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Sample records for affect disease progression

  1. Environmental factors affecting inflammatory bowel disease: have we made progress?

    PubMed

    Lakatos, Peter Laszlo

    2009-01-01

    The pathogenesis of inflammatory bowel disease (IBD) is only partially understood; various environmental and host (e.g. genetic, epithelial, immune, and nonimmune) factors are involved. The critical role for environmental factors is strongly supported by recent worldwide trends in IBD epidemiology. One important environmental factor is smoking. A meta-analysis partially confirms previous findings that smoking was found to be protective against ulcerative colitis and, after the onset of the disease, might improve its course, decreasing the need for colectomy. In contrast, smoking increases the risk of developing Crohn's disease and aggravates its course. The history of IBD is dotted by cyclic reports on the isolation of specific infectious agents responsible for Crohn's disease or ulcerative colitis. The more recently published cold chain hypothesis is providing an even broader platform by linking dietary factors and microbial agents. An additional, recent theory has suggested a breakdown in the balance between putative species of 'protective' versus 'harmful' intestinal bacteria - this concept has been termed dysbiosis resulting in decreased bacterial diversity. Other factors such as oral contraceptive use, appendectomy, dietary factors (e.g. refined sugar, fat, and fast food), perinatal events, and childhood infections have also been associated with both diseases, but their role is more controversial. Nonetheless, there is no doubt that economic development, leading to improved hygiene and other changes in lifestyle ('westernized lifestyle') may play a role in the increase in IBD. This review article focuses on the role of environmental factors in the pathogenesis and progression of IBDs.

  2. Clinical value of nutritional status in neurodegenerative diseases: What is its impact and how it affects disease progression and management?

    PubMed

    Tsagalioti, Eftyhia; Trifonos, Christina; Morari, Aggeliki; Vadikolias, Konstantinos; Giaginis, Constantinos

    2016-11-30

    Neurodegenerative diseases constitute a major problem of public health that is associated with an increased risk of mortality and poor quality of life. Malnutrition is considered as a major problem that worsens the prognosis of patients suffering from neurodegenerative diseases. In this aspect, the present review is aimed to critically collect and summarize all the available existing clinical data regarding the clinical impact of nutritional assessment in neurodegenerative diseases, highlighting on the crucial role of nutritional status in disease progression and management. According to the currently available clinical data, the nutritional status of patients seems to play a very important role in the development and progression of neurodegenerative diseases. A correct nutritional evaluation of neurodegenerative disease patients and a right nutrition intervention is essential in monitoring their disease.

  3. Rapid and Progressive Regional Brain Atrophy in CLN6 Batten Disease Affected Sheep Measured with Longitudinal Magnetic Resonance Imaging

    PubMed Central

    Sawiak, Stephen J.; Perumal, Sunthara Rajan; Rudiger, Skye R.; Matthews, Loren; Mitchell, Nadia L.; McLaughlan, Clive J.; Bawden, C. Simon; Palmer, David N.; Kuchel, Timothy; Morton, A. Jennifer

    2015-01-01

    Variant late-infantile Batten disease is a neuronal ceroid lipofuscinosis caused by mutations in CLN6. It is a recessive genetic lysosomal storage disease characterised by progressive neurodegeneration. It starts insidiously and leads to blindness, epilepsy and dementia in affected children. Sheep that are homozygous for a natural mutation in CLN6 have an ovine form of Batten disease Here, we used in vivo magnetic resonance imaging to track brain changes in 4 unaffected carriers and 6 affected Batten disease sheep. We scanned each sheep 4 times, between 17 and 22 months of age. Cortical atrophy in all sheep was pronounced at the baseline scan in all affected Batten disease sheep. Significant atrophy was also present in other brain regions (caudate, putamen and amygdala). Atrophy continued measurably in all of these regions during the study. Longitudinal MRI in sheep was sensitive enough to measure significant volume changes over the relatively short study period, even in the cortex, where nearly 40% of volume was already lost at the start of the study. Thus longitudinal MRI could be used to study the dynamics of progression of neurodegenerative changes in sheep models of Batten disease, as well as to assess therapeutic efficacy. PMID:26161747

  4. Disease progression and health care resource consumption in patients affected by hepatitis C virus in real practice setting

    PubMed Central

    Perrone, Valentina; Sangiorgi, Diego; Buda, Stefano; Degli Esposti, Luca

    2016-01-01

    Introduction Hepatitis C virus (HCV) infection represents serious health problems worldwide and is a major contributor to end-stage liver disease including cirrhosis and hepatocellular carcinoma (HCC). In Italy, ~2% of subjects are infected with HCV. The objective of this study was to describe treatment patterns, disease progression, and resource use in HCV. Methods An observational retrospective cohort analysis based on four Local Health Units administrative and laboratory databases was conducted. HCV-positive patients between January 1, 2009 and December 31, 2010 were included and followed-up for 1 year. To explore which covariates were associated to disease progression (cirrhosis, HCC, death for any cause), Cox proportional hazards models were performed. Results A total of 9,514 patients were analyzed of which 55.6% were male, aged 58.1±16.1, and prevalence 0.4%; 5.8% were positive to human immunodeficiency virus (HIV) infection, 3.0% to hepatitis B virus (HBV), and 1.6% to HCV+HBV+HIV; 26.1% had cirrhosis and 4.3% HCC. The majority of patients (76%) did not receive an antiviral treatment; the main factors affecting this decision were age, 44.1% of untreated patients being aged >65 years; 31% were affected by cirrhosis, 6.6% had ongoing substance or alcohol abuse, and 5.5% were affected by HCC. Disease progression in the observed timeframe was less frequent among treated patients (incidence rate per 100 patients/year: cirrhosis 2.1±0.7 vs 13.0±1.0, HCC 0.5±0.3 vs 3.6±0.5, death 0.5±0.3 vs 6.4±0.7). The annual expenditure for HCV management (drugs, hospitalizations, outpatient services) was €4,700 per patient. Conclusion This observational, real-life study shows that only a small proportion of patients received antiviral therapy in the territorial services investigated; among patients who were not treated, this is reflected in a disease progression and cost of management higher than treated patients. These results suggest the importance of better

  5. Progression of Liver Disease

    MedlinePlus

    ... The Progression of Liver Disease The Progression of Liver Disease There are many different types of liver ... may put your life in danger. The Healthy Liver Your liver helps fight infections and cleans your ...

  6. Rapidly progressive Alzheimer disease.

    PubMed

    Schmidt, Christian; Wolff, Martin; Weitz, Michael; Bartlau, Thomas; Korth, Carsten; Zerr, Inga

    2011-09-01

    Different rates of progression have been observed among patients with Alzheimer disease. Risk factors that accelerate deterioration have been identified and some are being discussed, such as genetics, comorbidity, and the early appearance of Alzheimer disease motor signs. Progressive forms of Alzheimer disease have been reported with rapid cognitive decline and disease duration of only a few years. This short review aims to provide an overview of the current knowledge of rapidly progressive Alzheimer disease. Furthermore, we suggest that rapid, in this context, should be defined as a Mini-Mental State Examination score decrease of 6 points per year.

  7. The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease

    PubMed Central

    2013-01-01

    Background Progressive supranuclear palsy (PSP) is a neurodegenerative disorder pathologically characterized by intracellular tangles of hyperphosphorylated tau protein distributed throughout the neocortex, basal ganglia, and brainstem. A genome-wide association study identified EIF2AK3 as a risk factor for PSP. EIF2AK3 encodes PERK, part of the endoplasmic reticulum’s (ER) unfolded protein response (UPR). PERK is an ER membrane protein that senses unfolded protein accumulation within the ER lumen. Recently, several groups noted UPR activation in Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, multiple system atrophy, and in the hippocampus and substantia nigra of PSP subjects. Here, we evaluate UPR PERK activation in the pons, medulla, midbrain, hippocampus, frontal cortex and cerebellum in subjects with PSP, AD, and in normal controls. Results We found UPR activation primarily in disease-affected brain regions in both disorders. In PSP, the UPR was primarily activated in the pons and medulla and to a much lesser extent in the hippocampus. In AD, the UPR was extensively activated in the hippocampus. We also observed UPR activation in the hippocampus of some elderly normal controls, severity of which positively correlated with both age and tau pathology but not with Aβ plaque burden. Finally, we evaluated EIF2AK3 coding variants that influence PERK activation. We show that a haplotype associated with increased PERK activation is genetically associated with increased PSP risk. Conclusions The UPR is activated in disease affected regions in PSP and the genetic evidence shows that this activation increases risk for PSP and is not a protective response. PMID:24252572

  8. In chronic kidney disease staging the use of the chronicity criterion affects prognosis and the rate of progression.

    PubMed

    Eriksen, B O; Ingebretsen, O C

    2007-11-01

    The Kidney Disease Outcomes Quality Initiative definition and staging of chronic kidney disease (CKD) have been adopted by most nephrologists but include a criterion of chronicity that has not been investigated. This criterion specifies that renal structural damage and/or reduction in glomerular filtration rate (GFR) should be present for periods lasting longer than 3 months. We examined the effects of changing this criterion to 6, 9, or 12 months on the prognosis and the rate of progression in population-based cohorts with CKD stages 3 and 4. A 12-month chronicity criterion significantly reduced the number of CKD patients relative to the 3-month criterion for both stages 3 and 4. For both stages, there were statistically significant differences in 5-year mortality between the 6- and 9-month cohorts. For stage 4, the 5-year cumulative incidence of renal failure significantly increased from 6 to 9 months, and the rate of change in GFR significantly decreased between the same two cohorts. The 5-year cumulative incidence of improvement in GFR lasting 1 year or more was significantly higher for the 3-month cohort than for the 12-month cohort in the stage 3 group. Hence, we suggest that the chronicity criterion is an important determinant of the characteristics of the population of patients with CKD stages 3 and 4. This may have practical consequences in both research and clinical work.

  9. Managing progressive renal disease before dialysis.

    PubMed Central

    Barrett, B. J.

    1999-01-01

    OBJECTIVE: To enhance awareness of issues affecting patients with chronic renal failure and to provide guidance for primary care practitioners managing such patients. QUALITY OF EVIDENCE: Randomized trials establish the efficacy of blood pressure control and angiotensin-converting enzyme (ACE) inhibition in slowing the progression of chronic renal disease. Some randomized trials and many prospective studies address management of anemia, hyperparathyroidism, and multidisciplinary predialysis care. The benefits of lipid lowering are suggested by randomized trials among patients without renal disease. MAIN MESSAGE: Progression of renal failure, particularly in patients with proteinuria, can be slowed by lowering blood pressure. Angiotensin-converting enzyme inhibitors are more beneficial than other antihypertensives in this situation. Partial correction of anemia with iron, erythropoietin, or androgens can improve quality of life and potentially prevent cardiac disease. Renal bone disease and secondary hyperparathyroidism can be prevented in part by early dietary phosphate restriction, use of calcium-containing phosphate binders, and activated vitamin D. Correction of acidosis could improve protein metabolism and bone and cardiovascular health. Treatment of hyperlipidemia might reduce cardiovascular disease. Early involvement of a nephrology-based multidisciplinary team has the potential to reduce morbidity and costs, enhance patients' knowledge of their condition, and prolong the period before dialysis is required. CONCLUSIONS: Care of patients with progressive renal failure is complex and requires attention to detail. Family doctors play a vital role in these efforts and should be involved in all aspects of care. PMID:10216796

  10. Dopamine Transporter Imaging Assessment of Parkinson’s Disease Progression

    DTIC Science & Technology

    2001-08-01

    terminal integrity, will provide a quantitative biomarker of Parkinson’s disease progression in subjects with early Parkinson’s disease during a rime...dopa on the rate of progression of Parkinson’s disease . All subjects have been and will be recruited and clinically evaluated through their participation...in early Parkinson’s disease , whether the rate of neuronal degeneration is affected by L-dopa, a potential neurotoxin, and whether the changes in

  11. Quantifying disease progression in amyotrophic lateral sclerosis.

    PubMed

    Simon, Neil G; Turner, Martin R; Vucic, Steve; Al-Chalabi, Ammar; Shefner, Jeremy; Lomen-Hoerth, Catherine; Kiernan, Matthew C

    2014-11-01

    Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of disease progression, with inherent clinical heterogeneity making disease quantitation difficult. Recent advances in understanding pathogenic mechanisms linked to the development of ALS impose an increasing need to develop strategies to predict and more objectively measure disease progression. This review explores phenotypic and genetic determinants of disease progression in ALS, and examines established and evolving biomarkers that may contribute to robust measurement in longitudinal clinical studies. With targeted neuroprotective strategies on the horizon, developing efficiencies in clinical trial design may facilitate timely entry of novel treatments into the clinic.

  12. Research Progress of Moyamoya Disease in Children

    PubMed Central

    Piao, Jianmin; Wu, Wei; Yang, Zhongxi; Yu, Jinlu

    2015-01-01

    During the onset of Moyamoya disease (MMD), progressive occlusion occurs at the end of the intracranial internal carotid artery, and compensatory net-like abnormal vessels develop in the skull base, generating the corresponding clinical symptoms. MMD can affect both children and adults, but MMD in pediatric patients exhibits distinct clinical features, and the treatment prognoses are different from adult patients. Children are the group at highest risk for MMD. In children, the disease mainly manifests as ischemia, while bleeding is the primary symptom in adults. The pathogenesis of MMD in children is still unknown, and some factors are distinct from those in adults. MMD in children could result in progressive, irreversible nerve functional impairment, and an earlier the onset corresponds to a worse prognosis. Therefore, active treatment at an early stage is highly recommended. The treatment methods for MMD in children mainly include indirect and direct surgeries. Indirect surgeries mainly include multiple burr-hole surgery (MBHS), encephalomyosynangiosis (EMS), and encephaloduroarteriosynangiosis (EDAS); direct surgeries mainly include intra- and extracranial vascular reconstructions that primarily consist of superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis. Indirect surgery, as a treatment for MMD in children, has shown a certain level of efficacy. However, a standard treatment approach should combine both indirect and direct procedures. Compared to MMD in adults, the treatment and prognosis of MMD in children has higher clinical significance. If the treatment is adequate, a satisfactory outcome is often achieved. PMID:26180513

  13. Research Progress of Moyamoya Disease in Children.

    PubMed

    Piao, Jianmin; Wu, Wei; Yang, Zhongxi; Yu, Jinlu

    2015-01-01

    During the onset of Moyamoya disease (MMD), progressive occlusion occurs at the end of the intracranial internal carotid artery, and compensatory net-like abnormal vessels develop in the skull base, generating the corresponding clinical symptoms. MMD can affect both children and adults, but MMD in pediatric patients exhibits distinct clinical features, and the treatment prognoses are different from adult patients. Children are the group at highest risk for MMD. In children, the disease mainly manifests as ischemia, while bleeding is the primary symptom in adults. The pathogenesis of MMD in children is still unknown, and some factors are distinct from those in adults. MMD in children could result in progressive, irreversible nerve functional impairment, and an earlier the onset corresponds to a worse prognosis. Therefore, active treatment at an early stage is highly recommended. The treatment methods for MMD in children mainly include indirect and direct surgeries. Indirect surgeries mainly include multiple burr-hole surgery (MBHS), encephalomyosynangiosis (EMS), and encephaloduroarteriosynangiosis (EDAS); direct surgeries mainly include intra- and extracranial vascular reconstructions that primarily consist of superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis. Indirect surgery, as a treatment for MMD in children, has shown a certain level of efficacy. However, a standard treatment approach should combine both indirect and direct procedures. Compared to MMD in adults, the treatment and prognosis of MMD in children has higher clinical significance. If the treatment is adequate, a satisfactory outcome is often achieved.

  14. Heart Disease Affects Women of All Ages

    MedlinePlus

    ... Home Current Issue Past Issues Heart Disease Affects Women of All Ages Past Issues / Winter 2007 Table ... of this page please turn Javascript on. Young Women: Lifestyle-related factors that increase heart disease risk ...

  15. Cognitive impairments in progression of Parkinson's disease.

    PubMed

    Stepkina, D A; Zakharov, V V; Yakhno, N N

    2010-01-01

    A total of 88 patients with progression of Parkinson's disease (PD) were studied. Cognitive impairments (CI) in PD were in most cases progressive in nature, predominantly because of increases in the severity of dysregulatory and neurodynamic disorders, impairments to visuospatial functions, and, in some cases, deficits in nominative speech function. A high frequency of transformation of moderate cognitive impairments to dementia was demonstrated over periods of 2-5 years. Predictors of the progression of CI in PD were identified: elderly age, later onset of disease, and the severity of PD. The greatest rate of progression of CI was seen in patients with initially more severe impairments of regulatory and visuospatial functions.

  16. Impact of cholesterol on disease progression.

    PubMed

    Lin, Chun-Jung; Lai, Cheng-Kuo; Kao, Min-Chuan; Wu, Lii-Tzu; Lo, U-Ging; Lin, Li-Chiung; Chen, Yu-An; Lin, Ho; Hsieh, Jer-Tsong; Lai, Chih-Ho; Lin, Chia-Der

    2015-06-01

    Cholesterol-rich microdomains (also called lipid rafts), where platforms for signaling are provided and thought to be associated with microbe-induced pathogenesis and lead to cancer progression. After treatment of cells with cholesterol disrupting or usurping agents, raft-associated proteins and lipids can be dissociated, and this renders the cell structure nonfunctional and therefore mitigates disease severity. This review focuses on the role of cholesterol in disease progression including cancer development and infectious diseases. Understanding the molecular mechanisms of cholesterol in these diseases may provide insight into the development of novel strategies for controlling these diseases in clinical scenarios.

  17. Affective cycling in thyroid disease

    SciTech Connect

    Tapp, A.

    1988-05-01

    Depression in an elderly man with primary recurrent unipolar depression responded to radioactive iodine treatment of a thyrotoxic nodule, without the addition of psychotropic medications. Two months later, manic symptoms developed concomitant with the termination of the hyperthyroid state secondary to the radioactive iodine treatment. Clinical implications of these findings in relation to the possible mechanism of action of thyroid hormones on affective cycling are discussed.

  18. [New therapies for children affected by bone diseases].

    PubMed

    Ballhausen, Diana; Dépraz, Nuria Garcia; Kern, Ilse; Unger, Sheila; Bonafé, Luisa

    2012-02-22

    Considerable progress has been achieved in recent years in treating children affected by bone diseases. Advances in the understanding of the molecular pathophysiology of genetic bone diseases have led to the development of enzyme replacement therapies for various lysosomal storage diseases, following the breakthrough initiated in treating Gaucher disease. Clinical studies are underway with tailored molecules correcting bone fragility and alleviating chronic bone pain and other manifestations of hypophosphatasia, or promoting growth of long bones in achondroplasia patients. We further report our very encouraging experience with intravenous bisphosphonate treatment in children suffering from secondary osteopenia and the high prevalence of calcium and vitamin D deficits in these severely disabled children.

  19. Treatment of affective disorders in cardiac disease.

    PubMed

    Mavrides, Nicole; Nemeroff, Charles B

    2015-06-01

    Patients with cardiovascular disease (CVD) commonly have syndromal major depression, and depression has been associated with an increased risk of morbidity and mortality. Prevalence of depression is between 17% and 47% in CVD patients. Pharmacologic and psychotherapeutic interventions have long been studied, and in general are safe and somewhat efficacious in decreasing depressive symptoms in patients with CVD. The impact on cardiac outcomes remains unclear. The evidence from randomized controlled clinical trials indicates that antidepressants, especially selective serotonin uptake inhibitors, are overwhelmingly safe, and likely to be effective in the treatment of depression in patients with CVD. This review describes the prevalence of depression in patients with CVD, the physiological links between depression and CVD, the treatment options for affective disorders, and the clinical trials that demonstrate efficacy and safety of antidepressant medications and psychotherapy in this patient population. Great progress has been made in understanding potential mediators between major depressive disorder and CVD--both health behaviors and shared biological risks such as inflammation.

  20. Treatment of affective disorders in cardiac disease

    PubMed Central

    Mavrides, Nicole; Nemeroff, Charles B.

    2015-01-01

    Patients with cardiovascular disease (CVD) commonly have syndromal major depression, and depression has been associated with an increased risk of morbidity and mortality. Prevalence of depression is between 17% and 47% in CVD patients. Pharmacologic and psychotherapeutic interventions have long been studied, and in general are safe and somewhat efficacious in decreasing depressive symptoms in patients with CVD. The impact on cardiac outcomes remains unclear. The evidence from randomized controlled clinical trials indicates that antidepressants, especially selective serotonin uptake inhibitors, are overwhelmingly safe, and likely to be effective in the treatment of depression in patients with CVD. This review describes the prevalence of depression in patients with CVD, the physiological links between depression and CVD, the treatment options for affective disorders, and the clinical trials that demonstrate efficacy and safety of antidepressant medications and psychotherapy in this patient population. Great progress has been made in understanding potential mediators between major depressive disorder and CVD—both health behaviors and shared biological risks such as inflammation. PMID:26246788

  1. Treatment of Parkinson's disease: problems with a progressing disease.

    PubMed

    Rinne, U K

    1981-01-01

    Long-term follow-up of parkinsonian patients has shown that although levodopa treatment significantly improves the parkinsonian symptoms and the quality of life of parkinsonian patients for several years, various distressing difficulties arise during chronic levodopa treatment, such as the loss of benefit, dyskinesias, on-off phenomena, postural instability and dementia. Clinical, neuropsychological, mortality and post-mortem brain studies indicate that levodopa as a replacement therapy does not modify the progression of the underlying pathology and the natural course of the disease. It seems that levodopa has only a limited period of optimal usefulness in the treatment of Parkinson's disease. However, at present there is no better or more potent therapeutic agent available than levodopa and it is still the primary treatment of Parkinson's disease. It would be reasonable not to begin levodopa treatment in patients with mild symptoms but to withhold levodopa until the severity of symptoms really makes its use necessary. Thus it is possible to get the maximal long functional benefit. Post-mortem brain studies have shown that in Parkinson's disease there is not only a progressive loss of dopaminergic substantia nigra neurons but there are also significant changes in the striatal dopamine receptors. In some patients a denervation supersensitivity seems to develop and in some others a loss of dopamine receptors in the striatum. However, in advanced parkinsonian patients with a deteriorating response to levodopa, there seem to be still enough dopamine receptors in the striatum for drugs stimulating the dopamine receptors directly to improve the parkinsonian disability. Indeed, recent evidence indicates that dopaminergic agonists, such as bromocriptine, seem to be a significant and valuable adjuvant therapy to levodopa in parkinsonian patients with a deteriorating response and/or the on-off phenomena. Although bromocriptine is not completely satisfactory, it is a

  2. Accuracy Improvement for Predicting Parkinson's Disease Progression.

    PubMed

    Nilashi, Mehrbakhsh; Ibrahim, Othman; Ahani, Ali

    2016-09-30

    Parkinson's disease (PD) is a member of a larger group of neuromotor diseases marked by the progressive death of dopamineproducing cells in the brain. Providing computational tools for Parkinson disease using a set of data that contains medical information is very desirable for alleviating the symptoms that can help the amount of people who want to discover the risk of disease at an early stage. This paper proposes a new hybrid intelligent system for the prediction of PD progression using noise removal, clustering and prediction methods. Principal Component Analysis (PCA) and Expectation Maximization (EM) are respectively employed to address the multi-collinearity problems in the experimental datasets and clustering the data. We then apply Adaptive Neuro-Fuzzy Inference System (ANFIS) and Support Vector Regression (SVR) for prediction of PD progression. Experimental results on public Parkinson's datasets show that the proposed method remarkably improves the accuracy of prediction of PD progression. The hybrid intelligent system can assist medical practitioners in the healthcare practice for early detection of Parkinson disease.

  3. Hummingbird sign in progressive supranuclear palsy disease.

    PubMed

    Pandey, Sanjay

    2012-02-01

    Progressive supranuclear palsy (PSP) is characterized by slowness, rigidity, bradykinesia, repeated falls, downgaze limitation and dementia. Midbrain atrophy on magnetic resonance imaging is highly suggestive of PSP and is described as "hummingbird sign". This sign is very helpful in differentiating PSP patients from those with Parkinson's disease.We hereby report a 72-year-old female case of PSP primarily diagnosed with Parkinson's disease.

  4. COMT Val158Met Polymorphism Modulates Huntington's Disease Progression

    PubMed Central

    Rebeix, Isabelle; Dupoux, Emmanuel; Durr, Alexandra; Brice, Alexis; Charles, Perrine; Cleret de Langavant, Laurent; Youssov, Katia; Verny, Christophe; Damotte, Vincent; Azulay, Jean-Philippe; Goizet, Cyril; Simonin, Clémence; Tranchant, Christine; Maison, Patrick; Rialland, Amandine; Schmitz, David; Jacquemot, Charlotte; Fontaine, Bertrand; Bachoud-Lévi, Anne-Catherine

    2016-01-01

    Little is known about the genetic factors modulating the progression of Huntington’s disease (HD). Dopamine levels are affected in HD and modulate executive functions, the main cognitive disorder of HD. We investigated whether the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, which influences dopamine (DA) degradation, affects clinical progression in HD. We carried out a prospective longitudinal multicenter study from 1994 to 2011, on 438 HD gene carriers at different stages of the disease (34 pre-manifest; 172 stage 1; 130 stage 2; 80 stage 3; 17 stage 4; and 5 stage 5), according to Total Functional Capacity (TFC) score. We used the Unified Huntington’s Disease Rating Scale to evaluate motor, cognitive, behavioral and functional decline. We genotyped participants for COMT polymorphism (107 Met-homozygous, 114 Val-homozygous and 217 heterozygous). 367 controls of similar ancestry were also genotyped. We compared clinical progression, on each domain, between groups of COMT polymorphisms, using latent-class mixed models accounting for disease duration and number of CAG (cytosine adenine guanine) repeats. We show that HD gene carriers with fewer CAG repeats and with the Val allele in COMT polymorphism displayed slower cognitive decline. The rate of cognitive decline was greater for Met/Met homozygotes, which displayed a better maintenance of cognitive capacity in earlier stages of the disease, but had a worse performance than Val allele carriers later on. COMT polymorphism did not significantly impact functional and behavioral performance. Since COMT polymorphism influences progression in HD, it could be used for stratification in future clinical trials. Moreover, DA treatments based on the specific COMT polymorphism and adapted according to disease duration could potentially slow HD progression. PMID:27657697

  5. COMT Val158Met Polymorphism Modulates Huntington's Disease Progression.

    PubMed

    de Diego-Balaguer, Ruth; Schramm, Catherine; Rebeix, Isabelle; Dupoux, Emmanuel; Durr, Alexandra; Brice, Alexis; Charles, Perrine; Cleret de Langavant, Laurent; Youssov, Katia; Verny, Christophe; Damotte, Vincent; Azulay, Jean-Philippe; Goizet, Cyril; Simonin, Clémence; Tranchant, Christine; Maison, Patrick; Rialland, Amandine; Schmitz, David; Jacquemot, Charlotte; Fontaine, Bertrand; Bachoud-Lévi, Anne-Catherine

    Little is known about the genetic factors modulating the progression of Huntington's disease (HD). Dopamine levels are affected in HD and modulate executive functions, the main cognitive disorder of HD. We investigated whether the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, which influences dopamine (DA) degradation, affects clinical progression in HD. We carried out a prospective longitudinal multicenter study from 1994 to 2011, on 438 HD gene carriers at different stages of the disease (34 pre-manifest; 172 stage 1; 130 stage 2; 80 stage 3; 17 stage 4; and 5 stage 5), according to Total Functional Capacity (TFC) score. We used the Unified Huntington's Disease Rating Scale to evaluate motor, cognitive, behavioral and functional decline. We genotyped participants for COMT polymorphism (107 Met-homozygous, 114 Val-homozygous and 217 heterozygous). 367 controls of similar ancestry were also genotyped. We compared clinical progression, on each domain, between groups of COMT polymorphisms, using latent-class mixed models accounting for disease duration and number of CAG (cytosine adenine guanine) repeats. We show that HD gene carriers with fewer CAG repeats and with the Val allele in COMT polymorphism displayed slower cognitive decline. The rate of cognitive decline was greater for Met/Met homozygotes, which displayed a better maintenance of cognitive capacity in earlier stages of the disease, but had a worse performance than Val allele carriers later on. COMT polymorphism did not significantly impact functional and behavioral performance. Since COMT polymorphism influences progression in HD, it could be used for stratification in future clinical trials. Moreover, DA treatments based on the specific COMT polymorphism and adapted according to disease duration could potentially slow HD progression.

