media control. Over six months, the assay was reproducible in stored samples and in serial samples from normal volunteers. The plasma P-Al activities of 35 volunteers averaged 141 +/- 8.2% (SEM). There was no diurnal variation. There was no difference in the P-Al activity after a 12 hour fast and 2 hours after a large meal in 4 healthy volunteers. There was no increase in activity (r = 0.16) with the subject's age. The average activity from 16 poorly-controlled diabetics was 131 +/- 11% (SEM). No alteration in activity was seen with samples from patients with uremia, liver dysfunction, hemophilia, thrombotic events, or adenocarcinoma. These results indicate that P-Al activity can be bioassayed in individual patient samples; however, pathologic states associated with abnormal P-Al-induced tissue factor activity presently remain unidentified.

Comorbidity of dementia with amyotrophic lateral sclerosis (ALS): insights from a large multicenter Italian cohort.

PubMed

Trojsi, Francesca; Siciliano, Mattia; Femiano, Cinzia; Santangelo, Gabriella; Lunetta, Christian; Calvo, Andrea; Moglia, Cristina; Marinou, Kalliopi; Ticozzi, Nicola; Drago Ferrante, Gianluca; Scialò, Carlo; Sorarù, Gianni; Conte, Amelia; Falzone, Yuri M; Tortelli, Rosanna; Russo, Massimo; Sansone, Valeria Ada; Chiò, Adriano; Mora, Gabriele; Poletti, Barbara; Volanti, Paolo; Caponnetto, Claudia; Querin, Giorgia; Sabatelli, Mario; Riva, Nilo; Logroscino, Giancarlo; Messina, Sonia; Fasano, Antonio; Monsurrò, Maria Rosaria; Tedeschi, Gioacchino; Mandrioli, Jessica

2017-11-01

To assess the association, at diagnosis, between amyotrophic lateral sclerosis (ALS) and dementia in a large cohort of well-characterized Italian patients. We investigated the phenotypic profile of 1638 incident patients with definite, probable or laboratory-supported probable ALS, diagnosed from January 2009 to December 2013 in 13 Italian Referral Centers, located in 10 Italian Regions, and classified in two independent subsamples accounting for presence or not of dementia. The collected ALS features, including survival and other follow-up data, were compared between the two subgroups using a one-way analysis of variance and Chi-square test, as appropriate, logistic regression models and Kaplan-Meier survival analysis. Between-subgroup comparisons showed an older age at clinical observation (p = .006), at onset and at diagnosis (p = .002) in demented versus non demented ALS patients. After adjustment for these variables, diagnosis of dementia was significantly associated with higher odds of family history of ALS (p = .001) and frontotemporal dementia (p = .003) and of bulbar onset (p = .004), and lower odds of flail leg phenotype (p = .019) and spinal onset (p = .008). The median survival time was shorter in demented versus non-demented patients, especially in case of classical, bulbar and flail limb phenotypes and both bulbar and spinal onset. Our multicenter study emphasized the importance of an early diagnosis of comorbid dementia in ALS patients, which may have clinical impact and prognostic relevance. Moreover, our results may give further inputs to validation of ALS-specific tools for the screening of cognitive impairment in clinical practice.

Racial differences in motor neuron disease.

PubMed

Gundogdu, Betul; Al-Lahham, Tawfiq; Kadlubar, Fred; Spencer, Horace; Rudnicki, Stacy A

2014-03-01

Our objective was to compare and contrast clinical features of black and white patients seen in the UAMS ALS/Motor Neuron Disease (MND) clinic from January 2001 to December 2010. Death certificate information was reviewed to determine race of Arkansans who died of ALS/MND between 1999 and 2006. We used a retrospective chart review of patients with ALS/MND seen at least once in our clinic and reviewed state death certificate data. Results showed that from 1999 to 2006, 466 Arkansas deaths were attributed (immediate or contributory) to ALS/MND; 17 (3.6%) were black, four (0.9%) other, and 445 (95.5%) white. During this period, the proportion of black Arkansans was 17%. From 2001 to 2010, we saw 330 patients with ALS/MND: 30 (9.1%) black, six (1.8%) other, 294 (89.1%) white. Average onset age for whites was 58.1 + 12.4 years, for blacks 52.8 + 13.0 (p = 0.038). Gender, onset site, time from symptom onset to first clinic visit and initial vital capacity were similar between the groups. Initial ALSFRS-R was 37.5 + 7.2 for whites and 30.8 + 8.5 (p = 0.004) for blacks. A first or second degree relative with ALS/MND was reported by 8.1% of whites and by none of the black patients (p = 0.15). Riluzole, PEG and non-invasive ventilation use was similar between the groups. Median tracheostomy-free survival was 36 months for white and 40 months for black patients (p = 0.475). In conclusion, although blacks appear relatively spared from ALS/MND, they present at an earlier age and are functionally worse at their first visit. Investigating the genetic make-up of blacks with the disease may help identify genes that modify risk of developing ALS/MND.

Racial differences in motor neuron disease

PubMed Central

GUNDOGDU, BETUL; AL-LAHHAM, TAWFIQ; SPENCER, HORACE; RUDNICKI, STACY A.

2014-01-01

Our objective was to compare and contrast clinical features of black and white patients seen in the UAMS ALS/Motor Neuron Disease (MND) clinic from January 2001 to December 2010. Death certificate information was reviewed to determine race of Arkansans who died of ALS/MND between 1999 and 2006. We used a retrospective chart review of patients with ALS/MND seen at least once in our clinic and reviewed state death certificate data. Results showed that from 1999 to 2006, 466 Arkansas deaths were attributed (immediate or contributory) to ALS/MND; 17 (3.6%) were black, four (0.9%) other, and 445 (95.5%) white. During this period, the proportion of black Arkansans was 17%. From 2001 to 2010, we saw 330 patients with ALS/MND: 30 (9.1%) black, six (1.8%) other, 294 (89.1%) white. Average onset age for whites was 58.1 ± 12.4 years, for blacks 52.8 ± 13.0 (p = 0.038). Gender, onset site, time from symptom onset to first clinic visit and initial vital capacity were similar between the groups. Initial ALSFRS-R was 37.5 ± 7.2 for whites and 30.8 ± 8.5 (p = 0.004) for blacks. A first or second degree relative with ALS/MND was reported by 8.1% of whites and by none of the black patients (p = 0.15). Riluzole, PEG and non-invasive ventilation use was similar between the groups. Median tracheostomy-free survival was 36 months for white and 40 months for black patients (p = 0.475). In conclusion, although blacks appear relatively spared from ALS/MND, they present at an earlier age and are functionally worse at their first visit. Investigating the genetic make-up of blacks with the disease may help identify genes that modify risk of developing ALS/MND. PMID:24067242

Role of the lower esophageal sphincter on esophageal acid exposure - a review of over 2000 patients.

PubMed

Tsuboi, Kazuto; Hoshino, Masato; Sundaram, Abhishek; Yano, Fumiaki; Mittal, Sumeet K

2012-01-01

Three lower esophageal sphincter (LES) characteristics associated with gastro-esophageal reflux disease (GERD) are, LES pressure = 6 mmHg, abdominal length (AL) <1 cm and overall length (OL) <2 cm. The objective of this study was to validate this relationship and evaluate the extent of impact various LES characteristics have on the degree of distal esophageal acid exposure. A retrospective review of a prospectively maintained database identified patients who underwent esophageal manometry and pH studies at Creighton University Medical Center between 1984 and 2008. Patients with esophageal body dysmotility, prior foregut surgery, missing data, no documented symptoms or no pH study, were excluded. Study subjects were categorized as follows: (1) normal LES (N-LES): patients with LES pressure of 6-26 mmHg, AL = 1.0 cm and OL = 2 cm; (2) incompetent LES (Inc-LES): patients with LES pressure <6.0 mmHg orAL <1 cm or OL <2 cm; and (3) hypertensive LES (HTN-LES): patients with LES pressure >26.0 mmHg with AL = 1 cm and OL = 2 cm. The DeMeester score was used to compare differences in acid exposure between different groups. Two thousand and twenty patients satisfied study criteria. Distal esophageal acid exposure as reflected by the DeMeester score in patients with Inc-LES (median=20.05) was significantly higher than in patients with an N-LES (median=9.5), which in turn was significantly higher than in patients with an HTN-LES. Increasing LES pressure and AL provided protection against acid exposure in a graded fashion. Increasing number of inadequate LES characteristics were associated with an increase both in the percentage of patients with abnormal DeMeester score and the degree of acid exposure. LES pressure (=6 mmHg) and AL (<1 cm) are associated with increased lower esophageal acid exposure, and need to be addressed for definitive management of GERD.

Is the effect of non-invasive ventilation on survival in amyotrophic lateral sclerosis age-dependent?

PubMed

Siirala, Waltteri; Aantaa, Riku; Olkkola, Klaus T; Saaresranta, Tarja; Vuori, Arno

2013-01-01

Hypoventilation due to respiratory muscle atrophy is the most common cause of death as a result of amyotrophic lateral sclerosis (ALS). Patients aged over 65 years and presenting bulbar symptoms are likely to have a poorer prognosis. The aim of the study was to assess the possible impact of age and treatment with non-invasive ventilation (NIV) on survival in ALS. Based on evidence from earlier studies, it was hypothesized that NIV increases rates of survival regardless of age. Eighty-four patients diagnosed with ALS were followed up on from January 2001 to June 2012. These patients were retrospectively divided into two groups according to their age at the time of diagnosis: Group 1 comprised patients aged ≤ 65 years while Group 2 comprised those aged > 65 years. Each group included 42 patients. NIV was tolerated by 23 patients in Group 1 and 18 patients in Group 2. Survival was measured in months from the date of diagnosis. The median age in Group 1 was 59 years (range 49 - 65) and 76 years in Group 2 (range 66 - 85). Among patients in Group 1 there was no difference in probability of survival between the NIV users and non-users (Hazard Ratio = 0.88, 95% CI 0.44 - 1.77, p = 0.7). NIV users in Group 2 survived longer than those following conventional treatment (Hazard Ratio = 0.25, CI 95% 0.11 - 0.55, p <0.001). ALS patients in Group 2 who did not use NIV had a 4-fold higher risk for death compared with NIV users. This retrospective study found that NIV use was associated with improved survival outcomes in ALS patients older than 65 years. Further studies in larger patient populations are warranted to determine which factors modify survival outcomes in ALS.

Impaired affective and cognitive theory of mind and behavioural change in amyotrophic lateral sclerosis.

PubMed

van der Hulst, Egberdina-Józefa; Bak, Thomas H; Abrahams, Sharon

2015-11-01

Executive and behavioural changes are well-recognised in classical amyotrophic lateral sclerosis (ALS), indicating a subclinical behavioural-variant frontotemporal dementia (bvFTD) in some patients. Social cognitive deficits in ALS have been recently described and an impairment was identified on a simple Theory of Mind (ToM) test, which assesses the judgement of the preference of another through direction of eye gaze. The present study further delineated this deficit, by distinguishing between Affective and Cognitive subcomponents, and determining the relationship to behavioural change, levels of empathy and self-awareness. The Cognitive-Affective Judgement of Preference Test was administered to 33 patients with ALS and 26 controls. Furthermore, a comprehensive neuropsychological battery and detailed behavioural assessment, with measures of empathy and awareness, were included. Patients with ALS showed a significant impairment in Affective ToM only when compared with healthy controls, with a deficit in 36% of patients; 12% showed an isolated Affective ToM deficit while 24% showed more generic ToM dysfunction. A Cognitive ToM deficit was found in 27% of patients, with 3% showing an isolated Cognitive ToM deficit. The patients with ALS showed reduced empathy (Fantasy scale) and increased behavioural dysfunction with high levels of apathy. In addition, patients with either an Affective and/or Cognitive ToM deficit exhibited poor self-awareness of their performance and abnormalities on verbal fluency, while those with an Affective ToM deficit also displayed higher levels of apathy and a naming deficit. Dysfunctional ToM is a prominent feature of the cognitive profile of ALS. This specific difficulty in identifying and distinguishing the feelings and thoughts of another from a self-perspective may underpin the social behavioural abnormalities present in some patients with ALS, manifest as apathy and loss of awareness. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Correlation between Forced Vital Capacity and Slow Vital Capacity for the assessment of respiratory involvement in Amyotrophic Lateral Sclerosis: a prospective study.

PubMed

Pinto, Susana; de Carvalho, Mamede

2017-02-01

Slow vital capacity (SVC) and forced vital capacity (FVC) are the most frequent used tests evaluating respiratory function in amyotrophic lateral sclerosis (ALS). No previous study has determined their interchangeability. To evaluate SVC-FVC correlation in ALS. Consecutive definite/probable ALS and primary lateral sclerosis (PLS) patients (2000-2014) in whom respiratory tests were performed at baseline/4-6months later were included. All were evaluated with revised ALS functional rating scale, the ALSFRS respiratory (R-subscore) and bulbar subscores, SVC, FVC, maximal inspiratory (MIP) and expiratory (MEP) pressures. SVC-FVC correlation was analysed by Pearson product-moment correlation test. Paired t-test compared baseline/follow-up values. Multilinear regression analysis modelled the relationship between tested variables. We included 592 ALS (332 men, mean onset age 62.6 ± 11.8 years, mean disease duration 15.4 ± 15 months) and 19 PLS (11 men, median age 54 years, median disease duration 5.5 years) patients. SVC and FVC predicted values decreased 2.15%/month and 2.08%/month, respectively. FVC and SVC were strongly correlated. Both were strongly correlated with MIP and MEP and moderately correlated with R-subscore for the all population and spinal-onset patients, but weakly correlated for bulbar-onset patients. FVC and SVC were strongly correlated and declined similarly. This correlation was preserved in bulbar-onset ALS and in spastic PLS patients.

Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: a systematic review and meta-analysis of individual patient data.

PubMed

2016-05-24

Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are important for malaria elimination efforts. An individual patient clinical data meta-analysis was undertaken to identify the determinants of gametocyte carriage and the comparative effects of four ACTs: artemether-lumefantrine (AL), artesunate/amodiaquine (AS-AQ), artesunate/mefloquine (AS-MQ), and dihydroartemisinin-piperaquine (DP). Factors associated with gametocytaemia prior to, and following, ACT treatment were identified in multivariable logistic or Cox regression analysis with random effects. All relevant studies were identified through a systematic review of PubMed. Risk of bias was evaluated based on study design, methodology, and missing data. The systematic review identified 169 published and 9 unpublished studies, 126 of which were shared with the WorldWide Antimalarial Resistance Network (WWARN) and 121 trials including 48,840 patients were included in the analysis. Prevalence of gametocytaemia by microscopy at enrolment was 12.1 % (5887/48,589), and increased with decreasing age, decreasing asexual parasite density and decreasing haemoglobin concentration, and was higher in patients without fever at presentation. After ACT treatment, gametocytaemia appeared in 1.9 % (95 % CI, 1.7-2.1) of patients. The appearance of gametocytaemia was lowest after AS-MQ and AL and significantly higher after DP (adjusted hazard ratio (AHR), 2.03; 95 % CI, 1.24-3.12; P = 0.005 compared to AL) and AS-AQ fixed dose combination (FDC) (AHR, 4.01; 95 % CI, 2.40-6.72; P < 0.001 compared to AL). Among individuals who had gametocytaemia before treatment, gametocytaemia clearance was significantly faster with AS-MQ (AHR, 1.26; 95 % CI, 1.00-1.60; P = 0.054) and slower with DP (AHR, 0.74; 95 % CI, 0.63-0.88; P = 0.001) compared to AL. Both recrudescent (adjusted odds ratio (AOR), 9.05; 95 % CI, 3.74-21.90; P < 0.001) and new (AOR, 3.03; 95 % CI, 1.66-5.54; P < 0.001) infections with asexual-stage parasites were strongly associated with development of gametocytaemia after day 7. AS-MQ and AL are more effective than DP and AS-AQ FDC in preventing gametocytaemia shortly after treatment, suggesting that the non-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics.

Interhemispheric connectivity in amyotrophic lateral sclerosis: A near-infrared spectroscopy and diffusion tensor imaging study.

PubMed

Kopitzki, Klaus; Oldag, Andreas; Sweeney-Reed, Catherine M; Machts, Judith; Veit, Maria; Kaufmann, Jörn; Hinrichs, Hermann; Heinze, Hans-Jochen; Kollewe, Katja; Petri, Susanne; Mohammadi, Bahram; Dengler, Reinhard; Kupsch, Andreas R; Vielhaber, Stefan

2016-01-01

Aim of the present study was to investigate potential impairment of non-motor areas in amyotrophic lateral sclerosis (ALS) using near-infrared spectroscopy (NIRS) and diffusion tensor imaging (DTI). In particular, we evaluated whether homotopic resting-state functional connectivity (rs-FC) of non-motor associated cortical areas correlates with clinical parameters and disease-specific degeneration of the corpus callosum (CC) in ALS. Interhemispheric homotopic rs-FC was assessed in 31 patients and 30 healthy controls (HCs) for 8 cortical sites, from prefrontal to occipital cortex, using NIRS. DTI was performed in a subgroup of 21 patients. All patients were evaluated for cognitive dysfunction in the executive, memory, and visuospatial domains. ALS patients displayed an altered spatial pattern of correlation between homotopic rs-FC values when compared to HCs ( p  = 0.000013). In patients without executive dysfunction a strong correlation existed between the rate of motor decline and homotopic rs-FC of the anterior temporal lobes (ATLs) (ρ = - 0.85, p  = 0.0004). Furthermore, antero-temporal homotopic rs-FC correlated with fractional anisotropy in the central corpus callosum (CC), corticospinal tracts (CSTs), and forceps minor as determined by DTI ( p  < 0.05). The present study further supports involvement of non-motor areas in ALS. Our results render homotopic rs-FC as assessed by NIRS a potential clinical marker for disease progression rate in ALS patients without executive dysfunction and a potential anatomical marker for ALS-specific degeneration of the CC and CSTs.

Quality of life and psychosocial issues in ventilated patients with amyotrophic lateral sclerosis and their caregivers.

PubMed

Kaub-Wittemer, Dagmar; Steinbüchel, Nicole von; Wasner, Maria; Laier-Groeneveld, Gerhard; Borasio, Gian Domenico

2003-10-01

Non-invasive ventilation (NIV) is an efficient palliative measure for symptoms of chronic hypoventilation in patients with amyotrophic lateral sclerosis (ALS), and can also lengthen survival. A subset of ALS patients undergoes tracheostomy ventilation (TV) for life prolongation. We investigated the quality of life (QOL) and psychosocial situation of 52 home ventilated ALS patients and their caregivers. The battery included sociodemographic, generic, and disease-specific variables, as well as the Profile of Mood States and the Munich Quality of Life Dimensions List. Data were compared between the NIV (n=32) and the TV (n=21) groups. Mean ventilation time was 14 months for NIV and 35 months for TV. Eighty-one percent of TV patients had been tracheotomized without informed consent. The data show a good overall QOL for both NIV and TV patients, but a very high burden of care for TV caregivers, 30% of whom rated their own QOL lower than their patient's QOL. Sexuality was an important issue. Thus, any assessment of QOL in a home palliative care situation should include the primary caregivers.

[Relationship between PMP, FN, vWF and Bleeding Degree in Patients with Acute Leukemia].

PubMed

Wang, Chang-Sheng; Zhao, Lian; Huang, Li-Yun; Yue, Xiao-He

2018-06-01

To detect the serum levels of platelet microparticle (PMP), fibronectin (FN), and von Willebrand Factor (vWF) in acute leukemia (AL) patients with thrombocytopenic and to analyze the relationship of the serum levels of PMP, FN and vWF with bleeding degree. One hundred and one newly diagnosed AL patients from May 2014 to May 2017 were enrolled the AL group. According to the WHO standard of bleeding stratification, 101 AL patients were divided into 5 sub groups: 0, 1, 2, 3 and 4 score groups; 52 normal persons subjected to physical examination were enrolled in control group. The PMP level was detected by flow cytometry; the FN and vWF levels were detected by ELISA. The levels of PMP, FN and vWF were compared between the AL group and the control group. The serum levels of PMP, FN and vWF were compared according to bleeding degree group. The relationship of bleeding degree with the serum levels of PMP, FN and vWF was analyzed. The patients with newly diagnosed acute leukemia aged 18 to 60, and accounted for 61.39%. The degree of bleeding was mainly 1 score, which accounted for 38.61%. The serum levels of PMP, vWF and FN AL groups were significantly higher than those in control group (6.06%±4.38% vs 0.89%±0.50%, 205.82±24.89 vs 58.04±13.35 µg/L, 398.29±46.93 vs 311.37±26.02 µg/L)(P<0.001). The serum levels of PMP, FN and vWF were different among 5 subgroup (P<0.01); the level of PMP and FN were the highest in 0 score group and the lowest in 4 score group; the vWF level was the highest in 4 score groups and the lowest in 0 score group. The bleeding degree in the patients with acute leukemia negatively correlated with PMP level, and positively with NF and vWF levels (r=-0.753, r=0.648, r=0.805). According to the relationship of the bleeding degree with serum levels of PMP, FN, vWF in patients, the detection of PMP, vWF and FN levels can help to evaluale the bleeding degree in the patients.

Prophy-Jet: Effect on Surface Roughness and Plaque Accumulation on Restorative Materials.

DTIC Science & Technology

1986-01-01

prophylaxis on orthodontic patients and caused no significant damage to wires or brackets . They recommended the Prophy-Jet for cleaning of occlusal pits...that, considering the advantages, the Prophy-Jet might be the preferred treatment, especially for orthodontic patients. Mishkin et al.(23) compared the...articles suggested that the Prophy-Jet is quite effective on orthodontic patients(12, 22), a split arch study comparing the gingival health of

The Clinical Presentation and Management of Systemic Light-Chain Amyloidosis in China.

PubMed

Huang, Xiang-Hua; Liu, Zhi-Hong

2016-04-01

Amyloidosis includes a group of diseases characterized by the extracellular deposition of various fibrillary proteins that can autoaggregate in a highly abnormal fibrillary conformation. The amyloid precursor protein of systemic light-chain (AL) amyloidosis is comprised of monoclonal light chains that are due to plasma cell dyscrasia. The clinical presentation of patients with AL amyloidosis varies from patient to patient. Current treatment strategies target the clone in order to decrease the production of the pathologic light chains. Recent advances in therapy have helped many patients with AL amyloidosis achieve hematologic and organ responses. AL amyloidosis is the most common type of systemic amyloidosis in China with increasing morbidity and a high mortality rate. The clinical presentation of AL amyloidosis is variable, and the median overall survival was found to be 36.3 months. The disease prognosis and risk stratification are linked to serialized measurement of cardiac biomarkers and free light chains. The treatment of AL amyloidosis is mainly based on chemotherapy and autologous hematopoietic stem cell transplantation (ASCT). The use of novel agents (thalidomide, lenalidomide, and bortezomib) alone and in combination with steroids and alkylating agents has shown efficacy and continues to be explored. AL amyloidosis is the most common type of systemic amyloidosis in China with increasing morbidity and a high mortality rate. The lack of prospective clinical trials using the current therapies is a challenge for evidence-based decision making concerning the treatment of AL amyloidosis. (1) AL amyloidosis is the most prevalent type of amyloidosis accounting for 65% of the amyloidosis-diagnosed patients in the UK and for 93% of the amyloidosis-diagnosed patients in China. The predisposition of men over women to develop AL amyloidosis might be higher in China than in Western countries (2:1 vs. 1.3:1). Both in the East and West, incidence increases with age. At the time of diagnosis, edema is twice as frequent and the proportion of renal involvement is higher in Chinese compared to Western patients. (2) Melphalan followed by ASCT is the current standard therapy but is restricted to eligible patients. The efficacy and safety of bortezomib combined with dexamethasone were proven in Western patients and recently confirmed in a Chinese cohort. Recent studies in China and the US indicate that bortezomib induction prior to ASCT increases the response rate. Thalidomide and lenalidomide have shown benefit, but toxicity and lack of clinical evidence exclude these agents from first-line therapy. The green tea extract epigallocatechin-3-gallate is under investigation as an inhibitor of AL amyloid formation and a compound that might dissolve amyloid.

Cognitive-behavioral screening reveals prevalent impairment in a large multicenter ALS cohort

PubMed Central

Factor-Litvak, Pam; Goetz, Raymond; Lomen-Hoerth, Catherine; Nagy, Peter L.; Hupf, Jonathan; Singleton, Jessica; Woolley, Susan; Andrews, Howard; Heitzman, Daragh; Bedlack, Richard S.; Katz, Jonathan S.; Barohn, Richard J.; Sorenson, Eric J.; Oskarsson, Björn; Fernandes Filho, J. Americo M.; Kasarskis, Edward J.; Mozaffar, Tahseen; Rollins, Yvonne D.; Nations, Sharon P.; Swenson, Andrea J.; Koczon-Jaremko, Boguslawa A.; Mitsumoto, Hiroshi

2016-01-01

Objectives: To characterize the prevalence of cognitive and behavioral symptoms using a cognitive/behavioral screening battery in a large prospective multicenter study of amyotrophic lateral sclerosis (ALS). Methods: Two hundred seventy-four patients with ALS completed 2 validated cognitive screening tests and 2 validated behavioral interviews with accompanying caregivers. We examined the associations between cognitive and behavioral performance, demographic and clinical data, and C9orf72 mutation data. Results: Based on the ALS Cognitive Behavioral Screen cognitive score, 6.5% of the sample scored below the cutoff score for frontotemporal lobar dementia, 54.2% scored in a range consistent with ALS with mild cognitive impairment, and 39.2% scored in the normal range. The ALS Cognitive Behavioral Screen behavioral subscale identified 16.5% of the sample scoring below the dementia cutoff score, with an additional 14.1% scoring in the ALS behavioral impairment range, and 69.4% scoring in the normal range. Conclusions: This investigation revealed high levels of cognitive and behavioral impairment in patients with ALS within 18 months of symptom onset, comparable to prior investigations. This investigation illustrates the successful use and scientific value of adding a cognitive-behavioral screening tool in studies of motor neuron diseases, to provide neurologists with an efficient method to measure these common deficits and to understand how they relate to key clinical variables, when extensive neuropsychological examinations are unavailable. These tools, developed specifically for patients with motor impairment, may be particularly useful in patient populations with multiple sclerosis and Parkinson disease, who are known to have comorbid cognitive decline. PMID:26802094

Cognitive-behavioral screening reveals prevalent impairment in a large multicenter ALS cohort.

PubMed

Murphy, Jennifer; Factor-Litvak, Pam; Goetz, Raymond; Lomen-Hoerth, Catherine; Nagy, Peter L; Hupf, Jonathan; Singleton, Jessica; Woolley, Susan; Andrews, Howard; Heitzman, Daragh; Bedlack, Richard S; Katz, Jonathan S; Barohn, Richard J; Sorenson, Eric J; Oskarsson, Björn; Fernandes Filho, J Americo M; Kasarskis, Edward J; Mozaffar, Tahseen; Rollins, Yvonne D; Nations, Sharon P; Swenson, Andrea J; Koczon-Jaremko, Boguslawa A; Mitsumoto, Hiroshi

2016-03-01

To characterize the prevalence of cognitive and behavioral symptoms using a cognitive/behavioral screening battery in a large prospective multicenter study of amyotrophic lateral sclerosis (ALS). Two hundred seventy-four patients with ALS completed 2 validated cognitive screening tests and 2 validated behavioral interviews with accompanying caregivers. We examined the associations between cognitive and behavioral performance, demographic and clinical data, and C9orf72 mutation data. Based on the ALS Cognitive Behavioral Screen cognitive score, 6.5% of the sample scored below the cutoff score for frontotemporal lobar dementia, 54.2% scored in a range consistent with ALS with mild cognitive impairment, and 39.2% scored in the normal range. The ALS Cognitive Behavioral Screen behavioral subscale identified 16.5% of the sample scoring below the dementia cutoff score, with an additional 14.1% scoring in the ALS behavioral impairment range, and 69.4% scoring in the normal range. This investigation revealed high levels of cognitive and behavioral impairment in patients with ALS within 18 months of symptom onset, comparable to prior investigations. This investigation illustrates the successful use and scientific value of adding a cognitive-behavioral screening tool in studies of motor neuron diseases, to provide neurologists with an efficient method to measure these common deficits and to understand how they relate to key clinical variables, when extensive neuropsychological examinations are unavailable. These tools, developed specifically for patients with motor impairment, may be particularly useful in patient populations with multiple sclerosis and Parkinson disease, who are known to have comorbid cognitive decline. © 2016 American Academy of Neurology.

Cognitive-behavioral longitudinal assessment in ALS: the Italian Edinburgh Cognitive and Behavioral ALS screen (ECAS).

PubMed

Poletti, Barbara; Solca, Federica; Carelli, Laura; Faini, Andrea; Madotto, Fabiana; Lafronza, Annalisa; Monti, Alessia; Zago, Stefano; Ciammola, Andrea; Ratti, Antonia; Ticozzi, Nicola; Abrahams, Sharon; Silani, Vincenzo

2018-08-01

The study presents data on the longitudinal administration of the Italian Edinburgh Cognitive and Behavioral ALS Screen (ECAS). We investigated cognitive-behavioral performance in a group of ALS patients over time and the feasibility of repeating the ECAS longitudinally compared with standard neuropsychological tests. Finally, correlations between clinical/genetic and cognitive/behavioral data were considered. One hundred and sixty-eight ALS patients were tested at baseline (T 0 ). Among these, 48 patients performed the ECAS after 6 months (T 1 ), 18 patients performed it at T 2 (12 months), and five patients were assessed after 24 months (T 3 ). Participants were also administered two cognitive test (FAB; MoCA) and psychological questionnaires (BDI; STAI/Y). The FBI was carried out with caregivers. No cognitive deterioration was found across follow-ups. In contrast, although scores did not change between T 0 and T 1 , scores improved significantly for ECAS Total/ALS Non-specific and Memory domains when the ECAS was repeated on three occasions (T 0 , T 1 , T 2 ). Apathy/Inertia was the most common behavioral symptom, but no worsening of behavioral scores was detected over time. After 12-24 months, patients were still able to perform the ECAS in total, in contrast to FAB and MoCA, which were only partially administrable. The significant improvement of some ECAS scores over time supports the presence of possible practice effects, particularly in the memory domain, highlighting the need to accommodate for these in longitudinal assessments, through healthy controls groups or alternate versions. This work represents the first Italian ECAS follow-up study and confirms ECAS feasibility in patients with increasing physical disability.

Distal Predominance of Electrodiagnostic Abnormalities in Early Stage Amyotrophic Lateral Sclerosis.

PubMed

Shayya, Luay; Babu, Suma; Pioro, Erik P; Li, Jianbo; Li, Yuebing

2018-05-09

We compare the electrodiagnostic (EDX) yield of limb muscles in revealing lower motor neuron (LMN) dysfunction by electromyography (EMG) in early stage amyotrophic lateral sclerosis (ALS). Single-site retrospective review Results: This study includes 122 consecutive patients with possible ALS as defined by revised El Escorial Criteria. Distal limb muscles show more frequent EMG abnormalities than proximal muscles. EDX yield is higher in the limb where weakness begins and when clinical signs of LMN dysfunction are evident. Adoption of Awaji criteria increases the yield of EMG positive segments significantly in the cervical (p<0.0005) and lumbosacral regions (P<0.0001), and upgrades 19 patients into probable and 1 patient into definite categories. Electromyographic abnormalities are distal limb-predominant in early stage ALS. A redefinition of an EDX-positive cervical or lumbosacral segment, with an emphasis on distal limb muscles, may result in an earlier ALS diagnosis. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Increased cerebrospinal fluid levels of cytokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1β (MIP-1β) in patients with amyotrophic lateral sclerosis.

PubMed

Martínez, H R; Escamilla-Ocañas, C E; Camara-Lemarroy, C R; González-Garza, M T; Moreno-Cuevas, J; García Sarreón, M A

2017-10-10

Neuroinflammation has recently been described in amyotrophic lateral sclerosis (ALS). However, the precise role of such proinflammatory cytokines as monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1β (MIP-1β) in ALS has not yet been determined. In this study, we determined cerebrospinal fluid (CSF) MCP-1 and MIP-1β levels and assessed their association with the duration and severity of ALS. Concentrations of MCP-1 and MIP-1β were determined in the CSF of 77 patients diagnosed with ALS and 13 controls. Cytokine levels were analysed in relation to ALS duration (<12months vs. >12months) and severity (<30points vs. >30points on the ALS Functional Rating Scale administered at hospital admission). Higher CSF MIP-1β (10.68pg/mL vs. 4.69pg/mL, P<.0001) and MCP-1 (234.89pg/mL vs. 160.95pg/mL, P=.011) levels were found in the 77 patients with ALS compared to controls. There were no differences in levels of either cytokine in relation to disease duration or severity. However, we did observe a significant positive correlation between MIP-1β and MCP-1 in patients with ALS. The increase in MIP-1β and MCP-1 levels suggests that these cytokines may have a synergistic effect on ALS pathogenesis. However, in our cohort, no association was found with either the duration or the clinical severity of the disease. Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Investigation of C9orf72 in 4 Neurodegenerative Disorders

PubMed Central

Xi, Zhengrui; Zinman, Lorne; Grinberg, Yakov; Moreno, Danielle; Sato, Christine; Bilbao, Juan M.; Ghani, Mahdi; Hernández, Isabel; Ruiz, Agustín; Boada, Mercè; Morón, Francisco J.; Lang, Anthony E.; Marras, Connie; Bruni, Amalia; Colao, Rosanna; Maletta, Raffaele G.; Puccio, Gianfranco; Rainero, Innocenzo; Pinessi, Lorenzo; Galimberti, Daniela; Morrison, Karen E.; Moorby, Catriona; Stockton, Joanne D.; Masellis, Mario; Black, Sandra E.; Hazrati, Lili-Naz; Liang, Yan; van Haersma de With, Jan; Fornazzari, Luis; Villagra, Roque; Rojas-Garcia, Ricardo; Clarimón, Jordi; Mayeux, Richard; Robertson, Janice; St George-Hyslop, Peter; Rogaeva, Ekaterina

2014-01-01

Objective To estimate the allele frequency of C9orf72 (G4C2) repeats in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer disease (AD), and Parkinson disease (PD). Design The number of repeats was estimated by a 2-step genotyping strategy. For expansion carriers, we sequenced the repeat flanking regions and obtained APOE genotypes and MAPT H1/H2 haplotypes. Setting Hospitals specializing in neurodegenerative disorders. Subjects We analyzed 520 patients with FTLD, 389 patients with ALS, 424 patients with AD, 289 patients with PD, 602 controls, 18 families, and 29 patients with PD with the LRRK2 G2019S mutation. Main Outcome Measure The expansion frequency. Results Based on a prior cutoff (>30 repeats), the expansion was detected in 9.3% of patients with ALS, 5.2% of patients with FTLD, and 0.7% of patients with PD but not in controls or patients with AD. It was significantly associated with family history of ALS or FTLD and age at onset of FTLD. Phenotype variation (ALS vs FTLD) was not associated with MAPT, APOE, or variability in the repeat flanking regions. Two patients with PD were carriers of 39 and 32 repeats with questionable pathological significance, since the 39-repeat allele does not segregate with PD. No expansion or intermediate alleles (20–29 repeats) were found among the G2019S carriers and AD cases with TAR DNA-binding protein 43–positive inclusions. Surprisingly, the frequency of the 10-repeat allele was marginally increased in all 4 neurodegenerative diseases compared with controls, indicating the presence of an unknown risk variation in the C9orf72 locus. Conclusions The C9orf72 expansion is a common cause of ALS and FTLD, but not of AD or PD. Our study raises concern about a reliable cutoff for the pathological repeat number, which is important in the utility of genetic screening. PMID:22964832

Auto-SCT improves survival in systemic light chain amyloidosis: a retrospective analysis with 14-year follow-up.

PubMed

Parmar, S; Kongtim, P; Champlin, R; Dinh, Y; Elgharably, Y; Wang, M; Bashir, Q; Shah, J J; Shah, N; Popat, U; Giralt, S A; Orlowski, R Z; Qazilbash, M H

2014-08-01

Optimal treatment approach continues to remain a challenge for systemic light chain amyloidosis (AL). So far, Auto-SCT is the only modality associated with long-term survival. However, failure to show survival benefit in randomized study raises questions regarding its efficacy. We present a comparative outcome analysis of Auto-SCT to conventional therapies (CTR) in AL patients treated over a 14-year period at our institution. Out of the 145 AL amyloidosis patients, Auto-SCT was performed in 80 patients with 1-year non-relapse mortality rate of 12.5%. Novel agents were used as part of induction therapy in 56% of transplant recipients vs 46% of CTR patients. Hematological and organ responses were seen in 74.6% and 39% in the Auto-SCT arm vs 53% and 12% in the CTR arm, respectively. The projected 5-year survival for Auto-SCT vs CTR was 63% vs 38%, respectively. Landmark analysis of patients alive at 1-year after diagnosis showed improved 5-year OS of 72% with Auto-SCT vs 65% in the CTR arm. In the multivariate analysis, age <60 years, induction therapy with novel agents, kidney only involvement and Auto-SCT were associated with improved survival. In conclusion, Auto-SCT is associated with long-term survival for patients with AL amyloidosis.

Addition of cyclophosphamide and higher doses of dexamethasone do not improve outcomes of patients with AL amyloidosis treated with bortezomib.

PubMed

Kastritis, E; Gavriatopoulou, M; Roussou, M; Fotiou, D; Ziogas, D C; Migkou, M; Eleutherakis-Papaiakovou, E; Panagiotidis, I; Kanellias, N; Psimenou, E; Papadopoulou, E; Pamboucas, C; Manios, E; Gakiopoulou, H; Ntalianis, A; Tasidou, A; Giannouli, S; Terpos, E; Dimopoulos, M A

2017-06-16

Bortezomib, in combination with dexamethasone (VD) or with the addition of cyclophosphamide (VCD), is highly effective in patients with amyloid light-chain (AL) amyloidosis. Currently, VCD is considered as a primary regimen for patients with AL, but it is not clear whether the addition of cyclophosphamide to VD further and significantly improves efficacy, given the substantial activity of bortezomib itself. We retrospectively compared the outcomes of 101 patients with AL amyloidosis who received VD (n=59) or VCD (n=42) in two consecutive periods. Early mortality after adjustment for Mayo stage was similar. On intent to treat, a hematologic response rate was 68% for patients treated with VD and 78% for VCD (P=0.26), while complete response+very good partial response (CR+VGPR) rate was 47.5% and 35%, respectively. Higher doses of dexamethasone or twice-weekly bortezomib were not associated with significantly higher CR+VGPR rates. Organ responses occurred in similar rates between the two groups. Median survival was similar (33 vs 36 months, P=0.45) even after adjustment for Mayo stage and dose and schedule of bortezomib and dexamethasone. In conclusion, bortezomib even with low doses of dexamethasone is effective for the treatment of AL amyloidosis; higher doses of dexamethasone and addition of cyclophosphamide do not seem to have a profound effect on efficacy and survival.

Comparison of optical coherence tomography findings and visual field changes in patients with primary open-angle glaucoma and amyotrophic lateral sclerosis.

PubMed

Liu, Ziyuan; Wang, Hongli; Fan, Dongsheng; Wang, Wei

2018-02-01

Recent studies revealing genetic connection of primary open angle glaucoma (POAG) and amyotrophic lateral sclerosis (ALS) have received particular attention. Exploring the evidence for common pathogenesis of these two progressive neurological disorders may assist in understanding the mechanism and searching for new treatment. Retinal nerve fiber layer (RNFL) defect and corresponding visual field (VF) impairment are well known neuropathy signs in glaucoma. In our study, thickness of certain retinal layer in ALS patients was analyzed to detect ganglion cell's soma and axon, and for first time visual field was examined for ALS. The correlation of retinal involvement and ALS progression were also investigated. The results were compared with those of POAG. The study may provide new knowledge for these two neurodegenerative diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study.

PubMed

Byrne, Susan; Elamin, Marwa; Bede, Peter; Shatunov, Aleksey; Walsh, Cathal; Corr, Bernie; Heverin, Mark; Jordan, Norah; Kenna, Kevin; Lynch, Catherine; McLaughlin, Russell L; Iyer, Parameswaran Mahadeva; O'Brien, Caoimhe; Phukan, Julie; Wynne, Brona; Bokde, Arun L; Bradley, Daniel G; Pender, Niall; Al-Chalabi, Ammar; Hardiman, Orla

2012-03-01

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons, associated with frontotemporal dementia (FTD) in about 14% of incident cases. We assessed the frequency of the recently identified C9orf72 repeat expansion in familial and apparently sporadic cases of ALS and characterised the cognitive and clinical phenotype of patients with this expansion. A population-based register of patients with ALS has been in operation in Ireland since 1995, and an associated DNA bank has been in place since 1999. 435 representative DNA samples from the bank were screened using repeat-primed PCR for the presence of a GGGGCC repeat expansion in C9orf72. We assessed clinical, cognitive, behavioural, MRI, and survival data from 191 (44%) of these patients, who comprised a population-based incident group and had previously participated in a longitudinal study of cognitive and behavioural changes in ALS. Samples from the DNA bank included 49 cases of known familial ALS and 386 apparently sporadic cases. Of these samples, 20 (41%) cases of familial ALS and 19 (5%) cases of apparently sporadic ALS had the C9orf72 repeat expansion. Of the 191 patients for whom phenotype data were available, 21 (11%) had the repeat expansion. Age at disease onset was lower in patients with the repeat expansion (mean 56·3 [SD 8·3] years) than in those without (61·3 [10·6] years; p=0·043). A family history of ALS or FTD was present in 18 (86%) of those with the repeat expansion. Patients with the repeat expansion had significantly more co-morbid FTD than patients without the repeat (50%vs 12%), and a distinct pattern of non-motor cortex changes on high-resolution 3 T magnetic resonance structural neuroimaging. Age-matched univariate analysis showed shorter survival (20 months vs 26 months) in patients with the repeat expansion. Multivariable analysis showed an increased hazard rate of 1·9 (95% 1·1-3·7; p=0·035) in those patients with the repeat expansion compared with patients without the expansion Patients with ALS and the C9orf72 repeat expansion seem to present a recognisable phenotype characterised by earlier disease onset, the presence of cognitive and behavioural impairment, specific neuroimaging changes, a family history of neurodegeneration with autosomal dominant inheritance, and reduced survival. Recognition of patients with ALS who carry an expanded repeat is likely to be important in the context of appropriate disease management, stratification in clinical trials, and in recognition of other related phenotypes in family members. Health Seventh Framework Programme, Health Research Board, Research Motor Neuron, Irish Motor Neuron Disease Association, The Motor Neurone Disease Association of Great Britain and Northern Ireland, ALS Association. Copyright © 2012 Elsevier Ltd. All rights reserved.

Cognitive and physiological dissociations in response to emotional pictures in patients with anorexia.

PubMed

Nandrino, Jean-Louis; Berna, Guillaume; Hot, Pascal; Dodin, Vincent; Latrée, Julie; Decharles, Sandra; Sequeira, Henrique

2012-01-01

Recent studies suggest that patients with anorexia may express dissociated cognitive and physiological reactivities to emotional stimuli. The present research aimed to compare subjective and autonomic responses to pleasant, unpleasant and neutral scenes during a categorization task and an activation rating task in anorexic (AN), alexithymic (AL), depressed (DEP) and control participants (CONT). The participants first categorized pictures according to their emotional valence, followed by a rating of their activation level, concomitant with the recording of skin conductance responses (SCRs). Main findings showed that the AN patients presented major difficulty in categorizing pictures, particularly neutral ones. Contrary to the AL participants, this difficulty did not induce significant increases of SCR amplitude in the AN patients. In the second task, the AN patients rated the intensity of activation of unpleasant pictures higher than the AL participants and that of pleasant ones higher than the AL and CONT participants. In addition, no significant linear correlation was observed between the intensity of activation ratings and SCR amplitude in the AN, AL or DEP participants contrarily to what was observed for control participants. This lack of relation suggests a non-specific disconnection between physiological and cognitive self-reported responses to emotional stimuli. Our results highlight a specific form of emotional processing in the AN patients distinct from that observed in alexithymia or depression and characterized by a dissociation between cognitive and physiological responses. This kind of disconnection could be associated with emotional regulation processes and may benefit the AN patients by lowering the psychological stress response. Copyright © 2011 Elsevier Inc. All rights reserved.

Senile Systemic Amyloidosis: Clinical Features at Presentation and Outcome

PubMed Central

Pinney, Jennifer H.; Whelan, Carol J.; Petrie, Aviva; Dungu, Jason; Banypersad, Sanjay M.; Sattianayagam, Prayman; Wechalekar, Ashutosh; Gibbs, Simon D. J.; Venner, Christopher P.; Wassef, Nancy; McCarthy, Carolyn A.; Gilbertson, Janet A.; Rowczenio, Dorota; Hawkins, Philip N.; Gillmore, Julian D.; Lachmann, Helen J.

2013-01-01

Background Cardiac amyloidosis is a fatal disease whose prognosis and treatment rely on identification of the amyloid type. In our aging population transthyretin amyloidosis (ATTRwt) is common and must be differentiated from other amyloid types. We report the clinical presentation, natural history, and prognostic features of ATTRwt compared with cardiac‐isolated AL amyloidosis and calculate the probability of disease diagnosis of ATTRwt from baseline factors. Methods and Results All patients with biopsy‐proven ATTRwt (102 cases) and isolated cardiac AL (36 cases) seen from 2002 to 2011 at the UK National Amyloidosis Center were included. Median survival from the onset of symptoms was 6.07 years in the ATTRwt group and 1.7 years in the AL group. Positive troponin, a pacemaker, and increasing New York Heart Association (NYHA) class were associated with worse survival in ATTRwt patients on univariate analysis. All patients with isolated cardiac AL and 24.1% of patients with ATTRwt had evidence of a plasma cell dyscrasia. Older age and lower N‐terminal pro‐B‐type natriuretic peptide (NT pro‐BNP) were factors significantly associated with ATTRwt. Patients aged 70 years and younger with an NT pro‐BNP <183 pmol/L were more likely to have ATTRwt, as were patients older than 70 years with an NT pro‐BNP <1420 pmol/L. Conclusions Factors at baseline associated with a worse outcome in ATTRwt are positive troponin T, a pacemaker, and NYHA class IV symptoms. The age of the patient at diagnosis and NT pro‐BNP level can aid in distinguishing ATTRwt from AL amyloidosis. PMID:23608605

Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group.

PubMed

Lai, E C; Felice, K J; Festoff, B W; Gawel, M J; Gelinas, D F; Kratz, R; Murphy, M F; Natter, H M; Norris, F H; Rudnicki, S A

1997-12-01

The objective of this study was to investigate the safety and efficacy of recombinant human insulinlike growth factor-I (rhIGF-I) in the treatment of sporadic ALS. A double-blind, placebo-controlled, randomized study of 266 patients was conducted at eight centers in North America. Placebo or rhIGF-I (0.05 mg/kg/day or 0.10 mg/kg/day) was administered for 9 months. The primary outcome measure was disease symptom progression, assessed by the rate of change (per patient slope) in the Appel ALS rating scale total score. The Sickness Impact Profile (SIP), a patient-perceived, health-related quality of life assessment, was a secondary outcome variable. Progression of functional impairment in patients receiving high-dose (0.10 mg/kg/day) rhIGF-I was 26% slower than in patients receiving placebo (p = 0.01). The high-dose treatment group was less likely to terminate the study due to protocol-defined markers of disease symptom progression, and members in this group exhibited a slower decline in quality of life, as assessed by the SIP. Patients receiving 0.05 mg/kg/day of rhIGF-I exhibited trends similar to those associated with high-dose treatment, suggesting a dose-dependent response. The incidence of clinically significant adverse experiences was comparable among the three treatment groups. Recombinant human insulin-like growth factor-I slowed the progression of functional impairment and the decline in health-related quality of life in patients with ALS with no medically important adverse effects.

A Phase 3, Double-Blind, Randomized Study of Arterolane Maleate-Piperaquine Phosphate vs Artemether-Lumefantrine for Falciparum Malaria in Adolescent and Adult Patients in Asia and Africa.

PubMed

Toure, Offianan Andre; Valecha, Neena; Tshefu, Antoinette K; Thompson, Ricardo; Krudsood, Srivicha; Gaye, Oumar; Rao, Bappanaidu Hoigegudde Krishnamurthy; Sagara, Issaka; Bose, Tarit Kumar; Mohanty, Sanjib; Rao, Ballamudi Srinivas; Anvikar, Anupkumar R; Mwapasa, Victor; Noedl, Harald; Arora, Sudershan; Roy, Arjun; Iyer, Sunil S; Sharma, Pradeep; Saha, Nilanjan; Jalali, Rajinder K; Tiacoh, Landry; Enosse, Sonia; Tangpukdee, Noppadon; Kokolomami, Jack; Ndiaye, Jean-Louis; Rao, Deepak; Yumva, Ntamabyaliro Nsengi; Sidibe, Bouran; Mohanty, Rajesh; Jha, A C; Nyirenda, Mulinda; Starzengruber, Peter; Swoboda, Paul

2016-04-15

Artemisinins, which are derived from plants, are subject to risk of supply interruption due to climatic changes. Consequently, an effort to identify a new synthetic antimalarial was initiated. A fixed-dose combination of arterolane maleate (AM), a new synthetic trioxolane, with piperaquine phosphate (PQP), a long half-life bisquinoline, was evaluated in patients with uncomplicatedPlasmodium falciparummalaria. In this multicenter, randomized, double-blind, comparative, parallel-group trial, 1072 patients aged 12-65 years withP. falciparummonoinfection received either AM-PQP (714 patients) once daily or artemether-lumefantrine (A-L; 358 patients) twice daily for 3 days. All patients were followed up until day 42. Of the 714 patients in the AM-PQP group, 638 (89.4%) completed the study; of the 358 patients in the A-L group, 301(84.1%) completed the study. In both groups, the polymerase chain reaction corrected adequate clinical and parasitological response (PCR-corrected ACPR) on day 28 in intent-to-treat (ITT) and per-protocol (PP) populations was 92.86% and 92.46% and 99.25% and 99.07%, respectively. The corresponding figures on day 42 in the ITT and PP populations were 90.48% and 91.34%, respectively. After adjusting for survival ITT, the PCR-corrected ACPR on day 42 was >98% in both groups. The overall incidence of adverse events was comparable. AM-PQP showed comparable efficacy and safety to A-L in the treatment of uncomplicatedP. falciparummalaria in adolescent and adult patients. AM-PQP demonstrated high clinical and parasitological response rates as well as rapid parasite clearance. India. CTRI/2009/091/000101. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Cardiac Amyloid Load: A Prognostic and Predictive Biomarker in Patients With Light-Chain Amyloidosis.

PubMed

Kristen, Arnt V; Brokbals, Eva; Aus dem Siepen, Fabian; Bauer, Ralf; Hein, Selina; Aurich, Matthias; Riffel, Johannes; Behrens, Hans-Michael; Krüger, Sandra; Schirmacher, Peter; Katus, Hugo A; Röcken, Christoph

2016-07-05

Cardiac amyloid load has not been analyzed for its effect on mortality in patients with amyloid light-chain (AL) cardiac amyloidosis. This study retrospectively compared histological amyloid load with common clinical predictors of mortality. This study assessed 216 patients with histologically confirmed cardiac amyloidosis at a single center with electrocardiography, echocardiography, and laboratory testing. AL amyloid deposits were usually distributed in a reticular/pericellular pattern, whereas transthyretin amyloid (ATTR) more commonly showed patchy deposits. Median amyloid load was 30.5%; no amyloid load was above 70%. During follow-up (median 19.1 months), 112 patients died. Chemotherapy had a significant effect on overall survival in AL amyloidosis (16.2 months vs. 1.4 months; p = 0.003). Patients with <20% AL amyloid load who responded to chemotherapy showed significantly better survival than nonresponders. According to univariate analysis, predictors of survival in AL amyloidosis included sex, Karnofsky index, New York Heart Association (NYHA) functional class, diastolic blood pressure, estimated glomerular filtration rate, N-terminal pro-B-type natriuretic peptide, mineralocorticoid receptor antagonists, low voltage, ineligibility for chemotherapy, response to chemotherapy, and amyloid load. Independent predictors of mortality by multivariate analysis included NYHA functional class (III vs. II), estimated glomerular filtration rate, responders to chemotherapy, and amyloid load. In ATTR amyloidosis, survival correlated with NYHA functional class, diastolic blood pressure, and use of diuretic agents. Following Cox regression analysis, NYHA functional class (III vs. II; p < 0.05) remained the only independent predictor of patient survival in ATTR amyloidosis. Early identification of subjects with AL amyloid is essential given that in late-stage disease with extensive amyloid load, our data suggested that outcomes are not affected by administration of chemotherapy. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

A Behavioral Test of Accepting Benefits that Cost Others: Associations with Conduct Problems and Callous-Unemotionality

PubMed Central

Sakai, Joseph T.; Dalwani, Manish S.; Gelhorn, Heather L.; Mikulich-Gilbertson, Susan K.; Crowley, Thomas J.

2012-01-01

Background Youth with conduct problems (CP) often make decisions which value self-interest over the interests of others. Self-benefiting behavior despite loss to others is especially common among youth with CP and callous-unemotional traits (CU). Such behavioral tendencies are generally measured using self- or observer-report. We are unaware of attempts to measure this tendency with a behavioral paradigm. Methods/Principal Findings In our AlAn's (altruism-antisocial) game a computer program presents subjects with a series of offers in which they will receive money but a planned actual charity donation will be reduced; subjects decide to accept or reject each offer. We tested (1) whether adolescent patients with CP (n = 20) compared with adolescent controls (n = 19) differed on AlAn's game outcomes, (2) whether youths with CP and CU differed significantly from controls without CP or CU, and (3) whether AlAn's game outcomes correlated significantly with CP and separately, CU severity. Patients with CP and CU compared with controls without these problems took significantly more money for themselves and left significantly less money in the charity donation; AlAn's game outcomes were significantly correlated with CU, but not CP. Conclusions/Significance In the AlAn's game adolescents with conduct problems and CU traits, compared with controls without CP/CU, are disposed to benefit themselves while costing others even in a novel situation, devoid of peer influences, where anonymity is assured, reciprocity or retribution are impossible, intoxication is absent and when the “other” to be harmed is considered beneficent. AlAn's game outcomes are associated with measures of CU. Results suggest that the AlAn's game provides an objective means of capturing information about CU traits. The AlAn's game, which was designed for future use in the MRI environment, may be used in studies attempting to identify the neural correlates of self-benefiting decision-making. PMID:22558367

Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial.

PubMed

Aggarwal, Swati P; Zinman, Lorne; Simpson, Elizabeth; McKinley, Jane; Jackson, Katherine E; Pinto, Hanika; Kaufman, Petra; Conwit, Robin A; Schoenfeld, David; Shefner, Jeremy; Cudkowicz, Merit

2010-05-01

In a pilot study, lithium treatment slowed progression of amyotrophic lateral sclerosis (ALS). We aimed to confirm or disprove these findings by assessing the safety and efficacy of lithium in combination with riluzole in patients with ALS. We did a double-blind, placebo-controlled trial with a time-to-event design. Between January and June, 2009, patients with ALS who were taking a stable dose of riluzole for at least 30 days were randomly assigned (1:1) by a centralised computer to receive either lithium or placebo. Patients, caregivers, investigators, and all site study staff with the exception of site pharmacists were masked to treatment assignment. The primary endpoint was the time to an event, defined as a decrease of at least six points on the revised ALS functional rating scale score or death. Interim analyses were planned for when 84 patients had been allocated treatment, 6 months later or after 55 events, and after 100 events. Analysis was by intention to treat. The stopping boundary for futility at the first interim analysis was a p value of at least 0.68. We used a log-rank test to compare the distributions of the time to an event between the lithium and placebo groups. This trial is registered with ClinicalTrials.gov, NCT00818389. At the first interim analysis, 22 of 40 patients in the lithium group had an event compared with 20 of 44 patients in the placebo group (log rank p=0.51). The hazard ratio of reaching the primary endpoint was 1.13 (95% CI 0.61-2.07). The study was stopped at the first interim analysis because criterion for futility was met (p=0.78). The difference in mean decline in the ALS functional rating scale score between the lithium group and the placebo group was 0.15 (95% CI -0.43 to 0.73, p=0.61). There were no major safety concerns. Falls (p=0.04) and back pain (p=0.05) were more common in the lithium group than in the placebo group. We found no evidence that lithium in combination with riluzole slows progression of ALS more than riluzole alone. The time-to-event endpoint and use of prespecified interim analyses enabled a clear result to be obtained rapidly. This design should be considered for future trials testing the therapeutic efficacy of drugs that are easily accessible to people with ALS. National Institute of Neurological Disorders and Stroke, ALS Association, and ALS Society of Canada. Copyright 2010 Elsevier Ltd. All rights reserved.

OPTN 691_692insAG is a founder mutation causing recessive ALS and increased risk in heterozygotes

PubMed Central

Goldstein, Orly; Nayshool, Omri; Nefussy, Beatrice; Traynor, Bryan J.; Renton, Alan E.; Gana-Weisz, Mali; Drory, Vivian E.

2016-01-01

Objective: To detect genetic variants underlying familial and sporadic amyotrophic lateral sclerosis (ALS). Methods: We analyzed 2 founder Jewish populations of Moroccan and Ashkenazi origins and ethnic matched controls. Exome sequencing of 2 sisters with ALS from Morocco was followed by genotyping the identified causative null mutation in 379 unrelated patients with ALS and 1,000 controls. The shared risk haplotype was characterized using whole-genome single nucleotide polymorphism array. Results: We identified 5 unrelated patients with ALS homozygous for the null 691_692insAG mutation in the optineurin gene (OPTN), accounting for 5.8% of ALS of Moroccan origin and 0.3% of Ashkenazi. We also identified a high frequency of heterozygous carriers among patients with ALS, 8.7% and 2.9%, respectively, compared to 0.75% and 1.0% in controls. The risk of carriers for ALS was significantly increased, with odds ratio of 13.46 and 2.97 in Moroccan and Ashkenazi Jews, respectively. We determined that 691_692insAG is a founder mutation in the tested populations with a minimal risk haplotype of 58.5 Kb, encompassing the entire OPTN gene. Conclusions: Our data show that OPTN 691_692insAG mutation is a founder mutation in Moroccan and Ashkenazi Jews. This mutation causes autosomal recessive ALS and significantly increases the risk to develop the disease in heterozygous carriers, suggesting both a recessive mode of inheritance and a dominant with incomplete penetrance. These data emphasize the important role of OPTN in ALS pathogenesis, and demonstrate the complex genetics of ALS, as the same mutation leads to different phenotypes and appears in 2 patterns of inheritance. PMID:26740678

Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis.

PubMed

Fogh, Isabella; Lin, Kuang; Tiloca, Cinzia; Rooney, James; Gellera, Cinzia; Diekstra, Frank P; Ratti, Antonia; Shatunov, Aleksey; van Es, Michael A; Proitsi, Petroula; Jones, Ashley; Sproviero, William; Chiò, Adriano; McLaughlin, Russell Lewis; Sorarù, Gianni; Corrado, Lucia; Stahl, Daniel; Del Bo, Roberto; Cereda, Cristina; Castellotti, Barbara; Glass, Jonathan D; Newhouse, Steven; Dobson, Richard; Smith, Bradley N; Topp, Simon; van Rheenen, Wouter; Meininger, Vincent; Melki, Judith; Morrison, Karen E; Shaw, Pamela J; Leigh, P Nigel; Andersen, Peter M; Comi, Giacomo P; Ticozzi, Nicola; Mazzini, Letizia; D'Alfonso, Sandra; Traynor, Bryan J; Van Damme, Philip; Robberecht, Wim; Brown, Robert H; Landers, John E; Hardiman, Orla; Lewis, Cathryn M; van den Berg, Leonard H; Shaw, Christopher E; Veldink, Jan H; Silani, Vincenzo; Al-Chalabi, Ammar; Powell, John

2016-07-01

Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset. To identify gene variants influencing survival in ALS. This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015. Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed by meta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis. Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 × 10-9) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 × 10-8). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38-1.89; P = 1.87 × 10-9), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208 CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11-1.24; P = 3.53 × 10-8), corresponding to a 4-month reduction in survival compared with TT carriers. This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival.

Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis

PubMed Central

Fogh, Isabella; Lin, Kuang; Tiloca, Cinzia; Rooney, James; Gellera, Cinzia; Diekstra, Frank P.; Ratti, Antonia; Shatunov, Aleksey; van Es, Michael A.; Proitsi, Petroula; Jones, Ashley; Sproviero, William; Chiò, Adriano; McLaughlin, Russell Lewis; Sorarù, Gianni; Corrado, Lucia; Stahl, Daniel; Bo, Roberto Del; Cereda, Cristina; Castellotti, Barbara; Glass, Jonathan D.; Newhouse, Steven; Dobson, Richard; Smith, Bradley N.; Topp, Simon; van Rheenen, Wouter; Meininger, Vincent; Melki, Judith; Morrison, Karen E.; Shaw, Pamela J.; Leigh, P. Nigel; Andersen, Peter M.; Comi, Giacomo P.; Ticozzi, Nicola; Mazzini, Letizia; D’Alfonso, Sandra; Traynor, Bryan J.; Van Damme, Philip; Robberecht, Wim; Brown, Robert H.; Landers, John E.; Hardiman, Orla; Lewis, Cathryn M.; van den Berg, Leonard H.; Shaw, Christopher E.; Veldink, Jan H.; Silani, Vincenzo; Al-Chalabi, Ammar; Powell, John

2017-01-01

IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset. OBJECTIVE To identify gene variants influencing survival in ALS. DESIGN, SETTING, AND PARTICIPANTS This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015. MAIN OUTCOMES AND MEASURES Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed by meta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis. RESULTS Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 × 10−9) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 × 10−8). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38–1.89; P = 1.87 × 10−9), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208 CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11–1.24; P = 3.53 × 10−8), corresponding to a 4-month reduction in survival compared with TT carriers. CONCLUSIONS AND RELEVANCE This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival. PMID:27244217

Diagnostic and prognostic significance of neurofilament light chain NF-L, but not progranulin and S100B, in the course of amyotrophic lateral sclerosis: Data from the German MND-net.

PubMed

Steinacker, Petra; Huss, André; Mayer, Benjamin; Grehl, Torsten; Grosskreutz, Julian; Borck, Guntram; Kuhle, Jens; Lulé, Dorothée; Meyer, Thomas; Oeckl, Patrick; Petri, Susanne; Weishaupt, Jochen; Ludolph, Albert C; Otto, Markus

2017-02-01

There is a need for diagnostic, prognostic, and monitoring blood biomarkers for ALS. We aimed to analyse and compare proposed candidate markers for disease progression in the course of ALS. Blood samples were taken from 125 ALS patients, including nine patients with C9orf72 or SOD1 mutation, at regular intervals of six months. ALS patients were characterized by the ALS functional rating scale (ALSFRS-R) and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). We quantified neurofilament light chain (NF-L), S100B, and progranulin (PGRN) and analysed it in relation to disease progression. Results showed that, at baseline, serum concentrations of NF-L but not PGRN or S100B discriminated significantly between ALS and controls. Within 24 months follow-up the marker concentrations remained stable. Baseline serum NF-L levels correlated with survival time, which was confirmed in subgroups with fast, intermediate, and slow disease progression and there was a weak association with disease duration. For S100B and PGRN we found an association with ALSFRS-R score changes and a trend for decreased levels in the fast progressor subgroup. In conclusion, serum NF-L in any ALS disease stage is a promising marker to support diagnosis and predict outcome, while serum PGRN and S100B are only of minor prognostic value.

Repeat expansion in C9ORF72 is not a major cause of amyotrophic lateral sclerosis among Iranian patients.

PubMed

Alavi, Afagh; Nafissi, Shahriar; Rohani, Mohammad; Shahidi, Gholamali; Zamani, Babak; Shamshiri, Hosein; Safari, Iman; Elahi, Elahe

2014-01-01

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in populations of European descent. It was recently found that a hexanucleotide repeat expansion in C9ORF72 is its most common cause in these populations. The contribution of C9ORF72 to ALS is notably lower in the Far East, but its role in other populations is unknown. Results of C9ORF72 screening in 78 unrelated Iranian ALS patients are reported here. The repeat expansion was observed in only 1 (5.9%) of the familial and 1 (1.6%) of the sporadic cases. These figures are to be compared, respectively, with 30% and 6.9% among patients of European ethnicity. Screenings of C9ORF72 in other Middle East countries will reveal whether the low contribution of C9ORF72 to ALS is a feature of the entire region. During the screenings, it was noted that in a single family, 3 individuals affected with ALS, Parkinson's disease, or frontotemporal dementia all carried the repeat expansion. The finding suggests the mutation does rarely contribute to the etiology of Parkinson's disease. Copyright © 2014 Elsevier Inc. All rights reserved.

An enhanced biometric-based authentication scheme for telecare medicine information systems using elliptic curve cryptosystem.

PubMed

Lu, Yanrong; Li, Lixiang; Peng, Haipeng; Yang, Yixian

2015-03-01

The telecare medical information systems (TMISs) enable patients to conveniently enjoy telecare services at home. The protection of patient's privacy is a key issue due to the openness of communication environment. Authentication as a typical approach is adopted to guarantee confidential and authorized interaction between the patient and remote server. In order to achieve the goals, numerous remote authentication schemes based on cryptography have been presented. Recently, Arshad et al. (J Med Syst 38(12): 2014) presented a secure and efficient three-factor authenticated key exchange scheme to remedy the weaknesses of Tan et al.'s scheme (J Med Syst 38(3): 2014). In this paper, we found that once a successful off-line password attack that results in an adversary could impersonate any user of the system in Arshad et al.'s scheme. In order to thwart these security attacks, an enhanced biometric and smart card based remote authentication scheme for TMISs is proposed. In addition, the BAN logic is applied to demonstrate the completeness of the enhanced scheme. Security and performance analyses show that our enhanced scheme satisfies more security properties and less computational cost compared with previously proposed schemes.

Serum C-Reactive Protein as a Prognostic Biomarker in Amyotrophic Lateral Sclerosis

PubMed Central

Lizio, Andrea; Maestri, Eleonora; Sansone, Valeria Ada; Mora, Gabriele; Miller, Robert G.; Appel, Stanley H.; Chiò, Adriano

2017-01-01

Importance Various factors have been proposed as possible candidates associated with the prognosis of amyotrophic lateral sclerosis (ALS); however, there is still no consensus on which biomarkers are reliable prognostic factors. C-reactive protein (CRP) is a biomarker of the inflammatory response that shows significant prognostic value for several diseases. Objective To examine the prognostic significance of CRP in ALS. Design, Setting, and Participants Patients’ serum CRP levels were evaluated from January 1, 2009, to June 30, 2015, in a large cohort of patients with ALS observed by an Italian tertiary multidisciplinary center. Results were replicated in an independent cohort obtained from a population-based registry of patients with ALS. A post hoc analysis was performed of the phase 2 trial of NP001 to determine whether stratification by levels of CRP improves differentiation of responders and nonresponders to the drug. Main Outcomes and Measures Serum CRP levels from the first examination were recorded to assess their effect on disease progression and survival. Results A total of 394 patients with ALS (168 women and 226 men; mean [SD] age at diagnosis, 60.18 [13.60] years) were observed in a tertiary multidisciplinary center, and the analysis was replicated in an independent cohort of 116 patients with ALS (50 women and 66 men; mean [SD] age at diagnosis, 67.00 [10.74] years) identified through a regional population-based registry. Serum CRP levels in the 394 patients with ALS correlated with severity of functional impairment, as measured by total score on the ALS Functional Rating Scale–Revised, at first evaluation (r = –0.14818; P = .004), and with patient survival (hazard ratio, 1.129; 95% CI, 1.033-1.234; P = .007). Similar results were found in the independent cohort (hazard ratio, 1.044; 95% CI, 1.016-1.056; P ≤ .001). Moreover, a post hoc analysis of the phase 2 trial of NP001 using the same CRP threshold showed that patients with elevated baseline CRP levels receiving the higher dose of NP001 had significantly less functional impairment after the treatment period compared with patients with normal baseline CRP, regardless of whether patients with normal CRP levels received NP001 or placebo (3.00 [3.62] vs –7.31 [6.23]; P = .04). Conclusions and Relevance These findings suggest that patients with ALS and elevated serum CRP levels progress more rapidly than do those with lower CRP levels and that this elevation may reflect a neuroinflammatory state potentially responsive to the immune regulators such as NP001. PMID:28384752

A Comparative Study to Assess the Predictability of Different IOL Power Calculation Formulas in Eyes of Short and Long Axial Length.

PubMed

Doshi, Dharmil; Limdi, Purvi; Parekh, Nilesh; Gohil, Neepa

2017-01-01

Accurate Intraocular Lens (IOL) power calculation in cataract surgery is very important for providing postoperative precise vision. Selection of most appropriate formula is difficult in high myopic and hypermetropic patients. To investigate the predictability of different IOL (Intra Ocular Lens) power calculation formulae in eyes with short and long Axial Length (AL) and to find out most accurate IOL power calculation formula in both groups. A prospective study was conducted on 80 consecutive patients who underwent phacoemulsification with monofocal IOL implantation after obtaining an informed and written consent. Preoperative keratometry was done by IOL Master. Axial length and anterior chamber depth was measured using A-scan machine ECHORULE 2 (BIOMEDIX). Patients were divided into two groups based on AL. (40 in each group). Group A with AL<22 mm and Group B with AL>24.5 mm. The IOL power calculation in each group was done by Haigis, Hoffer Q, Holladay-I, SRK/T formulae using the software of ECHORULE 2. The actual postoperative Spherical Equivalent (SE), Estimation error (E) and Absolute Error (AE) were calculated at one and half months and were used in data analysis. The predictive accuracy of each formula in each group was analyzed by comparing the Absolute Error (AE). The Kruskal Wallis test was used to compare differences in the (AE) of the formulae. A statistically significant difference was defined as p-value<0.05. In Group A, Hoffer Q, Holladay 1 and SRK/T formulae were equally accurate in predicting the postoperative refraction after cataract surgery (IOL power calculation) in eyes with AL less than 22.0 mm and accuracy of these three formulae was significantly higher than Haigis formula. Whereas in Group B, Hoffer Q, Holladay 1, SRK/T and Haigis formulae were equally accurate in predicting the postoperative refraction after cataract surgery (IOL power calculation) in eyes with AL more than 24.5 mm. Hoffer Q, Holladay 1 and SRK/T formulae were showing significantly higher accuracy than Haigis formula in predicting the postoperative refraction after cataract surgery (IOL power calculation) in eyes with AL less than 22.0 mm. In eyes with AL more than 24.5 mm Hoffer Q, Holladay 1, SRK/T and Haigis formulae were equally accurate.