  6. JAK INHIBITION AND PROGRESSIVE KIDNEY DISEASE

    PubMed Central

    Brosius, Frank C.; He, John Cijiang

    2015-01-01

    Purpose of review To review the role of JAK-STAT signaling in the progression of chronic kidney diseases. Recent findings The JAK-STAT pathway transmits signals from extracellular ligands, including many cytokines and chemokines. While these responses are best characterized in lymphoid cells, they also occur in kidney cells such as podocytes, mesangial cells, and tubular cells. JAK-STAT expression and signaling abnormalities occur in humans and animal models of different chronic kidney diseases. Enhanced expression and augmented activity of JAK1, JAK2 and STAT3 promote diabetic nephropathy and their inhibition appears to reduce disease. Activation of JAK-STAT signaling in autosomal dominant polycystic kidney disease may play an important role in cyst growth. Activation of JAK-STAT signaling promotes HIV-associated nephropathy and may also participate in the tubular responses to chronic obstructive uropathy. Based on data from experimental models, inhibition of JAK-STAT signaling, via increased expression of the suppressors of cytokine signaling proteins or pharmacologic inhibition of JAK and STAT proteins, could play a therapeutic role in multiple chronic kidney diseases. Summary Activation of the JAK-STAT pathway appears to play a role in the progression of some chronic kidney diseases. More work is needed to determine the specific role the pathway plays in individual diseases. PMID:25415616

  7. Predictors of autosomal dominant polycystic kidney disease progression.

    PubMed

    Schrier, Robert W; Brosnahan, Godela; Cadnapaphornchai, Melissa A; Chonchol, Michel; Friend, Keith; Gitomer, Berenice; Rossetti, Sandro

    2014-11-01

    Autosomal dominant polycystic kidney disease is a genetic disorder associated with substantial variability in its natural course within and between affected families. Understanding predictors for rapid progression of this disease has become increasingly important with the emergence of potential new treatments. This systematic review of the literature since 1988 evaluates factors that may predict and/or effect autosomal dominant polycystic kidney disease progression. Predicting factors associated with early adverse structural and/or functional outcomes are considered. These factors include PKD1 mutation (particularly truncating mutation), men, early onset of hypertension, early and frequent gross hematuria, and among women, three or more pregnancies. Increases in total kidney volume and decreases in GFR and renal blood flow greater than expected for a given age also signify rapid disease progression. Concerning laboratory markers include overt proteinuria, macroalbuminuria, and perhaps, elevated serum copeptin levels in affected adults. These factors and others may help to identify patients with autosomal dominant polycystic kidney disease who are most likely to benefit from early intervention with novel treatments.

  8. Metabonomics Research Progress on Liver Diseases

    PubMed Central

    2017-01-01

    Metabolomics as the new omics technique develops after genomics, transcriptomics, and proteomics and has rapid development at present. Liver diseases are worldwide public health problems. In China, chronic hepatitis B and its secondary diseases are the common liver diseases. They can be diagnosed by the combination of history, virology, liver function, and medical imaging. However, some patients seldom have relevant physical examination, so the diagnosis may be delayed. Many other liver diseases, such as drug-induced liver injury (DILI), alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), and autoimmune liver diseases, still do not have definite diagnostic markers; the diagnosis consists of history, medical imaging, and the relevant score. As a result, the clinical work becomes very complex. So it has broad prospects to explore the specific and sensitive biomarkers of liver diseases with metabolomics. In this paper, there are several summaries which are related to the current research progress and application of metabolomics on biomarkers of liver diseases. PMID:28321390

  9. [Progress in epigenetic research on Alzheimer disease].

    PubMed

    Yang, Nannan; Wei, Yang; Xu, Qian; Tang, Beisha

    2016-04-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder, which features mainly with memory impairment as the initial symptom of progressive loss of cognitive function. Its main pathological changes include senile plaques and neurofibrillary tangles. The pathogenesis of AD is still unclear, though it may be connected with aging, genetic factors and environmental factors. Among these, aging and environmental factors can be modified by epigenetics. In this paper, advances in the study of epigenetic mechanisms related to the pathogenesis of AD are reviewed.

  10. Dose-response thresholds for progressive diseases.

    PubMed

    Cox, Louis Anthony Tony

    2012-01-01

    Many diseases, including cancers, heart diseases, and lung diseases, can usefully be viewed as arising from disruption of feedback control systems that normally maintain homeostasis of tissues and cell populations. Excessive exposure can destabilize feedback control loops, leading to sustained elevation of variables to saturated levels and clinical consequences such as chronic unresolved inflammation, destruction of tissue (as in emphysema), proliferation of cell populations (as in lung cancer), and increases in reactive oxygen species and protease levels (as in coronary heart diseases and chronic obstructive lung disease). We propose a framework for understanding how exposure can destabilize normally homeostatic feedback control systems and create sustained imbalances and elevated levels of disease-related variables, by creating a new, locally stable, alternative equilibrium for the dynamic system, in addition to its normal (homeostatic) equilibrium. The resulting model, which we call alternative-equilibria (AE) theory, implies the existence of an exposure threshold below which transition to the alternative equilibrium (potential disease) state will not occur. Once this threshold is exceeded, progression to the alternative equilibrium continues spontaneously, even without further exposure. These predictions may help to explain patterns observed in experimental and epidemiological data for diseases such as COPD, silicosis, and inflammation-mediated lung cancer.

  11. Systemic and renal lipids in kidney disease development and progression

    PubMed Central

    Wahl, Patricia; Ducasa, Gloria Michelle

    2015-01-01

    Altered lipid metabolism characterizes proteinuria and chronic kidney diseases. While it is thought that dyslipidemia is a consequence of kidney disease, a large body of clinical and experimental studies support that altered lipid metabolism may contribute to the pathogenesis and progression of kidney disease. In fact, accumulation of renal lipids has been observed in several conditions of genetic and nongenetic origins, linking local fat to the pathogenesis of kidney disease. Statins, which target cholesterol synthesis, have not been proven beneficial to slow the progression of chronic kidney disease. Therefore, other therapeutic strategies to reduce cholesterol accumulation in peripheral organs, such as the kidney, warrant further investigation. Recent advances in the understanding of the biology of high-density lipoprotein (HDL) have revealed that functional HDL, rather than total HDL per se, may protect from both cardiovascular and kidney diseases, strongly supporting a role for altered cholesterol efflux in the pathogenesis of kidney disease. Although the underlying pathophysiological mechanisms responsible for lipid-induced renal damage have yet to be uncovered, several studies suggest novel mechanisms by which cholesterol, free fatty acids, and sphingolipids may affect glomerular and tubular cell function. This review will focus on the clinical and experimental evidence supporting a causative role of lipids in the pathogenesis of proteinuria and kidney disease, with a primary focus on podocytes. PMID:26697982

  12. Protein carbonylation, cellular dysfunction, and disease progression

    PubMed Central

    Dalle-Donne, Isabella; Aldini, Giancarlo; Carini, Marina; Colombo, Roberto; Rossi, Ranieri; Milzani, Aldo

    2006-01-01

    Carbonylation of proteins is an irreversible oxidative damage, often leading to a loss of protein function, which is considered a widespread indicator of severe oxidative damage and disease-derived protein dysfunction. Whereas moderately carbonylated proteins are degraded by the proteasomal system, heavily carbonylated proteins tend to form high-molecular-weight aggregates that are resistant to degradation and accumulate as damaged or unfolded proteins. Such aggregates of carbonylated proteins can inhibit proteasome activity. A large number of neurodegenerative diseases are directly associated with the accumulation of proteolysis-resistant aggregates of carbonylated proteins in tissues. Identification of specific carbonylated protein(s) functionally impaired and development of selective carbonyl blockers should lead to the definitive assessment of the causative, correlative or consequential role of protein carbonylation in disease onset and/or progression, possibly providing new therapeutic aproaches. PMID:16796807

  13. [ADPKD: predictors of Renal Disease progression].

    PubMed

    Scolari, Francesco; Dallera, Nadia; Saletti, Arianna; Terlizzi, Vincenzo; Izzi, Claudia

    2016-01-01

    Factors predicting rapid progression of kidney disease in ADPKD can be divided into genetic (non-modifiable) and clinical (modifiable) risk factors. Patients harbouring PKD1 mutations, in particular if truncating, have a more severe form of ADPKD. Clinical risk factors include decrease in glomerular filtration rate and renal blood flow at a young age; high total kidney volume; hypertension and urological complications <35 years; albuminuria/proteinuria. The renal disease is also more severe in males and in subjects with family history of ESRD <55 years. In recent years, two models for predicting progression in ADPKD have been published: the Mayo model, based on height-adjusted TKV, age and eGFR, and the Brest model, based on PKD gene mutation type, gender, and early onset of hypertension and urological complications. With the emergence of new disease-modifying therapies, prediction tools are essential. However, the high variability in ADPKD makes the predicting models difficult to apply on an individual patient basis. Thus, the above-mentioned predicting models should be viewed as complimentary to clinical evaluation and follow-up. In the future, an individual risk score linking genetic, imaging and clinical data might prove the most accurate way of predicting long-term outcome.

  14. Alcohol Use Accelerates HIV Disease Progression

    PubMed Central

    Rafie, Carlin; Lai, Shenghan; Sales, Sabrina; Page, John Bryan; Campa, Adriana

    2010-01-01

    Abstract The effects of alcohol abuse on HIV disease progression have not been definitively established. A prospective, 30-month, longitudinal study of 231 HIV+ adults included history of alcohol and illicit drug use, adherence to antiretroviral therapy (ART), CD4+ cell count, and HIV viral load every 6 months. Frequent alcohol users (two or more drinks daily) were 2.91 times (95% CI: 1.23–6.85, p = 0.015) more likely to present a decline of CD4 to ≤200 cells/μl, independent of baseline CD4+ cell count and HIV viral load, antiretroviral use over time, time since HIV diagnosis, age, and gender. Frequent alcohol users who were not on ART also increased their risk for CD4 cell decline to ≤200 cells/mm3 (HR = 7.76: 95% CI: 1.2–49.2, p = 0.03). Combined frequent alcohol use with crack-cocaine showed a significant risk of CD4+ cell decline (HR = 3.57: 95% CI: 1.24–10.31, p = 0.018). Frequent alcohol intake was associated with higher viral load over time (β = 0.259, p = 0.038). This significance was maintained in those receiving ART (β = 0.384, p = 0.0457), but not in those without ART. Frequent alcohol intake and the combination of frequent alcohol and crack-cocaine accelerate HIV disease progression. The effect of alcohol on CD4+ cell decline appears to be independent of ART, through a direct action on CD4 cells, although alcohol and substance abuse may lead to unmeasured behaviors that promote HIV disease progression. The effect of alcohol abuse on viral load, however, appears to be through reduced adherence to ART. PMID:20455765

  15. Gene therapy: progress in childhood disease.

    PubMed

    Ginn, Samantha L; Alexander, Ian E

    2012-06-01

    The recent sequencing of the human genome combined with the development of massively high throughput genetic analysis technologies is driving unprecedented growth in our knowledge of the molecular basis of disease. While this has already had a major impact on our diagnostic power, the therapeutic benefits remain largely unrealised. This review examines progress in the exciting and challenging field of gene therapy. In particular we focus on the treatment of genetic disease in infants and children where the most significant successes have been observed to date, despite the majority of trial participants being adults. Notably, gene transfer to the haematopoietic compartment has provided the clearest examples of therapeutic benefit, particularly in the context of primary immunodeficiencies. The triumphs and tribulations of these successes are explored, and the key challenges confronting researchers as they seek to further advance the field are defined and discussed.

  16. Crevicular Fluid Biomarkers and Periodontal Disease Progression

    PubMed Central

    Oh, Min; Braun, Thomas M.; Ramseier, Christoph A.; Sugai, Jim V.; Giannobile, William V.

    2014-01-01

    Aim Assess the ability of a panel of gingival crevicular fluid (GCF) biomarkers as predictors of periodontal disease progression (PDP). Materials and Methods 100 individuals participated in a 12-month longitudinal investigation and categorized into 4 groups according to their periodontal status. GCF, clinical parameters, and saliva were collected bi-monthly. Sub-gingival plaque and serum were collected bi-annually. For 6 months, no periodontal treatment was provided. At 6-months, patients received periodontal therapy and continued participation from 6-12 months. GCF samples were analyzed by ELISA for MMP-8, MMP-9, OPG, CRP and IL-1β. Differences in median levels of GCF biomarkers were compared between stable and progressing participants using Wilcoxon Rank Sum test (p=0.05). Clustering algorithm was used to evaluate the ability of oral biomarkers to classify patients as either stable or progressing. Results Eighty-three individuals completed the 6-month monitoring phase. With the exception of GCF C-reactive protein, all biomarkers were significantly higher in the PDP group compared to stable patients. Clustering analysis showed highest sensitivity levels when biofilm pathogens and GCF biomarkers were combined with clinical measures, 74% (95% CI = 61,86). Conclusions Signature of GCF fluid-derived biomarkers combined with pathogens and clinical measures provides a sensitive measure for discrimination of PDP (ClinicalTrials.gov NCT00277745). PMID:24303954

  17. Mapping Neurodegenerative Disease Onset and Progression.

    PubMed

    Seeley, William W

    2017-03-13

    Brain networks have been of long-standing interest to neurodegeneration researchers, including but not limited to investigators focusing on conventional prion diseases, which are known to propagate along neural pathways. Tools for human network mapping, however, remained inadequate, limiting our understanding of human brain network architecture and preventing clinical research applications. Until recently, neuropathological studies were the only viable approach to mapping disease onset and progression in humans but required large autopsy cohorts and laborious methods for whole-brain sectioning and staining. Despite important advantages, postmortem studies cannot address in vivo, physiological, or longitudinal questions and have limited potential to explore early-stage disease except for the most common disorders. Emerging in vivo network-based neuroimaging strategies have begun to address these issues, providing data that complement the neuropathological tradition. Overall, findings to date highlight several fundamental principles of neurodegenerative disease anatomy and pathogenesis, as well as some enduring mysteries. These principles and mysteries provide a road map for future research.

  18. Rosai-Dorfman disease affecting the maxilla

    PubMed Central

    Miniello, Thaís Gimenez; Araujo, Juliane Piragine; Sugaya, Norberto Nobuo; Elias, Fernando Melhem; de Almeida, Oslei Paes

    2016-01-01

    Rosai-Dorfman disease (RDD), formerly called sinus histiocytosis with massive lymphadenopathy, is a non-neoplastic proliferative histiocytic disorder with behavior ranging from highly aggressive to spontaneous remission. Although the lymph nodes are more commonly involved, any organ can be affected. This study aimed to describe the features and the follow-up of a case of extranodal RDD. Our patient was a 39-year-old woman who was referred with an 11-month history of pain in the right maxilla. On clinical examination, some upper right teeth presented full mobility with normal appearance of the surrounding gingiva. Radiographic exams showed an extensive bone reabsorption and maxillary sinus filled with homogeneous tissue, which sometimes showed polypoid formation. An incisional biopsy demonstrated a diffuse inflammatory infiltrate rich in foamy histiocytes displaying lymphocytes emperipolesis. Immunohistochemistry showed positivity for CD68 and S-100, and negativity for CD3, CD20, and CD30. Such features were consistent with the RDD diagnosis. The patient was referred to a hematologist and corticotherapy was administrated for 6 months. RDD is an uncommon disease that rarely affects the maxilla. In the present case, the treatment was conservative, and the patient is currently asymptomatic after 5 years of follow-up. PMID:28210574

  19. Regionality of disease progression predicts prognosis in amyotrophic lateral sclerosis.

    PubMed

    van der Kleij, Lisa A; Jones, Ashley R; Steen, I Nick; Young, Carolyn A; Shaw, Pamela J; Shaw, Christopher E; Leigh, P Nigel; Turner, Martin R; Al-Chalabi, Ammar

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurological syndrome in which motor neurons degenerate relentlessly. Although the site of onset and the rate of spread have been studied extensively, little is known about whether focal as opposed to diffuse disease affects prognosis. We therefore tested the hypothesis that regionality of disease burden is a prognostic factor in ALS. We analysed clinical data from two large multicentre, longitudinal trials. Regionality was defined as the difference in progression rates in three domains as measured by the revised ALS Functional Rating Scale, omitting the respiratory domain from analysis. We used death by trial end as the outcome variable and tested this by logistic regression against predictor variables including regionality and overall rate of disease progression. There were 561 patients. Regionality of disease was independently associated with significantly higher chance of death by study end (odds ratio most diffuse against most focal category 0.354 (0.191, 0.657), p = 0.001), with a direct relationship between degree of regionality and odds of death. We have shown using clinical trial data that focal disease is associated with a worse prognosis in ALS. Measures of regionality warrant further independent consideration in the development of future prognostic models.

  20. Gaucher disease: Progress and ongoing challenges.

    PubMed

    Mistry, Pramod K; Lopez, Grisel; Schiffmann, Raphael; Barton, Norman W; Weinreb, Neal J; Sidransky, Ellen

    Over the past decades, tremendous progress has been made in the field of Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Many of the colossal achievements took place during the course of the sixty-year tenure of Dr. Roscoe Brady at the National Institutes of Health. These include the recognition of the enzymatic defect involved, the isolation and characterization of the protein, the localization and characterization of the gene and its nearby pseudogene, as well as the identification of the first mutant alleles in patients. The first treatment for Gaucher disease, enzyme replacement therapy, was conceived of, developed and tested at the Clinical Center of the National Institutes of Health. Advances including recombinant production of the enzyme, the development of mouse models, pioneering gene therapy experiments, high throughput screens of small molecules and the generation of induced pluripotent stem cell models have all helped to catapult research in Gaucher disease into the twenty-first century. The appreciation that mutations in the glucocerebrosidase gene are an important risk factor for parkinsonism further expands the impact of this work. However, major challenges still remain, some of which are described here, that will provide opportunities, excitement and discovery for the next generations of Gaucher investigators.

  1. Glutathione dysregulation and the etiology and progression of human diseases

    PubMed Central

    Ballatori, Nazzareno; Krance, Suzanne M.; Notenboom, Sylvia; Shi, Shujie; Tieu, Kim; Hammond, Christine L.

    2009-01-01

    Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and as a result, disturbances in GSH homeostasis are implicated in the etiology and/or progression of a number of human diseases, including cancer, diseases of aging, cystic fibrosis, and cardiovascular, inflammatory, immune, metabolic, and neurodegenerative diseases. Because of GSH’s pleiotropic effects on cell functions, it has been quite difficult to define the role of GSH in the onset and/or the expression of human diseases, although significant progress is being made. GSH levels, turnover rates and/or oxidation state can be compromised by inherited or aquired defects in the enzymes, transporters, signaling molecules, or transcription factors that are involved in its homeostasis, or from exposure to reactive chemicals or metabolic intermediates. GSH deficiency or a decrease in the GSH/glutathione disulfide (GSSG) ratio manifests itself largely through an increased susceptibility to oxidative stress, and the resulting damage is thought to be involved in diseases such as cancer, Parkinson’s disease, and Alzheimer’s disease. In addition, imbalances in GSH levels affect immune system function, and are thought to play a role in the aging process. Just as low intracellular GSH levels decrease cellular antioxidant capacity, elevated GSH levels generally increase antioxidant capacity and resistance to oxidative stress, and this is observed in many cancer cells. The higher GSH levels in some tumor cells are also typically associated with higher levels of GSH-related enzymes and transporters. Although neither the mechanism nor the implications of these changes are well defined, the high GSH content makes cancer cells chemoresistant, which is a major factor that limits drug treatment. The present report highlights and integrates the growing connections between imbalances in GSH homeostasis and a multitude of human diseases

  2. Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression

    PubMed Central

    Azuma, Junya; Wong, Ronald J.; Morisawa, Takeshi; Hsu, Mark; Maegdefessel, Lars; Zhao, Hui; Kalish, Flora; Kayama, Yosuke; Wallenstein, Matthew B.; Deng, Alicia C.; Spin, Joshua M.; Stevenson, David K.; Dalman, Ronald L.; Tsao, Philip S.

    2016-01-01

    Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease. PMID:26894432

  3. Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression.

    PubMed

    Azuma, Junya; Wong, Ronald J; Morisawa, Takeshi; Hsu, Mark; Maegdefessel, Lars; Zhao, Hui; Kalish, Flora; Kayama, Yosuke; Wallenstein, Matthew B; Deng, Alicia C; Spin, Joshua M; Stevenson, David K; Dalman, Ronald L; Tsao, Philip S

    2016-01-01

    Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease.

  4. Multi-Trajectory Models of Chronic Kidney Disease Progression.

    PubMed

    Burckhardt, Philipp; Nagin, Daniel S; Padman, Rema

    2016-01-01

    An ever increasing number of people are affected by chronic kidney disease (CKD). A better understanding of the progression ofCKD and its complications is needed to address what is becoming a major burden for health-care systems worldwide. Utilizing a rich data set consisting of the Electronic Health Records (EHRs) of more than 33,000 patients from a leading community nephrology practice in Western Pennsylvania, we applied group-based trajectory modeling (GBTM) in order to detect patient risk groups and uncover typical progressions of CKD and related comorbidities and complications. We have found distinct risk groups with differing trajectories and are able to classify new patients into these groups with high accuracy (up to ≈ 90%). Our results suggest that multitrajectory modeling via GBTM can shed light on the developmental course ofCKD and the interactions between related complications.

  5. Multi-Trajectory Models of Chronic Kidney Disease Progression

    PubMed Central

    Burckhardt, Philipp; Nagin, Daniel S.; Padman, Rema

    2016-01-01

    An ever increasing number of people are affected by chronic kidney disease (CKD). A better understanding of the progression ofCKD and its complications is needed to address what is becoming a major burden for health-care systems worldwide. Utilizing a rich data set consisting of the Electronic Health Records (EHRs) of more than 33,000 patients from a leading community nephrology practice in Western Pennsylvania, we applied group-based trajectory modeling (GBTM) in order to detect patient risk groups and uncover typical progressions of CKD and related comorbidities and complications. We have found distinct risk groups with differing trajectories and are able to classify new patients into these groups with high accuracy (up to ≈ 90%). Our results suggest that multitrajectory modeling via GBTM can shed light on the developmental course ofCKD and the interactions between related complications. PMID:28269932

  6. Role of depression, stress, and trauma in HIV disease progression.

    PubMed

    Leserman, Jane

    2008-06-01

    Despite advances in HIV treatment, there continues to be great variability in the progression of this disease. This paper reviews the evidence that depression, stressful life events, and trauma account for some of the variation in HIV disease course. Longitudinal studies both before and after the advent of highly active antiretroviral therapies (HAART) are reviewed. To ensure a complete review, PubMed was searched for all English language articles from January 1990 to July 2007. We found substantial and consistent evidence that chronic depression, stressful events, and trauma may negatively affect HIV disease progression in terms of decreases in CD4 T lymphocytes, increases in viral load, and greater risk for clinical decline and mortality. More research is warranted to investigate biological and behavioral mediators of these psychoimmune relationships, and the types of interventions that might mitigate the negative health impact of chronic depression and trauma. Given the high rates of depression and past trauma in persons living with HIV/AIDS, it is important for healthcare providers to address these problems as part of standard HIV care.

  7. Social adjustment in adult males affected with progressive muscular dystrophy.

    PubMed

    Eggers, S; Zatz, M

    1998-02-07

    Adult male patients affected with Becker (BMD, N = 22), limb girdle (LGMD, N = 22) and facioscapulohumeral (FSHMD, N = 18) muscular dystrophy were interviewed to assess for the first time how the disease's severity and recurrence risk (RR) magnitude alter their social adjustment. BMD (X-linked recessive) is the severest form and confers an intermediate RR because all daughters will be carriers, LGMD (autosomal-recessive) is moderately severe with a low RR in the absence of consanguineous marriage, and FSHMD (autosomal-dominant) is clinically the mildest of these three forms of MD but with the highest RR, of 50%. Results of the semistructured questionnaire [WHO (1988): Psychiatric Disability Assessment Schedule] showed no significant difference between the three clinical groups, but more severely handicapped patients as well as patients belonging to lower socioeconomic levels from all clinical groups showed poorer social adjustment. Taken together, myopathic patients displayed intermediate social dysfunction compared to controls and schizophrenics studied by Jablensky [1988: WHO Psychiatric Disability Assessment Schedule]. Since the items of major dysfunction proportion among myopathic patients concern intimate relationships (70%), interest in working among those unemployed (67%), and social isolation (53%), emotional support and social and legal assistance should concentrate on these aspects. Interestingly, the results of this study also suggest that high RRs do not affect relationships to the opposite sex.

  8. Dopamine Transporter Imaging Assessment of Parkinson’s Disease Progression

    DTIC Science & Technology

    2000-08-01

    terminal integrity, will provide a quantitative biomarker of Parkinson’s disease progression in subjects with early Parkison’s disease during a nine month...the r te of progression of Parkinson’s disease . All subjects have been and will be recruited and clinically evaluated through their participation in...will directly evaluate in vivo the rate of ongoing dopaminergic ne ronal degeneration in early Parkinson’s disease , whether the rate of ongoing

  9. Progress Toward Eliminating Hepatitis A Disease in the United States.

    PubMed

    Murphy, Trudy V; Denniston, Maxine M; Hill, Holly A; McDonald, Marian; Klevens, Monina R; Elam-Evans, Laurie D; Nelson, Noele P; Iskander, John; Ward, John D

    2016-02-12

    Hepatitis A virus (HAV) disease disproportionately affects adolescents and young adults, American Indian/Alaska Native and Hispanic racial/ethnic groups, and disadvantaged populations. During 1996-2006, the Advisory Committee on Immunization Practices (ACIP) made incremental changes in hepatitis A (HepA) vaccination recommendations to increase coverage for children and persons at high risk for HAV infection. This report examines the temporal association of ACIP-recommended HepA vaccination and disparities (on the absolute scale) in cases of HAV disease and on seroprevalence of HAV-related protection (measured as antibody to HAV [anti-HAV]). ACIP-recommended childhood HepA vaccination in the United States has eliminated most absolute disparities in HAV disease by age, race/ethnicity, and geographic area with relatively modest ≥1-dose and ≥2-dose vaccine coverage. However, the increasing proportion of cases of HAV disease among adults with identified and unidentified sources of exposure underscores the importance of considering new strategies for preventing HAV infection among U.S. adults. For continued progress to be made toward elimination of HAV disease in the United States, additional strategies are needed to prevent HAV infection among an emerging population of susceptible adults. Notably, HAV infection remains endemic in much of the world, contributing to U.S. cases through international travel and the global food economy.

  10. A case of progressive aphasia without dementia: "temporal" Pick's disease?

    PubMed Central

    Scheltens, P; Hazenberg, G J; Lindeboom, J; Valk, J; Wolters, E C

    1990-01-01

    We report a patient who suffered from progressive aphasia for nine years, before developing mild behavioural disturbances. Sequential computed tomography (CT) scanning and magnetic resonance (MRI) imaging showed progressive bilateral temporal atrophy. The case is thought to be a temporal form of Pick's disease, in which isolated progressive aphasia was the only symptom over many years. Images PMID:2303835

  11. Diagnosis of dementia and treatment of Alzheimer's disease. Pharmacologic management of disease progression and cognitive impairment.

    PubMed Central

    van Reekum, R.; Simard, M.; Farcnik, K.

    1999-01-01

    OBJECTIVE: To highlight the importance of family physicians in the management of Alzheimer's disease (AD) and related dementias. To provide an update on the diagnostic workup of people with suspected dementia and on the pharmacologic management of cognitive impairment and disease progression in AD. QUALITY OF EVIDENCE: MEDLINE and Psychological Abstracts were searched using the terms "cognitive enhancers" or a specific drug name and "dementia (exp)." Evidence is generally limited but promising. Methodologic flaws in existing research likely to affect clinicians are briefly reviewed. MAIN MESSAGE: Increasing evidence suggests that early intervention can delay the progression of AD and improve the symptoms and function of those affected. Available treatments have modest but important effects on the outcome of patients with AD; some patients respond dramatically. Most currently available treatments are relatively safe in carefully selected cases. CONCLUSIONS: The diagnostic workup of most cases of dementia can at least be initiated in family physicians' offices. Beginning the workup is important because, for treating AD, the earlier you start, the better. Donepezil, vitamin E, and, in the near future, propentofylline are the main pharmacologic choices for improving cognition and slowing disease progression. PMID:10216793

  12. Lack of TNF-alpha receptor type 2 protects motor neurons in a cellular model of amyotrophic lateral sclerosis and in mutant SOD1 mice but does not affect disease progression.

    PubMed

    Tortarolo, Massimo; Vallarola, Antonio; Lidonnici, Dario; Battaglia, Elisa; Gensano, Francesco; Spaltro, Gabriella; Fiordaliso, Fabio; Corbelli, Alessandro; Garetto, Stefano; Martini, Elisa; Pasetto, Laura; Kallikourdis, Marinos; Bonetto, Valentina; Bendotti, Caterina

    2015-10-01

    Changes in the homeostasis of tumor necrosis factor α (TNFα) have been demonstrated in patients and experimental models of amyotrophic lateral sclerosis (ALS). However, the contribution of TNFα to the development of ALS is still debated. TNFα is expressed by glia and neurons and acts through the membrane receptors TNFR1 and TNFR2, which may have opposite effects in neurodegeneration. We investigated the role of TNFα and its receptors in the selective motor neuron death in ALS in vitro and in vivo. TNFR2 expressed by astrocytes and neurons, but not TNFR1, was implicated in motor neuron loss in primary SOD1-G93A co-cultures. Deleting TNFR2 from SOD1-G93A mice, there was partial but significant protection of spinal motor neurons, sciatic nerves, and tibialis muscles. However, no improvement of motor impairment or survival was observed. Since the sciatic nerves of SOD1-G93A/TNFR2-/- mice showed high phospho-TAR DNA-binding protein 43 (TDP-43) accumulation and low levels of acetyl-tubulin, two indices of axonal dysfunction, the lack of symptom improvement in these mice might be due to impaired function of rescued motor neurons. These results indicate the interaction between TNFR2 and membrane-bound TNFα as an innovative pathway involved in motor neuron death. Nevertheless, its inhibition is not sufficient to stop disease progression in ALS mice, underlining the complexity of this pathology. We show evidence of the involvement of neuronal and astroglial TNFR2 in the motor neuron degeneration in ALS. Both concur to cause motor neuron death in primary astrocyte/spinal neuron co-cultures. TNFR2 deletion partially protects motor neurons and sciatic nerves in SOD1-G93A mice but does not improve their symptoms and survival. However, TNFR2 could be a new target for multi-intervention therapies.

  13. Neglected tropical diseases: progress towards addressing the chronic pandemic.

    PubMed

    Molyneux, David H; Savioli, Lorenzo; Engels, Dirk

    2017-01-21

    The concept of neglected tropical diseases (NTDs) emerged more than a decade ago and has been recognised as a valid way to categorise diseases that affect the poorest individuals. Substantial progress in control and elimination has been achieved and policy momentum has been generated through continued bilateral, philanthropic, and non-governmental development organisation (NGDO) support, and donations of drugs from pharmaceutical companies. WHO has defined a Roadmap to reach 2020 targets, which was endorsed by member states in a World Health Assembly Resolution in 2013. NTDs have been included within the Sustainable Development Goal targets and are a crucial component of universal health coverage, conceptualised as "leaving no one behind". WHO reported that more than 1 billion people in 88 countries have benefited from preventive chemotherapy in 2014. The research agenda has defined the need for affordable products (diagnostics, drugs and insecticides). However challenges such as insecurity and weak health systems continue to prevail in the poorest countries, inhibiting progress in scaling up and also in achieving Roadmap goals.

  14. Stop chronic kidney disease progression: Time is approaching

    PubMed Central

    Sharaf El Din, Usama Abdel Azim; Salem, Mona Mansour; Abdulazim, Dina Ossama

    2016-01-01

    Progression of chronic kidney disease (CKD) is inevitable. However, the last decade has witnessed tremendous achievements in this field. Today we are optimistic; the dream of withholding this progression is about to be realistic. The recent discoveries in the field of CKD management involved most of the individual diseases leading the patients to end-stage renal disease. Most of these advances involved patients suffering diabetic kidney disease, chronic glomerulonephritis, polycystic kidney disease, renal amyloidosis and chronic tubulointerstitial disease. The chronic systemic inflammatory status and increased oxidative stress were also investigated. This inflammatory status influences the anti-senescence Klotho gene expression. The role of Klotho in CKD progression together with its therapeutic value are explored. The role of gut as a major source of inflammation, the pathogenesis of intestinal mucosal barrier damage, the role of intestinal alkaline phosphatase and the dietary and therapeutic implications add a novel therapeutic tool to delay CKD progression. PMID:27152262

  15. Progress Report on Alzheimer Disease: Volume III.

    ERIC Educational Resources Information Center

    National Inst. on Aging (DHHS/PHS), Bethesda, MD.

    This report summarizes advances in the understanding of Alzheimer's disease, the major cause of mental disability among older Americans. The demography of the disease is discussed, noting that approximately 2.5 million American adults are afflicted with the disease and that the large increase in the number of Alzheimer's disease patients is due to…

  16. HIV disease progression: immune activation, microbes, and a leaky gut.

    PubMed

    Douek, Daniel

    2007-01-01

    Recent findings indicate that the majority of all CD4+ T lymphocytes are lost during acute HIV infection, with mucosal compartments being most severely affected. The frequency of infection is very high in gut CD4+ T cells, and depletion of these cells persists into the chronic phase of infection. Infection is associated with increased gut permeability, with microbial translocation being evidenced by increased circulating lipopolysaccharide (LPS) levels. Plasma LPS levels correlate with systemic immune activation, which drives chronic HIV infection. Antiretroviral therapy reduces plasma LPS, and greater CD4+ T cell reconstitution is associated with lower LPS levels. These findings have a number of implications for therapeutic strategies. This article summarizes a presentation on HIV disease progression made by Daniel Douek, MD, PhD, at an International AIDS Society-USA Continuing Medical Education course in San Francisco in May 2007. The original presentation is available as a Webcast at www.iasusa.org.

  17. Ticks and Tickborne Diseases Affecting Military Personnel

    DTIC Science & Technology

    1989-09-01

    by disease transmission. Various bacteria , rickettsiae , viruses, and protozoans are transmitted to people via tick bites (see Chapter 4). Relatively...Ticks may harbor and transmit to people various disease agents such as protozoa, viruses, bacteria , rickettsiae , and toxins. Several factors are...Natural history. The causative agent of RMSF, Rickettsia rickettsii , is transmitted to man by several species of ticks. In the U.S., 2 of the most

  18. Frontal deficits differentiate progressive supranuclear palsy from Parkinson's disease.

    PubMed

    Lee, Young-Eun C; Williams, David R; Anderson, Jacqueline F I

    2016-03-01

    The clinical differentiation of progressive supranuclear palsy from Parkinson's disease can be challenging, due to overlapping clinical features and a lack of diagnostic markers. Abnormalities in cognitive function form part of the clinical spectrums of these diseases and distinctive cognitive profiles may be helpful in differentiating these diseases in the diagnostic period. A comprehensive neuropsychological test battery was administered to 12 patients with clinically diagnosed progressive supranuclear palsy and 12 patients with Parkinson's disease matched for age and disease duration. Effect size (Cohen's d) was calculated for cognitive tests that were significantly different between groups. Patients with progressive supranuclear palsy performed significantly worse than those with Parkinson's disease on measures of processing speed, verbal fluency, planning, verbal abstract reasoning, verbal memory, and made more perseverative responses on a set shifting task. Measures of executive function, manual dexterity and processing speed were most diagnostically useful (Cohen's d > 2.0) in differentiating between progressive supranuclear palsy and Parkinson's disease. These findings suggest that more severe and prominent 'frontal' cognitive deficits in patients with progressive parkinsonism would be helpful in predicting progressive supranuclear palsy rather than Parkinson's disease and these findings may contribute to the development of diagnostic criteria.

  19. Progress on Complications of Direct Bypass for Moyamoya Disease

    PubMed Central

    Yu, Jinlu; Shi, Lei; Guo, Yunbao; Xu, Baofeng; Xu, Kan

    2016-01-01

    Moyamoya disease (MMD) involves progressive occlusion of the intracranial internal carotid artery resulting in formation of moyamoya-like vessels at the base of the brain. It can be characterized by hemorrhage or ischemia. Direct vascular bypass is the main and most effective treatment of MMD. However, patients with MMD differ from those with normal cerebral vessels. MMD patients have unstable intracranial artery hemodynamics and a poor blood flow reserve; therefore, during the direct bypass of superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis, perioperative risk factors and anesthesia can affect the hemodynamics of these patients. When brain tissue cannot tolerate a high blood flow rate, it becomes prone to hyperperfusion syndrome, which leads to neurological function defects and can even cause intracranial hemorrhage in severe cases. The brain tissue is prone to infarction when hemodynamic equilibrium is affected. In addition, bypass vessels become susceptible to occlusion or atrophy when blood resistance increases. Even compression of the temporalis affects bypass vessels. Because the STA is used in MMD surgery, the scalp becomes ischemic and is likely to develop necrosis and infection. These complications of MMD surgery are difficult to manage and are not well understood. To date, no systematic studies of the complications that occur after direct bypass in MMD have been performed, and reported complications are hidden among various case studies; therefore, this paper presents a review and summary of the literature in PubMed on the complications of direct bypass in MMD. PMID:27499690

  20. Progress Report on Alzheimer's Disease: Volume II.

    ERIC Educational Resources Information Center

    National Inst. on Aging (DHHS/PHS), Bethesda, MD.

    This document provides an overview of the state of scientific study of Alzheimer's disease, a disease of catastrophic proportions whose symptoms include serious forgetfulness; changes in personality; confused, restless, and irritable behavior; and problems with judgment, concentration, writing, reading, speech, and naming of objects. It discusses…

  1. Posttraumatic Growth and HIV Disease Progression

    ERIC Educational Resources Information Center

    Milam, Joel

    2006-01-01

    The relationship between posttraumatic growth (PTG; perceiving positive changes since diagnosis) and disease status, determined by changes in viral load and CD4 count over time, was examined among 412 people living with HIV. In controlled multiple regression models, PTG was not associated with disease status over time for the entire sample.…

  2. A prediction model for progressive disease in systemic sclerosis

    PubMed Central

    Meijs, Jessica; Schouffoer, Anne A; Ajmone Marsan, Nina; Stijnen, Theo; Putter, Hein; Ninaber, Maarten K; Huizinga, Tom W J; de Vries-Bouwstra, Jeska K

    2015-01-01

    Objective To develop a model that assesses the risk for progressive disease in patients with systemic sclerosis (SSc) over the short term, in order to guide clinical management. Methods Baseline characteristics and 1 year follow-up results of 163 patients with SSc referred to a multidisciplinary healthcare programme were evaluated. Progressive disease was defined as: death, ≥10% decrease in forced vital capacity, ≥15% decrease in diffusing capacity for carbon monoxide, ≥10% decrease in body weight, ≥30% decrease in estimated-glomerular filtration rate, ≥30% increase in modified Rodnan Skin Score (with Δ≥5) or ≥0.25 increase in Scleroderma Health Assessment Questionnaire. The number of patients with progressive disease was determined. Univariable and multivariable logistic regression analyses were used to assess the probability of progressive disease for each individual patient. Performance of the prediction model was evaluated using a calibration plot and area under the receiver operating characteristic curve. Results 63 patients had progressive disease, including 8 patients who died ≤18 months after first evaluation. Multivariable analysis showed that friction rubs, proximal muscular weakness and decreased maximum oxygen uptake as % predicted, adjusted for age, gender and use of immunosuppressive therapy at baseline, were significantly associated with progressive disease. Using the prediction model, the predicted chance for progressive disease increased from a pretest chance of 37% to 67–89%. Conclusions Using the prediction model, the chance for progressive disease for individual patients could be doubled. Friction rubs, proximal muscular weakness and maximum oxygen uptake as % predicted were identified as relevant parameters. PMID:26688749

  3. Progress and Challenges in Infectious Disease Cartography.

    PubMed

    Kraemer, Moritz U G; Hay, Simon I; Pigott, David M; Smith, David L; Wint, G R William; Golding, Nick

    2016-01-01

    Quantitatively mapping the spatial distributions of infectious diseases is key to both investigating their epidemiology and identifying populations at risk of infection. Important advances in data quality and methodologies have allowed for better investigation of disease risk and its association with environmental factors. However, incorporating dynamic human behavioural processes in disease mapping remains challenging. For example, connectivity among human populations, a key driver of pathogen dispersal, has increased sharply over the past century, along with the availability of data derived from mobile phones and other dynamic data sources. Future work must be targeted towards the rapid updating and dissemination of appropriately designed disease maps to guide the public health community in reducing the global burden of infectious disease.

  4. [Research progress of transgenic Drosophila model of Alzheimer disease].

    PubMed

    Tan, Yan; Ji, Yu-Bin; Zhao, Jian

    2013-03-01

    Alzheimer disease (AD) is a common neurodegenerative disease. Drosophila has been regard as one of the ideal models for Alzheimer because of its unique advantage on genetic manipulation. AD transgenic drosophila models not only help to elucidate the pathogenesis of Alzheimer disease, but also provide potential screening models for drugs to treat the disease. In this review, we summarize the recent research progress using AD transgenic drosophila.

  5. Some risk factors for the progression of periodontal disease.

    PubMed

    Skaleric, U; Kovac-Kavcic, M

    2000-01-01

    Inflammatory periodontal disease is one of the most common diseases of mankind. Gingival inflammation is widespread, but advanced periodontitis is limited to relatively small subgroups of the population. Gingivitis is initiated by microbial plaque deposits on the dento-gingival interface but progression to periodontitis is modified by several environmental, behavioural, biological and health care variables. This paper reviews the reports dealing with some risk factors for periodontal disease published in recent years and compares the data with findings in a Ljubljana population. It is concluded that male smokers with lower education and low frequency of tooth brushing represent a risk population for progression of periodontal disease. Marital status and body mass need further study to be proved as risk factors for periodontitis. A socioecological model proposed by Hansen et al. (1993) should be used for understanding the interplay of different risk factors for progression of periodontal disease.

  6. Parameter on systemic conditions affected by periodontal diseases. American Academy of Periodontology.

    PubMed

    2000-05-01

    The American Academy of Periodontology has developed the following parameter on systemic conditions affected by periodontal diseases. It is well known that systemic conditions may affect the onset, progression, and treatment of such diseases (see Parameter on Periodontitis Associated With Systemic Conditions, pages 876-879). The concept of periodontal diseases as localized entities affecting only the teeth and supporting apparatus is increasingly being questioned. Periodontal diseases may have widespread systemic effects. While these effects may be limited in some individuals, periodontal infections may significantly impact systemic health in others, and may serve as risk indicators for certain systemic diseases or conditions. As part of the approach to establishing and maintaining health, patients should be informed of the possible effects of periodontal infection on their overall well-being. Given this information, patients should then be able to make informed decisions regarding their periodontal therapy.

  7. Reduced serum myostatin concentrations associated with genetic muscle disease progression.

    PubMed

    Burch, Peter M; Pogoryelova, Oksana; Palandra, Joe; Goldstein, Richard; Bennett, Donald; Fitz, Lori; Guglieri, Michela; Bettolo, Chiara Marini; Straub, Volker; Evangelista, Teresinha; Neubert, Hendrik; Lochmüller, Hanns; Morris, Carl

    2017-01-10

    Myostatin is a highly conserved protein secreted primarily from skeletal muscle that can potently suppress muscle growth. This ability to regulate skeletal muscle mass has sparked intense interest in the development of anti-myostatin therapies for a wide array of muscle disorders including sarcopenia, cachexia and genetic neuromuscular diseases. While a number of studies have examined the circulating myostatin concentrations in healthy and sarcopenic populations, very little data are available from inherited muscle disease patients. Here, we have measured the myostatin concentration in serum from seven genetic neuromuscular disorder patient populations using immunoaffinity LC-MS/MS. Average serum concentrations of myostatin in all seven muscle disease patient groups were significantly less than those measured in healthy controls. Furthermore, circulating myostatin concentrations correlated with clinical measures of disease progression for five of the muscle disease patient populations. These findings greatly expand the understanding of myostatin in neuromuscular disease and suggest its potential utility as a biomarker of disease progression.

  8. Progress and challenges in controlling neglected zoonotic diseases.

    PubMed

    Jarvis, Suzanne

    2015-01-24

    Suzanne Jarvis reports from the Fourth International Meeting on the Control of Neglected Zoonotic Diseases, hosted by the World Health Organization in Geneva in November. The meeting looked at progress that has been made in controlling these diseases and at what the next steps should be for further control.

  9. Recent achievements in restorative neurology: Progressive neuromuscular diseases

    SciTech Connect

    Dimitrijevic, M.R.; Kakulas, B.A.; Vrbova, G.

    1986-01-01

    This book contains 27 chapters. Some of the chapter titles are: Computed Tomography of Muscles in Neuromuscular Disease; Mapping the Genes for Muscular Dystrophy; Trophic Factors and Motor Neuron Development; Size of Motor Units and Firing Rate in Muscular Dystrophy; Restorative Possibilities in Relation to the Pathology of Progressive Neuromuscular Disease; and An Approach to the Pathogenesis of some Congenital Myopathies.

  10. Modeling Disease Progression via Fused Sparse Group Lasso

    PubMed Central

    Zhou, Jiayu; Liu, Jun; Narayan, Vaibhav A.; Ye, Jieping

    2013-01-01

    Alzheimer’s Disease (AD) is the most common neurodegenerative disorder associated with aging. Understanding how the disease progresses and identifying related pathological biomarkers for the progression is of primary importance in the clinical diagnosis and prognosis of Alzheimer’s disease. In this paper, we develop novel multi-task learning techniques to predict the disease progression measured by cognitive scores and select biomarkers predictive of the progression. In multi-task learning, the prediction of cognitive scores at each time point is considered as a task, and multiple prediction tasks at different time points are performed simultaneously to capture the temporal smoothness of the prediction models across different time points. Specifically, we propose a novel convex fused sparse group Lasso (cFSGL) formulation that allows the simultaneous selection of a common set of biomarkers for multiple time points and specific sets of biomarkers for different time points using the sparse group Lasso penalty and in the meantime incorporates the temporal smoothness using the fused Lasso penalty. The proposed formulation is challenging to solve due to the use of several non-smooth penalties. One of the main technical contributions of this paper is to show that the proximal operator associated with the proposed formulation exhibits a certain decomposition property and can be computed efficiently; thus cFSGL can be solved efficiently using the accelerated gradient method. To further improve the model, we propose two non-convex formulations to reduce the shrinkage bias inherent in the convex formulation. We employ the difference of convex (DC) programming technique to solve the non-convex formulations. We have performed extensive experiments using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Results demonstrate the effectiveness of the proposed progression models in comparison with existing methods for disease progression. We also perform

  11. Hypokinesia without decrement distinguishes progressive supranuclear palsy from Parkinson's disease.

    PubMed

    Ling, Helen; Massey, Luke A; Lees, Andrew J; Brown, Peter; Day, Brian L

    2012-04-01

    Repetitive finger tapping is commonly used to assess bradykinesia in Parkinson's disease. The Queen Square Brain Bank diagnostic criterion of Parkinson's disease defines bradykinesia as 'slowness of initiation with progressive reduction in speed and amplitude of repetitive action'. Although progressive supranuclear palsy is considered an atypical parkinsonian syndrome, it is not known whether patients with progressive supranuclear palsy have criteria-defined bradykinesia. This study objectively assessed repetitive finger tap performance and handwriting in patients with Parkinson's disease (n = 15), progressive supranuclear palsy (n = 9) and healthy age- and gender-matched controls (n = 16). The motion of the hand and digits was recorded in 3D during 15-s repetitive index finger-to-thumb tapping trials. The main finding was hypokinesia without decrement in patients with progressive supranuclear palsy, which differed from the finger tap pattern in Parkinson's disease. Average finger separation amplitude in progressive supranuclear palsy was less than half of that in controls and Parkinson's disease (P < 0.001 in both cases). Change in tap amplitude over consecutive taps was computed by linear regression. The average amplitude slope in progressive supranuclear palsy was nearly zero (0.01°/cycle) indicating a lack of decrement, which differed from the negative slope in patients with Parkinson's disease OFF levodopa (-0.20°/cycle, P = 0.002). 'Hypokinesia', defined as <50% of control group's mean amplitude, combined with 'absence of decrement', defined as mean positive amplitude slope, were identified in 87% of finger tap trials in the progressive supranuclear palsy group and only 12% in the Parkinson's disease OFF levodopa group. In progressive supranuclear palsy, the mean amplitude was not correlated with disease duration or other clinimetric scores. In Parkinson's disease, finger tap pattern was compatible with criteria-defined bradykinesia

  12. Drug Development for Alzheimer's Disease: Recent Progress

    PubMed Central

    Ji, Wonjin

    2010-01-01

    Alzheimer's disease, the most common cause of dementia, is characterized by two major pathological hallmarks: amyloid plaques and neurofibrillary tangles. Based on these two indicators, an amyloid cascade hypothesis was proposed, and accordingly, most current therapeutic approaches are now focused on the removal of β-amyloid peptides (Aβ from the brain. Additionally, strategies for blocking tau hyperphosphorylation and aggregation have been suggested, including the development of drugs that can block the formation of tangles. However, there are no true disease-modifying drugs in the current market, though many drugs based on theories other than Aβ and tau pathology are under development. The purpose of this review was to provide information on the current development of AD drugs and to discuss the issues related to drug development. PMID:22110351

  13. Repeat expansion disease: Progress and puzzles in disease pathogenesis

    PubMed Central

    La Spada, Albert R.; Taylor, J. Paul

    2015-01-01

    Repeat expansion mutations cause at least 22 inherited neurological diseases. The complexity of repeat disease genetics and pathobiology has revealed unexpected shared themes and mechanistic pathways among the diseases, for example, RNA toxicity. Also, investigation of the polyglutamine diseases has identified post-translational modification as a key step in the pathogenic cascade, and has shown that the autophagy pathway plays an important role in the degradation of misfolded proteins – two themes likely to be relevant to the entire neurodegeneration field. Insights from repeat disease research are catalyzing new lines of study that should not only elucidate molecular mechanisms of disease, but also highlight opportunities for therapeutic intervention for these currently untreatable disorders. PMID:20177426

  14. Estimating disease progression using panel data.

    PubMed

    Mandel, Micha

    2010-04-01

    Continuous-time Markov processes are frequently used to describe the evolution of a disease over different phases. Such modeling can provide estimates for important parameters that are defined on the paths of the process. A simple example is the mean first hitting time to a set of states. However, more interesting events are defined by several time points such as the first time the process stays in state j for at least Delta time units. These kinds of events are very important in relapsing-remitting diseases such as in multiple sclerosis (MS) where the focus is on a sustained worsening that lasts 6 months or longer. The current paper considers data on independent continuous Markov processes that are only observed intermittently. It reviews modeling and estimation, presents a new general concept of hitting times, and provides point and interval estimates for it. The methodology is applied to data from a phase III clinical trial of Avonex--a drug given to MS patients.

  15. CD1d expression on chronic lymphocytic leukemia B cells affects disease progression and induces T cell skewing in CD8 positive and CD4CD8 double negative T cells

    PubMed Central

    Zaborsky, Nadja; Gassner, Franz Josef; Asslaber, Daniela; Reinthaler, Petra; Denk, Ursula; Flenady, Sabine; Hofbauer, Josefina Piñón; Danner, Barbara; Rebhandl, Stefan; Harrer, Andrea; Geisberger, Roland; Greil, Richard; Egle, Alexander

    2016-01-01

    Chronic lymphocytic leukemia develops within a complex network driven by genetic mutations and microenvironmental interactions. Among the latter a complex interplay with the immune system is established by the clone. Next to a proposed recruitment of support from T and myeloid cells, potential anti-CLL immune reactions need to be subverted. By using TCL1 mice as a CLL model, we show that TCR-Vβ7+ NK1.1+ T cells are overrepresented in this disease model and constitute a main subset of peripheral CD3+ cells with biased TCR usage, showing that these cells account for a major part for T cell skewing in TCL1 mice. Moreover, we show that overrepresentation is dependent on CD1d expression in TCL1 mice, implicating that these cells belong to a NKT-like cell fraction which are restricted to antigen presented by the MHC-like surface marker CD1d. Accordingly, we observed a high fraction of CD161+ cells within overrepresented T cells in CLL patients and we found downregulation of CD1d on the surface of CLL cells, both in TCL1 mice and patients. Finally, we show that in TCL1 mice, CD1d deficiency resulted in shortened overall survival. Our results point to an interaction between CLL and CD161+ T cells that may represent a novel therapeutic target for immune modulation. PMID:27385215

  16. Alcohol’s Role in HIV Transmission and Disease Progression

    PubMed Central

    Pandrea, Ivona; Happel, Kyle I.; Amedee, Angela M.; Bagby, Gregory J.; Nelson, Steve

    2010-01-01

    Alcohol use has negative effects on HIV disease progression through several mechanisms, including transmission, viral replication, host immunity, and treatment efficacy. Research with animal models has explored the effect of alcohol intake on several aspects of simian immunodeficiency virus (SIV) disease progression. Data suggest that the increased SIV levels observed in alcohol-consuming animals may represent an increase in virus production as opposed to a decrease in host defense. Results also suggest that changes in nutritional balance and metabolism, as a possible consequence of a proinflammatory state, together with increased virus production in animals consuming alcohol, accelerate SIV and possibly HIV disease progression. Further studies using the animal model are necessary. PMID:23584062

  17. Lipid-Altering Therapies and the Progression of Atherosclerotic Disease

    SciTech Connect

    Wierzbicki, Anthony S.