A Comparative Study to Assess the Predictability of Different IOL Power Calculation Formulas in Eyes of Short and Long Axial Length

PubMed Central

Limdi, Purvi; Parekh, Nilesh; Gohil, Neepa

2017-01-01

Introduction Accurate Intraocular Lens (IOL) power calculation in cataract surgery is very important for providing postoperative precise vision. Selection of most appropriate formula is difficult in high myopic and hypermetropic patients. Aim To investigate the predictability of different IOL (Intra Ocular Lens) power calculation formulae in eyes with short and long Axial Length (AL) and to find out most accurate IOL power calculation formula in both groups. Materials and Methods A prospective study was conducted on 80 consecutive patients who underwent phacoemulsification with monofocal IOL implantation after obtaining an informed and written consent. Preoperative keratometry was done by IOL Master. Axial length and anterior chamber depth was measured using A-scan machine ECHORULE 2 (BIOMEDIX). Patients were divided into two groups based on AL. (40 in each group). Group A with AL<22 mm and Group B with AL>24.5 mm. The IOL power calculation in each group was done by Haigis, Hoffer Q, Holladay-I, SRK/T formulae using the software of ECHORULE 2. The actual postoperative Spherical Equivalent (SE), Estimation error (E) and Absolute Error (AE) were calculated at one and half months and were used in data analysis. The predictive accuracy of each formula in each group was analyzed by comparing the Absolute Error (AE). The Kruskal Wallis test was used to compare differences in the (AE) of the formulae. A statistically significant difference was defined as p-value<0.05. Results In Group A, Hoffer Q, Holladay 1 and SRK/T formulae were equally accurate in predicting the postoperative refraction after cataract surgery (IOL power calculation) in eyes with AL less than 22.0 mm and accuracy of these three formulae was significantly higher than Haigis formula. Whereas in Group B, Hoffer Q, Holladay 1, SRK/T and Haigis formulae were equally accurate in predicting the postoperative refraction after cataract surgery (IOL power calculation) in eyes with AL more than 24.5 mm. Conclusion Hoffer Q, Holladay 1 and SRK/T formulae were showing significantly higher accuracy than Haigis formula in predicting the postoperative refraction after cataract surgery (IOL power calculation) in eyes with AL less than 22.0 mm. In eyes with AL more than 24.5 mm Hoffer Q, Holladay 1, SRK/T and Haigis formulae were equally accurate. PMID:28273986

Metabolic Reprogramming in Amyotrophic Lateral Sclerosis.

PubMed

Szelechowski, M; Amoedo, N; Obre, E; Léger, C; Allard, L; Bonneu, M; Claverol, S; Lacombe, D; Oliet, S; Chevallier, S; Le Masson, G; Rossignol, R

2018-03-02

Mitochondrial dysfunction in the spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the neurometabolic alterations during early stages of the disease remain unknown. Here, we investigated the bioenergetic and proteomic changes in ALS mouse motor neurons and patients' skin fibroblasts. We first observed that SODG93A mice presymptomatic motor neurons display alterations in the coupling efficiency of oxidative phosphorylation, along with fragmentation of the mitochondrial network. The proteome of presymptomatic ALS mice motor neurons also revealed a peculiar metabolic signature with upregulation of most energy-transducing enzymes, including the fatty acid oxidation (FAO) and the ketogenic components HADHA and ACAT2, respectively. Accordingly, FAO inhibition altered cell viability specifically in ALS mice motor neurons, while uncoupling protein 2 (UCP2) inhibition recovered cellular ATP levels and mitochondrial network morphology. These findings suggest a novel hypothesis of ALS bioenergetics linking FAO and UCP2. Lastly, we provide a unique set of data comparing the molecular alterations found in human ALS patients' skin fibroblasts and SODG93A mouse motor neurons, revealing conserved changes in protein translation, folding and assembly, tRNA aminoacylation and cell adhesion processes.

Comparison of the Performance of the Warfarin Pharmacogenetics Algorithms in Patients with Surgery of Heart Valve Replacement and Heart Valvuloplasty.

PubMed

Xu, Hang; Su, Shi; Tang, Wuji; Wei, Meng; Wang, Tao; Wang, Dongjin; Ge, Weihong

2015-09-01

A large number of warfarin pharmacogenetics algorithms have been published. Our research was aimed to evaluate the performance of the selected pharmacogenetic algorithms in patients with surgery of heart valve replacement and heart valvuloplasty during the phase of initial and stable anticoagulation treatment. 10 pharmacogenetic algorithms were selected by searching PubMed. We compared the performance of the selected algorithms in a cohort of 193 patients during the phase of initial and stable anticoagulation therapy. Predicted dose was compared to therapeutic dose by using a predicted dose percentage that falls within 20% threshold of the actual dose (percentage within 20%) and mean absolute error (MAE). The average warfarin dose for patients was 3.05±1.23mg/day for initial treatment and 3.45±1.18mg/day for stable treatment. The percentages of the predicted dose within 20% of the therapeutic dose were 44.0±8.8% and 44.6±9.7% for the initial and stable phases, respectively. The MAEs of the selected algorithms were 0.85±0.18mg/day and 0.93±0.19mg/day, respectively. All algorithms had better performance in the ideal group than in the low dose and high dose groups. The only exception is the Wadelius et al. algorithm, which had better performance in the high dose group. The algorithms had similar performance except for the Wadelius et al. and Miao et al. algorithms, which had poor accuracy in our study cohort. The Gage et al. algorithm had better performance in both phases of initial and stable treatment. Algorithms had relatively higher accuracy in the >50years group of patients on the stable phase. Copyright © 2015 Elsevier Ltd. All rights reserved.

Blood Cell Palmitoleate-Palmitate Ratio Is an Independent Prognostic Factor for Amyotrophic Lateral Sclerosis

PubMed Central

Henriques, Alexandre; Blasco, Hélène; Fleury, Marie-Céline; Corcia, Philippe; Echaniz-Laguna, Andoni; Robelin, Laura; Rudolf, Gabrielle; Lequeu, Thiebault; Bergaentzle, Martine; Gachet, Christian; Pradat, Pierre-François; Marchioni, Eric; Andres, Christian R.; Tranchant, Christine; Gonzalez De Aguilar, Jose-Luis; Loeffler, Jean-Philippe

2015-01-01

Growing evidence supports a link between fatty acid metabolism and amyotrophic lateral sclerosis (ALS). Here we determined the fatty acid composition of blood lipids to identify markers of disease progression and survival. We enrolled 117 patients from two clinical centers and 48 of these were age and gender matched with healthy volunteers. We extracted total lipids from serum and blood cells, and separated fatty acid methyl esters by gas chromatography. We measured circulating biochemical parameters indicative of the metabolic status. Association between fatty acid composition and clinical readouts was studied, including ALS functional rating scale-revised (ALSFRS-R), survival, disease duration, site of onset and body mass index. Palmitoleate (16:1) and oleate (18:1) levels, and stearoyl-CoA desaturase indices (16:1/16:0 and 18:1/18:0) significantly increased in blood cells from ALS patients compared to healthy controls. Palmitoleate levels and 16:1/16:0 ratio in blood cells, but not body mass index or leptin concentrations, negatively correlated with ALSFRS-R decline over a six-month period (p<0.05). Multivariate Cox analysis, with age, body mass index, site of onset and ALSFRS-R as covariables, showed that blood cell 16:1/16:0 ratio was an independent prognostic factor for survival (hazard ratio=0.1 per unit of ratio, 95% confidence interval=0.01-0.57, p=0.009). In patients with high 16:1/16:0 ratio, survival at blood collection was extended by 10 months, as compared to patients with low ratio. The 16:1/16:0 index is an easy-to-handle parameter that predicts survival of ALS patients independently of body mass index. It therefore deserves further validation in larger cohorts for being used to assess disease outcome and effects of disease-modifying drugs. PMID:26147510

Blood Cell Palmitoleate-Palmitate Ratio Is an Independent Prognostic Factor for Amyotrophic Lateral Sclerosis.

PubMed

Henriques, Alexandre; Blasco, Hélène; Fleury, Marie-Céline; Corcia, Philippe; Echaniz-Laguna, Andoni; Robelin, Laura; Rudolf, Gabrielle; Lequeu, Thiebault; Bergaentzle, Martine; Gachet, Christian; Pradat, Pierre-François; Marchioni, Eric; Andres, Christian R; Tranchant, Christine; Gonzalez De Aguilar, Jose-Luis; Loeffler, Jean-Philippe

2015-01-01

Growing evidence supports a link between fatty acid metabolism and amyotrophic lateral sclerosis (ALS). Here we determined the fatty acid composition of blood lipids to identify markers of disease progression and survival. We enrolled 117 patients from two clinical centers and 48 of these were age and gender matched with healthy volunteers. We extracted total lipids from serum and blood cells, and separated fatty acid methyl esters by gas chromatography. We measured circulating biochemical parameters indicative of the metabolic status. Association between fatty acid composition and clinical readouts was studied, including ALS functional rating scale-revised (ALSFRS-R), survival, disease duration, site of onset and body mass index. Palmitoleate (16:1) and oleate (18:1) levels, and stearoyl-CoA desaturase indices (16:1/16:0 and 18:1/18:0) significantly increased in blood cells from ALS patients compared to healthy controls. Palmitoleate levels and 16:1/16:0 ratio in blood cells, but not body mass index or leptin concentrations, negatively correlated with ALSFRS-R decline over a six-month period (p<0.05). Multivariate Cox analysis, with age, body mass index, site of onset and ALSFRS-R as covariables, showed that blood cell 16:1/16:0 ratio was an independent prognostic factor for survival (hazard ratio=0.1 per unit of ratio, 95% confidence interval=0.01-0.57, p=0.009). In patients with high 16:1/16:0 ratio, survival at blood collection was extended by 10 months, as compared to patients with low ratio. The 16:1/16:0 index is an easy-to-handle parameter that predicts survival of ALS patients independently of body mass index. It therefore deserves further validation in larger cohorts for being used to assess disease outcome and effects of disease-modifying drugs.

Rapamycin treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial).

PubMed

Mandrioli, Jessica; D'Amico, Roberto; Zucchi, Elisabetta; Gessani, Annalisa; Fini, Nicola; Fasano, Antonio; Caponnetto, Claudia; Chiò, Adriano; Dalla Bella, Eleonora; Lunetta, Christian; Mazzini, Letizia; Marinou, Kalliopi; Sorarù, Gianni; de Biasi, Sara; Lo Tartaro, Domenico; Pinti, Marcello; Cossarizza, Andrea

2018-06-01

Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions. Rapamycin also expands regulatory T lymphocytes (Treg) and increased Treg levels are associated with slow progression in ALS patients.Therefore, we planned a randomized clinical trial testing Rapamycin treatment in ALS patients. RAP-ALS is a phase II randomized, double-blind, placebo-controlled, multicenter (8 ALS centers in Italy), clinical trial. The primary aim is to assess whether Rapamycin administration increases Tregs number in treated patients compared with control arm. Secondary aims include the assessment of safety and tolerability of Rapamycin in patients with ALS; the minimum dosage to have Rapamycin in cerebrospinal fluid; changes in immunological (activation and homing of T, B, NK cell subpopulations) and inflammatory markers, and on mTOR downstream pathway (S6RP phosphorylation); clinical activity (ALS Functional Rating Scale-Revised, survival, forced vital capacity); and quality of life (ALSAQ40 scale). Rapamycin potentially targets mechanisms at play in ALS (i.e., autophagy and neuroinflammation), with promising preclinical studies. It is an already approved drug, with known pharmacokinetics, already available and therefore with significant possibility of rapid translation to daily clinics. Findings will provide reliable data for further potential trials. The study protocol was approved by the Ethics Committee of Azienda Ospedaliero Universitaria of Modena and by the Ethics Committees of participating centers (Eudract n. 2016-002399-28) based on the Helsinki declaration.

Amino acids acting as transmitters in amyotrophic lateral sclerosis (ALS).

PubMed

Niebroj-Dobosz, I; Janik, P

1999-07-01

In amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of unknown origin, excitotoxic mechanisms are supposed to be involved. Divergent results are, however, presented either because of the heterogeneity of this disease, and/or different methodologies used to evaluate the excitotoxic amino acids content. The results of the most sensitive high performance liquid chromatography (HPLC) techniques with precolumn derivatization of fasting serum and CSF glutamate, aspartate, glycine and gamma-aminobutyric acid (GABA) in mild and severely progressing ALS cases are presented here. We studied 25 ALS patients with different course of the disease and controls, which consisted of 10 cases with other motor neuron diseases and 20 healthy, age-matched subjects. In the ALS patients with a mild course of the disease serum glutamate and aspartate content was either normal or slightly decreased, in all of these cases a rise in GABA and glycine was present. In the severely progressing ALS cases serum glutamate and aspartate was increased. The GABA content was either normal or increased, the glycine level appeared to be either normal or decreased. In CSF the amino acids changes in ALS were less pronounced as compared to serum. The most frequent finding was the increase in GABA concentration both in the mild and the severely progressing group. CSF glutamate in ALS patients with mild course of the disease was decreased, in the severely progressing cases the glutamate level appeared in a broad range from decreased to increased values. CSF aspartate was either normal or elevated, glycine values were present in a broad range from decreased to increased values. In the other tested motor neuron diseases no consistent changes in serum and CSF amino acids concentration was observed. The data from serum and CSF indicate that in ALS an imbalance between excitatory and inhibitory amino acids might be present in the brain, which may be induced in different ways in particular ALS patients. It may be an important factor for the mediation of neurons death.

Structural and functional evaluation of cortical motor areas in Amyotrophic Lateral Sclerosis.

PubMed

Cosottini, Mirco; Pesaresi, Ilaria; Piazza, Selina; Diciotti, Stefano; Cecchi, Paolo; Fabbri, Serena; Carlesi, Cecilia; Mascalchi, Mario; Siciliano, Gabriele

2012-03-01

The structural and functional data gathered with Magnetic Resonance Imaging (MRI) techniques about the brain cortical motor damage in Amyotrophic Lateral Sclerosis (ALS) are controversial. In fact some structural MRI studies showed foci of gray matter (GM) atrophy in the precentral gyrus, even in the early stage, while others did not. Most functional MRI (fMRI) studies in ALS reported hyperactivation of extra-primary motor cortices, while contradictory results were obtained on the activation of the primary motor cortex. We aimed to investigate the cortical motor circuitries in ALS patients by a combined structural and functional approach. Twenty patients with definite ALS and 16 healthy subjects underwent a structural examination with acquisition of a 3D T1-weighted sequence and fMRI examination during a maximal force handgrip task executed with the right-hand, the left-hand and with both hands simultaneously. The T1-weighted images were analyzed with Voxel-Based Morphometry (VBM) that showed several clusters of reduced cortical GM in ALS patients compared to controls including the pre and postcentral gyri, the superior, middle and inferior frontal gyri, the supplementary motor area, the superior and inferior parietal cortices and the temporal lobe, bilaterally but more extensive on the right side. In ALS patients a significant hypoactivation of the primary sensory motor cortex and frontal dorsal premotor areas as compared to controls was observed. The hypoactivated areas matched with foci of cortical atrophy demonstrated by VBM. The fMRI analysis also showed an enhanced activation in the ventral premotor frontal areas and in the parietal cortex pertaining to the fronto-parietal motor circuit which paralleled with disease progression rate and matched with cortical regions of atrophy. The hyperactivation of the fronto-parietal circuit was asymmetric and prevalent in the left hemisphere. VBM and fMRI identified structural and functional markers of an extended cortical damage within the motor circuit of ALS patients. The functional changes in non-primary motor cortices pertaining to fronto-parietal circuit suggest an over-recruitment of a pre-existing physiological sensory-motor network. However, the concomitant fronto-parietal cortical atrophy arises the possibility that such a hyper-activation reflects cortical hyper-excitability due to loss of inhibitory inter-neurons. Copyright © 2011 Elsevier Inc. All rights reserved.

Physical and cognitive fitness in young adulthood and risk of amyotrophic lateral sclerosis at an early age.

PubMed

Longinetti, E; Mariosa, D; Larsson, H; Almqvist, C; Lichtenstein, P; Ye, W; Fang, F

2017-01-01

There is a clinical impression that patients with amyotrophic lateral sclerosis (ALS) have a higher level of physical fitness and lower body mass index (BMI) than average. However, there is a lack of literature examining the relationship between cognitive fitness and ALS risk. In this study we explored the associations of both physical and cognitive fitness with future risk of ALS. Data on physical fitness, BMI, intelligence quotient (IQ) and stress resilience were collected from 1 838 376 Swedish men aged 17-20 years at conscription during 1968-2010. Their subsequent ALS diagnoses were identified through the Swedish Patient Register. Hazard ratios (HRs) and 95% CIs from flexible parametric models were used to assess age-specific associations of physical fitness, BMI, IQ and stress resilience with ALS. We identified 439 incident ALS cases during follow-up (mean age at diagnosis: 48 years). Individuals with physical fitness above the highest tertile tended to have a higher risk of ALS before the age of 45 years (range of HRs: 1.42-1.75; statistically significant associations at age 41-43 years) compared with others. Individuals with BMI ≥ 25 tended to have a lower risk of ALS at all ages (range of HRs: 0.42-0.80; statistically significant associations at age 42-48 years) compared with those with BMI < 25. Individuals with IQ above the highest tertile had a statistically significantly increased risk of ALS at an age of 56 years and above (range of HRs: 1.33-1.81), whereas individuals with stress resilience above the highest tertile had a lower risk of ALS at an age of 55 years and below (range of HRs: 0.47-0.73). Physical fitness, BMI, IQ and stress resilience in young adulthood might be associated with the development of ALS at an early age. © 2016 EAN.

'Six sigma approach' - an objective strategy in digital assessment of postoperative air leaks: a prospective randomised study.

PubMed

Bertolaccini, Luca; Rizzardi, Giovanna; Filice, Mary Jo; Terzi, Alberto

2011-05-01

Until now, only way to report air leaks (ALs) has been with an analogue score in an inherently subjective manner. The Six Sigma quality improvement methodology is a data-driven approach applicable to evaluate the quality of the quantification method of repetitive procedures. We applied the Six Sigma concept to improve the process of AL evaluation. A digital device for AL measurement (Drentech PALM, Redax S.r.l., Mirandola (MO), Italy) was applied to 49 consecutive patients, who underwent pulmonary intervention, compared with a similar population with classical chest drainage. Data recorded were postoperative AL, chest-tube removal days, number of chest roentgenograms, hospital length of stay; device setup time, average time rating AL and patient satisfaction. Bivariable comparisons were made using the Mann-Whitney test, the χ² test and Fisher's exact test. Analysis of quality was conducted using the Six Sigma methodology. There were no significant differences regarding AL (p=0.075), although not statistically significant; there was a reduction of postoperative chest X-rays (four vs five) and of hospital length of stay (6.5 vs 7.1 days); and a marginally significant difference was found between chest-tube removal days (p=0.056). There were significant differences regarding device setup time (p=0.001), average time rating AL (p=0.001), inter-observer variability (p=0.001) and patient satisfaction (p=0.002). Six Sigma analyses revealed accurate assessment of AL. Continuous digital measurement of AL reduces degree of variability of AL score, gives more assurance for tube removal, and reports AL without the apprehension of observer error. Efficiency and effectiveness improved with the use of a digital device. We have noted that the AL curves depict actually sealing of AL. The clinical importance of AL curves requires further study. Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

CSF neurofilament proteins as diagnostic and prognostic biomarkers for amyotrophic lateral sclerosis.

PubMed

Rossi, Daniela; Volanti, Paolo; Brambilla, Liliana; Colletti, Tiziana; Spataro, Rossella; La Bella, Vincenzo

2018-03-01

Elevated cerebrospinal fluid (CSF), Neurofilament Light (NF-L) and phosphorylated Heavy (pNF-H) chain levels have been found in Amyotrophic Lateral Sclerosis (ALS), with studies reporting a correlation of both neurofilaments (NFs) with the disease progression. Here, we measured NF-L and pNF-H concentrations in the CSF of ALS patients from a single tertiary Center and investigated their relationship with disease-related variables. A total of 190 ALS patients (Bulbar, 29.9%; Spinal, 70.1%; M/F = 1.53) and 130 controls with mixed neurological diseases were recruited. Demographic and clinical variables were recorded, and ΔFS was used to rate the disease progression. Controls were divided into two cohorts: (1) patients with non-inflammatory neurological diseases (CTL-1); (2) patients with acute/subacute inflammatory diseases and tumors, expected to lead to significant axonal and tissue damage (CTL-2). For each patient and control, CSF was taken at the time of the diagnostic work-up and stored following the published guidelines. CSF NF-L and pNF-H were assayed with commercially available ELISA-based methods. Standard curves (from independent ELISA kits) were highly reproducible for both NFs, with a coefficient of variation < 20%. We found that CSF NF-L and pNF-H levels in ALS were significantly increased when compared to CTL-1 (NF-L: ALS, 4.7 ng/ml vs CTL-1, 0.61 ng/ml, p < 0.001; pNF-H: ALS, 1.7 ng/ml vs CTL-1, 0.03 ng/ml, p < 0.0001), but not to CTL-2. Analysis of different clinical and prognostic variables disclosed meaningful correlations with both NF-L and pNF-H levels. Our results, from a relatively large ALS cohort, confirm that CSF NF-L and pNF-H represent valuable diagnostic and prognostic biomarkers in ALS.

Comparison of artemether-lumefantrine and chloroquine with and without primaquine for the treatment of Plasmodium vivax infection in Ethiopia: A randomized controlled trial

PubMed Central

Tadesse, Yehualashet; Melaku, Zenebe; Assef, Ashenafi; Kassa, Moges; Chatfield, Mark D.; Landman, Keren Z.; Chenet, Stella M.; Lucchi, Naomi W.; Udhayakumar, Venkatachalam; Zhou, Zhiyong; Shi, Ya Ping; Kachur, S. Patrick; Jima, Daddi; Kebede, Amha; Solomon, Hiwot; Mekasha, Addis; Alemayehu, Bereket Hailegiorgis; Malone, Joseph L.; Dissanayake, Gunewardena; Teka, Hiwot; Price, Ric N.

2017-01-01

Background Recent efforts in malaria control have resulted in great gains in reducing the burden of Plasmodium falciparum, but P. vivax has been more refractory. Its ability to form dormant liver stages confounds control and elimination efforts. To compare the efficacy and safety of primaquine regimens for radical cure, we undertook a randomized controlled trial in Ethiopia. Methods and findings Patients with normal glucose-6-phosphate dehydrogenase status with symptomatic P. vivax mono-infection were enrolled and randomly assigned to receive either chloroquine (CQ) or artemether-lumefantrine (AL), alone or in combination with 14 d of semi-supervised primaquine (PQ) (3.5 mg/kg total). A total of 398 patients (n = 104 in the CQ arm, n = 100 in the AL arm, n = 102 in the CQ+PQ arm, and n = 92 in the AL+PQ arm) were followed for 1 y, and recurrent episodes were treated with the same treatment allocated at enrolment. The primary endpoints were the risk of P. vivax recurrence at day 28 and at day 42. The risk of recurrent P. vivax infection at day 28 was 4.0% (95% CI 1.5%–10.4%) after CQ treatment and 0% (95% CI 0%–4.0%) after CQ+PQ. The corresponding risks were 12.0% (95% CI 6.8%–20.6%) following AL alone and 2.3% (95% CI 0.6%–9.0%) following AL+PQ. On day 42, the risk was 18.7% (95% CI 12.2%–28.0%) after CQ, 1.2% (95% CI 0.2%–8.0%) after CQ+PQ, 29.9% (95% CI 21.6%–40.5%) after AL, and 5.9% (95% CI 2.4%–13.5%) after AL+PQ (overall p < 0.001). In those not prescribed PQ, the risk of recurrence by day 42 appeared greater following AL treatment than CQ treatment (HR = 1.8 [95% CI 1.0–3.2]; p = 0.059). At the end of follow-up, the incidence rate of P. vivax was 2.2 episodes/person-year for patients treated with CQ compared to 0.4 for patients treated with CQ+PQ (rate ratio: 5.1 [95% CI 2.9–9.1]; p < 0.001) and 2.3 episodes/person-year for AL compared to 0.5 for AL+PQ (rate ratio: 6.4 [95% CI 3.6–11.3]; p < 0.001). There was no difference in the occurrence of adverse events between treatment arms. The main limitations of the study were the early termination of the trial and the omission of haemoglobin measurement after day 42, resulting in an inability to estimate the cumulative risk of anaemia. Conclusions Despite evidence of CQ-resistant P. vivax, the risk of recurrence in this study was greater following treatment with AL unless it was combined with a supervised course of PQ. PQ combined with either CQ or AL was well tolerated and reduced recurrence of vivax malaria by 5-fold at 1 y. Trial registration ClinicalTrials.gov NCT01680406 PMID:28510573

A Secure RFID Tag Authentication Protocol with Privacy Preserving in Telecare Medicine Information System.

PubMed

Li, Chun-Ta; Weng, Chi-Yao; Lee, Cheng-Chi

2015-08-01

Radio Frequency Identification (RFID) based solutions are widely used for providing many healthcare applications include patient monitoring, object traceability, drug administration system and telecare medicine information system (TMIS) etc. In order to reduce malpractices and ensure patient privacy, in 2015, Srivastava et al. proposed a hash based RFID tag authentication protocol in TMIS. Their protocol uses lightweight hash operation and synchronized secret value shared between back-end server and tag, which is more secure and efficient than other related RFID authentication protocols. Unfortunately, in this paper, we demonstrate that Srivastava et al.'s tag authentication protocol has a serious security problem in that an adversary may use the stolen/lost reader to connect to the medical back-end server that store information associated with tagged objects and this privacy damage causing the adversary could reveal medical data obtained from stolen/lost readers in a malicious way. Therefore, we propose a secure and efficient RFID tag authentication protocol to overcome security flaws and improve the system efficiency. Compared with Srivastava et al.'s protocol, the proposed protocol not only inherits the advantages of Srivastava et al.'s authentication protocol for TMIS but also provides better security with high system efficiency.

Robust and efficient biometrics based password authentication scheme for telecare medicine information systems using extended chaotic maps.

PubMed

Lu, Yanrong; Li, Lixiang; Peng, Haipeng; Xie, Dong; Yang, Yixian

2015-06-01

The Telecare Medicine Information Systems (TMISs) provide an efficient communicating platform supporting the patients access health-care delivery services via internet or mobile networks. Authentication becomes an essential need when a remote patient logins into the telecare server. Recently, many extended chaotic maps based authentication schemes using smart cards for TMISs have been proposed. Li et al. proposed a secure smart cards based authentication scheme for TMISs using extended chaotic maps based on Lee's and Jiang et al.'s scheme. In this study, we show that Li et al.'s scheme has still some weaknesses such as violation the session key security, vulnerability to user impersonation attack and lack of local verification. To conquer these flaws, we propose a chaotic maps and smart cards based password authentication scheme by applying biometrics technique and hash function operations. Through the informal and formal security analyses, we demonstrate that our scheme is resilient possible known attacks including the attacks found in Li et al.'s scheme. As compared with the previous authentication schemes, the proposed scheme is more secure and efficient and hence more practical for telemedical environments.

Blood trace metals in a sporadic amyotrophic lateral sclerosis geographical cluster.

PubMed

De Benedetti, Stefano; Lucchini, Giorgio; Del Bò, Cristian; Deon, Valeria; Marocchi, Alessandro; Penco, Silvana; Lunetta, Christian; Gianazza, Elisabetta; Bonomi, Francesco; Iametti, Stefania

2017-06-01

Amyotrophic lateral sclerosis (ALS) is a fatal disorder with unknown etiology, in which genetic and environmental factors interplay to determine the onset and the course of the disease. Exposure to toxic metals has been proposed to be involved in the etiology of the disease either through a direct damage or by promoting oxidative stress. In this study we evaluated the concentration of a panel of metals in serum and whole blood of a small group of sporadic patients, all living in a defined geographical area, for which acid mine drainage has been reported. ALS prevalence in this area is higher than in the rest of Italy. Results were analyzed with software based on artificial neural networks. High concentrations of metals (in particular Se, Mn and Al) were associated with the disease group. Arsenic serum concentration resulted lower in ALS patients, but it positively correlated with disease duration. Comet assay was performed to evaluate endogenous DNA damage that resulted not different between patients and controls. Up to now only few studies considered geographically well-defined clusters of ALS patients. Common geographical origin among patients and controls gave us the chance to perform metallomic investigations under comparable conditions of environmental exposure. Elaboration of these data with software based on machine learning processes has the potential to be extremely useful to gain a comprehensive view of the complex interactions eventually leading to disease, even in a small number of subjects.

Telephone-Based Cognitive-Behavioral Screening for Frontotemporal Changes in Patients with Amyotrophic Lateral Sclerosis (ALS)

PubMed Central

Christodoulou, Georgia; Gennings, Chris; Hupf, Jonathan; Factor-Litvak, Pam; Murphy, Jennifer; Goetz, Raymond R.; Mitsumoto, Hiroshi

2017-01-01

Objective To establish a valid and reliable battery of measures to evaluate frontotemporal dementia (FTD) in patients with ALS over the phone. Methods Thirty-one subjects were administered either in-person or telephone-based screening followed by the opposite mode of testing two weeks later, using a modified version of the UCSF Cognitive Screening Battery. Results Equivalence testing was performed for in-person and telephone-based tests. The standard ALS Cognitive Behavioral Screen (ALS-CBS) showed statistical equivalence at the 5% significance level when compared to a revised phone-version of the ALS-CBS. In addition, the Controlled Oral Word Association Test (COWAT) and Center for Neurologic Study-Lability Scale (CNS-LS) were also found to be equivalent at the 5% and 10% significance level respectively. Similarly, the Mini-Mental State Examination (MMSE) and the well-established Telephone Interview for Cognitive Status (TICS) were also statistically equivalent. Equivalence could not be claimed for the ALS-Frontal Behavioral Inventory (ALS-FBI) caregiver interview and the Written Verbal Fluency Index (WVFI). Conclusions Our study suggests that telephone-based versions of the ALS-CBS, COWAT, and CNS-LS may offer clinicians valid tools to detect frontotemporal changes in the ALS population. Development of telephone-based cognitive testing for ALS could become an integral resource for population-based research in the future. PMID:27121545

Telephone based cognitive-behavioral screening for frontotemporal changes in patients with amyotrophic lateral sclerosis (ALS).

PubMed

Christodoulou, Georgia; Gennings, Chris; Hupf, Jonathan; Factor-Litvak, Pam; Murphy, Jennifer; Goetz, Raymond R; Mitsumoto, Hiroshi

Our objective was to establish a valid and reliable battery of measures to evaluate frontotemporal dementia (FTD) in patients with ALS over the telephone. Thirty-one subjects were administered either in-person or by telephone-based screening followed by the opposite mode of testing two weeks later, using a modified version of the UCSF Cognitive Screening Battery. Equivalence testing was performed for in-person and telephone based tests. The standard ALS Cognitive Behavioral Screen (ALS-CBS) showed statistical equivalence at the 5% significance level compared to a revised phone version of the ALS-CBS. In addition, the Controlled Oral Word Association Test (COWAT) and Center for Neurologic Study-Lability Scale (CNS-LS) were also found to be equivalent at the 5% and 10% significance level, respectively. Similarly, the Mini-Mental State Examination (MMSE) and the well-established Telephone Interview for Cognitive Status (TICS) were also statistically equivalent. Equivalence could not be claimed for the ALS-Frontal Behavioral Inventory (ALS-FBI) caregiver interview and the Written Verbal Fluency Index (WVFI). In conclusion, our study suggests that telephone-based versions of the ALS-CBS, COWAT, and CNS-LS may offer clinicians valid tools to detect frontotemporal changes in the ALS population. Development of telephone based cognitive testing for ALS could become an integral resource for population based research in the future.

Aluminum in erythropoietin formulations: lyophilized versus liquid forms.

PubMed

Veiga, Marlei; Bohrer, Denise; Noremberg, Simone; Mattiazzi, Patricia; do Nascimento, Paulo C; de Carvalho, Leandro M

2013-01-01

Erythropoietin (EPO) formulations may comprise aluminum (Al) as a contaminant. Due to the toxicity of Al in chronic kidney disease patients, possible sources of Al were investigated. Since EPO formulations are stored in container-closure systems made of glass and rubber, and both contain Al, formulation ingredients may enable its leaching into the solution during shelf-life. Individual solutions of formulation ingredients were stored in new glass vials and in contact with the rubber stopper and kept at 4 ± 2 °C. For 12 months, aliquots of each solution were collected for analysis. Fifteen commercial samples of EPO were analyzed for their Al content. Aluminum was determined by atomic absorption spectrometry. Glass and rubber are sources of Al for EPO formulations. Storage assay showed that citrate and phosphate (used as buffers) extracted high amounts of Al from the container/closure parts. The most important difference, however, was found when comparing liquid and lyophilized samples. While in liquid forms the Al level reached 943 μg/L, in lyophilized forms the level did not exceed 20 μg/L. The container system was also confirmed as a source of Al in reconstituted lyophilized samples. Al in reconstituted samples stored in their own vials increased 19-fold in 12 months. Lyophilized powders stored for 2 years in glass vials contained less Al than in 1 month after dissolution. The difference in the Al measured in liquid forms of EPO and in lyophilized powders suggests that the latter would be the best pharmaceutical form for CKD patients.

A secure chaotic maps and smart cards based password authentication and key agreement scheme with user anonymity for telecare medicine information systems.

PubMed

Li, Chun-Ta; Lee, Cheng-Chi; Weng, Chi-Yao

2014-09-01

Telecare medicine information system (TMIS) is widely used for providing a convenient and efficient communicating platform between patients at home and physicians at medical centers or home health care (HHC) organizations. To ensure patient privacy, in 2013, Hao et al. proposed a chaotic map based authentication scheme with user anonymity for TMIS. Later, Lee showed that Hao et al.'s scheme is in no provision for providing fairness in session key establishment and gave an efficient user authentication and key agreement scheme using smart cards, in which only few hashing and Chebyshev chaotic map operations are required. In addition, Jiang et al. discussed that Hao et al.'s scheme can not resist stolen smart card attack and they further presented an improved scheme which attempts to repair the security pitfalls found in Hao et al.'s scheme. In this paper, we found that both Lee's and Jiang et al.'s authentication schemes have a serious security problem in that a registered user's secret parameters may be intentionally exposed to many non-registered users and this problem causing the service misuse attack. Therefore, we propose a slight modification on Lee's scheme to prevent the shortcomings. Compared with previous schemes, our improved scheme not only inherits the advantages of Lee's and Jiang et al.'s authentication schemes for TMIS but also remedies the serious security weakness of not being able to withstand service misuse attack.

Biometric Changes After Trabeculectomy with Contact and Non-contact Biometry.

PubMed

Alvani, Azam; Pakravan, Mohammad; Esfandiari, Hamed; Yaseri, Mehdi; Yazdani, Shahin; Ghahari, Elham

2016-02-01

To compare biometric changes measured with contact and noncontact methods after mitomycin-C-augmented trabeculectomy. In this prospective study, 31 eyes from 31 glaucoma patients scheduled for primary trabeculectomy were enrolled. Biometric parameters including axial length (AL), anterior chamber depth (ACD), and lens thickness (LT) were measured using contact ultrasound biometry (UD-6000 Ultrasonic A/B scanner biometer; Tomey Corporation, Nagoya, Japan) and a noncontact optical biometry device (Lenstar; Haag-Streit AG, Koeniz, Switzerland). Measurements were taken the day before trabeculectomy and then compared with measurements obtained 3 and 6 months after surgery. The AL and ACD were significantly decreased at 3 and 6 months compared with baseline values taken with each biometry method. There was a significant increase in LT measured by the Lenstar device at the 3- and 6-month follow-up. At both the 3- and 6-month follow-up, the mean AL measurement reduction with the Lenstar device was significantly lower than that of the A-scan ultrasound measurements. The mean ACD changes between the two devices were not significantly different. There is a small but significant decrease in the AL and ACD after trabeculectomy as measured with both the contact and noncontact methods. The amount of AL reduction measured is significantly smaller using the noncontact method, making it the preferable method for intraocular lens power calculation for patients who need cataract surgery combined with or after trabeculectomy. The LT measured by the Lenstar device increased significantly after the operation, which can be an early sign of the progression of cataractous changes after trabeculectomy.

Left atrial function in patients with light chain amyloidosis: A transthoracic 3D speckle tracking imaging study.

PubMed

Mohty, Dania; Petitalot, Vincent; Magne, Julien; Fadel, Bahaa M; Boulogne, Cyrille; Rouabhia, Dounia; ElHamel, Chahrazed; Lavergne, David; Damy, Thibaud; Aboyans, Victor; Jaccard, Arnaud

2018-04-01

Systemic light chain amyloidosis (AL) is characterized by the extracellular deposition of amyloid fibrils. Transthoracic echocardiography is the modality of choice to assess cardiac function in patients with AL. Whereas left ventricular (LV) function has been well studied in this patient population, data regarding the value of left atrial (LA) function in AL patients are lacking. In this study, we aim to examine the impact of LA volumes and function on survival in AL patients as assessed by real-time 3D echocardiography. A total of 77 patients (67±10 years, 60% men) with confirmed AL and 39 healthy controls were included. All standard 2D echocardiographic and 3D-LA parameters were obtained. Fourteen patients (18%) were in Mayo Clinic (MC) stage I, 30 (39%) in stage II, and 33 (43%) in stage III at initial evaluation. There was no significant difference among the MC stages groups in terms of age, gender, or cardiovascular risk factors. As compared to patients in MC II and MC I, those in MC III had significantly larger indexed 3D-LA volumes (MCIII: 46±15mL/m 2 , MC II: 38±12mL/m 2 , and MC I: 23±9mL/m 2 , p<0.0001), lower 3D-LA total emptying fraction (3D-tLAEF) (21±13% vs. 31±15% vs. 43±7%, respectively, p<0.0001), and worse 3D peak atrial longitudinal strain (3D-PALS) (11±9% vs. 18±13% vs. 20±7%, respectively, p=0.007). Two-year survival was significantly lower in patients with 3D-tLAEF <+34% (p=0.003) and in those with 3D-PALS <+14% (p=0.034). Both parameters provided incremental prognostic value over maximal LA volume in multivariate analysis. Functional LA parameters are progressively altered in AL patients according to the MC stage. A decrease in 3D-PALS is associated with worse outcome, independently of LA volume. Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

The risk of renal disease is increased in lambda myeloma with bone marrow amyloid deposits.

PubMed

Kozlowski, Piotr; Montgomery, Scott; Befekadu, Rahel; Hahn-Strömberg, Victoria

2017-01-01

Light chain amyloidosis (AL) is a rare deposition disease and is present in 10-15% of patients with myeloma (MM). In contrast to symptomatic AL in MM, presence of bone marrow (BM) amyloid deposits (AD) in MM is not connected to kidney damage. Renal AD but not BM-AD occur mostly in MM with lambda paraprotein (lambda MM). We investigated amyloid presence in BM clots taken at diagnosis in 84 patients with symptomatic MM and compared disease characteristics in MM with kappa paraprotein (kappa MM)/lambda MM with and without BM-AD. Lambda MM with BM-AD was compared with kappa MM without BM-AD, kappa MM with BM-AD, and lambda MM without BM-AD: lambda MM with BM-AD patients had a significantly higher mean creatinine level (4.23 mg/dL vs 1.69, 1.14, and 1.28 mg/dL, respectively) and a higher proportion presented with severe kidney failure (6/11 [55%] vs 6/32 [19%], 1/22 [5%], and 3/19 [16%], respectively). Proteinuria was more common in lambda MM with BM-AD patients compared with kappa MM without BM-AD patients (8/11 [73%] vs 5/32 [16%], respectively). Kidney damage was more common in lambda MM with BM-AD indicating presence of renal AD.

ALS syndrome in patients with HIV-1 infection.

PubMed

Verma, Ashok; Berger, Joseph R

2006-01-15

A viral etiology of amyotrophic lateral sclerosis (ALS) has been proposed because of the selective vulnerability of motor neurons to certain viruses. During the last 20 years, at least 19 cases of ALS or ALS-like disease have been reported in HIV-1 (HIV) seropositive individuals. To describe two cases of clinically definite ALS in patients with HIV infection and to review the previously reported cases of HIV-associated ALS syndrome. A multidisciplinary ALS center and Neuro-AIDS clinic at a tertiary care university hospital. We investigated and prospectively monitored two patients who had developed clinically definite ALS by El Escorial criteria several years after acquiring the HIV infection. The previously reported cases of ALS or ALS-like disease in patients with HIV infection were reviewed for comparison and contrast with the characteristics of sporadic ALS. The clinical course of ALS in our two HIV seropositive individuals mirrored that of classical sporadic ALS. A review of previously described 19 patients with ALS syndrome revealed clinically definite ALS in 4 cases and clinically probable or possible ALS in 15. ALS commenced at different stages of the HIV disease; in 7 patients, HIV infection was discovered contemporaneously with diagnosis of ALS. CD4+ T cell count ranged from 2 to 560 cells/mm3. Three (1 definite ALS) of the fatal cases were studied at autopsy and all exhibited pathology outside the motor neuron pool. Unlike our patients, 7 of 8 patients with HIV-associated ALS syndrome receiving HAART demonstrated at least partial recovery of their motor deficit. ALS-like syndrome can occur in association with HIV infection; however, the causal relationship remains uncertain. Patients with ALS syndrome related to HIV infection are generally younger in age and often demonstrate pathology outside the motor neuron system. Patients with HIV-associated ALS syndrome may improve following antiretroviral therapy. An aggressive HAART regimen to reduce viral load should be pursued in all such cases.

Cellular transplants in amyotrophic lateral sclerosis patients: an observational study.

PubMed

Gamez, Josep; Carmona, Francesc; Raguer, Nuria; Ferrer-Sancho, Jaume; Martín-Henao, Gregorio A; Martí-Beltrán, Sergi; Badia, Merce; Gratacós, Margarita; Rodriguez-Gónzalez, Esther; Seoane, Jose Luis; Pallero-Castillo, Mercedes; Burgos, Rosa; Puiggros, Carolina; Pasarin, Alejandro; Bori-Fortuny, Inmaculada

2010-09-01

Cytotherapy is a promising option for neurodegenerative disease treatment. Because of the fatal prognosis and imperative need for effective treatment, amyotrophic lateral sclerosis (ALS) patients request this therapy before its effectiveness has been verified. The increase in clinics offering cytotherapies but providing little scientific information has prompted considerable medical tourism. We present an observational study of Spanish ALS patients receiving cytotherapy, analyzing the experiences arising from the treatment (TX) and considering two progression markers, FVC and ALSFRS-R. Twelve ALS patients with a mean age of 48.6 years (SD 12.8) received cytotherapy 26.9 months (SD 15.8) after clinical onset. ALSFRS-R and FVC at TX were 32.3 (SD 6.8) and 63.4% (SD 15.3), respectively. TX involved transplants of olfactory ensheathing cells in three patients, and autologous mesenchymal stromal cells in the remainder. One patient died 33 months post-TX after surviving for 49 months. Five required mechanical non-invasive home ventilation 7.4 months post-TX. Two required invasive ventilation 13 months post-TX. Five patients needed gastrostomy feeding 23.3 months post-TX. Survival between clinical onset and the study end date was 50 months (SD 17.2). No significant adverse events or changes in the decline of FVC and ALSFRS-R compared with the disease's natural history were observed. Our observations suggest that these therapies do not halt the course of the disease. Cytotherapy cannot yet be considered a curative treatment for ALS.

Multi-institutional external validation of seminal vesicle invasion nomograms: head-to-head comparison of Gallina nomogram versus 2007 Partin tables.

PubMed

Zorn, Kevin C; Capitanio, Umberto; Jeldres, Claudio; Arjane, Philippe; Perrotte, Paul; Shariat, Shahrokh F; Lee, David I; Shalhav, Arieh L; Zagaja, Gregory P; Shikanov, Sergey A; Gofrit, Ofer N; Thong, Alan E; Albala, David M; Sun, Leon; Karakiewicz, Pierre I

2009-04-01

The Partin tables represent one of the most widely used prostate cancer staging tools for seminal vesicle invasion (SVI) prediction. Recently, Gallina et al. reported a novel staging tool for the prediction of SVI that further incorporated the use of the percentage of positive biopsy cores. We performed an external validation of the Gallina et al. nomogram and the 2007 Partin tables in a large, multi-institutional North American cohort of men treated with robotic-assisted radical prostatectomy. Clinical and pathologic data were prospectively gathered from 2,606 patients treated with robotic-assisted radical prostatectomy at one of four North American robotic referral centers between 2002 and 2007. Discrimination was quantified with the area under the receiver operating characteristics curve. The calibration compared the predicted and observed SVI rates throughout the entire range of predictions. At robotic-assisted radical prostatectomy, SVI was recorded in 4.2% of patients. The discriminant properties of the Gallina et al. nomogram resulted in 81% accuracy compared with 78% for the 2007 Partin tables. The Gallina et al. nomogram overestimated the true rate of SVI. Conversely, the Partin tables underestimated the true rate of SVI. The Gallina et al. nomogram offers greater accuracy (81%) than the 2007 Partin tables (78%). However, both tools are associated with calibration limitations that need to be acknowledged and considered before their implementation into clinical practice.

Variability in the initiation of resuscitation attempts by emergency medical services personnel during out-of-hospital cardiac arrest.

PubMed

Brooks, Steven C; Schmicker, Robert H; Cheskes, Sheldon; Christenson, Jim; Craig, Alan; Daya, Mohamud; Kudenchuk, Peter J; Nichol, Graham; Zive, Dana; Morrison, Laurie J

2017-08-01

Some patients with out-of-hospital cardiac arrest (OHCA) assessed by emergency medical services (EMS) do not receive attempts at resuscitation on the basis of perceived futility. 1) To measure variability in the initiation of resuscitation attempts in EMS-assessed OHCA patients across EMS agencies, 2) to evaluate the association between selected EMS agency characteristics and the proportion of patients receiving resuscitation attempts, and 3) to evaluate the association between proportion receiving resuscitation attempts and survival. A retrospective cohort study using data from 129 EMS agencies participating in the Resuscitation Outcomes Consortium (ROC) epidemiologic registry (EPISTRY) - Cardiac Arrest from 12/01/2005 to 12/31/2010. We included non-traumatic OHCA patients assessed by EMS. We included 86,912 OHCA patients. Overall, 54.8% had resuscitation attempted by EMS providers, varying from 23.9% to 100% (p=<0.001) across EMS agencies. The proportion of patients receiving a resuscitation attempt was 7.87% less (95% CI 3.73-12.0) among agencies with longer average response intervals (≥6min) compared with shorter average response intervals (<6min) and 16.9% less (95% CI 11.9-21.9) among agencies with higher levels of advanced life support (ALS) availability (≥50% of available units) compared with lower levels of ALS availability (<50% of available units). There was a moderate positive correlation between the proportion of patients with resuscitation attempts and survival to hospital discharge (r=0.54, p<0.001). The proportion of patients with OHCA who receive resuscitation attempts is variable across EMS agencies and is associated with EMS response interval, ALS unit availability and geographic region. On average, survival was higher among EMS agencies more likely to initiate resuscitation. Copyright © 2017 Elsevier B.V. All rights reserved.

Cellular changes in motor neuron cell culture produced by cytotoxic cerebrospinal fluid from patients with amyotrophic lateral sclerosis.

PubMed

Gomez-Pinedo, U; Yáñez, M; Matías-Guiu, J; Galán, L; Guerrero-Sola, A; Benito-Martin, M S; Vela, A; Arranz-Tagarro, J A; García, A G

2014-01-01

The neurotoxic effects of cerebrospinal fluid (CSF) from patients with amyotrophic lateral sclerosis (ALS) have been reported by various authors who have attributed this neurotoxicity to the glutamate in CSF-ALS. Cultures of rat embryonic cortical neurons were exposed to CSF from ALS patients during an incubation period of 24 hours. Optical microscopy was used to compare cellular changes to those elicited by exposure to 100μm glutamate, and confocal microscopy was used to evaluate immunohistochemistry for caspase-3, TNFα, and peripherin. In the culture exposed to CSF-ALS, we observed cells with nuclear fragmentation and scarce or null structural modifications to the cytoplasmic organelles or to plasma membrane maintenance. This did not occur in the culture exposed to glutamate. The culture exposed to CSF-ALS also demonstrated increases in caspase-3, TNFα, and in peripherin co-locating with caspase-3, but not with TNFα, suggesting that TNFα may play an early role in the process of apoptosis. CFS-ALS cytotoxicity is not related to glutamate. It initially affects the nucleus without altering the cytoplasmic membrane. It causes cytoplasmic apoptosis that involves an increase in caspase-3 co-located with peripherin, which is also overexpressed. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Progression of hippocampal degeneration in amyotrophic lateral sclerosis with or without memory impairment: distinction from Alzheimer disease.

PubMed

Takeda, Takahiro; Uchihara, Toshiki; Arai, Nobutaka; Mizutani, Toshio; Iwata, Makoto

2009-01-01

The hippocampal involvement in amyotrophic lateral sclerosis (ALS) patients has been known for more than a decade, however, its relationship to clinical manifestations including memory deficits and topographical differentiation from Alzheimer disease (AD) remain unclear. In order to clarify the anatomopathological features in the hippocampus and their relevance to disease-specific memory deficits in ALS patients, topography and cytopathology of the hippocampal lesions along the perforant pathway were quantitatively and semiquantitatively surveyed in 14 ALS patients with extramotor involvement. These pathological findings were compared with clinical characteristics assessed from their clinical records. Cytoplasmic inclusions initially appear in the granular cells of the dentate gyrus (DG) and superficial small neurons of the transentorhinal cortex (TEC) with mild subicular degeneration (stage I: inclusion stage). Subsequent gliosis and neuronal loss of the TEC, concomitant with presynaptic degeneration of the outer molecular layer of the DG, suggests an extension of the degeneration through the perforant pathway (stage II: early perforant stage). In a more advanced stage, the presynaptic degeneration is more evident with moderate to severe neuronal loss in the TEC (stage III: advanced perforant stage). This advanced stage was associated with episodic memory deficits mimicking AD in some ALS patients. This ALS pathology initiated by cytoplasmic inclusions and neuronal loss in layer II-III of the TEC is different from neurofibrillary tangles of AD, dominant in layer II-III of the entorhinal cortex. Because this involvement of the TEC-molecular DG projection and subiculum is specific to ALS, it will provide a basis for clinical characterization of memory deficits of ALS, which could be distinct from those of AD.

Axonal Dysfunction Precedes Motor Neuronal Death in Amyotrophic Lateral Sclerosis

PubMed Central

Iwai, Yuta; Shibuya, Kazumoto; Misawa, Sonoko; Sekiguchi, Yukari; Watanabe, Keisuke; Amino, Hiroshi; Kuwabara, Satoshi

2016-01-01

Wide-spread fasciculations are a characteristic feature in amyotrophic lateral sclerosis (ALS), suggesting motor axonal hyperexcitability. Previous excitability studies have shown increased nodal persistent sodium conductances and decreased potassium currents in motor axons of ALS patients, both of the changes inducing hyperexcitability. Altered axonal excitability potentially contributes to motor neuron death in ALS, but the relationship of the extent of motor neuronal death and abnormal excitability has not been fully elucidated. We performed multiple nerve excitability measurements in the median nerve at the wrist of 140 ALS patients and analyzed the relationship of compound muscle action potential (CMAP) amplitude (index of motor neuronal loss) and excitability indices, such as strength-duration time constant, threshold electrotonus, recovery cycle and current-threshold relationships. Compared to age-matched normal controls (n = 44), ALS patients (n = 140) had longer strength-duration time constant (SDTC: a measure of nodal persistent sodium current; p < 0.05), greater threshold changes in depolarizing threshold electrotonus (p < 0.05) and depolarizing current threshold relationship (i.e. less accommodation; (p < 0.05), greater superexcitability (a measure of fast potassium current; p < 0.05) and reduced late subexcitability (a measure of slow potassium current; p < 0.05), suggesting increased persistent sodium currents and decreased potassium currents. The reduced potassium currents were found even in the patient subgroups with normal CMAP (> 5mV). Regression analyses showed that SDTC (R = -0.22) and depolarizing threshold electrotonus (R = -0.22) increased with CMAP decline. These findings suggest that motor nerve hyperexcitability occurs in the early stage of the disease, and precedes motor neuronal loss in ALS. Modulation of altered ion channel function could be a treatment option for ALS. PMID:27383069

A specific prediction equation is necessary to estimate peak oxygen uptake in obese patients with metabolic syndrome.

PubMed

Debeaumont, D; Tardif, C; Folope, V; Castres, I; Lemaitre, F; Tourny, C; Dechelotte, P; Thill, C; Darmon, A; Coquart, J B

2016-06-01

The aims were to: (1) compare peak oxygen uptake ([Formula: see text]peak) predicted from four standard equations to actual [Formula: see text]peak measured from a cardiopulmonary exercise test (CPET) in obese patients with metabolic syndrome (MetS), and (2) develop a new equation to accurately estimate [Formula: see text]peak in obese women with MetS. Seventy-five obese patients with MetS performed a CPET. Anthropometric data were also collected for each participant. [Formula: see text]peak was predicted from four prediction equations (from Riddle et al., Hansen et al., Wasserman et al. or Gläser et al.) and then compared with the actual [Formula: see text]peak measured during the CPET. The accuracy of the predictions was determined with the Bland-Altman method. When accuracy was low, a new prediction equation including anthropometric variables was proposed. [Formula: see text]peak predicted from the equation of Wasserman et al. was not significantly different from actual [Formula: see text]peak in women. Moreover, a significant correlation was found between the predicted and actual values (p < 0.001, r = 0.69). In men, no significant difference was noted between actual [Formula: see text]peak and [Formula: see text]peak predicted from the prediction equation of Gläser et al., and these two values were also correlated (p = 0.03, r = 0.44). However, the LoA95% was wide, whatever the prediction equation or gender. Regression analysis suggested a new prediction equation derived from age and height for obese women with MetS. The methods of Wasserman et al. and Gläser et al. are valid to predict [Formula: see text]peak in obese women and men with MetS, respectively. However, the accuracy of the predictions was low for both methods. Consequently, a new prediction equation including age and height was developed for obese women with MetS. However, new prediction equation remains to develop in obese men with MetS.

Multidisciplinary ALS care improves quality of life in patients with ALS.

PubMed

Van den Berg, J P; Kalmijn, S; Lindeman, E; Veldink, J H; de Visser, M; Van der Graaff, M M; Wokke, J H J; Van den Berg, L H

2005-10-25

To examine the effect of multidisciplinary ALS care on the quality-of-life (QoL) in patients with ALS and their caregivers. In a cross-sectional study, 208 patients with ALS and their caregivers were interviewed. QoL was assessed using the 36-item Short Form Health Survey (SF-36) and two visual analogue scales (VAS). Criteria for multidisciplinary ALS care were: an ALS team headed by a consultant in rehabilitation medicine and consisting of at least a physical therapist, occupational therapist, speech pathologist, dietician and a social worker; use of the Dutch ALS consensus guidelines for ALS care; and at least six incident ALS patients per year. Clinical characteristics and functional loss of the 133 patients receiving multidisciplinary ALS care and the 75 patients receiving general ALS care were similar. The percentage of patients with adequate aids and appliances was higher in those with multidisciplinary ALS care (93.1 vs 81.3%, p = 0.008), whereas the number of visits to professional caregivers was similar in both groups. Patients in the multidisciplinary ALS care group had a better mental QoL on the SF-36 Mental Summary Score than those in the general care group (p = 0.01). The difference in QoL was most pronounced in the domains of Social Functioning and Mental Health, and was independent of the presence of aids and appliances. No significant differences were found in the SF-36 Physical Summary Score, VAS, or in QoL of caregivers of patients with ALS. High standard of care improves mental quality-of-life in patients with ALS.

Retroviruses and amyotrophic lateral sclerosis.

PubMed

Alfahad, Tariq; Nath, Avindra

2013-08-01

Amyotrophic lateral sclerosis (ALS) is a progressive, invariably fatal neurologic disorder resulting from upper and lower motor neuron degeneration, which typically develops during the sixth or seventh decade of life, and is diagnosed based on standard clinical criteria. Its underlying cause remains undetermined. The disease may occur with increased frequency within certain families, often in association with specific genomic mutations, while some sporadic cases have been linked to environmental toxins or trauma. Another possibility, first proposed in the 1970s, is that retroviruses play a role in pathogenesis. In this paper, we review the published literature for evidence that ALS is associated either with infection by an exogenous retrovirus or with the expression of human endogenous retroviral (HERV) sequences in cells of the central nervous system. A small percentage of persons infected with the human immunodeficiency virus-1 (HIV-1) or human T cell leukemia virus-1 (HTLV-1) develop ALS-like syndromes. While HTLV-1 associated ALS-like syndrome has several features that may distinguish it from classical ALS, HIV-infected patients may develop neurological manifestations that resemble classical ALS although it occurs at a younger age and they may show a dramatic improvement following the initiation of antiretroviral therapy. However, most patients with probable or definite ALS show no evidence of HIV-1 or HTLV-1 infection. In contrast, recent reports have shown a stronger association with HERV, as analysis of serum samples, and postmortem brain tissue from a number of patients with a classical ALS has revealed significantly increased expression of HERV-K, compared to controls. These findings suggest that endogenous retroviral elements are involved in the pathophysiology of ALS, but there is no evidence that they are the primary cause of the syndrome. Published by Elsevier B.V.

Separating the effect of reward from corrective feedback during learning in patients with Parkinson's disease.

PubMed

Freedberg, Michael; Schacherer, Jonathan; Chen, Kuan-Hua; Uc, Ergun Y; Narayanan, Nandakumar S; Hazeltine, Eliot

2017-06-01

Parkinson's disease (PD) is associated with procedural learning deficits. Nonetheless, studies have demonstrated that reward-related learning is comparable between patients with PD and controls (Bódi et al., Brain, 132(9), 2385-2395, 2009; Frank, Seeberger, & O'Reilly, Science, 306(5703), 1940-1943, 2004; Palminteri et al., Proceedings of the National Academy of Sciences of the United States of America, 106(45), 19179-19184, 2009). However, because these studies do not separate the effect of reward from the effect of practice, it is difficult to determine whether the effect of reward on learning is distinct from the effect of corrective feedback on learning. Thus, it is unknown whether these group differences in learning are due to reward processing or learning in general. Here, we compared the performance of medicated PD patients to demographically matched healthy controls (HCs) on a task where the effect of reward can be examined separately from the effect of practice. We found that patients with PD showed significantly less reward-related learning improvements compared to HCs. In addition, stronger learning of rewarded associations over unrewarded associations was significantly correlated with smaller skin-conductance responses for HCs but not PD patients. These results demonstrate that when separating the effect of reward from the effect of corrective feedback, PD patients do not benefit from reward.

Ethnic differences in lens parameters measured by ocular biometry in a cataract surgery population.

PubMed

Wang, Dajiang; Amoozgar, Behzad; Porco, Travis; Wang, Zhen; Lin, Shan C

2017-01-01

To investigate whether differences exist in lens position and other lens parameters among major ethnic groups with cataractous eyes, which may help explain racial differences in angle closure risk. This retrospective, cross-sectional study included 807 adult patients who had cataract surgery between years 2014 and 2016 at the University of California, San Francisco (UCSF). Adult patients of white, Asian, Hispanic and African-American ethnicity were included. Lens position (LP), defined as anterior chamber depth (ACD) + 1/2 lens thickness (LT), was assessed using measurements from optical biometry. Other assessed biometric parameters included axial length (AL), relative lens position (RLP) (defined as LP/AL), and anterior chamber depth (ACD). A total of 807 patients and 1361 eyes were included in this study from a database of patients having cataract surgery. Mean age was 69.2 years (age range from 18 to 101 years old), and 60.3% of patients were women. The mean LP measurements were 5.54±0.32 mm for white, 5.38±0.32 mm for Asian, 5.32±0.30 mm for Hispanic, and 5.40±0.28 mm for African-American participants. After adjusting for age, sex, and AL, significant differences were found when comparing LP in paired comparisons among White cohort with Asians (P<0.001), Hispanics (P<0.001) and African-Americans (P = 0.003). Additionally, when comparing RLP, similar significant results were found when comparing Whites with Asians (P<0.001), Hispanics (P<0.001) and African-Americans (P = 0.002). Lastly, pair-wise comparison of LT between ethnic groups showed significant differences while comparing Asians with Whites (P = 0.001) and Asians with African-Americans (P<0.001). The results of this study suggest that the LP of Hispanic, Asian, and African-American patients are significantly smaller than that of White patients, and among all ethnic groups, Hispanics and after Asians have the smallest LP (P<0.001) and RLP (P<0.001). These findings may have implications for the relative risk of angle closure and the potential IOP response after cataract surgery among different ethnic groups.

Combined riluzole and sodium phenylbutyrate therapy in transgenic amyotrophic lateral sclerosis mice.

PubMed

Del Signore, Steven J; Amante, Daniel J; Kim, Jinho; Stack, Edward C; Goodrich, Sarah; Cormier, Kerry; Smith, Karen; Cudkowicz, Merit E; Ferrante, Robert J

2009-04-01

Recent evidence suggests that transcriptional dysregulation may play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS). The histone deacetylase inhibitor, sodium phenylbutyrate (NaPB), is neuroprotective and corrects aberrant gene transcription in ALS mice and has recently been shown to be safe and tolerable in ALS patients while improving hypoacetylation. Since many patients are already on riluzole, it is important to ensure that any proposed therapy does not result in negative synergy with riluzole. The combined treatment of riluzole and NaPB significantly extended survival and improved both the clinical and neuropathological phenotypes in G93A transgenic ALS mice beyond either agent alone. Combination therapy increased survival by 21.5%, compared to the separate administration of riluzole (7.5%) and NaPB (12.8%), while improving both body weight loss and grip strength. The data show that the combined treatment was synergistic. In addition, riluzole/NaPB treatment ameliorated gross lumbar and ventral horn atrophy, attenuated lumbar ventral horn neuronal cell death, and decreased reactive astrogliosis. Riluzole/NaPB administration increased acetylation at H4 and increased NF-kappaB p50 translocation to the nucleus in G93A mice, consistent with a therapeutic effect. These data suggest that NaPB may not interfere with the pharmacologic action of riluzole in ALS patients.

Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial.

PubMed

2017-07-01

In a previous phase 3 study in patients with amyotrophic lateral sclerosis (ALS), edaravone did not show a significant difference in the Revised ALS Functional Rating Scale (ALSFRS-R) score compared with placebo. Post-hoc analysis of these data revealed that patients in an early stage with definite or probable diagnosis of ALS, defined by the revised El Escorial criteria, who met a select set of inclusion criteria showed a greater magnitude of effect than did the full study population. We aimed to substantiate this post-hoc result and assess safety and efficacy of edaravone in a phase 3 trial that focused on patients with early stage ALS who met the post-hoc analysis inclusion criteria. In this phase 3, randomised, double-blind, parallel-group study, patients aged 20-75 years with ALS of grade 1 or 2 in the Japan ALS Severity Classification, scores of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of 80% or more, definite or probable ALS according to the revised El Escorial criteria, and disease duration of 2 years or less were recruited from 31 hospitals in Japan. Eligible patients also had a decrease of 1-4 points in the ALSFRS-R score during a 12-week observation period before randomisation. Patients meeting all criteria were then randomly assigned 1:1 to receive 60 mg intravenous edaravone or intravenous saline placebo for 6 cycles (4 weeks per cycle with 2 weeks on, 2 weeks off) for a total treatment duration of 24 weeks. In cycle 1, the study drug or placebo was administered once per day for 14 days within a 14 day period, followed by the drug-free period. In cycle 2 and thereafter, the study drug or placebo was administered for 10 days within a 14 day period, followed by a 2 week drug-free period. Participants and investigators, including those assessing outcomes, were masked to treatment allocation. The primary efficacy outcome was the change in ALSFRS-R score from the baseline to 24 weeks (or at discontinuation if this was after the third cycle) after randomisation. The primary outcome was assessed in all patients who had received at least one treatment infusion, had at least one assessment post-baseline, and reached the end of cycle 3. For patients with missing values at the end of cycle 6, data were imputed by the last observation carried forward (LOCF) method, provided the patients had completed at least cycle 3. Safety was assessed in all patients who had received at least one treatment infusion and had at least one assessment post-baseline. This trial is registered with ClinicalTrials.gov, NCT01492686. Between Nov 28, 2011, and Sept 3, 2014, we screened 213 patients, and enrolled 192 as potential participants. Of these, 137 patients completed the observation period: 69 were randomly assigned to receive edaravone, and 68 were randomly assigned to receive placebo. 68 patients taking edaravone and 66 taking placebo were included in the primary efficacy analysis. For the primary outcome, the change in ALSFRS-R score was -5·01 (SE 0·64) in the edavarone group and -7·50 (0·66) in the placebo group. The least-squares mean difference between groups was 2·49 (SE 0·76, 95% CI 0·99-3·98; p=0·0013) in favour of edaravone. Treatment-emergent adverse events were reported in 58 (84%) patients receiving edaravone and 57 (84%) patients receiving placebo. 11 (16%) patients taking edaravone and 16 (24%) taking placebo had serious adverse events, and one (1%) patient receiving edaravone and four (6%) patients receiving placebo had adverse events (one dysphagia in edaravone group and one dyspnoea, two respiratory disorder, and one rash in the placebo group) that led to withdrawal. Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo. There is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria. Mitsubishi Tanabe Pharma Corporation. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Continuous oral hydration or with fractionated doses in acute diarrhea-induced dehydration in children].

PubMed

Mota-Hernández, Felipe; Gutiérrez-Camacho, Claudia; Cabrales-Martínez, Rosa Georgina; Villa-Contreras, Sofía

2002-01-01

To evaluate the safety and effectiveness of two oral rehydration techniques. A randomized clinical trial was conducted at the oral rehydration unit of Hospital Infantil de Mexico "Federico Gomez", between September 1998 and June 1999. Forty patients five-year old and younger children, dehydrated due to acute diarrhea, were given oral rehydration solution (ORS) ad libitum (AL group); another forty patients received ORS in fractionated doses (FD group). Clinical characteristics were similar in both groups. Results are presented as means, standard deviations and medians, according the distribution of simple and relative frequencies. The mean stool output in the AL group was 11.0 +/- 7.5 g/kg/h; as compared to 7.1 +/- 7.4 in the FD group (p = 0.03). ORS intake, rehydration time, and mean diuresis values were similar in both groups (p > 0.05). Six patients in the AL group and five in the FD group had high stool output (> 10 g/kg/h), that improved after administration of rice starch solution. One patient in the AL group and two in the FD group had persistent vomiting that improved with gastroclisis. No patient required intravenous rehydration. These results suggest that ORS administration ad libitum under supervision, is a technique as safe and effective as the fractionated doses technique, for the treatment of dehydrated children due to acute diarrhea.

Prognostic value of left atrial function in systemic light-chain amyloidosis: a cardiac magnetic resonance study.

PubMed

Mohty, Dania; Boulogne, Cyrille; Magne, Julien; Varroud-Vial, Nicolas; Martin, Sylvain; Ettaif, Hind; Fadel, Bahaa M; Bridoux, Frank; Aboyans, Victor; Damy, Thibaud; Jaccard, Arnaud

2016-09-01

Cardiac involvement in systemic light-chain amyloidosis (AL) imparts an adverse impact on outcome. The left atrium (LA), by virtue of its anatomical location and muscular wall, is commonly affected by the amyloid process. Although LA infiltration by amyloid fibrils leads to a reduction in its pump function, the infiltration of the left ventricular (LV) myocardium results in diastolic dysfunction with subsequent increase in filling pressures and LA enlargement. Even though left atrial volume (LAV) is an independent prognostic marker in many cardiomyopathies, its value in amyloid heart disease remains to be determined. In addition, few data are available as to the prognostic value of LA function in systemic AL. Using cardiac magnetic resonance (CMR), the current study aims to assess the prognostic significance of the maximal LAV and total LA emptying fraction (LAEF) in patients with AL. Fifty-four consecutive patients (age 66 ± 10 years, 59% males) with confirmed systemic AL and mean LV ejection fraction of 60 ± 12% underwent CMR. As compared with patients with no or minimal cardiac involvement (Mayo Clinic [MC] stage I), those at moderate and high risk (MC stages II and III) had significantly larger indexed maximal LAV (36 ± 15 vs. 46 ± 13 vs. 52 ± 19 mL/m(2), P = 0.03) and indexed minimal LAV (20 ± 6 vs. 34 ± 11 vs. 44 ± 17 mL/m(2), P < 0.001), lower LAEF (42 ± 9 vs. 26 ± 13 vs. 16 ± 9%, P < 0.0001) but similar LVEF. Furthermore, myocardial late gadolinium enhancement (LGE) was more frequent and significantly associated with lower LAEF. LAEF was also significantly lower in symptomatic (NHYA ≥ II, 22 ± 14%) as compared with asymptomatic patients (NYHA class I, 33 ± 13%, P = 0.006). Two-year survival rate was lower in patients with LAEF ≤ 16% as compared with those with LAEF > 16% (37 ± 11 vs. 94 ± 4%, P = 0.001). In multivariate analysis, lower LAEF remained independently associated with a higher risk of 2-year mortality (HR = 1.08 per 1% decrease, 95% CI: 1.02-1.15, P = 0.003). In patients with systemic AL, LAEF as assessed by CMR is associated with NYHA functional class, MC stage, myocardial LGE and 2-year mortality. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Dynamic effects of adrenaline (epinephrine) in out-of-hospital cardiac arrest with initial pulseless electrical activity (PEA).