    2007-04-15

    Lipids play a key role in the progression of atherosclerosis, and lipid-lowering therapies have been studied for 30 years in coronary disease. Measurement of the progression of atherosclerosis through carotid intima-media thickness, coronary mean lumen diameter, and, mostly recently, intravascular ultrasound is generally accepted. This article reviews the role of lipid-lowering therapies in changing the rate of atherosclerosis progression in the coronary and carotid circulations. Statins are the primary therapy used to reduce atherosclerosis and cardiovascular events, including strokes and transient ischemic attacks, and have benefits in reducing events in patients undergoing carotid endarterectomy. In contrast, data for other agents, including fibrates and nicotinic acid, in reducing the progression of atherosclerosis are less extensive and not as well known. There is increasing interest in optimizing the whole lipid profile, as this might deliver extra benefits over and above statin therapy alone. Initial proof of this concept has recently come from studies that measured the progression of atherosclerosis and showed that adding nicotinic acid to statin therapy and, more directly, infusion of high-density lipoprotein-like particles reduced progression and indeed might induce regression of the disease. It is likely that the management of significant carotid stenosis will become ever more drug focused and will be customized to the lipid profile of each patient with intervention reserved only for late-stage symptomatic disease.

  18. Augmentative and alternative communication for people with progressive neuromuscular disease.

    PubMed

    Ball, Laura J; Fager, Susan; Fried-Oken, Melanie

    2012-08-01

    Individuals with progressive neuromuscular disease often experience complex communication needs and consequently find that interaction using their natural speech may not sufficiently meet their daily needs. Increasingly, assistive technology advances provide accommodations for and/or access to communication. Assistive technology related to communication is referred to as augmentative and alternative communication (AAC). The nature of communication challenges in progressive neuromuscular diseases can be as varied as the AAC options currently available. AAC systems continue to be designed and implemented to provide targeted assistance based on an individual's changing needs.

  19. State of progress in treating cystic fibrosis respiratory disease

    PubMed Central

    2012-01-01

    Since the discovery of the gene associated with cystic fibrosis (CF), there has been tremendous progress in the care of patients with this disease. New therapies have entered the market and are part of the standard treatment of patients with CF, and have been associated with marked improvement in survival. Now there are even more promising therapies directed at different components of the pathophysiology of this disease. In this review, our current knowledge of the pathophysiology of lung disease in patients with CF is described, along with the current treatment of CF lung disease, and the therapies in development that offer great promise to our patients. PMID:22883684

  20. Clinical progression in Parkinson disease and the neurobiology of axons.

    PubMed

    Cheng, Hsiao-Chun; Ulane, Christina M; Burke, Robert E

    2010-06-01

    Despite tremendous growth in recent years in our knowledge of the molecular basis of Parkinson disease (PD) and the molecular pathways of cell injury and death, we remain without therapies that forestall disease progression. Although there are many possible explanations for this lack of success, one is that experimental therapeutics to date have not adequately focused on an important component of the disease process, that of axon degeneration. It remains unknown what neuronal compartment, either the soma or the axon, is involved at disease onset, although some have proposed that it is the axons and their terminals that take the initial brunt of injury. Nevertheless, this concept has not been formally incorporated into many of the current theories of disease pathogenesis, and it has not achieved a wide consensus. More importantly, in view of growing evidence that the molecular mechanisms of axon degeneration are separate and distinct from the canonical pathways of programmed cell death that mediate soma destruction, the possibility of early involvement of axons in PD has not been adequately emphasized as a rationale to explore the neurobiology of axons for novel therapeutic targets. We propose that ongoing degeneration of axons, not cell bodies, is the primary determinant of clinically apparent progression of disease, and that future experimental therapeutics intended to forestall disease progression will benefit from a new focus on the distinct mechanisms of axon degeneration.

  1. Accuracy Improvement for Predicting Parkinson’s Disease Progression

    PubMed Central

    Nilashi, Mehrbakhsh; Ibrahim, Othman; Ahani, Ali

    2016-01-01

    Parkinson’s disease (PD) is a member of a larger group of neuromotor diseases marked by the progressive death of dopamineproducing cells in the brain. Providing computational tools for Parkinson disease using a set of data that contains medical information is very desirable for alleviating the symptoms that can help the amount of people who want to discover the risk of disease at an early stage. This paper proposes a new hybrid intelligent system for the prediction of PD progression using noise removal, clustering and prediction methods. Principal Component Analysis (PCA) and Expectation Maximization (EM) are respectively employed to address the multi-collinearity problems in the experimental datasets and clustering the data. We then apply Adaptive Neuro-Fuzzy Inference System (ANFIS) and Support Vector Regression (SVR) for prediction of PD progression. Experimental results on public Parkinson’s datasets show that the proposed method remarkably improves the accuracy of prediction of PD progression. The hybrid intelligent system can assist medical practitioners in the healthcare practice for early detection of Parkinson disease. PMID:27686748

  2. An event-based model for disease progression and its application in familial Alzheimer's disease and Huntington's disease.

    PubMed

    Fonteijn, Hubert M; Modat, Marc; Clarkson, Matthew J; Barnes, Josephine; Lehmann, Manja; Hobbs, Nicola Z; Scahill, Rachael I; Tabrizi, Sarah J; Ourselin, Sebastien; Fox, Nick C; Alexander, Daniel C

    2012-04-15

    Understanding the progression of neurological diseases is vital for accurate and early diagnosis and treatment planning. We introduce a new characterization of disease progression, which describes the disease as a series of events, each comprising a significant change in patient state. We provide novel algorithms to learn the event ordering from heterogeneous measurements over a whole patient cohort and demonstrate using combined imaging and clinical data from familial Alzheimer's and Huntington's disease cohorts. Results provide new detail in the progression pattern of these diseases, while confirming known features, and give unique insight into the variability of progression over the cohort. The key advantage of the new model and algorithms over previous progression models is that they do not require a priori division of the patients into clinical stages. The model and its formulation extend naturally to a wide range of other diseases and developmental processes and accommodate cross-sectional and longitudinal input data.

  3. Progress in public-private partnerships to fight neglected diseases.

    PubMed

    Gustavsen, Kenneth; Hanson, Christy

    2009-01-01

    In the global fight against neglected tropical diseases (NTDs), public health partnerships involving donations of medicines by pharmaceutical companies are enabling access to treatment for millions of people worldwide. These partnerships collaborate with other disease programs and a range of key stakeholders to develop and improve programs to control and eliminate NTDs. Although progress is being made against NTDs, continued success depends on a policy environment that supports appropriate levels of engagement and collaboration from all participants.

  4. Avoiding permanent atrial fibrillation: treatment approaches to prevent disease progression

    PubMed Central

    Shukla, Ashish; Curtis, Anne B

    2014-01-01

    Atrial fibrillation (AF) is the most common sustained arrhythmia and a major global public health problem due to its associated morbidity, including stroke and heart failure, diminished quality of life, and increased mortality. AF often presents initially in a paroxysmal form and may progress to a more sustained form over time. Evidence from randomized controlled trials suggests that there may be no mortality benefit to using a rhythm control approach in comparison with rate control of AF. Nevertheless, sustained forms of AF may be associated with increased symptoms and cardiovascular morbidity, and consequently they remain an additional target for therapy. The present review evaluates the clinical correlates of arrhythmia progression and risk stratification techniques available to assess probability of AF progression. Further, currently available management options for arrhythmia control in AF are evaluated and their therapeutic effect and efficacy on disease progression are explored. PMID:24379678

  5. Potential biomarkers to follow the progression and treatment response of Huntington's disease.

    PubMed

    Disatnik, Marie-Hélène; Joshi, Amit U; Saw, Nay L; Shamloo, Mehrdad; Leavitt, Blair R; Qi, Xin; Mochly-Rosen, Daria

    2016-11-14

    Huntington's disease (HD) is a rare genetic disease caused by expanded polyglutamine repeats in the huntingtin protein resulting in selective neuronal loss. Although genetic testing readily identifies those who will be affected, current pharmacological treatments do not prevent or slow down disease progression. A major challenge is the slow clinical progression and the inability to biopsy the affected tissue, the brain, making it difficult to design short and effective proof of concept clinical trials to assess treatment benefit. In this study, we focus on identifying peripheral biomarkers that correlate with the progression of the disease and treatment benefit. We recently developed an inhibitor of pathological mitochondrial fragmentation, P110, to inhibit neurotoxicity in HD. Changes in levels of mitochondrial DNA (mtDNA) and inflammation markers in plasma, a product of DNA oxidation in urine, mutant huntingtin aggregates, and 4-hydroxynonenal adducts in muscle and skin tissues were all noted in HD R6/2 mice relative to wild-type mice. Importantly, P110 treatment effectively reduced the levels of these biomarkers. Finally, abnormal levels of mtDNA were also found in plasma of HD patients relative to control subjects. Therefore, we identified several potential peripheral biomarkers as candidates to assess HD progression and the benefit of intervention for future clinical trials.

  6. Osteoarthritis in the XXIst Century: Risk Factors and Behaviours that Influence Disease Onset and Progression

    PubMed Central

    Musumeci, Giuseppe; Aiello, Flavia Concetta; Szychlinska, Marta Anna; Di Rosa, Michelino; Castrogiovanni, Paola; Mobasheri, Ali

    2015-01-01

    Osteoarthritis (OA) is a growing public health problem across the globe, affecting more than half of the over 65 population. In the past, OA was considered a wear and tear disease, leading to the loss of articular cartilage and joint disability. Nowadays, thanks to advancements in molecular biology, OA is believed to be a very complex multifactorial disease. OA is a degenerative disease characterized by “low-grade inflammation” in cartilage and synovium, resulting in the loss of joint structure and progressive deterioration of cartilage. Although the disease can be dependent on genetic and epigenetic factors, sex, ethnicity, and age (cellular senescence, apoptosis and lubricin), it is also associated with obesity and overweight, dietary factors, sedentary lifestyle and sport injuries. The aim of this review is to highlight how certain behaviors, habits and lifestyles may be involved in the onset and progression of OA and to summarize the principal risk factors involved in the development of this complicated joint disorder. PMID:25785564

  7. Structural imaging biomarkers of Alzheimer's disease: predicting disease progression.

    PubMed

    Eskildsen, Simon F; Coupé, Pierrick; Fonov, Vladimir S; Pruessner, Jens C; Collins, D Louis

    2015-01-01

    Optimized magnetic resonance imaging (MRI)-based biomarkers of Alzheimer's disease (AD) may allow earlier detection and refined prediction of the disease. In addition, they could serve as valuable tools when designing therapeutic studies of individuals at risk of AD. In this study, we combine (1) a novel method for grading medial temporal lobe structures with (2) robust cortical thickness measurements to predict AD among subjects with mild cognitive impairment (MCI) from a single T1-weighted MRI scan. Using AD and cognitively normal individuals, we generate a set of features potentially discriminating between MCI subjects who convert to AD and those who remain stable over a period of 3 years. Using mutual information-based feature selection, we identify 5 key features optimizing the classification of MCI converters. These features are the left and right hippocampi gradings and cortical thicknesses of the left precuneus, left superior temporal sulcus, and right anterior part of the parahippocampal gyrus. We show that these features are highly stable in cross-validation and enable a prediction accuracy of 72% using a simple linear discriminant classifier, the highest prediction accuracy obtained on the baseline Alzheimer's Disease Neuroimaging Initiative first phase cohort to date. The proposed structural features are consistent with Braak stages and previously reported atrophic patterns in AD and are easy to transfer to new cohorts and to clinical practice.

  8. Ketogenic Diet Prevents Epileptogenesis and Disease Progression in Adult Mice and Rats

    PubMed Central

    Lusardi, Theresa A.; Akula, Kiran K.; Coffman, Shayla Q.; Ruskin, David; Masino, Susan A.; Boison, Detlev

    2015-01-01

    Epilepsy is a highly prevalent seizure disorder which tends to progress in severity and become refractory to treatment. Yet no therapy is proven to halt disease progression or to prevent the development of epilepsy. Because a high fat low carbohydrate ketogenic diet (KD) augments adenosine signaling in the brain and because adenosine not only suppresses seizures but also affects epileptogenesis, we hypothesized that a ketogenic diet might prevent epileptogenesis through similar mechanisms. Here, we tested this hypothesis in two independent rodent models of epileptogenesis. Using a pentylenetetrazole kindling paradigm in mice, we first show that a KD, but not a conventional antiepileptic drug (valproic acid), suppressed kindling-epileptogenesis. Importantly, after treatment reversal, increased seizure thresholds were maintained in those animals kindled in the presence of a KD, but not in those kindled in the presence of valproic acid. Next, we tested whether a KD can halt disease progression in a clinically relevant model of progressive epilepsy. Epileptic rats that developed spontaneous recurrent seizures after a pilocarpine-induced status epilepticus were treated with a KD or control diet (CD). Whereas seizures progressed in severity and frequency in the CD-fed animals, KD-fed animals showed a prolonged reduction of seizures, which persisted after diet reversal. KD-treatment was associated with increased adenosine and decreased DNA methylation, the latter being maintained after diet discontinuation. Our findings demonstrate that a KD prevented disease progression in two mechanistically different models of epilepsy, and suggest an epigenetic mechanism underlying the therapeutic effects. PMID:26256422

  9. Transient behavior of a stochastic process for screening progressive diseases.

    PubMed

    Houshyar, A; al-Khayyal, F A

    1991-01-01

    This paper extends a mathematical model developed by the authors for describing the stochastic process underlying the etiology of non-contagious progressive diseases. For a population with no prior history of scheduled screening, the number of undetected and detected diseased individuals in the population under an established screening policy is used to calculate the expected total screening cost at any given time during the transient period of the associated stochastic process. A graphical representation of our model shows the status of different subgroups of a particular age group at any time T, and provides a clear summary of the expected number of individuals whose disease remains undetected.

  10. A century for progress in the diagnosis of Wilson disease.

    PubMed

    Schilsky, Michael L

    2014-10-01

    The diagnosis of Wilson disease has evolved from the original description of a neurological syndrome by Wilson and other contemporaries at the turn of the 20th century to where we recognize that there is a spectrum of clinical liver and neuropsychiatric disease diagnosed by a combination of clinical and biochemical tests and more recently by molecular genetic analysis. The history of the evolution of the findings that help us establish a diagnosis of Wilson disease are presented in the following brief summary of a century of progress toward this end.

  11. Peripheral Biomarkers of Parkinson's Disease Progression and Pioglitazone Effects.

    PubMed

    Simon, David K; Simuni, Tanya; Elm, Jordan; Clark-Matott, Joanne; Graebner, Allison K; Baker, Liana; Dunlop, Susan R; Emborg, Marina; Kamp, Cornelia; Morgan, John C; Ross, G Webster; Sharma, Saloni; Ravina, Bernard

    2015-01-01

    Pioglitazone, an oral hypoglycemic agent, recently failed to show promise as a disease-modifying agent in a 44-week phase 2 placebo-controlled study in 210 Parkinson's disease (PD) subjects. We analyzed peripheral biomarkers, including leukocyte PGC-1α and target gene expression, plasma interleukin 6 (IL-6) as a marker of inflammation, and urine 8-hydroxydeoxyguanosine (8OHdG) as a marker of oxidative DNA damage. Baseline or changes from baseline in biomarker levels were not associated with the rate of progression of PD. Pioglitazone did not significantly alter biomarker levels. Other agents that more effectively target these mechanisms remain of potential interest as disease modifying therapies in PD.

  12. Emerging risk factors and markers of chronic kidney disease progression.

    PubMed

    Kronenberg, Florian

    2009-12-01

    Chronic kidney disease (CKD) is a common condition with an increasing prevalence. A number of comorbidities are associated with CKD and prognosis is poor, with many patients experiencing disease progression. Recognizing the factors associated with CKD progression enables high-risk patients to be identified and given more intensive treatment if necessary. The identification of new predictive markers might improve our understanding of the pathogenesis and progression of CKD. This Review discusses a number of emerging factors and markers for which epidemiological evidence from prospective studies indicates an association with progression of CKD. The following factors and markers are discussed: asymmetric dimethylarginine, factors involved in calcium-phosphate metabolism, adrenomedullin, A-type natriuretic peptide, N-terminal pro-brain natriuretic peptide, liver-type fatty acid binding protein, kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, apolipoprotein A-IV, adiponectin and some recently identified genetic polymorphisms. Additional epidemiological and experimental data are required before these markers can be broadly used for the prediction of CKD progression and before the risk factors can be considered as potential drug targets in clinical interventional trials.

  13. Immune Inflammation and Disease Progression in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Balestro, Elisabetta; Calabrese, Fiorella; Turato, Graziella; Lunardi, Francesca; Bazzan, Erica; Marulli, Giuseppe; Biondini, Davide; Rossi, Emanuela; Sanduzzi, Alessandro; Rea, Federico; Rigobello, Chiara; Gregori, Dario; Baraldo, Simonetta; Spagnolo, Paolo

    2016-01-01

    The clinical course in idiopathic pulmonary fibrosis (IPF) is highly heterogeneous, with some patients having a slow progression and others an accelerated clinical and functional decline. This study aims to clinically characterize the type of progression in IPF and to investigate the pathological basis that might account for the observed differences in disease behavior. Clinical and functional data were analyzed in 73 IPF patients, followed long-time as candidates for lung transplantation. The forced vital capacity (FVC) change/year (< or ≥10% predicted) was used to define “slow” or “rapid” disease progression. Pathological abnormalities were quantified in the explanted lung of 41 out of 73 patients undergoing lung transplantation. At diagnosis, slow progressors (n = 48) showed longer duration of symptoms and lower FVC than rapid progressors (n = 25). Eleven slow and 3 rapid progressors developed an acute exacerbation (AE) during follow-up. Quantitative lung pathology showed a severe innate and adaptive inflammatory infiltrate in rapid progressors, markedly increased compared to slow progressors and similar to that observed in patients experiencing AE. The extent of inflammation was correlated with the yearly FVC decline (r = 0.52, p = 0.005). In conclusion an innate and adaptive inflammation appears to be a prominent feature in the lung of patients with IPF and could contribute to determining of the rate of disease progression. PMID:27159038

  14. Immune Inflammation and Disease Progression in Idiopathic Pulmonary Fibrosis.

    PubMed

    Balestro, Elisabetta; Calabrese, Fiorella; Turato, Graziella; Lunardi, Francesca; Bazzan, Erica; Marulli, Giuseppe; Biondini, Davide; Rossi, Emanuela; Sanduzzi, Alessandro; Rea, Federico; Rigobello, Chiara; Gregori, Dario; Baraldo, Simonetta; Spagnolo, Paolo; Cosio, Manuel G; Saetta, Marina

    2016-01-01

    The clinical course in idiopathic pulmonary fibrosis (IPF) is highly heterogeneous, with some patients having a slow progression and others an accelerated clinical and functional decline. This study aims to clinically characterize the type of progression in IPF and to investigate the pathological basis that might account for the observed differences in disease behavior. Clinical and functional data were analyzed in 73 IPF patients, followed long-time as candidates for lung transplantation. The forced vital capacity (FVC) change/year (< or ≥10% predicted) was used to define "slow" or "rapid" disease progression. Pathological abnormalities were quantified in the explanted lung of 41 out of 73 patients undergoing lung transplantation. At diagnosis, slow progressors (n = 48) showed longer duration of symptoms and lower FVC than rapid progressors (n = 25). Eleven slow and 3 rapid progressors developed an acute exacerbation (AE) during follow-up. Quantitative lung pathology showed a severe innate and adaptive inflammatory infiltrate in rapid progressors, markedly increased compared to slow progressors and similar to that observed in patients experiencing AE. The extent of inflammation was correlated with the yearly FVC decline (r = 0.52, p = 0.005). In conclusion an innate and adaptive inflammation appears to be a prominent feature in the lung of patients with IPF and could contribute to determining of the rate of disease progression.

  15. Risk factor reduction in progression of angiographic coronary artery disease

    PubMed Central

    Lai, Hoang M.; Mercando, Anthony D.; Kalen, Phoenix; Desai, Harit V.; Gandhi, Kaushang; Sharma, Mala; Amin, Harshad; Lai, Trung M.

    2012-01-01

    Introduction To investigate differences between outpatients with progressive and nonprogressive coronary artery disease (CAD) measured by coronary angiography. Material and methods Chart reviews were performed in patients in an outpatient cardiology practice having ≥ 2 coronary angiographies ≥ 1 year apart. Progressive CAD was defined as 1) new non-obstructive or obstructive CAD in a previously disease-free vessel; or 2) new obstruction in a previously non-obstructive vessel. Coronary risk factors, comorbidities, cardiovascular events, medication use, serum low-density lipoprotein cholesterol (LDL-C), and blood pressure were used for analysis. Results The study included 183 patients, mean age 71 years. Mean follow-up duration was 11 years. Mean follow-up between coronary angiographies was 58 months. Of 183 patients, 108 (59%) had progressive CAD, and 75 (41%) had nonprogressive CAD. The use of statins, β-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and aspirin was not significantly different in patient with progressive CAD or nonprogressive CAD Mean arterial pressure was higher in patients with progressive CAD than in patients with nonprogressive CAD (97±13 mm Hg vs. 92±12 mm Hg) (p<0.05). Serum LDL-C was insignificantly higher in patients with progressive CAD (94±40 mg/dl) than in patients with nonprogressive CAD (81±34 mg/dl) (p=0.09). Conclusions Our data suggest that in addition to using appropriate medical therapy, control of blood pressure and serum LDL-C level may reduce progression of CAD. PMID:22851998

  16. The beneficial role of intensive exercise on Parkinson disease progression.

    PubMed

    Frazzitta, Giuseppe; Balbi, Pietro; Maestri, Roberto; Bertotti, Gabriella; Boveri, Natalia; Pezzoli, Gianni

    2013-06-01

    In the last decade, a considerable number of articles has shown that exercise is effective in improving motor performance in Parkinson disease. In particular, recent studies have focused on the efficacy of intensive exercise in achieving optimal results in the rehabilitation of patients with Parkinson disease. The effects of intensive exercise in promoting cell proliferation and neuronal differentiation in animal models are reported in a large cohort of studies, and these neuroplastic effects are probably related to increased expression of a variety of neurotrophic factors. The authors outline the relation between intensive exercises and neuroplastic activity on animal models of Parkinson disease and discuss the clinical results of different intensive strategies on motor performance and disease progression in patients with Parkinson disease.

  17. Impact of Disease Progression Date Determination on Progression-free Survival Estimates in Advanced Lung Cancer

    PubMed Central

    Qi, Yingwei; Ziegler, Allen; Katie, L.; Hillman, Shauna L.; Redman, Mary W.; Schild, Steven E.; Gandara, David R.; Adjei, Alex A.; Mandrekar, Sumithra J.

    2012-01-01

    PURPOSE Progression-free survival (PFS) based endpoints are controversial; however in advanced lung cancer, overall survival is largely influenced by the progression status. We thus evaluated the impact of progression date (PD) determination approach on PFS estimates. METHODS Individual patient data from 21 trials (14 NCCTG; 7 SWOG) were used. Reported progression date (RPD) was defined as either the scan date or the clinical deterioration date. PD was determined using 4 methods (M): RPD (M1), one day after last progression-free scan (M2), midpoint between last progression-free scan and RPD (M3), and using an interval censoring approach (M4). PFS was estimated using Kaplan-Meier (M1, M2, M3), and maximum likelihood (M4). Simulation studies were performed to understand the impact of the length of time elapsed between the last progression-free scan and the PD on time to progression (TTP) estimates. RESULTS PFS estimates using RPD were the highest, with M2 being the most conservative. M3 and M4 were similar due to majority of progressions occurring during treatment (i.e., frequent disease assessments). M3 was less influenced by the length of the assessment schedules (%difference from true TTP <1.5%) compared to M1 (11% to 30%) and M2 (-8% to -29%). The overall study conclusion was unaffected by the method used for randomized trials. CONCLUSION The magnitude of difference in the PFS estimates is large enough to alter trial conclusions in advanced lung cancer. Standards for PD determination, use of sensitivity analyses, and randomized trials are critical when designing trials and reporting efficacy using PFS based endpoints. PMID:22434489

  18. Latin America: native populations affected by early onset periodontal disease.

    PubMed

    Nowzari, Hessam; Botero, Javier Enrique

    2011-06-01

    Millions of individuals are affected by early onset periodontal disease in Latin America, a continent that includes more than 20 countries. The decision-makers claim that the disease is not commonly encountered. In 2009, 280,919 authorized immigrants were registered in the United States versus 5,460,000 unauthorized (2,600,000 in California). The objective of the present article is to raise awareness about the high prevalence of the disease among Latin Americans and the good prognosis of preventive measures associated with minimal financial cost.

  19. Mechanisms of Copper Ion Mediated Huntington's Disease Progression

    PubMed Central

    Fox, Jonathan H.; Kama, Jibrin A.; Lieberman, Gregory; Chopra, Raman; Dorsey, Kate; Chopra, Vanita; Volitakis, Irene; Cherny, Robert A.; Bush, Ashley I.; Hersch, Steven

    2007-01-01

    Huntington's disease (HD) is caused by a dominant polyglutamine expansion within the N-terminus of huntingtin protein and results in oxidative stress, energetic insufficiency and striatal degeneration. Copper and iron are increased in the striata of HD patients, but the role of these metals in HD pathogenesis is unknown. We found, using inductively-coupled-plasma mass spectroscopy, that elevations of copper and iron found in human HD brain are reiterated in the brains of affected HD transgenic mice. Increased brain copper correlated with decreased levels of the copper export protein, amyloid precursor protein. We hypothesized that increased amounts of copper bound to low affinity sites could contribute to pro-oxidant activities and neurodegeneration. We focused on two proteins: huntingtin, because of its centrality to HD, and lactate dehydrogenase (LDH), because of its documented sensitivity to copper, necessity for normoxic brain energy metabolism and evidence for altered lactate metabolism in HD brain. The first 171 amino acids of wild-type huntingtin, and its glutamine expanded mutant form, interacted with copper, but not iron. N171 reduced Cu2+ in vitro in a 1∶1 copper∶protein stoichiometry indicating that this fragment is very redox active. Further, copper promoted and metal chelation inhibited aggregation of cell-free huntingtin. We found decreased LDH activity, but not protein, and increased lactate levels in HD transgenic mouse brain. The LDH inhibitor oxamate resulted in neurodegeneration when delivered intra-striatially to healthy mice, indicating that LDH inhibition is relevant to neurodegeneration in HD. Our findings support a role of pro-oxidant copper-protein interactions in HD progression and offer a novel target for pharmacotherapeutics. PMID:17396163

  20. Progress and problems in the biology, diagnostics, and therapeutics of prion diseases

    PubMed Central

    Aguzzi, Adriano; Heikenwalder, Mathias; Miele, Gino

    2004-01-01

    The term “prion” was introduced by Stanley Prusiner in 1982 to describe the atypical infectious agent that causes transmissible spongiform encephalopathies, a group of infectious neurodegenerative diseases that include scrapie in sheep, Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy in cattle. Over the past twenty years, the word “prion” has been taken to signify various subtly different concepts. In this article, we refer to the prion as the transmissible principle underlying prion diseases, without necessarily implying any specific biochemical or structural identity. When Prusiner started his seminal work, the study of transmissible spongiform encephalopathies was undertaken by only a handful of scientists. Since that time, the “mad cow” crisis has put prion diseases on the agenda of both politicians and the media. Significant progress has been made in prion disease research, and many aspects of prion pathogenesis are now understood. And yet the diagnostic procedures available for prion diseases are not nearly as sensitive as they ought to be, and no therapeutic intervention has been shown to reliably affect the course of the diseases. This article reviews recent progress in the areas of pathogenesis of, diagnostics of, and therapy for prion diseases and highlights some conspicuous problems that remain to be addressed in each of these fields. PMID:15254579

  1. Exercise and disease progression in multiple sclerosis: can exercise slow down the progression of multiple sclerosis?

    PubMed Central

    Stenager, Egon

    2012-01-01

    It has been suggested that exercise (or physical activity) might have the potential to have an impact on multiple sclerosis (MS) pathology and thereby slow down the disease process in MS patients. The objective of this literature review was to identify the literature linking physical exercise (or activity) and MS disease progression. A systematic literature search was conducted in the following databases: PubMed, SweMed+, Embase, Cochrane Library, PEDro, SPORTDiscus and ISI Web of Science. Different methodological approaches to the problem have been applied including (1) longitudinal exercise studies evaluating the effects on clinical outcome measures, (2) cross-sectional studies evaluating the relationship between fitness status and MRI findings, (3) cross-sectional and longitudinal studies evaluating the relationship between exercise/physical activity and disability/relapse rate and, finally, (4) longitudinal exercise studies applying the experimental autoimmune encephalomyelitis (EAE) animal model of MS. Data from intervention studies evaluating disease progression by clinical measures (1) do not support a disease-modifying effect of exercise; however, MRI data (2), patient-reported data (3) and data from the EAE model (4) indicate a possible disease-modifying effect of exercise, but the strength of the evidence limits definite conclusions. It was concluded that some evidence supports the possibility of a disease-modifying potential of exercise (or physical activity) in MS patients, but future studies using better methodologies are needed to confirm this. PMID:22435073

  2. Exercise and disease progression in multiple sclerosis: can exercise slow down the progression of multiple sclerosis?

    PubMed

    Dalgas, Ulrik; Stenager, Egon

    2012-03-01

    It has been suggested that exercise (or physical activity) might have the potential to have an impact on multiple sclerosis (MS) pathology and thereby slow down the disease process in MS patients. The objective of this literature review was to identify the literature linking physical exercise (or activity) and MS disease progression. A systematic literature search was conducted in the following databases: PubMed, SweMed+, Embase, Cochrane Library, PEDro, SPORTDiscus and ISI Web of Science. Different methodological approaches to the problem have been applied including (1) longitudinal exercise studies evaluating the effects on clinical outcome measures, (2) cross-sectional studies evaluating the relationship between fitness status and MRI findings, (3) cross-sectional and longitudinal studies evaluating the relationship between exercise/physical activity and disability/relapse rate and, finally, (4) longitudinal exercise studies applying the experimental autoimmune encephalomyelitis (EAE) animal model of MS. Data from intervention studies evaluating disease progression by clinical measures (1) do not support a disease-modifying effect of exercise; however, MRI data (2), patient-reported data (3) and data from the EAE model (4) indicate a possible disease-modifying effect of exercise, but the strength of the evidence limits definite conclusions. It was concluded that some evidence supports the possibility of a disease-modifying potential of exercise (or physical activity) in MS patients, but future studies using better methodologies are needed to confirm this.

  3. Neuroprotective therapeutics for Alzheimer's disease: progress and prospects.

    PubMed

    Palmer, Alan M

    2011-03-01

    The number of people with Alzheimer's disease (AD) has never been greater and is set to increase substantially in the decades ahead as the proportion of the population aged 65 years or more rises sharply. There is therefore an urgent need for safe and effective pharmacotherapy to help combat the corresponding and substantial increase in disease burden. Increased understanding of disease aetiology and pathophysiology, particularly in relation to the loss of vulnerable neurons and the formation of plaques and tangles, has increased hope for medications that can slow (or perhaps even halt) the course of the disease. In this article I review the neurobiological basis of AD, current progress towards neuroprotective therapeutics, and prospects for the future.

  4. Type-1 cannabinoid receptor activity during Alzheimer's disease progression.

    PubMed

    Manuel, Iván; González de San Román, Estíbaliz; Giralt, M Teresa; Ferrer, Isidro; Rodríguez-Puertas, Rafael

    2014-01-01

    The activity of CB1 cannabinoid receptors was studied in postmortem brain samples of Alzheimer's disease (AD) patients during clinical deterioration. CB1 activity was higher at earlier AD stages in limited hippocampal areas and internal layers of frontal cortex, but a decrease was observed at the advanced stages. The pattern of modification appears to indicate initial hyperactivity of the endocannabinoid system in brain areas that lack classical histopathological markers at earlier stages of AD, indicating an attempt to compensate for the initial synaptic impairment, which is then surpassed by disease progression. These results suggest that initial CB1 stimulation might have therapeutic relevance.

  5. Current Progress in Therapeutic Gene Editing for Monogenic Diseases

    PubMed Central

    Prakash, Versha; Moore, Marc; Yáñez-Muñoz, Rafael J

    2016-01-01

    Programmable nucleases allow defined alterations in the genome with ease-of-use, efficiency, and specificity. Their availability has led to accurate and widespread genome engineering, with multiple applications in basic research, biotechnology, and therapy. With regard to human gene therapy, nuclease-based gene editing has facilitated development of a broad range of therapeutic strategies based on both nonhomologous end joining and homology-dependent repair. This review discusses current progress in nuclease-based therapeutic applications for a subset of inherited monogenic diseases including cystic fibrosis, Duchenne muscular dystrophy, diseases of the bone marrow, and hemophilia and highlights associated challenges and future prospects. PMID:26765770

  6. Current Progress in Therapeutic Gene Editing for Monogenic Diseases.

    PubMed

    Prakash, Versha; Moore, Marc; Yáñez-Muñoz, Rafael J

    2016-03-01

    Programmable nucleases allow defined alterations in the genome with ease-of-use, efficiency, and specificity. Their availability has led to accurate and widespread genome engineering, with multiple applications in basic research, biotechnology, and therapy. With regard to human gene therapy, nuclease-based gene editing has facilitated development of a broad range of therapeutic strategies based on both nonhomologous end joining and homology-dependent repair. This review discusses current progress in nuclease-based therapeutic applications for a subset of inherited monogenic diseases including cystic fibrosis, Duchenne muscular dystrophy, diseases of the bone marrow, and hemophilia and highlights associated challenges and future prospects.

  7. Juvenile Huntington's disease presenting as progressive myoclonic epilepsy.

    PubMed

    Gambardella, A; Muglia, M; Labate, A; Magariello, A; Gabriele, A L; Mazzei, R; Pirritano, D; Conforti, F L; Patitucci, A; Valentino, P; Zappia, M; Quattrone, A

    2001-08-28

    A 9-year-old girl, who had no family history of neurologic diseases in the first-degree relatives, had a 3-year history of progressive myoclonus epilepsy (PME). A thorough laboratory investigation was normal. As two sisters of her paternal grandmother were said to have Huntington's disease (HD), the authors looked for HD and found a CAG repeat expansion of 115 repeats. This diagnosis should be considered in addition to other causes in patients with PME. Moreover, the current case further supports the notion that HD should be considered even when a family history is not obvious.

  8. Sulodexide and glycosaminoglycans in the progression of renal disease.

    PubMed

    Masola, Valentina; Zaza, Gianluigi; Gambaro, Giovanni

    2014-02-01

    Experimental data in cell cultures and animal models suggest that sulodexide and glycosaminoglycans are potentially effective drugs to treat chronic kidney diseases and prevent progression to renal failure. However, no conclusive evidence support the use of them in human renal disease. In acute and chronic glomerulonephritis, only few studies have been performed. Sulodexide has been more intensely investigated in diabetic nephropathy (DN) where the body of data supports its effectiveness as an antialbuminuric agent in early stages. Unfortunately, there is no study in DN patients on the effect of sulodexide on clinical end points.

  9. Hepatitis C. Virus Infection: Mechanisms of Disease Progression

    DTIC Science & Technology

    2007-10-01

    military have rates of HCV infection similar to the general US population (1.6%). However, it is a younger population and its natural history of HCV ...infection has not been studied. Therefore, the clinical outcome of HCV -infected military subjects and risk factors contributing to disease progression...active duty military subjects infected with HCV , who will be enrolled and observed prospectively over four years (48 months). Liver biopsies are to be

  10. Translational neurophysiology in sheep: measuring sleep and neurological dysfunction in CLN5 Batten disease affected sheep

    PubMed Central

    Perentos, Nicholas; Martins, Amadeu Q.; Watson, Thomas C.; Bartsch, Ullrich; Mitchell, Nadia L.; Palmer, David N.; Jones, Matthew W.

    2015-01-01

    Creating valid mouse models of slowly progressing human neurological diseases is challenging, not least because the short lifespan of rodents confounds realistic modelling of disease time course. With their large brains and long lives, sheep offer significant advantages for translational studies of human disease. Here we used normal and CLN5 Batten disease affected sheep to demonstrate the use of the species for studying neurological function in a model of human disease. We show that electroencephalography can be used in sheep, and that longitudinal recordings spanning many months are possible. This is the first time such an electroencephalography study has been performed in sheep. We characterized sleep in sheep, quantifying characteristic vigilance states and neurophysiological hallmarks such as sleep spindles. Mild sleep abnormalities and abnormal epileptiform waveforms were found in the electroencephalographies of Batten disease affected sheep. These abnormalities resemble the epileptiform activity seen in children with Batten disease and demonstrate the translational relevance of both the technique and the model. Given that both spontaneous and engineered sheep models of human neurodegenerative diseases already exist, sheep constitute a powerful species in which longitudinal in vivo studies can be conducted. This will advance our understanding of normal brain function and improve our capacity for translational research into neurological disorders. PMID:25724202

  11. Risk Factors for Progression of Chronic Kidney Disease

    PubMed Central

    Staples, Amy; Wong, Craig

    2010-01-01

    Purpose of Review Provides an overview of the identified risk factors for chronic kidney disease (CKD) progression emphasizing the pediatric population. Recent findings Over the past ten years, there have been significant changes to our understanding and study of pre-terminal kidney failure. Recent refinements in the measurement of glomerular filtration rate (GFR) and GFR estimating equations are important tools for identification and association of risk factors for CKD progression in children. In pediatric CKD, lower level of kidney function at presentation, higher levels of proteinuria, and hypertension are known markers for a more rapid decline in GFR. Anemia and other reported risk factors from the pre-genomic era have need for further study and validation. Genome-wide association studies have identified genetic loci which have provided novel genetic risk factors for CKD progression. Summary With cohort studies of children with CKD becoming mature, they have started to yield important refinements to the assessment of CKD progression. While many of the traditional risk factors for renal progression will certainly be assessed, such cohorts will be important for evaluating novel risk factors identified by genome-wide studies. PMID:20090523

  12. Reevaluating measures of disease progression in facioscapulohumeral muscular dystrophy.

    PubMed

    Statland, Jeffrey M; McDermott, Michael P; Heatwole, Chad; Martens, William B; Pandya, Shree; van der Kooi, E L; Kissel, John T; Wagner, Kathryn R; Tawil, Rabi

    2013-04-01

    Recent advances in the understanding of the molecular pathophysiology of facioscapulohumeral muscular dystrophy (FSHD) have identified potential therapeutic targets. Consequently, an accurate understanding of disease progression in FSHD is crucial for the design of future clinical trials. Data from 228 subjects in 3 clinical trials and 1 natural history study were compared to examine disease progression in FSHD. All studies utilized the same techniques for manual muscle testing and maximum voluntary isometric contraction testing. Both techniques yield a total strength score that can be followed over time as an indicator of disease progression. Whereas natural history data showed a decrease in strength over 1 year, there was an apparent increase in strength at 6 months in 2 of the 3 clinical trials in both the placebo and treatment groups, that persisted for up to 1 year for maximum voluntary isometric contraction testing. Variability estimates from the clinical trial data were consistent with those seen in the natural history data. Patients in clinical trials in FSHD may have better outcomes than those in natural history studies, regardless of treatment assignment, emphasizing the importance of placebo groups and the need for caution when interpreting the strength results of controlled and uncontrolled trials.

  13. Predictors of rapid disease progression in autosomal dominant polycystic kidney disease.

    PubMed

    Corradi, Valentina; Gastaldon, Fiorella; Caprara, Carlotta; Giuliani, Anna; Martino, Francesca; Ferrari, Fiorenza; Ronco, Claudio

    2017-02-01

    Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases with a reported prevalence of 1:400 to 1:1000. Since the intact kidneys can compensate for the loss of glomerular filtration in ADPKD patients, renal insufficiency usually remains undetected until almost the fourth decade of life. Hereafter, reliable diagnostic and prognostic biomarkers to identify ADPKD progression are urgently needed. Several studies and systematic reviews tried to identify markers or predictors of rapid disease progression of ADPKD. The aim of this study is to review predictors of rapid disease progression of ADPKD that can be useful to the clinician. We will describe several factors associated with rapid progression of ADPKD derived from retrospective or cross-sectional studies, suggesting the best and most useful predictors that may help to patients management in clinical practice. We will attempt to identify the most useful predictors of rapid disease progression of ADPKD: established TKV growth rate >5% per year, annual estimated glomerular filtration rate decline >5 mL/min/1.73 m2, truncating PKD1 mutations and elevated plasma copeptin level. The combination of several factors that can predict the rapid ADPKD progression is more accurate than a single-marker strategy. The "PRO-PKD" risk scoring system combined with TKV, can be useful in order to evaluate the ADPKD patients and they appear to be appropriate predictors of progression disease. Moreover levels of copeptin and some urinary markers can be matched to these factors for improved patient assessment in rapid progression.

  14. Identification of mutations in Colombian patients affected with Fabry disease.

    PubMed

    Uribe, Alfredo; Mateus, Heidi Eliana; Prieto, Juan Carlos; Palacios, Maria Fernanda; Ospina, Sandra Yaneth; Pasqualim, Gabriela; da Silveira Matte, Ursula; Giugliani, Roberto

    2015-12-15

    Fabry Disease (FD) is an X-linked inborn error of glycosphingolipid catabolism, caused by a deficiency of the lisosomal α-galactosidase A (AGAL). The disorder leads to a vascular disease secondary to the involvement of kidney, heart and the central nervous system. The mutation analysis is a valuable tool for diagnosis and genetic counseling. Although more than 600 mutations have been identified, most mutations are private. Our objective was to describe the analysis of nine Colombian patients with Fabry disease by automated sequencing of the seven exons of the GLA gene. Two novel mutations were identified in two patients affected with the classical subtype of FD, in addition to other 6 mutations previously reported. The present study confirms the heterogeneity of mutations in Fabry disease and the importance of molecular analysis for genetic counseling, female heterozygotes detection as well as therapeutic decisions.

  15. Graft-versus-host disease affecting oral cavity. A review.

    PubMed

    Margaix-Muñoz, Maria; Bagán, José V; Jiménez, Yolanda; Sarrión, María-Gracia; Poveda-Roda, Rafael

    2015-02-01

    Graft versus host disease (GVHD) is one of the most frequent and serious complications of hematopoietic stem cell transplantation, and is regarded as the leading cause of late mortality unrelated to the underlying malignant disease. GVHD is an autoimmune and alloimmune disorder that usually affects multiple organs and tissues, and exhibits a variable clinical course. It can manifest in either acute or chronic form. The acute presentation of GVHD is potentially fatal and typically affects the skin, gastrointestinal tract and liver. The chronic form is characterized by the involvement of a number of organs, including the oral cavity. Indeed, the oral cavity may be the only affected location in chronic GVHD. The clinical manifestations of chronic oral GVHD comprise lichenoid lesions, hyperkeratotic plaques and limited oral aperture secondary to sclerosis. The oral condition is usually mild, though moderate to severe erosive and ulcerated lesions may also be seen. The diagnosis is established from the clinical characteristics, though confirmation through biopsy study is sometimes needed. Local corticosteroids are the treatment of choice, offering overall response rates of close to 50%. Extracorporeal photopheresis and systemic corticosteroids in turn constitute second line treatment. Oral chronic GVHD is not considered a determinant factor for patient survival, which is close to 52% five years after diagnosis of the condition. Key words:Chronic graft-versus-host disease, oral chronic graft-versus-host disease, pathogenics, management, survival.

  16. HCV Genome-Wide Genetic Analyses in Context of Disease Progression and Hepatocellular Carcinoma

    PubMed Central

    Donlin, Maureen J.; Lomonosova, Elena; Kiss, Alexi; Cheng, Xiaohong; Cao, Feng; Curto, Teresa M.; Di Bisceglie, Adrian; Tavis, John E.

    2014-01-01

    Hepatitis C virus (HCV) is a major cause of hepatitis and hepatocellular carcinoma (HCC) world-wide. Most HCV patients have relatively stable disease, but approximately 25% have progressive disease that often terminates in liver failure or HCC. HCV is highly variable genetically, with seven genotypes and multiple subtypes per genotype. This variation affects HCV’s sensitivity to antiviral therapy and has been implicated to contribute to differences in disease. We sequenced the complete viral coding capacity for 107 HCV genotype 1 isolates to determine whether genetic variation between independent HCV isolates is associated with the rate of disease progression or development of HCC. Consensus sequences were determined by sequencing RT-PCR products from serum or plasma. Positions of amino acid conservation, amino acid diversity patterns, selection pressures, and genome-wide patterns of amino acid covariance were assessed in context of the clinical phenotypes. A few positions were found where the amino acid distributions or degree of positive selection differed between in the HCC and cirrhotic sequences. All other assessments of viral genetic variation and HCC failed to yield significant associations. Sequences from patients with slow disease progression were under a greater degree of positive selection than sequences from rapid progressors, but all other analyses comparing HCV from rapid and slow disease progressors were statistically insignificant. The failure to observe distinct sequence differences associated with disease progression or HCC employing methods that previously revealed strong associations with the outcome of interferon α-based therapy implies that variable ability of HCV to modulate interferon responses is not a dominant cause for differential pathology among HCV patients. This lack of significant associations also implies that host and/or environmental factors are the major causes of differential disease presentation in HCV patients. PMID

  17. The factor structure of the UPDRS as an index of disease progression in Parkinson's disease.

    PubMed

    Evans, Jonathan R; Mason, Sarah L; Williams-Gray, Caroline H; Foltynie, Thomas; Trotter, Matthew; Barker, Roger A

    2011-01-01

    The optimum method for evaluating disease progression in Parkinson's disease (PD) has not been established, and this has implications for clinical trials. The majority of previous studies have utilized change on the Unified Parkinson's disease Rating Scale (UPDRS) as an index of progression. However, the UPDRS has not been validated for this purpose. We utilized exploratory factor analysis (EFA) to evaluate the longitudinal properties of the UPDRS as an index of disease progression in PD. Data was derived from a representative cohort of 122 PD patients followed from diagnosis and assessed every 18-24 months for up to 7.9 years. For each subject the rate of change of each item on the UPDRS-3 was calculated and an EFA was performed using this data. Results were compared with those of previously published EFAs in cross-sectional PD cohorts. The UPDRS-3 retains a stable factor structure when used as an index of disease evolution. The 27 items reduced to 6 factors which accounted for 61.0% of the variance in disease progression. A dominant factor was identified which incorporated axial (gait/postural stability) symptoms and signs. Our analysis indicates that the UPDRS captures meaningful aspects of disease progression in PD, and that it is possible to identify symptom/sign complexes which evolve independently of one another. Progression in PD is predominantly characterized by the development of axial symptoms and signs. This result has implications for pathogenesis and should also inform natural history models of PD thereby allowing identification of meaningful outcome measures for clinical trials of disease-modifying therapies.

  18. Developmental Regulation with Progressive Vision Loss: Use of Control Strategies and Affective Well-Being

    ERIC Educational Resources Information Center

    Schilling, Oliver K.; Wahl, Hans-Werner; Boerner, Kathrin; Horowitz, Amy; Reinhardt, Joann P.; Cimarolli, Verena R.; Brennan-Ing, Mark; Heckhausen, Jutta

    2016-01-01

    The present study addresses older adults' developmental regulation when faced with progressive and irreversible vision loss. We used the motivational theory of life span development as a conceptual framework and examined changes in older adults' striving for control over everyday goal achievement, and their association with affective well-being,…

  19. Progression from prehypertension to hypertension and risk of cardiovascular disease

    PubMed Central

    Ishikawa, Yukiko; Ishikawa, Joji; Ishikawa, Shizukiyo; Kario, Kazuomi; Kajii, Eiji

    2016-01-01

    Background Subjects with prehypertension (pre-HT; 120/80 to 139/89 mm Hg) have an increased risk of cardiovascular disease (CVD); however, whether the risk of pre-HT can be seen at the pre-HT status or only after progression to a hypertensive (HT; ≥140/90 mm Hg) state during the follow-up period is unknown. Methods The Jichi Medical Cohort study enrolled 12,490 subjects recruited from a Japanese general population. Of those, 2227 subjects whose BP data at baseline and at the middle of follow-up and tracking of CVD events were available (median follow-up period: 11.8 years). We evaluated the risk of HT in those with normal BP or pre-HT at baseline whose BP progressed to HT at the middle of follow-up compared with those whose BP remained at normal or pre-HT levels. Results Among the 707 normotensive patients at baseline, 34.1% and 6.6% of subjects progressed to pre-HT and HT, respectively, by the middle of follow-up. Among 702 subjects with pre-HT at baseline, 26.1% progressed to HT. During the follow-up period, there were 11 CVD events in normotensive patients and 16 CVD events in pre-HT patients at baseline. The subjects who progressed from pre-HT to HT had 2.95 times higher risk of CVD than those who remained at normal BP or pre-HT in a multivariable-adjusted Cox hazard model. Conclusion This relatively long-term prospective cohort study indicated that the CVD risk with pre-HT might increase after progression to HT; however, the number of CVD events was small. Therefore, the results need to be confirmed in a larger cohort. PMID:28135198

  20. Progress in spondylarthritis. Immunopathogenesis of spondyloarthritis: which cells drive disease?

    PubMed

    Melis, Lode; Elewaut, Dirk

    2009-01-01

    Spondyloarthritides, or SpA, form a cluster of chronic inflammatory diseases with the axial skeleton as the most typical disease localisation, although extra-articular manifestations such as intestinal inflammation may frequently occur during the course of the disease. This review summarises recent progress in our understanding of the immunopathogenesis of SpA with special emphasis on the cellular constituents considered to be responsible for the initiation and/or perpetuation of inflammation. There are several arguments favouring a role for haematopoietic cells in the pathophysiology of spondyloarthritis, including HLA-B27-associated dendritic cell disturbances, HLA-B27 misfolding properties and T helper 17 cells. In addition, recent studies have pointed toward a pivotal role for stromal cells. A major challenge, however, remains to determine how recently identified genetic associations such as interleukin-23 receptor polymorphisms may influence cellular targets in spondyloarthritis.

  1. A transcriptional network underlies susceptibility to kidney disease progression

    PubMed Central

    Laouari, Denise; Burtin, Martine; Phelep, Aurélie; Bienaime, Frank; Noel, Laure-Hélène; Lee, David C; Legendre, Christophe; Friedlander, Gérard; Pontoglio, Marco; Terzi, Fabiola

    2012-01-01

    The molecular networks that control the progression of chronic kidney diseases (CKD) are poorly defined. We have recently shown that the susceptibility to development of renal lesions after nephron reduction is controlled by a locus on mouse chromosome 6 and requires epidermal growth factor receptor (EGFR) activation. Here, we identified microphthalmia-associated transcription factor A (MITF-A), a bHLH-Zip transcription factor, as a modifier of CKD progression. Sequence analysis revealed a strain-specific mutation in the 5′ UTR that decreases MITF-A protein synthesis in lesion-prone friend virus B NIH (FVB/N) mice. More importantly, we dissected the molecular pathway by which MITF-A modulates CKD progression. MITF-A interacts with histone deacetylases to repress the transcription of TGF-α, a ligand of EGFR, and antagonizes transactivation by its related partner, transcription factor E3 (TFE3). Consistent with the key role of this network in CKD, Tgfa gene inactivation protected FVB/N mice from renal deterioration after nephron reduction. These data are relevant to human CKD, as we found that the TFE3/MITF-A ratio was increased in patients with damaged kidneys. Our study uncovers a novel transcriptional network and unveils novel potential prognostic and therapeutic targets for preventing human CKD progression. PMID:22711280

  2. A transcriptional network underlies susceptibility to kidney disease progression.

    PubMed

    Laouari, Denise; Burtin, Martine; Phelep, Aurélie; Bienaime, Frank; Noel, Laure-Hélène; Lee, David C; Legendre, Christophe; Friedlander, Gérard; Pontoglio, Marco; Terzi, Fabiola

    2012-08-01

    The molecular networks that control the progression of chronic kidney diseases (CKD) are poorly defined. We have recently shown that the susceptibility to development of renal lesions after nephron reduction is controlled by a locus on mouse chromosome 6 and requires epidermal growth factor receptor (EGFR) activation. Here, we identified microphthalmia-associated transcription factor A (MITF-A), a bHLH-Zip transcription factor, as a modifier of CKD progression. Sequence analysis revealed a strain-specific mutation in the 5' UTR that decreases MITF-A protein synthesis in lesion-prone friend virus B NIH (FVB/N) mice. More importantly, we dissected the molecular pathway by which MITF-A modulates CKD progression. MITF-A interacts with histone deacetylases to repress the transcription of TGF-α, a ligand of EGFR, and antagonizes transactivation by its related partner, transcription factor E3 (TFE3). Consistent with the key role of this network in CKD, Tgfa gene inactivation protected FVB/N mice from renal deterioration after nephron reduction. These data are relevant to human CKD, as we found that the TFE3/MITF-A ratio was increased in patients with damaged kidneys. Our study uncovers a novel transcriptional network and unveils novel potential prognostic and therapeutic targets for preventing human CKD progression.

  3. Regionally progressive accumulation of iron in Parkinson's disease as measured by quantitative susceptibility mapping.

    PubMed

    Guan, Xiaojun; Xuan, Min; Gu, Quanquan; Huang, Peiyu; Liu, Chunlei; Wang, Nian; Xu, Xiaojun; Luo, Wei; Zhang, Minming

    2017-04-01

    The progression of Parkinson's disease (PD) seems to vary according to the disease stage, which greatly influences the management of PD patients. However, the underlying mechanism of progression in PD remains unclear. This study was designed to explore the progressive pattern of iron accumulation at different stages in PD patients. Sixty right-handed PD patients and 40 normal controls were recruited. According to the disease stage, 45 patients with Hoehn-Yahr stage ≤ 2.5 and 15 patients with Hoehn-Yahr stage ≥ 3 were grouped into early-stage PD (EPD) and late-stage PD (LPD) groups, respectively. The iron content in the cardinal subcortical nuclei covering the cerebrum, cerebellum and midbrain was measured using quantitative susceptibility mapping (QSM). The substantia nigra pars compacta (SNc) showed significantly increased QSM values in the EPD patients compared with the controls. In the LPD patients, while the SNc continued to show increased QSM values compared with the controls and EPD patients, the regions showing increased QSM values spread to include the substantia nigra pars reticulata (SNr), red nucleus (RN) and globus pallidus (GP). Our data also indicated that iron deposition was more significant in the GP internal segment (GPi) than in the GP external segment. No other regions showed significant changes in QSM values among the groups. Therefore, we were able to confirm a regionally progressive pattern of iron accumulation in the different stages of PD, indicating that iron deposition in the SNc is affected exclusively in the early stages of the disease, while the SNr, RN and GP, and particularly the GPi segment, become involved in advanced stages of the disease. This is a preliminary study providing objective evidence of the iron-related progression in PD. Copyright © 2016 John Wiley & Sons, Ltd.