PubMed

Nordseth, Trond; Olasveengen, Theresa Mariero; Kvaløy, Jan Terje; Wik, Lars; Steen, Petter Andreas; Skogvoll, Eirik

2012-08-01

In cardiac arrest, pulseless electrical activity (PEA) is a challenging clinical syndrome. In a randomized study comparing intravenous (i.v.) access and drugs versus no i.v. access or drugs during advanced life support (ALS), adrenaline (epinephrine) improved return of spontaneous circulation (ROSC) in patients with PEA. Originating from this study, we investigated the time-dependent effects of adrenaline on clinical state transitions in patients with initial PEA, using a non-parametric multi-state statistical model. Patients with available defibrillator recordings were included, of whom 101 received adrenaline and 73 did not. There were significantly more state transitions in the adrenaline group than in the no-adrenaline group (rate ratio = 1.6, p<0.001). Adrenaline markedly increased the rate of transition from PEA to ROSC during ALS and slowed the rate of being declared dead; e.g. by 20 min 20% of patients in the adrenaline group had been declared dead and 25% had obtained ROSC, whereas 50% in the no-adrenaline group have been declared dead and 15% had obtained ROSC. The differential effect of adrenaline could be seen after approx. 10 min of ALS for most transitions. For both groups the probability of deteriorating from PEA to asystole was highest during the first 15 min. Adrenaline increased the rate of transition from PEA to ventricular fibrillation or -tachycardia (VF/VT), and from ROSC to VF/VT. Adrenaline has notable clinical effects during ALS in patients with initial PEA. The drug extends the time window for ROSC to develop, but also renders the patient more unstable. Further research should investigate the optimal dose, timing and mode of adrenaline administration during ALS. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

An analysis of prognostic factors after percutaneous endoscopic gastrostomy placement in Japanese patients with amyotrophic lateral sclerosis.

PubMed

Nagashima, Kazuaki; Furuta, Natsumi; Makioka, Kouki; Fujita, Yukio; Ikeda, Masaki; Ikeda, Yoshio

2017-05-15

A percutaneous endoscopic gastrostomy (PEG) is an useful intervention for feeding of amyotrophic lateral sclerosis (ALS) patients who have lost oral intake function. The aim of this study was to investigate the risk factors for early death and the survival after PEG placement. A total of 102 ALS patients who underwent PEG placement were enrolled in this study. Patients were divided into two groups; the poor prognosis group included patients who died or needed permanent mechanical ventilation within 30days after PEG placement, and the good prognosis group included patients who did not meet the criteria of the poor prognosis group. Clinical characteristics, respiratory function, and nutritional parameters were compared for the two groups to assess the correlations between clinical and laboratory variables and early death after PEG placement. Multivariate analysis between two groups revealed that higher arterial carbon dioxide pressure (PaCO 2 ) and aphagia before PEG placement were significantly associated with the poor prognosis group. Multivariate analysis for survival also revealed that higher PaCO 2 and shorter duration from onset to PEG placement were significantly associated with shorter survival after PEG placement. In conclusion, respiratory and nutritional parameters are revealed to be important prognostic factors for ALS patients who undergo PEG placement. Copyright © 2017 Elsevier B.V. All rights reserved.

Multidisciplinary ALS Telemedicine Care: The Store and Forward Method.

PubMed

Pulley, Michael T; Brittain, Rebecca; Hodges, Wayne; Frazier, Christine; Miller, Leslie; Matyjasik-Liggett, Maria; Maurer, Susan; Peters, Melissa; Solomon, Kimberly; Berger, Alan R

2018-05-26

ALS patients benefit from multidisciplinary care in an ALS clinic. We studied whether multidisciplinary care of ALS patients using the store and forward method of telemedicine was feasible and acceptable to patients and providers. ALS patients seen in the UF Jacksonville ALS clinic were eligible. A trained telemedicine nurse performed and recorded a multidisciplinary assessment of the patient in their home. Clinic team members reviewed the assessments, provided recommendations and the clinic director discussed the plan with the patient via videoconference. Patient and provider satisfaction was evaluated using surveys. 18 patients completed a total of 27 telemedicine visits. Patient satisfaction was excellent and provider satisfaction was very good. The store and forward method of telemedicine is an acceptable alternative to live telemedicine for the multidisciplinary care of ALS patients. This method of care may improve access to multidisciplinary care for this patient population. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Frontal and temporal lobe involvement on verbal fluency measures in amyotrophic lateral sclerosis.

PubMed

Lepow, Lauren; Van Sweringen, James; Strutt, Adriana M; Jawaid, Ali; MacAdam, Claire; Harati, Yadollah; Schulz, Paul E; York, Michele K

2010-11-01

Amyotrophic lateral sclerosis (ALS) has been associated with changes in frontal and temporal lobe-mediated cognitive and behavioral functions. Verbal fluency, a sensitive measure to these changes, was utilized to investigate phonemic and semantic abilities in 49 ALS patients and 25 healthy controls (HCs). A subset of the ALS patients was classified as ALS-intact, ALS with mild cognitive impairments (ALS-mild), and ALS with fronto-temporal dementia (ALS-FTD) based on a comprehensive neuropsychological evaluation. Clustering and switching, the underlying component processes of verbal fluency, were analyzed using Troyer's (Troyer, Moscovitch, & Winocur, 1997) and Abwender's (Abwender, Swan, Bowerman, & Connolly, 2001) scoring systems. ALS patients exhibited decreased fluency versus HCs. For phonemic fluency, the intact ALS sample generated fewer clusters and more switches than the ALS-mild and ALS-FTD patients using both scoring systems. This suggests temporal involvement in ALS patients, with increasing frontal lobe involvement in patients with greater cognitive dysfunction. For semantic fluency, similar results were obtained with a greater emphasis on declines in clustering or increased temporal lobe dysfunction. These results suggest that verbal fluency measures identify frontal and temporal lobe involvement in the cognitive decline associated with ALS, particularly when the component processes are evaluated. The clinical utility of these scoring systems with ALS patients is also discussed.

Increased Prognostic Value of Query Amyloid Late Enhancement Score in Light-Chain Cardiac Amyloidosis.

PubMed

Wan, Ke; Sun, Jiayu; Han, Yuchi; Liu, Hong; Yang, Dan; Li, Weihao; Wang, Jie; Cheng, Wei; Zhang, Qing; Zeng, Zhi; Chen, Yucheng

2018-02-23

Late gadolinium enhancement (LGE) pattern is a powerful imaging biomarker for prognosis of cardiac amyloidosis. It is unknown if the query amyloid late enhancement (QALE) score in light-chain (AL) amyloidosis could provide increased prognostic value compared with LGE pattern.Methods and Results:Seventy-eight consecutive patients with AL amyloidosis underwent contrast-enhanced cardiovascular magnetic resonance imaging. Patients with cardiac involvement were grouped by LGE pattern and analyzed using QALE score. Receiver operating characteristic curve was used to identify the optimal cut-off for QALE score in predicting all-cause mortality. Survival of these patients was analyzed with the Kaplan-Meier method and multivariate Cox regression. During a median follow-up of 34 months, 53 of 78 patients died. The optimal cut-off for QALE score to predict mortality at 12-month follow-up was 9.0. On multivariate Cox analysis, QALE score ≥9 (HR, 5.997; 95% CI: 2.665-13.497; P<0.001) and log N-terminal pro-brain natriuretic peptide (HR, 1.525; 95% CI: 1.112-2.092; P=0.009) were the only 2 independent predictors of all-cause mortality. On Kaplan-Meier analysis, patients with subendocardial LGE can be further risk stratified using QALE score ≥9. The QALE scoring system provides powerful independent prognostic value in AL cardiac amyloidosis. QALE score ≥9 has added value to differentiate prognosis in AL amyloidosis patients with a subendocardial LGE pattern.

Circadian course of the P300 ERP in patients with amyotrophic lateral sclerosis - implications for brain-computer interfaces (BCI).

PubMed

Erlbeck, Helena; Mochty, Ursula; Kübler, Andrea; Real, Ruben G L

2017-01-07

Accidents or neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) can lead to progressing, extensive, and complete paralysis leaving patients aware but unable to communicate (locked-in state). Brain-computer interfaces (BCI) based on electroencephalography represent an important approach to establish communication with these patients. The most common BCI for communication rely on the P300, a positive deflection arising in response to rare events. To foster broader application of BCIs for restoring lost function, also for end-users with impaired vision, we explored whether there were specific time windows during the day in which a P300 driven BCI should be preferably applied. The present study investigated the influence of time of the day and modality (visual vs. auditory) on P300 amplitude and latency. A sample of 14 patients (end-users) with ALS and 14 healthy age matched volunteers participated in the study and P300 event-related potentials (ERP) were recorded at four different times (10, 12 am, 2, & 4 pm) during the day. Results indicated no differences in P300 amplitudes or latencies between groups (ALS patients v. healthy participants) or time of measurement. In the auditory condition, latencies were shorter and amplitudes smaller as compared to the visual condition. Our findings suggest applicability of EEG/BCI sessions in patients with ALS throughout normal waking hours. Future studies using actual BCI systems are needed to generalize these findings with regard to BCI effectiveness/efficiency and other times of day.

Brain Painting: First Evaluation of a New Brain–Computer Interface Application with ALS-Patients and Healthy Volunteers

PubMed Central

Münßinger, Jana I.; Halder, Sebastian; Kleih, Sonja C.; Furdea, Adrian; Raco, Valerio; Hösle, Adi; Kübler, Andrea

2010-01-01

Brain–computer interfaces (BCIs) enable paralyzed patients to communicate; however, up to date, no creative expression was possible. The current study investigated the accuracy and user-friendliness of P300-Brain Painting, a new BCI application developed to paint pictures using brain activity only. Two different versions of the P300-Brain Painting application were tested: A colored matrix tested by a group of ALS-patients (n = 3) and healthy participants (n = 10), and a black and white matrix tested by healthy participants (n = 10). The three ALS-patients achieved high accuracies; two of them reaching above 89% accuracy. In healthy subjects, a comparison between the P300-Brain Painting application (colored matrix) and the P300-Spelling application revealed significantly lower accuracy and P300 amplitudes for the P300-Brain Painting application. This drop in accuracy and P300 amplitudes was not found when comparing the P300-Spelling application to an adapted, black and white matrix of the P300-Brain Painting application. By employing a black and white matrix, the accuracy of the P300-Brain Painting application was significantly enhanced and reached the accuracy of the P300-Spelling application. ALS-patients greatly enjoyed P300-Brain Painting and were able to use the application with the same accuracy as healthy subjects. P300-Brain Painting enables paralyzed patients to express themselves creatively and to participate in the prolific society through exhibitions. PMID:21151375

How Do Korsakoff Patients Learn New Concepts?

ERIC Educational Resources Information Center

Pitel, Anne Lise; Beaunieux, Helene; Guillery-Girard, Berengere; Witkowski, Thomas; de la Sayette, Vincent; Viader, Fausto; Desgranges, Beatrice; Eustache, Francis

2009-01-01

The goal of the present investigation was to assess semantic learning in Korsakoff patients (KS), compared with uncomplicated alcoholics (AL) and control subjects (CS), taking the nature of the information to-be-learned and the episodic memory profiles of the three groups into account. Ten new complex concepts, each illustrated by a photo and…

Functional Cardiac Magnetic Resonance Imaging (MRI) in the Assessment of Myocardial Viability and Perfusion

PubMed Central

2003-01-01

Executive Summary Objective The objective of this health technology policy assessment was to determine the effectiveness safety and cost-effectiveness of using functional cardiac magnetic resonance imaging (MRI) for the assessment of myocardial viability and perfusion in patients with coronary artery disease and left ventricular dysfunction. Results Functional MRI has become increasingly investigated as a noninvasive method for assessing myocardial viability and perfusion. Most patients in the published literature have mild to moderate impaired LV function. It is possible that the severity of LV dysfunction may be an important factor that can alter the diagnostic accuracy of imaging techniques. There is some evidence of comparable or better performance of functional cardiac MRI for the assessment of myocardial viability and perfusion compared with other imaging techniques. However limitations to most of the studies included: Functional cardiac MRI studies that assess myocardial viability and perfusion have had small sample sizes. Some studies assessed myocardial viability/perfusion in patients who had already undergone revascularization, or excluded patients with a prior MI (Schwitter et al., 2001). Lack of explicit detail of patient recruitment. Patients with LVEF >35%. Interstudy variability in post MI imaging time(including acute or chronic MI), when patients with a prior MI were included. Poor interobserver agreement (kappa statistic) in the interpretation of the results. Traditionally, 0.80 is considered “good”. Cardiac MRI measurement of myocardial perfusion to as an adjunct tool to help diagnose CAD (prior to a definitive coronary angiography) has also been examined in some studies, with methodological limitations, yielding comparable results. Many studies examining myocardial viability and perfusion report on the accuracy of imaging methods with limited data on long-term patient outcome and management. Kim et al. (2000) revealed that the transmural extent of hyperenhancement was significantly related to the likelihood of improvement in contractility after revascularization. However, the LVEF in the patient population was 43% prior to revascularization. It is important to know whether the technique has the same degree of accuracy in patients who have more severe LV dysfunction and who would most benefit from an assessment of myocardial viability. “Substantial” viability used as a measure of a patient’s ability to recover after revascularization has not been definitively reported (how much viability is enough?). Patients with severe LV dysfunction are more likely to have mixtures of surviving myocardium, including normal, infarcted, stunned and hibernating myocardium (Cowley et al., 1999). This may lead to a lack of homogeneity of response to testing and to revascularization and contribute to inter- and intra-study differences. There is a need for a large prospective study with adequate follow-up time for patients with CAD and LV dysfunction (LVEF<35%) comparing MRI and an alternate imaging technique. There is some evidence that MRI has comparable sensitivity, specificity and accuracy to PET for determining myocardial viability. However, there is a lack of evidence comparing the accuracy of these two techniques to predict LV function recovery. In addition, some studies refer to PET as the gold standard for the assessment of myocardial viability. Therefore, PET may be an ideal noninvasive imaging comparator to MRI for a prospective study with follow-up. To date, there is a lack of cost-effectiveness analyses (or any economic analyses) of functional cardiac MRI versus an alternate noninvasive imaging method for the assessment of myocardial viability/perfusion. Conclusion There is some evidence that the accuracy of functional cardiac MRI compares favourably with alternate imaging techniques for the assessment of myocardial viability and perfusion. There is insufficient evidence whether functional cardiac MRI can better select which patients [who have CAD and severe LV dysfunction (LVEF <35%)] may benefit from revascularization compared with an alternate noninvasive imaging technology. There is insufficient evidence whether functional cardiac MRI can better select which patients should proceed to invasive coronary angiography for the definitive diagnosis of CAD, compared with an alternate noninvasive imaging technology. There is a need for a large prospective (potentially multicentre) study with adequate follow-up time for patients with CAD and LV dysfunction (LVEF<35%) comparing MRI and PET. Since longer follow-up time may be associated with restenosis or graft occlusion, it has been suggested to have serial measurements after revascularization (Cowley et al., 1999). PMID:23074446

Varying levels of small microcalcifications and macrophages in ATTR and AL cardiac amyloidosis: implications for utilizing nuclear medicine studies to subtype amyloidosis.

PubMed

Stats, Miriam A; Stone, James R

2016-01-01

Recently, there has been much interest in using nuclear medicine studies to noninvasively identify and subtype cardiac amyloidosis. In particular, modified bone scans using (99m)Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ((99m)Tc-DPD) and (99m)Tc-pyrophosphate ((99m)Tc-PYP) are being used to selectively identify patients with ATTR amyloidosis rather than AL amyloidosis. The morphologic basis underlying the selectivity of these imaging modalities for ATTR amyloidosis has been unclear. To determine if variations in microcalcifications and/or macrophages within ATTR and AL amyloidosis might be responsible for the selectivity for these imaging modalities, 8 endomyocardial biopsies of ATTR amyloidosis and 7 endomyocardial biopsies of AL amyloidosis were stained with von Kossa calcium stains and with immunohistochemistry for the macrophage marker CD68. Compared with AL amyloidosis, there was a greater density of small microcalcifications in cases of ATTR amyloidosis (mean=16.8 vs. 6.5 per 200× field, P=.008). In contrast, there were fewer macrophages in ATTR amyloidosis compared with AL amyloidosis (mean=2.5 vs. 11.7 per 200× field, P=.0004). The density of microcalcifications within each group was not related to patient age, echocardiographic features of cardiac function, or serum levels of calcium and creatinine. These data suggest that microcalcifications but not macrophages likely underlie the selectivity of modified bone scans for ATTR amyloidosis and suggest that other pathologic entities containing microcalcifications might also result in positive scans with these imaging modalities. Copyright © 2016 Elsevier Inc. All rights reserved.

Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease

PubMed Central

Lim, M. A.; Selak, M. A.; Xiang, Z.; Krainc, D.; Neve, R. L.; Kraemer, B. C.; Watts, J. L.

2012-01-01

A growing body of research indicates that amyotrophic lateral sclerosis (ALS) patients and mouse models of ALS exhibit metabolic dysfunction. A subpopulation of ALS patients possesses higher levels of resting energy expenditure and lower fat-free mass compared to healthy controls. Similarly, two mutant copper zinc superoxide dismutase 1 (mSOD1) mouse models of familial ALS possess a hypermetabolic phenotype. The pathophysiological relevance of the bioenergetic defects observed in ALS remains largely elusive. AMP-activated protein kinase (AMPK) is a key sensor of cellular energy status and thus might be activated in various models of ALS. Here, we report that AMPK activity is increased in spinal cord cultures expressing mSOD1, as well as in spinal cord lysates from mSOD1 mice. Reducing AMPK activity either pharmacologically or genetically prevents mSOD1-induced motor neuron death in vitro. To investigate the role of AMPK in vivo, we used Caenorhabditis elegans models of motor neuron disease. C. elegans engineered to express human mSOD1 (G85R) in neurons develops locomotor dysfunction and severe fecundity defects when compared to transgenic worms expressing human wild-type SOD1. Genetic reduction of aak-2, the ortholog of the AMPK α2 catalytic subunit in nematodes, improved locomotor behavior and fecundity in G85R animals. Similar observations were made with nematodes engineered to express mutant tat-activating regulatory (TAR) DNA-binding protein of 43 kDa molecular weight. Altogether, these data suggest that bioenergetic abnormalities are likely to be pathophysiologically relevant to motor neuron disease. PMID:22262909

Comparison of GnRh Agonist Microdose Flare Up and GnRh Antagonist/Letrozole in Treatment of Poor Responder Patients in Intra Cytoplaspic Sperm Injection: Randomized Clinical Trial.

PubMed

Nabati, Azar; Peivandi, Sepideh; Khalilian, Alireza; Mirzaeirad, Sina; Hashemi, Seyyed Abbas

2015-08-06

the prevalence of infertility is up to 10 to 15 % which 9 to 24 % of them are Poor Ovarian Responders (POR). This study was designed to compare two methods of GnRH Agonist Microdose Flareup (MF) and GnRH Antagonist/Letrozole (AL) in treatment of these patients. this randomized clinical trial study consisted of 123 patients. In the first step of treatment in both methods FSH, LH, estradiol, anderostandion, testestron in third day of menstruation period and the thickness of endometrium by Transvaginal sonography were evaluated. At the time of HCG injection the thickness of endometrium and follicles which were more than 14mm ware established and hormones were evaluated. Two weeks later serum βhCG and after 6 to 8 weeks Transvaginal sonography were applied to prove the pregnancy. there were 61 patients with mean age of 38.7±4.58 in MF group and 62 patients with mean age of 38.5±4.6 in AL group (P=0.80). At the time of hCG injection there were significant increase in the level of LH,estradiol, thickness of endometrium and follicles more than 14mm in MF patients (P<0.0001). The mean time of ovary stimulation in MF group was 10.72±1.5 and in AL was 8.45±1.2 (P<0.0001). The mean level of gonadotropin which were used was 80.6±20.1 in MF patients and 64.7±16.4 in AL group (P<0.0001). 18 % of MF group and 38.7% in AL group had no normal cycle of ovulation (OR: 2.87, 95% CI: 1.25-6.57, P=0.011). The mean numbers of oocyte and normal fetus in MF was 5.83±3.5 and 3.7±2.5 and in AL was 3±1.69 and 1.4±1.33 (P<0.0001). The number of chemical pregnancy in MF group was 10 (16.4%) and in AL was 3 (4.8%) (OR:3.85, 95%CI:1.06-14.77, P=0.037). Clinical pregnancy in 10 patients (16.4%) of MF group and 3 (4.8%)in AL was reported. OR: 3.85, 95%CI: 1.06-14.77, P=0.037). this study showed that MF method of pregnancy leads to more positive results in pregnancy based on chemical and clinical evaluation in comparison with AL and is advised for poor responder patients.

Comparison of GnRh Agonist Microdose Flare Up and GnRh Antagonist/Letrozole in Treatment of Poor Responder Patients in Intra Cytoplaspic Sperm Injection: Randomized Clinical Trial

PubMed Central

Nabati, Azar; Peivandi, Sepideh; Khalilian, Alireza; Mirzaeirad, Sina; Hashemi, Seyyed Abbas

2016-01-01

Backgrounds: the prevalence of infertility is up to 10 to 15 % which 9 to 24 % of them are Poor Ovarian Responders (POR). This study was designed to compare two methods of GnRH Agonist Microdose Flareup (MF) and GnRH Antagonist/Letrozole (AL) in treatment of these patients. Methods and Materials: this randomized clinical trial study consisted of 123 patients. In the first step of treatment in both methods FSH, LH, estradiol, anderostandion, testestron in third day of menstruation period and the thickness of endometrium by Transvaginal sonography were evaluated. At the time of HCG injection the thickness of endometrium and follicles which were more than 14mm ware established and hormones were evaluated. Two weeks later serum βhCG and after 6 to 8 weeks Transvaginal sonography were applied to prove the pregnancy. Results: there were 61 patients with mean age of 38.7±4.58 in MF group and 62 patients with mean age of 38.5±4.6 in AL group (P=0.80). At the time of hCG injection there were significant increase in the level of LH, estradiol, thickness of endometrium and follicles more than 14mm in MF patients (P<0.0001). The mean time of ovary stimulation in MF group was 10.72±1.5 and in AL was 8.45±1.2 (P<0.0001). The mean level of gonadotropin which were used was 80.6±20.1 in MF patients and 64.7±16.4 in AL group (P<0.0001). 18 % of MF group and 38.7% in AL group had no normal cycle of ovulation (OR: 2.87, 95% CI: 1.25-6.57, P=0.011). The mean numbers of oocyte and normal fetus in MF was 5.83±3.5 and 3.7±2.5 and in AL was 3±1.69 and 1.4±1.33 (P<0.0001). The number of chemical pregnancy in MF group was 10 (16.4%) and in AL was 3 (4.8%) (OR 3.85, 95% CI: 1.06-14.77, P=0.037). Clinical pregnancy in 10 patients (16.4%) of MF group and 3 (4.8%)in AL was reported. OR 3.85, 95% CI: 1.06-14.77, P=0.037). Conclusion: this study showed that MF method of pregnancy leads to more positive results in pregnancy based on chemical and clinical evaluation in comparison with AL and is advised for poor responder patients. PMID:26573041

Family health care decision making and self-efficacy with patients with ALS at the end of life

PubMed Central

NOLAN, MARIE T.; KUB, JOAN; HUGHES, MARK T.; TERRY, PETER B.; ASTROW, ALAN B.; CARBO, CYNTHIA A.; THOMPSON, RICHARD E.; CLAWSON, LORA; TEXEIRA, KENNETH; SULMASY, DANIEL P.

2008-01-01

Objective: Persons with ALS differ from those with other terminal illnesses in that they commonly retain capacity for decision making close to death. The role patients would opt to have their families play in decision making at the end of life may therefore be unique. This study compared the preferences of patients with ALS for involving family in health care decisions at the end of life with the actual involvement reported by the family after death. Methods: A descriptive correlational design with 16 patient–family member dyads was used. Quantitative findings were enriched with in-depth interviews of a subset of five family members following the patient's death. Results: Eighty-seven percent of patients had issued an advance directive. Patients who would opt to make health care decisions independently (i.e., according to the patient's preferences alone) were most likely to have their families report that decisions were made in the style that the patient preferred. Those who preferred shared decision making with family or decision making that relied upon the family were more likely to have their families report that decisions were made in a style that was more independent than preferred. When interviewed in depth, some family members described shared decision making although they had reported on the survey that the patient made independent decisions. Significance of results: The structure of advance directives may suggest to families that independent decision making is the ideal, causing them to avoid or underreport shared decision making. Fear of family recriminations may also cause family members to avoid or underreport shared decision making. Findings from this study might be used to guide clinicians in their discussions of treatments and health care decision making with persons with ALS and their families. PMID:18662421

Evaluation of Patient Satisfaction Using the EORTC IN-PATSAT32 Questionnaire and Surgical Outcome in Single-Port Surgery for Benign Adnexal Disease: Observational Comparison with Traditional Laparoscopy

PubMed Central

Buda, Alessandro; Passoni, Paolo; Bargossi, Lorena; Baldo, Romina; Milani, Rodolfo

2013-01-01

Laparoscopic surgery has been demonstrated as a valid approach in almost all gynaecologic procedures including malignant diseases. Benefits of the minimally invasive approach over traditional open surgery have been well demonstrated in terms of minimal perioperative morbidity and reduced postoperative pain and hospital stay duration, with consequent quick postoperative recovery (Medeiros et al. (2009)). Single-port surgery resurfaced in gynaecology surgery in recent years and renewed interest among other surgeons and within the industry to develop this field (Podolsky et al. (2009)). Patient satisfaction is emerging as an increasingly important measure of quality which represents a complex entity that is dependent on patient demographics, comorbidities, disease, and, to a large extent, patient expectations (Tomlinson and Ko (2006)). It can be broadly thought to refer to all relevant experiences and processes associated with health care delivery (Jackson et al. (2001)). In this study we aim to compare single-port surgery (SPS) with conventional laparoscopy in terms of patient satisfaction using the EORTC IN-PATSAT32 questionnaire. We also evaluate the main surgical outcomes of both minimally invasive approaches. PMID:24371418

Development of a model to guide decision making in amyotrophic lateral sclerosis multidisciplinary care.

PubMed

Hogden, Anne; Greenfield, David; Nugus, Peter; Kiernan, Matthew C

2015-10-01

Patients with amyotrophic lateral sclerosis (ALS) face numerous decisions for symptom management and quality of life. Models of decision making in chronic disease and cancer care are insufficient for the complex and changing needs of patients with ALS . The aim was to examine the question: how can decision making that is both effective and patient-centred be enacted in ALS multidisciplinary care? Fifty-four respondents (32 health professionals, 14 patients and eight carers) from two specialized ALS multidisciplinary clinics participated in semi-structured interviews. Interviews were transcribed, coded and analysed thematically. Comparison of stakeholder perspectives revealed six key themes of ALS decision making. These were the decision-making process; patient-centred focus; timing and planning; information sources; engagement with specialized ALS services; and access to non-specialized services. A model, embedded in the specialized ALS multidisciplinary clinic, was derived to guide patient decision making. The model is cyclic, with four stages: 'Participant Engagement'; 'Option Information'; 'Option Deliberation'; and 'Decision Implementation'. Effective and patient-centred decision making is enhanced by the structure of the specialized ALS clinic, which promotes patients' symptom management and quality of life goals. However, patient and carer engagement in ALS decision making is tested by the dynamic nature of ALS, and patient and family distress. Our model optimizes patient-centred decision making, by incorporating patients' cyclic decision-making patterns and facilitating carer inclusion in decision processes. The model captures the complexities of patient-centred decision making in ALS. The framework can assist patients and carers, health professionals, researchers and policymakers in this challenging disease environment. © 2013 John Wiley & Sons Ltd.

Differential effects of phosphate binders on pre-dialysis serum bicarbonate in end-stage kidney disease patients on maintenance haemodialysis

PubMed Central

2013-01-01

Background Phosphate binders’ constituents have alkalotic or acidotic properties and may contribute to acid base balance in haemodialysis patients. This study aimed to investigate the differential effects of phosphate binders on pre-dialysis serum bicarbonate in End Stage Kidney Disease patients on maintenance haemodialysis. Methods Stable out-patients having satellite haemodialysis for at least 3 months were retrospectively studied for 18 months, excluding those with other medical causes for metabolic acidosis. Blood results were censored for inpatient episodes, at the time of death, renal transplant or dialysis modality change. Multivariable multilevel mixed-effects linear regression was used and five groups of phosphate binders were compared: Group A(Calcium (Ca) and/or Aluminium (Al) binders); B(Sevelamer hydrochloride (SH) alone); C(lanthanum carbonate (LC) alone); D(SH and Ca/Al), E(LC and Ca/Al). Results Of 320 patients, 292 were eligible for analysis with a mean follow-up of 15.54 (standard deviation, SD 3.98) months. Similar mean pre-dialysis serum levels of bicarbonate were observed at all 6 month-interval analyses. At 18th months, observed mean serum bicarbonate levels in mmol/L were Group B: 21.58 (SD 2.82, P<0.001), C: 23.29 (SD 2.80, P=0.02), D: 21.56 (SD 3.00, P<0.001), and E: 21.29 (SD 3.62, P=0.92) compared with Group A: 22.98 (SD 2.77). Mean serum bicarbonate was related to total SH dose in mmol/L: 22.34 (SD 2.56) for SH <2.5 g/day, 21.61 (SD 2.62) for SH 2.5-4.8 g/day, 21.04 (SD 3.31) for SH >4.8 g/day compared with 22.85 (SD 2.91) for non-users; P-trend<0.001. Conclusions Phosphate binders’ constituents may contribute to/protect against a predisposition to pre-dialysis metabolic acidosis. This may be dose dependant in patients taking Sevelamer Hydrochloride. PMID:24079654

An improved biometrics-based authentication scheme for telecare medical information systems.

PubMed

Guo, Dianli; Wen, Qiaoyan; Li, Wenmin; Zhang, Hua; Jin, Zhengping

2015-03-01

Telecare medical information system (TMIS) offers healthcare delivery services and patients can acquire their desired medical services conveniently through public networks. The protection of patients' privacy and data confidentiality are significant. Very recently, Mishra et al. proposed a biometrics-based authentication scheme for telecare medical information system. Their scheme can protect user privacy and is believed to resist a range of network attacks. In this paper, we analyze Mishra et al.'s scheme and identify that their scheme is insecure to against known session key attack and impersonation attack. Thereby, we present a modified biometrics-based authentication scheme for TMIS to eliminate the aforementioned faults. Besides, we demonstrate the completeness of the proposed scheme through BAN-logic. Compared to the related schemes, our protocol can provide stronger security and it is more practical.

"Patients with amyotrophic lateral sclerosis (ALS) are usually nice persons"-How physicians experienced in ALS see the personality characteristics of their patients.

PubMed

Mehl, Theresa; Jordan, Berit; Zierz, Stephan

2017-01-01

Physicians experienced in the treatment of patients with amyotrophic lateral sclerosis (ALS) occasionally describe these patients as "nice" persons. ALS experienced physicians ( n  =   36) were asked to assess the personality characteristics of ALS patients using a multidimensional personality questionnaire based on the five-factor model of personality. Control groups consisted of physicians experienced in Myasthenia gravis (MG) ( n  =   21) and lung cancer (LC) ( n  =   36). In the dimension Agreeableness ALS patients were rated significantly higher than the other groups ( p  <   .001). This was mainly due to the high scores for converse adjective pairs "stubborn-compliant" and "selfish-helpful". The dimension Agreeableness is very similar to "niceness". Results support the anecdotal description of ALS patients as "nice" persons. Personality characteristics of ALS patients differentiate them from other patient groups. It remains open whether the "nice" personality structure is linked to the susceptibility to the disease.

On the Relationship Between Attention Processing and P300-Based Brain Computer Interface Control in Amyotrophic Lateral Sclerosis

PubMed Central

Riccio, Angela; Schettini, Francesca; Simione, Luca; Pizzimenti, Alessia; Inghilleri, Maurizio; Olivetti-Belardinelli, Marta; Mattia, Donatella; Cincotti, Febo

2018-01-01

Our objective was to investigate the capacity to control a P3-based brain-computer interface (BCI) device for communication and its related (temporal) attention processing in a sample of amyotrophic lateral sclerosis (ALS) patients with respect to healthy subjects. The ultimate goal was to corroborate the role of cognitive mechanisms in event-related potential (ERP)-based BCI control in ALS patients. Furthermore, the possible differences in such attentional mechanisms between the two groups were investigated in order to unveil possible alterations associated with the ALS condition. Thirteen ALS patients and 13 healthy volunteers matched for age and years of education underwent a P3-speller BCI task and a rapid serial visual presentation (RSVP) task. The RSVP task was performed by participants in order to screen their temporal pattern of attentional resource allocation, namely: (i) the temporal attentional filtering capacity (scored as T1%); and (ii) the capability to adequately update the attentive filter in the temporal dynamics of the attentional selection (scored as T2%). For the P3-speller BCI task, the online accuracy and information transfer rate (ITR) were obtained. Centroid Latency and Mean Amplitude of N200 and P300 were also obtained. No significant differences emerged between ALS patients and Controls with regards to online accuracy (p = 0.13). Differently, the performance in controlling the P3-speller expressed as ITR values (calculated offline) were compromised in ALS patients (p < 0.05), with a delay in the latency of P3 when processing BCI stimuli as compared with Control group (p < 0.01). Furthermore, the temporal aspect of attentional filtering which was related to BCI control (r = 0.51; p < 0.05) and to the P3 wave amplitude (r = 0.63; p < 0.05) was also altered in ALS patients (p = 0.01). These findings ground the knowledge required to develop sensible classes of BCI specifically designed by taking into account the influence of the cognitive characteristics of the possible candidates in need of a BCI system for communication. PMID:29892218

Cerebral saturation in cardiac arrest patients measured with near-infrared technology during pre-hospital advanced life support. Results from Copernicus I cohort study.

PubMed

Genbrugge, Cornelia; De Deyne, Cathy; Eertmans, Ward; Anseeuw, Kurt; Voet, Dirk; Mertens, Ilse; Sabbe, Marc; Stroobants, Jan; Bruckers, Liesbeth; Mesotten, Dieter; Jans, Frank; Boer, Willem; Dens, Jo

2018-03-23

To date, monitoring options during pre-hospital advanced life support (ALS) are limited. Regional cerebral saturation (rSO 2 ) may provide more information concerning the brain during ALS. We hypothesized that an increase in rSO 2 during ALS in out-of hospital cardiac arrest (OHCA) patients is associated with return of spontaneous circulation (ROSC). A prospective, non-randomized multicenter study was conducted in the pre-hospital setting of six hospitals in Belgium. Cerebral saturation was measured during pre-hospital ALS by a medical emergency team in OHCA patients. Cerebral saturation was continuously measured until ALS efforts were terminated or until the patient with sustained ROSC (>20 min) arrived at the emergency department. To take the longitudinal nature of the data into account, a linear mixed model was used. The correlation between the repeated measures of a patient was handled by means of ​a random intercept and a random slope. Our primary analysis tested the association of rSO 2 with ROSC. Of the 329 patients 110 (33%) achieved ROSC. First measured rSO 2 was 30% ± 18 in the ROSC group and 24% ± 15 in the no-ROSC group (p = .004; mean ± SD). Higher mean rSO 2 values were observed in the ROSC group compared to the no-ROSC group (41% ± 13 versus 33% ± 13 respectively; p < 0.001). The median increase in rSO 2, measured from start until two minutes before ROSC, was higher in the ROSC group (ROSC group 17% (IQR 6-29)) than in the no-ROSC group (8% (IQR 2-13); p < 0.001). An increase in rSO 2 above 15% was associated with ROSC (OR 4.5; 95%CI 2.747-7.415; p < 0.001). Regional cerebral saturation measurements can be used during pre-hospital ALS as an additional marker to predict ROSC. An increase of at least 15% in rSO 2 during ALS is associated with a higher probability of ROSC. Copyright © 2018 Elsevier B.V. All rights reserved.

Multi-Institutional External Validation of Seminal Vesicle Invasion Nomograms: Head-to-Head Comparison of Gallina Nomogram Versus 2007 Partin Tables

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zorn, Kevin C.; Capitanio, Umberto; Jeldres, Claudio

2009-04-01

Purpose: The Partin tables represent one of the most widely used prostate cancer staging tools for seminal vesicle invasion (SVI) prediction. Recently, Gallina et al. reported a novel staging tool for the prediction of SVI that further incorporated the use of the percentage of positive biopsy cores. We performed an external validation of the Gallina et al. nomogram and the 2007 Partin tables in a large, multi-institutional North American cohort of men treated with robotic-assisted radical prostatectomy. Methods and Materials: Clinical and pathologic data were prospectively gathered from 2,606 patients treated with robotic-assisted radical prostatectomy at one of four Northmore » American robotic referral centers between 2002 and 2007. Discrimination was quantified with the area under the receiver operating characteristics curve. The calibration compared the predicted and observed SVI rates throughout the entire range of predictions. Results: At robotic-assisted radical prostatectomy, SVI was recorded in 4.2% of patients. The discriminant properties of the Gallina et al. nomogram resulted in 81% accuracy compared with 78% for the 2007 Partin tables. The Gallina et al. nomogram overestimated the true rate of SVI. Conversely, the Partin tables underestimated the true rate of SVI. Conclusion: The Gallina et al. nomogram offers greater accuracy (81%) than the 2007 Partin tables (78%). However, both tools are associated with calibration limitations that need to be acknowledged and considered before their implementation into clinical practice.« less

Attempted validation of the NUn score and inflammatory markers as predictors of esophageal anastomotic leak and major complications.

PubMed

Findlay, J M; Tilson, R C; Harikrishnan, A; Sgromo, B; Marshall, R E K; Maynard, N D; Gillies, R S; Middleton, M R

2015-10-01

The ability to predict complications following esophagectomy/extended total gastrectomy would be of great clinical value. A recent study demonstrated significant correlations between anastomotic leak (AL) and numerical values of C-reactive protein (CRP), white cell count (WCC) and albumin measured on postoperative day (POD) 4. A predictive model comprising all three (NUn score >10) was found to be highly sensitive and discriminant in predicting AL and complications. We attempted a retrospective validation in our center. Data were collected on all resections performed during a 5-year period (April 2008-2013) using prospectively maintained databases. Our biochemistry laboratory uses a maximum CRP value (156 mg/L), unlike that of the original study; otherwise all variables and outcome measures were comparable. Analysis was performed for all patients with complete blood results on POD4. Three hundred twenty-six patients underwent resection, of which 248 had POD4 bloods. There were 21 AL overall (6.44%); 16 among those with complete POD4 blood results (6.45%). There were 8 (2.45%) in-hospital deaths; 7 (2.82%) in those with POD4 results. No parameters were associated with AL or complication severity on univariate analysis. WCC was associated with AL in multivariate binary logistic regression with albumin and CRP (OR 1.23 [95% CI 1.03-1.47]; P = 0.021). When a binary variable of CRP ≥ 156 mg/L was used rather than an absolute value, no factors were significant. Mean NUn was 8.30 for AL, compared with 8.40 for non-AL (P = 0.710 independent t-test). NUn > 10 predicted 0 of 16 leaks (sensitivity 0.00%, specificity 94.4%, receiver operator curve [ROC] area under the curve [AUC] 0.485; P = 0.843). NUn > 7.65 was 93% sensitive and 21.6% specific. ROC for WCC alone was comparable with NUn (AUC 0.641 [0.504-0.779]; P = 0.059; WCC > 6.89 93.8% sensitive, 20.7% specific; WCC > 15 6.3% sensitive and 97% specific). There were no associations between any parameters and other complications. In a comparable cohort with the original study, we demonstrated a similar multivariate association between WCC alone on POD4 and subsequent demonstration of AL, but not albumin or CRP (measured up to 156 mg/L). The NUn score overall (calculated with this caveat) and a threshold of 10 was not found to have clinical utility in predicting AL or complications. © 2014 International Society for Diseases of the Esophagus.

Physician perceptions about living organ donation in patients with Amyotrophic Lateral Sclerosis.

PubMed

Ansari, S; Bromberg, M B; Gibson, S B

2017-09-01

Patients with Amyotrophic Lateral Sclerosis (ALS) have expressed desire to become living organ donors but are unable to do so with current organ donation policies. Our objective is to assess ALS patient's interest in organ donation, and perceived concerns of this practice by ALS neurologists. An electronic survey was administered to ALS neurologists across the United States regarding living organ donation in ALS patients prior to respiratory failure. 52 complete responses were received from 121 invites. 67% (35/52) of neurologists expressed no concerns about living organ donation in ALS patients, and 33% had concerns. The concerns related to respiratory failure, anesthesia exposure and renal dysfunction. With their concerns addressed, 71% of neurologists reported that they would endorse living organ donation. 49% of neurologists reported being asked by a patient for information regarding living organ donation. ALS neurologists felt that 22.8% of ALS patients (median 19%) would be interested in learning more about organ donation, while only 6% of neurologists broach this subject with their patients. Our results indicate that 1 in every 4 ALS patients may be interested in exploring options for living organ donation, and this topic is not routinely addressed by ALS clinics. These results indicate an unexplored area of patient interest. To honor a patient's wishes to donate, the transplant community will have to accommodate living organ donation from terminally ill patients, and address neurologist concerns. Such a practice could benefit two groups of patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.

PubMed

Majounie, Elisa; Renton, Alan E; Mok, Kin; Dopper, Elise G P; Waite, Adrian; Rollinson, Sara; Chiò, Adriano; Restagno, Gabriella; Nicolaou, Nayia; Simon-Sanchez, Javier; van Swieten, John C; Abramzon, Yevgeniya; Johnson, Janel O; Sendtner, Michael; Pamphlett, Roger; Orrell, Richard W; Mead, Simon; Sidle, Katie C; Houlden, Henry; Rohrer, Jonathan D; Morrison, Karen E; Pall, Hardev; Talbot, Kevin; Ansorge, Olaf; Hernandez, Dena G; Arepalli, Sampath; Sabatelli, Mario; Mora, Gabriele; Corbo, Massimo; Giannini, Fabio; Calvo, Andrea; Englund, Elisabet; Borghero, Giuseppe; Floris, Gian Luca; Remes, Anne M; Laaksovirta, Hannu; McCluskey, Leo; Trojanowski, John Q; Van Deerlin, Vivianna M; Schellenberg, Gerard D; Nalls, Michael A; Drory, Vivian E; Lu, Chin-Song; Yeh, Tu-Hsueh; Ishiura, Hiroyuki; Takahashi, Yuji; Tsuji, Shoji; Le Ber, Isabelle; Brice, Alexis; Drepper, Carsten; Williams, Nigel; Kirby, Janine; Shaw, Pamela; Hardy, John; Tienari, Pentti J; Heutink, Peter; Morris, Huw R; Pickering-Brown, Stuart; Traynor, Bryan J

2012-04-01

We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. Full funding sources listed at end of paper (see Acknowledgments). Copyright © 2012 Elsevier Ltd. All rights reserved.

Botulinum toxin type A for the treatment of sialorrhoea in amyotrophic lateral sclerosis: a clinical and neurophysiological study.

PubMed

Gilio, Francesca; Iacovelli, Elisa; Frasca, Vittorio; Gabriele, Maria; Giacomelli, Elena; Picchiori, Floriana; Soldo, Pietro; Cipriani, Anna Maria; Ruoppolo, Giovanni; Inghilleri, Maurizio

2010-08-01

Botulinum toxin type A (BoNT/A) has been proposed as an alternative treatment for sialorrhoea in patients with amyotrophic lateral sclerosis (ALS). In an open-label prospective study, BoNT/A was injected into the parotid glands bilaterally using anatomic landmarks in 26 ALS patients with bulbar symptoms. Two weeks after injection the severity of sialorrhoea and the related disability were evaluated subjectively and objectively. A group of healthy subjects acted as controls for saliva production. Patients also underwent electrophysiological tests to evaluate possible toxin effects in the nearby non-injected muscles by comparing the amplitude of compound motor action potentials (cMAPs) elicited by electrical stimulation and recorded from the orbicularis oculi and masseter muscles. After BoNT/A injections, of the 26 patients treated, 23 reported that the severity of sialorrhoea improved and the disabling symptoms diminished. Cotton roll weight also decreased after BoNT/A injection, suggesting a reduction in saliva production. Two patients complained of dry mouth. BoNT/A injection left the cMAP amplitude unchanged, suggesting that botulinum toxin does not significantly affect the non-injected facial and masticatory muscles. In conclusion, intraparotid anatomically-guided BoNT/A injection is an effective, easy, and safe treatment for sialorrhoea in patients with bulbar symptoms related to ALS.

Concentrated ERP Delivered in a Group Setting: A Replication Study.

PubMed

Havnen, Audun; Hansen, Bjarne; Öst, Lars-Göran; Kvale, Gerd

2017-09-01

In a previous effectiveness study (Havnen et al., 2014), 35 obsessive compulsive disorder (OCD) patients underwent Concentrated Exposure Treatment (cET), which is a newly developed group treatment format delivered over four consecutive days. The primary aims of the present study were to evaluate the treatment results for a new sample of OCD patients receiving the cET treatment approach and to replicate the effectiveness study described in Havnen et al. (2014). Forty-two OCD patients underwent cET treatment. Treatment was delivered by different therapists than in Havnen et al. (2014), except for two groups led by the developers of the treatment. Assessments of OCD symptom severity, treatment satisfaction, and occupational impairment were included. The results showed a significant reduction in Yale-Brown Obsessive Compulsive Scale scores from pre-treatment to post-treatment, which was maintained at 6-month follow-up. At post-treatment, 74% of the sample was remitted; at 6-month follow-up, 60% were recovered. The sample showed a very high degree of overall treatment satisfaction. The results from the present study were statistically compared with those obtained in the previous study. The analyses showed that the study samples had comparable demographic data and equal application of treatment. The outcome of the present and original study did not differ significantly on primary and secondary outcome measures. This study shows that cET was successfully replicated in a new patient sample treated by different therapists than the original study. The results indicate that cET is well accepted by the patients, and the potential for dissemination is discussed.

Protein misfolding, amyotrophic lateral sclerosis and guanabenz: protocol for a phase II RCT with futility design (ProMISe trial).

PubMed

Bella, Eleonora Dalla; Tramacere, Irene; Antonini, Giovanni; Borghero, Giuseppe; Capasso, Margherita; Caponnetto, Claudia; Chiò, Adriano; Corbo, Massimo; Eleopra, Roberto; Filosto, Massimiliano; Giannini, Fabio; Granieri, Enrico; Bella, Vincenzo La; Lunetta, Christian; Mandrioli, Jessica; Mazzini, Letizia; Messina, Sonia; Monsurrò, Maria Rosaria; Mora, Gabriele; Riva, Nilo; Rizzi, Romana; Siciliano, Gabriele; Silani, Vincenzo; Simone, Isabella; Sorarù, Gianni; Volanti, Paolo; Lauria, Giuseppe

2017-08-11

Recent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS. Protocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial. The study protocol was approved by the Ethics Committee of IRCCS 'Carlo Besta Foundation' of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Respiratory Pattern and Tidal Volumes Differ for Pressure Support and Volume-assured Pressure Support in Amyotrophic Lateral Sclerosis.

PubMed

Nicholson, Trevor T; Smith, Sean B; Siddique, Teepu; Sufit, Robert; Ajroud-Driss, Senda; Coleman, John M; Wolfe, Lisa F

2017-07-01

Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease resulting in respiratory failure and death. Use of noninvasive ventilation (NIV) improves survival. However, use of volume-assured pressure support (VAPS) has not been extensively studied in ALS. To explore the clinical usefulness of a detailed evaluation of device-recorded NIV data in the management of chronic respiratory failure in ALS, and to determine whether there are differences in efficacy between patients using VAPS or PS. We performed a retrospective chart review of 271 patients with ALS using either PS or VAPS, along with an evaluation of device-recorded data to explore differences in attainment of goal tidal volumes (Vt) and ratio of respiratory rate to tidal volume (f/Vt), in addition to triggering and cycling ability. Two hundred and fifteen patients were using PS, while 56 were using VAPS. There were no significant differences in demographic data, symptoms, pulmonary function, or patient compliance. Compared with VAPS, achieved Vt was significantly lower for PS while f/Vt was significantly higher. Percent spontaneous triggering was relatively preserved in both cohorts, whereas percent spontaneous cycling was considerably decreased in both. Furthermore, there was no association found between spontaneous triggering or cycling, and pulmonary function, indicating the presence of low spontaneous breath cycling or triggering ability is difficult to predict. Examination of device data for exhaled tidal volumes and f/Vt may be of use in evaluating efficacy of NIV in ALS. VAPS provides more reliable goal Vt than does PS, and is associated with decreased f/Vt. Spontaneous cycling is decreased in ALS despite preservation of triggering ability. Although a set backup rate may address decreased triggering, perhaps more importantly, setting a sufficient fixed inspiratory time would address the issue of decreased cycling.

Trends of quality of life changes in amyotrophic lateral sclerosis patients.

PubMed

Shamshiri, Hosein; Fatehi, Farzad; Abolfazli, Roya; Harirchian, Mohammad Hossein; Sedighi, Behnaz; Zamani, Babak; Roudbari, Ali; Razazian, Nazanin; Khamseh, Fatemeh; Nafissi, Shahriar

2016-09-15

Amyotrophic lateral sclerosis (ALS) is an incurable progressive neurodegenerative disease and thus the assessment of quality of life (QOL) changes and factors that may influence its course is valuable in the meantime. The present study aimed to assess the deterioration rate of QOL and influencing factors in different subgroups of Iranian ALS patients. 132 patients were evaluated in this prospective multicenter observational study. QOL was measured using ALS Assessment Questionnaire (ALSAQ-40) during 1year follow up and its progression rate was assessed in different subgroups of patients according to age, sex, stage of disease, riluzole consumption, onset type. Also physical disability and functional disability were measured using MMT and ALSFRS-R scores respectively and their progression rates were compared with ALSAQ-40 changes. Significant deterioration of the scores of ALSAQ-40 during study was consistent in all of its domains (p=0.000). There was a significant negative correlation between ALSFRS-R and MMT changes and ALSAQ-40 change (p=0.000) and this was consistently observed in all domains of ALSAQ-40 (p=0.00). ALSAQ-40 deterioration rate was shown to be significantly lower in severe/terminal stages compared to mild/moderate stages (p=0.00). Significantly higher deterioration rate was observed in bulbar onset versus limb onset patients [F (1,130)=4.52, p=0.04] but no significant difference was observed among other subgroups according to age, sex and riluzole consumption. All domains of QOL significantly deteriorate during ALS course and there is a significant correlation between their changes and progression of physical and functional disabilities. Rate of degradation of QOL may be different at different stages of the disease. QOL worsens independent of factors such as sex, age and consumption of riluzole; but onset type (bulbar versus limb) is an imperative factor in quality of life changes during the disease course. Copyright © 2016 Elsevier B.V. All rights reserved.

Does the index-to-ring finger length ratio (2D:4D) differ in amyotrophic lateral sclerosis (ALS)? Results from an international online case–control study

PubMed Central

Parkin Kullmann, Jane Alana

2017-01-01

Objectives The ratio of the length of the index finger (2D) to the ring finger (4D) (2D:4D) has been reported to be lower (ie, 2D<4D) in people with amyotrophic lateral sclerosis (ALS) than non-ALS controls. This has led to suggestions that exposure to increased prenatal testosterone, which also lowers this ratio, could be a risk factor for ALS. In an attempt to test this hypothesis, we examined 2D:4Ds from large numbers of patients with ALS and controls. Setting An online multilingual questionnaire enabling respondents to measure their own index and ring finger lengths. Participants Of the initial 949 respondents, 572 remained for analysis after elimination for inability to straighten fingers, not answering the question, statistical outliers and aged <40 years. Respondents remaining for analysis were 202 patients with ALS (125 males, 77 females) and 370 non-ALS controls (112 males, 258 females). Results Unpaired t-tests with 95% CIs were used to assess differences in mean 2D:4Ds. Males had significantly lower mean 2D:4Ds than females, in both ALS and control groups, for both left and right hands. No significant differences were found in 2D:4Ds between ALS and control groups, in either males or females, for either left or right hands. Receiver operating characteristic curves showed no power for 2D:4Ds to predict ALS status in either males or females. Conclusions 2D:4Ds did not differ between patients with ALS and controls in this study. This was despite the dataset being large enough to confirm the established finding of lower 2D:4Ds in males compared with females. These findings do not support the hypothesis that exposure to increased prenatal testosterone is a risk factor for ALS. A putative lower 2D:4D has been proposed to explain the link between ALS and exercise, but our results indicate that other exercise-related factors are more likely to explain this association. PMID:28784596

Evaluation of a new continuous mononuclear cell collection procedure in a single transplant center cohort enriched for AL amyloidosis patients.

PubMed

Pudusseri, Anita; Smith, India; Sarnacki, Diane; Brauneis, Dina; Shelton, Anthony; Sanchorawala, Vaishali; Sloan, J Mark; Sarosiek, Shayna; Quillen, Karen

2018-04-26

The Spectra Optia continuous mononuclear cell (CMNC) program is newly available, and herein validated in a single-center cohort enriched with AL amyloidosis patients to collect a target CD34+ yield of 2.5 × 10 6 cells/kg within 2 days. Consecutive autologous transplant patients in 2016 are included. Patients undergo leukapheresis with Optia CMNC and Spectra v4.7 over a 2-day cycle. Data collection includes collection efficiency, adverse events and engraftment kinetics. 36 leukapheresis procedures on 18 patients are included. The diagnoses are AL amyloidosis (9), myeloma (7), lymphoma (2), and scleroderma (1). Median age is 60; 12 are men. Plerixafor was employed pre-emptively in 6 cycles. Median blood CD34+ on Day 1 of leukapheresis was 46 cells/uL. Median number of blood volumes processed on Day 1 was 3.1. All collection cycles were completed within 2 days; only one in a heavily pretreated lymphoma patient did not reach the target requiring a second mobilization attempt. Mean collection efficiencies were comparable between the two devices. There were 2 adverse events: tubing rupture on the Optia; and one case of hypotension. All 18 patients underwent high-dose chemotherapy: median cell dose infused was 7.7 × 10 6 CD34+ cells/kg. Median days to neutrophil and platelet engraftment were 10 and 13 respectively. The Optia CMNC collection protocol is safe and effective in a small single-center autologous stem cell transplant cohort enriched for high-risk patients with AL amyloidosis and cardiac involvement. Caution is needed for tubing setup because there is less cumulative experience with Optia. Copyright © 2018 Elsevier Ltd. All rights reserved.

Dynamic markers of altered gait rhythm in amyotrophic lateral sclerosis

NASA Technical Reports Server (NTRS)

Hausdorff, J. M.; Lertratanakul, A.; Cudkowicz, M. E.; Peterson, A. L.; Kaliton, D.; Goldberger, A. L.

2000-01-01

Amyotrophic lateral sclerosis (ALS) is a disorder marked by loss of motoneurons. We hypothesized that subjects with ALS would have an altered gait rhythm, with an increase in both the magnitude of the stride-to-stride fluctuations and perturbations in the fluctuation dynamics. To test for this locomotor instability, we quantitatively compared the gait rhythm of subjects with ALS with that of normal controls and with that of subjects with Parkinson's disease (PD) and Huntington's disease (HD), pathologies of the basal ganglia. Subjects walked for 5 min at their usual pace wearing an ankle-worn recorder that enabled determination of the duration of each stride and of stride-to-stride fluctuations. We found that the gait of patients with ALS is less steady and more temporally disorganized compared with that of healthy controls. In addition, advanced ALS, HD, and PD were associated with certain common, as well as apparently distinct, features of altered stride dynamics. Thus stride-to-stride control of gait rhythm is apparently compromised with ALS. Moreover, a matrix of markers based on gait dynamics may be useful in characterizing certain pathologies of motor control and, possibly, in quantitatively monitoring disease progression and evaluating therapeutic interventions.

Identification of plasma microRNAs as a biomarker of sporadic Amyotrophic Lateral Sclerosis.

PubMed

Takahashi, Ikuko; Hama, Yuka; Matsushima, Masaaki; Hirotani, Makoto; Kano, Takahiro; Hohzen, Hideki; Yabe, Ichiro; Utsumi, Jun; Sasaki, Hidenao

2015-10-24

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease, which leads to the loss of upper and lower motor neurons, with a currently unknown etiology. Specific biomarkers could help in early detection and diagnosis, and could also act as indicators of disease progression and therapy effectiveness. MicroRNAs (miRNAs) are small (18-25 nucleotides), single-stranded non-coding RNA molecules that play important regulatory roles in animals and plants by targeting mRNAs for cleavage or translational repression, and are essential for nervous system development. Many of the genes associated with genetic ALS have pathological biological pathways related to RNA metabolism, and their pathogenesis may be affecting the maturing processes of miRNA. We compared miRNA from the plasma of sALS patients and healthy controls using two cohorts; a discovery cohort analyzed with microarray (16 sALS patients and ten healthy controls) and a validation cohort confirmed with qPCR (48 sALS patients, 47 healthy controls and 30 disease controls). We measured the total amount of extracted RNA along with a spike-in control that ensured the quality of our quantification. A percentage of the 10-40 nt RNAs extracted from the total RNA showed a significant increase in ALS patients. There was a negative correlation between total RNA concentration and disease duration from onset to end point. Three of the miRNAs were up-regulated and six were down-regulated significantly in the discovery cohort. Since an internal control is required as a sample stability indicator of both the patients and controls in microarray analysis, we selected the miRNA showing the smallest dispersion and equivalency between the two groups' mean value, and decided to use hsa-miR-4516. We found hsa-miR-4649-5p to be up-regulated, and hsa-miR-4299 to be down-regulated, where each was not influenced by clinical characteristics. EPHA4, a target gene linked to the nervous system which has also been reported to be a disease modifier of ALS, is the common and most notable target gene of hsa-miR-4649-5p and hsa-miR-4299. We have shown the relationship circulating plasma miRNA has with both healthy controls and diseased patients. Hsa-miR-4649-5p and hsa-miR-4299 have the potential to be ALS diagnosis biomarkers.

Can the accuracy of multifocal intraocular lens power calculation be improved to make patients spectacle free?

PubMed

Ramji, Hasnain; Moore, Johnny; Moore, C B Tara; Shah, Sunil

2016-04-01

To optimise intraocular lens (IOL) power calculation techniques for a segmental multifocal IOL, LENTIS™ MPlus(®) (Oculentis GmbH, Berlin, Germany) and assess outcomes. A retrospective consecutive non-randomised case series of patients receiving the MPlus(®) IOL following cataract surgery or clear lens extraction was performed at a privately owned ophthalmic hospital, Midland Eye, Solihull, UK. Analysis was undertaken of 116 eyes, with uncomplicated lens replacement surgery using the LENTIS™ MPlus(®) lenses. Pre-operative biometry data were stratified into short (<22.00 mm) and long axial lengths (ALs) (≥22.00 mm). IOL power predictions were calculated with SRK/T, Holladay I, Hoffer Q, Holladay II and Haigis formulae and compared to the final manifest refraction. These were compared with the OKULIX ray tracing method and the stratification technique suggested by the Royal College of Ophthalmologists (RCOphth). Using SRK/T for long eyes and Hoffer Q for short eyes, 64% achieved postoperative subjective refractions of ≤±0.25 D, 83%≤±0.50 D and 93%≤±0.75 D, with a maximum predictive error of 1.25D. No specific calculation method performed best across all ALs; however for ALs under 22 mm Hoffer Q and Holliday I methods performed best. Excellent but equivalent overall refractive results were found between all biometry methods used in this multifocal IOL study. For eyes with ALs under 22 mm Hoffer Q and Holliday I performed best. Current techniques mean that patients are still likely to need top up glasses for certain situations. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dynamics of the cognitive procedural learning in alcoholics with Korsakoff's syndrome.

PubMed

Beaunieux, Hélène; Pitel, Anne L; Witkowski, Thomas; Vabret, François; Viader, Fausto; Eustache, Francis

2013-06-01

While procedures acquired before the development of amnesia are likely to be preserved in alcoholic patients with Korsakoff's syndrome, the ability of Korsakoff patients (KS) to learn new cognitive procedures is called in question. According to the Adaptive Control of Thoughts model, learning a new cognitive procedure requires highly controlled processes in the initial cognitive phase, which may be difficult for KS with episodic and working memory deficits. The goals of the present study were to examine the learning dynamics of KS compared with uncomplicated alcoholic patients (AL) and control subjects (CS) and to determine the contribution of episodic and working memory abilities in cognitive procedural learning performance. Fourteen KS, 15 AL, and 15 CS were submitted to 40 trials (4 daily learning sessions) of the Tower of Toronto task (disk-transfer task similar to the tower of Hanoi task) as well as episodic and working memory tasks. The 10 KS who were able to perform the cognitive procedural learning task obtained lower results than both CS and AL. The cognitive phase was longer in the Korsakoff's syndrome group than in the other 2 groups but did not differ between the 3 groups any more when episodic memory abilities were controlled. Our results indicate that KS have impaired cognitive procedural learning abilities compared with both AL and CS. Episodic memory deficits observed in KS result in a delayed transition from the cognitive learning phase to more advanced learning phases and, as a consequence, in an absence of automation of the procedure within 40 trials. Copyright © 2012 by the Research Society on Alcoholism.

A safety analysis of edaravone (MCI-186) during the first six cycles (24 weeks) of amyotrophic lateral sclerosis (ALS) therapy from the double-blind period in three randomized, placebo-controlled studies.

PubMed

Kalin, Alexander; Medina-Paraiso, Elvia; Ishizaki, Kaoru; Kim, Alex; Zhang, Yannong; Saita, Takanori; Wasaki, Masahiko

2017-10-01

There continues to be a need for new therapies to treat ALS. Provide an overview of safety for edaravone in ALS patients during the first six cycles of treatment. Analysis was based on three randomised, placebo-controlled clinical trials. Endpoints included treatment-emergent adverse events (TEAEs), including AEs leading to discontinuation, serious adverse events (SAEs), and deaths. The analysis included a total of 368 patients (184 in the edaravone group and placebo group, respectively). Of those, 94.6% of the edaravone group and 90.2% of placebo group completed six cycles of therapy. Baseline characteristics were comparable between the two groups. TEAE incidence in the edaravone group and placebo group was 87.5% and 87.0%, respectively. TEAEs ocurring at ≥2% incidence in the edaravone group compared to placebo were contusion (14.7% vs. 8.7%), gait disturbance (12.5% vs. 9.2%), headache (8.2% vs. 5.4%), eczema (6.5% vs. 2.2%), dermatitis contact (6.0% vs. 3.3%), respiratory disorder (4.3% vs. 1.1%), and glucose urine present (3.8% vs. 1.6%). There was no imbalance in TEAEs leading to discontinuation (2.2% [edaravone], and 5.4% [placebo]). SAE incidence was 17.4% in the edaravone group and 22.3% in placebo group. Treatment-emergent deaths occurred in 2.2% in the edaravone group and 1.1% in placebo group, all respiratory in nature and attributed to worsening ALS. Data collected from three double-blind assessments found that while some TEAEs were more common in the edaravone group compared to placebo, the overall incidences of SAEs, deaths, and discontinuations due to AEs were similar or less for edaravone compared to placebo.

Patterns of prefrontal dysfunction in alcoholics with and without Korsakoff’s syndrome, patients with Parkinson’s disease, and patients with rupture and repair of the anterior communicating artery

PubMed Central

Dirksen, Courtney L; Howard, Julie A; Cronin-Golomb, Alice; Oscar-Berman, Marlene

2006-01-01

This study compared patterns of frontal-lobe dysfunction in alcoholics with Korsakoff’s syndrome (KS: n = 9), non-Korsakoff alcoholics (AL: n = 28), patients with Parkinson’s disease (PD: n = 18), and patients with rupture and repair of the anterior communicating artery (ACoA: n = 4) relative to healthy non-neurological control (NC) participants (n = 70). The tests administered were sensitive to functions of dorsolateral prefrontal and orbito-frontal subsystems. Measures included perseverative errors on the Wisconsin Card Sorting Test (WCST-pe), errors on object alternation (OA), errors on Trails B, number of words generated on the Controlled Oral Word Association Test (COWAT), and number of categories completed on the WCST (WCST-cc). KS patients were as impaired as AL participants on orbitofrontal measures and, on dorsolateral prefrontal measures, were impaired relative to AL participants, whose performance did not differ from controls. Patients with PD also were impaired on tests of orbitofrontal and dorsolateral prefrontal functioning but to a lesser extent than the KS patients. Moreover, most of the PD deficits were driven by the impaired performance of patients whose initial symptoms were on the right side of the body. The ACoA patients were significantly impaired on tests of orbitofrontal but not dorsolateral prefrontal functioning relative to the control group. Together, the results confirm different patterns of frontal-system impairments in patient groups having compromised frontal lobe functioning consequent to varying etiologies. PMID:19412479

Do oral aluminium phosphate binders cause accumulation of aluminium to toxic levels?

PubMed Central

2011-01-01

Background Aluminium (Al) toxicity was frequent in the 1980s in patients ingesting Al containing phosphate binders (Alucaps) whilst having HD using water potentially contaminated with Al. The aim of this study was to determine the risk of Al toxicity in HD patients receiving Alucaps but never exposed to contaminated dialysate water. Methods HD patients only treated with Reverse Osmosis(RO) treated dialysis water with either current or past exposure to Alucaps were given standardised DFO tests. Post-DFO serum Al level > 3.0 μmol/L was defined to indicate toxic loads based on previous bone biopsy studies. Results 39 patients (34 anuric) were studied. Mean dose of Alucap was 3.5 capsules/d over 23.0 months. Pre-DFO Al levels were > 1.0 μmol/L in only 2 patients and none were > 3.0 μmol/L. No patients had a post DFO Al levels > 3.0 μmol/L. There were no correlations between the serum Al concentrations (pre-, post- or the incremental rise after DFO administration) and the total amount of Al ingested. No patients had unexplained EPO resistance or biochemical evidence of adynamic bone. Conclusions Although this is a small study, oral aluminium exposure was considerable. Yet no patients undergoing HD with RO treated water had evidence of Al toxicity despite doses equivalent to 3.5 capsules of Alucap for 2 years. The relationship between the DFO-Al results and the total amount of Al ingested was weak (R2 = 0.07) and not statistically significant. In an era of financial prudence, and in view of the recognised risk of excess calcium loading in dialysis patients, perhaps we should re-evaluate the risk of using Al-based phosphate binders in HD patients who remain uric. PMID:21992770

Automated database-guided expert-supervised orientation for immunophenotypic diagnosis and classification of acute leukemia

PubMed Central

Lhermitte, L; Mejstrikova, E; van der Sluijs-Gelling, A J; Grigore, G E; Sedek, L; Bras, A E; Gaipa, G; Sobral da Costa, E; Novakova, M; Sonneveld, E; Buracchi, C; de Sá Bacelar, T; te Marvelde, J G; Trinquand, A; Asnafi, V; Szczepanski, T; Matarraz, S; Lopez, A; Vidriales, B; Bulsa, J; Hrusak, O; Kalina, T; Lecrevisse, Q; Martin Ayuso, M; Brüggemann, M; Verde, J; Fernandez, P; Burgos, L; Paiva, B; Pedreira, C E; van Dongen, J J M; Orfao, A; van der Velden, V H J

2018-01-01

Precise classification of acute leukemia (AL) is crucial for adequate treatment. EuroFlow has previously designed an AL orientation tube (ALOT) to guide towards the relevant classification panel (T-cell acute lymphoblastic leukemia (T-ALL), B-cell precursor (BCP)-ALL and/or acute myeloid leukemia (AML)) and final diagnosis. Now we built a reference database with 656 typical AL samples (145 T-ALL, 377 BCP-ALL, 134 AML), processed and analyzed via standardized protocols. Using principal component analysis (PCA)-based plots and automated classification algorithms for direct comparison of single-cells from individual patients against the database, another 783 cases were subsequently evaluated. Depending on the database-guided results, patients were categorized as: (i) typical T, B or Myeloid without or; (ii) with a transitional component to another lineage; (iii) atypical; or (iv) mixed-lineage. Using this automated algorithm, in 781/783 cases (99.7%) the right panel was selected, and data comparable to the final WHO-diagnosis was already provided in >93% of cases (85% T-ALL, 97% BCP-ALL, 95% AML and 87% mixed-phenotype AL patients), even without data on the full-characterization panels. Our results show that database-guided analysis facilitates standardized interpretation of ALOT results and allows accurate selection of the relevant classification panels, hence providing a solid basis for designing future WHO AL classifications. PMID:29089646

Evaluated the adverse effects of cadmium and aluminum via drinking water to kidney disease patients: Application of a novel solid phase microextraction method.