  4. The effects of electroshock on immune function and disease progression in juvenile spring chinook salmon

    USGS Publications Warehouse

    VanderKooi, S.P.; Maule, A.G.; Schreck, C.B.

    2001-01-01

    Although much is known about the effects of electroshock on fish physiology, consequences to the immune system and disease progression have not received attention. Our objectives were to determine the effects of electroshock on selected immune function in juvenile spring chinook salmon Oncorhynchus tshawytscha, the mechanism of any observed alteration, and the effects of electroshock on disease progression. We found that the ability of anterior kidney leukocytes to generate antibody-producing cells (APC) was suppressed 3 h after a pulsed-DC electroshock (300 V, 50 Hz, 8 ms pulse width) but recovered within 24 h. This response was similar in timing and magnitude to that of fish subjected to an acute handling stress. The mechanism of suppression is hypothesized to be via an elevation of plasma cortisol concentrations in response to stress. Other monitored immune functions, skin mucous lysozyme levels, and respiratory burst activity were not affected by exposure to electroshock. The progression of a Renibacterium salmoninarum (RS) infection may have been altered after exposure to an electroshock. The electroshock did not affect infection severity or the number of mortalities, but may have accelerated the time to death. The limited duration of APC suppression and lack of effects on lysozyme and respiratory burst, as well as infection severity and mortality levels in RS-infected fish, led us to conclude that electrofishing under the conditions we tested is a safe procedure in regards to immunity and disease.

  5. Epigenetics of Progression of Chronic Kidney Disease: Fact or Fantasy?

    PubMed Central

    Wing, Maria R.; Ramezani, Ali; Gill, Harindarpal S.; Devaney, Joseph M.; Raj, Dominic S.

    2013-01-01

    Summary Epigenetic modifications are important in the normal functioning of the cell, from regulating dynamic expression of essential genes and associated proteins to repressing those that are unneeded. Epigenetic changes are essential for development and functioning of the kidney, and aberrant methylation, histone modifications, and expression of microRNA could lead to chronic kidney disease (CKD). Here, epigenetic modifications modulate transforming growth factor β signaling, inflammation, profibrotic genes, and the epithelial-to-mesenchymal transition, promoting renal fibrosis and progression of CKD. Identification of these epigenetic changes is important because they are potentially reversible and may serve as therapeutic targets in the future to prevent subsequent renal fibrosis and CKD. In this review we discuss the different types of epigenetic control, methods to study epigenetic modifications, and how epigenetics promotes progression of CKD. PMID:24011578

  6. Dynamics of collateral circulation in progressive asymptomatic carotid disease.

    PubMed

    Moll, F L; Eikelboom, B C; Vermeulen, F E; van Lier, H J; Schulte, B P

    1986-03-01

    Inadequacy of collateral arterial flow is the major risk factor for hemispheric infarction in association with spontaneous occlusion of the ipsilateral carotid artery. This prospective study was designed to measure the adaptation of collateral cerebral circulation through the circle of Willis in patients in whom a unilateral carotid stenosis of hemodynamic consequence develops asymptomatically. The collateral cerebral potential is assessed by ocular pneumoplethysmography (OPG) during proximal common carotid artery compression, measuring the collateral ophthalmic artery pressure (COAP). During an average follow-up of almost 3 years (maximum more than 7 years), 45 patients showed asymptomatic development of a unilateral hemodynamically significant carotid stenosis according to OPG evidence. In these patients the mean index COAP/brachial artery pressure did not change on the side of stenosis progression (p greater than 0.05). The developed carotid stenosis had only reduced collateral circulation to the contralateral hemisphere. The risk of inadequate collateral cerebral circulation remained during progression of asymptomatic extracranial arterial obstructive disease.

  7. Celiac disease: progress towards diagnosis and definition of pathogenic mechanisms.

    PubMed

    Rossi, Mauro; Bot, Adrian

    2011-08-01

    The current issue of the International Reviews of Immunology is dedicated entirely to Celiac Disease (CD). Recent development of additional biomarkers and diagnostics resulted in a sharp revision of the prevalence of this condition, with a previously unrecognized subclinical occurrence in the adult population. This was paralleled by groundbreaking progress in understanding its molecular pathogenesis: while gluten-derived peptides activate the innate immunity, post-translationally modified gluten elicits an adaptive immunity. These arms amplify each other, resulting in a self- perpetuating autoimmune condition, influenced by disturbances of the gut flora and mucus chemistry. The process evolves dramatically in a subset of patients with vulnerable immune homeostasis (eg. Treg cells) explaining the progressive, aggravating syndrome in the clinically overt version of CD. In depth understanding of the pathogenesis of CD thus creates the premises of developing novel, more accurate animal models that should support a rationale development of new prophylactic and therapeutic interventions.

  8. Quantifying Parkinson's disease progression by simulating gait patterns

    NASA Astrophysics Data System (ADS)

    Cárdenas, Luisa; Martínez, Fabio; Atehortúa, Angélica; Romero, Eduardo

    2015-12-01

    Modern rehabilitation protocols of most neurodegenerative diseases, in particular the Parkinson Disease, rely on a clinical analysis of gait patterns. Currently, such analysis is highly dependent on both the examiner expertise and the type of evaluation. Development of evaluation methods with objective measures is then crucial. Physical models arise as a powerful alternative to quantify movement patterns and to emulate the progression and performance of specific treatments. This work introduces a novel quantification of the Parkinson disease progression using a physical model that accurately represents the main gait biomarker, the body Center of Gravity (CoG). The model tracks the whole gait cycle by a coupled double inverted pendulum that emulates the leg swinging for the single support phase and by a damper-spring System (SDP) that recreates both legs in contact with the ground for the double phase. The patterns generated by the proposed model are compared with actual ones learned from 24 subjects in stages 2,3, and 4. The evaluation performed demonstrates a better performance of the proposed model when compared with a baseline model(SP) composed of a coupled double pendulum and a mass-spring system. The Frechet distance measured differences between model estimations and real trajectories, showing for stages 2, 3 and 4 distances of 0.137, 0.155, 0.38 for the baseline and 0.07, 0.09, 0.29 for the proposed method.

  9. Metatranscriptomic Analysis of Pycnopodia helianthoides (Asteroidea) Affected by Sea Star Wasting Disease.

    PubMed

    Gudenkauf, Brent M; Hewson, Ian

    2015-01-01

    Sea star wasting disease (SSWD) describes a suite of symptoms reported in asteroids of the North American Pacific Coast. We performed a metatranscriptomic survey of asymptomatic and symptomatic sunflower star (Pycnopodia helianthoides) body wall tissues to understand holobiont gene expression in tissues affected by SSWD. Metatranscriptomes were highly variable between replicate libraries, and most differentially expressed genes represented either transcripts of associated microorganisms (particularly Pseudomonas and Vibrio relatives) or low-level echinoderm transcripts of unknown function. However, the pattern of annotated host functional genes reflects enhanced apoptotic and tissue degradation processes and decreased energy metabolism, while signalling of death-related proteins was greater in asymptomatic and symptomatic tissues. Our results suggest that the body wall tissues of SSWD-affected asteroids may undergo structural changes during disease progression, and that they are stimulated to undergo autocatalytic cell death processes.

  10. Metatranscriptomic Analysis of Pycnopodia helianthoides (Asteroidea) Affected by Sea Star Wasting Disease

    PubMed Central

    Gudenkauf, Brent M.; Hewson, Ian

    2015-01-01

    Sea star wasting disease (SSWD) describes a suite of symptoms reported in asteroids of the North American Pacific Coast. We performed a metatranscriptomic survey of asymptomatic and symptomatic sunflower star (Pycnopodia helianthoides) body wall tissues to understand holobiont gene expression in tissues affected by SSWD. Metatranscriptomes were highly variable between replicate libraries, and most differentially expressed genes represented either transcripts of associated microorganisms (particularly Pseudomonas and Vibrio relatives) or low-level echinoderm transcripts of unknown function. However, the pattern of annotated host functional genes reflects enhanced apoptotic and tissue degradation processes and decreased energy metabolism, while signalling of death-related proteins was greater in asymptomatic and symptomatic tissues. Our results suggest that the body wall tissues of SSWD-affected asteroids may undergo structural changes during disease progression, and that they are stimulated to undergo autocatalytic cell death processes. PMID:26020776

  11. A neurodegenerative disease affecting synaptic connections in Drosophila mutant for the tumor suppressor morphogen Patched

    PubMed Central

    Gazi, Michal; Shyamala, Baragur V.; Bhat, Krishna Moorthi

    2009-01-01

    The tumor-suppressor morphogen, Patched (Ptc), has extensive homology to the Niemann-Pick-C 1 (NPC1) protein. The NPC disease is a paediatric, progressive and fatal neurodegenerative disorder thought to be due to an abnormal accumulation of cholesterol in neurons. Here, we report that patched mutant adults develop a progressive neurodegenerative disease and their brain contains membranous and lamellar inclusions. There is also a significant reduction in the number of synaptic terminals in the brain of the mutant adults. Interestingly, feeding cholesterol to wild type flies generates inclusions in the brain, but does not cause the disease. However, feeding cholesterol to mutant flies increases synaptic connections and suppresses the disease. Our results suggest that sequestration of cholesterol in the mutant brain in the form of membranous material and inclusions affects available pool of cholesterol for cellular functions. This, in turn, negatively affects the synaptic number and contributes to the disease-state. Consistent with this, in ptc mutants there is a reduction in the pool of cholesterol esters, and cholesterol-mediated suppression of the disease accompanies an increase in cholesterol esters. We further show that Ptc does not function directly in this process since gain-of-function for Hedgehog also induces the same disease with a reduction in the level of cholesterol esters. We believe that loss of function for ptc causes neurodegeneration via two distinct ways: de-repression of genes that interfere with lipid trafficking, and de-repression of genes outside of the lipid trafficking; the functions of both classes of genes ultimately converge on synaptic connections. PMID:19635474

  12. Tracking motor impairments in the progression of Huntington's disease.

    PubMed

    Long, Jeffery D; Paulsen, Jane S; Marder, Karen; Zhang, Ying; Kim, Ji-In; Mills, James A

    2014-03-01

    The Unified Huntington's Disease Rating Scale is used to characterize motor impairments and establish motor diagnosis. Little is known about the timing of diagnostic confidence level categories and the trajectory of motor impairments during the prodromal phase. Goals of this study were to estimate the timing of categories, model the prodromal trajectory of motor impairments, estimate the rate of motor impairment change by category, and provide required sample size estimates for a test of efficacy in clinical trials. In total, 1010 gene-expanded participants from the Neurobiological Predictors of Huntington's Disease (PREDICT-HD) trial were analyzed. Accelerated failure time models were used to predict the timing of categories. Linear mixed effects regression was used to model the longitudinal motor trajectories. Age and length of gene expansion were incorporated into all models. The timing of categories varied significantly by gene expansion, with faster progression associated with greater expansion. For the median expansion, the third diagnostic confidence level category was estimated to have a first occurrence 1.5 years before diagnosis, and the second and first categories were estimated to occur 6.75 years and 19.75 years before diagnosis, respectively. Motor impairments displayed a nonlinear prodromal course. The motor impairment rate of change increased as the diagnostic confidence level increased, with added acceleration for higher progression scores. Motor items can detect changes in motor impairments before diagnosis. Given a sufficiently high progression score, there is evidence that the diagnostic confidence level can be used for prodromal staging. Implications for Huntington's disease research and the planning of clinical trials of efficacy are discussed.

  13. Effect of maraviroc on HIV disease progression-related biomarkers.

    PubMed

    Romero-Sánchez, M Concepción; Machmach, Kawthar; Gonzalez-Serna, Alejandro; Genebat, Miguel; Pulido, Ildefonso; García-García, María; Alvarez-Ríos, Ana Isabel; Ferrando-Martinez, Sara; Ruiz-Mateos, Ezequiel; Leal, Manuel

    2012-11-01

    The potential effect of blocking the CCR5 receptor on HIV disease progression biomarkers is not well understood. We showed that an 8-day maraviroc (MVC) monotherapy clinical test (MCT) can be used in selecting patients to receive MVC-containing combined antiretroviral therapy (cART). Using this MCT model, we assessed the effect of MVC on several HIV disease progression biomarkers during the MCT (MVC-specific effect) and following short-term (12-week) cART. We compared 45 patients on MVC monotherapy with a control group of 25 patients on MVC-sparing cART. We found that MVC did not modify any biomarkers in patients that had no virological response after the MCT. MVC-specific effects in patients with virological responses included increased CD8(+) T-cell activation and senescence levels, preservation of an increase in soluble CD14 (sCD14), and a decrease in D dimer levels. After 12 weeks, MVC-containing cART increased CD8(+) T-cell counts and preserved CD4(+) T-cell senescence levels compared with MVC-sparing cART. Moreover, there was a decrease in sCD14 levels in patients that received MVC-containing cART. In conclusion, effects compatible with CD8(+) T-cell redistribution in peripheral blood were observed after MVC therapy. However, MVC was associated with a favorable profile in HIV disease progression biomarkers only in patients with a virological response. These results support a potential clinical benefit of a therapy which includes MVC in HIV-infected patients.

  14. Total Kidney Volume as a Biomarker of Disease Progression in Autosomal Dominant Polycystic Kidney Disease

    PubMed Central

    Tangri, Navdeep; Hougen, Ingrid; Alam, Ahsan; Perrone, Ronald; McFarlane, Phil; Pei, York

    2017-01-01

    Purpose of review: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by the formation of kidney cysts and kidney enlargement, which progresses to kidney failure by the fifth to seventh decade of life in a majority of patients. Disease progression is evaluated primarily through serum creatinine and estimated glomerular filtration rate (eGFR) measurements; however, it is known that serum creatinine and eGFR values typically do not change until the fourth or fifth decade of life. Until recently, therapy only existed to target complications of ADPKD. As therapeutic agents continue to be investigated for use in ADPKD, a suitable biomarker of disease progression in place of serum creatinine is needed. Sources of information: This review summarizes recent research regarding the use of total kidney volume as a biomarker in ADPKD, as presented at the Canadian Society of Nephrology symposium held in April 2015. Findings: Measurement of patients’ total kidney volume made using ultrasound (US) or magnetic resonance imaging (MRI) has been shown by the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study to be directly correlated with both increases in cyst volume and change in glomerular filtration rate (GFR). Additional studies have shown total kidney volume to have an association with complications of ADPKD as well. Limitations: Areas for further study continue to exist in comparison of methods of measuring total kidney volume. Implications: We believe that the evidence suggests that total kidney volume may be an appropriate surrogate marker for ADPKD disease progression. PMID:28321323

  15. The reproduction in women affected by cooley disease

    PubMed Central

    Pafumi, Carlo; Leanza, Vito; Coco, Luana; Vizzini, Stefania; Ciotta, Lilliana; Messina, Alessandra; Leanza, Gianluca; Zarbo, Giuseppe; D'Agati, Alfio; Palumbo, Marco Antonio; Iemmola, Alessandra; Gulino, Ferdinando Antonio; Teodoro, Maria Cristina; Attard, Matthew; Plesca, Alina Cristina; Soares, Catarina; Kouloubis, Nina; Chammas, Mayada

    2011-01-01

    The health background management and outcomes of 5 pregnancies in 4 women affected by Cooley Disease, from Paediatric Institute of Catania University, are described, considering the preconceptual guidances and cares for such patients. These patients were selected among a group of 100 thalassemic women divided into three subgroups, according to their first and successive menstruation characteristics: i) patients with primitive amenorrhoea, ii) patients with secondary amenorrhoea and iii) patients with normal menstruation. Only one woman, affected by primitive amenorrhoea, needed the induction of ovulation. A precise and detailed pre-pregnancy assessment was effected before each conception. This was constituted by a series of essays, including checks for diabetes and hypothyroidism, for B and C hepatitis and for blood group antibodies. Moreover were evaluated: cardiac function, rubella immunity and transaminases. Other pregnancy monitoring, and cares during labour and delivery were effected according to usual obstetrics practice. All the women were in labour when she were 38 week pregnant, and the outcome were five healthy babies born at term, weighting between 2600 and 3200gs. The only complication was the Caesarean section. The improvements of current treatments, especially in the management of iron deposits, the prolongation of survival rate, will result in a continuous increase of pregnancies in thalassemic women. Pregnancy is now a real possibility for women affected by such disease. We are furthermore studying the possibility to collect the fetus' umbilical cord blood, after the delivery, to attempt eterologus transplantation to his mother trying to get a complete marrow reconstitution. PMID:22184526

  16. Cytokines: Roles in atherosclerosis disease progression and potential therapeutic targets

    PubMed Central

    Moss, Joe W. E.; Ramji, Dipak P.

    2017-01-01

    Atherosclerosis, the primary cause of cardiovascular disease (CVD), is a chronic inflammatory disorder in the walls of medium and large arteries. CVD is currently responsible for about one in three global deaths and this is expected to rise in the future due to an increase in the prevalence of obesity and diabetes. Current therapies for atherosclerosis mainly modulate lipid homeostasis and whilst successful at reducing the risk of a CVD-related death, they are associated with considerable residual risk and various side effects. There is therefore a need for alternative therapies aimed at regulating inflammation in order to reduce atherogenesis. This review will highlight the key role cytokines play during disease progression as well as potential therapeutic strategies to target them. PMID:27357616

  17. Directed Progression Brain Networks in Alzheimer's Disease: Properties and Classification

    PubMed Central

    Young, Karl; Asif, Danial; Jutla, Inderjit; Liang, Michael; Wilson, Scott; Landsberg, Adam S.; Schuff, Norbert

    2014-01-01

    Abstract This article introduces a new approach in brain connectomics aimed at characterizing the temporal spread in the brain of pathologies like Alzheimer's disease (AD). The main instrument is the development of “directed progression networks” (DPNets), wherein one constructs directed edges between nodes based on (weakly) inferred directions of the temporal spreading of the pathology. This stands in contrast to many previously studied brain networks where edges represent correlations, physical connections, or functional progressions. In addition, this is one of a few studies showing the value of using directed networks in the study of AD. This article focuses on the construction of DPNets for AD using longitudinal cortical thickness measurements from magnetic resonance imaging data. The network properties are then characterized, providing new insights into AD progression, as well as novel markers for differentiating normal cognition (NC) and AD at the group level. It also demonstrates the important role of nodal variations for network classification (i.e., the significance of standard deviations, not just mean values of nodal properties). Finally, the DPNets are utilized to classify subjects based on their global network measures using a variety of data-mining methodologies. In contrast to most brain networks, these DPNets do not show high clustering and small-world properties. PMID:24901258

  18. Early Statin Use and the Progression of Alzheimer Disease

    PubMed Central

    Lin, Feng-Cheng; Chuang, Yun-Shiuan; Hsieh, Hui-Min; Lee, Tzu-Chi; Chiu, Kuei-Fen; Liu, Ching-Kuan; Wu, Ming-Tsang

    2015-01-01

    Abstract The protective effect of statin on Alzheimer disease (AD) is still controversial, probably due to the debate about when to start the use of statin and the lack of any large-scale randomized evidence that actually supports the hypothesis. The purpose of this study was to examine the protective effect of early statin use on mild-to-moderate AD in the total Taiwanese population. This was a total population-based case-control study, using the total population of Taiwanese citizens seen in general medical practice; therefore, the findings can be applied to the general population. The study patients were those with newly diagnosed dementia (ICD-9 290.x) and prescribed any acetylcholinesterase inhibitors (AChEI) from the Taiwan National Health Insurance dataset in 1997 to 2008. The newly diagnosed eligible mild-to-moderate AD patients were traced from the dates of their index dates, which was defined as the first day to receive any AChEI treatment, back to 1 year (exposure period) to categorize them into AD with early statin use and without early statin use. Early statin use was defined as patients using statin before AChEI treatment. Alzheimer disease patients with early statin use were those receiving any statin treatment during the exposure period. Then, we used propensity-score-matched strategy to match these 2 groups as 1:1. The matched study patients were followed-up from their index dates. The primary outcome was the discontinuation of AChEI treatment, indicating AD progression. There were 719 mild-to-moderate AD-paired patients with early statin use and without early statin use for analyses. Alzheimer disease progression was statistically lower in AD patients with early statin use than those without (P = 0.00054). After adjusting for other covariates, mild-to-moderate AD patients with early stain use exhibited a 0.85-risk (95% CI = 0.76–0.95, P = 0.0066) to have AD progression than those without. Early statin use was significantly associated

  19. Risk Factors for Development and Progression of Chronic Kidney Disease

    PubMed Central

    Tsai, Wan-Chuan; Wu, Hon-Yen; Peng, Yu-Sen; Ko, Mei-Ju; Wu, Ming-Shiou; Hung, Kuan-Yu; Wu, Kwan-Dun; Chu, Tzong-Shinn; Chien, Kuo-Liong

    2016-01-01

    Abstract The risk factors influencing the natural course of chronic kidney disease (CKD) are complex and heterogeneous, and few systematic reviews to date have focused on this issue. The aim of the study is to identify the risk factors for disease development and progression in each stage of CKD. We conducted electronic literature searches of PubMed, MEDLINE, Scopus, and the Cochrane Library up to October 15, 2012, for observational studies evaluating the risk factors on the development or progression of CKD. Eligible studies should have collected repeated information that could evaluate changes in renal function. Extracted information from all the included studies was synthesized narratively. Quality assessments were performed using the Newcastle–Ottawa Scale. An exploratory random-effects meta-analysis was performed where feasible to pool effect sizes across studies for a specific risk factor in a specific outcome. We identified 38 cohort studies and 2 case-control studies from 40 articles, with a total of 318,898 participants from 14 countries. The follow-up duration ranged from 1.5 to 16 years. The majority of the included studies were of high quality. The baseline CKD stages of the included studies ranged from normal to later stages, and only 19 studies could be classified into a specific range of CKD stages during follow-up. Three risk factors from studies of the same baseline and follow-up CKD stages were eligible for the exploratory meta-analysis, including male sex, substantial proteinuria, and diabetes. The hazard ratios for the progression from CKD stages 3–5 to end-stage renal disease (ESRD) were 1.37 (95% confidence interval 1.17–1.62), 1.64 (1.01–2.66), and 1.16 (0.98–1.38) for male sex, substantial proteinuria, and diabetes, respectively. In conclusion, our analyses comprehensively summarize the initiating and perpetuating factors for CKD. Male sex and substantial proteinuria are significant perpetuating factors for the progression from

  20. Connected speech as a marker of disease progression in autopsy-proven Alzheimer’s disease

    PubMed Central

    Ahmed, Samrah; Haigh, Anne-Marie F.; de Jager, Celeste A.

    2013-01-01

    Although an insidious history of episodic memory difficulty is a typical presenting symptom of Alzheimer’s disease, detailed neuropsychological profiling frequently demonstrates deficits in other cognitive domains, including language. Previous studies from our group have shown that language changes may be reflected in connected speech production in the earliest stages of typical Alzheimer’s disease. The aim of the present study was to identify features of connected speech that could be used to examine longitudinal profiles of impairment in Alzheimer’s disease. Samples of connected speech were obtained from 15 former participants in a longitudinal cohort study of ageing and dementia, in whom Alzheimer’s disease was diagnosed during life and confirmed at post-mortem. All patients met clinical and neuropsychological criteria for mild cognitive impairment between 6 and 18 months before converting to a status of probable Alzheimer’s disease. In a subset of these patients neuropsychological data were available, both at the point of conversion to Alzheimer’s disease, and after disease severity had progressed from the mild to moderate stage. Connected speech samples from these patients were examined at later disease stages. Spoken language samples were obtained using the Cookie Theft picture description task. Samples were analysed using measures of syntactic complexity, lexical content, speech production, fluency and semantic content. Individual case analysis revealed that subtle changes in language were evident during the prodromal stages of Alzheimer’s disease, with two-thirds of patients with mild cognitive impairment showing significant but heterogeneous changes in connected speech. However, impairments at the mild cognitive impairment stage did not necessarily entail deficits at mild or moderate stages of disease, suggesting non-language influences on some aspects of performance. Subsequent examination of these measures revealed significant linear trends

  1. The APOE locus advances disease progression in late onset familial Alzheimer`s disease but is not causative

    SciTech Connect

    Crawford, F.; Bennett, C.; Osborne, A.

    1994-09-01

    An association has been observed in several independent data sets between late onset Alzheimer`s disease (AD) and the APOE locus on chromosomes 19. We have examined the genotype in family history positive (FHP) and family history negative (FHN) cases and find a distortion of the APOE allele frequencies in accord with previous studies. However, when we examined the allele distribution of the at-risk siblings of the FHP group we found an excess of the {epsilon}4 allele which also differs significantly from historic controls but not from the affected siblings. The age distribution of the affected and unaffected siblings was similar, suggesting that the allelic frequency distortion in the unaffected siblings was not due to their being below the mean age of onset. Lod score linkage analysis, with age dependent onset and nonstringent specification of the genetic parameters, did not suggest linkage to the APOE locus. Furthermore, an analysis of variance of the age of disease-free survival suggested that APOE genotype contributes a small fraction of the total variance, indicating that the APOE locus is a poor predictor of disease-free survival time within late onset families. We suggest that the APOE locus enhances the rate of progression of the disease in otherwise predisposed individuals and that variation at this locus is not able in and of itself to cause this disease.

  2. Progressive Supranuclear Palsy

    MedlinePlus

    Progressive supranuclear palsy (PSP) is a rare brain disease. It affects brain cells that control the movement of your eyes. This leads to ... speech, vision and swallowing problems. Doctors sometimes confuse PSP with Parkinson's disease or Alzheimer's disease. PSP has ...