PubMed

Panhwar, Abdul Haleem; Kazi, Tasneem Gul; Naeemullah; Afridi, Hassan Imran; Shah, Faheem; Arain, Mohammad Balal; Arain, Salma Aslam

2016-04-01

In present study aluminum (Al) and cadmium (Cd) were determined in ground water samples and assesses human health risks associated with elevated concentrations of toxic metals in dissolved form, using a novel solid phase microextraction (SPμE). Ground water sample (n=200) and biological sample (blood) of patients having chronic kidney disorders (CKD) along with healthy control subjects of same area (southern part of Pakistan) were collected. A simple system, including the micropipette tip packed with modified ionic liquid-activated carbon cloth (IL-ACC) coated with 8-hydroxyqunilone (8-HQ) attached to syringe. The analytes in water and acid digested blood samples were manually drawn for 2-10 cycles (drawing/discharging) at different pH range. The analytes sorbed on coated ACC were then desorbed with 2.0molL(-1) HNO3 in ethanol by drawing/discharging cycles for 1-5 times. The concentration of extracted analytes was determined by electrothermal atomic absorption spectrometer. The influence of different variables on the extraction efficiency of Cd and Al, were optimized. The Al and Cd concentrations in groundwater were found to be elevated than recommended limits by the World Health Organization. The urinary N-acetyl-h-glucosaminidase values were significantly higher in CKD patients as compared to refrent subjects (p<0.001). The significant variation in levels of Cd and Al were observed in blood samples of CKD patients than referents subjects (p<0.01). The strong positive correlation among Al and Cd levels in groundwater versus blood samples of CKD patients (r=0.82-0.85) p<0.01) was observed than those values calculated for referent subjects (r=0.425-0.536). Copyright © 2016 Elsevier B.V. All rights reserved.

Effect of a passive exhalation port on tracheostomy ventilation in amyotrophic lateral sclerosis patients: a randomized controlled trial.

PubMed

Vianello, Andrea; Arcaro, Giovanna; Molena, Beatrice; Iovino, Silvia; Gallan, Federico; Turato, Cristian; Marchese-Ragona, Rosario

2018-02-01

Amyotrophic lateral sclerosis (ALS) patients often require long-term tracheostomy ventilation (LT-TV) because of progressive ventilatory failure. Although widely used for non-invasive ventilation (NIV), passive exhalation port systems have not been gaining popularity for TV because of the possibility of carbon dioxide (CO 2 ) rebreathing. The current study set out to investigate the effect of a Whisper Swivel connector in comparison to an active exhalation valve on gas exchange and symptoms in ALS patients requiring LT-TV. A prospective randomized controlled trial was carried out to compare the clinical outcome of ten ALS patients receiving LT-TV by means of a Trilogy 100 ventilator with a Whisper Swivel passive exhalation port (group A) and of 10 ALS patients connected to an Airox Legendair ventilator with an active exhalation valve (group B). The study's main outcome measure was CO 2 retention at the 30-day follow-up assessment. One patient in each of the two cohorts showed significant CO 2 retention. At the 30-day assessment, scores on the following measures were not significantly different in the two groups: the Borg dyspnea scale {2 [1-3] vs. 1 [1-3]; P=0.2891}, the visual analogue scale (VAS) dyspnea {20 [10-85] vs. 20 [0-50]; P=0.8571}, the Epworth sleepiness scale (ESS) {8 [4-10] vs. 5.5 [0-12]; P=0.1443}, the EuroQol-VAS (EQ-VAS) {55 [50-80] vs. 50 [30-80]; P=0.4593} and the relative stress scale (RSS) {49 [30-65] vs. 52 [25-64]; P=0.8650}. At the 3-month follow-up assessment, the numbers of hospitalizations and deaths were likewise similar in the two groups. The efficacy of the Whisper Swivel connector is similar to that of an active exhalation valve in ALS patients undergoing LT-TV.

A randomized trial to determine the duration of analgesia following a 15- and a 30-minute application of acupuncture-like TENS on patients with chronic low back pain.

PubMed

Tousignant-Laflamme, Yannick; Laroche, Claudia; Beaulieu, Christine; Bouchard, Ann-Julie; Boucher, Sabrina; Michaud-Létourneau, Mélanie

2017-05-01

Acupuncture-like TENS (AL-TENS) has been shown to produce prolonged pain relief, but no study has yet investigated its duration on a population suffering from chronic low back pain (CLPB). Our objective was to quantify the duration and magnitude of analgesia induced by a 15- or 30-minute application of AL-TENS. We recruited a sample of 11 participants presenting with CLBP and conducted a randomized, crossover study, where participants were given AL-TENS for 15 and 30 minutes on two separate occasions. The pain intensity of their CLBP was assessed with a visual analogue scale before, during, and after AL-TENS applications. Magnitude and duration of analgesia were determined for each subject and for both AL-TENS application times. The AL-TENS applications induced a clinically and statistically significant (p = 0.003) analgesia in all participants. Median duration of analgesia was 9 hours and 10 hours 30 minutes following the 15- and 30-minute AL-TENS applications, respectively; this 1.5-hour difference was not statistically significant (p = 0.55). Furthermore, we observed no significant difference in the magnitude of analgesia between both applications of AL-TENS (p > 0.56), suggesting that the duration of application of AL-TENS does not influence the magnitude of analgesia. Our results suggest that clinicians could use a 15-minute AL-TENS application to provide significant analgesia in patients presenting with low back pain since if provides a comparable analgesia versus a 30-minute application.

Single-dose pharmacokinetics and tolerability of oral delta-9- tetrahydrocannabinol in patients with amyotrophic lateral sclerosis.

PubMed

Joerger, Markus; Wilkins, Justin; Fagagnini, Stefania; Baldinger, Reto; Brenneisen, Rudolf; Schneider, Ursula; Goldman, Bea; Weber, Markus

2012-06-01

Cannabinoids exert neuroprotective and symptomatic effects in amyotrophic lateral sclerosis (ALS). We assessed the pharmacokinetics (PK) and tolerability of delta-9-tetrahydrocannabinol (THC) in ALS patients. Nine patients received THC single oral doses of 5mg and 10mg, separated by a wash-out period of two weeks. Blood samples for the determination of THC, 11-nor-9-carboxy-THC (THC-COOH) and hydroxy-THC (THC-OH) were taken up to 8 hours after intake. Adverse events were assessed by visual analogue scales (VAS). Plasma concentrations of the active metabolite THC-OH were submitted to sequential pharmacokinetic-pharmacodynamic population modeling on individual heart rate as a proxy for THC's cardiovasculatory effects. Drowsiness, euphoria, orthostasis, sleepiness, vertigo and weakness were significantly more frequent in patients receiving 10mg compared to 5 mg THC. A marked interindividual variability was found for the absorption of oral THC (84%) and elimination of THC-COOH (45%). PK data did not support any clinically relevant deviation from linear PK in the investigated range of concentrations. Plasma concentrations of THC-OH were positively correlated with the individual heart rate. An E(max-model) was successfully fitted to individual heart rate, with a THC-OH plasma concentration of 3.2 x 10(-4) μmol/L for EC(50) and an E(max) of 93 bpm for heart rate. The higher 10mg dose of THC was dose-limiting in patients with ALS. High interindividual PK variability requires individuell titration of THC for potential therapeutic use in patients with ALS.

Population-Based Surveillance of Amyotrophic Lateral Sclerosis in New Jersey, 2009–2011

PubMed Central

Jordan, Heather; Fagliano, Jerald; Rechtman, Lindsay; Lefkowitz, Daniel; Kaye, Wendy

2015-01-01

Background Limited epidemiological data exist about amyotrophic lateral sclerosis (ALS) in the United States (US). The Agency for Toxic Substances and Disease Registry maintains the National ALS Registry and funded state and metropolitan surveillance projects to obtain reliable, timely information about ALS in defined geographic areas. Methods Neurologists submitted case reports for ALS patients under their care between January 1, 2009 and December 31, 2011 who were New Jersey residents. A medical record verification form and electromyogram (EMG) report were requested for a sample of case reports. Incidence rates were standardized to the 2000 US Standard Population. Results The average crude annual incidence rate was 1.87 per 100,000 person-years, the average age-adjusted annual incidence rate was 1.67 per 100,000 person-years, and the point prevalence rate on December 31, 2011 was 4.40 per 100,000 persons. Average annual incidence rates and point prevalence rates were statistically higher for men compared with women; Whites compared with Blacks/African Americans and Asians; and non-Hispanics compared with Hispanics. Conclusions The project findings contribute new, population-based, state-specific information to epidemiological data regarding ALS. The findings are generally consistent with previously published surveillance studies conducted in the US and abroad. PMID:25323440

Comparing axonal excitability in past polio to amyotrophic lateral sclerosis.

PubMed

Liang, Christina; Ng, Karl

2014-10-01

Poliomyelitis causes selective destruction of anterior horn cells and usually has a stable disease course post-infection. We assessed the excitability characteristics in patients with a stable course after past poliomyelitis and compared them with changes described in amyotrophic lateral sclerosis (ALS). The excitability characteristics of motor and sensory nerves were studied in 10 subjects with stable past poliomyelitis. Motor rheobase was increased, but there were no significant changes in strength-duration properties or depolarizing threshold electrotonus, as have been seen in previous studies of ALS. There is minimal change in axonal excitability properties in patients with stable past poliomyelitis. The results may signify sufficient compensation in the stable state of the disease. Increased subexcitability in 1 subject with demonstrable hyperexcitability may represent compensation for increased ectopic activity rather than a different process in surviving motor neurons. Muscle Nerve 50: 602-604, 2014. Copyright © 2014 Wiley Periodicals, Inc.

Japanese version of the ALS-FTD-Questionnaire (ALS-FTD-Q-J).

PubMed

Watanabe, Yasuhiro; Beeldman, Emma; Raaphorst, Joost; Izumi, Yuishin; Yoshino, Hiide; Masuda, Michihito; Atsuta, Naoki; Ito, Satoru; Adachi, Tadashi; Adachi, Yoshiki; Yokota, Osamu; Oda, Masaya; Hanashima, Ritsuko; Ogino, Mieko; Ichikawa, Hiroo; Hasegawa, Kazuko; Kimura, Hideki; Shimizu, Toshio; Aiba, Ikuko; Yabe, Hayato; Kanba, Makoto; Kusumi, Kimiyoshi; Aoki, Tetsuya; Hiroe, Yu; Watanabe, Hirohisa; Nishiyama, Kazutoshi; Nomoto, Masahiro; Sobue, Gen; Nakashima, Kenji

2016-08-15

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share common clinical, genetic and neuropathological features. Some ALS patients have behavioral/personality changes, which could result in significant obstacles in the care provided by family members and caregivers. An easy screening tool would contribute greatly to the evaluation of these symptoms. We translated the ALS-FTD-Questionnaire, developed in the Netherlands, into Japanese (ALS-FTD-Q-J) and examined the clinimetric properties (internal consistency, construct and clinical validity). Patients with ALS and/or behavioral variant FTD (bvFTD) were evaluated alongside healthy controls in this multicenter study. All ALS patients, regardless of bvFTD status, were further evaluated by the frontal behavioral inventory (FBI) and for frontal/executive function, cognition, anxiety/depression, and motor functions. Data from 146 subjects were analyzed: ALS (92), ALS-bvFTD (6), bvFTD (16), and healthy controls (32). The internal consistency of the ALS-FTD-Q-J was good (Cronbach α=0.92). The ALS-FTD-Q-J showed construct validity as it exhibited a high correlation with the FBI (r=0.79). However, correlations were moderate with anxiety/depression and low with cognitive scales, in contrast to the original report, i.e. a moderate correlation with cognition and a low correlation with anxiety/depression. The ALS-FTD-Q-J discriminated ALS patients from (ALS-)bvFTD patients and controls. Thus, the ALS-FTD-Q-J is useful for evaluating Japanese ALS/FTD patients. Copyright © 2016 Elsevier B.V. All rights reserved.

Distinct Clinical Features and Outcomes in Motor Neuron Disease Associated with Behavioural Variant Frontotemporal Dementia.

PubMed

Cortés-Vicente, Elena; Turon-Sans, Janina; Gelpi, Ellen; Clarimón, Jordi; Borrego-Écija, Sergi; Dols-Icardo, Oriol; Illán-Gala, Ignacio; Lleó, Alberto; Illa, Isabel; Blesa, Rafael; Al-Chalabi, Ammar; Rojas-García, Ricard

2018-06-08

To determine the motor phenotype and outcome in a clinically ascertained group of patients with motor neuron disease (MND) and frontotemporal dementia (FTD). This is an observational retrospective clinical study of patients fulfilling the clinical criteria for MND-FTD. A contemporary series of patients with amyotrophic lateral sclerosis (ALS) without dementia were included for comparison. Demographic, clinical, genetic, and neuropathological data were collected. A descriptive and comparative data analysis was performed. We identified 22 patients with MND-FTD. Selective distal upper limb muscle weakness and atrophy with non-significant lower limb weakness during follow-up was the most frequent motor pattern, present in 18 patients - in 15 of them associated with severe dysphagia. Aspiration pneumonia was the most common cause of death (12/19; 63%) despite gastrostomy. One-third of the patients did not develop upper motor neuron dysfunction. When compared to classic ALS without dementia (n = 162), these features were significantly different. A neuro-pathological examination was performed on 7 patients, and it confirmed the presence of MND with TDP43 protein aggregates in all patients. The MND-FTD patients frequently displayed a distinctive motor pattern characterized by weakness and atrophy in distal upper limb muscles and dysphagia, with no or little spreading to other regions. These features may help to define specific subgroups of patients, which is important with regard to clinical management, outcome, and research. © 2018 S. Karger AG, Basel.

Long term outcomes of cardiac transplant for immunoglobulin light chain amyloidosis: The Mayo Clinic experience

PubMed Central

Grogan, Martha; Gertz, Morie; McCurdy, Arleigh; Roeker, Lindsey; Kyle, Robert; Kushwaha, Sudhir; Daly, Richard; Dearani, Joseph; Rodeheffer, Richard; Frantz, Robert; Lacy, Martha; Hayman, Suzanne; McGregor, Christopher; Edwards, Brooks; Dispenzieri, Angela

2016-01-01

AIM: To determine the outcome of orthotopic heart transplantation (OHT) in immunoglobulin light chain (AL) amyloidosis. METHODS: The medical records of patients with AL who underwent orthotopic heart transplantation at the Mayo Clinic in Rochester Minnesota from 1992 to 2011 were reviewed. Patients met at least one of the following at: New York Heart Association class IV heart failure, ventricular thickness > 15 mm, ejection fraction < 40%. Selection guidelines for heart transplant included age < 60 years, absence of multiple myeloma and significant extra-cardiac organ involvement. Baseline characteristics including age, gender, organ involvement, and New York Heart Association functional class were recorded. Laboratory data, waiting time until heart transplant, and type of treatment of the underlying plasma cell disorder were recorded. Survival from the time of OHT was calculated using Kaplan-Meier survival curves. Survival of patients undergoing OHT for AL was compared to that of non-amyloid patients undergoing OHT during the same time period. RESULTS: Twenty-three patients (median age 53 years) with AL received OHT. There were no deaths in the immediate perioperative period. Twenty patients have died post OHT. For the entire cohort, the median overall survival was 3.5 years (95%CI: 1.2, 8.2 years). The 1-year survival post OHT was 77%, the 2-year survival 65%, and the 5-year survival 43%. The 5-year survival for non-amyloid patients undergoing OHT during the same era was 85%. Progressive amyloidosis contributed to death in twelve patients. Of those without evidence of progressive amyloidosis, the cause of death included complications of autologous hematopoietic stem cell transplantation for 3 patients, post-transplant lymphoproliferative disorder for 2 patients; and for the remaining one death was related to each of the following causes: acute rejection; cardiac vasculopathy; metastatic melanoma; myelodysplastic syndrome; and unknown. Eight patients had rejection at a median of 1.8 mo post OHT (range 0.4 to 4.9 mo); only one patient died of rejection. Median survival of seven patients who achieved a complete hematologic response to either chemotherapy or autologous hematopoietic stem cell transplantation was 10.8 years. CONCLUSION: Our data demonstrate that long term survival after heart transplant is feasible in AL patients with limited extra-cardiac involvement who achieve complete hematologic response. PMID:27358783

A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results.

PubMed

Saccà, Francesco; Quarantelli, Mario; Rinaldi, Carlo; Tucci, Tecla; Piro, Raffaele; Perrotta, Gaetano; Carotenuto, Barbara; Marsili, Angela; Palma, Vincenzo; De Michele, Giuseppe; Brunetti, Arturo; Brescia Morra, Vincenzo; Filla, Alessandro; Salvatore, Marco

2012-01-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease with motor neuron degeneration. Riluzole is the only available treatment. Two-thirds of ALS patients present with growth hormone (GH) deficiency. The aim of this study is to determine if add-on of GH to riluzole, with an individually regulated dose based on Insulin-like growth factor 1 (IGF-I) production, was able to reduce neuronal loss in the motor cortex, reduce mortality, and improve motor function of ALS patients. Patients with definite/probable ALS, in treatment with riluzole, aged 40-85 years, and with disease duration ≤3 years were enrolled. The study was randomized, placebo controlled, and double blind. Before treatment, patients were tested with a GH releasing hormone (GHRH) + arginine test. The initial dose of GH was 2 IU s.c. every other day, and was progressively increased to a maximum of 8 IU. Primary endpoint was N-acetylaspartate/(creatine + choline) (NAA/Cre + Cho) ratio in motor cortex assessed by magnetic resonance spectroscopy performed at months 0, 6, and 12. Secondary endpoints were mortality and ALS functional rating scale revised (ALSFRS-R). The NAA/(Cre + Cho) ratio decreased in all patients who completed the trial. No significant difference was noted between treated and placebo group. At baseline, although IGF-I levels were within the normal range, 73% of patients had GH deficiency, being severe in half of them. Compared with bulbar onset, spinal-onset patients showed more depressed GH response to the GHRH + arginine stimulation test (10.4 ± 7.0 versus 15.5 ± 8.1 ng/mL; p < 0.05). Insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] increased from 2.1 ± 1.0 at baseline to 4.6 ± 1.9 at 12 months (p < 0.001). Insulin-like growth factor (IGF) binding protein 3 (IGFBP-3) decreased from 8,435 ± 4,477 ng/mL at baseline to 3,250 ± 1,780 ng/mL at 12 months (p < 0.001). The results show that GH exerted no effect on cerebral NAA or clinical progression assessed by ALSFRS-R. Two-thirds of ALS patients had GH deficit, with higher levels in the bulbar-onset group. During follow-up, patients showed progressive increase in HOMA-IR and decrease in IGFBP-3 levels.

IntAct: Intraoperative Fluorescence Angiography (IFA) to Prevent Anastomotic Leak in Rectal Cancer Surgery: A Randomised Controlled Trial.

PubMed

Armstrong, G; Croft, J; Corrigan, N; Brown, J M; Goh, V; Quirke, P; Hulme, C; Tolan, D; Kirby, A; Cahill, R; O'Connell, R; Miskovic, D; Coleman, M; Jayne, D G

2018-05-11

Anastomotic leak (AL) is a major complication of rectal cancer surgery. Despite advances in surgical practice, rates of AL have remained static at around 10-15%. The aetiology of AL is multifactorial, but one of the most crucial risk factors, which is mostly under the control of the surgeon, is blood supply to the anastomosis. The MRC/NIHR IntAct study will determine whether assessment of anastomotic perfusion using a fluorescent dye (Indocyanine Green) and near-infrared laparoscopy can minimise the rate of anastomotic leak as compared to conventional white light laparoscopy. Two mechanistic sub-studies will explore the role of the rectal microbiome in AL and the predictive value of CT angiography/perfusion studies. IntAct is a prospective, unblinded, parallel group, multicentre, European, randomised controlled trial comparing surgery with intraoperative fluorescence angiography (IFA) against standard care (surgery with no IFA). The primary end-point is rate of clinical anastomotic leak at 90-days following surgery. Secondary endpoints include all AL (clinical and radiological), change in planned anastomosis, complications and re-interventions, use of stoma, cost effectiveness of the intervention and quality of life. Patients should have a diagnosis of adenocarcinoma of the rectum suitable for potentially curative surgery by anterior resection. Over three years, 880 patients from 25 European centres will be recruited and followed up for 90 days. IntAct will rigorously evaluate the use of IFA in rectal cancer surgery and explore the role of the microbiome in AL and the predictive value of preoperative CT angiography/perfusion scanning. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Trial of early noninvasive ventilation for ALS: A pilot placebo-controlled study.

PubMed

Jacobs, Teresa L; Brown, Devin L; Baek, Jonggyu; Migda, Erin M; Funckes, Timothy; Gruis, Kirsten L

2016-11-01

To evaluate the use and tolerability of noninvasive positive pressure ventilation (NIV) in patients with amyotrophic lateral sclerosis (ALS) early in their disease by comparing active NIV and sham NIV in patients not yet eligible for NIV use as recommended by practice guidelines. This was a single-center, prospective, double-blind, randomized, placebo (sham)-controlled pilot trial. Patients with ALS were randomized to receive either sham NIV or active NIV and underwent active surveillance approximately every 3 months until they reached a forced vital capacity (FVC) <50% or required NIV for clinical symptom management. In total, 54 participants were randomized. The mean NIV use was 2.0 hours (95% confidence interval [CI] 1.1-3.0) per day in the sham NIV treatment group and 3.3 hours (CI 2.0-4.6) per day in the active NIV group, which did not differ by treatment group (p = 0.347). The majority of sham NIV participants (88%) and active NIV participants (73%) reported only mild or no problem with NIV use. Difference of change in FVC through the treatment period by group (0.44 per month) favored active NIV (p = 0.049). Survival and changes in maximal inspiratory or expiratory pressure did not differ between treatment groups. The efficacy of early NIV in ALS should be tested in randomized, placebo-controlled trials. The trial is registered on clinicaltrials.gov (NCT00580593). This study provides Class II evidence that for patients with ALS, adherence with NIV and sham NIV are similar. © 2016 American Academy of Neurology.

High-dose melphalan and autologous stem cell transplantation for AL amyloidosis: recent trends in treatment-related mortality and 1-year survival at a single institution

PubMed Central

Seldin, D. C.; Andrea, N.; Berenbaum, I.; Berk, J. L.; Connors, L.; Dember, L. M.; Doros, G.; Fennessey, S.; Finn, K.; Girnius, S.; Lerner, A.; Libbey, C.; Meier-Ewert, H. K.; O’Connell, R.; O’Hara, C.; Quillen, K.; Ruberg, F. L.; Sam, F.; Segal, A.; Shelton, A.; Skinner, M.; Sloan, J. M.; Wiesman, J. F.; Sanchorawala, V.

2017-01-01

Treatment with high-dose melphalan chemotherapy supported by hematopoietic rescue with autologous stem cells produces high rates of hematologic responses and improvement in survival and organ function for patients with AL amyloidosis. Ongoing clinical trials explore pre-transplant induction regimens, post-transplant consolidation or maintenance approaches, and compare transplant to non-transplant regimens. To put these studies into context, we reviewed our recent experience with transplant for AL amyloidosis in the Amyloid Treatment and Research Program at Boston Medical Center and Boston University School of Medicine. Over the past 10 years, there was a steady reduction in rates of treatment-related mortality and improvement in 1-year survival, now approximately 5% and 90%, respectively, based upon an intention-to-treat analysis. Median overall survival of patients treated with this approach at our center exceeds 7.5 years. PMID:21838459

Aripiprazole Lauroxil Compared with Paliperidone Palmitate in Patients with Schizophrenia: An Indirect Treatment Comparison.

PubMed

Cameron, Chris; Zummo, Jacqueline; Desai, Dharmik N; Drake, Christine; Hutton, Brian; Kotb, Ahmed; Weiden, Peter J

Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic recently approved for treatment of schizophrenia on the basis of a large-scale trial of two doses of AL versus placebo. There are no direct-comparison studies with paliperidone palmitate (PP; long-acting antipsychotic used most often in acute settings) for the acute psychotic episode. To indirectly compare efficacy and safety of the pivotal AL study with all PP studies meeting indirect comparison criteria. Systematic searches of MEDLINE, Embase, Cochrane CENTRAL, PsycINFO, ClinicalTrials.gov, International Clinical Trials Registry Platform, and gray literature were performed to identify randomized controlled trials of PP with similar designs to the AL trial. Bayesian network meta-analysis compared treatments with respect to symptom response and tolerability issues including weight gain, akathisia, parkinsonism, and likelihood of treatment-emergent adverse events. Three appropriate PP studies were identified for indirect comparison. Both doses of AL (441 mg and 882 mg monthly) were used and compared with two efficacious doses of PP (156 mg and 234 mg monthly). All four active-treatment conditions were associated with comparable reductions in acute symptoms (Positive and Negative Syndrome Scale) versus placebo and were of similar magnitude (range of mean difference -8.12 to -12.01, with overlapping 95% credible intervals). Between-group comparisons of active-treatment arms were associated with summary estimates of magnitude near 0. No clinically meaningful differences in selected safety or tolerability parameter incidence were found between active treatments. These results suggest that both AL and PP are effective for treatment of adults experiencing acute exacerbation of schizophrenia. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Identifying who will benefit from non-invasive ventilation in amyotrophic lateral sclerosis/motor neurone disease in a clinical cohort.

PubMed

Berlowitz, David J; Howard, Mark E; Fiore, Julio F; Vander Hoorn, Stephen; O'Donoghue, Fergal J; Westlake, Justine; Smith, Anna; Beer, Fiona; Mathers, Susan; Talman, Paul

2016-03-01

Respiratory failure is associated with significant morbidity and is the predominant cause of death in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS). This study aimed to determine the effect of non-invasive ventilatory (NIV) support on survival and pulmonary function decline across MND/ALS phenotypes. Cohort recruited via a specialist, multidisciplinary clinic. Patients were categorised into four clinical phenotypes (ALS, flail arm, flail leg and primary lateral sclerosis) according to site of presenting symptom and the pattern of upper versus lower motor neurone involvement. NIV was initiated according to current consensus practice guidelines. Between 1991 and 2011, 1198 patients diagnosed with ALS/MND were registered. 929 patients (77.5%) fulfilled the selection criteria and their data were analysed. Median tracheostomy free survival from symptom onset was 28 months in NIV-treated patients compared to 15 months in untreated (Univariate Cox regression HR=0.61 (0.51 to 0.73), p<0.001). The positive survival effect of NIV persisted when the model was adjusted for age, gender, riluzole and percutaneous endoscopic gastrostomy use (HR=0.72 (0.60 to 0.88, p=0.001). In contrast with the only randomised controlled trial, NIV statistically significantly increased survival by 19 months in those with ALS-bulbar onset (Univariate HR=0.50 (0.36 to 0.70), multivariate HR=0.59 (0.41 to 0.83)). These data confirm that NIV improves survival in MND/ALS. The overall magnitude of benefit is 13 months and was largest in those with ALS-bulbar disease. Future research should explore the optimal timing of NIV initiation within phenotypes in order to optimise respiratory function, quality of life and survival. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

A secure and robust password-based remote user authentication scheme using smart cards for the integrated EPR information system.

PubMed

Das, Ashok Kumar

2015-03-01

An integrated EPR (Electronic Patient Record) information system of all the patients provides the medical institutions and the academia with most of the patients' information in details for them to make corrective decisions and clinical decisions in order to maintain and analyze patients' health. In such system, the illegal access must be restricted and the information from theft during transmission over the insecure Internet must be prevented. Lee et al. proposed an efficient password-based remote user authentication scheme using smart card for the integrated EPR information system. Their scheme is very efficient due to usage of one-way hash function and bitwise exclusive-or (XOR) operations. However, in this paper, we show that though their scheme is very efficient, their scheme has three security weaknesses such as (1) it has design flaws in password change phase, (2) it fails to protect privileged insider attack and (3) it lacks the formal security verification. We also find that another recently proposed Wen's scheme has the same security drawbacks as in Lee at al.'s scheme. In order to remedy these security weaknesses found in Lee et al.'s scheme and Wen's scheme, we propose a secure and efficient password-based remote user authentication scheme using smart cards for the integrated EPR information system. We show that our scheme is also efficient as compared to Lee et al.'s scheme and Wen's scheme as our scheme only uses one-way hash function and bitwise exclusive-or (XOR) operations. Through the security analysis, we show that our scheme is secure against possible known attacks. Furthermore, we simulate our scheme for the formal security verification using the widely-accepted AVISPA (Automated Validation of Internet Security Protocols and Applications) tool and show that our scheme is secure against passive and active attacks.

Increased Serum Al Levels in Hemodialysis Patients Kept Enhanced during a 2-Year Prospective Study.

PubMed

Reina de la Torre, Maria L; Lopez García de la Serrana, Herminia; Martí Del Moral, Loreto; Palomares Bayo, Magdalena; Navarro-Alarcón, Miguel

2017-07-01

The regulation of mineral homeostasis is altered in hemodialysis patients with renal insufficiency, producing increased risk for secondary diseases like cardiovascular ones. We hypothesized that risen serum aluminum (Al) concentration in hemodialysis patients kept enhanced during a 2-year longitudinal study is associated with enhanced cardiovascular risk and influenced by medical treatments. This study reports the prospective monitoring of serum Al levels in six-monthly samplings over 2 years in 116 hemodialysis patients and a control group of 50 healthy adults. The influence of other factors like sex, age, kidney transplant, disease etiology, and drug consumption was also considered. At each sampling, serum Al levels were significantly higher in the patients than in the healthy controls (P < 0.05). Levels in the patient group were statistically significantly lower at the third and fourth versus first and second samplings, which may be related to Al accumulation in tissues. Increased Al levels in patients were positively and significantly related to serum calcium (Ca) and uric acid levels. Serum Al concentrations were significantly lower in patients receiving vasodilators and diuretics. Higher serum Al levels in hemodialyzed patients administered with phosphate binders or anti-hyperkalemics are attributable to their usual Al salt content. The consumption of antianemic drugs increases Al absorption by forming more bioavailable complexes with the compounds in these drugs. In conclusion, this is the first study to indicate that cardiovascular problems associated with elevated serum Al levels in hemodialysis patients may be in part mitigated by administrating vasodilators and diuretics, which reduce these levels.

What influences patient decision-making in amyotrophic lateral sclerosis multidisciplinary care? A study of patient perspectives.

PubMed

Hogden, Anne; Greenfield, David; Nugus, Peter; Kiernan, Matthew C

2012-01-01

Patients with amyotrophic lateral sclerosis (ALS) are required to make decisions concerning quality of life and symptom management over the course of their disease. Clinicians perceive that patients' ability to engage in timely decision-making is extremely challenging. However, we lack patient perspectives on this issue. This study aimed to explore patient experiences of ALS, and to identify factors influencing their decision-making in the specialized multidisciplinary care of ALS. An exploratory study was conducted. Fourteen patients from two specialized ALS multidisciplinary clinics participated in semistructured interviews that were audio recorded and transcribed. Data were analyzed for emergent themes. Decision-making was influenced by three levels of factors, ie, structural, interactional, and personal. The structural factor was the decision-making environment of specialized multidisciplinary ALS clinics, which supported decision-making by providing patients with disease-specific information and specialized care planning. Interactional factors were the patient experiences of ALS, including patients' reaction to the diagnosis, response to deterioration, and engagement with the multidisciplinary ALS team. Personal factors were patients' personal philosophies, including their outlook on life, perceptions of control, and planning for the future. Patient approaches to decision-making reflected a focus on the present, rather than anticipating future progression of the disease and potential care needs. Decision-making for symptom management and quality of life in ALS care is enhanced when the patient's personal philosophy is supported by collaborative relationships between the patient and the multidisciplinary ALS team. Patients valued the support provided by the multidisciplinary team; however, their focus on living in the present diverged from the efforts of health professionals to prepare patients and their carers for the future. The challenge facing health professionals is how best to engage each patient in decision-making for their future needs, to bridge this gap.

Ischaemic stroke management at Al-Shifa Hospital in the Gaza Strip: a clinical audit.

PubMed

Abukaresh, Amir; Al-Abadlah, Rami; Böttcher, Bettina; El-Essi, Khamis

2018-02-21

In the 2014 Palestinian annual health report, cerebrovascular accident was ranked as the third leading cause of death in the occupied Palestinian territory. Cerebrovascular accident is also one the most common causes of disability worldwide. Good management decreases mortality and morbidity. The aim of this study was to assess the current management of patients with ischaemic stroke at the Al-Shifa Hospital and to compare this with international guidelines. For this clinical audit, we used simple random sampling to select files of patients admitted with the diagnosis of ischaemic stroke to the Al-Shifa Hospital. Data collection sheets were completed, and clinical practice was compared with the 2013 American Stroke Association guidelines. Between January and June, 2016, 254 patients were admitted with ischaemic stroke, haemorrhagic stroke, or transient ischaemic attack. We selected 55 patient files. The International Classification of Diseases coding for cerebral infarction in patient files was relatively good, with 92% of files correctly coded. However, we found a substantial weakness in the documentation of duration, progression of symptoms (documented in 20% of files only), and physiotherapy assessment. Most essential acute investigations were done on time (for all [100%] patients needing blood count, renal function tests, and CT scan and for 42 [76%] patients needing ECG). However, thrombolytic drugs were not used because they were not available. Long-term antiplatelet therapy was provided properly to 51 (92%) patients discharged from hospital. However, the initial doses of antiplatelet therapy were generally lower than the international recommendations. Findings also showed a marked inconformity of blood pressure management, especially with respect to the treatment decision and the choice of antihypertensive drug. No local guidelines exist. Furthermore, the lack of availability of thrombolysis medication and the poor deviation in blood pressure management show a lack of evidence-based practice. These findings point to the urgent need for the development of local, evidence-based guidelines. None. Copyright © 2018 Elsevier Ltd. All rights reserved.

Lateral and posterior pillar grade changes during the treatment of Perthes disease in older patients using skin traction and range of motion exercises.

PubMed

Sugimoto, Yoshihisa; Akazawa, Hirofumi; Mitani, Shigeru; Tanaka, Masato; Nakagomi, Tadashi; Asaumi, Koji; Ozaki, Toshifumi

2006-03-01

The lateral pillar (LP) grade changes detected during treatment periods have received a lot of attention recently. Lappin et al. reported LP collapses in 92 of 275 (33%) patients during the treatment, but did not provide information for comparing treatment methods and age of onset of the disease. The purpose of this study was to review radiological changes in LP grade in older patients with Perthes disease during 20 months of treatment with skin traction and ROM exercises. We have also reported any grade changes in the posterior pillar (PP) classification. Twenty-one patients with unilateral disease who were 9 years or older at the onset of symptoms had been followed until skeletal maturity. Out of 21 older patients with Perthes disease, our study had two (9.5%) who experienced LP collapse and two (9.5%) who experienced PP collapse during the first 20 months of treatment. The average time from onset to hospitalization in hips, initially classified as LP group C and PP group C, was significantly longer than in LP and PP groups A and B. The LP collapse in two hips and PP collapse in two hips occurred during months 4-8 of treatment. On the other hand, of the patients allowed to ambulate with the Pogo stick orthosis from months 8 to 12 and without a brace from months 10 to 15, none had a collapse of their LPs or PPs during these periods. Lappin et al. reported that 92 of 275 patients (33%) who were managed conservatively in several hospitals experienced LP collapse during their treatment periods. Our results suggest that older patients with this disease treated with skin traction and ROM exercises rarely suffer a LP collapse, as compared with the Lappin et al. report.

The processing of actions and action-words in amyotrophic lateral sclerosis patients.

PubMed

Papeo, Liuba; Cecchetto, Cinzia; Mazzon, Giulia; Granello, Giulia; Cattaruzza, Tatiana; Verriello, Lorenzo; Eleopra, Roberto; Rumiati, Raffaella I

2015-03-01

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with prime consequences on the motor function and concomitant cognitive changes, most frequently in the domain of executive functions. Moreover, poorer performance with action-verbs versus object-nouns has been reported in ALS patients, raising the hypothesis that the motor dysfunction deteriorates the semantic representation of actions. Using action-verbs and manipulable-object nouns sharing semantic relationship with the same motor representations, the verb-noun difference was assessed in a group of 21 ALS-patients with severely impaired motor behavior, and compared with a normal sample's performance. ALS-group performed better on nouns than verbs, both in production (action and object naming) and comprehension (word-picture matching). This observation implies that the interpretation of the verb-noun difference in ALS cannot be accounted by the relatedness of verbs to motor representations, but has to consider the role of other semantic and/or morpho-phonological dimensions that distinctively define the two grammatical classes. Moreover, this difference in the ALS-group was not greater than the noun-verb difference in the normal sample. The mental representation of actions also involves an executive-control component to organize, in logical/temporal order, the individual motor events (or sub-goals) that form a purposeful action. We assessed this ability with action sequencing tasks, requiring participants to re-construct a purposeful action from the scrambled presentation of its constitutive motor events, shown in the form of photographs or short sentences. In those tasks, ALS-group's performance was significantly poorer than controls'. Thus, the executive dysfunction manifested in the sequencing deficit -but not the selective verb deficit- appears as a consistent feature of the cognitive profile associated with ALS. We suggest that ALS can offer a valuable model to study the relationship between (frontal) motor centers and the executive-control machinery housed in the frontal brain, and the implications of executive dysfunctions in tasks such as action processing. Copyright © 2014 Elsevier Ltd. All rights reserved.

The effect of N-acetyl cysteine (NAC) on aluminum phosphide poisoning inducing cardiovascular toxicity: a case-control study.

PubMed

Taghaddosinejad, Fakhreddin; Farzaneh, Esmaeil; Ghazanfari-Nasrabad, Mahdi; Eizadi-Mood, Nastaran; Hajihosseini, Morteza; Mehrpour, Omid

2016-01-01

Aluminum phosphide (AlP) is a very effective indoor and outdoor pesticide. We investigated the effects of N-acetyl cysteine (NAC) on the survival time, hemodynamics, and cardiac biochemical parameters at various time intervals in some cases of AlP poisoning. This research was a case-control study to evaluate 63 AlP poisoned patients during 2010-2012. Patients with cardiovascular complications of AlP to be treated with intravenous NAC plus conventional treatment were considered as the case group and compared with patients who did not receive NAC. NAC infusion was administered to the case group at 300 mg/kg for 20 h. The data gathered included age, sex, heart rate, Systolic blood pressure (SBP), creatine phosphokinase (CPK), creatine kinase MB (CK-MB), and ECG at the admission time and 12, 18, and 24 h after admission. Analysis of repeated measures was performed to check the variability of parameters over time. The mean ages in the case and control groups were 26.65 ± 1.06 (19-37 years) and 28.39 ± 1.11 (18-37 years), respectively (P = 0.266). Most of the patients were female (56.5%). CK-MB means were significantly different between the two groups, but no differences between the other variables were observed. Also, CK-MB, CPK, heart rate, and systolic blood pressure means became significantly different over time (0, 12, 18, and 24 h) in both groups (P < 0.001). NAC prevented sharp heart rate fluctuations in AlP patients in the case group. Regarding the outcomes, 17 patients died (10 patients in the control and 7 patients in the case groups). No side-effects of NAC were observed. Our patients could be managed by the positive role of NAC as the biochemical index of cardiotoxicity was found to elevate in both the case and control groups. Therefore, for the management protocol optimization, NAC evaluation should be done in further cases.

A Cross-Validation of the Keane and Penk MMPI Scales as Measures of Post-Traumatic Stress Disorder.

ERIC Educational Resources Information Center

Watson, Charles G.; And Others

1986-01-01

Compared scores of post-traumatic stress disorder (PTSD) patients, psychiatric patients who did not meet PTSD criteria, and normals on the Keane et al PTSD scale and Penk Combat Scales for the Minnesota Multiphasic Personality Inventory. Results confirmed the validities of the PTSO scale and, to a lesser degree, Penk Combat Intensity Scales as…

Comparison of the clinical and cognitive features of genetically positive ALS patients from the largest tertiary center in Serbia.

PubMed

Marjanović, Ivan V; Selak-Djokić, Biljana; Perić, Stojan; Janković, Milena; Arsenijević, Vladimir; Basta, Ivana; Lavrnić, Dragana; Stefanova, Elka; Stević, Zorica

2017-06-01

Discovering novel mutations in C9orf72, FUS, ANG, and TDP-43 genes in ALS patients arises necessities for better clinical characterizations of these subjects. The aim is to determine clinical and cognitive profile of genetically positive Serbian ALS patients. 241 ALS patients were included in the study (17 familiar and 224 apparently sporadic). The following genes were analyzed: SOD1, C9orf72, ANG, FUS, and TDP-43. An extensive battery of classic neuropsychological tests was used in 27 ALS patients (22 SOD1 positive and 5 SOD1 negative) and 82 healthy controls (HCs). Overall 37 (15.4%) of 241 ALS patients carried mutations in tested genes-among 17 familiar ALS patients 16 (94.1%) were positive and among 224 apparently sporadic 21 (9.4%) had causative mutation. Mutations in SOD1 gene were the most common, representing 27 (73.0%) of all genetically positive ALS patients. The main clinical characteristics of SOD1 positive patients were: spinal onset in lower extremities, common sphincter and sensitive disturbances, and dysexecutive syndrome. Within SOD1 positive patients, we noticed somewhat earlier onset in patients with A145G, sensory and sphincter disturbances were dominant in patients with L144F, while D90A patients had significant sensory involvement. SOD1 negative group consisted of ten (27.0%) patients (six C9orf72, two ANG, one TDP-43, and one patient baring triple FUS, C9orf72 expansion, and ANG variants). Bulbar involvement and more extensive neuropsychological impairment (including executive, visuospatial, and memory difficulties) were the main features of SOD1 negative cohort. Our results suggest that meaningful clinical suspicion of certain ALS genotype might be made based on thorough clinical evaluation of patients.

Comparison of methods of evaluating hearing benefit of middle ear surgery.

PubMed

Toner, J G; Smyth, G D

1993-01-01

The objective of this paper is to compare two methods of predicting the level of subjective patient benefit following reconstructive middle ear surgery. This should have always been an important consideration in advising patients regarding surgery, but assumes even more relevance in these days of clinical audit and cost benefit analysis. The two methods studied were the '15/30 dB rule of thumb' (Smyth and Patterson, 1985) and the 'Glasgow plot' (Browning et al., 1991). The predictions of benefit for each of the two methods were compared to the assessment of actual benefits by the patient post-operatively. The results of this comparison in 153 patients were analysed, the rule of thumb was found to be somewhat more sensitive in predicting patient benefit.

Effect of Presymptomatic Body Mass Index and Consumption of Fat and Alcohol on Amyotrophic Lateral Sclerosis.

PubMed

Huisman, Mark H B; Seelen, Meinie; van Doormaal, Perry T C; de Jong, Sonja W; de Vries, Jeanne H M; van der Kooi, Anneke J; de Visser, Marianne; Schelhaas, H Jurgen; van den Berg, Leonard H; Veldink, Jan H

2015-10-01

Because dietary intake may influence pathophysiologic mechanisms in sporadic amyotrophic lateral sclerosis (ALS), the association between premorbid dietary intake and the risk of sporadic ALS will provide insight into which mechanisms are possibly involved in ALS pathophogenesis. To systematically determine the association between premorbid dietary intake and the risk of sporadic ALS. A population-based case-control study was conducted in a general community setting in the Netherlands from January 1, 2006, to September 30, 2011. Analysis was conducted April 1, 2013, to November 15, 2014. All patients with a new diagnosis of possible, probable (laboratory supported), or definite ALS according to the revised El Escorial criteria were included and multiple sources were used to ensure complete case ascertainment. Of 986 eligible patients, 674 gave informed consent and returned a complete questionnaire; 2093 controls randomly selected from the general practitioners' registers and frequency matched to the patients for sex and age were included. We studied the premorbid intake of nutrients in association with the risk of ALS by using a 199-item food frequency questionnaire adjusted for confounding factors and corrected for multiple comparisons while minimizing recall bias. Presymptomatic total daily energy intake in patients, reported as mean (SD), was significantly higher compared with controls (2258 [730] vs 2119 [619] kcal/day; P < .01), and presymptomatic body mass index (calculated as weight in kilograms divided by height in meters squared) was significantly lower in patients (25.7 [4.0] vs 26.0 [3.7]; P = .02). With values reported as odds ratio (95% CI), higher premorbid intake of total fat (1.14; 1.07-1.23; P < .001), saturated fat (1.43; 1.25-1.64; P < .001), trans-fatty acids (1.03; 1.01-1.05; P < .001), and cholesterol (1.08; 1.05-1.12; P < .001) was associated with an increased risk of ALS; higher intake of alcohol (0.91; 0.84-0.99; P = .03) was associated with a decreased risk of ALS. These associations were independent of total energy intake, age, sex, body mass index, educational level, smoking, and lifetime physical activity. No significant associations between dietary intake and survival were found. The combination of independent positive associations of a low premorbid body mass index and a high fat intake together with prior evidence from ALS mouse models transgenic for SOD1 and earlier reports on premorbid body mass index support a role for increased resting energy expenditure before clinical onset of ALS.

Inverting the power dynamic: The process of first sessions of psychotherapy with therapists of color and non-Latino white patients.

PubMed

Okun, Lia; Chang, Doris F; Kanhai, Gregory; Dunn, Jordan; Easley, Hailey

2017-07-01

The present study is the first to apply Trawalter, Richeson, and Shelton's (2009) stress and coping framework to qualitatively examine interracial interactions in initial sessions of psychotherapy. The sample included 22 dyads: 15 therapists of color administering various treatment modalities to 15 treatment-seeking non-Latino White (NLW) patients and a comparison group of 7 intraracial (NLW-NLW) dyads. In Phase 1, videorecordings of the first session of treatment were analyzed using inductive thematic analysis (TA) to describe patient and therapist behaviors. In Phase 2, a deductive TA approach was used to interpret and cluster those dyadic behaviors according to Trawalter et al.'s (2009) framework. NLW patients paired with therapists of color made more efforts to bridge differences and more often questioned the therapist's professional qualifications compared with those matched with NLW therapists. Therapists of color made more self-disclosures than NLW therapists and maintained a more formal stance, compared with NLW therapists. The deductive TA operationalized 4 of Trawalter and colleagues' (2009) coping responses within a therapeutic framework. Findings highlight the ability of therapists' of color to engage positively with their NLW patients even in the face of challenges to their expertise and credibility. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Verbal communication impacts quality of life in patients with amyotrophic lateral sclerosis.

PubMed

Felgoise, Stephanie H; Zaccheo, Vincenzo; Duff, Jason; Simmons, Zachary

2016-01-01

Global quality of life (QoL) in patients with ALS has been found to be independent of overall physical function. However, the relationship between verbal communication ability and QoL has not been explored. This was a retrospective study using data from a study validating the ALS-Specific QoL Questionnaire (ALSSQoL). Speech function was assessed using the first question on the ALS Functional Rating Scale (ALSFRS), ranging from 4 (normal speech) to 0 (loss of useful speech). There were 338 participants for whom data were available for speech function and for all ALSSQoL subscales. Analysis of variance revealed that QoL varied among individuals with different functional abilities for speech (F (4,333) = 5.13, p = 0.001). Specifically, poorer QoL was related to initial impairments in verbal communication ability (p = 0.005). QoL also was poorer in those with no speech ability compared to those with normal speech (p = 0.008). In conclusion, the ability to communicate verbally, unlike overall physical function, is directly related to overall QoL in patients with ALS. The initial period of speech impairment appears to have a particularly strong impact on QoL, and may be an important time for intervention.

Elevation of Plasmin-α2-plasmin Inhibitor Complex Predicts the Diagnosis of Systemic AL Amyloidosis in Patients with Monoclonal Protein.

PubMed

Ishiguro, Kazuya; Hayashi, Toshiaki; Yokoyama, Yoshihiro; Aoki, Yuka; Onodera, Kei; Ikeda, Hiroshi; Ishida, Tadao; Nakase, Hiroshi

2018-03-15

Objective The complication of systemic immunoglobulin light chain (AL) amyloidosis in patients with monoclonal immunoglobulin affects the prognosis, but amyloid deposition in tissues is sometimes difficult to detect due to bleeding tendencies and preferential distributions. However, fibrinolysis is known to be exacerbated in patients with systemic AL amyloidosis specifically. We therefore explored new biomarkers for predicting a diagnosis of systemic AL amyloidosis focusing on coagulation and fibrinolysis markers. Methods We reviewed the clinical features and treatment outcomes of patients with serum monoclonal protein, including primary systemic AL amyloidosis and multiple myeloma (MM), treated at our hospital between January 2008 and December 2014. Results Among several biomarkers, only the serum level of plasmin-α2-plasmin inhibitor complex (PIC) in patients with systemic AL amyloidosis (n=26) at the diagnosis was significantly higher than in patients with MM without AL amyloidosis (n=26) (mean±standard deviation, 3.69±2.82 μg/mL vs. 1.23±0.97 μg/mL, p<0.01). The cut-off for predicting a diagnosis of systemic AL amyloidosis in patients with serum monoclonal protein was 1.72 μg/mL with 84.6% sensitivity and 80.8% specificity. Hepatic involvement resulted in a significantly higher PIC level than no involvement in patients with systemic AL amyloidosis. The serum PIC level was also associated with the hematological response of systemic AL amyloidosis. Conclusion PIC is a useful biomarker for the diagnosis and management of patients with systemic AL amyloidosis.

Measuring Patient Adherence to Malaria Treatment: A Comparison of Results from Self-Report and a Customised Electronic Monitoring Device

PubMed Central

Bruxvoort, Katia; Festo, Charles; Cairns, Matthew; Kalolella, Admirabilis; Mayaya, Frank; Kachur, S. Patrick; Schellenberg, David; Goodman, Catherine

2015-01-01

Background Self-report is the most common and feasible method for assessing patient adherence to medication, but can be prone to recall bias and social desirability bias. Most studies assessing adherence to artemisinin-based combination therapies (ACTs) have relied on self-report. In this study, we use a novel customised electronic monitoring device—termed smart blister packs—to examine the validity of self-reported adherence to artemether-lumefantrine (AL) in southern Tanzania. Methods Smart blister packs were designed to look identical to locally available AL blister packs and to record the date and time each tablet was removed from packaging. Patients obtaining AL at randomly selected health facilities and drug stores were followed up at home three days later and interviewed about each dose of AL taken. Blister packs were requested for pill count and extraction of smart blister pack data. Results Data on adherence from both self-report verified by pill count and smart blister packs were available for 696 of 1,204 patients. There was no difference between methods in the proportion of patients assessed to have completed treatment (64% and 67%, respectively). However, the percentage taking the correct number of pills for each dose at the correct times (timely completion) was higher by self-report than smart blister packs (37% vs. 24%; p<0.0001). By smart blister packs, 64% of patients completing treatment did not take the correct number of pills per dose or did not take each dose at the correct time interval. Conclusion Smart blister packs resulted in lower estimates of timely completion of AL and may be less prone to recall and social desirability bias. They may be useful when data on patterns of adherence are desirable to evaluate treatment outcomes. Improved methods of collecting self-reported data are needed to minimise bias and maximise comparability between studies. PMID:26214848

Assessment and nutrition education in patients with amyotrophic lateral sclerosis.

PubMed

Almeida, Claudinéa S; Stanich, Patricia; Salvioni, Cristina C S; Diccini, Solange

2016-11-01

Neurological patients with amyotrophic lateral sclerosis (ALS)often deteriorate to a worsening nutritional status. The aim of this study was to compare the nutritional status and food intake after nutrition education in patients with ALS. Clinical, anthropometric and functional variables were analyzed. Fifty-three patients were monitored at an early stage of the disease. The average score on the functionality scale was 33 points. Initially only 3.8% were classified as low body weight. After three months, 50% showed significant variation in anthropometric measures related to muscle mass and body fat reserves without association with clinical variables. After nutritional guidance, there was an increase in the intake of all food groups, especially the dairy group (p <0.05).The change of the nutritional status occurs early in patients with amyotrophic lateral sclerosis, even in those previously eutrophic or over weight. There was an increase in food intake after nutritional guidance according to the food guide adapted to the Brazilian population.

The impact of type and number of bowel resections on anastomotic leakage risk in advanced ovarian cancer surgery.

PubMed

Grimm, Christoph; Harter, Philipp; Alesina, Pier F; Prader, Sonia; Schneider, Stephanie; Ataseven, Beyhan; Meier, Beate; Brunkhorst, Violetta; Hinrichs, Jakob; Kurzeder, Christian; Heitz, Florian; Kahl, Annett; Traut, Alexander; Groeben, Harald T; Walz, Martin; du Bois, Andreas

2017-09-01

To identify risk factors for anastomotic leakage (AL) in patients undergoing primary advanced ovarian cancer surgery and to evaluate the prognostic implication of AL on overall survival in these patients. We analyzed our institutional database for primary EOC and included all consecutive patients treated by debulking surgery including any type of full circumferential bowel resection beyond appendectomy between 1999 and 2015. We performed logistic regression models to identify risk factors for AL and log-rank tests and Cox proportional hazards models to evaluate the association between AL and survival. AL occurred in 36/800 (4.5%; 95% confidence interval [3%-6%]) of all patients with advanced ovarian cancer and 36/518 (6.9% [5%-9%]) patients undergoing bowel resection during debulking surgery. One hundred fifty-six (30.1%) patients had multiple bowel resections. In these patients, AL rate per patient was only slightly higher (9.0% [5%-13%]) than in patients with rectosigmoid resection only (6.9% [4%-10%]), despite the higher number of anastomosis. No independent predictive factors for AL were identified. AL was independently associated with shortened overall survival (HR 1.9 [1.2-3.4], p=0.01). In the present study, no predictive pre- and/or intraoperative risk factors for AL were identified. AL rate was mainly influenced by rectosigmoid resection and only marginally increased by additional bowel resections. Copyright © 2017 Elsevier Inc. All rights reserved.

Long-term effect of diode laser irradiation compared to sodium fluoride varnish in the treatment of dentine hypersensitivity in periodontal maintenance patients: a randomized controlled clinical study.

PubMed

Yilmaz, Hasan Guney; Kurtulmus-Yilmaz, Sevcan; Cengiz, Esra

2011-11-01

The aim of this clinical study was to evaluate and compare the desensitizing effects of a gallium?aluminum?arsenide (GaAlAs) laser and sodium fluoride (NaF) varnish on dentine hypersensitivity (DH) in periodontal maintenance patients. The use of lasers opens a new dimension in the treatment of DH. Forty-eight patients with 244 teeth affected by DH were included in the trial. To be included in the study, the subjects had to have 4 or more hypersensitive teeth at different quadrants. Selected teeth were randomly assigned to a GaAlAs laser group, placebo laser group, NaF varnish group, or a placebo NaF varnish group. Laser therapy was performed at 8.5?J/cm(2) energy density. In the placebo laser group, the same laser without laser emission was used. In the NaF varnish group, the varnish was painted at the cervical region of the teeth. In the placebo NaF varnish group, the same treatment procedures were performed with a saline solution. DH was assessed with a visual analog scale (VAS); immediately, at 1 week, and at 1, 3, and 6 months after treatments. Intra-group time-dependent data were analyzed by Friedman's test, and Wilcoxon's rank sum test was used to evaluate the differences within groups. GaAlAs laser and NaF varnish treatments resulted in a significant reduction in the VAS scores immediately after treatments that were maintained throughout the study when compared to the baseline and placebo treatments. In the NaF group, there was a significant increase in the VAS scores at 3 and 6 months compared to at 1 week and 1 month. The placebo treatments showed no significant changes in VAS scores throughout the study period. Within the limits of the study, GaAlAs laser irradiation was effective in the treatment of DH, and it is a more comfortable and faster procedure than traditional DH treatment.

A proteomic network approach across the ALS-FTD disease spectrum resolves clinical phenotypes and genetic vulnerability in human brain.

PubMed

Umoh, Mfon E; Dammer, Eric B; Dai, Jingting; Duong, Duc M; Lah, James J; Levey, Allan I; Gearing, Marla; Glass, Jonathan D; Seyfried, Nicholas T

2018-01-01

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlap in clinical presentation, neuropathology, and genetic underpinnings. The molecular basis for the overlap of these disorders is not well established. We performed a comparative unbiased mass spectrometry-based proteomic analysis of frontal cortical tissues from postmortem cases clinically defined as ALS, FTD, ALS and FTD (ALS/FTD), and controls. We also included a subset of patients with the C9orf72 expansion mutation, the most common genetic cause of both ALS and FTD Our systems-level analysis of the brain proteome integrated both differential expression and co-expression approaches to assess the relationship of these differences to clinical and pathological phenotypes. Weighted co-expression network analysis revealed 15 modules of co-expressed proteins, eight of which were significantly different across the ALS-FTD disease spectrum. These included modules associated with RNA binding proteins, synaptic transmission, and inflammation with cell-type specificity that showed correlation with TDP-43 pathology and cognitive dysfunction. Modules were also examined for their overlap with TDP-43 protein-protein interactions, revealing one module enriched with RNA-binding proteins and other causal ALS genes that increased in FTD/ALS and FTD cases. A module enriched with astrocyte and microglia proteins was significantly increased in ALS cases carrying the C9orf72 mutation compared to sporadic ALS cases, suggesting that the genetic expansion is associated with inflammation in the brain even without clinical evidence of dementia. Together, these findings highlight the utility of integrative systems-level proteomic approaches to resolve clinical phenotypes and genetic mechanisms underlying the ALS-FTD disease spectrum in human brain. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

Clinical characteristics of long-term survival with non-invasive ventilation and factors affecting the transition to invasive ventilation in ALS.

PubMed

Hirose, Takahiko; Kimura, Fumiharu; Tani, Hiroki; Ota, Shin; Tsukahara, Akihiro; Sano, Eri; Shigekiyo, Taro; Nakamura, Yoshitsugu; Kakiuchi, Kensuke; Motoki, Mikiko; Unoda, Kiichi; Ishida, Simon; Nakajima, Hideto; Arawaka, Shigeki

2018-04-20

Introduction We evaluated post non-invasive ventilation survival and factors for the transition to tracheostomy in amyotrophic lateral sclerosis. Methods We analyzed 197 patients using a prospectively-collected database, with 114 patients since 2000. Results Of 114 patients, 59 patients underwent non-invasive ventilation (NIV), which prolonged the total median survival time to 43 months compared with 32 months without treatment. The best post-NIV survival was associated with a lack of bulbar symptoms, higher measured pulmonary function, and a slower rate of progression at diagnosis. The transition rate from NIV to tracheostomy gradually decreased over the years. Patients using NIV for more than 6 months were more likely to refuse tracheostomy and to be female. Discussion This study confirmed a positive survival effect with NIV, which was less effective in patients with bulbar dysfunction. Further studies are necessary to determine the best timing for using NIV with ALS in patients with bulbar dysfunction. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Screening of SOD1, FUS and TARDBP genes in patients with amyotrophic lateral sclerosis in central-southern China.

PubMed

Hou, Lihua; Jiao, Bin; Xiao, Tingting; Zhou, Lu; Zhou, Zhifan; Du, Juan; Yan, Xinxiang; Wang, Junling; Tang, Beisha; Shen, Lu

2016-09-08

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons of the brain, brainstem and spinal cord. To date, mutations in more than 30 genes have been linked to the pathogenesis of ALS. Among them, SOD1, FUS and TARDBP are ranked as the three most common genes associated with ALS. However, no mutation analysis has been reported in central-southern China. In this study, we sequenced SOD1, FUS and TARDBP in a central-southern Chinese cohort of 173 patients with ALS (15 familial ALS and 158 sporadic ALS) to detect mutations. As a result, five missense mutations in SOD1, namely, p.D101N, p.D101G, p.C111Y, p.N86S and p.V87A, were identified in three unrelated familial probands and three sporadic cases; two mutations in FUS were found in two unrelated familial probands, including an insertion mutation (p.P525_Y526insY) and a missense mutation (p.R521H); no variants of TARDBP were observed in patients. Therefore, SOD1 mutations were present in 20.0% of familial ALS patients and 1.9% of sporadic ALS patients, while FUS mutations were responsible for 13.3% of familial ALS cases, and TARDBP mutations were rare in either familial or sporadic ALS cases. This study broadens the known mutational spectrum in patients with ALS and further demonstrates the necessity for genetic screening in ALS patients from central-southern China.

[Relation of MBL ExonI 54 and NFκB1-94ins/del ATTG Polymorphism with Fever during Neutropenia in Patients with Acute Leukaemia after Chemotherapy].

PubMed

Xu, Wen-Ning; Jiang, Zu-Jun; Li, Yong-Hua; Xiao, Hao-Wen; Gao, Yang; Pang, Yan; Ouyang, Lin; Liu, Zeng-Hui; Zhang, Le-Qing; Wang, Yang; Xiao, Yang

2015-10-01

To explore the correlation between MBL ExonI 54 and NFκB1-94ins/del ATTG polymorphism and fever during neutropenia in patients with acute leukaemia (AL) (except M3) after first chemotherapy in Chinese Han population. Blood samples obtained from 76 fever patients with AL during neutropenia episodes were detected to analyse single nucleotide polymorphism (SNP) in the MBL ExonI 54 and NFκB1-94ins/del ATTG gene, and analyse the correlation between above-mentioned 2 polymorphisms and fever during neutropenia of AL patients after chemotherapy. In 76 patients, no correlation were found between MBL ExonI 54 and NFκB1-94ins/del ATTG polymorphism and fever during neutropenia in patients with acute leukaemia after chemotherapy (P > 0.05). No significant relation were found in sex, age, underlying disease, disease status or degrees of neutropenia in febrile neutropenia between MBL ExonI 54 and NFκB1-94ins/del ATTG polymorphism (P > 0.05). However, patients with MBL ExonI 54 mutation presented longer febrile duration with a median of 5 days compared to 3 days of patients with wildtype MBL ExonI 54 genotype (P < 0.05). There is no clear correlation between MBL ExonI 54 and NFκB1-94ins/del ATTG polymorphism and fever during neutropenia in patients with acute leukaemia after chemotherapy. However, the patients with MBL ExonI 54 mutation have been observed to present a longer febrile duration.

Association of Regulatory T-Cell Expansion With Progression of Amyotrophic Lateral Sclerosis: A Study of Humans and a Transgenic Mouse Model.

PubMed

Sheean, Rebecca K; McKay, Fiona C; Cretney, Erika; Bye, Christopher R; Perera, Nirma D; Tomas, Doris; Weston, Richard A; Scheller, Karlene J; Djouma, Elvan; Menon, Parvathi; Schibeci, Stephen D; Marmash, Najwa; Yerbury, Justin J; Nutt, Stephen L; Booth, David R; Stewart, Graeme J; Kiernan, Mathew C; Vucic, Steve; Turner, Bradley J

2018-06-01

Neuroinflammation appears to be a key modulator of disease progression in amyotrophic lateral sclerosis (ALS) and thereby a promising therapeutic target. The CD4+Foxp3+ regulatory T-cells (Tregs) infiltrating into the central nervous system suppress neuroinflammation and promote the activation of neuroprotective microglia in mouse models of ALS. To our knowledge, the therapeutic association of host Treg expansion with ALS progression has not been studied in vivo. To assess the role of Tregs in regulating the pathophysiology of ALS in humans and the therapeutic outcome of increasing Treg activity in a mouse model of the disease. This prospective multicenter human and animal study was performed in hospitals, outpatient clinics, and research institutes. Clinical and function assessment, as well as immunological studies, were undertaken in 33 patients with sporadic ALS, and results were compared with 38 healthy control participants who were consecutively recruited from the multidisciplinary ALS clinic at Westmead Hospital between February 1, 2013, and December 31, 2014. All data analysis on patients with ALS was undertaken between January 2015 and December 2016. Subsequently, we implemented a novel approach to amplify the endogenous Treg population using peripheral injections of interleukin 2/interleukin 2 monoclonal antibody complexes (IL-2c) in transgenic mice that expressed mutant superoxide dismutase 1 (SOD1), a gene associated with motor neuron degeneration. In patients with ALS, Treg levels were determined and then correlated with disease progression. Circulating T-cell populations, motor neuron size, glial cell activation, and T-cell and microglial gene expression in spinal cords were determined in SOD1G93A mice, as well as the association of Treg amplification with disease onset and survival time in mice. The cohort of patients with ALS included 24 male patients and 9 female patients (mean [SD] age at assessment, 58.9 [10.9] years). There was an inverse correlation between total Treg levels (including the effector CD45RO+ subset) and rate of disease progression (R = -0.40, P = .002). Expansion of the effector Treg population in the SOD1G93A mice was associated with a significant slowing of disease progression, which was accompanied by an increase in survival time (IL-2c-treated mice: mean [SD], 160.6 [10.8] days; control mice: mean [SD], 144.9 [10.6] days; P = .003). Importantly, Treg expansion was associated with preserved motor neuron soma size and marked suppression of astrocytic and microglial immunoreactivity in the spinal cords of SOD1G93A mice, as well as elevated neurotrophic factor gene expression in spinal cord and peripheral nerves. These findings establish a neuroprotective effect of Tregs, possibly mediated by suppression of toxic neuroinflammation in the central nervous system. Strategies aimed at enhancing the Treg population and neuroprotective activity from the periphery may prove therapeutically useful for patients with ALS.

Effects of advanced life support versus basic life support on the mortality rates of patients with trauma in prehospital settings: a study protocol for a systematic review and meta-analysis

PubMed Central

Kondo, Yutaka; Fukuda, Tatsuma; Uchimido, Ryo; Hifumi, Toru; Hayashida, Kei

2017-01-01

Introduction Advanced life support (ALS) is thought to be associated with improved survival in prehospital trauma care when compared with basic life support (BLS). However, evidence on the benefits of prehospital ALS for patients with trauma is controversial. Therefore, we aim to clarify if ALS improves mortality in patients with trauma when compared with BLS by conducting a systematic review and meta-analysis of the recent literature. Methods and analysis We will perform searches in PubMed, Embase and the Cochrane Central Register of Controlled Trials for published observational studies, controlled before-and-after studies, randomised controlled trials and other controlled trials conducted in humans and published until March 2017. We will screen search results, assess study selection, extract data and assess the risk of bias in duplicate; disagreements will be resolved through discussions. Data from clinically homogeneous studies will be pooled using a random-effects meta-analysis, heterogeneity of effects will be assessed using the χ2 test of homogeneity, and any observed heterogeneity will be quantified using the I2 statistic. Last, the Grading of Recommendations Assessment, Development and Evaluation approach will be used to rate the quality of the evidence. Ethics and dissemination Our study does not require ethical approval as it is based on findings of previously published articles. Results will be disseminated through publication in a peer-reviewed journal, presentations at relevant conferences and publications for patient information. Trial registration number PROSPERO (International Prospective Register of Systematic Reviews) registration number CRD42017054389. PMID:29061611

Noninvasive ventilation reduces energy expenditure in amyotrophic lateral sclerosis.

PubMed

Georges, Marjolaine; Morélot-Panzini, Capucine; Similowski, Thomas; Gonzalez-Bermejo, Jesus

2014-02-07

Amyotrophic lateral sclerosis (ALS) leads to chronic respiratory failure. Diaphragmatic dysfunction, a major driver of dyspnea and mortality, is associated with a shift of the burden of ventilation to extradiaphragmatic inspiratory muscles, including neck muscles. Besides, energy expenditure is often abnormally high in ALS, and this is associated with a negative prognostic value. We hypothesized that noninvasive ventilation (NIV) would relieve inspiratory neck muscles and reduce resting energy expenditure (REE). Using indirect calorimetry, we measured REE during spontaneous breathing (REESB) and NIV (REENIV) in 16 ALS patients with diaphragmatic dysfunction, during the first 3 months of NIV. Measured values were compared with predicted REE (REEpred)(Harris-Benedict equation). NIV abolished inspiratory neck muscle activity. Even though our patients were not hypermetabolic, on the contrary, with a REESB that was lower than REEpred (average 11%), NIV did reduce energy expenditure. Indeed, median REENIV, in this population with a mean body mass index of 21.4 kg.m-2, was 1149 kcal/24 h [interquartile 970-1309], lower than REESB (1197 kcal/24 h, 1054-1402; mean difference 7%; p = 0.03, Wilcoxon). REESB and REENIV were correlated with forced vital capacity and maximal inspiratory pressure. NIV can reduce energy expenditure in ALS patients probably by alleviating the ventilatory burden imposed on inspiratory neck muscles to compensate diaphragm weakness. It remains to be elucidated whether or not, in which population, and to what extent, NIV can be beneficial in ALS through the corresponding reduction in energy expenditure.

Vascular endothelial growth factor and amyotrophic lateral sclerosis: the interplay with exercise and noninvasive ventilation.

PubMed

Carilho, Rita; de Carvalho, Mamede; Swash, Michael; Pinto, Susana; Pinto, Anabela; Costa, Júlia

2014-04-01

We evaluated plasma vascular endothelial growth factor (VEGF) levels in patients with amyotrophic lateral sclerosis (ALS) with reference to the effects of respiratory failure, noninvasive ventilation (NIV), and exercise. We studied plasma VEGF levels in 83 ALS patients, 20 healthy controls, and 10 patients with other disorders. There were 4 groups of ALS patients: G1, 27 patients without respiratory problems; G2, 14 patients stabilized on nocturnal NIV; G3, 30 patients presenting with respiratory failure; G4, 12 patients on an aerobic exercise protocol. VEGF plasma levels did not differ significantly between ALS patients and controls, or between ALS groups. In G3, the mean VEGF levels increased 75% during NIV. In G4, the mean VEGF level increased by 300% during the exercise program. VEGF levels did not change during the course of the disease. VEGF levels in ALS depend on changes in ventilation and exercise but are probably not affected by the disease process itself. Copyright © 2013 Wiley Periodicals, Inc.

Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial.

PubMed

Brooks, B R; Thisted, R A; Appel, S H; Bradley, W G; Olney, R K; Berg, J E; Pope, L E; Smith, R A

2004-10-26

Patients with ALS commonly exhibit pseudobulbar affect. The authors conducted a multicenter, randomized, double-blind, controlled, parallel, three-arm study to test a defined combination of dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) (AVP-923) for the treatment of pseudobulbar affect in ALS. Q inhibits the rapid first-pass metabolism of DM. The effects of AVP-923 (30 mg of DM plus 30 mg of Q) given twice daily for 28 days were compared with those of its components. Patients were evaluated on days 1, 15, and 29. The primary efficacy variable was the change from baseline in the Center for Neurologic Study Lability Scale (CNS-LS) score. Secondary efficacy variables were laughing/crying episode rates and changes in Visual Analog Scales for Quality of Life (QOL) and Relationships (QOR). Efficacy was evaluated in intention-to-treat subjects who were not poor metabolizers of DM (n = 65 for AVP-923, n = 30 for DM, and n = 34 for Q). Safety was assessed in all randomized subjects (n = 140). AVP-923 patients experienced 3.3-point greater improvements in CNS-LS than DM patients (p = 0.001) and 3.7-point greater improvements than Q patients (p < 0.001). AVP-923 patients exhibited lower overall episode rates, improved QOL scores, and improved QOR scores (p < 0.01 for all endpoints). Adverse effects were mostly mild or moderate; treatment-related discontinuation was 24% for AVP-923, 6% for DM, and 8% for Q. AVP-923 palliates pseudobulbar affect in ALS. Overall benefits of treatment are reflected in fewer episodes of crying and laughing and improvements in overall quality of life and quality of relationships.

Ultrasound assessment of diaphragmatic function in patients with amyotrophic lateral sclerosis.

PubMed

Fantini, Riccardo; Mandrioli, Jessica; Zona, Stefano; Antenora, Federico; Iattoni, Andrea; Monelli, Marco; Fini, Nicola; Tonelli, Roberto; Clini, Enrico; Marchioni, Alessandro

2016-07-01

Evaluation of diaphragm function in Amyotrophic Lateral Sclerosis (ALS) is critical in determining when to commence non-invasive mechanical ventilation (NIV). Currently, forced vital capacity (FVC) and sniff nasal inspiratory pressure (SNIP) are volitional measures for this evaluation, but require collaboration and are poorly specific. The primary aim of this study was to assess whether diaphragmatic thickness measured by ultrasound (US) correlates with lung function impairment in ALS patients. The secondary aim was then to compare US diaphragm thickness index (ΔTdi) with a new parameter (ΔTmax index). 41 patients with ALS and 30 healthy subjects were enrolled in the study. All subjects underwent spirometry, SNIP and diaphragm US evaluation, while arterial blood gases were measured in some patients only. US assessed diaphragm thickness (Tdi) at tidal volume (Vt) or total lung capacity (TLC), and their ratio (ΔTmax) were recorded. Changes (Δ) in Tdi indices during tidal volume (ΔTdiVt) and maximal inspiration (ΔTdiTLC) were also assessed. ΔTdiTLC (p <0.001) and ΔTmax (p = 0.007), but not ΔTdiVt, differed between patients and controls. Significant correlation (p < 0.05) was found between ΔTdiTLC, ΔTmax and FVC. The ROC curve analysis for comparison of individual testing showed better accuracy with Δtmax than with ΔtdiTLC for FVC (AUC 0.76 and 0.27) and SNIP (AUC 0.71 and 0.25). Diaphragm thickness assessed by ultrasound significantly correlates with global respiratory alterations in patients with ALS. ΔTmax represents a new US index of early diaphragmatic dysfunction, better related with the routinely performed lung function tests. © 2016 Asian Pacific Society of Respirology.

The genotype-phenotype landscape of familial amyotrophic lateral sclerosis in Australia.

PubMed

McCann, E P; Williams, K L; Fifita, J A; Tarr, I S; O'Connor, J; Rowe, D B; Nicholson, G A; Blair, I P

2017-09-01

Amyotrophic lateral sclerosis (ALS) is a clinically and genetically heterogeneous fatal neurodegenerative disease. Around 10% of ALS cases are hereditary. ALS gene discoveries have provided most of our understanding of disease pathogenesis. We aimed to describe the genetic landscape of ALS in Australia by assessing 1013 Australian ALS patients for known ALS mutations by direct sequencing, whole exome sequencing or repeat primed polymerase chain reaction. Age of disease onset and disease duration were used for genotype-phenotype correlations. We report 60.8% of Australian ALS families in this cohort harbour a known ALS mutation. Hexanucleotide repeat expansions in C9orf72 accounted for 40.6% of families and 2.9% of sporadic patients. We also report ALS families with mutations in SOD1 (13.7%), FUS (2.4%), TARDBP (1.9%), UBQLN2 (.9%), OPTN (.5%), TBK1 (.5%) and CCNF (.5%). We present genotype-phenotype correlations between these genes as well as between gene mutations. Notably, C9orf72 hexanucleotide repeat expansion positive patients experienced significantly later disease onset than ALS mutation patients. Among SOD1 families, p.I114T positive patients had significantly later onset and longer survival. Our report highlights a unique spectrum of ALS gene frequencies among patients from the Australian population, and further, provides correlations between specific ALS mutations with disease onset and/or duration. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Do the components of heat and moisture exchanger filters affect their humidifying efficacy and the incidence of nosocomial pneumonia?

PubMed

Thomachot, L; Vialet, R; Arnaud, S; Barberon, B; Michel-Nguyen, A; Martin, C

1999-05-01

To compare the efficiency of two heat and moisture exchange filters (HMEFs) of different compositions of the humidifying capacity and the rate of bronchial colonization and ventilator-associated pneumonia in patients in the intensive care unit (ICU). Prospective, randomized study. ICU of a university hospital. All patients who required mechanical ventilation for 24 hrs or more during the study period. At admission to the ICU, patients were randomly assigned to one of two groups. In one group, the patients were ventilated with Humid-Vent Filter Light HMEF. The condensation surface was made of paper impregnated with CaCl2. The filter membrane was made of polypropylene. In the other group, the patients were ventilated with the Clear ThermAl HMEF (Intersurgical, France). The condensation surface was made of plastic foam impregnated with AlCl2. The filter membrane was made of two polymer fibers (modacrylic and polypropylene). In both groups, HMEFs were changed daily. Seventy-seven patients were ventilated for 19+/-7 days with the Humid-Vent Filter Light HMEF and 63 patients for 17+/-6 days with the Clear ThermAl HMEF. Patients ventilated with the Humid-Vent Filter Light underwent 8.7+/-3.7 tracheal aspirations and 1.2+/-2.0 instillations per day and those with the Clear ThermAl, 8.2+/-3.9 and 1.5+/-2.4 per day, respectively (NS). The abundance of tracheal secretions and the presence of blood and viscosity, as evaluated by semiquantitative scales, were similar in both groups. One episode of tracheal tube occlusion was observed with the Humid-Vent Filter Light HMEF and none with the other HMEF (NS). Tracheal colonization was observed at a rate of 91% with the Humid-Vent Filter Light and 97% with the Clear ThermAl (NS). The rate of ventilator-associated pneumonia was similar in both groups (35%). Bacteria responsible for tracheal colonization and pneumonia were similar in both groups. Despite differences in their components, the two HMEFs that were tested achieved similar performances in terms of humidification and heating of inspired gases. Only one episode of endotracheal tube occlusion was detected, and very few patients (three in each group) had to be switched to an active heated humidifier. No difference was observed either in the rate of tracheal colonization or of ventilator-associated pneumonia. These data show that the Humid-Vent Filter Light and the Clear ThermAl HMEFs are suited for use with ICU patients.

Clinical epidemiology of amyotrophic lateral sclerosis in Liguria, Italy: An update of LIGALS register.

PubMed

Scialò, Carlo; Novi, Giovanni; Bandettini di Poggio, Monica; Canosa, Antonio; Sormani, Maria Pia; Mandich, Paola; Origone, Paola; Truffelli, Romina; Mancardi, Giovanni Luigi; Caponnetto, Claudia

Our objectives were: (1) to assess amyotrophic lateral sclerosis (ALS) incidence and its trend over time in Liguria, an Italian north-western region, performing an analysis of data prospectively collected from 1 January 2009 to 31 December 2014; (2) to determine the mean and median survival in the 2009-2014 Ligurian ALS incident cases; and (3) to evaluate the presence of disease prognostic factors. The Liguria Register for ALS (LIGALS) is an ongoing, multicentre prospective register enrolling all ALS incident cases in Liguria. Cases were identified using several concurrent sources. ALS diagnosis was based on El Escorial revised criteria (EEC-R). Two hundred and ninety-eight patients were enrolled in this study. The mean annual crude incidence rate in the 2009-2014 period was 3.11/100,000 population (95% CI 2.77-3.49); the point prevalence at 31 December 2014 was 7.85/100,000 (95% CI 6.54-9.36) population. Survival analysis demonstrated a median survival from symptom onset of 37.0 months (95% CI 32.0-42.0). In conclusion, ALS crude incidence in Liguria is higher compared to other Italian regions. Clinical and epidemiological data are comparable with those of the Italian ALS population. Survival analysis showed that higher age at onset, bulbar onset, definite EEC-R diagnostic category and a shorter diagnostic delay are related with worse outcomes.

Does the index-to-ring finger length ratio (2D:4D) differ in amyotrophic lateral sclerosis (ALS)? Results from an international online case-control study.

PubMed

Parkin Kullmann, Jane Alana; Pamphlett, Roger

2017-08-07

The ratio of the length of the index finger (2D) to the ring finger (4D) (2D:4D) has been reported to be lower (ie, 2D<4D) in people with amyotrophic lateral sclerosis (ALS) than non-ALS controls. This has led to suggestions that exposure to increased prenatal testosterone, which also lowers this ratio, could be a risk factor for ALS. In an attempt to test this hypothesis, we examined 2D:4Ds from large numbers of patients with ALS and controls. An online multilingual questionnaire enabling respondents to measure their own index and ring finger lengths. Of the initial 949 respondents, 572 remained for analysis after elimination for inability to straighten fingers, not answering the question, statistical outliers and aged <40 years. Respondents remaining for analysis were 202 patients with ALS (125 males, 77 females) and 370 non-ALS controls (112 males, 258 females). Unpaired t-tests with 95% CIs were used to assess differences in mean 2D:4Ds. Males had significantly lower mean 2D:4Ds than females, in both ALS and control groups, for both left and right hands. No significant differences were found in 2D:4Ds between ALS and control groups, in either males or females, for either left or right hands. Receiver operating characteristic curves showed no power for 2D:4Ds to predict ALS status in either males or females. 2D:4Ds did not differ between patients with ALS and controls in this study. This was despite the dataset being large enough to confirm the established finding of lower 2D:4Ds in males compared with females. These findings do not support the hypothesis that exposure to increased prenatal testosterone is a risk factor for ALS. A putative lower 2D:4D has been proposed to explain the link between ALS and exercise, but our results indicate that other exercise-related factors are more likely to explain this association. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Timing, severity of deficits, and clinical improvement after surgery for spinal dural arteriovenous fistulas.

PubMed

Safaee, Michael M; Clark, Aaron J; Burkhardt, Jan-Karl; Winkler, Ethan A; Lawton, Michael T

2018-04-20

OBJECTIVE Spinal dural arteriovenous fistulas (dAVFs) are rare vascular abnormalities caused by arteriovenous shunting. They often form at the dural root sleeve between a radicular feeding artery and draining medullary vein causing venous congestion and edema, decreased perfusion, and ischemia of the spinal cord. Treatment consists of either surgical ligation of the draining vein or selective embolization via an endovascular approach. There is a paucity of data on which modality provides more durable and effective outcomes. METHODS The authors performed a retrospective review of a prospectively maintained database by the senior author to assess clinical outcomes in patients undergoing surgical treatment of spinal dAVFs. Preoperative and postoperative motor and Aminoff-Logue Scale (ALS) scores were collected. RESULTS A total of 41 patients with 44 spinal dAVFs were identified, with a mean patient age of 64 years. The mean symptom duration was 14 months, with weakness (82%), urinary symptoms (47%), and sensory symptoms (29%) at presentation. The fistula locations were as follows: 30 thoracic, 9 lumbar, 3 sacral, and 2 cervical. Five patients had normal motor and ALS scores at presentation. Among the remaining 36 patients with motor deficits or abnormal gait and micturition at presentation, 78% experienced an improvement while the remaining 22% continued to be stable. There was a trend toward improved outcomes in patients with shorter symptom duration; mean symptom duration among patients with clinical improvement was 13 months compared with 22 months among those without improvement. Additionally, rates of improvement were higher for lower thoracic and lumbosacral dAVFs (85% and 83%) compared with those in the upper thoracic spine (57%). No patient developed recurrent fistulas or worsening neurological deficits. CONCLUSIONS Surgery is associated with excellent outcomes in the treatment of spinal dAVFs. Early diagnosis and treatment are critical, with a trend toward improved outcomes. No patient in this study had fistula recurrence or worsening of symptoms. Among patients with abnormal motor or ALS scores, 78% improved after surgery. Therapeutic embolization is an option for some lesions, but for cases with unfavorable anatomy where embolization is not feasible, surgery is a safe option associated with high success.

Axial loading screw fixation for chevron type osteotomies of the distal first metatarsal: a retrospective outcomes analysis.

PubMed

Murphy, Ryan M; Fallat, Lawrence M; Kish, John P

2014-01-01

The distal chevron osteotomy is a widely accepted technique for the treatment of hallux abductovalgus deformity. Although the osteotomy is considered to be stable, displacements of the capital fragment has been described. We propose a new method for fixation of the osteotomy involving the axial loading screw (ALS) used in addition to single screw fixation. We believe this method will provide a more mechanically stable construct. We reviewed the charts of 46 patients in whom 52 feet underwent a distal chevron osteotomy that was fixated with either 1 screw or 2 screws that included the ALS. We hypothesized that the ALS group would have fewer displacements and would heal more quickly than the single screw fixation group. We found that the group with ALS fixation had healed at a mean of 6.5 weeks and that the group with single screw fixation had healed at 9.53 weeks (p = .001). Also, 8 cases occurred of displacement of the capital fragment in the single screw, control group compared with 2 cases of displacement in the ALS group. However, this finding was not statistically significant. The addition of the ALS to single screw fixation allowed the patients to heal approximately 3 weeks earlier than single screw fixation alone. The ALS is a fixation option for the surgeon to consider when osseous correction of hallux abducto valgus is performed. Copyright © 2014 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p.

PubMed

Stewart, Heather; Rutherford, Nicola J; Briemberg, Hannah; Krieger, Charles; Cashman, Neil; Fabros, Marife; Baker, Matt; Fok, Alice; DeJesus-Hernandez, Mariely; Eisen, Andrew; Rademakers, Rosa; Mackenzie, Ian R A

2012-03-01

Two studies recently identified a GGGGCC hexanucleotide repeat expansion in a non-coding region of the chromosome 9 open-reading frame 72 gene (C9ORF72) as the cause of chromosome 9p-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In a cohort of 231 probands with ALS, we identified the C9ORF72 mutation in 17 familial (27.4%) and six sporadic (3.6%) cases. Patients with the mutation presented with typical motor features of ALS, although subjects with the C9ORF72 mutation had more frequent bulbar onset, compared to those without this mutation. Dementia was significantly more common in ALS patients and families with the C9ORF72 mutation and was usually early-onset FTD. There was striking clinical heterogeneity among the members of individual families with the mutation. The associated neuropathology was a combination of ALS with TDP-ir inclusions and FTLD-TDP. In addition to TDP-43-immunoreactive pathology, a consistent and specific feature of cases with the C9ORF72 mutation was the presence of ubiquitin-positive, TDP-43-negative inclusions in a variety of neuroanatomical regions, such as the cerebellar cortex. These findings support the C9ORF72 mutation as an important newly recognized cause of ALS, provide a more detailed characterization of the associated clinical and pathological features and further demonstrate the clinical and molecular overlap between ALS and FTD.

The ALS patient care database: goals, design, and early results. ALS C.A.R.E. Study Group.

PubMed

Miller, R G; Anderson, F A; Bradley, W G; Brooks, B R; Mitsumoto, H; Munsat, T L; Ringel, S P

2000-01-11

The ALS Patient Care Database was created to improve the quality of care for patients with ALS by 1) providing neurologists with data to evaluate and improve their practices, 2) publishing data on temporal trends in the care of patients with ALS, and 3) developing hypotheses to be tested during formal clinical trials. Substantial variations exist in managing ALS, but there has been no North American database to measure outcomes in ALS until now. This observational database is open to all neurologists practicing in North America, who are encouraged to enroll both incident and prevalent ALS patients. Longitudinal data are collected at intervals of 3 to 6 months by using standard data collection instruments. Forms are submitted to a central data coordinating center, which mails quarterly reports to participating neurologists. Beginning in September 1996 through November 30, 1998, 1,857 patients were enrolled at 83 clinical sites. On enrollment, patients had a mean age of 58.6 years +/-12.9 (SD) years (range, 20.1 to 95.1 years), 92% were white, and 61% were men. The mean interval between onset of symptoms and diagnosis was 1.2+/-1.6 years (range, 0 to 31.9 years). Riluzole was the most frequently used disease-specific therapy (48%). Physical therapy was the most common nonpharmacologic intervention (45%). The primary caregiver was generally the spouse (77%). Advance directives were in place at the time of death for 70% of 213 enrolled patients who were reported to have died. The ALS Patient Care Database appears to provide valuable data on physician practices and patient-focused outcomes in ALS.

Dysfunction of bulbar central pattern generator in ALS patients with dysphagia during sequential deglutition.

PubMed

Aydogdu, Ibrahim; Tanriverdi, Zeynep; Ertekin, Cumhur

2011-06-01

The aim of this study is to investigate a probable dysfunction of the central pattern generator (CPG) in dysphagic patients with ALS. We investigated 58 patients with ALS, 23 patients with PD, and 33 normal subjects. The laryngeal movements and EMG of the submental muscles were recorded during sequential water swallowing (SWS) of 100ml of water. The coordination of SWS and respiration was also studied in some normal cases and ALS patients. Normal subjects could complete the SWS optimally within 10s using 7 swallows, while in dysphagic ALS patients, the total duration and the number of swallows were significantly increased. The novel finding was that the regularity and rhythmicity of the swallowing pattern during SWS was disorganized to irregular and arhythmic pattern in 43% of the ALS patients. The duration and speed of swallowing were the most sensitive parameters for the disturbed oropharyngeal motility during SWS. The corticobulbar control of swallowing is insufficient in ALS, and the swallowing CPG cannot work very well to produce segmental muscle activation and sequential swallowing. CPG dysfunction can result in irregular and arhythmical sequential swallowing in ALS patients with bulbar plus pseudobulbar types. The arhythmical SWS pattern can be considered as a kind of dysfunction of CPG in human ALS cases with dysphagia. Copyright © 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Respiratory outcomes of patients with amyotrophic lateral sclerosis: an Italian nationwide survey.

PubMed

Vitacca, Michele; Vianello, Andrea

2013-09-01

Despite recommendations, respiratory therapies remain partially underutilized in patients with amyotrophic lateral sclerosis (ALS), and different practices are described in different countries. We surveyed attitudes and practice in Italy on ALS and other neuromuscular diseases (NMDs). A questionnaire on ALS/NMD management was mailed to 178 pneumology units, which we classified into high-volume and low-volume centers according to the number of ALS/NMD patients followed in the last 5 years. Seventy-six pneumology units (43%) responded, and the responding units had 1,772 ALS patients and 1,490 NMD patients. Difficulty clearing respiratory secretions and disturbed sleep were the main reasons the ALS patients were referred to pneumology units. Vital capacity (measured in the sitting position) and arterial blood gases were measured regularly, while respiratory muscle function and cough ability were routinely assessed in over 85% of the pneumology units (mainly in high-volume centers), and 94% of pneumology units could provide noninvasive ventilation. Treatment of NMDs was similar to that of ALS, except for tracheostomy, which was less frequently performed in patients with NMDs. A multidisciplinary team approach to care was employed in approximately 90% of the responding pneumology units. Approximately a third of the units accessed palliative care services. Combined pulmonary function evaluation, long-term noninvasive ventilation, and assisted cough have become usual practices for ALS patients. Italian practices for ALS did not significantly differ from the approach to other NMDs.

Personalized Medication Response Prediction for Attention-Deficit Hyperactivity Disorder: Learning in the Model Space vs. Learning in the Data Space

PubMed Central

Wong, Hin K.; Tiffin, Paul A.; Chappell, Michael J.; Nichols, Thomas E.; Welsh, Patrick R.; Doyle, Orla M.; Lopez-Kolkovska, Boryana C.; Inglis, Sarah K.; Coghill, David; Shen, Yuan; Tiño, Peter

2017-01-01

Attention-Deficit Hyperactive Disorder (ADHD) is one of the most common mental health disorders amongst school-aged children with an estimated prevalence of 5% in the global population (American Psychiatric Association, 2013). Stimulants, particularly methylphenidate (MPH), are the first-line option in the treatment of ADHD (Reeves and Schweitzer, 2004; Dopheide and Pliszka, 2009) and are prescribed to an increasing number of children and adolescents in the US and the UK every year (Safer et al., 1996; McCarthy et al., 2009), though recent studies suggest that this is tailing off, e.g., Holden et al. (2013). Around 70% of children demonstrate a clinically significant treatment response to stimulant medication (Spencer et al., 1996; Schachter et al., 2001; Swanson et al., 2001; Barbaresi et al., 2006). However, it is unclear which patient characteristics may moderate treatment effectiveness. As such, most existing research has focused on investigating univariate or multivariate correlations between a set of patient characteristics and the treatment outcome, with respect to dosage of one or several types of medication. The results of such studies are often contradictory and inconclusive due to a combination of small sample sizes, low-quality data, or a lack of available information on covariates. In this paper, feature extraction techniques such as latent trait analysis were applied to reduce the dimension of on a large dataset of patient characteristics, including the responses to symptom-based questionnaires, developmental health factors, demographic variables such as age and gender, and socioeconomic factors such as parental income. We introduce a Bayesian modeling approach in a “learning in the model space” framework that combines existing knowledge in the literature on factors that may potentially affect treatment response, with constraints imposed by a treatment response model. The model is personalized such that the variability among subjects is accounted for by a set of subject-specific parameters. For remission classification, this approach compares favorably with conventional methods such as support vector machines and mixed effect models on a range of performance measures. For instance, the proposed approach achieved an area under receiver operator characteristic curve of 82–84%, compared to 75–77% obtained from conventional regression or machine learning (“learning in the data space”) methods. PMID:28443027

An Improved and Secure Biometric Authentication Scheme for Telecare Medicine Information Systems Based on Elliptic Curve Cryptography.

PubMed

Chaudhry, Shehzad Ashraf; Mahmood, Khalid; Naqvi, Husnain; Khan, Muhammad Khurram

2015-11-01

Telecare medicine information system (TMIS) offers the patients convenient and expedite healthcare services remotely anywhere. Patient security and privacy has emerged as key issues during remote access because of underlying open architecture. An authentication scheme can verify patient's as well as TMIS server's legitimacy during remote healthcare services. To achieve security and privacy a number of authentication schemes have been proposed. Very recently Lu et al. (J. Med. Syst. 39(3):1-8, 2015) proposed a biometric based three factor authentication scheme for TMIS to confiscate the vulnerabilities of Arshad et al.'s (J. Med. Syst. 38(12):136, 2014) scheme. Further, they emphasized the robustness of their scheme against several attacks. However, in this paper we establish that Lu et al.'s scheme is vulnerable to numerous attacks including (1) Patient anonymity violation attack, (2) Patient impersonation attack, and (3) TMIS server impersonation attack. Furthermore, their scheme does not provide patient untraceability. We then, propose an improvement of Lu et al.'s scheme. We have analyzed the security of improved scheme using popular automated tool ProVerif. The proposed scheme while retaining the plusses of Lu et al.'s scheme is also robust against known attacks.

A first approach to a neuropsychological screening tool using eye-tracking for bedside cognitive testing based on the Edinburgh Cognitive and Behavioural ALS Screen.

PubMed

Keller, Jürgen; Krimly, Amon; Bauer, Lisa; Schulenburg, Sarah; Böhm, Sarah; Aho-Özhan, Helena E A; Uttner, Ingo; Gorges, Martin; Kassubek, Jan; Pinkhardt, Elmar H; Abrahams, Sharon; Ludolph, Albert C; Lulé, Dorothée

2017-08-01

Reliable assessment of cognitive functions is a challenging task in amyotrophic lateral sclerosis (ALS) patients unable to speak and write. We therefore present an eye-tracking based neuropsychological screening tool based on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), a standard screening tool for cognitive deficits in ALS. In total, 46 ALS patients and 50 healthy controls matched for age, gender and education were tested with an oculomotor based and a standard paper-and-pencil version of the ECAS. Significant correlation between both versions was observed for ALS patients and healthy controls in the ECAS total score and in all of its ALS-specific domains (all r > 0.3; all p < 0.05). The eye-tracking version of the ECAS reliably distinguished between ALS patients and healthy controls in the ECAS total score (p < 0.05). Also, cognitively impaired and non-impaired patients could be reliably distinguished with a specificity of 95%. This study provides first evidence that the eye-tracking based ECAS version is a promising approach for assessing cognitive deficits in ALS patients who are unable to speak or write.

Anastomotic leakage after colorectal surgery: diagnostic accuracy of CT.

PubMed

Kauv, Paul; Benadjaoud, Samir; Curis, Emmanuel; Boulay-Coletta, Isabelle; Loriau, Jerome; Zins, Marc

2015-12-01

To evaluate the diagnostic accuracy of CT in postoperative colorectal anastomotic leakage (AL). Two independent blinded radiologists reviewed 153 CTs performed for suspected AL within 60 days after surgery in 131 consecutive patients, with (n = 58) or without (n = 95) retrograde contrast enema (RCE). Results were compared to original interpretations. The reference standard was reoperation or consensus (a radiologist and a surgeon) regarding clinical, laboratory, radiological, and follow-up data after medical treatment. AL was confirmed in 34/131 patients. For the two reviewers and original interpretation, sensitivity of CT was 82 %, 87 %, and 71 %, respectively; specificity was 84 %, 84 %, and 92 %. RCE significantly increased the positive predictive value (from 40 % to 88 %, P = 0.0009; 41 % to 92 %, P = 0.0016; and 40 % to 100 %, P = 0.0006). Contrast extravasation was the most sensitive (reviewers, 83 % and 83 %) and specific (97 % and 97 %) sign and was significantly associated with AL by univariate analysis (P < 0.0001 and P < 0.0001). By multivariate analysis with recursive partitioning, CT with RCE was accurate to confirm or rule out AL with contrast extravasation. CT with RCE is accurate for diagnosing postoperative colorectal AL. Contrast extravasation is the most reliable sign. RCE should be performed during CT for suspected AL. • CT accurately diagnosed clinically suspected colorectal AL and showed good interobserver agreement • Contrast extravasation was the most sensitive and specific CT sign • Retrograde contrast enema during CT improved positive predictive value • Retrograde contrast enema decreased false-negative or indeterminate original CT interpretations.

Writing errors as a result of frontal dysfunction in Japanese patients with amyotrophic lateral sclerosis.

PubMed

Tsuji-Akimoto, Sachiko; Hamada, Shinsuke; Yabe, Ichiro; Tamura, Itaru; Otsuki, Mika; Kobashi, Syoji; Sasaki, Hidenao

2010-12-01

Loss of communication is a critical problem for advanced amyotrophic lateral sclerosis (ALS) patients. This loss of communication is mainly caused by severe dysarthria and disability of the dominant hand. However, reports show that about 50% of ALS patients have mild cognitive dysfunction, and there are a considerable number of case reports on Japanese ALS patients with agraphia. To clarify writing disabilities in non-demented ALS patients, eighteen non-demented ALS patients and 16 controls without neurological disorders were examined for frontal cognitive function and writing ability. To assess writing errors statistically, we scored them on their composition ability with the original writing error index (WEI). The ALS and control groups did not differ significantly with regard to age, years of education, or general cognitive level. Two patients could not write a letter because of disability of the dominant hand. The WEI and results of picture arrangement tests indicated significant impairment in the ALS patients. Auditory comprehension (Western Aphasia Battery; WAB IIC) and kanji dictation also showed mild impairment. Patients' writing errors consisted of both syntactic and letter-writing mistakes. Omission, substitution, displacement, and inappropriate placement of the phonic marks of kana were observed; these features have often been reported in Japanese patients with agraphia resulted from a frontal lobe lesion. The most frequent type of error was an omission of kana, the next most common was a missing subject. Writing errors might be a specific deficit for some non-demented ALS patients.

Comparison of current recommended regimens of atropinization in organophosphate poisoning.

PubMed

Connors, Nicholas J; Harnett, Zachary H; Hoffman, Robert S

2014-06-01

Atropine is the mainstay of therapy in organophosphate (OP) toxicity, though research and consensus on dosing is lacking. In 2004, as reported by Eddleston et al. (J Toxicol Clin Toxicol 42(6):865-75, 2004), they noted variation in recommended regimens. We assessed revisions of original references, additional citations, and electronic sources to determine the current variability in atropine dosing recommendations. Updated editions of references from Eddleston et al.'s work, texts of Internal and Emergency Medicine, and electronic resources were reviewed for atropine dosing recommendations. For comparison, recommendations were assessed using the same mean dose (23.4 mg) and the highest dose (75 mg) of atropine as used in the original paper. Recommendations were also compared with the dosing regimen from the World Health Organization (WHO). Thirteen of the original recommendations were updated and 15 additional references were added giving a convenience sample of 28. Sufficient information to calculate time to targeted dose was provided by 24 of these samples. Compared to 2004, current recommendations have greatly increased the speed of atropinization with 13/24 able to reach the mean and high atropine dose within 30 min compared to 1/36 in 2004. In 2004, there were 13 regimens where the maximum time to reach 75 mg was over 18 h, whereas now, there are 2. While only one recommendation called for doubling the dose for faster escalation in 2004, 15 of the 24 current works include dose doubling. In 2004, Eddleston et al. called for an evidence-based guideline for the treatment of OP poisoning that could be disseminated worldwide. Many current recommendations can adequately treat patients within 1 h. While the WHO recommendations remain slow to treat patients with OP poisoning, other authorities are close to a consensus on rapid atropinization.

Self-regulation of brain rhythms in the precuneus: a novel BCI paradigm for patients with ALS

NASA Astrophysics Data System (ADS)

Fomina, Tatiana; Lohmann, Gabriele; Erb, Michael; Ethofer, Thomas; Schölkopf, Bernhard; Grosse-Wentrup, Moritz

2016-12-01

Objective. Electroencephalographic (EEG) brain-computer interfaces (BCIs) hold promise in restoring communication for patients with completely locked-in stage amyotrophic lateral sclerosis (ALS). However, these patients cannot use existing EEG-based BCIs, arguably because such systems rely on brain processes that are impaired in the late stages of ALS. In this work, we introduce a novel BCI designed for patients in late stages of ALS based on high-level cognitive processes that are less likely to be affected by ALS. Approach. We trained two ALS patients via EEG-based neurofeedback to use self-regulation of theta or gamma oscillations in the precuneus for basic communication. Because there is a tight connection between the precuneus and consciousness, precuneus oscillations are arguably generated by high-level cognitive processes, which are less likely to be affected by ALS than processes linked to the peripheral nervous system. Main results. Both patients learned to self-regulate their precuneus oscillations and achieved stable online decoding accuracy over the course of disease progression. One patient achieved a mean online decoding accuracy in a binary decision task of 70.55% across 26 training sessions, and the other patient achieved 59.44% across 16 training sessions. We provide empirical evidence that these oscillations were cortical in nature and originated from the intersection of the precuneus, cuneus, and posterior cingulate. Significance. Our results establish that ALS patients can employ self-regulation of precuneus oscillations for communication. Such a BCI is likely to be available to ALS patients as long as their consciousness supports communication.

Thermoregulation and Stress Hormone Recovery After Exercise Dehydration: Comparison of Rehydration Methods

PubMed Central

McDermott, Brendon P.; Casa, Douglas J.; Lee, Elaine; Yamamoto, Linda; Beasley, Kathleen; Emmanuel, Holly; Anderson, Jeffrey; Pescatello, Linda; Armstrong, Lawrence E.; Maresh, Carl

2013-01-01

Context: Athletic trainers recommend and use a multitude of rehydration (REHY) methods with their patients. The REHY modality that most effectively facilitates recovery is unknown. Objective: To compare 5 common REHY methods for thermoregulatory and stress hormone recovery after exercise dehydration (EXDE) in trained participants. Design: Randomized, cross-over, controlled study. Patients or Other Participants: Twelve physically active, non–heat-acclimatized men (age = 23 ± 4 years, height = 180 ± 6 cm, mass = 81.3 ± 3.7 kg, V̇o2max = 56.9 ± 4.4 mL·min−1·kg−1, body fat = 7.9% ± 3%) participated. Intervention(s): Participants completed 20-hour fluid restriction and 2-hour EXDE; they then received no fluid (NF) or REHY (half-normal saline) via ad libitum (AL), oral (OR), intravenous (IV), or combination IV and OR (IV + OR) routes for 30 minutes; and then were observed for another 30 minutes. Main Outcome Measure(s): Body mass, rectal temperature, 4-site mean weighted skin temperature, plasma stress hormone concentrations, and environmental symptoms questionnaire (ESQ) score. Results: Participants were hypohydrated (body mass −4.23% ± 0.22%) post-EXDE. Rectal temperature for the NF group was significantly greater than for the IV group (P = .023) at 30 minutes after beginning REHY (REHY30) and greater than OR, IV, and IV + OR (P ≤ .009) but not AL (P = .068) at REHY60. Mean weighted skin temperature during AL was less than during IV + OR at REHY5 (P = .019). The AL participants demonstrated increased plasma cortisol concentrations compared with IV + OR, independent of time (P = .015). No differences existed between catecholamine concentrations across treatments (P > .05). The ESQ score was increased at REHY60 for NF, AL, OR, and IV (P < .05) but not for IV + OR (P = .217). The NF ESQ score was greater than that of IV + OR at REHY60 (P = .012). Conclusions: Combination IV + OR REHY reduced body temperature to a greater degree than OR and AL REHY when compared with NF. Future studies addressing clinical implications are needed. PMID:24143900

Correlation of cadmium and aluminum in blood samples of kidney disorder patients with drinking water and tobacco smoking: related health risk.

PubMed

Panhwar, Abdul Haleem; Kazi, Tasneem Gul; Afridi, Hassan Imran; Arain, Salma Aslam; Arain, Mariam Shahzadi; Brahaman, Kapil Dev; Naeemullah; Arain, Sadaf Sadia

2016-02-01

The combined exposure to aluminum (Al) and cadmium (Cd) causes more pronounced adverse health effects on humans. The kidneys are the main organs affected by internal exposure to Cd and Al via food and non-food items. The objective of present study was to measure the Al and Cd concentrations in cigarettes tobacco (branded and non-branded) and drinking water (domestic treated, ground and lake water) samples in southern part of Pakistan, to assess the risk due to ingestion of water and inhalation of cigarettes smoke containing high concentrations of both elements. The study population (kidney disorder and healthy) divided into two group based on consuming lake and ground water, while smoking non-branded cigarette as exposed, while drinking domestic treated water and smoking branded cigarette as non-exposed. Electrothermal atomic absorption spectrometry was used to determined Cd and Al concentrations in tobacco, drinking water and blood samples. The resulted data indicated that the levels of Al and Cd in lake and underground water were higher than the permissible limit in drinking water recommended by the World Health Organization. The biochemical parameters of exposed and referent patients, especially urinary N-acetyl-h-glucosaminidase, were used as a biomarkers of kidney disorder. Exposed kidney disorder patients have higher levels of Cd and Al than the exposed referents subjects, while difference was significant when compared to resulted data of non-exposed patients and referents (p = 0.01-0.001). The pearson correlation showed positive correlation between both toxic element concentrations in water, cigarettes versus blood samples of exposed subjects (r = 0.20-0.67 and 0.71-0.82), while lower values were observed for non-exposed subjects (r = 0.123-0.423 and 0.331-0.425), respectively.

Advance care planning for patients with amyotrophic lateral sclerosis.

PubMed

Levi, Benjamin H; Simmons, Zachary; Hanna, Courtney; Brothers, Allyson; Lehman, Erik; Farace, Elana; Bain, Megan; Stewart, Renee; Green, Michael J

2017-08-01

To determine whether an advance care planning (ACP) decision-aid could improve communication about end-of-life treatment wishes between patients with amyotrophic lateral sclerosis (ALS) and their clinicians. Forty-four patients with ALS (>21, English-speaking, without dementia) engaged in ACP using an interactive computer based decision-aid. Before participants completed the intervention, and again three months later, their clinicians reviewed three clinical vignettes, and made treatment decisions (n = 18) for patients. After patients indicated their agreement with the team's decisions, concordance was calculated. The mean concordance between patient wishes and the clinical team decisions was significantly higher post-intervention (post = 91.9%, 95% CI = 87.8, 96.1, vs. pre = 52.4%, 95% CI = 41.9, 62.9; p <0.001). Clinical team members reported greater confidence that their decisions accurately represented each patient's wishes post-intervention (mean = 6.5) compared to pre-intervention (mean = 3.3, 1 = low, 10 = high, p <0.001). Patients reported high satisfaction (mean = 26.4, SD = 3.2; 6 = low, 30 = high) and low decisional conflict (mean = 28.8, SD = 8.2; 20 = low, 80 = high) with decisions about end-of-life care, and high satisfaction with the decision-aid (mean = 52.7, SD = 5.7, 20 = low, 60 = high). Patient knowledge regarding ACP increased post-intervention (pre = 47.8% correct responses vs. post = 66.3%; p <0.001) without adversely affecting patient anxiety or self-determination. A computer based ACP decision-aid can significantly improve clinicians' understanding of ALS patients' wishes with regard to end-of-life medical care.

Mining Online Social Network Data for Biomedical Research: A Comparison of Clinicians’ and Patients’ Perceptions About Amyotrophic Lateral Sclerosis Treatments

PubMed Central

Bromberg, Mark; Bhargava, Shivani; Wicks, Paul; Zeng-Treitler, Qing

2012-01-01

Background While only one drug is known to slow the progress of amyotrophic lateral sclerosis (ALS), numerous drugs can be used to treat its symptoms. However, very few randomized controlled trials have assessed the efficacy, safety, and side effects of these drugs. Due to this lack of randomized controlled trials, consensus among clinicians on how to treat the wide range of ALS symptoms and the efficacy of these treatments is low. Given the lack of clinical trials data, the wide range of reported symptoms, and the low consensus among clinicians on how to treat those symptoms, data on the prevalence and efficacy of treatments from a patient’s perspective could help advance the understanding of the symptomatic treatment of ALS. Objective To compare clinicians’ and patients’ perspectives on the symptomatic treatment of ALS by comparing data from a traditional survey study of clinicians with data from a patient social network. Methods We used a survey of clinicians’ perceptions by Forshew and Bromberg as our primary data source and adjusted the data from PatientsLikeMe to allow for comparisons. We first extracted the 14 symptoms and associated top four treatments listed by Forshew and Bromberg. We then searched the PatientsLikeMe database for the same symptom–treatment pairs. The PatientsLikeMe data are structured and thus no preprocessing of the data was required. Results After we eliminated pairs with a small sample, 15 symptom–treatment pairs remained. All treatments identified as useful were prescription drugs. We found similarities and discrepancies between clinicians’ and patients’ perceptions of treatment prevalence and efficacy. In 7 of the 15 pairs, the differences between the two groups were above 10%. In 3 pairs the differences were above 20%. Lorazepam to treat anxiety and quinine to treat muscle cramps were among the symptom–treatment pairs with high concordance between clinicians’ and patients’ perceptions. Conversely, amitriptyline to treat labile emotional effect and oxybutynin to treat urinary urgency displayed low agreement between clinicians and patients. Conclusions Assessing and comparing the efficacy of the symptomatic treatment of a complex and rare disease such as ALS is not easy and needs to take both clinicians’ and patients’ perspectives into consideration. Drawing a reliable profile of treatment efficacy requires taking into consideration many interacting aspects (eg, disease stage and severity of symptoms) that were not covered in the present study. Nevertheless, pilot studies such as this one can pave the way for more robust studies by helping researchers anticipate and compensate for limitations in their data sources and study design. PMID:22721865

Multicenter Analysis of Long-Term Oncologic Impact of Anastomotic Leakage After Laparoscopic Total Mesorectal Excision

PubMed Central

Kang, Jeonghyun; Choi, Gyu-Seog; Oh, Jae Hwan; Kim, Nam Kyu; Park, Jun Seok; Kim, Min Jung; Lee, Kang Young; Baik, Seung Hyuk

2015-01-01

Abstract This study aims to validate the oncologic outcomes of anastomotic leakage (AL) after laparoscopic total mesorectal excision (TME) in a large multicenter cohort. The impact of AL after laparoscopic TME for rectal cancer surgery has not yet been clearly described. This was a multicenter retrospective study of 1083 patients who underwent laparoscopic TME for nonmetastatic rectal cancer (stage 0–III). AL was defined as an anastomotic complication within 30 days of surgery irrespective of requiring a reoperation or interventional radiology. Estimated local recurrence (LR), disease-free survival (DFS), and overall survival (OS) were compared between the leakage group and the no leakage group using the log-rank method. Multivariate Cox-regression analysis was used to adjust confounding for survival. The incidence of AL was 6.4%. Mortality within 30 days of surgery occurred in 1 patient (1.4%) in the leakage group and 2 patients (0.2%) in the no leakage group. The leakage group showed a higher LR rate (6.4% vs 1.8%, P = 0.011). Five-year DFS and OS were significantly lower in the leakage group than the no leakage group (DFS 71.7% vs 82.1%, P = 0.016, OS 81.8% vs 93.5%, P = 0.007). Multivariate analysis showed that AL was an independent poor prognostic factor for DFS and OS (hazard ratio [HR] = 1.6; 95% confidence intervals [CI]: 1.0–2.6; P = 0.042, HR = 2.1; 95% CI: 1.0–4.2; P = 0.028, respectively). AL after laparoscopic TME was significantly associated with an increased rate of LR, systemic recurrence and poor OS. PMID:26200636

Aluminium Involvement in Neurotoxicity

PubMed Central

Fulgenzi, Alessandro; Vietti, Daniele; Ferrero, Maria Elena

2014-01-01

The aetiology of neurodegenerative diseases (ND) seems to involve susceptibility genes and environmental factors. Toxic metals are considered major environmental pollutants. Following our study of a case of multiple sclerosis (MS) improvement due to removal of aluminium (Al) and other toxic metals, we have examined the possible relationship between Al intoxication and ND. We used the slow intravenous treatment with the chelating agent EDTA (calcium disodium ethylene diamine tetraacetic acid) (chelation test) to remove Al and detected it in the urine collected from the patients for 12 hours. Patients affected by MS represented 85.6% of total ND. Al was present in 44.8% of cases comprehensive of ND and healthy patients. Al levels were significantly higher in ND patients than in healthy subjects. We here show that treatment of patients affected by Al burden with ten EDTA chelation therapies (EDTA intravenous administration once a week) was able to significantly reduce Al intoxication. PMID:25243176

Neuropsychological study of amyotrophic lateral sclerosis and parkinsonism-dementia complex in Kii peninsula, Japan

PubMed Central

2014-01-01

Background The Kii peninsula of Japan is one of the foci of amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS/PDC) in the world. The purpose of this study is to clarify the neuropsychological features of the patients with ALS/PDC of the Kii peninsula (Kii ALS/PDC). Methods The medical interview was done on 13 patients with Kii ALS/PDC, 12 patients with Alzheimer’s disease, 10 patients with progressive supranuclear palsy, 10 patients with frontotemporal lobar degeneration and 10 patients with dementia with Lewy bodies. These patients and their carer/spouse were asked to report any history of abulia-apathy, hallucination, personality change and other variety of symptoms. Patients also underwent brain magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and neuropsychological tests comprising the Mini Mental State Examination, Raven’s Colored Progressive Matrices, verbal fluency, and Paired-Associate Word Learning Test and some of them were assessed with the Frontal Assessment Battery (FAB). Results All patients with Kii ALS/PDC had cognitive dysfunction including abulia-apathy, bradyphrenia, hallucination, decrease of extraversion, disorientation, and delayed reaction time. Brain MRI showed atrophy of the frontal and/or temporal lobes, and SPECT revealed a decrease in cerebral blood flow of the frontal and/or temporal lobes in all patients with Kii ALS/PDC. Disorientation, difficulty in word recall, delayed reaction time, and low FAB score were recognized in Kii ALS/PDC patients with cognitive dysfunction. Conclusions The core neuropsychological features of the patients with Kii ALS/PDC were characterized by marked abulia-apathy, bradyphrenia, and hallucination. PMID:25041813

Effects of low-level laser therapy on burning mouth syndrome.

PubMed

Valenzuela, S; Lopez-Jornet, P

2017-02-01

To investigate low-level laser therapy (LLLT) applied to treat burning mouth syndrome (BMS). This prospective, comparative, partially blinded, single-centre, clinical trial of GaAlAs Laser, with 815 nm wavelength, included 44 BMS patients divided randomly into three groups: Group I (n = 16): GaAlAs laser 815 nm wavelength, 1 W output power, continuous emissions, 4 s, 4 J and fluence rate 133·3 J cm -2 ; Group II (n = 16): GaAlAs infrared laser, 815 nm wavelength, 1 W output power, continuous emissions, 6 s, 6 J and fluence rate 200 J cm -2 ; Group III (n = 12) placebo group, sham laser. All groups received a weekly dose for 4 weeks. Pain intensity was recorded using a 10-cm visual analogue scale; patients responded to the oral health impact profile (OHIP-14), xerostomia severity test and the hospital anxiety-depression scale (HAD). These assessments were performed at baseline, 2 and 4 weeks. LLLT decreased pain intensity and improved OHIP-14 scores significantly from baseline to 2 weeks in groups I and II compared with the placebo group. No statistically significant differences were found from 2 to 4 weeks. Overall improvements in visual analogue scale (VAS) scores from baseline to the end of treatment were as follows: Group I 15·7%; Group II 15·6%; Group III placebo 7·3%. LLLT application reduces symptoms slightly in BMS patients. © 2016 John Wiley & Sons Ltd.

Using respiratory rate and thoracic movement to assess respiratory insufficiency in amyotrophic lateral sclerosis: a preliminary study.

PubMed

Siirala, Waltteri; Saaresranta, Tarja; Vuori, Arno; Salanterä, Sanna; Olkkola, Klaus T; Aantaa, Riku

2012-12-27

Hypoventilation due to respiratory insufficiency is the most common cause of death in amyotrophic lateral sclerosis (ALS) and non-invasive ventilation (NIV) can be used as a palliative treatment. The current guidelines recommend performing spirometry, and recording nocturnal oxyhemoglobin saturation and arterial blood gas analysis to assess the severity of the hypoventilation. We examined whether the respiratory rate and thoracic movement were reliable preliminary clinical signs in the development of respiratory insufficiency in patients with ALS. We measured the respiratory rate and thoracic movement, performed respiratory function tests and blood gas analysis, and recorded subjective hypoventilation symptoms in 42 ALS patients over a 7-year period. We recommended NIV if the patient presented with hypoventilation matching the current guidelines. We divided patients retrospectively into two groups: those to whom NIV was recommended within 6 months of the diagnosis (Group 1) and those to whom NIV was recommended 6 months after the diagnosis (Group 2). We used the Mann Whitney U test for comparisons between the two groups. The mean partial pressure of arterial carbon dioxide in the morning in Group 1 was 6.3 (95% confidence interval 5.6-6.9) kPa and in Group 2 5.3 (5.0-5.6) kPa (p = 0.007). The mean respiratory rate at the time of diagnosis in Group 1 was 21 (18-24) breaths per minute and 16 (14-18) breaths per minute in Group 2 (p = 0.005). The mean thoracic movement was 2.9 (2.2-3.6) cm in Group 1 and 4.0 (3.4-4.8) cm in Group 2 (p = 0.01). We observed no other differences between the groups. Patients who received NIV within six months of the diagnosis of ALS had higher respiratory rates and smaller thoracic movement compared with patients who received NIV later. Further studies with larger numbers of patients are needed to establish if these measurements can be used as a marker of hypoventilation in ALS.

Examining the language and behavioural profile in FTD and ALS-FTD.

PubMed

Saxon, Jennifer A; Thompson, Jennifer C; Jones, Matthew; Harris, Jennifer M; Richardson, Anna Mt; Langheinrich, Tobias; Neary, David; Mann, David Ma; Snowden, Julie S

2017-08-01

A proportion of patients with behavioural variant frontotemporal dementia (bvFTD) develop amyotrophic lateral sclerosis (ALS). It is currently unknown whether the behavioural and cognitive syndrome in bvFTD with ALS (ALS-FTD) is indistinguishable from that of bvFTD alone. A retrospective cohort of 241 patients with clinical diagnoses of bvFTD (n=185) or ALS-FTD (n=56) was examined with respect to behavioural, cognitive and neuropsychiatric symptoms. Features were rated as present or absent based on information recorded from clinical interviews and detailed neuropsychological assessment. A number of behavioural and affective changes were reported more frequently in bvFTD than ALS-FTD: social disinhibition (p<0.001), inertia (p<0.001), loss of sympathy and empathy (p = 0.008), repetitive behaviours (p<0.001) and dietary changes (p<0.001). Warmth of affect demonstrated in the clinic setting was reported more often in ALS-FTD than bvFTD (p<0.001). Executive impairments occurred equally in both groups. Language impairments were more common in ALS-FTD than bvFTD: agrammatism (p<0.017) and impaired sentence comprehension (p<0.036). Psychotic features were relatively rare and did not distinguish the groups. Our findings suggest differences between bvFTD and ALS-FTD. In particular, while changes in social behaviour are prominent in bvFTD alone, there may be a comparatively greater degree of language impairment in ALS-FTD. Prospective exploration of the pattern of differences between these groups will be essential. Identification of a distinct neuropsychological phenotype in ALS-FTD may have clinical implications for early diagnosis, disease management and care planning and theoretical implications for our understanding of the relationship between ALS and FTD. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

S23. INTRODUCING COMPASS: COMPARING BRAIN ACTIVITY ACROSS PATIENTS WITH DIFFERENTIAL TREATMENT RESPONSE IN SCHIZOPHRENIA – AN OBSERVATIONAL STUDY

PubMed Central

Iglesias, Sandra; Siemerkus, Jakob; Bischof, Martin; Tomiello, Sara; Schöbi, Dario; Weber, Lilian; Heinzle, Jakob; Möller, Julian; Egger, Stephan; Gerke, Wolfgang; Baumgartner, Markus; Kawohl, Wolfram; Borgwardt, Stefan; Kaiser, Stefan; Haker, Helene; Stephan, Klaas Enno

2018-01-01

Abstract Background Present pharmacological treatment approaches in schizophrenia rest on “neuroleptic” drugs, all of which act as antagonists at dopamine D2/D3 receptors but additionally display major variability in their binding capacity to neurotransmitter receptors (Van Os & Kapur 2009). At present, the choice of any particular drug does not rest on any principled criteria: Once individual treatment has been started, therapeutic efficacy is monitored clinically, and a switch to a different drug is initiated when clear improvements remain absent after a few weeks. It is presently not possible to predict in advance which patients will respond well to a particular drug and who will experience little or no benefit (Case et al. 2011; Kapur et al. 2012). For instance, clozapine and olanzapine are often prescribed after other antipsychotics have shown to be ineffective in patients with schizophrenia or related disorders due to their pronounced side-effects. Both drugs, clozapine and olanzapine, share certain pharmacodynamic properties with comparatively low affinity towards dopamine D2-receptors, but very high affinity towards muscarinic receptors – a unique constellation that distinguishes them from other common antipsychotics. Importantly, previous studies have shown that a subgroup of schizophrenia patients might particularly benefit from these properties (Raedler et al. 2003, Scarr et al. 2009). Here, we present an ongoing observational study (COMPASS) which builds on these observations and addresses the question whether functional readouts of dopaminergic and muscarinic systems in individual patients could enable personalised treatment predictions. Guided by the dysconnection hypothesis of schizophrenia (Stephan et al., 2009), which postulates aberrant interactions between NMDA receptors and neuromodulators like dopamine/acetylcholine, the COMPASS study adopts a neuromodeling approach. The focus is on EEG/fMRI paradigms and computational models with empirically demonstrated sensitivity for altered function of NMDA, dopamine and muscarinic receptors, respectively. Methods To detect even small effect sizes, the study aims to recruit N=120 patients with schizophrenia who begin treatment with, switch to, or augment medication with olanzapine or clozapine. If possible, a replication sample (an additional N=120) will be recruited, too. Patients will be examined +/- 96h relative to treatment onset. Data acquisition encompasses the following measurements: Clinical interview, EEG (working memory, reward learning under volatility, auditory MMN under volatility, “resting”-state), MRI (optional; fMRI during auditory MMN under volatility, “resting”-state, and structural imaging), blood samples (genetic and biochemical analyses). After 2 and 8 weeks a clinical follow-up is conducted. Results The study is ongoing. Discussion The EEG/fMRI data will be analysed by computational models that infer functional states of glutamatergic, dopaminergic, and cholinergic systems (for review, Stephan et al. 2015). Model parameter estimates will serve as features in machine learning analyses of treatment prediction (Brodersen et al. 2014). If successful, this proof-of-concept study will lead to clinically useful tests for predicting the efficacy of clozapine/olanzapine prior to or during very early treatment. This could have a significant impact on clinical management as it would enable predicting, at an early stage, the therapeutic benefit for individual patients. Our neuromodeling approach to individual predictions may thus provide a principled basis for treatment decisions, help spare side-effects and enable informed switches in treatment strategy.

Amyotrophic lateral sclerosis: increased solubility of skin collagen

NASA Technical Reports Server (NTRS)

Ono, S.; Yamauchi, M.

1992-01-01

We studied the solubility of skin collagen from six patients with amyotrophic lateral sclerosis (ALS) and six controls. The amount of collagen extracted with neutral salt solution was significantly greater in patients with ALS than in controls. In addition, there was a statistically significant increase in the proportion of collagen extracted from ALS patients with increased duration of illness. The collagen solubilized by pepsin and cyanogen bromide treatments was significantly higher in ALS patients than in controls, and its proportion was positively and significantly associated with duration of illness in ALS patients. These results indicate that the metabolism of skin collagen may be affected in the disease process of ALS, causing an increase in immature soluble collagen in the tissue, which is the opposite to that which occurs in the normal aging process.

HFE p.H63D polymorphism does not influence ALS phenotype and survival.

PubMed

Chiò, Adriano; Mora, Gabriele; Sabatelli, Mario; Caponnetto, Claudia; Lunetta, Christian; Traynor, Bryan J; Johnson, Janel O; Nalls, Mike A; Calvo, Andrea; Moglia, Cristina; Borghero, Giuseppe; Monsurrò, Maria Rosaria; La Bella, Vincenzo; Volanti, Paolo; Simone, Isabella; Salvi, Fabrizio; Logullo, Francesco O; Nilo, Riva; Giannini, Fabio; Mandrioli, Jessica; Tanel, Raffaella; Murru, Maria Rita; Mandich, Paola; Zollino, Marcella; Conforti, Francesca L; Penco, Silvana; Brunetti, Maura; Barberis, Marco; Restagno, Gabriella

2015-10-01

It has been recently reported that the p.His63Asp polymorphism of the HFE gene accelerates disease progression both in the SOD1 transgenic mouse and in amyotrophic lateral sclerosis (ALS) patients. We have evaluated the effect of HFE p.His63Asp polymorphism on the phenotype in 1351 Italian ALS patients (232 of Sardinian ancestry). Patients were genotyped for the HFE p.His63Asp polymorphism (CC, GC, and GG). All patients were also assessed for C9ORF72, TARDBP, SOD1, and FUS mutations. Of the 1351 ALS patients, 363 (29.2%) were heterozygous (GC) for the p.His63Asp polymorphism and 30 (2.2%) were homozygous for the minor allele (GG). Patients with CC, GC, and GG polymorphisms did not significantly differ by age at onset, site of onset of symptoms, and survival; however, in SOD1 patients with CG or GG polymorphism had a significantly longer survival than those with a CC polymorphism. Differently from what observed in the mouse model of ALS, the HFE p.His63Asp polymorphism has no effect on ALS phenotype in this large series of Italian ALS patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Japanese-style intensive medical care improves prognosis for acute liver failure and the perioperative management of liver transplantation.

PubMed

Inoue, K; Watanabe, T; Maruoka, N; Kuroki, Y; Takahashi, H; Yoshiba, M

2010-12-01

The Japanese style of intensive medical care for acute liver failure has yielded high survival rates. The care system comprises artificial liver support (ALS) together with treatment for the underlying disease. Plasma exchange in combination with high-volume hemodiafiltration using an high performance membrane has become the standard ALS system. It is safe, efficiently removing more low and middle molecular weight toxic substances than other methods because of the large volumes of buffer (more than 200 L per session), resulting in recovery from coma in patients with severe fulminant hepatitis, a status comparable with the ahepatic state. This ALS is therefore an effective tool to sustain patients with fulminant hepatitis in a favorable condition until liver function recovers or liver transplantation becomes available. The accompanying treatment for underlying disease serves to limit the liver destruction that hampers regeneration. The treatment has remarkably improved the prognosis for patients with subacute types of fulminant hepatitis, which generally carry a less favorable prognosis than the acute type. This treatment system thus provides more time for physicians to assess the indications for liver transplantation as well as giving the patient a greater chance of undergoing transplantation. Copyright © 2010 Elsevier Inc. All rights reserved.

Surgical improvement of speech disorder caused by amyotrophic lateral sclerosis.

PubMed

Saigusa, Hideto; Yamaguchi, Satoshi; Nakamura, Tsuyoshi; Komachi, Taro; Kadosono, Osamu; Ito, Hiroyuki; Saigusa, Makoto; Niimi, Seiji

2012-12-01

Amyotrophic lateral sclerosis (ALS) is a progressive debilitating neurological disease. ALS disturbs the quality of life by affecting speech, swallowing and free mobility of the arms without affecting intellectual function. It is therefore of significance to improve intelligibility and quality of speech sounds, especially for ALS patients with slowly progressive courses. Currently, however, there is no effective or established approach to improve speech disorder caused by ALS. We investigated a surgical procedure to improve speech disorder for some patients with neuromuscular diseases with velopharyngeal closure incompetence. In this study, we performed the surgical procedure for two patients suffering from severe speech disorder caused by slowly progressing ALS. The patients suffered from speech disorder with hypernasality and imprecise and weak articulation during a 6-year course (patient 1) and a 3-year course (patient 2) of slowly progressing ALS. We narrowed bilateral lateral palatopharyngeal wall at velopharyngeal port, and performed this surgery under general anesthesia without muscle relaxant for the two patients. Postoperatively, intelligibility and quality of their speech sounds were greatly improved within one month without any speech therapy. The patients were also able to generate longer speech phrases after the surgery. Importantly, there was no serious complication during or after the surgery. In summary, we performed bilateral narrowing of lateral palatopharyngeal wall as a speech surgery for two patients suffering from severe speech disorder associated with ALS. With this technique, improved intelligibility and quality of speech can be maintained for longer duration for the patients with slowly progressing ALS.

Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders.

PubMed

Lattante, Serena; Millecamps, Stéphanie; Stevanin, Giovanni; Rivaud-Péchoux, Sophie; Moigneu, Carine; Camuzat, Agnès; Da Barroca, Sandra; Mundwiller, Emeline; Couarch, Philippe; Salachas, François; Hannequin, Didier; Meininger, Vincent; Pasquier, Florence; Seilhean, Danielle; Couratier, Philippe; Danel-Brunaud, Véronique; Bonnet, Anne-Marie; Tranchant, Christine; LeGuern, Eric; Brice, Alexis; Le Ber, Isabelle; Kabashi, Edor

2014-09-09

The aim of this study was to establish the frequency of ATXN2 polyglutamine (polyQ) expansion in large cohorts of patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), and to evaluate whether ATXN2 could act as a modifier gene in patients carrying the C9orf72 expansion. We screened a large cohort of French patients (1,144 ALS, 203 FTD, 168 FTD-ALS, and 109 PSP) for ATXN2 CAG repeat length. We included in our cohort 322 carriers of the C9orf72 expansion (202 ALS, 63 FTD, and 57 FTD-ALS). We found a significant association with intermediate repeat size (≥29 CAG) in patients with ALS (both familial and sporadic) and, for the first time, in patients with familial FTD-ALS. Of interest, we found the co-occurrence of pathogenic C9orf72 expansion in 23.2% of ATXN2 intermediate-repeat carriers, all in the FTD-ALS and familial ALS subgroups. In the cohort of C9orf72 carriers, 3.1% of patients also carried an intermediate ATXN2 repeat length. ATXN2 repeat lengths in patients with PSP and FTD were found to be similar to the controls. ATXN2 intermediary repeat length is a strong risk factor for ALS and FTD-ALS. Furthermore, we propose that ATXN2 polyQ expansions could act as a strong modifier of the FTD phenotype in the presence of a C9orf72 repeat expansion, leading to the development of clinical signs featuring both FTD and ALS. © 2014 American Academy of Neurology.

Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders

PubMed Central

Lattante, Serena; Millecamps, Stéphanie; Stevanin, Giovanni; Rivaud-Péchoux, Sophie; Moigneu, Carine; Camuzat, Agnès; Da Barroca, Sandra; Mundwiller, Emeline; Couarch, Philippe; Salachas, François; Hannequin, Didier; Meininger, Vincent; Pasquier, Florence; Seilhean, Danielle; Couratier, Philippe; Danel-Brunaud, Véronique; Bonnet, Anne-Marie; Tranchant, Christine; LeGuern, Eric; Brice, Alexis; Le Ber, Isabelle

2014-01-01

Objective: The aim of this study was to establish the frequency of ATXN2 polyglutamine (polyQ) expansion in large cohorts of patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), and to evaluate whether ATXN2 could act as a modifier gene in patients carrying the C9orf72 expansion. Methods: We screened a large cohort of French patients (1,144 ALS, 203 FTD, 168 FTD-ALS, and 109 PSP) for ATXN2 CAG repeat length. We included in our cohort 322 carriers of the C9orf72 expansion (202 ALS, 63 FTD, and 57 FTD-ALS). Results: We found a significant association with intermediate repeat size (≥29 CAG) in patients with ALS (both familial and sporadic) and, for the first time, in patients with familial FTD-ALS. Of interest, we found the co-occurrence of pathogenic C9orf72 expansion in 23.2% of ATXN2 intermediate-repeat carriers, all in the FTD-ALS and familial ALS subgroups. In the cohort of C9orf72 carriers, 3.1% of patients also carried an intermediate ATXN2 repeat length. ATXN2 repeat lengths in patients with PSP and FTD were found to be similar to the controls. Conclusions: ATXN2 intermediary repeat length is a strong risk factor for ALS and FTD-ALS. Furthermore, we propose that ATXN2 polyQ expansions could act as a strong modifier of the FTD phenotype in the presence of a C9orf72 repeat expansion, leading to the development of clinical signs featuring both FTD and ALS. PMID:25098532

[Physiological parameters of breathing and the impact of non-invasive ventilation (NIV) on patients with amyotrophic lateral sclerosis (ALS)].

PubMed

Czudaj, K-P; Suchi, S; Schönhofer, B

2009-12-01

Amyotrophic lateral sclerosis (ALS), as a consequence of the progressive failure of respiratory muscles, often causes chronic ventilatory failure (CVF), indicated by hypercapnia. This study analyses the physiological parameters of breathing in patients with ALS over time and the variables which influence survival time. In this observational study we analysed the data of physiological parameters (respiratory function, blood gas levels and breathing during sleep), as well as survival rate (according to Kaplan-Meier) of all 85 ALS patients who stayed in our hospital during the period of 1st January 2003 until 31st December 2007. After ALS had been diagnosed, all patients ran through standardised pneumological diagnostics during the observation period, this procedure was repeated every 3-6 months. If hypercapnia (carbon dioxide tension pCO(2) > 45 mm Hg) was detected, non-invasive ventilation (NIV) was indicated and offered to the respective patients. In the course of the observation, the parameters of respiratory function IVC (inspiratory vital capacity) and FEV1 (forced expiratory volume after 1 second) have shown a significant reduction by 14-15% per year. Half of the patients died within 3.1 years after ALS had been diagnosed. IVC and FEV1 had no impact on the survival time. In contrast, pCO(2) correlates negatively with the survival time. The period between diagnosis of ALS and manifestation of hypercapnia is about 1.9 +/- 2.4 years. In spite of a clear indication, some of the patients did not comply with NIV or did not accept it (19 patients, 22%). Twenty-eight patients (33%) started NIV with a good compliance. The survival rate of patients with NIV was 1.27 years on average--after the initial measurement of hypercapnia. The survival time of hypercapnic patients without NIV was only 0.12 years. Hypercapnia has a significant impact on the prognosis for ALS patients. In the case of CVF (hypercapnia), the survival time of ALS patients is significantly reduced. NIV is able to significantly increase the survival time of ALS patients with hypercapnia. Georg Thieme Verlag KG Stuttgart-New York.

Comparing methods to combine functional loss and mortality in clinical trials for amyotrophic lateral sclerosis

PubMed Central

van Eijk, Ruben PA; Eijkemans, Marinus JC; Rizopoulos, Dimitris

2018-01-01

Objective Amyotrophic lateral sclerosis (ALS) clinical trials based on single end points only partially capture the full treatment effect when both function and mortality are affected, and may falsely dismiss efficacious drugs as futile. We aimed to investigate the statistical properties of several strategies for the simultaneous analysis of function and mortality in ALS clinical trials. Methods Based on the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we simulated longitudinal patterns of functional decline, defined by the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) and conditional survival time. Different treatment scenarios with varying effect sizes were simulated with follow-up ranging from 12 to 18 months. We considered the following analytical strategies: 1) Cox model; 2) linear mixed effects (LME) model; 3) omnibus test based on Cox and LME models; 4) composite time-to-6-point decrease or death; 5) combined assessment of function and survival (CAFS); and 6) test based on joint modeling framework. For each analytical strategy, we calculated the empirical power and sample size. Results Both Cox and LME models have increased false-negative rates when treatment exclusively affects either function or survival. The joint model has superior power compared to other strategies. The composite end point increases false-negative rates among all treatment scenarios. To detect a 15% reduction in ALSFRS-R decline and 34% decline in hazard with 80% power after 18 months, the Cox model requires 524 patients, the LME model 794 patients, the omnibus test 526 patients, the composite end point 1,274 patients, the CAFS 576 patients and the joint model 464 patients. Conclusion Joint models have superior statistical power to analyze simultaneous effects on survival and function and may circumvent pitfalls encountered by other end points. Optimizing trial end points is essential, as selecting suboptimal outcomes may disguise important treatment clues. PMID:29593436

Microarray analysis of peripheral blood lymphocytes from ALS patients and the SAFE detection of the KEGG ALS pathway

PubMed Central

2011-01-01

Background Sporadic amyotrophic lateral sclerosis (sALS) is a motor neuron disease with poorly understood etiology. Results of gene expression profiling studies of whole blood from ALS patients have not been validated and are difficult to relate to ALS pathogenesis because gene expression profiles depend on the relative abundance of the different cell types present in whole blood. We conducted microarray analyses using Agilent Human Whole Genome 4 × 44k Arrays on a more homogeneous cell population, namely purified peripheral blood lymphocytes (PBLs), from ALS patients and healthy controls to identify molecular signatures possibly relevant to ALS pathogenesis. Methods Differentially expressed genes were determined by LIMMA (Linear Models for MicroArray) and SAM (Significance Analysis of Microarrays) analyses. The SAFE (Significance Analysis of Function and Expression) procedure was used to identify molecular pathway perturbations. Proteasome inhibition assays were conducted on cultured peripheral blood mononuclear cells (PBMCs) from ALS patients to confirm alteration of the Ubiquitin/Proteasome System (UPS). Results For the first time, using SAFE in a global gene ontology analysis (gene set size 5-100), we show significant perturbation of the KEGG (Kyoto Encyclopedia of Genes and Genomes) ALS pathway of motor neuron degeneration in PBLs from ALS patients. This was the only KEGG disease pathway significantly upregulated among 25, and contributing genes, including SOD1, represented 54% of the encoded proteins or protein complexes of the KEGG ALS pathway. Further SAFE analysis, including gene set sizes >100, showed that only neurodegenerative diseases (4 out of 34 disease pathways) including ALS were significantly upregulated. Changes in UBR2 expression correlated inversely with time since onset of disease and directly with ALSFRS-R, implying that UBR2 was increased early in the course of ALS. Cultured PBMCs from ALS patients accumulated more ubiquitinated proteins than PBMCs from healthy controls in a serum-dependent manner confirming changes in this pathway. Conclusions Our study indicates that PBLs from sALS patients are strong responders to systemic signals or local signals acquired by cell trafficking, representing changes in gene expression similar to those present in brain and spinal cord of sALS patients. PBLs may provide a useful means to study ALS pathogenesis. PMID:22027401

Complete Genome Sequence of Bordetella pertussis Strain VA-190 Isolated from a Vaccinated 10-Year-Old Patient with Whooping Cough.

PubMed

Eby, Joshua C; Turner, Lauren; Nguyen, Bryan; Kang, June; Neville, Carly; Temple, Louise

2016-09-15

The number of cases of pertussis has increased in the United States despite vaccination. We present the genome of an isolate of Bordetella pertussis from a vaccinated patient from Virginia. The genome was sequenced by long-read methodology and compared to that of a clinical isolate used for laboratory studies, D420. Copyright © 2016 Eby et al.

Executive functioning in chronic alcoholism and Korsakoff syndrome.