  3. Progressive biparietal atrophy: an atypical presentation of Alzheimer's disease.

    PubMed Central

    Ross, S J; Graham, N; Stuart-Green, L; Prins, M; Xuereb, J; Patterson, K; Hodges, J R

    1996-01-01

    OBJECTIVES: To define the clinical, neuropsychological, and radiological features of bilateral parietal lobe atrophy. METHODS: Four patients underwent a comprehensive longitudinal neuropsychological assessment, as well as MRI and HMPAO-SPECT. RESULTS: The consistent findings in the patients were early visuospatial problems, agraphia of a predominantly peripheral (or apraxic) type, and difficulty with bimanual tasks, all of which outweighted deficits in memory and language until later in the course of the illness. As the disease progressed, impairments in the phonological aspects of language and in auditory-verbal short term memory were often striking, perhaps reflecting spread from the parietal lobe to perisylvian language areas. Three patients went on to develop a global dementia and fulfilled the criteria for a clinical diagnosis of probable Alzheimer's disease; the fourth patient has only recently been identified. Neuroimaging disclosed bilateral parietal lobe atrophy (MRI) and hypoperfusion (SPECT), which was out of proportion to that seen elsewhere in the brain. One patient has died and had pathologically confirmed Alzheimer's disease with particular concentration in both superior parietal lobes. CONCLUSIONS: Bilateral biparietal atrophy is a recognisable clinical syndrome which can be the presenting feature of Alzheimer's disease. Although the label "posterior cortical atrophy" has been applied to such cases, review of the medical literature suggests that this broad rubric actually consists of two main clinical syndromes with features reflecting involvement of the occipitotemporal (ventral) and biparietal (dorsal) cortical areas respectively. Images PMID:8890778

  4. Natural Progression of Canine Glycogen Storage Disease Type IIIa

    PubMed Central

    Brooks, Elizabeth D; Yi, Haiqing; Austin, Stephanie L; Thurberg, Beth L; Young, Sarah P; Fyfe, John C; Kishnani, Priya S; Sun, Baodong

    2016-01-01

    Glycogen storage disease type IIIa (GSD IIIa) is caused by a deficiency of glycogen debranching enzyme activity. Hepatomegaly, muscle degeneration, and hypoglycemia occur in human patients at an early age. Long-term complications include liver cirrhosis, hepatic adenomas, and generalized myopathy. A naturally occurring canine model of GSD IIIa that mimics the human disease has been described, with progressive liver disease and skeletal muscle damage likely due to excess glycogen deposition. In the current study, long-term follow-up of previously described GSD IIIa dogs until 32 mo of age (n = 4) and of family-owned GSD IIIa dogs until 11 to 12 y of age (n = 2) revealed that elevated concentrations of liver and muscle enzyme (AST, ALT, ALP, and creatine phosphokinase) decreased over time, consistent with hepatic cirrhosis and muscle fibrosis. Glycogen deposition in many skeletal muscles; the tongue, diaphragm, and heart; and the phrenic and sciatic nerves occurred also. Furthermore, the urinary biomarker Glc4, which has been described in many types of GSD, was first elevated and then decreased later in life. This urinary biomarker demonstrated a similar trend as AST and ALT in GSD IIIa dogs, indicating that Glc4 might be a less invasive biomarker of hepatocellular disease. Finally, the current study further demonstrates that the canine GSD IIIa model adheres to the clinical course in human patients with this disorder and is an appropriate model for developing novel therapies. PMID:26884409

  5. Assessing Risk of Disease Progression and Pharmacological Management of Autosomal Dominant Polycystic Kidney Disease

    PubMed Central

    Soroka, Steven; Alam, Ahsan; Bevilacqua, Micheli; Girard, Louis-Philippe; Komenda, Paul; Loertscher, Rolf; McFarlane, Philip; Pandeya, Sanjaya; Tam, Paul; Bichet, Daniel G.

    2017-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder worldwide. The disease is characterized by renal cysts and progressive renal failure due to progressive enlargement of cysts and renal fibrosis. An estimated 45% to 70% of patients with ADPKD progress to end-stage renal disease by age 65 years. Although both targeted and nontargeted therapies have been tested in patients with ADPKD, tolvaptan is currently the only pharmacological therapy approved in Canada for the treatment of ADPKD. The purpose of this consensus recommendation is to develop an evidence-informed recommendation for the optimal management of adult patients with ADPKD. This document focuses on the role of genetic testing, the role of renal imaging, predicting the risk of disease progression, and pharmacological treatment options for ADPKD. These areas of focus were derived from 2 national surveys that were disseminated to nephrologists and patients with ADPKD with the aim of identifying unmet needs in the management of ADPKD in Canada. Specific recommendations are provided for the treatment of ADPKD with tolvaptan. PMID:28321325

  6. Modeling Disease Progression: Angiotensin II Indirectly Inhibits Nitric Oxide Production via ADMA Accumulation in Spontaneously Hypertensive Rats

    PubMed Central

    Wang, Haidong; Jiang, Hao; Liu, Haochen; Zhang, Xue; Ran, Guimei; He, Hua; Liu, Xiaoquan

    2016-01-01

    Nitric oxide (NO) production impairment is involved in the onset and development of hypertension. Although NO production impairment in spontaneously hypertensive rat (SHR) has been reported in a variety of researches, the time course of this progressive procedure, as well as its relationship with asymmetric dimethylarginine (ADMA) and angiotensin II (Ang II), has not been quantified. The aim of this research is to establish a mechanism-based disease progression model to assess Ang II and ADMA's inhibition of NO production in SHR's disease progression with/without ramipril's intervention. SHR were randomly divided into three groups: one disease group (n = 8) and two treatment groups (n = 8 for each group): standard treatment group (receiving ramipril 2 mg/kg*day) and intensive treatment group (receiving ramipril 10 mg/kg*day). ADMA, Ang II, NO, and SBP were determined weekly. Intensive treatment with ramipril was found to have no further attenuation of plasma NO and ADMA than standard treatment beyond its significantly stronger antihypertensive effects. Four linked turnover models were developed to characterize the profiles of ADMA, Ang II, NO, and SBP during hypertensive disease progression with/without ramipril intervention. Our model described Ang II and ADMA's contribution to NO production impairment and their responses to ramipril treatment throughout the disease progression in SHR. Model simulations suggested that Ang II affected NO production mainly through inhibiting ADMA elimination rather than affecting nitric oxide synthase (NOS) directly. PMID:27909412

  7. Management of almond leaf scorch disease: long term data on yield, tree vitality, and disease progress

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Almond leaf scorch (ALS) disease has been a chronic problem for California almond growers. This disease is caused by the bacterial pathogen Xylella fastidiosa and is transmitted by xylem-feeding insects. Previous research suggested that retaining, rather than roguing, ALS-affected trees may be more ...

  8. Inferring biomarkers for Mycobacterium avium subsp. paratuberculosis infection and disease progression in cattle using experimental data

    PubMed Central

    Magombedze, Gesham; Shiri, Tinevimbo; Eda, Shigetoshi; Stabel, Judy R.

    2017-01-01

    Available diagnostic assays for Mycobacterium avium subsp. paratuberculosis (MAP) have poor sensitivities and cannot detect early stages of infection, therefore, there is need to find new diagnostic markers for early infection detection and disease stages. We analyzed longitudinal IFN-γ, ELISA-antibody and fecal shedding experimental sensitivity scores for MAP infection detection and disease progression. We used both statistical methods and dynamic mathematical models to (i) evaluate the empirical assays (ii) infer and explain biological mechanisms that affect the time evolution of the biomarkers, and (iii) predict disease stages of 57 animals that were naturally infected with MAP. This analysis confirms that the fecal test is the best marker for disease progression and illustrates that Th1/Th2 (IFN-γ/ELISA antibodies) assays are important for infection detection, but cannot reliably predict persistent infections. Our results show that the theoretical simulated macrophage-based assay is a potential good diagnostic marker for MAP persistent infections and predictor of disease specific stages. We therefore recommend specifically designed experiments to test the use of a based assay in the diagnosis of MAP infections. PMID:28317944

  9. Inferring biomarkers for Mycobacterium avium subsp. paratuberculosis infection and disease progression in cattle using experimental data

    NASA Astrophysics Data System (ADS)

    Magombedze, Gesham; Shiri, Tinevimbo; Eda, Shigetoshi; Stabel, Judy R.

    2017-03-01

    Available diagnostic assays for Mycobacterium avium subsp. paratuberculosis (MAP) have poor sensitivities and cannot detect early stages of infection, therefore, there is need to find new diagnostic markers for early infection detection and disease stages. We analyzed longitudinal IFN-γ, ELISA-antibody and fecal shedding experimental sensitivity scores for MAP infection detection and disease progression. We used both statistical methods and dynamic mathematical models to (i) evaluate the empirical assays (ii) infer and explain biological mechanisms that affect the time evolution of the biomarkers, and (iii) predict disease stages of 57 animals that were naturally infected with MAP. This analysis confirms that the fecal test is the best marker for disease progression and illustrates that Th1/Th2 (IFN-γ/ELISA antibodies) assays are important for infection detection, but cannot reliably predict persistent infections. Our results show that the theoretical simulated macrophage-based assay is a potential good diagnostic marker for MAP persistent infections and predictor of disease specific stages. We therefore recommend specifically designed experiments to test the use of a based assay in the diagnosis of MAP infections.

  10. UPDRS activity of daily living score as a marker of Parkinson's disease progression.

    PubMed

    Harrison, Madaline B; Wylie, Scott A; Frysinger, Robert C; Patrie, James T; Huss, Diane S; Currie, Lillian J; Wooten, G Frederick

    2009-01-30

    The activities of daily living (ADL) subscore of the Unified Parkinson's Disease Rating Scale (UPDRS) captures the impact of Parkinson's disease (PD) on daily function and may be less affected than other subsections by variability associated with drug cycle and motor fluctuations. We examined UPDRS mentation, ADL and motor subscores in 888 patients with idiopathic PD. Multiple linear regression analyses determined the association between disease duration and UPDRS subscores as a function of medication status at examination and in a subset of patients with multiple examinations. Independent of medication status and across cross-sectional and longitudinal analyses, ADL subscores showed a stronger and more stable association with disease duration than other UPDRS subscores after adjusting for age of disease onset. The association between disease duration and the motor subscore depended on medication status. The strong association between ADL subscore and disease duration in PD suggests that this measure may serve as a better marker of disease progression than signs and symptoms assessed in other UPDRS sections.

  11. Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia.

    PubMed

    An, Ping; Penugonda, Sudhir; Thorball, Christian W; Bartha, Istvan; Goedert, James J; Donfield, Sharyne; Buchbinder, Susan; Binns-Roemer, Elizabeth; Kirk, Gregory D; Zhang, Wenyan; Fellay, Jacques; Yu, Xiao-Fang; Winkler, Cheryl A

    2016-03-01

    Human APOBEC3 cytidine deaminases are intrinsic resistance factors to HIV-1. However, HIV-1 encodes a viral infectivity factor (Vif) that degrades APOBEC3 proteins. In vitro APOBEC3F (A3F) anti-HIV-1 activity is weaker than A3G but is partially resistant to Vif degradation unlike A3G. It is unknown whether A3F protein affects HIV-1 disease in vivo. To assess the effect of A3F gene on host susceptibility to HIV- acquisition and disease progression, we performed a genetic association study in six well-characterized HIV-1 natural cohorts. A common six-Single Nucleotide Polymorphism (SNP) haplotype of A3F tagged by a codon-changing variant (p. I231V, with allele (V) frequency of 48% in European Americans) was associated with significantly lower set-point viral load and slower rate of progression to AIDS (Relative Hazards (RH) = 0.71, 95% CI: 0.56, 0.91) and delayed development of pneumocystis pneumonia (PCP) (RH = 0.53, 95% CI: 0.37-0.76). A validation study in the International Collaboration for the Genomics of HIV (ICGH) showed a consistent association with lower set-point viral load. An in vitro assay revealed that the A3F I231V variant may influence Vif mediated A3F degradation. Our results provide genetic epidemiological evidence that A3F modulates HIV-1/AIDS disease progression.

  12. Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia

    PubMed Central

    An, Ping; Penugonda, Sudhir; Thorball, Christian W.; Bartha, Istvan; Goedert, James J.; Donfield, Sharyne; Buchbinder, Susan; Binns-Roemer, Elizabeth; Kirk, Gregory D.; Zhang, Wenyan; Fellay, Jacques; Yu, Xiao-Fang; Winkler, Cheryl A.

    2016-01-01

    Human APOBEC3 cytidine deaminases are intrinsic resistance factors to HIV-1. However, HIV-1 encodes a viral infectivity factor (Vif) that degrades APOBEC3 proteins. In vitro APOBEC3F (A3F) anti-HIV-1 activity is weaker than A3G but is partially resistant to Vif degradation unlike A3G. It is unknown whether A3F protein affects HIV-1 disease in vivo. To assess the effect of A3F gene on host susceptibility to HIV- acquisition and disease progression, we performed a genetic association study in six well-characterized HIV-1 natural cohorts. A common six-Single Nucleotide Polymorphism (SNP) haplotype of A3F tagged by a codon-changing variant (p. I231V, with allele (V) frequency of 48% in European Americans) was associated with significantly lower set-point viral load and slower rate of progression to AIDS (Relative Hazards (RH) = 0.71, 95% CI: 0.56, 0.91) and delayed development of pneumocystis pneumonia (PCP) (RH = 0.53, 95% CI: 0.37–0.76). A validation study in the International Collaboration for the Genomics of HIV (ICGH) showed a consistent association with lower set-point viral load. An in vitro assay revealed that the A3F I231V variant may influence Vif mediated A3F degradation. Our results provide genetic epidemiological evidence that A3F modulates HIV-1/AIDS disease progression. PMID:26942578

  13. Selective surgical management of progressive familial intrahepatic cholestasis (Byler's disease).

    PubMed

    Emond, J C; Whitington, P F

    1995-12-01

    Progressive familial intrahepatic cholestasis (PFIC) presents in early childhood with pruritus, jaundice, hepatomegaly, and growth failure. Medical therapy is unsuccessful, with progression from cholestasis to hepatic fibrosis, cirrhosis, and ultimately death before the age of 10 years. Because of evidence that biliary diversion can arrest or reverse progression to hepatic fibrosis, we have used partial biliary diversion (PBD) as primary therapy in PFIC, reserving orthotopic liver transplantation (OLT) for children who have progressive disease or established cirrhosis. Seventeen children with PFIC (aged 2 months to 19 years) have been treated. PBD was performed in eight cases. In these procedures, a 10-cm properistaltic jejunal segment was anastomosed to the side of the gallbladder, terminating as an end stoma for the collection and discard of bile. Eleven patients with hepatic insufficiency (or end-stage cirrhosis) received OLT using standard techniques, at the average age of 4 years. Six of the eight children treated with PBD had complete resolution of clinical symptoms and remain well 1 to 13 years postoperatively. These six patients have conjugated bilirubin values of less than 0.3 mg/dL, normal transaminases, and a serum bile salt concentration of less than 10 nmol/mL. All have had either reversal or no progression of the hepatic fibrosis. Postoperative bleeding complications occurred in two (25%), which required reoperation. One patient had an adhesive intestinal obstruction that was managed surgically 9 months postoperatively. Two patients had no benefit from PBD, and all of them had severe bridging fibrosis (1) or cirrhosis (3). These and nine others with cirrhosis at the time of presentation received orthotopic liver transplantation; of these, eight are alive (1 to 5 years postoperatively). These results show the importance of establishing a correct diagnosis in children with cholestasis. Clinical symptoms often are severe in children with PFIC before the

  14. Oral necrotizing microvasculitis in a patient affected by Kawasaki disease.

    PubMed

    Scardina, Giuseppe Alessandro; Fucà, Gerlandina; Carini, Francesco; Valenza, Vincenzo; Spicola, Michele; Procaccianti, Paolo; Messina, Pietro; Maresi, Emiliano

    2007-12-01

    Kawasaki disease (KD) was first described in 1967 by Kawasaki, who defined it as "mucocutaneous lymph node syndrome". KD is an acute systemic vasculitis, which mainly involves medium calibre arteries; its origin is unknown, and it is observed in children under the age of 5, especially in their third year. The principal presentations of KD include fever, bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, and cervical lymphadenopathy. Within KD, oral mucositis - represented by diffuse mucous membrane erythema, lip and tongue reddening and lingual papillae hypertrophy with subsequent development of strawberry tongue - can occur both in the acute stage of the disease (0-9 days), and in the convalescence stage (>25 days) as a consequence of the pharmacological treatment. KD vascular lesions are defined as systemic vasculitis instead of systemic arteritis. This study analyzed the anatomical-pathological substrata of oral mucositis in a baby affected by Kawasaki disease and suddenly deceased for cardiac tamponade caused by coronary aneurysm rupture (sudden cardiac death of a mechanical type).

  15. Blood platelets in the progression of Alzheimer's disease.

    PubMed

    Gowert, Nina S; Donner, Lili; Chatterjee, Madhumita; Eisele, Yvonne S; Towhid, Seyda T; Münzer, Patrick; Walker, Britta; Ogorek, Isabella; Borst, Oliver; Grandoch, Maria; Schaller, Martin; Fischer, Jens W; Gawaz, Meinrad; Weggen, Sascha; Lang, Florian; Jucker, Mathias; Elvers, Margitta

    2014-01-01

    Alzheimer's disease (AD) is characterized by neurotoxic amyloid-ß plaque formation in brain parenchyma and cerebral blood vessels known as cerebral amyloid angiopathy (CAA). Besides CAA, AD is strongly related to vascular diseases such as stroke and atherosclerosis. Cerebrovascular dysfunction occurs in AD patients leading to alterations in blood flow that might play an important role in AD pathology with neuronal loss and memory deficits. Platelets are the major players in hemostasis and thrombosis, but are also involved in neuroinflammatory diseases like AD. For many years, platelets were accepted as peripheral model to study the pathophysiology of AD because platelets display the enzymatic activities to generate amyloid-ß (Aß) peptides. In addition, platelets are considered to be a biomarker for early diagnosis of AD. Effects of Aß peptides on platelets and the impact of platelets in the progression of AD remained, however, ill-defined. The present study explored the cellular mechanisms triggered by Aß in platelets. Treatment of platelets with Aß led to platelet activation and enhanced generation of reactive oxygen species (ROS) and membrane scrambling, suggesting enhanced platelet apoptosis. More important, platelets modulate soluble Aß into fibrillar structures that were absorbed by apoptotic but not vital platelets. This together with enhanced platelet adhesion under flow ex vivo and in vivo and platelet accumulation at amyloid deposits of cerebral vessels of AD transgenic mice suggested that platelets are major contributors of CAA inducing platelet thrombus formation at vascular amyloid plaques leading to vessel occlusion critical for cerebrovascular events like stroke.

  16. Disease origin and progression in amyotrophic lateral sclerosis: an immunology perspective.

    PubMed

    Malaspina, Andrea; Puentes, Fabiola; Amor, Sandra

    2015-03-01

    The immune system is inextricably linked with many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), a devastating neuromuscular disorder affecting motor cell function with an average survival of 3 years from symptoms onset. In ALS, there is a dynamic interplay between the resident innate immune cells, that is, microglia and astrocytes, which may become progressively harmful to motor neurons. Although innate and adaptive immune responses are associated with progressive neurodegeneration, in the early stages of ALS immune activation pathways are primarily considered to be beneficial promoting neuronal repair of the damaged tissues, though a harmful effect of T cells at this stage of disease has also been observed. In addition, although auto-antibodies against neuronal antigens are present in ALS, it is unclear whether these arise as a primary or secondary event to neuronal damage, and whether the auto-antibodies are indeed pathogenic. Understanding how the immune system contributes to the fate of motor cells in ALS may shed light on the triggers of disease as well as on the mechanisms contributing to the propagation of the pathology. Immune markers may also act as biomarkers while pathways involved in immune action may be targets of new therapeutic strategies. Here, we review the modalities by which the immune system senses the core pathological process in motor neuron disorders, focusing on tissue-specific immune responses in the neuromuscular junction and in the neuroaxis observed in affected individuals and in animal models of ALS. We elaborate on existing data on the immunological fingerprint of ALS that could be used to identify clues on the disease origin and patterns of progression.

  17. EXPLORATORY ANALYSIS OF SEVEN ALZHEIMER’S DISEASE GENES: DISEASE PROGRESSION

    PubMed Central

    Ruiz, Agustín; Hernández, Isabel; Ronsende-Roca, Maiteé; González-Pérez, Antonio; Rodriguez-Noriega, Emma; Ramírez-Lorca, Reposo; Mauleón, Ana; Moreno-Rey, Concha; Boswell, Lucie; Tune, Larry; Valero, Sergi; Alegret, Montserrat; Gayán, Javier; Becker, James T.; Real, Luis Miguel; Tárraga, Lluís; Ballard, Clive; Terrin, Michael; Sherman, Stephanie; Payami, Haydeh; López, Oscar L.; Mintzer, Jacobo E.; Boada, Mercè

    2014-01-01

    The relationships between GWAS-identified and replicated genetic variants associated to Alzheimer’s disease (AD) risk and disease progression or therapeutic responses in AD patients are almost unexplored. 701 AD patients with at least three different cognitive evaluations and genotypic information for APOE and six GWAS-significant SNPs were selected for this study. Mean differences in GDS and MMSE were evaluated using non-parametric tests, GLM and mixed models for repeated measurements. Each chart was also reviewed for evidence of treatment with any cholinesterase inhibitor (AChEI), memantine or both. Relationships between therapeutic protocols, genetic markers and progression were explored using stratified analysis looking for specific effects on progression in each therapeutic category separately. Neither calculation rendered a Bonferroni-corrected statistically significant difference in any genetic marker. Mixed model results suggested differences in the average point in MMSE test for patients carrying PICALM GA or AA genotype compared to GG carriers at the end of the follow up (MMSE mean difference= −0.57 C.I.95%[−1.145−0.009], p=0.047). This observations remained unaltered after covariate adjustments although did not achieve predefined multiple testing significance threshold. PICALM SNP also displayed a significant effect protecting against rapid progression during pharmacogenetics assays although it observed effect displayed heterogeneity among AD therapeutic protocols (p=0.039). None of studied genetic markers was convincingly linked to AD progression or drug response. However, by using different statistical approaches, PICALM rs3851179 marker displayed consistent but weak effects on disease progression phenotypes. PMID:23036585

  18. Accumulation of NKT cells in Progressive Nonalcoholic Fatty Liver Disease

    PubMed Central

    Syn, Wing-Kin; Oo, Ye Htun; Pereira, Thiago A; Karaca, Gamze F; Jung, Youngmi; Omenetti, Alessia; Witek, Rafal P; Choi, Steve S; Guy, Cynthia D; Fearing, Caitlin M; Teaberry, Vanessa; Pereira, Fausto E L; Adams, David H; Diehl, Anna Mae

    2010-01-01

    Liver inflammation is greater in nonalcoholic steatohepatitis (NASH) than steatosis, suggesting that immune responses contribute to NAFLD progression. Livers normally contain many natural killer T (NKT) cells which produce factors that modulate inflammatory and fibrogenic responses. Such cells are relatively depleted in steatosis, but their status in more advanced NAFLD is uncertain. We hypothesized that NKT cells accumulate and promote fibrosis progression in NASH. We aimed to determine if livers become enriched with NKT cells during NASH-related fibrosis; identify responsible mechanisms; and assess if NKT cells stimulate fibrogenesis. NKT cells were analyzed in wild type mice and Ptc+/-mice with an overly-active Hedgehog (Hh) pathway, before and after feeding methionine choline deficient (MCD) diets to induce NASH-related fibrosis; effects of NKT cell-derived factors on hepatic stellate cells (HSC) were examined and fibrogenesis was evaluated in CD1d-deficient mice which lack NKT cells; NKT cells were quantified in human cirrhotic and non-diseased livers. During NASH-related fibrogenesis in wild-type mice, Hh pathway activation occurred, leading to induction of factors that promoted NKT cell recruitment, retention and viability, plus liver enrichment with NKT cells. Ptc+/- mice accumulated more NKT cells and developed worse liver fibrosis; CD1d-deficient mice which lack NKT cells were protected from fibrosis. NKT cell-conditioned medium stimulated HSC to become myofibroblastic. Liver explants were 2-fold enriched with NKT cells in patients with non-NASH cirrhosis, and 4-fold enriched in patients with NASH-cirrhosis. In conclusion, Hh pathway activation leads to hepatic enrichment with NKT cells that contribute to fibrosis progression in NASH. PMID:20512988

  19. Understanding the interaction between psychosocial stress and immune-related diseases: a stepwise progression.

    PubMed

    Kemeny, Margaret E; Schedlowski, Manfred

    2007-11-01

    For many years, anecdotal evidence and clinical observations have suggested that exposure to psychosocial stress can affect disease outcomes in immune-related disorders such as viral infections, chronic autoimmune diseases and tumors. Experimental evidence in humans supporting these observations was, however, lacking. Studies published in the last 2 decades in Brain, Behavior and Immunity and other journals have demonstrated that acute and chronic psychological stress can induce pronounced changes in innate and adaptive immune responses and that these changes are predominantly mediated via neuroendocrine mediators from the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal axis. In addition, psychological stress has predicted disease outcomes using sophisticated models such as viral challenge, response to vaccination, tracking of herpesvirus latency, exploration of tumor metastasis and healing of experimental wounds, as well as epidemiological investigations of disease progression and mortality. These studies have contributed significantly to our understanding that the neuroendocrine-immune interaction is disturbed in many pathophysiological conditions, that stress can contribute to this disturbance, and that malfunction in these communication pathways can play a significant role in the progression of disease processes. There are, however, significant gaps in the extant literature. In the coming decade(s), it will be essential to further analyze neuroendocrine-immune communication during disease states and to define the specific pathways linking the central nervous system to the molecular events that control important disease-relevant processes. This knowledge will provide the basis for new therapeutic pharmacological and non-pharmacological behavioral approaches to the treatment of chronic diseases via specific modulation of nervous system-immune system communication.

  20. IgA nephropathy factors that predict and accelerate progression to end-stage renal disease.

    PubMed

    Huang, Lan; Guo, Feng-Ling; Zhou, Jin; Zhao, Ya-Juan

    2014-04-01

    IgA nephropathy (IgAN) or Berger's disease is a slowly progressing disease that leads to end-stage renal disease in 50 % of the patients within 25 years of the disease. However, several factors are associated with the accelerated progression of this disease causing early development of end-stage disease. Persistent proteinuria or hematuria, poorly controlled hypertension, elevated serum creatinine and prevalent glomerulosclerosis are some of the risk factors that expedite the deteriorative effects of IgAN. Thus, the progression of the disease can be delayed if the associated risk factors are handled and addressed in the nick of time.

  1. Smart garments in chronic disease management: progress and challenges

    NASA Astrophysics Data System (ADS)

    Khosla, Ajit

    2012-10-01

    This paper presents the progress made developments in the area of Smart Garments for chronic disease management over last 10 years. A large number of health monitoring smart garments and wearable sensors have been manufactured to monitor patient's physiological parameters such as electrocardiogram, blood pressure, body temperature, heart rate, oxygen saturation, while patient is not in hospital. In last few years with the advancement in smartphones and cloud computing it is now possible to send the measure physiological data to any desired location. However there are many challenges in the development of smart garment systems. The two major challenges are development of new lightweight power sources and there is a need for global standardization and a road map for development of smart garments. In this paper we will discuss current state-of-theart smart garments and wearable sensor systems. Also discussed will be the new emerging trends in smart garment research and development.

  2. Distinct patterns of sirtuin expression during progression of Alzheimer's disease.

    PubMed

    Lutz, Mirjam I; Milenkovic, Ivan; Regelsberger, Günther; Kovacs, Gabor G

    2014-06-01

    Aging is one of the major risk factors for Alzheimer's disease (AD). Sirtuins are associated with prolonged life span. To examine whether the expression levels of sirtuins associate with the progression of AD or not, we performed a comparative immunoblotting and immunohistochemical study of SIRT1, 3, and 5 in the entorhinal cortex and hippocampal subregions and white matter in 45 cases grouped according to Braak and Braak stages of neurofibrillary degeneration. In addition, we compared the expression levels with the local load of tau and amyloid-beta deposits, evaluated using morphometry. Our study revealed that (1) the neuronal subcellular redistribution of SIRT1 parallels the decrease in its expression, suggesting stepwise loss of neuroprotection dependent on the neuronal population; (2) in contrast to SIRT1 and 3, expression of SIRT5 increases during the progression of AD; (3) which might be related to its appearance in activated microglial cells. The complex patterns of the expression of sirtuins in relation to tissue damage should be taken into account when searching for therapies interacting with sirtuins.