PubMed

Maharasingam, Malini; Macniven, Jamie A B; Mason, Oliver J

2013-01-01

Korsakoff syndrome (KS) is characterized by dense anterograde and retrograde amnesia. There is often a temporal gradient to the retrograde amnesia, with earlier memories more readily recalled than recent memories. Executive functioning has also been found to be impaired in KS. However, research comparing executive functioning between chronic alcoholics (AL) and patients with KS has been relatively sparse to date. In a group comparison design, executive functioning in 15 KS patients and 16 chronic alcoholic patients was assessed using the Behavioural Assessment of the Dysexecutive Syndrome test (BADS) and other secondary measures. The KS group was found to be significantly more impaired than the AL group on overall performance on the BADS (p < .05). Korsakoff patients are significantly more impaired in executive functioning than non-Korsakoff chronic alcoholics. We thank the participants of the study and also acknowledge the support of the University of Nottingham, particularly Nadina Lincoln, and the North East London NHS Foundation Trust. We are also very grateful to the anonymous reviewers of earlier drafts of this manuscript for their invaluable comments.

Mutations in FUS cause FALS and SALS in French and French Canadian populations

PubMed Central

Belzil, V. V.; Valdmanis, P. N.; Dion, P. A.; Daoud, H.; Kabashi, E.; Noreau, A.; Gauthier, J.; Hince, P.; Desjarlais, A.; Bouchard, J. -P.; Lacomblez, L.; Salachas, F.; Pradat, P. -F.; Camu, W.; Meininger, V.; Dupré, N.; Rouleau, G. A.

2009-01-01

Background: The identification of mutations in the TARDBP and more recently the identification of mutations in the FUS gene as the cause of amyotrophic lateral sclerosis (ALS) is providing the field with new insight about the mechanisms involved in this severe neurodegenerative disease. Methods: To extend these recent genetic reports, we screened the entire gene in a cohort of 200 patients with ALS. An additional 285 patients with sporadic ALS were screened for variants in exon 15 for which mutations were previously reported. Results: In total, 3 different mutations were identified in 4 different patients, including 1 3-bp deletion in exon 3 of a patient with sporadic ALS and 2 missense mutations in exon 15 of 1 patient with familial ALS and 2 patients with sporadic ALS. Conclusions: Our study identified sporadic patients with mutations in the FUS gene. The accumulation and description of different genes and mutations helps to develop a more comprehensive picture of the genetic events underlying amyotrophic lateral sclerosis. PMID:19741216

Mutations in FUS cause FALS and SALS in French and French Canadian populations.

PubMed

Belzil, V V; Valdmanis, P N; Dion, P A; Daoud, H; Kabashi, E; Noreau, A; Gauthier, J; Hince, P; Desjarlais, A; Bouchard, J-P; Lacomblez, L; Salachas, F; Pradat, P-F; Camu, W; Meininger, V; Dupré, N; Rouleau, G A

2009-10-13

The identification of mutations in the TARDBP and more recently the identification of mutations in the FUS gene as the cause of amyotrophic lateral sclerosis (ALS) is providing the field with new insight about the mechanisms involved in this severe neurodegenerative disease. To extend these recent genetic reports, we screened the entire gene in a cohort of 200 patients with ALS. An additional 285 patients with sporadic ALS were screened for variants in exon 15 for which mutations were previously reported. In total, 3 different mutations were identified in 4 different patients, including 1 3-bp deletion in exon 3 of a patient with sporadic ALS and 2 missense mutations in exon 15 of 1 patient with familial ALS and 2 patients with sporadic ALS. Our study identified sporadic patients with mutations in the FUS gene. The accumulation and description of different genes and mutations helps to develop a more comprehensive picture of the genetic events underlying amyotrophic lateral sclerosis.

Comparison of Different Stem Cell Mobilization Regimens in AL Amyloidosis Patients.

PubMed

Lisenko, Katharina; Wuchter, Patrick; Hansberg, Marion; Mangatter, Anja; Benner, Axel; Ho, Anthony D; Goldschmidt, Hartmut; Hegenbart, Ute; Schönland, Stefan

2017-11-01

High-dose melphalan (HDM) and autologous blood stem cell transplantation (ABSCT) is an effective treatment for transplantation-eligible patients with systemic light chain (AL) amyloidosis. Whereas most centers use granulocyte colony-stimulating factor (G-CSF) alone for mobilization of peripheral blood stem cells (PBSC), the application of mobilization chemotherapy might offer specific advantages. We retrospectively analyzed 110 patients with AL amyloidosis who underwent PBSC collection. Major eligibility criteria included age <70 years and cardiac insufficiency New York Heart Association ≤III°. Before mobilization, 67 patients (61%) had been pretreated with induction therapy, including 17 (15%) patients who had received melphalan. Chemo-mobilization was performed with either cyclophosphamide, doxorubicin, dexamethasone (CAD)/G-CSF (n = 78, 71%); ifosfamide/G-CSF (n = 14, 13%); or other regimens (n = 8, 7%). AL amyloidosis patients with predominant heart involvement and/or status post heart transplantation were mobilized with G-CSF only (n = 10, 9%). PBSC collection was successful in 101 patients (92%) at first attempt. The median number of CD34 + cells was 8.7 (range, 2.1 to 45.5) × 10 6 CD34 + /kg collected in a median of 1 leukapheresis (LP) session. Compared with G-CSF-only mobilization, a chemo-mobilization with CAD/G-CSF or ifosfamide/G-CSF had a positive impact on the number of collected CD34 + cell number/kg per LP (P <.001, multivariate). Melphalan-containing previous therapy and higher age had a significant negative impact on quantity of collected CD34 + cells. Median common toxicity criteria (CTC) grade of nonhematologic toxicity was II (range, 0 to IV). Life-threatening CTC grade IV adverse events were observed in 3 patients with no fatalities. Cardiovascular events were observed in 17 patients (22%) upon CAD/G-CSF mobilization (median CTC: grade 3; range, 1 to 4). Toxicity in patients undergoing ifosfamide/G-CSF mobilization was higher than in with those who received G-CSF-only mobilization. HDM and ABSCT were performed in 100 patients. Compared with >6.5 × 10 6 transplanted CD34 + cells/kg, an ABSCT with <3 × 10 6 CD34 + cells/kg was associated with a longer duration to leukocyte reconstitution >1 × 10 9 /L and a reduced platelet count <150 × 10 9 /L 1 year after ASCT. Our results show that CAD chemotherapy is very effective in PBSC mobilization and has a tolerable toxicity profile in AL amyloidosis patients. A further toxicity reduction by omission of doxorubicin might be considered. Because of advanced nonhematologic toxicity, ifosfamide administration cannot be recommended. However, G-CSF mobilization alone is also safe and effective. Considering the hematopoietic reconstitution and long-term stem cell function, our results provide a rationale to collect and transplant as many as >6.5 × 10 6 CD34 + cells/kg, if feasible with reasonable effort. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Mutations in FUS are the most frequent genetic cause in juvenile sporadic ALS patients of Chinese origin.

PubMed

Zou, Zhang-Yu; Liu, Ming-Sheng; Li, Xiao-Guang; Cui, Li-Ying

2016-01-01

Juvenile onset ALS is a very rare form of motor neuron disease, with the first symptoms of motor neuron degeneration manifested before 25 years of age. Mutations in the alsin (ALS2), senataxin (SETX), and spatacsin (SPG11) genes have been associated with familial ALS with juvenile onset and slow progression, whereas the genetic architecture of sporadic juvenile ALS remains unclear. We screened mutations in C9orf72, SOD1, FUS, TARDBP, ANG, VCP and PFN1 in 16 juvenile sporadic ALS patients. Four cases (25%) carrying FUS mutations and one individual (6%) harbouring a SOD1 mutation were identified. All cases had an aggressive disease course. Our results suggest that FUS mutations are the most frequent genetic cause in early-onset sporadic ALS patients of Chinese origin. Genetic testing of FUS should be performed in early-onset ALS patients especially those with an aggressive disease course.

Potential skin involvement in ALS: revisiting Charcot's observation - a review of skin abnormalities in ALS.

PubMed

Paré, Bastien; Gros-Louis, François

2017-07-26

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons of the brain and spinal cord, leading to progressive paralysis and death. Interestingly, many skin changes have been reported in ALS patients, but never as yet fully explained. These observations could be due to the common embryonic origin of the skin and neural tissue known as the ectodermal germ layer. Following the first observation in ALS patients' skin by Dr Charcot in the 19th century, in the absence of bedsores unlike other bedridden patients, other morphological and molecular changes have been observed. Thus, the skin could be of interest in the study of ALS and other neurodegenerative diseases. This review summarizes skin changes reported in the literature over the years and discusses about a novel in vitro ALS tissue-engineered skin model, derived from patients, for the study of ALS.

Study of the HFE gene common polymorphisms in French patients with sporadic amyotrophic lateral sclerosis.

PubMed

Praline, Julien; Blasco, Hélène; Vourc'h, Patrick; Rat, Valérian; Gendrot, Chantal; Camu, William; Andres, Christian R

2012-06-15

Our objective was to investigate whether the C282Y (p.Cys 282 Tyr) and H63D (p. His 63 Asp) HFE polymorphisms were associated with sporadic amyotrophic lateral sclerosis (SALS) in the French population. We searched for a relation of HFE polymorphisms with the clinical characteristics of the disease. The HFE polymorphisms were studied in 824 patients with SALS and 583 controls. We compared the frequency of the polymorphisms between SALS and controls groups by univariate and multivariate statistics, taking into account gender, site, age-at-onset and survival. We did not observe significant difference in the frequency of H63D polymorphism between SALS and control group. We observed a significant difference for C282Y between patients and controls with a low frequency of the Y allele in patients (3.2%) compared to our control group (5.9%). Disease duration, distribution of gender, site-of-onset, age-at-onset did not differ between groups taking into account genotypes of each polymorphism. Our results in this large cohort of ALS patients indicate that H63D polymorphism is not associated with SALS in the French population. This conclusion does not exclude a weak effect of the HFE gene polymorphisms in certain ALS populations, or an effect of other rare HFE gene variants. Copyright © 2012 Elsevier B.V. All rights reserved.

Longitudinal left ventricular function for prediction of survival in systemic light-chain amyloidosis: incremental value compared with clinical and biochemical markers.

PubMed

Buss, Sebastian J; Emami, Mostafa; Mereles, Derliz; Korosoglou, Grigorios; Kristen, Arnt V; Voss, Andreas; Schellberg, Dieter; Zugck, Christian; Galuschky, Christian; Giannitsis, Evangelos; Hegenbart, Ute; Ho, Anthony D; Katus, Hugo A; Schonland, Stefan O; Hardt, Stefan E

2012-09-18

The aim of the study was to determine whether longitudinal left ventricular (LV) function provides prognostic information in a large cohort of patients with systemic light-chain (AL) amyloidosis. AL amyloidosis is associated with a high incidence of cardiovascular events. Reduced myocardial longitudinal function is one of the hallmarks of myocardial involvement in this rare disease. Two hundred six consecutive patients with biopsy-proven AL amyloidosis were investigated in this prospective observational study. Echocardiographic imaging parameters, mean tissue Doppler-derived longitudinal strain (LS), and two-dimensional global longitudinal strain (2D-GLS) of the LV, cardiac serological biomarkers, and comprehensive clinical disease characteristics were assessed. The primary endpoint was all-cause mortality or heart transplantation. After a median follow-up of 1207 days, LS and 2D-GLS were significant predictors of survival in AL amyloidosis. The cutoff values discriminating survivors from nonsurvivors were -10.65% for LS and -11.78% for 2D-GLS. In a multivariable echocardiographic Cox model, only diastolic dysfunction and 2D-GLS remained as independent predictors of survival. In comprehensive clinical models, 2D-GLS (p < 0.0001), diastolic dysfunction (p < 0.01), the pathologic free light chains (p < 0.05), cardiac troponin-T (cTnT) (p < 0.01), and the Karnofsky index (p < 0.001) remained as independent predictors. 2D-GLS delineated a superior prognostic value compared with that derived from pathologic free light chains or cTnT in patients evaluated before firstline chemotherapy (n = 113; p < 0.0001), and remained the only independent predictor besides the Karnofsky index in subjects with preserved LV ejection fraction (≥50%; n = 127; p < 0.01). LS and 2D-GLS both offered significant incremental information (p < 0.001) for the assessment of outcome compared with clinical variables (age, Karnofsky index, and New York Heart Association functional class) and serological biomarkers. In the largest serial investigation reported so far, reduced LV longitudinal function served as an independent predictor of survival in AL amyloidosis and offered incremental information beyond standard clinical and serological parameters. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

The evil of good is better: Making the case for basic life support transport for penetrating trauma victims in an urban environment.

PubMed

Rappold, Joseph F; Hollenbach, Kathryn A; Santora, Thomas A; Beadle, Dania; Dauer, Elizabeth D; Sjoholm, Lars O; Pathak, Abhijit; Goldberg, Amy J

2015-09-01

Controversy remains over the ideal way to transport penetrating trauma victims in an urban environment. Both advance life support (ALS) and basic life support (BLS) transports are used in most urban centers. A retrospective cohort study was conducted at an urban Level I trauma center. Victims of penetrating trauma transported by ALS, BLS, or police from January 1, 2008, to November 31, 2013, were identified. Patient survival by mode of transport and by level of care received was analyzed using logistic regression. During the study period, 1,490 penetrating trauma patients were transported by ALS (44.8%), BLS (15.6%), or police (39.6%) personnel. The majority of injuries were gunshot wounds (72.9% for ALS, 66.8% for BLS, 90% for police). Median transport minutes were significantly longer for ALS (16 minutes) than for BLS (14.5 minutes) transports (p = 0.012). After adjusting for transport time and Injury Severity Score (ISS), among victims with an ISS of 0 to 30, there was a 2.4-fold increased odds of death (95% confidence interval [CI], 1.3-4.4) if transported by ALS as compared with BLS. With an ISS of greater than 30, this relationship did not exist (odds ratio, 0.9; 95% CI, 0.3-2.7). When examined by type of care provided, patients with an ISS of 0 to 30 given ALS support were 3.7 times more likely to die than those who received BLS support (95% CI, 2.0-6.8). Among those with an ISS of greater than 30, no relationship was evident (odds ratio, 0.9; 95% CI, 0.3-2.7). Among penetrating trauma victims with an ISS of 30 or lower, an increased odds of death was identified for those treated and/or transported by ALS personnel. For those with an ISS of greater than 30, no survival advantage was identified with ALS transport or care. Results suggest that rapid transport may be more important than increased interventions. Therapeutic study, level IV.

Use of gastrografin in the management of worm-induced small bowel obstruction in children.

PubMed

Hamid, Raashid; Bhat, Nisar; Baba, Aejaz; Mufti, Gowhar; Khursheed, Sheikh; Wani, Sajad A; Ali, Imran; Hassan, Faheem

2015-12-01

Ascaris-induced small bowel obstruction (SBO) is a common sequel of Ascaris lumbricoides (AL) infestation. Most cases respond to conservative treatment practiced in different centers worldwide. We conceived a prospective randomized trial to compare the conservative treatment with gastrografin administered in addition to the conservative treatment. This prospective randomized study was conducted between January 2011 and June 2014 at Department of Paediatric and Neonatal Surgery, a tertiary-care hospital. Patients were divided into two groups, one group received conservative treatment and the other received gastrografin in addition to conservative treatment. Forty patients having uncomplicated AL-induced SBO were included in each group. Gastrografin was administered through nasogastric tube and serial clinical and radiological monitoring was performed. The duration of hospital stay, time between admission and first oral feed, passage of worms/flatus were compared in the two groups. Student's t test was used for comparing these variables. Average time for passage of flatus or worms and resolution of abdominal signs and was shorter in gastrografin group as compared to the conservative group. This difference was found to be statistically significant. The average duration of hospital stay in gastrografin group was 25.20 ± 8.01 h whereas it was 61.12 ± 14.64 h in the conservative group (P < 0.001). The difference in the operation rate was statistically insignificant (2 in gastrografin group and 3 in the conservative group).No serious adverse reaction was noted after gastrografin administration. Use of gastrografin resulted in faster relief of signs and symptoms of AL-induced SBO, early passage of worms/flatus and return to oral feeds. However, the role of gastrografin role in reducing the likelihood of laparotomy remains inconclusive. Adverse effects of gastrografin can be prevented if it is used in well-hydrated patients.

Non-invasive ventilation in amyotrophic lateral sclerosis: a 10 year population based study.

PubMed

Chiò, Adriano; Calvo, Andrea; Moglia, Cristina; Gamna, Federica; Mattei, Alessio; Mazzini, Letizia; Mora, Gabriele

2012-04-01

To evaluate the clinical characteristics and outcome of non-invasive ventilation (NIV) in an epidemiological based series of amyotrophic lateral sclerosis (ALS) patients. The study was performed using data from the Piemonte and Valle d'Aosta Register for ALS, a prospective epidemiological register enrolling all ALS incident cases in two Italian regions. Among the 1260 patients incident in the period 1995-2004, 259 (20.6%) underwent NIV. Young male patients and subjects attending the tertiary ALS centres were more likely to undergo NIV. There was a progressive significant increase in the use of NIV during the study but was limited to patients attending the ALS tertiary centres. Median survival after NIV was 289 days (95% CI 255 to 333). In an epidemiological setting, NIV represents an increasingly utilised option for the treatment of respiratory disturbances in ALS and has favourable effects on survival, in particular among patients followed by tertiary ALS centres. Sociocultural factors, such as age, gender and marital status, strongly influence the probability of undergoing NIV. Efforts should be made to remove these obstacles in order to spread the use of NIV in all ALS patients with respiratory failure.

Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion.

PubMed

Locatelli, Franco; Merli, Pietro; Pagliara, Daria; Li Pira, Giuseppina; Falco, Michela; Pende, Daniela; Rondelli, Roberto; Lucarelli, Barbarella; Brescia, Letizia Pomponia; Masetti, Riccardo; Milano, Giuseppe Maria; Bertaina, Valentina; Algeri, Mattia; Pinto, Rita Maria; Strocchio, Luisa; Meazza, Raffaella; Grapulin, Lavinia; Handgretinger, Rupert; Moretta, Alessandro; Bertaina, Alice; Moretta, Lorenzo

2017-08-03

Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children with acute leukemia (AL) either relapsed or at high-risk of treatment failure. We developed a novel method of graft manipulation based on negative depletion of αβ T and B cells and conducted a prospective trial evaluating the outcome of children with AL transplanted with this approach. Eighty AL children, transplanted between September 2011 and September 2014, were enrolled in the trial. All children were given a fully myeloablative preparative regimen. Anti-T-lymphocyte globulin from day -5 to -3 was used for preventing graft rejection and graft-versus-host disease (GVHD); no patient received any posttransplantation GVHD prophylaxis. Two children experienced primary graft failure. The cumulative incidence of skin-only, grade 1-2 acute GVHD was 30%; no patient developed extensive chronic GVHD. Four patients died, the cumulative incidence of nonrelapse mortality being 5%, whereas 19 relapsed, resulting in a 24% cumulative incidence of relapse. With a median follow-up of 46 months for surviving patients, the 5-year probability of chronic GVHD-free, relapse-free survival (GRFS) is 71%. Total body irradiation-containing preparative regimen was the only variable favorably influencing relapse incidence and GRFS. The outcomes of these 80 patients are comparable to those of 41 and 51 children given transplantation from an HLA-identical sibling or a 10/10 allelic-matched unrelated donor in the same period. These data indicate that haplo-HSCT after αβ T- and B-cell depletion represents a competitive alternative for children with AL in need of urgent allograft. This trial was registered at www.clinicaltrials.gov as #NCT01810120. © 2017 by The American Society of Hematology.

Independent Prognostic Value of Stroke Volume Index in Patients With Immunoglobulin Light Chain Amyloidosis.

PubMed

2018-05-01

Heart involvement is the most important prognostic determinant in AL amyloidosis patients. Echocardiography is a cornerstone for the diagnosis and provides important prognostic information. We studied 754 patients with AL amyloidosis who underwent echocardiographic assessment at the Mayo Clinic, including a Doppler-derived measurement of stroke volume (SV) within 30 days of their diagnosis to explore the prognostic role of echocardiographic variables in the context of a well-established soluble cardiac biomarker staging system. Reproducibility of SV, myocardial contraction fraction, and left ventricular strain was assessed in a separate, yet comparable, study cohort of 150 patients from the Pavia Amyloidosis Center. The echocardiographic measures most predictive for overall survival were SV index <33 mL/min, myocardial contraction fraction <34%, and cardiac index <2.4 L/min/m 2 with respective hazard ratios (95% confidence intervals) of 2.95 (2.37-3.66), 2.36 (1.96-2.85), and 2.32 (1.91-2.80). For the subset that had left ventricular strain performed, the prognostic cut point was -14% (hazard ratios, 2.70; 95% confidence intervals, 1.84-3.96). Each parameter was independent of systolic blood pressure, Mayo staging system (NT-proBNP [N-terminal pro-B-type natriuretic peptide] and troponin), and ejection fraction on multivariable analysis. Simple predictive models for survival, including biomarker staging along with SV index or left ventricular strain, were generated. SV index prognostic performance was similar to left ventricular strain in predicting survival in AL amyloidosis, independently of biomarker staging. Because SV index is routinely calculated and widely available, it could serve as the preferred echocardiographic measure to predict outcomes in AL amyloidosis patients. © 2018 American Heart Association, Inc.

Discrete mitochondrial aberrations in the spinal cord of sporadic ALS patients.

PubMed

Delic, Vedad; Kurien, Crupa; Cruz, Josean; Zivkovic, Sandra; Barretta, Jennifer; Thomson, Avery; Hennessey, Daniel; Joseph, Jaheem; Ehrhart, Jared; Willing, Alison E; Bradshaw, Patrick; Garbuzova-Davis, Svitlana

2018-08-01

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord leading to muscle atrophy, paralysis, and death. Mitochondrial dysfunction is a major contributor to motor neuron degeneration associated with ALS progression. Mitochondrial abnormalities have been determined in spinal cords of animal disease models and ALS patients. However, molecular mechanisms leading to mitochondrial dysfunction in sporadic ALS (sALS) patients remain unclear. Also, segmental or regional variation in mitochondrial activity in the spinal cord has not been extensively examined in ALS. In our study, the activity of mitochondrial electron transport chain complex IV was examined in post-mortem gray and white matter of the cervical and lumbar spinal cords from male and female sALS patients and controls. Mitochondrial distribution and density in spinal cord motor neurons, lateral funiculus, and capillaries in gray and white matter were analyzed by immunohistochemistry. Results showed that complex IV activity was significantly decreased only in gray matter in both cervical and lumbar spinal cords from ALS patients. In ALS cervical and lumbar spinal cords, significantly increased mitochondrial density and altered distribution were observed in motor neurons, lateral funiculus, and cervical white matter capillaries. Discrete decreased complex IV activity in addition to changes in mitochondria distribution and density determined in the spinal cord in sALS patients are novel findings. These explicit mitochondrial defects in the spinal cord may contribute to ALS pathogenesis and should be considered in development of therapeutic approaches for this disease. © 2018 Wiley Periodicals, Inc.

A comparative study of two prediction models for brain tumor progression

NASA Astrophysics Data System (ADS)

Zhou, Deqi; Tran, Loc; Wang, Jihong; Li, Jiang

2015-03-01

MR diffusion tensor imaging (DTI) technique together with traditional T1 or T2 weighted MRI scans supplies rich information sources for brain cancer diagnoses. These images form large-scale, high-dimensional data sets. Due to the fact that significant correlations exist among these images, we assume low-dimensional geometry data structures (manifolds) are embedded in the high-dimensional space. Those manifolds might be hidden from radiologists because it is challenging for human experts to interpret high-dimensional data. Identification of the manifold is a critical step for successfully analyzing multimodal MR images. We have developed various manifold learning algorithms (Tran et al. 2011; Tran et al. 2013) for medical image analysis. This paper presents a comparative study of an incremental manifold learning scheme (Tran. et al. 2013) versus the deep learning model (Hinton et al. 2006) in the application of brain tumor progression prediction. The incremental manifold learning is a variant of manifold learning algorithm to handle large-scale datasets in which a representative subset of original data is sampled first to construct a manifold skeleton and remaining data points are then inserted into the skeleton by following their local geometry. The incremental manifold learning algorithm aims at mitigating the computational burden associated with traditional manifold learning methods for large-scale datasets. Deep learning is a recently developed multilayer perceptron model that has achieved start-of-the-art performances in many applications. A recent technique named "Dropout" can further boost the deep model by preventing weight coadaptation to avoid over-fitting (Hinton et al. 2012). We applied the two models on multiple MRI scans from four brain tumor patients to predict tumor progression and compared the performances of the two models in terms of average prediction accuracy, sensitivity, specificity and precision. The quantitative performance metrics were calculated as average over the four patients. Experimental results show that both the manifold learning and deep neural network models produced better results compared to using raw data and principle component analysis (PCA), and the deep learning model is a better method than manifold learning on this data set. The averaged sensitivity and specificity by deep learning are comparable with these by the manifold learning approach while its precision is considerably higher. This means that the predicted abnormal points by deep learning are more likely to correspond to the actual progression region.

Effects of advanced life support versus basic life support on the mortality rates of patients with trauma in prehospital settings: a study protocol for a systematic review and meta-analysis.

PubMed

Kondo, Yutaka; Fukuda, Tatsuma; Uchimido, Ryo; Hifumi, Toru; Hayashida, Kei

2017-10-22

Advanced life support (ALS) is thought to be associated with improved survival in prehospital trauma care when compared with basic life support (BLS). However, evidence on the benefits of prehospital ALS for patients with trauma is controversial. Therefore, we aim to clarify if ALS improves mortality in patients with trauma when compared with BLS by conducting a systematic review and meta-analysis of the recent literature. We will perform searches in PubMed, Embase and the Cochrane Central Register of Controlled Trials for published observational studies, controlled before-and-after studies, randomised controlled trials and other controlled trials conducted in humans and published until March 2017. We will screen search results, assess study selection, extract data and assess the risk of bias in duplicate; disagreements will be resolved through discussions. Data from clinically homogeneous studies will be pooled using a random-effects meta-analysis, heterogeneity of effects will be assessed using the χ 2 test of homogeneity, and any observed heterogeneity will be quantified using the I 2 statistic. Last, the Grading of Recommendations Assessment, Development and Evaluation approach will be used to rate the quality of the evidence. Our study does not require ethical approval as it is based on findings of previously published articles. Results will be disseminated through publication in a peer-reviewed journal, presentations at relevant conferences and publications for patient information. PROSPERO (International Prospective Register of Systematic Reviews) registration number CRD42017054389. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Decision-making among patients and their family in ALS care: a review.

PubMed

Foley, Geraldine; Hynes, Geralyn

2018-05-01

Practice guidelines in ALS care emphasise the role of the patient and their family in the decision-making process. We aimed to examine the ALS patient/family relationship in the decision-making process and to ascertain how patients and their family can shape one another's decisions pertaining to care. We conducted a review of peer-reviewed empirical research, published in full and in English between January 2007 and January 2017, relating to care decision-making among ALS patients and their family. Database sources included: Medline; CINAHL; AMED; PsycINFO; PsycARTICLES; and Social Sciences Full Text. A narrative synthesis was undertaken. Forty-seven studies from the empirical literature were extracted. The family viewpoint was captured primarily from family members with direct care-giving duties. Patients' cognitive status was not routinely assessed. The findings revealed that the decision-making process in ALS care can be contoured by patients' and family caregivers' perceived responsibilities to one another and to the wider family. Greater attention to family member roles beyond the primary caregiver role is needed. Strategies that integrate cognitively-impaired patients into the family decision-making process require investigation. Identification of the domains in which ALS patients and their family members support one another in the decision-making process could facilitate the development of patient/family decision-making tools in ALS care.

Risk factors for respiratory failure of motor neuron disease in a multiracial Asian population.

PubMed

Deng, Xiao; Hao, Ying; Xiao, Bin; Tan, Eng-King; Lo, Yew-Long

2017-05-01

Motor neuron disease (MND) is a devastating degenerative disorder. Amyotrophic Lateral Sclerosis (ALS) is the most common and severe form of MND. Respiratory failure arising from ventilator musculature atrophy is the most common cause of death for ALS patients. Exploring the factors correlated with respiratory failure can contribute to disease management. To characterize the clinical features of MND and determine the factors that may affect respiratory failure of MND patients. The case records of all MND patients seen in Singapore General Hospital (SGH) between January 2004 and December 2014 were examined. Demographic, clinical information were collected by reviewing case records. Mortality data, if not available from records, were obtained via phone call interview of family members. Demographic data and clinical treatments were compared between Respiratory support group and Non-respiratory support group. There were 73 patients included in our study. 49 (67.1%) patients died during follow-up. The mean age of onset was 58±11.1years. With regard to treatment, 63% needed feeding support, and 42.5% required ventilation aid. The median overall survival was 36months from symptom onset. Chi-square tests showed there was significantly higher percentage of respiratory support needed in Chinese than in other races (P=0.016). Compared with non-feeding support patients, patients with feeding support were more likely to require assisted ventilation (P=0.001). We report for the first time that the need of feeding support is significantly associated with assisted ventilation. Chinese MND patients may be more inclined to require respiratory support. Copyright © 2017 Elsevier Ltd. All rights reserved.

Multi-parametric spinal cord MRI as potential progression marker in amyotrophic lateral sclerosis.

PubMed

El Mendili, Mohamed-Mounir; Cohen-Adad, Julien; Pelegrini-Issac, Mélanie; Rossignol, Serge; Morizot-Koutlidis, Régine; Marchand-Pauvert, Véronique; Iglesias, Caroline; Sangari, Sina; Katz, Rose; Lehericy, Stéphane; Benali, Habib; Pradat, Pierre-François

2014-01-01

To evaluate multimodal MRI of the spinal cord in predicting disease progression and one-year clinical status in amyotrophic lateral sclerosis (ALS) patients. After a first MRI (MRI1), 29 ALS patients were clinically followed during 12 months; 14/29 patients underwent a second MRI (MRI2) at 11±3 months. Cross-sectional area (CSA) that has been shown to be a marker of lower motor neuron degeneration was measured in cervical and upper thoracic spinal cord from T2-weighted images. Fractional anisotropy (FA), axial/radial/mean diffusivities (λ⊥, λ//, MD) and magnetization transfer ratio (MTR) were measured within the lateral corticospinal tract in the cervical region. Imaging metrics were compared with clinical scales: Revised ALS Functional Rating Scale (ALSFRS-R) and manual muscle testing (MMT) score. At MRI1, CSA correlated significantly (P<0.05) with MMT and arm ALSFRS-R scores. FA correlated significantly with leg ALFSRS-R scores. One year after MRI1, CSA predicted (P<0.01) arm ALSFSR-R subscore and FA predicted (P<0.01) leg ALSFRS-R subscore. From MRI1 to MRI2, significant changes (P<0.01) were detected for CSA and MTR. CSA rate of change (i.e. atrophy) highly correlated (P<0.01) with arm ALSFRS-R and arm MMT subscores rate of change. Atrophy and DTI metrics predicted ALS disease progression. Cord atrophy was a better biomarker of disease progression than diffusion and MTR. Our study suggests that multimodal MRI could provide surrogate markers of ALS that may help monitoring the effect of disease-modifying drugs.

Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients.

PubMed

Lam, Larry; Chin, Lydia; Halder, Ramesh C; Sagong, Bien; Famenini, Sam; Sayre, James; Montoya, Dennis; Rubbi, Liudmilla; Pellegrini, Matteo; Fiala, Milan

2016-10-01

We have investigated transcriptional and epigenetic differences in peripheral blood mononuclear cells (PBMCs) of monozygotic female twins discordant in the diagnosis of amyotrophic lateral sclerosis (ALS). Exploring DNA methylation differences by reduced representation bisulfite sequencing (RRBS), we determined that, over time, the ALS twin developed higher abundances of the CD14 macrophages and lower abundances of T cells compared to the non-ALS twin. Higher macrophage signature in the ALS twin was also shown by RNA sequencing (RNA-seq). Moreover, the twins differed in the methylome at loci near several genes, including EGFR and TNFRSF11A, and in the pathways related to the tretinoin and H3K27me3 markers. We also tested cytokine production by PBMCs. The ALS twin's PBMCs spontaneously produced IL-6 and TNF-α, whereas PBMCs of the healthy twin produced these cytokines only when stimulated by superoxide dismutase (SOD)-1. These results and flow cytometric detection of CD45 and CD127 suggest the presence of memory T cells in both twins, but effector T cells only in the ALS twin. The ALS twin's PBMC supernatants, but not the healthy twin's, were toxic to rat cortical neurons, and this toxicity was strongly inhibited by an IL-6 receptor antibody (tocilizumab) and less well by TNF-α and IL-1β antibodies. The putative neurotoxicity of IL-6 and TNF-α is in agreement with a high expression of these cytokines on infiltrating macrophages in the ALS spinal cord. We hypothesize that higher macrophage abundance and increased neurotoxic cytokines have a fundamental role in the phenotype and treatment of certain individuals with ALS.-Lam, L., Chin, L., Halder, R. C., Sagong, B., Famenini, S., Sayre, J., Montoya, D., Rubbi L., Pellegrini, M., Fiala, M. Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients. © FASEB.

Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients

PubMed Central

Lam, Larry; Chin, Lydia; Halder, Ramesh C.; Sagong, Bien; Famenini, Sam; Sayre, James; Montoya, Dennis; Rubbi, Liudmilla; Pellegrini, Matteo; Fiala, Milan

2016-01-01

We have investigated transcriptional and epigenetic differences in peripheral blood mononuclear cells (PBMCs) of monozygotic female twins discordant in the diagnosis of amyotrophic lateral sclerosis (ALS). Exploring DNA methylation differences by reduced representation bisulfite sequencing (RRBS), we determined that, over time, the ALS twin developed higher abundances of the CD14 macrophages and lower abundances of T cells compared to the non-ALS twin. Higher macrophage signature in the ALS twin was also shown by RNA sequencing (RNA-seq). Moreover, the twins differed in the methylome at loci near several genes, including EGFR and TNFRSF11A, and in the pathways related to the tretinoin and H3K27me3 markers. We also tested cytokine production by PBMCs. The ALS twin’s PBMCs spontaneously produced IL-6 and TNF-α, whereas PBMCs of the healthy twin produced these cytokines only when stimulated by superoxide dismutase (SOD)-1. These results and flow cytometric detection of CD45 and CD127 suggest the presence of memory T cells in both twins, but effector T cells only in the ALS twin. The ALS twin’s PBMC supernatants, but not the healthy twin’s, were toxic to rat cortical neurons, and this toxicity was strongly inhibited by an IL-6 receptor antibody (tocilizumab) and less well by TNF-α and IL-1β antibodies. The putative neurotoxicity of IL-6 and TNF-α is in agreement with a high expression of these cytokines on infiltrating macrophages in the ALS spinal cord. We hypothesize that higher macrophage abundance and increased neurotoxic cytokines have a fundamental role in the phenotype and treatment of certain individuals with ALS.—Lam, L., Chin, L., Halder, R. C., Sagong, B., Famenini, S., Sayre, J., Montoya, D., Rubbi L., Pellegrini, M., Fiala, M. Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients. PMID:27368295

The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brains

PubMed Central

Conlon, Erin G; Lu, Lei; Sharma, Aarti; Yamazaki, Takashi; Tang, Timothy; Shneider, Neil A; Manley, James L

2016-01-01

An expanded GGGGCC hexanucleotide in C9ORF72 (C9) is the most frequent known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It has been proposed that expanded transcripts adopt G-quadruplex (G-Q) structures and associate with proteins, but whether this occurs and contributes to disease is unknown. Here we show first that the protein that predominantly associates with GGGGCC repeat RNA in vitro is the splicing factor hnRNP H, and that this interaction is linked to G-Q formation. We then show that G-Q RNA foci are more abundant in C9 ALS patient fibroblasts and astrocytes compared to those without the expansion, and more frequently colocalize with hnRNP H. Importantly, we demonstrate dysregulated splicing of multiple known hnRNP H-target transcripts in C9 patient brains, which correlates with elevated insoluble hnRNP H/G-Q aggregates. Together, our data implicate C9 expansion-mediated sequestration of hnRNP H as a significant contributor to neurodegeneration in C9 ALS/FTD. DOI: http://dx.doi.org/10.7554/eLife.17820.001 PMID:27623008

The incidence and survival of acute de novo leukaemias in Estonia and in a well-defined region of western Sweden during 1982-1996: a survey of patients aged > or =65 years.

PubMed

Luik, E; Palk, K; Everaus, H; Varik, M; Aareleid, T; Wennström, L; Juntikka, E-L; Safai-Kutti, S; Stockelberg, D; Holmberg, E; Kutti, J

2004-07-01

To compare the incidence and survival of acute de novo leukaemias with particular reference to political/socio-economic and environmental factors in two neighbouring countries over the three 5-year periods (1982-1996). The present report covers only patients diagnosed when aged > or =65 years. A well-defined area of Sweden, the so-called Western Swedish Health Care Region and Estonia. Population-wise, the western Swedish Region and Estonia are very similar; area-wise they are also well comparable. The number of acute de novo leukaemias was quite dissimilar in the two countries (Estonia, n = 137, Sweden, n = 354). The age standardized incidence rates regarding the total number of acute de novo leukaemias was 5.31 per 100,000 inhabitants/year for Estonia and 7.99 for Sweden, this difference being statistically significant. However, the difference was merely attributable to incidence rates as regards acute myeloblastic leukaemias (AML); on the contrary, differences as regards acute lymphoblastic leukaemias (ALL) and non-classifiable, undifferentiated or biphenotypic acute leukaemias (uAL) were negligible. The relative survival for the total material of patients was significantly higher for Swedish when compared with Estonian patients (P < 0.001). Thus, the relative survival for the total material of patients aged > or =65 years in Estonia at 1 year was 8.5% and at 3 years 3.5% respectively. The corresponding figures for the Swedish patients were considerably higher, 22.7 and 7.7% respectively. This difference, however, applied only for patients with AML (P < 0.001), whereas the results for patients with ALL and uAL were equally dismal. The results clearly reflect how political and socio-economic factors may influence the survival of acute leukemia patients in two neighbouring countries.

Cloud-assisted mutual authentication and privacy preservation protocol for telecare medical information systems.

PubMed

Li, Chun-Ta; Shih, Dong-Her; Wang, Chun-Cheng

2018-04-01

 With the rapid development of wireless communication technologies and the growing prevalence of smart devices, telecare medical information system (TMIS) allows patients to receive medical treatments from the doctors via Internet technology without visiting hospitals in person. By adopting mobile device, cloud-assisted platform and wireless body area network, the patients can collect their physiological conditions and upload them to medical cloud via their mobile devices, enabling caregivers or doctors to provide patients with appropriate treatments at anytime and anywhere. In order to protect the medical privacy of the patient and guarantee reliability of the system, before accessing the TMIS, all system participants must be authenticated.  Mohit et al. recently suggested a lightweight authentication protocol for cloud-based health care system. They claimed their protocol ensures resilience of all well-known security attacks and has several important features such as mutual authentication and patient anonymity. In this paper, we demonstrate that Mohit et al.'s authentication protocol has various security flaws and we further introduce an enhanced version of their protocol for cloud-assisted TMIS, which can ensure patient anonymity and patient unlinkability and prevent the security threats of report revelation and report forgery attacks.  The security analysis proves that our enhanced protocol is secure against various known attacks as well as found in Mohit et al.'s protocol. Compared with existing related protocols, our enhanced protocol keeps the merits of all desirable security requirements and also maintains the efficiency in terms of computation costs for cloud-assisted TMIS.  We propose a more secure mutual authentication and privacy preservation protocol for cloud-assisted TMIS, which fixes the mentioned security weaknesses found in Mohit et al.'s protocol. According to our analysis, our authentication protocol satisfies most functionality features for privacy preservation and effectively cope with cloud-assisted TMIS with better efficiency. Copyright © 2018 Elsevier B.V. All rights reserved.

Impact of an early respiratory care programme with non-invasive ventilation adaptation in patients with amyotrophic lateral sclerosis.

PubMed

Vitacca, M; Montini, A; Lunetta, C; Banfi, P; Bertella, E; De Mattia, E; Lizio, A; Volpato, E; Lax, A; Morini, R; Paneroni, M

2018-03-01

Forced vital capacity (FVC) <80% is one of the key indications for starting non-invasive ventilation (NIV) in amyotrophic lateral sclerosis (ALS). It was hypothesized that a very early start of NIV could lengthen the free interval before death compared to later-start NIV; as a secondary outcome, the survival rate of patients on NIV without tracheotomy was also evaluated. This retrospective study was conducted on 194 ALS patients, divided into a later group (LG) with FVC <80% at NIV prescription (n = 129) and a very early group (VEG) with FVC ≥80% at NIV prescription (n = 65). Clinical and respiratory functional data and time free to death between groups over a 3-year follow-up were compared. At 36 months from diagnosis, mortality was 35% for the VEG versus 52.7% for the LG (P = 0.022). Kaplan-Meier survival curves adjusted for tracheotomy showed a lower probability of death (P = 0.001) for the VEG as a whole (P = 0.001) and for the non-bulbar (NB) subgroup (P = 0.007). Very early NIV was protective of survival for all patients [hazard ratio (HR) 0.45; 95% confidence interval (CI) 0.28-0.74; P = 0.001] and for the NB subgroup (HR 0.43; 95% CI 0.23-0.79; P = 0.007), whilst a tracheotomy was protective for all patients (HR 0.27; 95% CI 0.15-0.50; P = 0.000) and both NB (HR 0.26; 95% CI 0.12-0.56; P = 0.001) and bulbar subgroups (HR 0.29; 95% CI 0.11-0.77; P = 0.013). Survival in VEG patients on NIV without tracheotomy was three times that for the LG (43.1% vs. 14.7%). Very early NIV prescription prolongs the free time from diagnosis to death in NB ALS patients whilst tracheotomy reduces the mortality risk in all patients. © 2017 EAN.

Tracheostomy mechanical ventilation in patients with amyotrophic lateral sclerosis: clinical features and survival analysis.

PubMed

Spataro, Rossella; Bono, Valeria; Marchese, Santino; La Bella, Vincenzo

2012-12-15

Tracheostomy mechanical ventilation (TMV) is performed in amyotrophic lateral sclerosis (ALS) patients with a respiratory failure or when the non-invasive ventilation (NIV) is no longer effective. We evaluated the clinical characteristics and survival of a cohort of tracheostomized ALS patients, followed in a single ALS Clinical Center. Between 2001 and 2010, 87 out of 279 ALS patients were submitted to TMV. Onset was spinal in 62 and bulbar in 25. After tracheostomy, most patients were followed up through telephone interviews to caregivers. A complete survival analysis could be performed in fifty-two TMV patients. 31.3% ALS patients underwent tracheostomy, with a male prevalence (M/F=1.69) and a median age of 61 years (interquartile range=47-66). After tracheostomy, nearly all patients were under home care. TMV ALS patients were more likely than non-tracheostomized (NT) patients to be implanted with a PEG device, although the bulbar-/spinal-onset ratio did not differ between the two groups. Kaplan-Meyer analysis showed that tracheostomy increases median survival (TMV, 47 months vs NT, 31 months, p=0.008), with the greatest effect in patients younger than 60 at onset (TMV ≤ 60 years, 57.5 months vs NT ≤ 60 years, 38.5 months, p=0.002). TMV is increasingly performed in ALS patients. Nearly all TMV patients live at home and most of them are fed through a PEG device. Survival after tracheostomy is generally increased, with the stronger effect in patients younger than 60. This survival advantage is apparently lost when TMV is performed in patients older than 60. The results of this study might be useful for the decision-making process of patients and their families about this advanced palliative care. Copyright © 2012. Published by Elsevier B.V.

Data showing levels of interleukin-1β and nitric oxide in the plasma of uropathogenic E. coli infected UTI patients.

PubMed

Verma, Vivek; Arora, Renu; Dhanda, Rakesh Singh; Gaind, Rajni; Yadav, Manisha

2018-08-01

Urinary tract infections (UTI) are a major cause of morbidity, affecting at least four million women worldwide, 65-75% of these infections are caused by Uropathogenic Escherichia coli (UPEC) (Foxman, 2010) [1]. Repertoire of virulence factors carried by UPEC provides the ability to precede urinary tract and additionally they provoke pro-inflammatory responses (Cirl et al., 2008; Verma et al., 2016) [2], [3]. In context to UPEC infected UTI patients, the levels of pro-inflammatory cytokine IL-1β and enzymatic antioxidant nitric oxide (NO) have not been reported worldwide till date, including India. In this data article, we report for the first time the levels of IL-1β and nitric oxide in the plasma of UPEC infected UTI patients. Data includes a profile of pro-inflammatory cytokine IL-1β and NO in the plasma of the confirmed UPEC infected UTI patients ( N  = 30) versus healthy controls ( N  = 40) from the present pilot study. The levels of IL-1β in plasma were significantly higher ( p  < 0.0001) in patients (252.3 ± 6.49 pg/ml) as compared to healthy controls (127.6 ± 3.98 pg/ml), whereas plasma levels of NO were significantly lower ( p  < 0.0001) in UPEC infected UTI patients (60.29 ± 1.1 μM) as compared to healthy controls (106.3 ± 8.75 μM).

Impact of health education on compliance among patients of chronic diseases in Al Qassim, Saudi Arabia.

PubMed

Sharaf, Fawzy

2010-11-01

The aim of this study is to assess the impact of health education on diet, smoking and exercise among patients with chronic diseases (coronary artery disease, hypertension and type 2 diabetes mellitus) in Al Qassim Region in Saudi Arabia. We used data from a clustered experimental study in selected primary health care (PHC) centers in Al-Qassim. The study was conducted during January to October 2009 to assess the impact of an enhanced health education program on smoking, diet and exercise. The intervention comprised refresher training of PHC centers' staff to improve communication skills and use of health education materials. Special health education sessions in the PHC centers were also organized with the help of medical students from Qassim University. Target population included patients of chronic diseases as well as patients visiting for other complaints. Baseline and end-line surveys were conducted to assess the impact of health education program on the prevalence of smoking, unhealthy diet and physical inactivity. The sample size was estimated to detect the impact of health education on these risk factors. Data were analyzed using SPSS (version 11.5) to conduct multivariate analysis to assess the impact of health education among chronic disease patients. At baseline, chronic disease patients had generally healthier diet and did more exercise than patients of other diseases. Among chronic disease patients, significant improvements in smoking, diet and exercise habits were observed at end-line survey compared to baseline. These changes persisted after controlling for age, sex, marital status and education. We conclude that health education for patients visiting the PHC centers for follow-up of chronic diseases will significantly improve compliance to doctor's advice regarding smoking, diet and exercise.

Burden of rare variants in ALS genes influences survival in familial and sporadic ALS.

PubMed

Pang, Shirley Yin-Yu; Hsu, Jacob Shujui; Teo, Kay-Cheong; Li, Yan; Kung, Michelle H W; Cheah, Kathryn S E; Chan, Danny; Cheung, Kenneth M C; Li, Miaoxin; Sham, Pak-Chung; Ho, Shu-Leong

2017-10-01

Genetic variants are implicated in the development of amyotrophic lateral sclerosis (ALS), but it is unclear whether the burden of rare variants in ALS genes has an effect on survival. We performed whole genome sequencing on 8 familial ALS (FALS) patients with superoxide dismutase 1 (SOD1) mutation and whole exome sequencing on 46 sporadic ALS (SALS) patients living in Hong Kong and found that 67% had at least 1 rare variant in the exons of 40 ALS genes; 22% had 2 or more. Patients with 2 or more rare variants had lower probability of survival than patients with 0 or 1 variant (p = 0.001). After adjusting for other factors, each additional rare variant increased the risk of respiratory failure or death by 60% (p = 0.0098). The presence of the rare variant was associated with the risk of ALS (Odds ratio 1.91, 95% confidence interval 1.03-3.61, p = 0.03), and ALS patients had higher rare variant burden than controls (MB, p = 0.004). Our findings support an oligogenic basis with the burden of rare variants affecting the development and survival of ALS. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Chromogranin A levels in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

PubMed

Verde, Federico; Steinacker, Petra; Oeckl, Patrick; Weishaupt, Jochen H; Rosenbohm, Angela; Silani, Vincenzo; Ludolph, Albert C; Otto, Markus

2018-07-01

Chromogranin A (CgA) is a protein found in large dense-core vesicles of neuroendocrine cells and neurons and regulating secretion. A relevance to amyotrophic lateral sclerosis (ALS) was suggested as its overexpression accelerates disease onset in model systems and it interacts with mutant forms of SOD1. Recently, increased cerebrospinal fluid (CSF) CgA levels have been reported in ALS patients relative to controls. With the aim of confirming this finding, we measured CgA and phosphorylated neurofilament heavy chain (pNFH), an established ALS biomarker, in the CSF of 32 ALS patients and 32 disease controls. ALS patients had clearly increased pNFH levels (p < 0.0001), while CgA levels were only modestly lower relative to controls (p = 0.0265), with wide value overlap and consequently poor discriminative performance. CgA did not correlate with any disease parameters among ALS patients. Our findings suggest that CgA is not a promising clinical biomarker for ALS. Copyright © 2018 Elsevier Inc. All rights reserved.

Provision of assistive technology devices among people with ALS in Germany: a platform-case management approach.

PubMed

Funke, Andreas; Spittel, Susanne; Grehl, Torsten; Grosskreutz, Julian; Kettemann, Dagmar; Petri, Susanne; Weyen, Ute; Weydt, Patrick; Dorst, Johannes; Ludolph, Albert C; Baum, Petra; Oberstadt, Moritz; Jordan, Berit; Hermann, Andreas; Wolf, Joachim; Boentert, Matthias; Walter, Bertram; Gajewski, Nadine; Maier, André; Münch, Christoph; Meyer, Thomas

2018-01-30

The procurement of assistive technology devices (ATD) is an essential component of managed care in ALS. The objective was to analyze the standards of care for ATD and to identify challenges in the provision process. A cohort study design was used. We investigated the provision of 11,364 ATD in 1494 patients with ALS at 12 ALS centers in Germany over four years. Participants were patients that entered a case management program for ATD including systematic assessment of ATD on a digital management platform. Wheelchairs (requested in 65% of patients), orthoses (52%), bathroom adaptations (49%), and communication devices (46%) were the most needed ATD. There was a wide range in the number of indicated ATD per patient: 1 to 4 ATD per patient in 45% of patients, 5 to 20 ATD in 48%, and >20 ATD in 7% of patients. Seventy percent of all requested ATD were effectively delivered. However, an alarming failure rate during procurement was found in ATD that are crucial for ALS patients such as powered wheelchairs (52%), communication devices (39%), or orthoses (21%). Leading causes for not providing ATD were the refusal by health insurances, the decision by patients, and the death of the patient before delivery of the device. The need for ATD was highly prevalent among ALS patients. Failed or protracted provision posed substantial barriers to ATD procurement. Targeted national strategies and the incorporation of ATD indication criteria in international ALS treatment guidelines are urgently needed to overcome these barriers.

Laryngeal response patterns influence the efficacy of mechanical assisted cough in amyotrophic lateral sclerosis

PubMed Central

Andersen, Tiina; Sandnes, Astrid; Brekka, Anne Kristine; Hilland, Magnus; Clemm, Hege; Fondenes, Ove; Tysnes, Ole-Bjørn; Heimdal, John-Helge; Halvorsen, Thomas; Vollsæter, Maria; Røksund, Ola Drange

2017-01-01

Background Most patients with amyotrophic lateral sclerosis (ALS) are treated with mechanical insufflation–exsufflation (MI-E) in order to improve cough. This method often fails in ALS with bulbar involvement, allegedly due to upper-airway malfunction. We have studied this phenomenon in detail with laryngoscopy to unravel information that could lead to better treatment. Methods We conducted a cross-sectional study of 20 patients with ALS and 20 healthy age-matched and sex-matched volunteers. We used video-recorded flexible transnasal fibre-optic laryngoscopy during MI-E undertaken according to a standardised protocol, applying pressures of ±20 to ±50 cm H2O. Laryngeal movements were assessed from video files. ALS type and characteristics of upper and lower motor neuron symptoms were determined. Results At the supraglottic level, all patients with ALS and bulbar symptoms (n=14) adducted their laryngeal structures during insufflation. At the glottic level, initial abduction followed by subsequent adduction was observed in all patients with ALS during insufflation and exsufflation. Hypopharyngeal constriction during exsufflation was observed in all subjects, most prominently in patients with ALS and bulbar symptoms. Healthy subjects and patients with ALS and no bulbar symptoms (n=6) coordinated their cough well during MI-E. Conclusions Laryngoscopy during ongoing MI-E in patients with ALS and bulbar symptoms revealed laryngeal adduction especially during insufflation but also during exsufflation, thereby severely compromising the size of the laryngeal inlet in some patients. Individually customised settings can prevent this and thereby improve and extend the use of non-invasive MI-E. PMID:27174631

[Clinical polymorphism of amyotrophic lateral sclerosis].

PubMed

Kovrazhkina, E A; Razinskaya, O D; Gubsky, L V

To clarify clinical polymorphism of amyotrophic lateral sclerosis (ALS). The study was based on records of a hospital personalized register. Ninety-four patients, aged from 25 to 81 years, diagnosed with ALS according to El Escorial criteria were included. Electromyography and, if necessary, transcranial magnetic stimulation and magnetic-resonance tomography were used to confirm the diagnosis. Disease progression was assessed with the ARSFRS. Age at disease onset, progression rate and duration of survival of patients, rare symptoms of ALS ('extramotor'), time for palliative care (gastrostomy, non-invasive and invasive lung ventilation) and provision of the care to the patient, family history were recorded in a specially designed questionnaire. Most of the patients had sporadic ALS, only two familial cases were identified. Spinal onset ALS was found in 66.0% of the patients, bulbar onset in 29.8%, diffuse onset (spinal and bulbar motor neurons were affected simultaneously) in 4.2%. Moderate ALS progression was observed in 42.6% of the patients, mean time till death was 3.0±1.2 years. A slow progression was found in patients with cervical, low back and bulbar onset. A rapid and even 'momentary' type of progression was in diffuse and breast onset. An extremely slow progression with the long-term hospital treatment and survival >5 years was found in 9.7%. Rare ALS symptoms were represented by specific cognitive and psychological impairments, a type of frontal/temporal dysfunction, but only 5 (5.3%) patients were diagnosed with ALS-dementia. Signs of pathological muscle fatigue (myasthenic syndrome) were identified in 18 (19.1%), extrapyramidal disorders in 5 (5.3%), coordination disorders in 4 (4.3%), pain in 12 (12.8%), sensory symptoms in 5 (5.3%) of the patients. ALS is a multisystemic neurodegeneration disease though the progressive motor neuron death determines the fatal outcome.

Head injury does not alter disease progression or neuropathologic outcomes in ALS.

PubMed

Fournier, Christina N; Gearing, Marla; Upadhyayula, Saila R; Klein, Mitch; Glass, Jonathan D

2015-04-28

To study the effects of head injury on disease progression and on neuropathologic outcomes in amyotrophic lateral sclerosis (ALS). Patients with ALS were surveyed to obtain head injury history, and medical records were reviewed. Linear regression was performed to determine if head injury was a predictor for mean monthly decline of Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R), while controlling for confounders. Head injury history was obtained from family members of ALS autopsy cases. The frequency of tau proteinopathy, brain TDP-43 inclusions, and pathologic findings of Alzheimer disease (AD) were examined in ALS cases with head injury compared to cases without. Logistic regression was performed with each neuropathologic diagnosis as an outcome measure and head injury as a predictor variable. No difference was seen in rate of decline of the ALSFRS-R between patients with head injury (n = 24) and without (n = 76), with mean monthly decline of -0.9 for both groups (p = 0.18). Of 47 ALS autopsy cases (n = 9 with head injury, n = 38 without), no significant differences were seen in the frequency of tau proteinopathy (11% with head injury; 24% without), TDP-43 in the brain (44% with head injury; 45% without), or AD pathology (33% with head injury; 26% without). Independent logistic regression models showed head injury was not a predictor of tau pathology (p = 0.42) or TDP-43 in the brain (p = 0.99). Head injury was not associated with faster disease progression in ALS and did not result in a specific neuropathologic phenotype. The tau pathology described with chronic traumatic encephalopathy was found in ALS autopsy cases both with and without head injury. © 2015 American Academy of Neurology.

Impact on children of a parent with ALS: a case-control study.

PubMed

Calvo, Vincenzo; Bianco, Francesca; Benelli, Enrico; Sambin, Marco; Monsurrò, Maria R; Femiano, Cinzia; Querin, Giorgia; Sorarù, Gianni; Palmieri, Arianna

2015-01-01

Numerous studies have explored how patients and their caregivers cope with amyotrophic lateral sclerosis (ALS), but the literature completely lacks research on the psychological impact of the disease on patients' children. The aim of our study was to investigate the emotional and psychological impact of a parent with ALS on school-age children and adolescents in terms of problem behavior, adjustment, and personality characteristics. The study involved 23 children (mean age = 10.62 years, six females) with a parent suffering from ALS, and both their parents. Children were matched for age, gender, and birth-order with a control group of children with healthy parents. They were administered the Youth Self Report (YSR) questionnaire and the Rorschach Comprehensive System, and their healthy parent completed the Child Behavior Checklist (CBCL). Findings clearly showed that, compared with controls, children with a parent who had ALS had several clinically significant adverse emotional and behavioral consequences, with emotional and behavioral problems, internalizing problems, anxiety and depressive symptoms. Children of a parent with ALS scored higher than controls for the Total Problems, Internalizing Problems, Anxious/Depressed and Withdrawn/Depressed scales in the YSR. A relevant percentage of children fell within the clinical range (42.9%) and borderline range (28.6%) for Internalizing Problems. The Rorschach CS confirmed the substantial impact of ALS in a parent on their offspring in terms of internalizing behavior and depression, with adjustment difficulties, psychological pain, and thought problems. Our findings indicate that school-aged children and adolescents with a parent who has ALS are vulnerable and carry a substantially higher risk of internalizing behavior, depressive symptoms, and reactive problems than children with healthy parents. Families affected may need support to cope with such an overwhelming disease.

Phenotypic and genotypic studies of ALS cases in ALS-SMA families.

PubMed

Corcia, Philippe; Vourc'h, Patrick; Blasco, Helene; Couratier, Philippe; Dangoumau, Audrey; Bellance, Remi; Desnuelle, Claude; Viader, Fausto; Pautot, Vivien; Millecamps, Stephanie; Bakkouche, Salah; Salachas, FranÇois; Andres, Christian R; Meininger, Vincent; Camu, William

2018-08-01

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most frequent motor neuron disorders in adulthood and infancy, respectively. There is a growing literature supporting common pathophysiological patterns between those disorders. One important clinical issue for that is the co-occurrence of both diseases within a family. To collect families in which ALS and SMA patients co-exist and describe the phenotype and the genotype of ALS patients. Nine families with co-occurrence of SMA and ALS have been gathered over the last 15 years. Epidemiological, phenotype and genetic status were collected. Out of the nine families, six corresponded to the criteria of familial ALS (FALS). Clinical data were available for 11 patients out of the 15 ALS cases. Mean age of onset was 58.5 years, site of onset was lower limbs in nine cases (81.8%), median duration was 22 months. Four ALS patients carried a mutation: three mutations in SOD1 gene (G147N in two cases and one with E121G) and one repeat expansion in the C9ORF72 gene. Three patients had abnormal SMN1 copy numbers. While the high proportion of familial history of ALS cases in these ALS-SMA pedigrees could have suggested that these familial clusters of the two most frequent MND rely on a genetic background, we failed to exclude that this occurred by chance.

SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis.

PubMed

Le Ber, Isabelle; Camuzat, Agnès; Guerreiro, Rita; Bouya-Ahmed, Kawtar; Bras, Jose; Nicolas, Gael; Gabelle, Audrey; Didic, Mira; De Septenville, Anne; Millecamps, Stéphanie; Lenglet, Timothée; Latouche, Morwena; Kabashi, Edor; Campion, Dominique; Hannequin, Didier; Hardy, John; Brice, Alexis

2013-11-01

Mutations in the SQSTM1 gene, coding for p62, are a cause of Paget disease of bone and amyotrophic lateral sclerosis (ALS). Recently, SQSTM1 mutations were confirmed in ALS, and mutations were also identified in 3 patients with frontotemporal dementia (FTD), suggesting a role for SQSTM1 in FTD. To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients. A SQSTM1 mutation was first identified in a multiplex family with FTD by use of whole-exome sequencing. To evaluate the frequency of SQSTM1 mutations, we sequenced this gene in a cohort of patients with FTD or FTD-ALS, with no mutations in known FTD and ALS genes. Primary care or referral center. An overall cohort of 188 French patients, including 132 probands with FTD and 56 probands with FTD-ALS. Frequency of SQSTM1 mutations in patients with FTD or FTD-ALS; description of associated phenotypes. We identified 4 heterozygous missense mutations in 4 unrelated families with FTD; only 1 family had clinical symptoms of Paget disease of bone, and only 1 family had clinical symptoms of FTD-ALS, possibly owing to the low penetrance of some of the clinical manifestations. Although the frequency of the mutations is low in our series (4 of 188 patients [2%]), our results, similar to those already reported, support a direct pathogenic role of p62 in different types of FTD.

Semantic memory assessment in 15 patients with amyotrophic lateral sclerosis.

PubMed

Hervieu-Bègue, M; Rouaud, O; Graule Petot, A; Catteau, A; Giroud, M

2016-01-01

A total of 30 to 50% of amyotrophic lateral sclerosis patients suffer from cognitive disorders. The aim of the study is to characterize these disorders and to assess semantic memory in non-demented ALS patients. The secondary aim is to look for a link between disease type and neuropsychological characteristics. Patients were followed in an ALS center in Dijon. The following neuropsychological tests were used in this study: Folstein test, BREF test, verbal fluency, Isaac test, GRESEM test and TOP 30 test. Fifteen ALS patients were included. Nine of them (60%) were suffering from a semantic memory disorder. There was no correlation between ALS characteristics and the semantic memory disorder. This is the first study to reveal a semantic memory disorder in ALS. This result accentuates the hypothesis that ALS and semantic dementia are two phenotypes of the same degenerative process linked to TDP 43 proteinopathy. Copyright © 2016. Published by Elsevier Masson SAS.

Low IDL-B and high LDL-1 subfraction levels in serum of ALS patients.

PubMed

Delaye, J B; Patin, F; Piver, E; Bruno, C; Vasse, M; Vourc'h, P; Andres, C R; Corcia, P; Blasco, H

2017-09-15

Converging evidence highlights that lipid metabolism plays a key role in ALS pathophysiology. Dyslipidemia has been described in ALS patients and may be protective but peripheral lipoprotein subclasses have never been studied. We collected sera from 30 ALS patients and 30 gender and age-matched controls. We analyzed 11 distinct lipoprotein subclasses by linear polyacrylamide gel electrophoresis (Lipoprint, Quantimetrix Corporation, USA). We also measured lipoprotein (a), apolipoprotein B, and apolipoprotein E levels. ALS patients had significant higher total cholesterol, HDL-cholesterol, and LDL-cholesterol levels than controls (p<0.0001, p=0.0007, and p=0.0065, respectively). The LDL-1 subfraction concentration was higher (1.03±0.41 vs. 0.71±0.28mmol/L; p=0.0006) and the IDL-B subfraction lower (6.5±2% vs. 8.0±2%; p=0.001) in ALS patients than controls. Our preliminary work confirmed the association between ALS and dyslipidemia. The low IDL-B levels may explain the hepatic steatosis frequently reported in ALS. The high levels of the cholesterol-rich LDL-1 subfraction is consistent with previously reported hypercholesterolemia. This study describes, for the first time, the distribution of serum lipoproteins in ALS patients, with low IDL-B and high LDL-1 subfraction level. Copyright © 2017 Elsevier B.V. All rights reserved.

Characteristics of pain in amyotrophic lateral sclerosis

PubMed Central

Hanisch, Frank; Skudlarek, Anika; Berndt, Janine; Kornhuber, Malte E

2015-01-01

Background Pain is an often underestimated and neglected symptom in amyotrophic lateral sclerosis (ALS). Methods In a cross-sectional survey, 46 patients with ALS, 46 age- and gender matched population-based controls, and 23 diseased controls with myotonic dystrophy type 2 (DM2) were screened for occurrence, type, distribution, and treatment of pain and cramps. Data were collected with the use of the short form brief pain inventory (BPI). Results Pain was reported in 78% of ALS patients,79% of DM2 patients, and 54% of controls (P < 0.05). More ALS patients than controls reported moderate to severe pain (42% vs. 20%). Pain in ALS patients interfered significantly more with daily activities than in controls (median pain interference score: 3.0 vs. 1.2, P < 0.05), especially enjoyment of life (5.0 vs. 1.0) and mood (3.0 vs. 1.0). There was no correlation between the duration of the disease and the severity of pain. Movement-induced cramps were reported in 63% of ALS patients, mostly in the distal extremities. There was no difference in the duration of ALS disease between patients reporting cramps and those who did not. Discussion Our study showed that pain was a relatively frequent symptom which had an important impact on the quality of life. Pain that requires treatment can occur at every stage of ALS. PMID:25642388

Cost-effectiveness of artemisinin-naphthoquine versus artemether-lumefantrine for the treatment of uncomplicated malaria in Papua New Guinean children.

PubMed

Moore, Brioni R; Davis, Wendy A; Clarke, Philip M; Robinson, Leanne J; Laman, Moses; Davis, Timothy M E

2017-10-30

A recent randomized trial showed that artemisinin-naphthoquine (AN) was non-inferior to artemether-lumefantrine (AL) for falciparum malaria and superior for vivax malaria in young Papua New Guinean children. The aim of this study was to compare the cost-effectiveness of these two regimens. An incremental cost-effectiveness analysis was performed using data from 231 children with Plasmodium falciparum and/or Plasmodium vivax infections in an open-label, randomized, parallel-group trial. Recruited children were randomized 1:1 to receive once daily AN for 3 days with water or twice daily AL for 3 days given with fat. World Health Organisation (WHO) definitions were used to determine clinical/parasitological outcomes. The cost of transport between the home and clinic, plus direct health-care costs, served as a basis for determining each regimen's incremental cost per incremental treatment success relative to AL by Day 42 and its cost per life year saved. In the usual care setting, AN was more effective for the treatment of uncomplicated malaria in children aged 0.5-5.9 years. AL and AN were equally efficacious for the treatment of falciparum malaria, however AN had increased anti-malarial treatment costs per patient of $10.46, compared with AL. AN was the most effective regimen for treatment of vivax malaria, but had increased treatment costs of $14.83 per treatment success compared with AL. Whilst AN has superior overall efficacy for the treatment of uncomplicated malaria in PNG children, AL was the less costly regimen. An indicative extrapolation estimated the cost per life year saved by using AN instead of AL to treat uncomplicated malaria to be $12,165 for girls and $12,469 for boys (discounted), which means AN may not be cost-effective and affordable for PNG at current cost. However, AN may become acceptable should it become WHO prequalified and/or should donated/subsidized drug supply become available.

Long-term outcome for Down syndrome patients with hematopoietic disorders.

PubMed

Li, Meng-Ju; Lee, Ni-Chung; Yang, Yung-Li; Yen, Hsiu-Ju; Chang, Hsiu-Hao; Chien, Yin-Hsiu; Lu, Meng-Yao; Jou, Shiann-Tarng; Lin, Kai-Hsin; Hwu, Wuh-Liang; Lin, Dong-Tsamn

2016-02-01

Although Down syndrome (DS) patients have a higher risk of developing transient myeloproliferative disorder (TMD) and acute leukemia, very little data is available on long-term outcome in Taiwanese patients. The current study was designed to determine the clinical characteristics and treatment outcome of DS patients with TMD or acute leukemia (AL). In 25 consecutive DS patients with TMD or AL enrolled from 1990 to 2012, clinical manifestations and treatment protocols were investigated and GATA1 (GATA binding protein 1) mutations were identified. Among 16 DS-acute myeloid leukemia (DS-AML) patients, clinical outcomes were compared between survivors and nonsurvivors. Most of our DS patients had TMD (32%), acute megakaryoblastic leukemia (24%), or acute erythromegakaryoblastic leukemia (16%). The median follow-up time was 22.5 months (1-230 months). The age was younger and the hemoglobin (Hb) level and platelet count were higher in TMD patients than in leukemia patients. Among DS-AML patients, the Hb level was higher in survivors than nonsurvivors (8.8 ± 2.7 g/dL vs. 5.8 ± 2.4 g/dL; p = 0.044) and the age was older in relapsed patients than in nonrelapsed patients (43.8 ± 18 months old vs. 21.6 ± 8.6 months old; p = 0.025). The 3-year overall survival (OS) rate was 44%, higher in patients receiving appropriate chemotherapy than in those receiving inadequate treatment (63.6% vs. 0%, p = 0.001), and higher in those diagnosed with TMD or AL after 2008 than before 2008 (33.3% vs. 75%; p = 0.119). Outcome in DS-AML patients is optimal if appropriate treatment is provided. With modification of the treatment strategy in 2008, OS increased in Taiwan. Copyright © 2015. Published by Elsevier B.V.

Influence of arterial hypertension, type 2 diabetes and cardiovascular risk factors on ALS outcome: a population-based study.

PubMed

Moglia, Cristina; Calvo, Andrea; Canosa, Antonio; Bertuzzo, Davide; Cugnasco, Paolo; Solero, Luca; Grassano, Maurizio; Bersano, Enrica; Cammarosano, Stefania; Manera, Umberto; Pisano, Fabrizio; Mazzini, Letizia; Dalla Vecchia, Laura A; Mora, Gabriele; Chiò, Adriano

2017-11-01

To assess the prognostic influence of pre-morbid type 2 diabetes mellitus, arterial hypertension and cardiovascular (CV) risk profile on ALS phenotype and outcome in a population-based cohort of Italian patients. A total of 650 ALS patients from the Piemonte/Valle d'Aosta Register for ALS, incident in the 2007-2011 period, were recruited. Information about premorbid presence of type 2 diabetes mellitus, arterial hypertension was collected at the time of diagnosis. Patients' CV risk profile was calculated according to the Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice (JBS2). At the univariate analysis, the presence of pre-morbid arterial hypertension was associated with a higher age at onset of ALS and a shorter survival, and patients with a high CV risk profile had a worse prognosis than those with a low CV risk profile. The Cox multivariable analysis did not confirm such findings. Type 2 diabetes mellitus did not modify either the phenotype or the prognosis of ALS patients. This study performed on a large population-based cohort of ALS patients has demonstrated that arterial hypertension, type 2 diabetes and CV risk factors, calculated using the Framingham equation, do not influence ALS phenotype and prognosis.

Blue and UV fluorescence of biological fluids and carbon nanodots

NASA Astrophysics Data System (ADS)

Kuznetsov, A.; Frorip, A.; Ots-Rosenberg, M.; Sünter, A.

2013-11-01

Comparative optical study of biofluids (serum, urine, hemodialysate) and carbon nanodots (CND) aqueous solutions has been done. Biofluids were collected from chronic kidney diseases patients (CKD Pts) as well as from normal controls (NCs). Sugar derived CND and oxidized graphene solutions were prepared and used. Fluorescence and excitation spectra have mainly been measured and compared for two sets of subjects. For both family of subjects typical fluorescence with parameters λexсmax/ λemmax = 320+/-5/420+/-5 nm is observed and has many analogeous properties. New effective method of additional similarity identification with use of aluminum salts Al2 (SO4)3, Al (N03)3 and AlCl3 is proposed. Aluminum ions induce the fluorescence band at 380 nm in all substances investigated. Plenty of similar features (12) in optical properties create a united platform for further investigation of the topic - the nature of endogenous near UV and visible fluorescence in biofluids and CND.

ATXN2 is a modifier of phenotype in ALS patients of Sardinian ancestry

PubMed Central

Borghero, Giuseppe; Pugliatti, Maura; Marrosu, Francesco; Marrosu, Maria Giovanna; Murru, Maria Rita; Floris, Gianluca; Cannas, Antonino; Parish, Leslie D.; Cau, Tea B.; Loi, Daniela; Ticca, Anna; Traccis, Sebastiano; Manera, Umberto; Canosa, Antonio; Moglia, Cristina; Calvo, Andrea; Barberis, Marco; Brunetti, Maura; Renton, Alan E.; Nalls, Mike A.; Traynor, Bryan J.; Restagno, Gabriella; Chiò, Adriano

2016-01-01

Intermediate-length CAG expansions (encoding 27–33 glutamines, polyQ) of the Ataxin2 (ATXN2) gene represent a risk factor for amyotrophic lateral sclerosis (ALS). Recently, it has been proposed that ≥31 CAG expansions may influence ALS phenotype. We assessed whether ATXN2 intermediate-length polyQ expansions influence ALS phenotype in a series of 375 patients of Sardinian ancestry. Controls were 247 neurologically healthy subjects, resident in the study area, age- and gender-matched to cases. The frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (4 patients vs. no control, p = 0.0001). All patients with ≥31 polyQ repeats had a spinal onset versus 73.3% of patients with <31 polyQ repeats. Patients with an increased number of polyQ repeats have a shorter survival than those with <31 repeats (1.2 vs. 4.2 years, p = 0.035). In this large series of ALS patients of Sardinian ancestry, we have found that ≥31 polyQ repeats of the ATXN2 gene influenced patients' phenotype, being associated to a spinal onset and a significantly shorter survival. PMID:26208502

Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS.

PubMed

Luisier, Raphaelle; Tyzack, Giulia E; Hall, Claire E; Mitchell, Jamie S; Devine, Helen; Taha, Doaa M; Malik, Bilal; Meyer, Ione; Greensmith, Linda; Newcombe, Jia; Ule, Jernej; Luscombe, Nicholas M; Patani, Rickie

2018-05-22

Mutations causing amyotrophic lateral sclerosis (ALS) strongly implicate ubiquitously expressed regulators of RNA processing. To understand the molecular impact of ALS-causing mutations on neuronal development and disease, we analysed transcriptomes during in vitro differentiation of motor neurons (MNs) from human control and patient-specific VCP mutant induced-pluripotent stem cells (iPSCs). We identify increased intron retention (IR) as a dominant feature of the splicing programme during early neural differentiation. Importantly, IR occurs prematurely in VCP mutant cultures compared with control counterparts. These aberrant IR events are also seen in independent RNAseq data sets from SOD1- and FUS-mutant MNs. The most significant IR is seen in the SFPQ transcript. The SFPQ protein binds extensively to its retained intron, exhibits lower nuclear abundance in VCP mutant cultures and is lost from nuclei of MNs in mouse models and human sporadic ALS. Collectively, we demonstrate SFPQ IR and nuclear loss as molecular hallmarks of familial and sporadic ALS.

Funding agencies and disease organizations: resources and recommendations to facilitate ALS clinical research.

PubMed

Chad, David A; Bidichandani, Sanjay; Bruijn, Lucie; Capra, J Donald; Dickie, Brian; Ferguson, John; Figlewicz, Denise; Forsythe, Melissa; Kaufmann, Petra; Kirshner, Annette; Monti, William

2013-05-01

Ten groups presented their perspectives on facilitating clinical research in ALS including four federal agencies, four disease organizations, one foundation and one advocacy group. The federal agencies (National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, Office of Rare Diseases Research, Department of Defense) encourage fostering a team approach between pre-clinical and clinical research investigators, coordinating with patient groups in the early phases of clinical studies, enhancing private and public partnerships, and investigating the interplay between genetic susceptibility and environmental exposure. The disease organizations (Muscular Dystrophy Association, ALS Association, ALS Society of Canada, and the Motor Neurone Disease Association UK) support fellowship training programs to develop ALS clinician scientists, and encourage work on the epidemiology of ALS, on genetic and epigenetic mechanisms that are relevant to ALS pathogenesis, on developing ALS registries and biobanks, and building bridges of collaboration among study groups. The Foundation supports innovative projects, including stem-cell research, and Patient Advocacy is committed to supporting excellence in ALS research and patient care, and believes strongly in enhancing communication between patients and members of the research community.

Defective cholesterol metabolism in amyotrophic lateral sclerosis[S

PubMed Central

Abdel-Khalik, Jonas; Yutuc, Eylan; Crick, Peter J.; Gustafsson, Jan-Åke; Warner, Margaret; Roman, Gustavo; Talbot, Kevin; Gray, Elizabeth; Turner, Martin R.; Wang, Yuqin

2017-01-01

As neurons die, cholesterol is released in the central nervous system (CNS); hence, this sterol and its metabolites may represent a biomarker of neurodegeneration, including in amyotrophic lateral sclerosis (ALS), in which altered cholesterol levels have been linked to prognosis. More than 40 different sterols were quantified in serum and cerebrospinal fluid (CSF) from ALS patients and healthy controls. In CSF, the concentration of cholesterol was found to be elevated in ALS samples. When CSF metabolite levels were normalized to cholesterol, the cholesterol metabolite 3β,7α-dihydroxycholest-5-en-26-oic acid, along with its precursor 3β-hydroxycholest-5-en-26-oic acid and product 7α-hydroxy-3-oxocholest-4-en-26-oic acid, were reduced in concentration, whereas metabolites known to be imported from the circulation into the CNS were not found to differ in concentration between groups. Analysis of serum revealed that (25R)26-hydroxycholesterol, the immediate precursor of 3β-hydroxycholest-5-en-26-oic acid, was reduced in concentration in ALS patients compared with controls. We conclude that the acidic branch of bile acid biosynthesis, known to be operative in-part in the brain, is defective in ALS, leading to a failure of the CNS to remove excess cholesterol, which may be toxic to neuronal cells, compounded by a reduction in neuroprotective 3β,7α-dihydroxycholest-5-en-26-oic acid. PMID:27811233

KATP Channel Expression and Genetic Polymorphisms Associated with Progression and Survival in Amyotrophic Lateral Sclerosis.

PubMed

Vidal-Taboada, José M; Pugliese, Marco; Salvadó, Maria; Gámez, Josep; Mahy, Nicole; Rodríguez, Manuel J

2018-02-28

The ATP-sensitive potassium (K ATP ) channel directly regulates the microglia-mediated inflammatory response following CNS injury. To determine the putative role of the K ATP channel in amyotrophic lateral sclerosis (ALS) pathology, we investigated whether ALS induces changes in K ATP channel expression in the spinal cord and motor cortex. We also characterized new functional variants of human ABCC8, ABCC9, KCNJ8, and KCNJ11 genes encoding for the K ATP channel and analyzed their association with ALS risk, rate of progression, and survival in a Spanish ALS cohort. The expression of ABCC8 and KCNJ8 genes was enhanced in the spinal cord of ALS samples, and KCNJ11 increased in motor cortex of ALS samples, as determined by real-time polymerase chain reaction. We then sequenced the exons and regulatory regions of K ATP channel genes from a subset of 28 ALS patients and identified 50 new genetic variants. For the case-control association analysis, we genotyped five selected polymorphisms with predicted functional relevance in 185 Spanish ALS (134 spinal ALS and 51 bulbar ALS) patients and 493 controls. We found that bulbar ALS patients presenting the G/G genotype of the rs4148646 variant of ABCC8 and the T/T genotype of the rs5219 variant of KCNJ11 survived longer than other ALS patients presenting other genotypes. Also, the C/C genotype of the rs4148642 variant of ABCC8 and the T/C genotype of the rs148416760 variant of ABCC9 modified the progression rate in spinal ALS patients. Our results suggest that the K ATP channel plays a role in the pathophysiological mechanisms of ALS.

The effects of two different low level laser therapies in the treatment of patients with chronic low back pain: A double-blinded randomized clinical trial.

PubMed

Koldaş Doğan, Şebnem; Ay, Saime; Evcik, Deniz

2017-01-01

The purpose of this study was to compare the effectiveness of two different laser therapy regimens on pain, lumbar range of motions (ROM) and functional capacity in patients with chronic low back pain (CLBP). Forty nine patients with CLBP were randomly assigned into two groups. Group 1 (n= 20) received hot-pack + laser therapy 1 (wavelength of 850 nm Gallium-Aluminum-Arsenide (Ga-Al-As) laser); group 2 (n= 29) received hot-pack + laser therapy 2 (wavelength of 650 nm Helyum-Neon (He-Ne), 785 ve 980 nm Gal-Al-As combined plaque laser) for 15 sessions. Pain severity, patient's and physician's global assessments were evaluated with visual analogue scale (VAS). Modified Schober test, right and left lateral flexion measurements were done. Modified Oswestry Disability Questionnaire (MODQ) was used for evaluation of functional disability. Measurements were done before and after the treatment. After treatment there were statistically significant improvements in pain severity, patient's and physician's global assessment, ROM and MODQ scores in both groups (P< 0.05). After the treatment there were statistically significant differences between the groups in lateral flexion measurements and MODQ scores (P< 0.05) except in pain severity, Modified Schober test, patient's and physician's global assessments (P> 0.05) in favor of those patients who received combined plaque laser therapy (group 2). Laser therapy applied with combined He-Ne and Ga-Al-As provides more improvements in lateral flexion measurements and disability of the patients, however no superiority of the two different laser devices to one another were detected on pain severity.

Evaluating the levels of interleukin-1 family cytokines in sporadic amyotrophic lateral sclerosis.

PubMed

Italiani, Paola; Carlesi, Cecilia; Giungato, Paola; Puxeddu, Ilaria; Borroni, Barbara; Bossù, Paola; Migliorini, Paola; Siciliano, Gabriele; Boraschi, Diana

2014-05-23

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease leading to the death of affected individuals within years. The involvement of inflammation in the pathogenesis of neurodegenerative diseases, including ALS, is increasingly recognized but still not well understood. The aim of this study is to evaluate the levels of inflammation-related IL-1 family cytokines (IL-1β, IL-18, IL-33, IL-37) and their endogenous inhibitors (IL-1Ra, sIL-1R2, IL-18BP, sIL-1R4) in patients with sporadic ALS (sALS), METHODS: Sera were collected from 144 patients (125 patients were characterized by disease form, duration, and disability, using the revised ALS functional rating scale (ALSFRS-R) and from 40 matched controls. Cerebrospinal fluid (CSF) was collected from 54 patients with sALS and 65 patients with other non-infectious non-oncogenic diseases as controls. Cytokines and inhibitors were measured by commercial ELISA. Among the IL-1 family cytokines tested total IL-18, its endogenous inhibitor IL-18BP, and the active form of the cytokine (free IL-18) were significantly higher in the sALS sera than in controls. No correlation between these soluble mediators and different clinical forms of sALS or the clinical setting of the disease was found. IL-18BP was the only mediator detectable in the CSF of patients. Among the IL-1 family cytokines, only IL-18 correlates with this disease and may therefore have a pathological role in sALS. The increase of total IL-18 suggests the activation of IL-18-cleaving inflammasome. Whether IL-18 upregulation in circulation of sALS patients is a consequence of inflammation or one of the causes of the pathology still needs to be addressed.

Evaluating the levels of interleukin-1 family cytokines in sporadic amyotrophic lateral sclerosis

PubMed Central

2014-01-01

Background Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease leading to the death of affected individuals within years. The involvement of inflammation in the pathogenesis of neurodegenerative diseases, including ALS, is increasingly recognized but still not well understood. The aim of this study is to evaluate the levels of inflammation-related IL-1 family cytokines (IL-1β, IL-18, IL-33, IL-37) and their endogenous inhibitors (IL-1Ra, sIL-1R2, IL-18BP, sIL-1R4) in patients with sporadic ALS (sALS), Methods Sera were collected from 144 patients (125 patients were characterized by disease form, duration, and disability, using the revised ALS functional rating scale (ALSFRS-R) and from 40 matched controls. Cerebrospinal fluid (CSF) was collected from 54 patients with sALS and 65 patients with other non-infectious non-oncogenic diseases as controls. Cytokines and inhibitors were measured by commercial ELISA. Results Among the IL-1 family cytokines tested total IL-18, its endogenous inhibitor IL-18BP, and the active form of the cytokine (free IL-18) were significantly higher in the sALS sera than in controls. No correlation between these soluble mediators and different clinical forms of sALS or the clinical setting of the disease was found. IL-18BP was the only mediator detectable in the CSF of patients. Conclusions Among the IL-1 family cytokines, only IL-18 correlates with this disease and may therefore have a pathological role in sALS. The increase of total IL-18 suggests the activation of IL-18-cleaving inflammasome. Whether IL-18 upregulation in circulation of sALS patients is a consequence of inflammation or one of the causes of the pathology still needs to be addressed. PMID:24884937

Potential Role of Gut Microbiota in ALS Pathogenesis and Possible Novel Therapeutic Strategies.

PubMed

Mazzini, Letizia; Mogna, Luca; De Marchi, Fabiola; Amoruso, Angela; Pane, Marco; Aloisio, Irene; Cionci, Nicole Bozzi; Gaggìa, Francesca; Lucenti, Ausiliatrice; Bersano, Enrica; Cantello, Roberto; Di Gioia, Diana; Mogna, Giovanni

2018-05-18

Recent preclinical studies suggest that dysfunction of gastrointestinal tract may play a role in amyotrophic lateral sclerosis (ALS) pathogenesis through a modification of the gut microbiota brain axis. Our study is the first focused on microbiota analysis in ALS patients. Our aim was to study the main human gut microbial groups and the overall microbial diversity in ALS and healthy subjects. Moreover we have examined the influence of a treatment with a specific bacteriotherapy composed of Lactobacillus strains (Lactobacillus fermentum, Lactobacillus delbrueckii, Lactobacillus plantarum, Lactobacillus salivarius) acting on the gastrointestinal barrier. We enrolled 50 ALS patients and 50 healthy controls, matched for sex, age, and origin. Fecal samples were used for total genomic DNA extraction. Enterobacteria, Bifidobacterium spp., Lactobacillus spp., Clostridium sensu stricto, Escherichia coli and yeast were quantified using quantitative polymerase chain reaction approach. Denaturing gradient gel electrophoresis analyses were performed to investigate total eubacteria and yeasts populations. Patients were randomized to double-blind treatment either with microorganisms or placebo for 6 months and monitored for clinical progression and microbiota composition. The comparison between ALS subjects and healthy group revealed a variation in the intestinal microbial composition with a higher abundance of E. coli and enterobacteria and a low abundance of total yeast in patients. Polymerase chain reaction denaturing gradient gel electrophoresis analysis showed a cluster distinction between the bacterial profiles of ALS patients and the healthy subjects. The complexity of the profiles in both cases may indicate that a real dysbiosis status is not evident in the ALS patients although differences between healthy and patients exist. The effects of the progression of the disease and of the bacteriotherapy on the bacterial and yeast populations are currently in progress. Our preliminary results confirm that there is a difference in the microbiota profile in ALS patients.

Familial ALS

PubMed Central

Boylan, Kevin

2015-01-01

Synopsis Genes linked to ALS susceptibility are being identified at an increasing rate owing to advances in molecular genetic technology. Genetic mechanisms in ALS pathogenesis appear to exert major effects in ~10% of patients, but genetic factors at some level may be important components of disease risk in most ALS patients. Identification of gene variants associated with ALS has informed concepts of the pathogenesis of ALS, aided the identification of therapeutic targets, facilitated research to develop new ALS biomarkers, and supported the establishment of clinical diagnostic tests for ALS-linked genes. Translation of this knowledge to ALS therapy development is ongoing. PMID:26515623

A secure and efficient chaotic map-based authenticated key agreement scheme for telecare medicine information systems.

PubMed

Mishra, Dheerendra; Srinivas, Jangirala; Mukhopadhyay, Sourav

2014-10-01

Advancement in network technology provides new ways to utilize telecare medicine information systems (TMIS) for patient care. Although TMIS usually faces various attacks as the services are provided over the public network. Recently, Jiang et al. proposed a chaotic map-based remote user authentication scheme for TMIS. Their scheme has the merits of low cost and session key agreement using Chaos theory. It enhances the security of the system by resisting various attacks. In this paper, we analyze the security of Jiang et al.'s scheme and demonstrate that their scheme is vulnerable to denial of service attack. Moreover, we demonstrate flaws in password change phase of their scheme. Further, our aim is to propose a new chaos map-based anonymous user authentication scheme for TMIS to overcome the weaknesses of Jiang et al.'s scheme, while also retaining the original merits of their scheme. We also show that our scheme is secure against various known attacks including the attacks found in Jiang et al.'s scheme. The proposed scheme is comparable in terms of the communication and computational overheads with Jiang et al.'s scheme and other related existing schemes. Moreover, we demonstrate the validity of the proposed scheme through the BAN (Burrows, Abadi, and Needham) logic.

Syntactic processing as a marker for cognitive impairment in amyotrophic lateral sclerosis

PubMed Central

Tsermentseli, Stella; Leigh, P. Nigel; Taylor, Lorna J.; Radunovic, Aleksandar; Catani, Marco; Goldstein, Laura H.

2016-01-01

Despite recent interest in cognitive changes in patients with amyotrophic lateral sclerosis (ALS), investigations of language function looking at the level of word, sentence and discourse processing are relatively scarce. Data were obtained from 26 patients with sporadic ALS and 26 healthy controls matched for age, education, gender, anxiety, depression and executive function performance. Standardized language tasks included confrontation naming, semantic access, and syntactic comprehension. Quantitative production analysis (QPA) was used to analyse connected speech samples of the Cookie Theft picture description task. Results showed that the ALS patients were impaired on standardized measures of grammatical comprehension and action/verb semantics. At the level of discourse, ALS patients were impaired on measures of syntactic complexity and fluency; however, the latter could be better explained by disease related factors. Discriminant analysis revealed that syntactic measures differentiated ALS patients from controls. In conclusion, patients with ALS exhibit deficits in receptive and expressive language on tasks of comprehension and connected speech production, respectively. Our findings suggest that syntactic processing deficits seem to be the predominant feature of language impairment in ALS and that these deficits can be detected by relatively simple language tests. PMID:26312952

Syntactic processing as a marker for cognitive impairment in amyotrophic lateral sclerosis.

PubMed

Tsermentseli, Stella; Leigh, P Nigel; Taylor, Lorna J; Radunovic, Aleksandar; Catani, Marco; Goldstein, Laura H

2015-01-01

Despite recent interest in cognitive changes in patients with amyotrophic lateral sclerosis (ALS), investigations of language function looking at the level of word, sentence and discourse processing are relatively scarce. Data were obtained from 26 patients with sporadic ALS and 26 healthy controls matched for age, education, gender, anxiety, depression and executive function performance. Standardized language tasks included confrontation naming, semantic access, and syntactic comprehension. Quantitative production analysis (QPA) was used to analyse connected speech samples of the Cookie Theft picture description task. Results showed that the ALS patients were impaired on standardized measures of grammatical comprehension and action/verb semantics. At the level of discourse, ALS patients were impaired on measures of syntactic complexity and fluency; however, the latter could be better explained by disease related factors. Discriminant analysis revealed that syntactic measures differentiated ALS patients from controls. In conclusion, patients with ALS exhibit deficits in receptive and expressive language on tasks of comprehension and connected speech production, respectively. Our findings suggest that syntactic processing deficits seem to be the predominant feature of language impairment in ALS and that these deficits can be detected by relatively simple language tests.

The Perseverative Thinking Questionnaire in Patients with Persecutory Delusions.

PubMed

Černis, Emma; Dunn, Graham; Startup, Helen; Kingdon, David; Wingham, Gail; Evans, Nicole; Lister, Rachel; Pugh, Katherine; Cordwell, Jacinta; Mander, Helen; Freeman, Daniel

2016-07-01

Ruminative negative thinking has typically been considered as a factor maintaining common emotional disorders and has recently been shown to maintain persecutory delusions in psychosis. The Perseverative Thinking Questionnaire (PTQ) (Ehring et al., 2011) is a transdiagnostic measure of ruminative negative thinking that shows promise as a "content-free" measure of ruminative negative thinking. The PTQ has not previously been studied in a psychosis patient group. In this study we report for the first time on the psychometric properties of Ehring et al.'s PTQ in such a group. The PTQ was completed by 142 patients with current persecutory delusions and 273 non-clinical participants. Participants also completed measures of worry and paranoia. A confirmatory factor analysis was performed on the clinical group's PTQ responses to assess the factor structure of the measure. Differences between groups were used to assess criterion reliability. A three lower-order factor structure of the PTQ (core characteristics of ruminative negative thinking, perceived unproductiveness, and capturing mental capacity) was replicated in the clinical sample. Patients with persecutory delusions were shown to experience significantly higher levels of ruminative negative thinking on the PTQ than the general population sample. The PTQ demonstrated high internal reliability. This study did not include test-retest data, and did not compare the PTQ against a measure of depressive rumination but, nevertheless, lends support for the validity of the PTQ as a measure of negative ruminative thinking in patients with psychosis.

SQSTM1 Mutations in French Patients With Frontotemporal Dementia or Frontotemporal Dementia With Amyotrophic Lateral Sclerosis

PubMed Central

Le Ber, Isabelle; Camuzat, Agnès; Guerreiro, Rita; Bouya-Ahmed, Kawtar; Bras, Jose; Nicolas, Gael; Gabelle, Audrey; Didic, Mira; De Septenville, Anne; Millecamps, Stéphanie; Lenglet, Timothée; Latouche, Morwena; Kabashi, Edor; Campion, Dominique; Hannequin, Didier; Hardy, John; Brice, Alexis

2014-01-01

IMPORTANCE Mutations in the SQSTM1 gene, coding for p62, are a cause of Paget disease of bone and amyotrophic lateral sclerosis (ALS). Recently, SQSTM1 mutations were confirmed in ALS, and mutations were also identified in 3 patients with frontotemporal dementia (FTD), suggesting a role for SQSTM1 in FTD. OBJECTIVE To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients. DESIGN A SQSTM1 mutation was first identified in a multiplex family with FTD by use of whole-exome sequencing. To evaluate the frequency of SQSTM1 mutations, we sequenced this gene in a cohort of patients with FTD or FTD-ALS, with no mutations in known FTD and ALS genes. SETTING Primary care or referral center. PARTICIPANTS An overall cohort of 188 French patients, including 132 probands with FTD and 56 probands with FTD-ALS. MAIN OUTCOMES AND MEASURES Frequency of SQSTM1 mutations in patients with FTD or FTD-ALS; description of associated phenotypes. RESULTS We identified 4 heterozygous missense mutations in 4 unrelated families with FTD; only 1 family had clinical symptoms of Paget disease of bone, and only 1 family had clinical symptoms of FTD-ALS, possibly owing to the low penetrance of some of the clinical manifestations. CONCLUSIONS AND RELEVANCE Although the frequency of the mutations is low in our series (4 of 188 patients [2%]), our results, similar to those already reported, support a direct pathogenic role of p62 in different types of FTD. PMID:24042580

Comparison of the biometric values obtained by two different A-mode ultrasound devices (Eye Cubed vs. PalmScan): A Transversal, descriptive, and comparative study

PubMed Central

2010-01-01

Background To assess the reliability of the measurements obtained with the PalmScan™, when compared with another standardized A-mode ultrasound device, and assess the consistency and correlation between the two methods. Methods Transversal, descriptive, and comparative study. We recorded the axial length (AL), anterior chamber depth (ACD) and lens thickness (LT) obtained with two A-mode ultrasounds (PalmScan™ A2000 and Eye Cubed™) using an immersion technique. We compared the measurements with a two-sample t-test. Agreement between the two devices was assessed with Bland-Altman plots and 95% limits of agreement. Results 70 eyes of 70 patients were enrolled in this study. The measurements with the Eye Cubed™ of AL and ACD were shorter than the measurements taken by the PalmScan™. The differences were not statistically significant regarding AL (p < 0.4) but significant regarding ACD (p < 0.001). The highest agreement between the two devices was obtained during LT measurement. The PalmScan™ measurements were shorter, but not statistically significantly (p < 0.2). Conclusions The values of AL and LT, obtained with both devices are not identical, but within the limits of agreement. The agreement is not affected by the magnitude of the ocular dimensions (but only between range of 20 mm to 27 mm of AL and 3.5 mm to 5.7 mm of LT). A correction of about 0.5 D could be considered if an intraocular lens is being calculated. However due to the large variability of the results, the authors recommend discretion in using this conversion factor, and to adjust the power of the intraocular lenses based upon the personal experience of the surgeon. PMID:20334670

Comparison of the biometric values obtained by two different A-mode ultrasound devices (Eye Cubed vs. PalmScan): a transversal, descriptive, and comparative study.

PubMed

Velez-Montoya, Raul; Shusterman, Eugene Mark; López-Miranda, Miriam Jessica; Mayorquin-Ruiz, Mariana; Salcedo-Villanueva, Guillermo; Quiroz-Mercado, Hugo; Morales-Cantón, Virgilio

2010-03-24

To assess the reliability of the measurements obtained with the PalmScan, when compared with another standardized A-mode ultrasound device, and assess the consistency and correlation between the two methods. Transversal, descriptive, and comparative study. We recorded the axial length (AL), anterior chamber depth (ACD) and lens thickness (LT) obtained with two A-mode ultrasounds (PalmScan A2000 and Eye Cubed) using an immersion technique. We compared the measurements with a two-sample t-test. Agreement between the two devices was assessed with Bland-Altman plots and 95% limits of agreement. 70 eyes of 70 patients were enrolled in this study. The measurements with the Eye Cubed of AL and ACD were shorter than the measurements taken by the PalmScan. The differences were not statistically significant regarding AL (p < 0.4) but significant regarding ACD (p < 0.001). The highest agreement between the two devices was obtained during LT measurement. The PalmScan measurements were shorter, but not statistically significantly (p < 0.2). The values of AL and LT, obtained with both devices are not identical, but within the limits of agreement. The agreement is not affected by the magnitude of the ocular dimensions (but only between range of 20 mm to 27 mm of AL and 3.5 mm to 5.7 mm of LT). A correction of about 0.5 D could be considered if an intraocular lens is being calculated. However due to the large variability of the results, the authors recommend discretion in using this conversion factor, and to adjust the power of the intraocular lenses based upon the personal experience of the surgeon.

Religiousness is positively associated with quality of life of ALS caregivers.

PubMed

Calvo, Andrea; Moglia, Cristina; Ilardi, Antonio; Cammarosano, Stefania; Gallo, Sara; Canosa, Antonio; Mastro, Enza; Montuschi, Anna; Chiò, Adriano

2011-05-01

It has been repeatedly shown that religiousness and spirituality have positive effects on quality of life (QoL) and outcome in ALS patients. here are, however, very few data on the impact of religiousness/spirituality on ALS caregivers. We determined the impact of religiousness on caregivers and its correlation with quality of life, depression and anxiety. A total of 75 consecutive ALS patients and their informal caregivers were interviewed using tests evaluating religiousness, depression, anxiety, quality of life and satisfaction with life. Results showed that there was a significant correlation between patients and caregivers' public and total religiousness. Caregivers' private religiousness was related to their age and education level, while their public religiousness was related only to their education level. Caregivers' quality of life was related to their private religiousness and satisfaction with life with their total religiousness. We conclude that religiousness is positively associated with ALS caregivers' quality of life and satisfaction with life, in a measure similar to that observed in ALS patients. Health care professionals caring for ALS patients should consider that the needs of the caregivers include religious/spiritual concerns.

A differential autophagy-dependent response to DNA double-strand breaks in bone marrow mesenchymal stem cells from sporadic ALS patients.

PubMed

Wald-Altman, Shane; Pichinuk, Edward; Kakhlon, Or; Weil, Miguel

2017-05-01

Amyotrophic lateral sclerosis (ALS) is an incurable motor neurodegenerative disease caused by a diversity of genetic and environmental factors that leads to neuromuscular degeneration and has pathophysiological implications in non-neural systems. Our previous work showed abnormal levels of mRNA expression for biomarker genes in non-neuronal cell samples from ALS patients. The same genes proved to be differentially expressed in the brain, spinal cord and muscle of the SOD1 G93A ALS mouse model. These observations support the idea that there is a pathophysiological relevance for the ALS biomarkers discovered in human mesenchymal stem cells (hMSCs) isolated from bone marrow samples of ALS patients (ALS-hMSCs). Here, we demonstrate that ALS-hMSCs are also a useful patient-based model to study intrinsic cell molecular mechanisms of the disease. We investigated the ALS-hMSC response to oxidative DNA damage exerted by neocarzinostatin (NCS)-induced DNA double-strand breaks (DSBs). We found that the ALS-hMSCs responded to this stress differently from cells taken from healthy controls (HC-hMSCs). Interestingly, we found that ALS-hMSC death in response to induction of DSBs was dependent on autophagy, which was initialized by an increase of phosphorylated (p)AMPK, and blocked by the class III phosphoinositide 3-kinase (PI3K) and autophagy inhibitor 3-methyladenine (3MeA). ALS-hMSC death in response to DSBs was not apoptotic as it was caspase independent. This unique ALS-hMSC-specific response to DNA damage emphasizes the possibility that an intrinsic abnormal regulatory mechanism controlling autophagy initiation exists in ALS-patient-derived hMSCs. This mechanism may also be relevant to the most-affected tissues in ALS. Hence, our approach might open avenues for new personalized therapies for ALS. © 2017. Published by The Company of Biologists Ltd.

A differential autophagy-dependent response to DNA double-strand breaks in bone marrow mesenchymal stem cells from sporadic ALS patients

PubMed Central

Wald-Altman, Shane; Pichinuk, Edward; Kakhlon, Or

2017-01-01

ABSTRACT Amyotrophic lateral sclerosis (ALS) is an incurable motor neurodegenerative disease caused by a diversity of genetic and environmental factors that leads to neuromuscular degeneration and has pathophysiological implications in non-neural systems. Our previous work showed abnormal levels of mRNA expression for biomarker genes in non-neuronal cell samples from ALS patients. The same genes proved to be differentially expressed in the brain, spinal cord and muscle of the SOD1G93A ALS mouse model. These observations support the idea that there is a pathophysiological relevance for the ALS biomarkers discovered in human mesenchymal stem cells (hMSCs) isolated from bone marrow samples of ALS patients (ALS-hMSCs). Here, we demonstrate that ALS-hMSCs are also a useful patient-based model to study intrinsic cell molecular mechanisms of the disease. We investigated the ALS-hMSC response to oxidative DNA damage exerted by neocarzinostatin (NCS)-induced DNA double-strand breaks (DSBs). We found that the ALS-hMSCs responded to this stress differently from cells taken from healthy controls (HC-hMSCs). Interestingly, we found that ALS-hMSC death in response to induction of DSBs was dependent on autophagy, which was initialized by an increase of phosphorylated (p)AMPK, and blocked by the class III phosphoinositide 3-kinase (PI3K) and autophagy inhibitor 3-methyladenine (3MeA). ALS-hMSC death in response to DSBs was not apoptotic as it was caspase independent. This unique ALS-hMSC-specific response to DNA damage emphasizes the possibility that an intrinsic abnormal regulatory mechanism controlling autophagy initiation exists in ALS-patient-derived hMSCs. This mechanism may also be relevant to the most-affected tissues in ALS. Hence, our approach might open avenues for new personalized therapies for ALS. PMID:28213588

Altered cortical beta-band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis.

PubMed

Proudfoot, Malcolm; Rohenkohl, Gustavo; Quinn, Andrew; Colclough, Giles L; Wuu, Joanne; Talbot, Kevin; Woolrich, Mark W; Benatar, Michael; Nobre, Anna C; Turner, Martin R

2017-01-01

Continuous rhythmic neuronal oscillations underpin local and regional cortical communication. The impact of the motor system neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) on the neuronal oscillations subserving movement might therefore serve as a sensitive marker of disease activity. Movement preparation and execution are consistently associated with modulations to neuronal oscillation beta (15-30 Hz) power. Cortical beta-band oscillations were measured using magnetoencephalography (MEG) during preparation for, execution, and completion of a visually cued, lateralized motor task that included movement inhibition trials. Eleven "classical" ALS patients, 9 with the primary lateral sclerosis (PLS) phenotype, and 12 asymptomatic carriers of ALS-associated gene mutations were compared with age-similar healthy control groups. Augmented beta desynchronization was observed in both contra- and ipsilateral motor cortices of ALS patients during motor preparation. Movement execution coincided with excess beta desynchronization in asymptomatic mutation carriers. Movement completion was followed by a slowed rebound of beta power in all symptomatic patients, further reflected in delayed hemispheric lateralization for beta rebound in the PLS group. This may correspond to the particular involvement of interhemispheric fibers of the corpus callosum previously demonstrated in diffusion tensor imaging studies. We conclude that the ALS spectrum is characterized by intensified cortical beta desynchronization followed by delayed rebound, concordant with a broader concept of cortical hyperexcitability, possibly through loss of inhibitory interneuronal influences. MEG may potentially detect cortical dysfunction prior to the development of overt symptoms, and thus be able to contribute to the assessment of future neuroprotective strategies. Hum Brain Mapp 38:237-254, 2017. © 2016 Wiley Periodicals, Inc. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Multi-Parametric Spinal Cord MRI as Potential Progression Marker in Amyotrophic Lateral Sclerosis

PubMed Central

El Mendili, Mohamed-Mounir; Cohen-Adad, Julien; Pelegrini-Issac, Mélanie; Rossignol, Serge; Morizot-Koutlidis, Régine; Marchand-Pauvert, Véronique; Iglesias, Caroline; Sangari, Sina; Katz, Rose; Lehericy, Stéphane; Benali, Habib; Pradat, Pierre-François

2014-01-01

Objective To evaluate multimodal MRI of the spinal cord in predicting disease progression and one-year clinical status in amyotrophic lateral sclerosis (ALS) patients. Materials and Methods After a first MRI (MRI1), 29 ALS patients were clinically followed during 12 months; 14/29 patients underwent a second MRI (MRI2) at 11±3 months. Cross-sectional area (CSA) that has been shown to be a marker of lower motor neuron degeneration was measured in cervical and upper thoracic spinal cord from T2-weighted images. Fractional anisotropy (FA), axial/radial/mean diffusivities (λ⊥, λ//, MD) and magnetization transfer ratio (MTR) were measured within the lateral corticospinal tract in the cervical region. Imaging metrics were compared with clinical scales: Revised ALS Functional Rating Scale (ALSFRS-R) and manual muscle testing (MMT) score. Results At MRI1, CSA correlated significantly (P<0.05) with MMT and arm ALSFRS-R scores. FA correlated significantly with leg ALFSRS-R scores. One year after MRI1, CSA predicted (P<0.01) arm ALSFSR-R subscore and FA predicted (P<0.01) leg ALSFRS-R subscore. From MRI1 to MRI2, significant changes (P<0.01) were detected for CSA and MTR. CSA rate of change (i.e. atrophy) highly correlated (P<0.01) with arm ALSFRS-R and arm MMT subscores rate of change. Conclusion Atrophy and DTI metrics predicted ALS disease progression. Cord atrophy was a better biomarker of disease progression than diffusion and MTR. Our study suggests that multimodal MRI could provide surrogate markers of ALS that may help monitoring the effect of disease-modifying drugs. PMID:24755826

Pfmdr1 copy number and arteminisin derivatives combination therapy failure in falciparum malaria in Cambodia.

PubMed

Lim, Pharath; Alker, Alisa P; Khim, Nimol; Shah, Naman K; Incardona, Sandra; Doung, Socheat; Yi, Poravuth; Bouth, Denis Mey; Bouchier, Christiane; Puijalon, Odile Mercereau; Meshnick, Steven R; Wongsrichanalai, Chansuda; Fandeur, Thierry; Le Bras, Jacques; Ringwald, Pascal; Ariey, Frédéric

2009-01-12

The combination of artesunate and mefloquine was introduced as the national first-line treatment for Plasmodium falciparum malaria in Cambodia in 2000. However, recent clinical trials performed at the Thai-Cambodian border have pointed to the declining efficacy of both artesunate-mefloquine and artemether-lumefantrine. Since pfmdr1 modulates susceptibility to mefloquine and artemisinin derivatives, the aim of this study was to assess the link between pfmdr1 copy number, in vitro susceptibility to individual drugs and treatment failure to combination therapy. Blood samples were collected from P. falciparum-infected patients enrolled in two in vivo efficacy studies in north-western Cambodia: 135 patients were treated with artemether-lumefantrine (AL group) in Sampovloun in 2002 and 2003, and 140 patients with artesunate-mefloquine (AM group) in Sampovloun and Veal Veng in 2003 and 2004. At enrollment, the in vitro IC50 was tested and the strains were genotyped for pfmdr1 copy number by real-time PCR. The pfmdr1 copy number was analysed for 115 isolates in the AM group, and for 109 isolates in the AL group. Parasites with increased pfmdr1 copy number had significantly reduced in vitro susceptibility to mefloquine, lumefantrine and artesunate. There was no association between pfmdr1 polymorphisms and in vitro susceptibilities. In the patients treated with AM, the mean pfmdr1copy number was lower in subjects with adequate clinical and parasitological response compared to those who experienced late treatment failure (n = 112, p < 0.001). This was not observed in the patients treated with AL (n = 96, p = 0.364). The presence of three or more copies of pfmdr1 were associated with recrudescence in artesunate-mefloquine treated patients (hazard ratio (HR) = 7.80 [95%CI: 2.09-29.10], N = 115), p = 0.002) but not with recrudescence in artemether-lumefantrine treated patients (HR = 1.03 [95%CI: 0.24-4.44], N = 109, p = 0.969). This study shows that pfmdr1 copy number is a molecular marker of AM treatment failure in falciparum malaria on the Thai-Cambodian border. However, while it is associated with increased IC50 for lumefantrine, pfmdr1 copy number is not associated with AL treatment failure in the area, suggesting involvement of other molecular mechanisms in AL treatment failures in Cambodia.

Dysphagia in amyotrophic lateral sclerosis: prevalence and clinical findings.

PubMed

Ruoppolo, G; Schettino, I; Frasca, V; Giacomelli, E; Prosperini, L; Cambieri, C; Roma, R; Greco, A; Mancini, P; De Vincentiis, M; Silani, V; Inghilleri, M

2013-12-01

To characterize swallowing deficits in amyotrophic lateral sclerosis (ALS); investigate the delay in dysphagia onset; estimate correlations between dysphagia severity and patients' functional status; identify the symptom(s) most likely to predict dysphagia. A group of 49 consecutive patients with ALS, 14 with bulbar onset and 35 with spinal onset, underwent swallowing evaluation including bedside and fiberoptic endoscopic examination to detect dysphagia. Patients with dysphagia were more likely than those without to have bulbar onset ALS (P = 0.02); more severely impaired chewing (P = 0.01); and tongue muscle deficits (P = 0.001). The only variable measured at first examination significantly associated with dysphagia was a more than mild tongue muscle deficit. The only variable useful in predicting dysphagia was a chewing deficit. In 10 of the 49 patients studied, swallowing evaluation disclosed an impaired cough reflex. Dysphagia in patients with ALS correlates significantly with bulbar onset and with oral swallowing impairment. Fiberoptic swallowing evaluation is a useful tool for detecting swallowing deficits and laryngeal sensitivity in patients with ALS. An impaired cough reflex is an unexpected finding in many patients with ALS. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Screening UBQLN-2 in French frontotemporal lobar degeneration and frontotemporal lobar degeneration-amyotrophic lateral sclerosis patients.

PubMed

Lattante, Serena; Le Ber, Isabelle; Camuzat, Agnès; Pariente, Jérémie; Brice, Alexis; Kabashi, Edor

2013-08-01

The ubiquilin-2 gene (UBQLN-2) is the only amyotrophic lateral sclerosis (ALS)-related gene mapping on the X chromosome. Mutations in the PXX domain of UBQLN-2 have been first described in ALS patients with a mutational frequency of 2.6% in familial ALS cases with no evidence of male-to-male transmission. Different populations have been further tested with mutations largely distributed in the gene and lower frequency of positive cases. To determine the genetic contribution of UBQLN-2 in frontotemporal lobar degeneration (FTLD) and FTLD-ALS, we screened a cohort of 136 French patients, identifying a missense variant (c.1006A>G; p.T336A) in 1 FTLD patient whose biological relevance to disease is questionable. We conclude that UBQLN-2 mutations related to ALS/FTLD are extremely rare in French FTLD and FTLD-ALS patients and should not be analyzed systematically. Copyright © 2013. Published by Elsevier Inc.

Myasthenia gravis and amyotrophic lateral sclerosis: A pathogenic overlap.

PubMed

Gotaas, Håvard Torvik; Skeie, Geir Olve; Gilhus, Nils Erik

2016-06-01

The aim was to examine potential joint disease mechanisms for myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) through the examination of long-term patient cohorts for comorbidity. Recent studies support early involvement of the neuromuscular junction in ALS patients with subsequent degeneration of motor neurons. Medical records at Haukeland University Hospital from 1987 to 2012 were examined for International Classification of Diseases diagnostic codes for MG and ALS. Sera were re-tested for antibodies to acetylcholine receptor, titin, MuSK and GM1. We report one patient with both MG and ALS, and another 3 patients with suggestive evidence of both conditions. This is far more than expected from prevalence and incidence figures in this area if the disorders were unrelated. Our data suggest that immunological mechanisms in the neuromuscular junction are relevant in ALS pathogenesis. Attention should be given to possible therapeutic targets in the neuromuscular junction and muscle in ALS patients. Copyright © 2016 Elsevier B.V. All rights reserved.

Prospective study of cost of care at multidisciplinary ALS centers adhering to American Academy of Neurology (AAN) ALS practice parameters.

PubMed

Boylan, Kevin; Levine, Todd; Lomen-Hoerth, Catherine; Lyon, Mary; Maginnis, Kimberly; Callas, Peter; Gaspari, Celeste; Tandan, Rup

2015-01-01

Multidisciplinary care in ALS is associated with longer survival, improved quality of life, and reduced hospital admissions, but there are no published data on institutional costs associated with multidisciplinary ALS care at U.S. centers. We prospectively examined institutional costs, adherence to AAN Practice Parameters and patient satisfaction in multidisciplinary ALS clinics at 18 U.S. ALS centers. Centers reported patient volumes; direct costs for staff salary/benefits, supplies and equipment; and institutional non-salary and overhead costs over a three-month period. In 1117 patients seen during this period, mean age was 61.5 years (range 25-91 years), 56% were male, and mean ALSFRS-R score was 29. Mean total salary/benefit cost per clinic day for all providers was $2964 (range $1692-$5236 across centers). Mean salary/benefit cost per patient per clinic was $507 (range $258-$806 across centers). Differences among centers in reporting non-salary costs prevented meaningful analysis. Practice parameter adherence and patient satisfaction were high. This prospective collaborative study demonstrates the direct financial burden of evidence-based multidisciplinary ALS care in the U.S.; more refined non-salary and overhead cost data are needed to evaluate the full cost impact of care. These data may be useful in supporting evidence-based models of patient centered care for ALS.

ATXN2 with intermediate-length CAG/CAA repeats does not seem to be a risk factor in hereditary spastic paraplegia.

PubMed

Nielsen, Troels Tolstrup; Svenstrup, Kirsten; Budtz-Jørgensen, Esben; Eiberg, Hans; Hasholt, Lis; Nielsen, Jørgen E

2012-10-15

Hereditary spastic paraplegia (HSP) confines a group of heterogeneous neurodegenerative disorders characterized by progressive spasticity and lower limb weakness. Age of onset is highly variable even in familial cases with known mutations suggesting that the disease is modulated by other yet unknown parameters. Although progressive gait disturbances, lower limb spasticity and extensor plantar responses are hallmarks of HSP these characteristics are also found in other neurodegenerative disorders, e.g. amytrophic lateral sclerosis (ALS). HSP has been linked to ALS and frontotemporal degeneration with motor neuron disease (FTD-MND), since TDP-43 positive inclusions have recently been found in an HSP subtype, and TDP-43 are found in abundance in pathological inclusions of both ALS and FTD-MND. Furthermore, ataxin-2 (encoded by the gene ATXN2), a polyglutamine containing protein elongated in spinocerebellar ataxia type 2, has been shown to be a modulator of TDP-43 induced toxicity in ALS animal and cell models. Finally, it has been shown that ATXN2 with non-pathogenic intermediate-length CAG/CAA repeat elongations (encoding the polyglutamine tract) is a genetic risk factor of ALS. Considering the similarities in the disease phenotype and the neuropathological link between ALS and HSP we hypothesized that intermediate-length CAG/CAA repeats in ATXN2 could be a modulator of HSP. We show that in a cohort of 181 HSP patients 4.9 % of the patients had intermediate-length CAG/CAA repeats in ATXN2 which was not significantly different from the frequencies in a Danish control cohort or in American and European control populations. However, the mean age of onset was significantly lower in HSP patients with intermediate-length CAG/CAA repeats in ATXN2 compared to patients with normal length repeats. Based on these results we conclude that ATXN2 is most likely not a risk factor of HSP, whereas it might serve as a modulator of age of onset. Copyright © 2012 Elsevier B.V. All rights reserved.

Preclinical models for interrogating drug action in human cancers using Stable Isotope Resolved Metabolomics (SIRM).

PubMed

Lane, Andrew N; Higashi, Richard M; Fan, Teresa W-M

2016-07-01

In this review we compare the advantages and disadvantages of different model biological systems for determining the metabolic functions of cells in complex environments, how they may change in different disease states, and respond to therapeutic interventions. All preclinical drug-testing models have advantages and drawbacks. We compare and contrast established cell, organoid and animal models with ex vivo organ or tissue culture and in vivo human experiments in the context of metabolic readout of drug efficacy. As metabolism reports directly on the biochemical state of cells and tissues, it can be very sensitive to drugs and/or other environmental changes. This is especially so when metabolic activities are probed by stable isotope tracing methods, which can also provide detailed mechanistic information on drug action. We have developed and been applying Stable Isotope-Resolved Metabolomics (SIRM) to examine metabolic reprogramming of human lung cancer cells in monoculture, in mouse xenograft/explant models, and in lung cancer patients in situ (Lane et al. 2011; T. W. Fan et al. 2011; T. W-M. Fan et al. 2012; T. W. Fan et al. 2012; Xie et al. 2014b; Ren et al. 2014a; Sellers et al. 2015b). We are able to determine the influence of the tumor microenvironment using these models. We have now extended the range of models to fresh human tissue slices, similar to those originally described by O. Warburg (Warburg 1923), which retain the native tissue architecture and heterogeneity with a paired benign versus cancer design under defined cell culture conditions. This platform offers an unprecedented human tissue model for preclinical studies on metabolic reprogramming of human cancer cells in their tissue context, and response to drug treatment (Xie et al. 2014a). As the microenvironment of the target human tissue is retained and individual patient's response to drugs is obtained, this platform promises to transcend current limitations of drug selection for clinical trials or treatments. Development of ex vivo human tissue and animal models with humanized organs including bone marrow and liver show considerable promise for analyzing drug responses that are more relevant to humans. Similarly using stable isotope tracer methods with these improved models in advanced stages of the drug development pipeline, in conjunction with tissue biopsy is expected significantly to reduce the high failure rate of experimental drugs in Phase II and III clinical trials.

Synaptic dysfunction and altered excitability in C9ORF72 ALS/FTD.

PubMed

Starr, Alexander; Sattler, Rita

2018-08-15

Amyotrophic lateral sclerosis (ALS) is characterized by a progressive degeneration of upper and lower motor neurons, resulting in fatal paralysis due to denervation of the muscle. Due to genetic, pathological and symptomatic overlap, ALS is now considered a spectrum disease together with frontotemporal dementia (FTD), the second most common cause of dementia in individuals under the age of 65. Interestingly, in both diseases, there is a large prevalence of RNA binding proteins (RBPs) that are mutated and considered disease-causing, or whose dysfunction contribute to disease pathogenesis. The most common shared genetic mutation in ALS/FTD is a hexanucleuotide repeat expansion within intron 1 of C9ORF72 (C9). Three potentially overlapping, putative toxic mechanisms have been proposed: loss of function due to haploinsufficient expression of the C9ORF72 mRNA, gain of function of the repeat RNA aggregates, or RNA foci, and repeat-associated non-ATG-initiated translation (RAN) of the repeat RNA into toxic dipeptide repeats (DPRs). Regardless of the causative mechanism, disease symptoms are ultimately caused by a failure of neurotransmission in three regions: the brain, the spinal cord, and the neuromuscular junction. Here, we review C9 ALS/FTD-associated synaptic dysfunction and aberrant neuronal excitability in these three key regions, focusing on changes in morphology and synapse formation, excitability, and excitotoxicity in patients, animal models, and in vitro models. We compare these deficits to those seen in other forms of ALS and FTD in search of shared pathways, and discuss the potential targeting of synaptic dysfunctions for therapeutic intervention in ALS and FTD patients. Copyright © 2018 Elsevier B.V. All rights reserved.

The enigma of aluminum deposition in bone tissue from a patient with chronic kidney disease: a case report.

PubMed

Meira, Rodrigo Dias de; Carbonara, Cinthia Esbrile Moraes; Quadros, Kélcia Rosana da Silva; Santos, Carolina Urbini Dos; Schincariol, Patrícia; Pêssoa, Gustavo de Souza; Arruda, Marco Aurélio Zezzi; Jorgetti, Vanda; Oliveira, Rodrigo Bueno de

2018-06-04

About four decades ago, the relationship between dialysis-dementia and aluminum (Al) began to be established. The restriction of drugs containing Al and improvements on water quality used for dialysis resulted in the clinical disappearance of Al intoxication. However, high prevalence of Al deposition in bone tissue from Brazilian dialysis patients is still being detected. Through the case report of a patient on hemodialysis (HD) for one year, presenting significant Al deposition in bone tissue, we speculated if this problem is not being underestimated. We used extensive investigation to identify potential sources of Al exposure with a careful review of medication history and water quality controls. Al concentration was measured by different methods, including mass spectrometry, in poly-electrolyte concentrate solutions and solution for peritoneal dialysis, in an attempt to elucidate the possible sources of contamination. The objective of this case report is to alert the medical community about a potential high prevalence of Al deposition in bone tissue and to discuss the possible sources of contamination in patients with chronic kidney disease (CKD).

Using technology to improve access to specialist care in amyotrophic lateral sclerosis: A systematic review.

PubMed

Hobson, Esther V; Baird, Wendy O; Cooper, Cindy L; Mawson, Sue; Shaw, Pamela J; Mcdermott, Christopher J

2016-01-01

Our objective was to review the evidence for using technology to improve access to specialist care for patients with amyotrophic lateral sclerosis (ALS) and their carers. Medline, Google Scholar and the Cochrane library were searched for articles describing technology that enabled clinical care of patients with ALS or their carers where the patient/carer and clinician were not in the same location. Two applications were identified: telemedicine to facilitate video conferencing as an alternative to outpatient consultations and telehealth monitoring for patients with respiratory failure. One randomized controlled trial using telehealth in patients with respiratory failure including 22 patients with ALS was identified. While rates of hospitalization were reduced, overall mortality was unchanged and there were too few patients with ALS in the study to detect significant benefit. In conclusion, there is limited evidence to support the use of telemedicine or telehealth in the care of patients with ALS. Future research needs to develop an understanding of the key beneficial aspects of the traditional specialist ALS service and how these factors could be delivered using technology. Successful evaluation and implementation of technologies to facilitate access to specialist care will only be possible if all the relevant impacts of an intervention are understood and measured.

[Expressions of EMMPRIN and its ligand CyPA in gingival crevicular fluid of chronic periodontitis patients].

PubMed

He, Yan-ping; Xie, Ming; Jiao, Ting

2016-02-01

To detect the expressions of EMMPRIN and its ligand CyPA in gingival crevicular fluid (GCF) of chronic periodontitis (CP) patients and explore their possible relation to the status of periodontal inflammation. GCF of CP patients (group CP) and periodontitis-free patients with intact dentition (the control group) were collected and assayed for EMMPRIN and CyPA expressions by ELISA. The clinical periodontal status of these patients were examined. Statistical analysis was performed by use of SPSS 17.0 software package. Spearman's correlation analysis was utilized to determine the relationships between the expressions of EMMPRIN and CyPA in GCF and the clinical parameters. In addition, analysis of variance (ANOVA) was used for comparing the difference between group CP and the control group. In group CP, GCF volume was positively correlated with EMMPRIN total amount, CyPA total amount and some clinical periodontal indexes (GI,SBI,AL). EMMPRIN total amount was positively correlated with GCF volume, CyPA total amount and some of clinical periodontal indexes (GI,SBI,AL), but it was negatively correlated with smoking status (P<0.05). Moreover, CyPA total amount was positively correlated with GCF volume, EMMPRIN total amount and some of clinical periodontal indexes (GI,SBI,AL). In the control group,there were significant positive correlations among GCF volume, EMMPRIN total amount and CyPA total amount. The difference of GCF, EMMPRIN and CyPA between the 2 groups were statistically significant (P<0.05). EMMPRIN and its ligand CyPA in GCF of periodontitis-free patients with intact dentition and CP patients were all detected. As the progress of periodontal inflammation, GCF secretion increases, as well as the expressions of EMMPRIN and CyPA in GCF.

Impact of disease, cognitive and behavioural factors on caregiver outcome in amyotrophic lateral sclerosis.

PubMed

Watermeyer, Tamlyn J; Brown, Richard G; Sidle, Katie C L; Oliver, David J; Allen, Christopher; Karlsson, Joanna; Ellis, Cathy; Shaw, Christopher E; Al-Chalabi, Ammar; Goldstein, Laura H

2015-01-01

Up to 50% of patients with amyotrophic lateral sclerosis (ALS) show mild to moderate cognitive-behavioural change alongside their progressive functional impairment. This study examines the relative impact of patients' disease symptoms, behavioural change and current executive function and social cognition abilities on psychosocial outcomes in spouse caregivers of people with ALS. Thirty-five spouse caregivers rated their own levels of depression and anxiety, subjective burden and marital satisfaction. Caregivers also rated their partner's everyday behaviour. The patients were assessed for disease severity and cognitive function, with composite scores derived for executive function and social cognition. Regression analyses revealed that caregiver burden was predicted by the severity of patients' limb involvement and behavioural problems. Depression was predicted by patients' limb involvement, while behavioural problems and patient age predicted caregiver anxiety. Current marital satisfaction was predicted by patient behavioural problems beyond the level of pre-illness marital satisfaction. In conclusion, the study highlights the potential impact of ALS patients' functional impairment and behavioural change on ALS caregivers' psychosocial functioning. Clinical communication with ALS families should emphasise both physical and psychological challenges presented by the disease.

Efficient detection of Zika virus RNA in patients' blood from the 2016 outbreak in Campinas, Brazil.

PubMed

Judice, Carla Cristina; Tan, Jeslin J L; Parise, Pierina Lorencini; Kam, Yiu-Wing; Milanez, Guilherme Paier; Leite, Juliana Almeida; Caserta, Leonardo Cardia; Arns, Clarice Weis; Resende, Mariangela Ribeiro; Angerami, Rodrigo; Amaral, Eliana; Junior, Renato Passini; Freitas, André Ricardo Ribas; Costa, Fabio Trindade Maranhão; Proenca-Modena, Jose Luiz; Ng, Lisa F P

2018-03-05

Infection with Zika virus (ZIKV), a mosquito-borne flavivirus has been casually linked with increased congenital microcephaly in Brazil from 2015 through 2016. Sensitive and specific diagnosis of patients with Zika fever (ZIKF) remains critical for patient management. We developed a ZIKV NS5 qRT-PCR assay by combining primers described by Balm et al. and a new Taqman probe. The assay was evaluated and compared with another assay described by Lanciotti et al. (ZIKV 1107) using 51 blood and 42 urine samples from 54 suspected ZIKV patients. ZIKV NS5 performed better in terms of sensitivity with more samples detected as ZIKV-positive (n = 37) than ZIKV 1107 (n = 34) for urine, and ZIKV-positive (n = 29) than ZIKV 1107 (n = 26) for blood. Both assays displayed good overall agreement for urine (κappa = 0.770) and blood (κappa = 0.825) samples. Improved availability of validated diagnostic tests, such ZIKV NS5 qRT-PCR, will be critical to ensure adequate and accurate ZIKV diagnosis.

Metacognitions in patients with hallucinations and obsessive-compulsive disorder: the superstition factor.

PubMed

García-Montes, José M; Pérez-Alvarez, Marino; Soto Balbuena, Cristina; Perona Garcelán, Salvador; Cangas, Adolfo J

2006-08-01

On the basis of the analogy between intrusive thoughts and auditory hallucinations established by Morrison et al. [(1995). Intrusive thoughts and auditory hallucinations: a cognitive approach. Behavioural and Cognitive Psychotherapy, 23, 265-280], the present work compares the metacognitive beliefs and processes of five groups of patients (current hallucinators, never-hallucinated people with a diagnosis of schizophrenia, recovered hallucinators, obsessive-compulsive disorder (OCD) patients, and a clinical control group) and a non-clinical group. The results show that of the five metacognitive factors considered in this study, two were found to be different in the current hallucinators group in comparison to any other group in the design. Likewise, it is found that the metacognitive beliefs of the current hallucinators coincide with those of the OCD patients in various factors, particularly that relating to superstition, and this is interpreted as lending support to the model of Morrison et al. (1995). Furthermore, the results are discussed in the light of existing research on Thought-Action Fusion, stressing the role that may be played by superstitious beliefs and magical thinking in auditory hallucinations and OCD.

Analysis of some chosen elements of cerebrospinal fluid and serum in amyotrophic lateral sclerosis patients by total reflection X-ray fluorescence

NASA Astrophysics Data System (ADS)

Ostachowicz, B.; Lankosz, M.; Tomik, B.; Adamek, D.; Wobrauschek, P.; Streli, C.; Kregsamer, P.

2006-11-01

Trace elements play an important role in the human central nervous system. Significant variations of the concentration of trace elements in body fluids may occur in neurodegenerative diseases. In the present work an investigation of the elemental composition of the serum, and the cerebrospinal fluid in amyotrophic lateral sclerosis patients and a control group was performed. For the analysis of the body fluids Total reflection X-ray Fluorescence (TXRF) spectrometry was used. The samples were taken during routine diagnostic procedures. Na, Mg, Cl, K, Ca, Cu, Zn, and Br were determined in both fluids. In order to validate the results of analysis a serum standard reference material was measured. A t-test was applied to check if the mean concentrations of the elements are different for ALS and the control group. For the serum samples higher values for Br were found in the ALS group, for the cerebrospinal fluid lower values of Na, Mg and Zn as well as higher Ca values were found in the ALS group compared to the control group.

ANXA11 mutations prevail in Chinese ALS patients with and without cognitive dementia.

PubMed

Zhang, Kang; Liu, Qing; Liu, Keqiang; Shen, Dongchao; Tai, Hongfei; Shu, Shi; Ding, Qingyun; Fu, Hanhui; Liu, Shuangwu; Wang, Zhili; Li, Xiaoguang; Liu, Mingsheng; Zhang, Xue; Cui, Liying

2018-06-01

To investigate the genetic contribution of ANXA11 , a gene associated with amyotrophic lateral sclerosis (ALS), in Chinese ALS patients with and without cognitive dementia. Sequencing all the coding exons of ANXA11 and intron-exon boundaries in 18 familial amyotrophic lateral sclerosis (FALS), 353 unrelated sporadic amyotrophic lateral sclerosis (SALS), and 12 Chinese patients with ALS-frontotemporal lobar dementia (ALS-FTD). The transcripts in peripheral blood generated from a splicing mutation were examined by reverse transcriptase PCR. We identified 6 nonsynonymous heterozygous mutations (5 novel and 1 recurrent), 1 splice site mutation, and 1 deletion of 10 amino acids (not accounted in the mutant frequency) in 11 unrelated patients, accounting for a mutant frequency of 5.6% (1/18) in FALS, 2.3% (8/353) in SALS, and 8.3% (1/12) in ALS-FTD. The deletion of 10 amino acids was detected in 1 clinically undetermined male with an ALS family history who had atrophy in hand muscles and myotonic discharges revealed by EMG. The novel p. P36R mutation was identified in 1 FALS index, 1 patient with SALS, and 1 ALS-FTD. The splicing mutation (c.174-2A>G) caused in-frame skipping of the entire exon 6. The rest missense mutations including p.D40G, p.V128M, p.S229R, p.R302C and p.G491R were found in 6 unrelated patients with SALS. The ANXA11 gene is one of the most frequently mutated genes in Chinese patients with SALS. A canonical splice site mutation leading to skipping of the entire exon 6 further supports the loss-of-function mechanism. In addition, the study findings further expand the ANXA11 phenotype, first highlighting its pathogenic role in ALS-FTD.

Transanal drainage tube placement to prevent anastomotic leakage following colorectal cancer surgery with double stapling reconstruction.

PubMed

Matsuda, Mutsuhito; Tsuruta, Masashi; Hasegawa, Hirotoshi; Okabayashi, Koji; Kondo, Takayuki; Shimada, Takehiro; Yahagi, Masashi; Yoshikawa, Yusuke; Kitagawa, Yuko

2016-05-01

Anastomotic leakage (AL) is a critical complication of colorectal cancer surgery. The transanal drainage tube (TDT) is designed to prevent AL caused by decompression and stasis at the anastomosis. We conducted this study to investigate the feasibility of using the TDT to prevent AL following double-stapling technique reconstruction (DST). The subjects of this study were 179 patients who underwent curative resection and DST reconstruction for sigmoid colon and rectal cancer in our institution between 2008 and 2013. We analyzed the effectiveness of the TDT for preventing AL. A TDT was placed in 78 patients (43.6 %, TDT group) and not placed in the remaining 101 patients (56.4 %, NTDT group). AL developed in 2 (2.6 %) patients from the TDT group and in 14 (13.9 %) patients from the NTDT group (p = 0.009). Univariate analysis revealed that AL was significantly correlated with tumor distance from the anal verge (AV), the number of staples, and TDT placement. Multivariate analysis revealed a significantly positive correlation between AL and AV [OR 0.877 (0.783-0.982) p = 0.023] and a significantly negative correlation between AL and TDT placement [OR 0.07 (0.013-0.374) p = 0.002]. Anastomotic decompression with TDT placement may prevent AL after colorectal cancer surgery with DST reconstruction.

Longitudinal study of prognostic factors in established periodontitis patients.

PubMed

Machtei, E E; Dunford, R; Hausmann, E; Grossi, S G; Powell, J; Cummins, D; Zambon, J J; Genco, R J

1997-02-01

Numerous indicators for disease progression have been described in the last decade. The purpose of this study was to examine, longitudinally, a large battery of clinical, microbiological, and immunological indicators, to try to determine whether the presence of one or a combination of these parameters at baseline, would correlate positively with increased attachment and or bone loss (true prognostic factors). Following initial screening, 79 patients with established periodontitis were monitored longitudinally for one year. Whole mouth clinical measurements, plaque gingival and calculus indices, together with pocket depth and attachment level measurements, were repeated every three months. Full mouth radiographic survey, performed at baseline and 12 months, served to determine changes in crestal bone height using an image enhancement technique. Subgingival plaque samples were taken at baseline and every 3 months. Immunofluorescence assays were performed for the a battery of target microorganisms. Serum and GCF samples for IgG subclasses analysis were obtained at each visit and assayed using ELISA techniques. Likewise blood, samples were also drawn at each visit for a quantitative analysis of serum cotinine level. The overall mean attachment loss (AL) and bone loss (BL) were almost identical (0.159 mm and 0.164 mm, respectively). Individual patients variation was large (-0.733 to +1.004 mm). An overall 6.89% of sites were active; individual patients' means ranged from 0-28.9%. Mean pocket depth (PD) showed minimal change over the study period (-0.033 mm) thus suggesting that most if not all the AL was accompained by concomitant gingival recession. Smokers exhibited greater AL and radiographic BL compared to non-smokers. Likewise, patients' cotinine level showed direct correlation with outcomes of progressive periodontal breakdown. Past severity of periodontal involvement, as reflected in the patients baseline PD, AL and crestal bone height, showed good correlation with longitudinal changes in the periodontium. This correlation was higher for crestal BL as the outcome variable, while somewhat smaller for change in AL as the outcome variable. Bacteroides forsythus (Bf.), Prevotella intermedia (Pi.) and Porphyromonas gingivalis (Pg.) were frequently found in these patients. The presence of these microorganisms at baseline was associated with further disease progression. Subjects with mean baseline pocket depth equal or greater than 3.2 mm were at greater risk for future bone loss 1 year later (O.R. 2.97; C.I. 1.02-8.70). Smokers were at significantly greater risk for further attachment loss when compared to non-smokers (O.R. 5.41; C.I. 1.50-19.5). Subjects that harbored B. forsythus at baseline, were at seven times greater risk for increased pocket depth (O.R. 7.84; C.I.1.74-35.3). In conclusion, past periodontal destruction, smoking habits, Bf., Pg., & Pi. are prognostic factors for further periodontal breakdown. When designing clinical trials, or when evaluating epidemiological data, it is most important to balance for these factors. Also, treatment strategies should attempt to eliminate or modify these factors.

Reaching and Grasping a Glass of Water by Locked-In ALS Patients through a BCI-Controlled Humanoid Robot

PubMed Central

Spataro, Rossella; Chella, Antonio; Allison, Brendan; Giardina, Marcello; Sorbello, Rosario; Tramonte, Salvatore; Guger, Christoph; La Bella, Vincenzo

2017-01-01

Locked-in Amyotrophic Lateral Sclerosis (ALS) patients are fully dependent on caregivers for any daily need. At this stage, basic communication and environmental control may not be possible even with commonly used augmentative and alternative communication devices. Brain Computer Interface (BCI) technology allows users to modulate brain activity for communication and control of machines and devices, without requiring a motor control. In the last several years, numerous articles have described how persons with ALS could effectively use BCIs for different goals, usually spelling. In the present study, locked-in ALS patients used a BCI system to directly control the humanoid robot NAO (Aldebaran Robotics, France) with the aim of reaching and grasping a glass of water. Four ALS patients and four healthy controls were recruited and trained to operate this humanoid robot through a P300-based BCI. A few minutes training was sufficient to efficiently operate the system in different environments. Three out of the four ALS patients and all controls successfully performed the task with a high level of accuracy. These results suggest that BCI-operated robots can be used by locked-in ALS patients as an artificial alter-ego, the machine being able to move, speak and act in his/her place. PMID:28298888

A secure and efficient uniqueness-and-anonymity-preserving remote user authentication scheme for connected health care.

PubMed

Das, Ashok Kumar; Goswami, Adrijit

2013-06-01

Connected health care has several applications including telecare medicine information system, personally controlled health records system, and patient monitoring. In such applications, user authentication can ensure the legality of patients. In user authentication for such applications, only the legal user/patient himself/herself is allowed to access the remote server, and no one can trace him/her according to transmitted data. Chang et al. proposed a uniqueness-and-anonymity-preserving remote user authentication scheme for connected health care (Chang et al., J Med Syst 37:9902, 2013). Their scheme uses the user's personal biometrics along with his/her password with the help of the smart card. The user's biometrics is verified using BioHashing. Their scheme is efficient due to usage of one-way hash function and exclusive-or (XOR) operations. In this paper, we show that though their scheme is very efficient, their scheme has several security weaknesses such as (1) it has design flaws in login and authentication phases, (2) it has design flaws in password change phase, (3) it fails to protect privileged insider attack, (4) it fails to protect the man-in-the middle attack, and (5) it fails to provide proper authentication. In order to remedy these security weaknesses in Chang et al.'s scheme, we propose an improvement of their scheme while retaining the original merit of their scheme. We show that our scheme is efficient as compared to Chang et al.'s scheme. Through the security analysis, we show that our scheme is secure against possible attacks. Further, we simulate our scheme for the formal security verification using the widely-accepted AVISPA (Automated Validation of Internet Security Protocols and Applications) tool to ensure that our scheme is secure against passive and active attacks. In addition, after successful authentication between the user and the server, they establish a secret session key shared between them for future secure communication.

Localization and expression of ciliary neurotrophic factor (CNTF) in postmortem sciatic nerve from patients with motor neuron disease and diabetic neuropathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, D.A.; Gross, L.; Wittrock, D.A.

1996-08-01

Ciliary neurotrophic factor (CNTF) is thought to play an important role in the maintenance of the mature motor system. The factor is found most abundantly in myelinating Schwann cells in the adult sciatic nerve. Lack of neuronal growth factors has been proposed as one possible etiology of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Growth factor replacement therapies are currently being evaluated as a treatment for motor neuron disease. In this report we determined whether the expression of CNTF in sciatic nerve differed in patients with motor neuron disease compared to controls or patients with another form ofmore » axonopathy. We identified 8 patients (7 with ALS and 1 with SMA) with motor neuron disease and 6 patients with diabetic motor neuropathy who had autopsy material available. Immunoperoxidase staining showed reduced CNTF expression in nerves of patients with motor neuron disease but not in patients with diabetic motor neuropathy. Decreased CNTF appears be associated with primary motor neuron disease rather than a generalized process of axon loss. This result supports suggestions that CNTF deficiency may be an important factor in the development of motor neuron disease. 20 refs., 4 figs., 1 tab.« less

Tenecteplase versus alteplase in stroke thrombolysis: An individual patient data meta-analysis of randomized controlled trials.

PubMed

Huang, Xuya; MacIsaac, Rachael; Thompson, John Lp; Levin, Bruce; Buchsbaum, Richard; Haley, E Clarke; Levi, Christopher; Campbell, Bruce; Bladin, Christopher; Parsons, Mark; Muir, Keith W

2016-07-01

Tenecteplase, a modified plasminogen activator with higher fibrin specificity and longer half-life, may have advantages over alteplase in acute ischemic stroke thrombolysis. We undertook an individual patient data meta-analysis of randomized controlled trials that compared alteplase with tenecteplase in acute stroke. Eligible studies were identified by a MEDLINE search, and individual patient data were acquired. We compared clinical outcomes including modified Rankin Scale at three months, early neurological improvement at 24 h, intracerebral hemorrhage, symptomatic intracerebral hemorrhage, and mortality at three months between all dose tiers of tenecteplase and alteplase. Three relevant studies (Haley et al., Parsons et al., and ATTEST) included 291 patients and investigated three doses of tenecteplase (0.1, 0.25, 0.4 mg/kg). There were no differences between any dose of tenecteplase and alteplase for either efficacy or safety end points. Tenecteplase 0.25 mg/kg had the greatest odds to achieve early neurological improvement (OR [95%CI] 3.3 [1.5, 7.2], p = 0.093), excellent functional outcome (modified Rankin Scale 0-1) at three months (OR [95%CI] 1.9 [0.8, 4.4], p = 0.28), with reduced odds of intracerebral hemorrhage (OR [95%CI] 0.6 [0.2, 1.8], P = 0.43) compared with alteplase. Only 19 patients were treated with tenecteplase 0.4 mg/kg, which showed increased odds of symptomatic intracerebral hemorrhage compared with alteplase (OR [95% CI] 6.2 [0.7, 56.3]). While no significant differences between tenecteplase and alteplase were found, point estimates suggest potentially greater efficacy of 0.25 and 0.1 mg/kg doses with no difference in symptomatic intracerebral hemorrhage, and potentially higher symptomatic intracerebral hemorrhage risk with the 0.4 mg/kg dose. Further investigation of 0.25 mg/kg tenecteplase is warranted. © 2016 World Stroke Organization.

Early diagnosis of amyotrophic lateral sclerosis mimic syndromes: pros and cons of current clinical diagnostic criteria.

PubMed

Cortés-Vicente, Elena; Pradas, Jesús; Marín-Lahoz, Juan; De Luna, Noemi; Clarimón, Jordi; Turon-Sans, Janina; Gelpí, Ellen; Díaz-Manera, Jordi; Illa, Isabel; Rojas-Garcia, Ricard

2017-08-01

To describe the frequency and clinical characteristics of patients referred to a tertiary neuromuscular clinic as having amyotrophic lateral sclerosis (ALS) but who were re-diagnosed as having an ALS mimic syndrome, and to identify the reasons that led to the revision of the diagnosis. We reviewed the final diagnosis of all patients prospectively registered in the Sant Pau-MND register from 1 January 2004 to 31 December 2015. A detailed clinical evaluation and a clinically-guided electrophysiological study were performed at first evaluation. Twenty of 314 (6.4%) patients included were re-diagnosed as having a condition other than ALS, in 18 cases already at first evaluation. An alternative specific diagnosis was identified in 17 of those 20, consisting of a wide range of conditions. The main finding leading to an alternative diagnosis was the result of the electrophysiological study. Fifty per cent did not fulfil the El Escorial revised criteria (EECr) for ALS. The most common clinical phenotype at onset in patients with ALS mimic syndromes was progressive muscular atrophy (PMA). Misdiagnosing ALS is still a common problem. Early identification of ALS mimic syndromes is possible based on atypical clinical features and a clinically-guided electrophysiological study. Patients should be attended in specialised centres. The application of EECr helps to identify ALS misdiagnoses.

Coping strategies and psychological distress in caregivers of patients with Amyotrophic Lateral Sclerosis (ALS).

PubMed

Siciliano, Mattia; Santangelo, Gabriella; Trojsi, Francesca; Di Somma, Carmela; Patrone, Manila; Femiano, Cinzia; Monsurrò, Maria Rosaria; Trojano, Luigi; Tedeschi, Gioacchino

2017-08-01

Amyotrophic lateral sclerosis (ALS) causes distress in caregivers. The present study aims to examine the association between coping strategies and psychological distress in caregivers of ALS patients. Coping strategies were assessed in 96 ALS informal caregivers by means of the Coping Inventory for Stressful Situations. Data about caregivers' demographic characteristics, levels of burden, depression and anxiety (psychological distress) were also gathered by standardised questionnaires. Patients' clinical, cognitive and behavioural disturbances were evaluated by ALS specific assessment tools. Sequential logistic regression analysis showed that emotion-oriented coping strategy was significantly associated with high levels of depressive (p < 0.01) and anxiety (p < 0.05) symptoms and high levels of burden (p < 0.05), after controlling for all other variables. Moreover, a significant relationship of patients' functional dependence levels with burden experienced by caregivers was observed. No relationships were detected between task-oriented and avoidance-oriented coping strategies and caregivers' levels of psychological distress. The present study supported the mediating effects of coping strategies on intensity of burden, depression and anxiety experienced by ALS caregivers. These findings suggest that interventions aimed at reducing utilisation of maladaptive coping strategies may improve well-being in ALS caregivers, and, possibly, management of symptoms in ALS patients.

Immunoglobulins G from Sera of Amyotrophic Lateral Sclerosis Patients Induce Oxidative Stress and Upregulation of Antioxidative System in BV-2 Microglial Cell Line

PubMed Central

Milošević, Milena; Milićević, Katarina; Božić, Iva; Lavrnja, Irena; Stevanović, Ivana; Bijelić, Dunja; Dubaić, Marija; Živković, Irena; Stević, Zorica; Giniatullin, Rashid; Andjus, Pavle

2017-01-01

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with a very fast progression, no diagnostic tool for the presymptomatic phase, and still no effective treatment of the disease. Although ALS affects motor neurons, the overall pathophysiological condition points out to the non-cell autonomous mechanisms, where astrocytes and microglia play crucial roles in the disease progression. We have already shown that IgG from sera of ALS patients (ALS IgG) induce calcium transients and an increase in the mobility of acidic vesicles in cultured rat astrocytes. Having in mind the role of microglia in neurodegeneration, and a well-documented fact that oxidative stress is one of the many components contributing to the disease, we decided to examine the effect of ALS IgG on activation, oxidative stress and antioxidative system of BV-2 microglia, and to evaluate their acute effect on cytosolic peroxide, pH, and on reactive oxygen species (ROS) generation. All tested ALS IgGs (compared to control IgG) induced oxidative stress (rise in nitric oxide and the index of lipid peroxidation) followed by release of TNF-α and higher antioxidative defense (elevation of Mn- and CuZn-superoxide dismutase, catalase, and glutathione reductase with a decrease of glutathione peroxidase and glutathione) after 24 h treatment. Both ALS IgG and control IgG showed same localization on the membrane of BV-2 cells following 24 h treatment. Cytosolic peroxide and pH alteration were evaluated with fluorescent probes HyPer and SypHer, respectively, having in mind that HyPer also reacts to pH changes. Out of 11 tested IgGs from ALS patients, 4 induced slow exponential rise of HyPer signal, with maximal normalized fluorescence in the range 0.2–0.5, also inducing similar increase of SypHer intensity, but of a lower amplitude. None of the control IgGs induced changes with neither of the indicators. Acute ROS generation was detected in one out of three tested ALS samples with carboxy-H2DCFDA. The observed phenomena demonstrate the potential role of inflammatory humoral factors, IgGs, as potential triggers of the activation in microglia, known to occur in later stages of ALS. Therefore, revealing the ALS IgG signaling cascade in microglial cells could offer a valuable molecular biomarker and/or a potential therapeutic target. PMID:29218049

The fused in sarcoma protein forms cytoplasmic aggregates in motor neurons derived from integration-free induced pluripotent stem cells generated from a patient with familial amyotrophic lateral sclerosis carrying the FUS-P525L mutation.

PubMed

Liu, Xinxiu; Chen, Jiayu; Liu, Wenchao; Li, Xiaogang; Chen, Qi; Liu, Tao; Gao, Shaorong; Deng, Min

2015-07-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons (MNs) and has no effective treatment. Mutations in the fused in sarcoma (FUS) gene and abnormal aggregation of FUS protein have been reported in ALS. However, the mechanisms involved in ALS are poorly understood. Clinical drug trails have failed due to a lack of appropriate disease models, including a lack of access to MNs from ALS patients. Induced pluripotent stem (iPS) cells derived from patients with ALS provide an indispensable resource for in vitro mechanistic studies and for future patient-specific cell-based therapies. Previous reports demonstrated that viral-based ALS-iPS cells generated from fibroblasts harvested from Caucasian populations are ideal for basic research; however, ALS-iPS cells are precluded from cell-based therapeutic applications because of the risks associated with the integration of viral sequences into the genome and inconvenience associated with dermal biopsies. To establish a model for use in clinical applications, using episomal vectors, we generated an integration-free iPS cell line from peripheral blood mononuclear cells (PBMCs) harvested from a familial ALS (FALS) patient carrying the FUS-P525L mutation and a healthy control. Furthermore, we successfully differentiated ALS patient-specific iPS cells into MNs and subsequently detected cytoplasmic mislocalization and formation of FUS protein aggregates in MNs due to the FUS-P525L mutation. Our findings offer a cell-based disease model for use in further elucidating ALS pathogenesis and provide a tool for exploring gene repair coupled with cell replacement therapy.

Termination of Resuscitation Rules to Predict Neurological Outcomes in Out-of-Hospital Cardiac Arrest for an Intermediate Life Support Prehospital System.

PubMed

Cheong, Randy Wang Long; Li, Huihua; Doctor, Nausheen Edwin; Ng, Yih Yng; Goh, E Shaun; Leong, Benjamin Sieu-Hon; Gan, Han Nee; Foo, David; Tham, Lai Peng; Charles, Rabind; Ong, Marcus Eng Hock

2016-01-01

Futile resuscitation can lead to unnecessary transports for out-of-hospital cardiac arrest (OHCA). The Basic Life Support (BLS) and Advanced Life Support (ALS) termination of resuscitation (TOR) guidelines have been validated with good results in North America. This study aims to evaluate the performance of these two rules in predicting neurological outcomes of OHCA patients in Singapore, which has an intermediate life support Emergency Medical Services (EMS) system. A retrospective cohort study was carried out on Singapore OHCA data collected from April 2010 to May 2012 for the Pan-Asian Resuscitation Outcomes Study (PAROS). The outcomes of each rule were compared to the actual neurological outcomes of the patients. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and predicted transport rates of each test were evaluated. A total of 2,193 patients had cardiac arrest of presumed cardiac etiology. TOR was recommended for 1,411 patients with the BLS-TOR rule, with a specificity of 100% (91.9, 100.0) for predicting poor neurological outcomes, PPV 100% (99.7, 100.0), sensitivity 65.7% (63.6, 67.7), NPV 5.6% (4.1, 7.5), and transportation rate 35.6%. Using the ALS-TOR rule, TOR was recommended for 587 patients, specificity 100% (91.9, 100.0) for predicting poor neurological outcomes, PPV 100% (99.4, 100.0), sensitivity 27.3% (25.4, 29.3), NPV 2.7% (2.0, 3.7), and transportation rate 73.2%. BLS-TOR predicted survival (any neurological outcome) with specificity 93.4% (95% CI 85.3, 97.8) versus ALS-TOR 98.7% (95% CI 92.9, 99.8). Both the BLS and ALS-TOR rules had high specificities and PPV values in predicting neurological outcomes, the BLS-TOR rule had a lower predicted transport rate while the ALS-TOR rule was more accurate in predicting futility of resuscitation. Further research into unique local cultural issues would be useful to evaluate the feasibility of any system-wide implementation of TOR.

Back to the future: estimating pre-injury brain volume in patients with traumatic brain injury.

PubMed

Ross, David E; Ochs, Alfred L; D Zannoni, Megan; Seabaugh, Jan M

2014-11-15

A recent meta-analysis by Hedman et al. allows for accurate estimation of brain volume changes throughout the life span. Additionally, Tate et al. showed that intracranial volume at a later point in life can be used to estimate reliably brain volume at an earlier point in life. These advancements were combined to create a model which allowed the estimation of brain volume just prior to injury in a group of patients with mild or moderate traumatic brain injury (TBI). This volume estimation model was used in combination with actual measurements of brain volume to test hypotheses about progressive brain volume changes in the patients. Twenty six patients with mild or moderate TBI were compared to 20 normal control subjects. NeuroQuant® was used to measure brain MRI volume. Brain volume after the injury (from MRI scans performed at t1 and t2) was compared to brain volume just before the injury (volume estimation at t0) using longitudinal designs. Groups were compared with respect to volume changes in whole brain parenchyma (WBP) and its 3 major subdivisions: cortical gray matter (GM), cerebral white matter (CWM) and subcortical nuclei+infratentorial regions (SCN+IFT). Using the normal control data, the volume estimation model was tested by comparing measured brain volume to estimated brain volume; reliability ranged from good to excellent. During the initial phase after injury (t0-t1), the TBI patients had abnormally rapid atrophy of WBP and CWM, and abnormally rapid enlargement of SCN+IFT. Rates of volume change during t0-t1 correlated with cross-sectional measures of volume change at t1, supporting the internal reliability of the volume estimation model. A logistic regression analysis using the volume change data produced a function which perfectly predicted group membership (TBI patients vs. normal control subjects). During the first few months after injury, patients with mild or moderate TBI have rapid atrophy of WBP and CWM, and rapid enlargement of SCN+IFT. The magnitude and pattern of the changes in volume may allow for the eventual development of diagnostic tools based on the volume estimation approach. Copyright © 2014 Elsevier Inc. All rights reserved.

Statistical quantifiers of memory for an analysis of human brain and neuro-system diseases

NASA Astrophysics Data System (ADS)

Demin, S. A.; Yulmetyev, R. M.; Panischev, O. Yu.; Hänggi, Peter

2008-03-01

On the basis of a memory function formalism for correlation functions of time series we investigate statistical memory effects by the use of appropriate spectral and relaxation parameters of measured stochastic data for neuro-system diseases. In particular, we study the dynamics of the walk of a patient who suffers from Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and compare against the data of healthy people (CO - control group). We employ an analytical method which is able to characterize the stochastic properties of stride-to-stride variations of gait cycle timing. Our results allow us to estimate quantitatively a few human locomotion function abnormalities occurring in the human brain and in the central nervous system (CNS). Particularly, the patient's gait dynamics are characterized by an increased memory behavior together with sizable fluctuations as compared with the locomotion dynamics of healthy patients. Moreover, we complement our findings with peculiar features as detected in phase-space portraits and spectral characteristics for the different data sets (PD, HD, ALS and healthy people). The evaluation of statistical quantifiers of the memory function is shown to provide a useful toolkit which can be put to work to identify various abnormalities of locomotion dynamics. Moreover, it allows one to diagnose qualitatively and quantitatively serious brain and central nervous system diseases.

Comparison of the new biometer OA-1000 with IOLMaster and Tomey AL-3000.

PubMed

Goebels, Susanne Christiane; Seitz, Berthold; Langenbucher, Achim

2013-09-01

The OA-1000 (Tomey, Japan) is a new optical biometer, which allows measurements of axial length (AL), anterior chamber depth (ACD) and corneal thickness (CT) due to partial coherence interferometry (PCI) technology. The aim of this study was to compare the OA-1000 results with those obtained with the IOLMaster and contact applanation A-scan ultrasonography. We examined 133 eyes of 75 patients with age related cataract. Mean age was 72.0 ± 9.5 years. Biometry measurements of AL and ACD were performed with the Tomey OA-1000 based on PCI, the IOLMaster based on PCI (AL) and slit projection (ACD), and the Tomey AL-3000 based on contact applanation A-scan ultrasonography. Mean AL using the IOLMaster was 23.21 ± 1.08 mm, using the AL-3000 was 22.79 ± 1.04 mm, using the OA-1000 it was 22.97 ± 1.1 mm. Mean ACD using the IOLMaster was 2.99 ± 0.41 mm, using the OA-1000 3.40 ± 0.46 mm, using the Tomey AL-3000 it was 2.93 ± 0.43 mm. Mean difference between the AL and ACD measured with the OA-1000 and the IOLMaster was 0.22 ± 0.047 mm and 0.40 ± 0.33 mm, between OA-1000 and the AL-3000 it was 0.19 ± 0.23 mm and 0.47 ± 0.33 mm, and between IOLMaster and AL-3000 it was 0.42 ± 0.23 and 0.09 ± 0.36 mm. For AL the correlation coefficient R between IOLMaster and OA-1000 was 0.999, between IOLMaster and AL-3000 it was 0.976, between AL-3000 and OA-1000 it was 0.977. For ACD R between IOLMaster and OA-1000 was 0.735, between IOLMaster and AL-3000 it was 0.822, between AL-3000 and OA-1000 it was 0.716 (all p < 0.001). Compared with other used clinical instruments the OA-1000 generates accurate results. Although differences were found, the OA-1000 provided results that correlated well with the values of IOLMaster and AL-3000.

Patients with Amyotrophic Lateral Sclerosis Have High Interest in and Limited Access to Genetic Testing.

PubMed

Wagner, Karin N; Nagaraja, Haikady; Allain, Dawn C; Quick, Adam; Kolb, Stephen; Roggenbuck, Jennifer

2017-06-01

Although genetic testing for amyotrophic lateral sclerosis (ALS) is widely available, it is unknown what proportion of patients with ALS have access to genetic counseling and testing, and patient attitudes towards ALS genetic testing have not been studied. We conducted a national survey of ALS patients enrolled in the Agency for Toxic Substances and Disease Registry, which consisted of multiple choice questions and two 12 item Likert scale series assessing respondents' experience with and attitude toward genetic testing. The survey had an 8 % response rate, with 449 completed responses. Genetic testing was offered to 33.4 % and completed by 67.1 % of those offered. A minority of respondents (12.5 %) saw a genetic counselor, and were much more likely to be offered genetic testing (p = 0.0001). Respondents with a family history of ALS (8.4 %) were more likely to be offered testing (p = 0.0001) and complete testing (p = 0.05). Respondents with a family history of ALS were more likely to report a favorable attitude towards genetic testing (p = 0.0003), as were respondents who saw a genetic counselor (p = 0.02). The majority of respondents (82.7 %) felt that genetic testing should be offered to all patients with ALS. Our results indicate that ALS patients may have limited access to genetic testing, but perceive benefit from this service. Development of practice guidelines for genetic testing in ALS, to include the routine offer of genetic counseling, may result in broader and more consistent access to these services.

Prognostic significance of interventricular septal thickness in patients with AL amyloidosis.

PubMed

Cho, Hyunsoo; Kim, Soo-Jeong; Shim, Chi Young; Hong, Geu-Ru; Ha, Jong-Won; Kim, Yu Ri; Yang, Woo Ick; Chung, Haerim; Jang, Ji Eun; Cheong, June-Won; Min, Yoo Hong; Kim, Jin Seok

2017-09-01

The major prognostic determinant of immunoglobulin light chain (AL) amyloidosis is cardiac involvement. However, the role of interventricular septal thickness (IVST), which reflects the extent of cardiac involvement, remains unclear. Therefore, we analyzed 77 patients with newly diagnosed AL amyloidosis and evaluated the prognostic role of IVST. Fifty patients (64.9%) had cardiac involvement and 17 patients (22.1%) showed IVST >15mm. Among all patients, the revised Mayo Clinic Stage III-IV and IVST >15mm were independently associated with inferior overall survival (OS) in a multivariable analysis. IVST >15mm was also adversely prognostic for OS in a subgroup of advanced-stage (revised Mayo Clinic stage III-IV) patients in a multivariable analysis (P<0.001). Furthermore, advanced-stage patients with IVST >15mm did not show survival benefit from treatment with bortezomib-based regimens and/or autologous stem-cell transplantation (ASCT). Our study demonstrated that IVST >15mm is adversely prognostic independent of the revised Mayo Clinic staging system in patients with AL amyloidosis. In addition, the degree of IVST might be used as a useful prognostic indicator that can guide the management of patients with AL amyloidosis especially at an advanced stage. Copyright © 2017 Elsevier Ltd. All rights reserved.

A prospective algorithm for the management of air leaks after pulmonary resection.

PubMed

Cerfolio, R J; Tummala, R P; Holman, W L; Zorn, G L; Kirklin, J K; McGiffin, D C; Naftel, D C; Pacifico, A D

1998-11-01

Air leaks (ALs) are a common complication after pulmonary resection, yet there is no consensus on their management. An algorithm for the management of chest tubes (CT) and ALs was applied prospectively to 101 consecutive patients who underwent elective pulmonary resection. Air leaks were graded daily as forced expiratory only, expiratory only, inspiratory only, or continuous. All CTs were kept on 20 cm of suction until postoperative day 2 and were then converted to water seal. On postoperative day 3, if both a pneumothorax and AL were present, the CT was placed to 10 cm H2O of suction. If a pneumothorax was present without an AL, the CT was returned to 20 cm H2O of suction. Air leaks that persisted after postoperative day 7 were treated with talc slurry. There were 101 patients (67 men); on postoperative day 1, 26 had ALs and all were expiratory only. Univariable analysis showed a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) (p = 0.005), increased age (p = 0.007), increased ratio of residual volume to total lung capacity (RV/TLC) (p = 0.04), increased RV (p = 0.02), and an increased functional residual capacity (FRC) (p = 0.02) to predict the presence of an AL on postoperative day 1. By postoperative day 2, 22 patients had expiratory ALs. After 12 hours of water seal, 13 of the 22 patients' ALs had stopped, and 3 more sealed by the morning of postoperative day 3. However, 2 of the 6 patients whose ALs continued experienced a pneumothorax. Five of the 6 patients with ALs on postoperative day 4 still had ALs on postoperative day 7, and all were treated by talc slurry through the CT. All ALs resolved within 24 hours after talc slurry. Most ALs after pulmonary resection are expiratory only. A low FEV1/FVC ratio, increased age, increased RV/TLC ratio, increased RV, and an increased FRC were predictors of having an ALs on postoperative day 1. Conversion from suction to water seal is an effective way of sealing expiratory AL, and pneumothorax is rare. If an expiratory AL does not stop by postoperative day 4 it will probably persist until postoperative day 7, and talc slurry may be an effective treatment.

The influence of insurance status on waiting times in German acute care hospitals: an empirical analysis of new data

PubMed Central

2009-01-01

Background There is an ongoing debate in Germany about the assumption that patients with private health insurance (PHI) benefit from better access to medical care, including shorter waiting times (Lüngen et al. 2008), compared to patients with statutory health insurance (SHI). Problem Existing analyses of the determinants for waiting times in Germany are a) based on patient self-reports and b) do not cover the inpatient sector. This paper aims to fill both gaps by (i) generating new primary data and (ii) analyzing waiting times in German hospitals. Methods We requested individual appointments from 485 hospitals within an experimental study design, allowing us to analyze the impact of PHI versus SHI on waiting times (Asplin et al. 2005). Results In German acute care hospitals patients with PHI have significantly shorter waiting times than patients with SHI. Conclusion Discrimination in waiting times by insurance status does occur in the German acute hospital sector. Since there is very little transparency in treatment quality in Germany, we do not know whether discrimination in waiting times leads to discrimination in the quality of treatment. This is an important issue for future research. PMID:20025744

Is language impairment more common than executive dysfunction in amyotrophic lateral sclerosis?

PubMed

Taylor, Lorna J; Brown, Richard G; Tsermentseli, Stella; Al-Chalabi, Ammar; Shaw, Christopher E; Ellis, Catherine M; Leigh, P Nigel; Goldstein, Laura H

2013-05-01

Systematic explorations of language abilities in patients with amyotrophic lateral sclerosis (ALS) are lacking in the context of wider cognitive change. Neuropsychological assessment data were obtained from 51 patients with ALS and 35 healthy controls matched for age, gender and IQ. Composite scores were derived for the domains of language and executive functioning. Domain impairment was defined as a composite score ≤5th centile relative to the control mean. Cognitive impairment was also classified using recently published consensus criteria. The patients with ALS were impaired on language and executive composite scores. Language domain impairment was found in 43% of patients with ALS, and executive domain impairment in 31%. Standardised language and executive composite scores correlated in the ALS group (r=0.68, p<0.001). Multiple regression analyses indicated that scores on the executive composite accounted for 44% of the variance in language composite scores. Language impairments are at least as prevalent as executive dysfunction in ALS. While the two domains are strongly associated, executive dysfunction does not fully account for the profile of language impairments observed, further highlighting the heterogeneity of cognitive impairment in non-demented patients with ALS.

Impaired Perception of Emotional Expression in Amyotrophic Lateral Sclerosis.

PubMed

Oh, Seong Il; Oh, Ki Wook; Kim, Hee Jin; Park, Jin Seok; Kim, Seung Hyun

2016-07-01

The increasing recognition that deficits in social emotions occur in amyotrophic lateral sclerosis (ALS) is helping to explain the spectrum of neuropsychological dysfunctions, thus supporting the view of ALS as a multisystem disorder involving neuropsychological deficits as well as motor deficits. The aim of this study was to characterize the emotion perception abilities of Korean patients with ALS based on the recognition of facial expressions. Twenty-four patients with ALS and 24 age- and sex-matched healthy controls completed neuropsychological tests and facial emotion recognition tasks [ChaeLee Korean Facial Expressions of Emotions (ChaeLee-E)]. The ChaeLee-E test includes facial expressions for seven emotions: happiness, sadness, anger, disgust, fear, surprise, and neutral. The ability to perceive facial emotions was significantly worse among ALS patients performed than among healthy controls [65.2±18.0% vs. 77.1±6.6% (mean±SD), p=0.009]. Eight of the 24 patients (33%) scored below the 5th percentile score of controls for recognizing facial emotions. Emotion perception deficits occur in Korean ALS patients, particularly regarding facial expressions of emotion. These findings expand the spectrum of cognitive and behavioral dysfunction associated with ALS into emotion processing dysfunction.

Quality improvement in neurology: amyotrophic lateral sclerosis quality measures: report of the quality measurement and reporting subcommittee of the American Academy of Neurology.

PubMed

Miller, Robert G; Brooks, Benjamin Rix; Swain-Eng, Rebecca J; Basner, Robert C; Carter, Gregory T; Casey, Patricia; Cohen, Adam B; Dubinsky, Richard; Forshew, Dallas; Jackson, Carlayne E; Kasarskis, Ed; Procaccini, Nicholas J; Sanjak, Mohammed; Tolin, Fredrik P

2013-12-10

Amyotrophic lateral sclerosis (ALS) is a lethal, progressive neurodegenerative disease characterized by loss of motor neurons.(1) Patients with ALS lose function in the limbs, speech, swallowing, and breathing muscles. The cause of the disease is still not known for most patients. Approximately 25,000 people in the United States have ALS, and 5,000 people are diagnosed with ALS annually in the United States.(1) Most patients die from respiratory failure 2 to 5 years after onset of symptoms. Cognitive dysfunction is seen in 20% to 50% of patients.(2) The disease burden for patients and caregivers is enormous. The average cost of care has been estimated at $50,000 per patient per year.(3.)

Glutamate and aspartate are decreased in the skin in amyotrophic lateral sclerosis

NASA Technical Reports Server (NTRS)

Ono, S.; Yamauchi, M.

1992-01-01

We measured the levels of amino acids in biopsied skin from eight patients with amyotrophic lateral sclerosis (ALS) and seven controls. The most conspicuous changes in ALS patients were as follows. First, the contents of the acidic amino acids glutamate and aspartate were significantly decreased in ALS, and were negatively and significantly associated with the duration of illness. Second, the levels of the collagen-associated amino acids hydroxyproline, proline, glycine, alanine, and hydroxylysine were significantly decreased in ALS, and correlated inversely with the duration of illness. These results suggest that there are abnormalities of acidic amino acids and collagen-associated amino acids in the skin of patients with ALS. These changes may underlie the pathogenesis of ALS.

Efficacy of Botulinum toxin A for the treatment of Bladder pain syndrome: A systematic review.

PubMed

Ochoa Vargas, D C; García Perdómo, H A

2018-04-01

To determine the efficacy and safety of BTX-A, compared with other interventions for the treatment of BPS to improve quality of life. This systematic review fulfils all the requirements of the Cochrane manual and PRISMA reporting guidelines. The PROSPERO registration number is: CRD42016039480.Clinical trials without language discrimination were included. BPS patients over 18 y/o that were treated with BTX-A were included. Studies were searched in published databases and no published literature from inception to the present day. Risk of bias analysis was done using the Cochrane risk of bias tool. 88 articles were found with the designed search strategies. After exclusions, four studies were included in the qualitative analyses. Kasyan et al., 2012 compared BTX-A with hydrodistention. Manning et al., 2014 compared the injection of BTX-A with the injection of normal saline in previously hydrodistended bladders. In both cases, primary end point was measured by the O'Leary-Sant questionnaire score. El-Bahnasy et al., 2009 compared BTX-A with BCG administration, through Global Response Assessment. Kuo et al., 2015 compared hydrodistention plus suburothelial injections of BTX-A with hydrodistension plus normal saline injections. Reduction in pain was estimated by VAS bladder pain score. A similar efficacy to their controls had been found in Kasyan and Manning studies. El-Bahnasy had found improvement in BTX-A in all parameters. Kuo el al. 2015, found a significantly reduction in pain in the BTX-A group. Regarding the risk of bias, three studies did not have adequate descriptions of selection, performance and detection bias. The study of Manning had low risk of selection, attrition and reporting bias. There is not enough evidence to conclude the efficacy of BTX-A for the treatment of interstitial cystitis to improve quality of life. Copyright © 2017 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

Robust anonymous authentication scheme for telecare medical information systems.

PubMed

Xie, Qi; Zhang, Jun; Dong, Na

2013-04-01

Patient can obtain sorts of health-care delivery services via Telecare Medical Information Systems (TMIS). Authentication, security, patient's privacy protection and data confidentiality are important for patient or doctor accessing to Electronic Medical Records (EMR). In 2012, Chen et al. showed that Khan et al.'s dynamic ID-based authentication scheme has some weaknesses and proposed an improved scheme, and they claimed that their scheme is more suitable for TMIS. However, we show that Chen et al.'s scheme also has some weaknesses. In particular, Chen et al.'s scheme does not provide user's privacy protection and perfect forward secrecy, is vulnerable to off-line password guessing attack and impersonation attack once user's smart card is compromised. Further, we propose a secure anonymity authentication scheme to overcome their weaknesses even an adversary can know all information stored in smart card.

Evaluation of two minimal-preparation regimes for CT colonography: optimising image quality and patient acceptability.

PubMed

Pollentine, A; Mortimer, A; McCoubrie, P; Archer, L

2012-08-01

To compare a 2 day bowel preparation regime of barium, iodine and a mild stimulant laxative with a 1 day iodine-only regime for CT colonography (CTC). 100 consecutive patients underwent CTC. The first 50 patients (Regime 1) ingested 1 bisacodyl tablet twice a day 3 days before CTC and 1 dose each of 50 ml of barium and 20 ml of iodinated contrast per day starting 2 days before CTC. The second 50 patients (Regime 2) ingested 3 doses of iodinated contrast over 24 h prior to CTC. Volumes of residual stool and fluid, and the effectiveness of stool and fluid tagging, were graded according to methods established by Taylor et al (Taylor S, Slaker A, Burling D, Tam E, Greenhalgh R, Gartner L, et al. CT colonography: optimisation, diagnostic performance and patient acceptability of reduced-laxative regimens using barium-based faecal tagging. Eur Radiol 2008; 18: 32-42). A 3 day low-residue diet was taken by both cohorts. Questionnaires rating the side-effects and burden of the bowel preparation were compared to a control cohort of patients undergoing barium enema. The proportion of colons producing none/scattered stool (score 1) was 90.3% with Regime 1 and 65.0% with Regime 2 (p<0.005). Any residual stool was significantly better tagged with Regime 1 (score 5), with 91.7% of Regime 1 exhibiting optimum tagging vs 71.3% of Regime 2 (p<0.05). No significant differences in side-effects between the bowel preparation regimes for CTC were elicited. Bowel preparation for barium enema was tolerated significantly worse than both of the CTC bowel preparation regimes. Regime 1, containing a 3 day preparation of a mild laxative, barium and iodine, produced a significantly better prepared colon, with no difference in patient acceptability.

Repair-oriented classification of aortic insufficiency: impact on surgical techniques and clinical outcomes.

PubMed

Boodhwani, Munir; de Kerchove, Laurent; Glineur, David; Poncelet, Alain; Rubay, Jean; Astarci, Parla; Verhelst, Robert; Noirhomme, Philippe; El Khoury, Gébrine

2009-02-01

Valve repair for aortic insufficiency requires a tailored surgical approach determined by the leaflet and aortic disease. Over the past decade, we have developed a functional classification of AI, which guides repair strategy and can predict outcome. In this study, we analyze our experience with a systematic approach to aortic valve repair. From 1996 to 2007, 264 patients underwent elective aortic valve repair for aortic insufficiency (mean age - 54 +/- 16 years; 79% male). AV was tricuspid in 171 patients bicuspid in 90 and quadricuspid in 3. One hundred fifty three patients had type I dysfunction (aortic dilatation), 134 had type II (cusp prolapse), and 40 had type III (restrictive). Thirty six percent (96/264) of the patients had more than one identified mechanism. In-hospital mortality was 1.1% (3/264). Six patients experienced early repair failure; 3 underwent re-repair. Functional classification predicted the necessary repair techniques in 82-100% of patients, with adjunctive techniques being employed in up to 35% of patients. Mid-term follow up (median [interquartile range]: 47 [29-73] months) revealed a late mortality rate of 4.2% (11/261, 10 cardiac). Five year overall survival was 95 +/- 3%. Ten patients underwent aortic valve reoperation (1 re-repair). Freedoms from recurrent Al (>2+) and from AV reoperation at 5 years was 88 +/- 3% and 92 +/- 4% respectively and patients with type I (82 +/- 9%; 93 +/- 5%) or II (95 +/- 5%; 94 +/- 6%) had better outcomes compared to type III (76 +/- 17%; 84 +/- 13%). Aortic valve repair is an acceptable therapeutic option for patients with aortic insufficiency. This functional classification allows a systematic approach to the repair of Al and can help to predict the surgical techniques required as well as the durability of repair. Restrictive cusp motion (type III), due to fibrosis or calcification, is an important predictor for recurrent Al following AV repair.

Percutaneous endoscopic gastrostomy in patients with amyotrophic lateral sclerosis: Mortality and complications.

PubMed

Carbó Perseguer, J; Madejón Seiz, A; Romero Portales, M; Martínez Hernández, J; Mora Pardina, J S; García-Samaniego, J

2018-03-26

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes severe dysphagia and weight loss. Percutaneous endoscopic gastrostomy (PEG) is currently the technique of choice for the enteral nutrition of these patients. To analyse mortality and complications in a series of patients diagnosed with ALS who underwent PEG, and to evaluate factors related to patient survival after the procedure. We performed a prospective, observational study including all patients diagnosed with ALS and treated by our hospital's Gastroenterology Department in the period 1997-2013. We studied mortality, complications, and clinical and biochemical parameters, and correlated these with the survival rate. The study included a total of 57 patients, of whom 49 were ultimately treated with PEG. ALS onset was bulbar in 30 patients and spinal in 19. Mortality during the procedure and at 30 days was 2% (n = 1). Six patients (12.2%) experienced major complications; 17 (34.7%) experienced less serious complications which were easily resolved with conservative treatment. No significant differences were observed in forced vital capacity, albumin level, or age between patients with (n = 6) and without (n = 43) major complications. PEG is an effective, relatively safe procedure for the enteral nutrition of patients with ALS, although not without morbidity and mortality. Neither forced vital capacity nor the form of presentation of ALS were associated with morbidity in PEG. Copyright © 2018 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Practice Parameter update: The care of the patient with amyotrophic lateral sclerosis: Multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review)

PubMed Central

Miller, R G.; Jackson, C E.; Kasarskis, E J.; England, J D.; Forshew, D; Johnston, W; Kalra, S; Katz, J S.; Mitsumoto, H; Rosenfeld, J; Shoesmith, C; Strong, M J.; Woolley, S C.

2009-01-01

Objective: To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS). Methods: The authors analyzed studies from 1998 to 2007 to update the 1999 practice parameter. Topics covered in this section include breaking the news, multidisciplinary clinics, symptom management, cognitive and behavioral impairment, communication, and palliative care for patients with ALS. Results: The authors identified 2 Class I studies, 8 Class II studies, and 30 Class III studies in ALS, but many important areas have been little studied. More high-quality, controlled studies of symptomatic therapies and palliative care are needed to guide management and assess outcomes in patients with ALS. Recommendations: Multidisciplinary clinic referral should be considered for managing patients with ALS to optimize health care delivery and prolong survival (Level B) and may be considered to enhance quality of life (Level C). For the treatment of refractory sialorrhea, botulinum toxin B should be considered (Level B) and low-dose radiation therapy to the salivary glands may be considered (Level C). For treatment of pseudobulbar affect, dextromethorphan and quinidine should be considered if approved by the US Food and Drug Administration (Level B). For patients who develop fatigue while taking riluzole, withholding the drug may be considered (Level C). Because many patients with ALS demonstrate cognitive impairment, which in some cases meets criteria for dementia, screening for cognitive and behavioral impairment should be considered in patients with ALS (Level B). Other management strategies all lack strong evidence. GLOSSARY ALS = amyotrophic lateral sclerosis; ALS-FTD = amyotrophic lateral sclerosis with a dementia meeting the Neary criteria for frontotemporal dementia; ALSbi = amyotrophic lateral sclerosis with behavioral impairment; ALSci = amyotrophic lateral sclerosis with cognitive impairment; BTxA = botulinum toxin type A; BTxB = botulinum toxin type B; DM = dextromethorphan; FDA = Food and Drug Administration; FTD = frontotemporal dementia; NIV = noninvasive ventilation; PEG = percutaneous endoscopic gastrostomy; Q = quinidine. PMID:19822873

A review and comparison of methods for recreating individual patient data from published Kaplan-Meier survival curves for economic evaluations: a simulation study.

PubMed

Wan, Xiaomin; Peng, Liubao; Li, Yuanjian

2015-01-01

In general, the individual patient-level data (IPD) collected in clinical trials are not available to independent researchers to conduct economic evaluations; researchers only have access to published survival curves and summary statistics. Thus, methods that use published survival curves and summary statistics to reproduce statistics for economic evaluations are essential. Four methods have been identified: two traditional methods 1) least squares method, 2) graphical method; and two recently proposed methods by 3) Hoyle and Henley, 4) Guyot et al. The four methods were first individually reviewed and subsequently assessed regarding their abilities to estimate mean survival through a simulation study. A number of different scenarios were developed that comprised combinations of various sample sizes, censoring rates and parametric survival distributions. One thousand simulated survival datasets were generated for each scenario, and all methods were applied to actual IPD. The uncertainty in the estimate of mean survival time was also captured. All methods provided accurate estimates of the mean survival time when the sample size was 500 and a Weibull distribution was used. When the sample size was 100 and the Weibull distribution was used, the Guyot et al. method was almost as accurate as the Hoyle and Henley method; however, more biases were identified in the traditional methods. When a lognormal distribution was used, the Guyot et al. method generated noticeably less bias and a more accurate uncertainty compared with the Hoyle and Henley method. The traditional methods should not be preferred because of their remarkable overestimation. When the Weibull distribution was used for a fitted model, the Guyot et al. method was almost as accurate as the Hoyle and Henley method. However, if the lognormal distribution was used, the Guyot et al. method was less biased compared with the Hoyle and Henley method.

A Review and Comparison of Methods for Recreating Individual Patient Data from Published Kaplan-Meier Survival Curves for Economic Evaluations: A Simulation Study

PubMed Central

Wan, Xiaomin; Peng, Liubao; Li, Yuanjian

2015-01-01

Background In general, the individual patient-level data (IPD) collected in clinical trials are not available to independent researchers to conduct economic evaluations; researchers only have access to published survival curves and summary statistics. Thus, methods that use published survival curves and summary statistics to reproduce statistics for economic evaluations are essential. Four methods have been identified: two traditional methods 1) least squares method, 2) graphical method; and two recently proposed methods by 3) Hoyle and Henley, 4) Guyot et al. The four methods were first individually reviewed and subsequently assessed regarding their abilities to estimate mean survival through a simulation study. Methods A number of different scenarios were developed that comprised combinations of various sample sizes, censoring rates and parametric survival distributions. One thousand simulated survival datasets were generated for each scenario, and all methods were applied to actual IPD. The uncertainty in the estimate of mean survival time was also captured. Results All methods provided accurate estimates of the mean survival time when the sample size was 500 and a Weibull distribution was used. When the sample size was 100 and the Weibull distribution was used, the Guyot et al. method was almost as accurate as the Hoyle and Henley method; however, more biases were identified in the traditional methods. When a lognormal distribution was used, the Guyot et al. method generated noticeably less bias and a more accurate uncertainty compared with the Hoyle and Henley method. Conclusions The traditional methods should not be preferred because of their remarkable overestimation. When the Weibull distribution was used for a fitted model, the Guyot et al. method was almost as accurate as the Hoyle and Henley method. However, if the lognormal distribution was used, the Guyot et al. method was less biased compared with the Hoyle and Henley method. PMID:25803659

MRI in patients with chronic pubalgia: Is precise useful information provided to the surgeon? A case-control study.

PubMed

Larbi, A; Pesquer, L; Reboul, G; Omoumi, P; Perozziello, A; Abadie, P; Loriaut, P; Copin, P; Ducouret, E; Dallaudière, B

2016-10-01

Recent studies described that MRI is a good examination to assess damage in chronic athletic pubalgia (AP). However, to our knowledge, no studies focus on systematic correlation of precise tendon or parietal lesion in MRI with surgery and histological assessment. Therefore, we performed a case-control study to determine if MRI can precisely assess Adductor longus (AL) tendinopathy and parietal lesion, compared with surgery and histology. MRI can determine if AP comes from pubis symphysis, musculotendinous or inguinal orifice structures. Eighteen consecutive patients were enrolled from November 2011 to April 2013 for chronic AP. To constitute a control group, we also enrolled 18 asymptomatic men. All MRI were reviewed in consensus by 2 skeletal radiologists for pubic symphysis, musculotendinous, abdominal wall assessment and compared to surgery and histology findings. Regarding pubis symphysis, we found 4 symmetric bone marrow oedema (14%), 2 secondary cleft (7%) and 2 superior ligaments lesions (7%). For AL tendon, we mainly found 13 asymmetric bone marrow oedema (46%), 15 hyperaemia (54%). Regarding abdominal wall, the deep inguinal orifice size in the group of symptomatic athletes and the control group was respectively 27.3±6.4mm and 23.8±6.3mm. The correlation between MRI and surgery/histology was low: 20% for the AL tendon and 9% for the abdominal wall. If we chose the criteria "affected versus unaffected", this correlation became higher: 100% for AL tendon and 73% for the abdominal wall. MRI chronic athletic pubalgia concerns preferentially AL tendinopathy and deep inguinal canal dehiscence with high correlation to surgery/histology when only considering the item "affected versus unaffected" despite low correlation when we try to precisely grade these lesions. III: case-control study. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Oral motor functions, speech and communication before a definitive diagnosis of amyotrophic lateral sclerosis.

PubMed

Makkonen, Tanja; Korpijaakko-Huuhka, Anna-Maija; Ruottinen, Hanna; Puhto, Riitta; Hollo, Kirsi; Ylinen, Aarne; Palmio, Johanna

2016-01-01

The aim of this study was to explore the cranial nerve symptoms, speech disorders and communicative effectiveness of Finnish patients with diagnosed or possible amyotrophic lateral sclerosis (ALS) at their first assessment by a speech-language pathologist. The group studied consisted of 30 participants who had clinical signs of bulbar deterioration at the beginning of the study. They underwent a thorough clinical speech and communication examination. The cranial nerve symptoms and ability to communicate were compared in 14 participants with probable or definitive ALS and in 16 participants with suspected or possible ALS. The initial type of ALS was also assessed. More deterioration in soft palate function was found in participants with possible ALS than with diagnosed ALS. Likewise, a slower speech rate combined with more severe dysarthria was observed in possible ALS. In both groups, there was some deterioration in communicative effectiveness. In the possible ALS group the diagnostic delay was longer and speech therapy intervention actualized later. The participants with ALS showed multidimensional decline in communication at their first visit to the speech-language pathologist, but impairments and activity limitations were more severe in suspected or possible ALS. The majority of persons with bulbar-onset ALS in this study were in the latter diagnostic group. This suggests that they are more susceptible to delayed diagnosis and delayed speech therapy assessment. It is important to start speech therapy intervention during the diagnostic processes particularly if the person already shows bulbar symptoms. Copyright © 2016. Published by Elsevier Inc.

Anti-müllerian hormone and ovarian reserve in systemic lupus erythematosus.

PubMed

Martins, Nádia Filipa Esteves; Seixas, Maria Inês; Pereira, Joaquim Polido; Costa, Maria Manuela; Fonseca, João Eurico

2017-12-01

Systemic lupus erythematosus (SLE) is a chronic immune-mediated inflammatory disease that affects predominantly females during childbearing age (Lateef and Petri Best Pract Res Clin Rheumatol 27(3):435-447, 2013). Fertility in SLE patients is considered to be normal (Clowse et al. Arthritis Care Res (Hoboken) 64(5):668-674, 2012; Ekblom-Kullberg et al. Scand J Rheumatol 38:375-380, 2009) but several known factors may negatively influence fertility. Immune mechanisms are also thought to be an important cause of premature ovarian senescence, characterized by reduced ovarian reserve markers such as anti-Müllerian hormone (AMH) (Oktem et al. Obstet Gynecol Surv 70(3):196-210, 2015; Bermas and Sammaritano Fertil Res Pract 1:13, 2015; Østensen Int J Clin Rheumtol 8(1):27-37, 2013; Ulug et al. Am J Reprod Immunol 72(1):85-88, 2014; Lawrenz et al. Lupus 20(11):1193-1197, 2011). We evaluated the ovarian reserve of women in reproductive age with SLE, by measuring AMH levels and we compared it to that of non-SLE women. We also analyzed the association of SLE disease characteristics with AMH levels. AMH levels were decreased in this population of SLE women, accounting for a high proportion of women with criteria for low ovarian reserve. Age and SLE damage were associated with abnormally lower AMH levels in our SLE patients. In this way, SLE may have a negative influence on the ovarian reserve.

Artificial intelligence in neurodegenerative disease research: use of IBM Watson to identify additional RNA-binding proteins altered in amyotrophic lateral sclerosis.

PubMed

Bakkar, Nadine; Kovalik, Tina; Lorenzini, Ileana; Spangler, Scott; Lacoste, Alix; Sponaugle, Kyle; Ferrante, Philip; Argentinis, Elenee; Sattler, Rita; Bowser, Robert

2018-02-01

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no effective treatments. Numerous RNA-binding proteins (RBPs) have been shown to be altered in ALS, with mutations in 11 RBPs causing familial forms of the disease, and 6 more RBPs showing abnormal expression/distribution in ALS albeit without any known mutations. RBP dysregulation is widely accepted as a contributing factor in ALS pathobiology. There are at least 1542 RBPs in the human genome; therefore, other unidentified RBPs may also be linked to the pathogenesis of ALS. We used IBM Watson ® to sieve through all RBPs in the genome and identify new RBPs linked to ALS (ALS-RBPs). IBM Watson extracted features from published literature to create semantic similarities and identify new connections between entities of interest. IBM Watson analyzed all published abstracts of previously known ALS-RBPs, and applied that text-based knowledge to all RBPs in the genome, ranking them by semantic similarity to the known set. We then validated the Watson top-ten-ranked RBPs at the protein and RNA levels in tissues from ALS and non-neurological disease controls, as well as in patient-derived induced pluripotent stem cells. 5 RBPs previously unlinked to ALS, hnRNPU, Syncrip, RBMS3, Caprin-1 and NUPL2, showed significant alterations in ALS compared to controls. Overall, we successfully used IBM Watson to help identify additional RBPs altered in ALS, highlighting the use of artificial intelligence tools to accelerate scientific discovery in ALS and possibly other complex neurological disorders.

Comparative analysis of targeted metabolomics: dominance-based rough set approach versus orthogonal partial least square-discriminant analysis.

PubMed

Blasco, H; Błaszczyński, J; Billaut, J C; Nadal-Desbarats, L; Pradat, P F; Devos, D; Moreau, C; Andres, C R; Emond, P; Corcia, P; Słowiński, R

2015-02-01

Metabolomics is an emerging field that includes ascertaining a metabolic profile from a combination of small molecules, and which has health applications. Metabolomic methods are currently applied to discover diagnostic biomarkers and to identify pathophysiological pathways involved in pathology. However, metabolomic data are complex and are usually analyzed by statistical methods. Although the methods have been widely described, most have not been either standardized or validated. Data analysis is the foundation of a robust methodology, so new mathematical methods need to be developed to assess and complement current methods. We therefore applied, for the first time, the dominance-based rough set approach (DRSA) to metabolomics data; we also assessed the complementarity of this method with standard statistical methods. Some attributes were transformed in a way allowing us to discover global and local monotonic relationships between condition and decision attributes. We used previously published metabolomics data (18 variables) for amyotrophic lateral sclerosis (ALS) and non-ALS patients. Principal Component Analysis (PCA) and Orthogonal Partial Least Square-Discriminant Analysis (OPLS-DA) allowed satisfactory discrimination (72.7%) between ALS and non-ALS patients. Some discriminant metabolites were identified: acetate, acetone, pyruvate and glutamine. The concentrations of acetate and pyruvate were also identified by univariate analysis as significantly different between ALS and non-ALS patients. DRSA correctly classified 68.7% of the cases and established rules involving some of the metabolites highlighted by OPLS-DA (acetate and acetone). Some rules identified potential biomarkers not revealed by OPLS-DA (beta-hydroxybutyrate). We also found a large number of common discriminating metabolites after Bayesian confirmation measures, particularly acetate, pyruvate, acetone and ascorbate, consistent with the pathophysiological pathways involved in ALS. DRSA provides a complementary method for improving the predictive performance of the multivariate data analysis usually used in metabolomics. This method could help in the identification of metabolites involved in disease pathogenesis. Interestingly, these different strategies mostly identified the same metabolites as being discriminant. The selection of strong decision rules with high value of Bayesian confirmation provides useful information about relevant condition-decision relationships not otherwise revealed in metabolomics data. Copyright © 2014 Elsevier Inc. All rights reserved.

RandomForest4Life: a Random Forest for predicting ALS disease progression.

PubMed

Hothorn, Torsten; Jung, Hans H

2014-09-01

We describe a method for predicting disease progression in amyotrophic lateral sclerosis (ALS) patients. The method was developed as a submission to the DREAM Phil Bowen ALS Prediction Prize4Life Challenge of summer 2012. Based on repeated patient examinations over a three- month period, we used a random forest algorithm to predict future disease progression. The procedure was set up and internally evaluated using data from 1197 ALS patients. External validation by an expert jury was based on undisclosed information of an additional 625 patients; all patient data were obtained from the PRO-ACT database. In terms of prediction accuracy, the approach described here ranked third best. Our interpretation of the prediction model confirmed previous reports suggesting that past disease progression is a strong predictor of future disease progression measured on the ALS functional rating scale (ALSFRS). We also found that larger variability in initial ALSFRS scores is linked to faster future disease progression. The results reported here furthermore suggested that approaches taking the multidimensionality of the ALSFRS into account promise some potential for improved ALS disease prediction.

The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis.

PubMed

Fukunaga, Kohji; Shinoda, Yasuharu; Tagashira, Hideaki

2015-01-01

Amyotrophic lateral sclerosis (ALS) patients exhibit diverse pathologies such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction in motor neurons. Five to ten percent of patients have familial ALS, a form of the disease caused by mutations in ALS-related genes, while sporadic forms of the disease occur in 90-95% of patients. Recently, it was reported that familial ALS patients exhibit a missense mutation in SIGMAR1 (c.304G > C), which encodes sigma-1 receptor (Sig-1R), substituting glutamine for glutamic acid at amino acid residue 102 (p.E102Q). Expression of that mutant Sig-1R(E102Q) protein reduces mitochondrial ATP production, inhibits proteasome activity and causes mitochondrial injury, aggravating ER stress-induced neuronal death in neuro2A cells. In this issue, we discuss mechanisms underlying mitochondrial impairment seen in ALS motor neurons and propose that therapies that protect mitochondria might improve the quality of life (QOL) of ALS patients and should be considered for clinical trials. Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

Fall prevention and monitoring of assisted living patients: an exploratory study of physician perspectives.

PubMed

Nyrop, Kirsten A; Zimmerman, Sheryl; Sloane, Philip D; Bangdiwala, Srikant

2012-06-01

Explore physician perspectives on their involvement in fall prevention and monitoring for residential care/assisted living (RC/AL) residents. Exploratory cross-sectional study; mailed questionnaire. Four RC/AL communities, North Carolina. Primary physicians for RC/AL residents. Past Behavior and future Intentions of physicians with regard to (1) fall risk assessment and (2) collaboration with RC/AL staff to reduce falls and fall risks among RC/AL residents were explored using Theory of Planned Behavior (TPB) constructs. Predictor variables examined (1) physicians' views on their own responsibilities (Attitude), (2) their views of expectations from important referent groups (Subjective Norms), and (3) perceived constraints on engaging in fall prevention and monitoring (Perceived Behavioral Control). Physicians reported conducting fall risk assessments of 47% of RC/AL patients and collaborating with RC/AL staff to reduce fall risks for 36% of RC/AL patients (Behavior). These proportions increased to 75% and 62%, respectively, for future Intentions. TPB-based models explained approximately 60% of the variance in self-reported Behavior and Intentions. Physician's involvement in fall prevention and monitoring was significantly associated (P < .05) with their perceptions of barriers and facilitators-ease, time, reimbursement, and expertise. This study provides first data on physician beliefs regarding their involvement in fall risk assessment of RC/AL patients and collaboration with RC/AL staff to reduce fall risks of individual patients. Challenges to physician involvement identified in our study are not unique or specific to the RC/AL setting, and instead relate to clinical practice and reimbursement constraints in general. Copyright © 2012 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.

External cardioversion in patients with persistent atrial fibrillation: a reappraisal of the effects of electrode pad position and transthoracic impedance on cardioversion success.

PubMed

Chen, Chien-Jen; Guo, G Bih-Fang

2003-11-01

The optimal methods to perform external cardioversion of atrial fibrillation (AF) have yet to be conclusively determined. This study was performed to examine the relative efficacy of different pad positions on cardioversion success and the relationship between the transthoracic impedance (TTI) and energy requirement for AF cardioversion. Seventy patients with persistent AF undergoing elective cardioversion were randomly assigned to an electrode pad position situated either over the ventricular apex-right infraclavicular area (AL group, n = 31 ) or over the right lower sternal border-left infrascapular area close to the spine (AP group, n = 39). Energy was delivered at an initial 100 joules (J) and then increased to 150 J, 200 J, 300 J, and 360 J if needed. Energy and TTI readings were recorded. Mean TTI was significantly lower in the AP group than in the AL group. However, the cumulative success rates at each energy level were similar in the two groups (23% vs 19.4%, 41% vs 45.2%, 66.7% vs 74.2%, 79.5% vs 77.4%, and 84.6% vs 83.9% at 100 J, 150 J, 200 J, 300 J and 360 J, respectively). In the AP group, converters showed slightly lower TTI compared to nonconverters. In the AL group, converters showed significantly lower TTI compared to nonconverters. However, for all patients as a group, TTI was the only predictor for cardioversion success and showed a significant relationship to the energy required for cardioversion, which can be described by a quadratic equation. Rather than pad position. TTI is the single factor that significantly affects cardioversion and correlates with energy requirement. The relationship between energy requirement and TTI further allows estimation of energy requirements to achieve a successfil cardioversion.

Prognostic Value of Cd95, Active Caspase-3, and Bcl-2 Expression in Adult Patients With De Novo Acute Lymphoblastic Leukemia.

PubMed

Montiel-Cervantes, Laura Arcelia; Reyes-Maldonado, Elba; Garcia-Chavez, Jaime; Hernandez-Caballero, Alvaro; Molina-Aguilar, Rubiraida; Garcia-Ruiz Esparza, Miriam America; Vela-Ojeda, Jorge

2018-04-18

Acute lymphoblastic leukemia is an aggressive malignant disease with high mortality rates in adults. The expression levels of CD95, active caspase-3, and Bcl-2 were determined in 111 patients with de novo acute lymphoblastic leukemia (ALL) and correlated with overall survival (OS) and disease-free survival (DFS). The immunophenotyped ok leukemia and the expression of CD95, active caspase-3, and Bcl-2, were determined by flow cytometry. Apoptotic variables were correlated by Spearman test, and survival by Kaplan-Meier method. Log-rank test was used to compare survival curves. From a total of 111 patients, 56 cases were B-ALL, 16 T-ALL, 16 B-ALL/CD33 + , and 23 ambiguous lineage-AL (AmbLin-AL). The median expression of CD95 (61.5%) and active-caspase-3 (19.4%) was higher in T-ALL (p < 0.05), whereas Bcl-2 was lower in T-ALL (p < 0.038). There was a highly significant correlation in B-ALL, B-ALL/CD33 + and AmbLin-AL between CD95 and Bcl-2, CD95-Active caspase-3, and Bcl-2-Active caspase-3; while in T-ALL, there was only a correlation between CD95-Active caspase-3, and Bcl-2-Active caspase-3. OS and DFS were better for T-ALL than the other groups, especially in patients having higher values of CD95 and active caspase 3, and lower values of Bcl-2. The worse survival rates were observed in patients with B-ALL/CD33 + , and AmbLin-AL. The prognosis of ALL in adults is influenced by the expression levels of Bcl-2, active-caspase-3, and CD95. Copyright © 2018 IMSS. Published by Elsevier Inc. All rights reserved.

Association between nutritional status and disease severity using the amyotrophic lateral sclerosis (ALS) functional rating scale in ALS patients.

PubMed

Park, Yongsoon; Park, Jinhee; Kim, Yeonsun; Baek, Heejoon; Kim, Seung Hyun

2015-01-01

The nutritional status of patients with amyotrophic lateral sclerosis (ALS) has been shown to be associated with mortality. However, there have not been, to our knowledge, any studies on the association between nutritional status and disease severity. The present study investigated the hypothesis that nutritional status was negatively associated with disease severity using the ALS functional rating scale (ALSFRS-R). One hundred ninety-three Korean ALS patients were divided into tertiles based on their ALSFRS-R score. Dietary intake was measured using 24 h recall and nutritional status was determined by body mass index (BMI) and geriatric nutritional risk index (GNRI). BMI and GNRI were significantly lower in patients in the lowest tertile of ALSFRS-R. BMI and GNRI also correlated with ALSFRS-R score, bulbar score, albumin levels, total lymphocyte count, and total daily energy expenditure. Intakes of energy and most nutrients were significantly lower in patients in the lowest tertiles of ALSFRS-R, but significances disappeared after adjusting for energy intake. Intakes of vegetables, grains, seasonings, and oils were also significantly lower in patients in the lowest tertile of ALSFRS-R. In addition, patients in the lowest tertile of ALSFRS-R were significantly younger at disease onset, had a longer duration of ALS, less regular exercise, and less sun exposure. Nutritional status, as assessed by BMI and GNRI, was negatively associated with disease severity using ALSFRS-R. The present study suggested that intake of nutrients decreases with disease progression in ALS patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Liver transplantation: history, outcomes and perspectives

PubMed Central

Meirelles, Roberto Ferreira; Salvalaggio, Paolo; de Rezende, Marcelo Bruno; Evangelista, Andréia Silva; Guardia, Bianca Della; Matielo, Celso Eduardo Lourenço; Neves, Douglas Bastos; Pandullo, Fernando Luis; Felga, Guilherme Eduardo Gonçalves; Alves, Jefferson André da Silva; Curvelo, Lilian Amorim; Diaz, Luiz Gustavo Guedes; Rusi, Marcela Balbo; Viveiros, Marcelo de Melo; de Almeida, Marcio Dias; Pedroso, Pamella Tung; Rocco, Rodrigo Andrey; Meira, Sérgio Paiva

2015-01-01

In 1958 Francis Moore described the orthotopic liver transplantation technique in dogs. In 1963, Starzl et al. performed the first liver transplantation. In the first five liver transplantations no patient survived more than 23 days. In 1967, stimulated by Calne who used antilymphocytic serum, Starzl began a successful series of liver transplantation. Until 1977, 200 liver transplantations were performed in the world. In that period, technical problems were overcome. Roy Calne, in 1979, used the first time cyclosporine in two patients who had undergone liver transplantation. In 1989, Starzl et al. reported a series of 1,179 consecutives patients who underwent liver transplantation and reported a survival rate between one and five years of 73% and 64%, respectively. Finally, in 1990, Starzl et al. reported successful use of tacrolimus in patents undergoing liver transplantation and who had rejection despite receiving conventional immunosuppressive treatment. Liver Transplantation Program was initiated at Hospital Israelita Albert Einstein in 1990 and so far over 1,400 transplants have been done. In 2013, 102 deceased donors liver transplantations were performed. The main indications for transplantation were hepatocellular carcinoma (38%), hepatitis C virus (33.3%) and alcohol liver cirrhosis (19.6%). Of these, 36% of patients who underwent transplantation showed biological MELD score > 30. Patient and graft survival in the first year was, 82.4% and 74.8%, respectively. A major challenge in liver transplantation field is the insufficient number of donors compared with the growing demand of transplant candidates. Thus, we emphasize that appropriated donor/receptor selection, allocation and organ preservation topics should contribute to improve the number and outcomes in liver transplantation. PMID:25993082

Genomic variants in the FTO gene are associated with sporadic amyotrophic lateral sclerosis in Greek patients.

PubMed

Mitropoulos, Konstantinos; Merkouri Papadima, Eleni; Xiromerisiou, Georgia; Balasopoulou, Angeliki; Charalampidou, Kyriaki; Galani, Vasiliki; Zafeiri, Krystallia-Vassiliki; Dardiotis, Efthymios; Ralli, Styliani; Deretzi, Georgia; John, Anne; Kydonopoulou, Kyriaki; Papadopoulou, Elpida; di Pardo, Alba; Akcimen, Fulya; Loizedda, Annalisa; Dobričić, Valerija; Novaković, Ivana; Kostić, Vladimir S; Mizzi, Clint; Peters, Brock A; Basak, Nazli; Orrù, Sandro; Kiskinis, Evangelos; Cooper, David N; Gerou, Spyridon; Drmanac, Radoje; Bartsakoulia, Marina; Tsermpini, Evangelia-Eirini; Hadjigeorgiou, Georgios M; Ali, Bassam R; Katsila, Theodora; Patrinos, George P

2017-12-08

Amyotrophic lateral sclerosis (ALS) is a devastating disease whose complex pathology has been associated with a strong genetic component in the context of both familial and sporadic disease. Herein, we adopted a next-generation sequencing approach to Greek patients suffering from sporadic ALS (together with their healthy counterparts) in order to explore further the genetic basis of sporadic ALS (sALS). Whole-genome sequencing analysis of Greek sALS patients revealed a positive association between FTO and TBC1D1 gene variants and sALS. Further, linkage disequilibrium analyses were suggestive of a specific disease-associated haplotype for FTO gene variants. Genotyping for these variants was performed in Greek, Sardinian, and Turkish sALS patients. A lack of association between FTO and TBC1D1 variants and sALS in patients of Sardinian and Turkish descent may suggest a founder effect in the Greek population. FTO was found to be highly expressed in motor neurons, while in silico analyses predicted an impact on FTO and TBC1D1 mRNA splicing for the genomic variants in question. To our knowledge, this is the first study to present a possible association between FTO gene variants and the genetic etiology of sALS. In addition, the next-generation sequencing-based genomics approach coupled with the two-step validation strategy described herein has the potential to be applied to other types of human complex genetic disorders in order to identify variants of clinical significance.

Comparison of the extraction and determination of serum exosome and miRNA in serum and the detection of miR-27a-3p in serum exosome of ALS patients.

PubMed

Xu, Qian; Zhao, Yuying; Zhou, Xiaoyan; Luan, Jing; Cui, Yazhou; Han, Jinxiang

2018-02-01

Amyotrophic Lateral Sclerosis (ALS) is a muscle-bone degenerative disease, which lacks a specific index for diagnosis. In our previous studies, we found that exosomes mediated the interaction mechanism between muscle and bone at the cellular level, and myoblast exosomes can transfer miR-27a-3p to promote osteoblast mineralization. Therefore, we suppose that the expression of miR-27a-3p in the serum exosomes of ALS patients also changes. In this study, we used healthy human serum as a sample to find out the conditions and methods for extraction and detection. Then through comparison of the expression of miR-27a-3p in the serum exosomes of 10 ALS patients and healthy subjects, we found that in the ALS patients miR-27a-3p was down-regulated, and may be involved in the development of ALS, and therefore has potential as a reference for the diagnosis of ALS in the clinic.

2A4 binds soluble and insoluble light chain aggregates from AL amyloidosis patients and promotes clearance of amyloid deposits by phagocytosis †.

PubMed

Renz, Mark; Torres, Ronald; Dolan, Philip J; Tam, Stephen J; Tapia, Jose R; Li, Lauri; Salmans, Joshua R; Barbour, Robin M; Shughrue, Paul J; Nijjar, Tarlochan; Schenk, Dale; Kinney, Gene G; Zago, Wagner

2016-09-01

Amyloid light chain (AL) amyloidosis is characterized by misfolded light chain (LC) (amyloid) deposition in various peripheral organs, leading to progressive dysfunction and death. There are no regulatory agency-approved treatments for AL amyloidosis, and none of the available standard of care approaches directly targets the LC protein that constitutes the amyloid. NEOD001, currently in late-stage clinical trials, is a conformation-specific, anti-LC antibody designed to specifically target misfolded LC aggregates and promote phagocytic clearance of AL amyloid deposits. The present study demonstrated that the monoclonal antibody 2A4, the murine form of NEOD001, binds to patient-derived soluble and insoluble LC aggregates and induces phagocytic clearance of AL amyloid in vitro. 2A4 specifically labeled all 21 fresh-frozen organ samples studied, which were derived from 10 patients representing both κ and λ LC amyloidosis subtypes. 2A4 immunoreactivity largely overlapped with thioflavin T-positive labeling, and 2A4 bound both soluble and insoluble LC aggregates extracted from patient tissue. Finally, 2A4 induced macrophage engagement and phagocytic clearance of AL amyloid deposits in vitro. These findings provide further evidence that 2A4/NEOD001 can effectively clear and remove human AL-amyloid from tissue and further support the rationale for the evaluation of NEOD001 in patients with AL amyloidosis.

Tactile event-related potentials in amyotrophic lateral sclerosis (ALS): Implications for brain-computer interface.

PubMed

Silvoni, S; Konicar, L; Prats-Sedano, M A; Garcia-Cossio, E; Genna, C; Volpato, C; Cavinato, M; Paggiaro, A; Veser, S; De Massari, D; Birbaumer, N

2016-01-01

We investigated neurophysiological brain responses elicited by a tactile event-related potential paradigm in a sample of ALS patients. Underlying cognitive processes and neurophysiological signatures for brain-computer interface (BCI) are addressed. We stimulated the palm of the hand in a group of fourteen ALS patients and a control group of ten healthy participants and recorded electroencephalographic signals in eyes-closed condition. Target and non-target brain responses were analyzed and classified offline. Classification errors served as the basis for neurophysiological brain response sub-grouping. A combined behavioral and quantitative neurophysiological analysis of sub-grouped data showed neither significant between-group differences, nor significant correlations between classification performance and the ALS patients' clinical state. Taking sequential effects of stimuli presentation into account, analyses revealed mean classification errors of 19.4% and 24.3% in healthy participants and ALS patients respectively. Neurophysiological correlates of tactile stimuli presentation are not altered by ALS. Tactile event-related potentials can be used to monitor attention level and task performance in ALS and may constitute a viable basis for future BCIs. Implications for brain-computer interface implementation of the proposed method for patients in critical conditions, such as the late stage of ALS and the (completely) locked-in state, are discussed. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.