  3. Effects of lowering LDL cholesterol on progression of kidney disease.

    PubMed

    Haynes, Richard; Lewis, David; Emberson, Jonathan; Reith, Christina; Agodoa, Lawrence; Cass, Alan; Craig, Jonathan C; de Zeeuw, Dick; Feldt-Rasmussen, Bo; Fellström, Bengt; Levin, Adeera; Wheeler, David C; Walker, Rob; Herrington, William G; Baigent, Colin; Landray, Martin J

    2014-08-01

    Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignificant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibe versus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% confidence interval [95% CI], 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecified tertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 [38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD.

  4. Effects of Lowering LDL Cholesterol on Progression of Kidney Disease

    PubMed Central

    Haynes, Richard; Lewis, David; Emberson, Jonathan; Reith, Christina; Agodoa, Lawrence; Cass, Alan; Craig, Jonathan C.; de Zeeuw, Dick; Feldt-Rasmussen, Bo; Fellström, Bengt; Levin, Adeera; Wheeler, David C.; Walker, Rob; Herrington, William G.; Baigent, Colin; Landray, Martin J.; Baigent, Colin; Landray, Martin J.; Reith, Christina; Emberson, Jonathan; Wheeler, David C.; Tomson, Charles; Wanner, Christoph; Krane, Vera; Cass, Alan; Craig, Jonathan; Neal, Bruce; Jiang, Lixin; Hooi, Lai Seong; Levin, Adeera; Agodoa, Lawrence; Gaziano, Mike; Kasiske, Bertram; Walker, Rob; Massy, Ziad A.; Feldt-Rasmussen, Bo; Krairittichai, Udom; Ophascharoensuk, Vuddidhej; Fellström, Bengt; Holdaas, Hallvard; Tesar, Vladimir; Wiecek, Andrzej; Grobbee, Diederick; de Zeeuw, Dick; Grönhagen-Riska, Carola; Dasgupta, Tanaji; Lewis, David; Herrington, Will; Mafham, Marion; Majoni, William; Wallendszus, Karl; Grimm, Richard; Pedersen, Terje; Tobert, Jonathan; Armitage, Jane; Baxter, Alex; Bray, Christopher; Chen, Yiping; Chen, Zhengming; Hill, Michael; Knott, Carol; Parish, Sarah; Simpson, David; Sleight, Peter; Young, Alan; Collins, Rory

    2014-01-01

    Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignificant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibe versus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% confidence interval [95% CI], 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecified tertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 [38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD. PMID:24790178

  5. Deficiency of AXL in Bone Marrow-Derived Cells Does Not Affect Advanced Atherosclerotic Lesion Progression.

    PubMed

    Subramanian, Manikandan; Proto, Jonathan D; Matsushima, Glenn K; Tabas, Ira

    2016-12-13

    AXL, a member of the TAM (Tyro3, Axl, MerTK) family of receptors, plays important roles in cell survival, clearance of dead cells (efferocytosis), and suppression of inflammation, which are processes that critically influence atherosclerosis progression. Whereas MerTK deficiency promotes defective efferocytosis, inflammation, and plaque necrosis in advanced murine atherosclerosis, the role of Axl in advanced atherosclerosis progression is not known. Towards this end, bone marrow cells from Axl(-/-) or wild-type mice were transplanted into lethally irradiated Ldlr(-/-) mice. These chimeric mice were then fed the Western-type diet (WD) for 17 weeks. We demonstrate that lesional macrophages in WT mice express Axl but that Axl deficiency in bone marrow-derived cells does not affect lesion size, cellularity, necrosis, or inflammatory parameters in advanced atherosclerotic plaques. Moreover, apoptosis of lesional cells was unaffected, and we found no evidence of defective lesional efferocytosis. In contrast to previously reported findings with MerTK deficiency, hematopoietic cell-Axl deficiency in WD-fed Ldlr(-/-) mice does not affect the progression of advanced atherosclerosis or lesional processes associated with TAM receptor signaling. These findings suggest a heretofore unappreciated TAM receptor hierarchy in advanced atherosclerosis.

  6. Deficiency of AXL in Bone Marrow-Derived Cells Does Not Affect Advanced Atherosclerotic Lesion Progression

    PubMed Central

    Subramanian, Manikandan; Proto, Jonathan D.; Matsushima, Glenn K.; Tabas, Ira

    2016-01-01

    AXL, a member of the TAM (Tyro3, Axl, MerTK) family of receptors, plays important roles in cell survival, clearance of dead cells (efferocytosis), and suppression of inflammation, which are processes that critically influence atherosclerosis progression. Whereas MerTK deficiency promotes defective efferocytosis, inflammation, and plaque necrosis in advanced murine atherosclerosis, the role of Axl in advanced atherosclerosis progression is not known. Towards this end, bone marrow cells from Axl−/− or wild-type mice were transplanted into lethally irradiated Ldlr−/− mice. These chimeric mice were then fed the Western-type diet (WD) for 17 weeks. We demonstrate that lesional macrophages in WT mice express Axl but that Axl deficiency in bone marrow-derived cells does not affect lesion size, cellularity, necrosis, or inflammatory parameters in advanced atherosclerotic plaques. Moreover, apoptosis of lesional cells was unaffected, and we found no evidence of defective lesional efferocytosis. In contrast to previously reported findings with MerTK deficiency, hematopoietic cell-Axl deficiency in WD-fed Ldlr−/− mice does not affect the progression of advanced atherosclerosis or lesional processes associated with TAM receptor signaling. These findings suggest a heretofore unappreciated TAM receptor hierarchy in advanced atherosclerosis. PMID:27958361

  7. Structural Imaging and Parkinson’s Disease: Moving Toward Quantitative Markers of Disease Progression

    PubMed Central

    Sterling, N.W.; Lewis, M.M.; Du, G.; Huang, X.

    2016-01-01

    Parkinson’s disease (PD) is a progressive age-related neurodegenerative disorder. Although the pathological hallmark of PD is dopaminergic cell death in the substantia nigra pars compacta, widespread neurodegenerative changes occur throughout the brain as disease progresses. Postmortem studies, for example, have demonstrated the presence of Lewy pathology, apoptosis, and loss of neurotransmitters and interneurons in both cortical and subcortical regions of PD patients. Many in vivo structural imaging studies have attempted to gauge PD-related pathology, particularly in gray matter, with the hope of identifying an imaging biomarker. Reports of brain atrophy in PD, however, have been inconsistent, most likely due to differences in the studied populations (i.e. different disease stages and/or clinical subtypes), experimental designs (i.e. cross-sectional vs. longitudinal), and image analysis methodologies (i.e. automatic vs. manual segmentation). This review attempts to summarize the current state of gray matter structural imaging research in PD in relationship to disease progression, reconciling some of the differences in reported results, and to identify challenges and future avenues. PMID:27258697

  8. Biomarkers for disease progression and AAV therapeutic efficacy in feline Sandhoff disease.

    PubMed

    Bradbury, Allison M; Gray-Edwards, Heather L; Shirley, Jamie L; McCurdy, Victoria J; Colaco, Alexandria N; Randle, Ashley N; Christopherson, Pete W; Bird, Allison C; Johnson, Aime K; Wilson, Diane U; Hudson, Judith A; De Pompa, Nicholas L; Sorjonen, Donald C; Brunson, Brandon L; Jeyakumar, Mylvaganam; Platt, Frances M; Baker, Henry J; Cox, Nancy R; Sena-Esteves, Miguel; Martin, Douglas R

    2015-01-01

    The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are progressive neurodegenerative disorders that are caused by a mutation in the enzyme β-N-acetylhexosaminidase (Hex). Due to the recent emergence of novel experimental treatments, biomarker development has become particularly relevant in GM2 gangliosidosis as an objective means to measure therapeutic efficacy. Here we describe blood, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and electrodiagnostic methods for evaluating disease progression in the feline SD model and application of these approaches to assess AAV-mediated gene therapy. SD cats were treated by intracranial injections of the thalami combined with either the deep cerebellar nuclei or a single lateral ventricle using AAVrh8 vectors encoding feline Hex. Significantly altered in untreated SD cats, blood and CSF based biomarkers were largely normalized after AAV gene therapy. Also reduced after treatment were expansion of the lysosomal compartment in peripheral blood mononuclear cells and elevated activity of secondary lysosomal enzymes. MRI changes characteristic of the gangliosidoses were documented in SD cats and normalized after AAV gene therapy. The minimally invasive biomarkers reported herein should be useful to assess disease progression of untreated SD patients and those in future clinical trials.

  9. Spatiotemporal and species-specific patterns of diseases affecting crustose coralline algae in Curaçao

    NASA Astrophysics Data System (ADS)

    Quéré, G.; Steneck, R. S.; Nugues, M. M.

    2015-03-01

    Distribution and abundance of coral diseases have been well documented, but only a few studies considered diseases affecting crustose coralline algae (CCA), particularly at the species level. We investigated the spatiotemporal dynamics of diseases affecting CCA along the south coast of Curaçao, southern Caribbean. Two syndromes were detected: the Coralline White Band Syndrome (CWBS) previously described and the Coralline White Patch Disease (CWPD) reported here for the first time. Diseases were present at all six study sites, and our results did not reveal a relationship between disease occurrence and human influence. Both diseases were more prevalent on the shallower reef flat than on the deeper reef slope, and during the warm/rainy season than during the cold/dry season. The patterns observed were consistent with a positive link between temperature and disease occurrence. Reef flat communities were dominated by Neogoniolithon mamillare and Paragoniolithon solubile, whereas deeper habitats were dominated by Hydrolithon boergesenii. Diseases affected all the species encountered, and no preferable host was detected. There was a significant relationship between both disease occurrences and CCA cover. Monitoring of affected patches revealed that 90 % of lesions in CWBS increased in size, whereas 88 % of CWPD lesions regenerated over time. CWBS linear progression rate did not vary between seasons or species and ranged from 0.15 to 0.36 cm month-1, which is in the same order of magnitude as rates previously documented. We conclude that diseases have the potential to cause major loss in CCA cover, particularly in shallow waters. As CCA play a key role in reef ecosystems, our study suggests that the emergence of diseases affecting these algae may pose a real threat to coral reef ecosystems. The levels of disease reported here will provide a much-needed local baseline allowing future comparisons.

  10. Plasma viscosity increase with progression of peripheral arterial atherosclerotic disease.

    PubMed

    Poredos, P; Zizek, B

    1996-03-01

    -macroglobulin (r=0.78, P < 0.01). These results indicate that in patients with peripheral arterial disease plasma viscosity increases with the progression of the atherosclerotic process and is correlated with the clinical stages of the disease.

  11. CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer's Disease.

    PubMed

    Zhang, Deng-Feng; Li, Jin; Wu, Huan; Cui, Yue; Bi, Rui; Zhou, He-Jiang; Wang, Hui-Zhen; Zhang, Chen; Wang, Dong; Kong, Qing-Peng; Li, Tao; Fang, Yiru; Jiang, Tianzi; Yao, Yong-Gang

    2016-03-01

    The immune response is highly active in Alzheimer's disease (AD). Identification of genetic risk contributed by immune genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort, followed by a multiple-stage study focusing on Complement Factor H (CFH) gene. Effects of the risk SNPs on AD-related neuroimaging endophenotypes were evaluated through magnetic resonance imaging scan, and the effects on AD cerebrospinal fluid biomarkers (CSF) and CFH expression changes were measured in aged and AD brain tissues and AD cellular models. Our results showed that the AD-associated top immune genes reported in Europeans (CR1, CD33, CLU, and TREML2) have weak effects in Chinese, whereas CFH showed strong effects. In particular, rs1061170 (P(meta)=5.0 × 10(-4)) and rs800292 (P(meta)=1.3 × 10(-5)) showed robust associations with AD, which were confirmed in multiple world-wide sample sets (4317 cases and 16 795 controls). Rs1061170 (P=2.5 × 10(-3)) and rs800292 (P=4.7 × 10(-4)) risk-allele carriers have an increased entorhinal thickness in their young age and a higher atrophy rate as the disease progresses. Rs800292 risk-allele carriers have higher CSF tau and Aβ levels and severe cognitive decline. CFH expression level, which was affected by the risk-alleles, was increased in AD brains and cellular models. These comprehensive analyses suggested that CFH is an important immune factor in AD and affects multiple pathological changes in early life and during disease progress.

  12. Progressive multifocal leukoencephalopathy and other forms of JC virus disease.

    PubMed

    Brew, Bruce J; Davies, Nicholas W S; Cinque, Paola; Clifford, David B; Nath, Avindra

    2010-12-01

    Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the brain caused by the JC virus (JCV). PML usually occurs via reactivation of JCV when an immune system becomes compromised. A diagnosis of PML is normally made on the basis of distinguishing neurological features at presentation, characteristic brain MRI changes and the presence of JCV DNA in cerebrospinal fluid. PML has a 3 month mortality rate of 20-50%, so prompt intervention is essential. Currently, reconstitution of the immune system affords the best prognosis for this condition. When PML is first suspected, and where possible, immunosuppressant or immunomodulatory therapy should be suspended or reduced. If PML is associated with a protein therapy that has a long half-life the use of plasma exchange to accelerate the removal of the drug from the circulation may aid the restoration of immune system function. Rapid improvements in immune function, however, might lead to transient worsening of the disease. In this Review, we critically appraise the controversies surrounding JCV infection, and provide practical management guidelines for PML.

  13. Workshop report: The effects of psychological variables on the progression of HIV-1 disease.

    PubMed

    Kopnisky, Kathy L; Stoff, David M; Rausch, Dianne M

    2004-05-01

    The reciprocal interactions between the neuroendocrine, immune, and autonomic nervous systems are complicated, yet worthy of examination. A body of literature suggests that psychological factors such as stress, or psychiatric conditions such as major depression, may influence the immune system thereby altering host susceptibility to viral, or other types of infection. Alternately, in an attempt to limit infection and replication, the anti-viral host response, via innate and acquired immunity and subsequent release of pro-inflammatory cytokines and additional anti-viral mediators, may affect mood, cognition emotion, and possibly precipitate a psychiatric disorder. In order to address what is known regarding neuroendocrine-immune interactions in the context of HIV infection, the Center for Mental Health Research on AIDS convened a panel of scientists from diverse areas of expertise. Their primary charge was to examine whether stress-induced activation of the neuroendocrine system affects the immune system in a manner that negatively influences HIV disease progression, and whether HIV infection influences the central nervous system and behavior. The ensuing report summarizes their deliberations as they discussed the current body of information and identified outstanding critical questions in the areas of research. The group consensus was that the biological mediators of psychological status can play an important role in mediating HIV disease progression, particularly in subgroups of vulnerable patients; furthermore, they identified candidate biological mediators and mechanisms of disease progression. The Workgroup outlined the inherent challenges and limitations of such research and provided recommendations as to the future directions of research utilizing human, animal, and in vitro models of HIV-1 infection and stress.

  14. Analysis of genetic copy number changes in cervical disease progression

    PubMed Central

    2010-01-01

    Background Cervical dysplasia and tumorigenesis have been linked with numerous chromosomal aberrations. The goal of this study was to evaluate 35 genomic regions associated with cervical disease and to select those which were found to have the highest frequency of aberration for use as probes in fluorescent in-situ hybridization. Methods The frequency of gains and losses using fluorescence in-situ hybridization were assessed in these 35 regions on 30 paraffin-embedded cervical biopsy specimens. Based on this assessment, 6 candidate fluorescently labeled probes (8q24, Xp22, 20q13, 3p14, 3q26, CEP15) were selected for additional testing on a set of 106 cervical biopsy specimens diagnosed as Normal, CIN1, CIN2, CIN3, and SCC. The data were analyzed on the basis of signal mean, % change of signal mean between histological categories, and % positivity. Results The study revealed that the chromosomal regions with the highest frequency of copy number gains and highest combined sensitivity and specificity in high-grade cervical disease were 8q24 and 3q26. The cytological application of these two probes was then evaluated on 118 ThinPrep™ samples diagnosed as Normal, ASCUS, LSIL, HSIL and Cancer to determine utility as a tool for less invasive screening. Using gains of either 8q24 or 3q26 as a positivity criterion yielded specificity (Normal +LSIL+ASCUS) of 81.0% and sensitivity (HSIL+Cancer) of 92.3% based on a threshold of 4 positive cells. Conclusions The application of a FISH assay comprised of chromosomal probes 8q24 and 3q26 to cervical cytology specimens confirms the positive correlation between increasing dysplasia and copy gains and shows promise as a marker in cervical disease progression. PMID:20712890

  15. Haematuria as a risk factor for chronic kidney disease progression in glomerular diseases: A review.

    PubMed

    Moreno, Juan Antonio; Yuste, Claudia; Gutiérrez, Eduardo; Sevillano, Ángel M; Rubio-Navarro, Alfonso; Amaro-Villalobos, Juan Manuel; Praga, Manuel; Egido, Jesús

    2016-04-01

    Haematuria has long been considered to be a benign condition associated with glomerular diseases. However, new evidences suggest that haematuria has a pathogenic role in promoting kidney disease progression. An increased risk for end-stage renal disease has been reported in adolescents and young adults with persistent microscopic haematuria. A persistent impairment of renal function has been also reported following macroscopic haematuria-associated acute kidney injury in immunoglobulin A nephropathy. Haematuria-induced renal damage has been related to oxidant, cytotoxic and inflammatory effects induced by haemoglobin or haem released from red blood cells. The pathophysiological origin of haematuria may be due to a more fragile and easily ruptured glomerular filtration barrier, as reported in several glomerular diseases. In this review we describe a number of the key issues associated with the epidemiology and pathogenesis of haematuria-associated diseases, provide an update of recent knowledge on the role of haematuria on renal function outcome and discuss specific therapeutic approaches in this setting. KEY SUMMARY POINTS: 1. Glomerular haematuria is a common observation in a number of renal diseases that may lead to persistent renal injury. 2. Haematuria in children differs from that in adults in specific aspects, particularly in the frequency of glomerular diseases and renal disease outcome. 3. Regular follow-up of renal function in children with isolated microhaematuria may be recommended.

  16. Modulation of TGF-beta signaling during progression of chronic liver diseases.

    PubMed

    Matsuzaki, Koichi

    2009-01-01

    A large body of work has established roles for epithelial cells as important mediators of progressive fibrosis and carcinogenesis. Transforming growth factor-beta (TGF-beta) and pro-inflammatory cytokines are important inducers of fibro-carcinogenesis. TGF-beta signaling involves phosphorylation of Smad3 at middle linker and/or C-terminal regions. Reversible shifting of Smad3-dependent signaling between tumor-suppression and oncogenesis in hyperactive Ras-expressing epithelial cells indicates that Smad3 phosphorylated at the C-terminal region (pSmad3C) transmits a tumor-suppressive TGF-beta signal, while oncogenic activities such as cell proliferation and invasion are promoted by Smad3 phosphorylated at the linker region (pSmad3L). Notably, pSmad3L-mediated signaling promotes extracellular matrix deposition by activated mesenchymal cells. During progression of chronic liver diseases, hepatic epithelial hepatocytes undergo transition from the tumor-suppressive pSmad3C pathway to the fibrogenic/oncogenic pSmad3L pathway, accelerating liver fibrosis and increasing risk of hepatocellular carcinoma. c-Jun N-terminal kinase activated by pro-inflammatory cytokines is mediating this perturbed hepatocytic TGF-beta signaling. Thus, TGF-beta signaling of hepatocytes affected by chronic inflammation offers a general framework for understanding the molecular mechanisms of human fibro-carcinogenesis during progression of chronic liver diseases.

  17. Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression.

    PubMed

    Bruneteau, Gaëlle; Simonet, Thomas; Bauché, Stéphanie; Mandjee, Nathalie; Malfatti, Edoardo; Girard, Emmanuelle; Tanguy, Marie-Laure; Behin, Anthony; Khiami, Frédéric; Sariali, Elhadi; Hell-Remy, Caroline; Salachas, François; Pradat, Pierre-François; Fournier, Emmanuel; Lacomblez, Lucette; Koenig, Jeanine; Romero, Norma Beatriz; Fontaine, Bertrand; Meininger, Vincent; Schaeffer, Laurent; Hantaï, Daniel

    2013-08-01

    Amyotrophic lateral sclerosis is a typically rapidly progressive neurodegenerative disorder affecting motor neurons leading to progressive muscle paralysis and death, usually from respiratory failure, in 3-5 years. Some patients have slow disease progression and prolonged survival, but the underlying mechanisms remain poorly understood. Riluzole, the only approved treatment, only modestly prolongs survival and has no effect on muscle function. In the early phase of the disease, motor neuron loss is initially compensated for by collateral reinnervation, but over time this compensation fails, leading to progressive muscle wasting. The crucial role of muscle histone deacetylase 4 and its regulator microRNA-206 in compensatory reinnervation and disease progression was recently suggested in a mouse model of amyotrophic lateral sclerosis (transgenic mice carrying human mutations in the superoxide dismutase gene). Here, we sought to investigate whether the microRNA-206-histone deacetylase 4 pathway plays a role in muscle compensatory reinnervation in patients with amyotrophic lateral sclerosis and thus contributes to disease outcome differences. We studied muscle reinnervation using high-resolution confocal imaging of neuromuscular junctions in muscle samples obtained from 11 patients with amyotrophic lateral sclerosis, including five long-term survivors. We showed that the proportion of reinnervated neuromuscular junctions was significantly higher in long-term survivors than in patients with rapidly progressive disease. We analysed the expression of muscle candidate genes involved in the reinnervation process and showed that histone deacetylase 4 upregulation was significantly greater in patients with rapidly progressive disease and was negatively correlated with the extent of muscle reinnervation and functional outcome. Conversely, the proposed regulator of histone deacetylase 4, microRNA-206, was upregulated in both patient groups, but did not correlate with disease

  18. An advanced case of indium lung disease with progressive emphysema

    PubMed Central

    Nakano, Makiko; Tanaka, Akiyo; Hirata, Miyuki; Kumazoe, Hiroyuki; Wakamatsu, Kentaro; Kamada, Dan; Omae, Kazuyuki

    2016-01-01

    Objectives: To report the occurrence of an advanced case of indium lung disease with severely progressive emphysema in an indium-exposed worker. Case report: A healthy 42-year-old male smoker was employed to primarily grind indium-tin oxide (ITO) target plates, exposing him to indium for 9 years (1998-2008). In 2004, an epidemiological study was conducted on indium-exposed workers at the factory in which he worked. The subject's serum indium concentration (In-S) was 99.7 μg/l, while his serum Krebs von den Lungen-6 level was 2,350 U/ml. Pulmonary function tests showed forced vital capacity (FVC) of 4.17 l (91.5% of the JRS predicted value), forced expiratory volume in 1 s (FEV1) of 3.19 l (80.8% of predicted), and an FEV1-to-FVC ratio of 76.5%. A high-resolution chest computed tomography (HRCT) scan showed mild interlobular septal thickening and mild emphysematous changes. In 2008, he was transferred from the ITO grinding workplace to an inspection work section, where indium concentrations in total dusts had a range of 0.001-0.002 mg/m3. In 2009, the subject's In-S had increased to 132.1 μg/l, and pulmonary function tests revealed obstructive changes. In addition, HRCT scan showed clear evidence of progressive lung destruction with accompanying severe centrilobular emphysema and interlobular septal thickening in both lung fields. The subject's condition gradually worsened, and in 2015, he was registered with the Japan Organ Transplant Network for lung transplantation (LTx). Conclusions: Heavy indium exposure is a risk factor for emphysema, which can lead to a severity level that requires LTx as the final therapeutic option. PMID:27488043

  19. In silico regulatory analysis for exploring human disease progression

    PubMed Central

    Holloway, Dustin T; Kon, Mark; DeLisi, Charles

    2008-01-01

    Background An important goal in bioinformatics is to unravel the network of transcription factors (TFs) and their targets. This is important in the human genome, where many TFs are involved in disease progression. Here, classification methods are applied to identify new targets for 152 transcriptional regulators using publicly-available targets as training examples. Three types of sequence information are used: composition, conservation, and overrepresentation. Results Starting with 8817 TF-target interactions we predict an additional 9333 targets for 152 TFs. Randomized classifiers make few predictions (~2/18660) indicating that our predictions for many TFs are significantly enriched for true targets. An enrichment score is calculated and used to filter new predictions. Two case-studies for the TFs OCT4 and WT1 illustrate the usefulness of our predictions: • Many predicted OCT4 targets fall into the Wnt-pathway. This is consistent with known biology as OCT4 is developmentally related and Wnt pathway plays a role in early development. • Beginning with 15 known targets, 354 predictions are made for WT1. WT1 has a role in formation of Wilms' tumor. Chromosomal regions previously implicated in Wilms' tumor by cytological evidence are statistically enriched in predicted WT1 targets. These findings may shed light on Wilms' tumor progression, suggesting that the tumor progresses either by loss of WT1 or by loss of regions harbouring its targets. • Targets of WT1 are statistically enriched for cancer related functions including metastasis and apoptosis. Among new targets are BAX and PDE4B, which may help mediate the established anti-apoptotic effects of WT1. • Of the thirteen TFs found which co-regulate genes with WT1 (p ≤ 0.02), 8 have been previously implicated in cancer. The regulatory-network for WT1 targets in genomic regions relevant to Wilms' tumor is provided. Conclusion We have assembled a set of features for the targets of human TFs and used them to

  20. Uric acid as a risk factor for progression of non-diabetic chronic kidney disease? The Mild to Moderate Kidney Disease (MMKD) Study.

    PubMed

    Sturm, Gisela; Kollerits, Barbara; Neyer, Ulrich; Ritz, Eberhard; Kronenberg, Florian

    2008-04-01

    The kidney is one of the organs most prominently affected by aging. This can be seen by a loss of renal mass which is caused by a decrease in the number of nephrons resulting in hyperfiltration, hypertrophy and elevations in glomerular pressure. The factors influencing aging of the kidney are not fully elucidated. Epidemiological, experimental and interventional studies resulted in inconsistent results and have not firmly established whether uric acid levels affect progression of Chronic Kidney Disease (CKD). Therefore, we analyzed whether uric acid levels predict the progression of CKD in the Mild to Moderate Kidney Disease Study comprising at baseline 227 Caucasian patients aged 18-65 years with primary non-diabetic CKD of various degrees of renal impairment. Of them, 177 completed a prospective follow-up of 7 years. Primary endpoint was progression of CKD defined as doubling of baseline serum creatinine and/or terminal renal failure. Patients who reached a progression endpoint (n =6 5) were significantly older, had higher baseline serum creatinine and protein excretion rates as well as lower Glomerular Filtration Rate (GFR). Uric acid levels were only higher in patients with progression of disease when patients with uric acid-lowering drugs were excluded from the analysis. Cox regression analysis revealed that increasing uric acid levels predict disease progression only when the analysis was not adjusted for baseline kidney function parameters. As soon as we adjusted the analysis for GFR and proteinuria this association completely vanished. In summary, our prospective 7 year follow-up study in patients with non-diabetic primary CKD did not support uric acid as an independent predictor for CKD progression.

  1. Optical coherence tomography findings in Huntington's disease: a potential biomarker of disease progression.

    PubMed

    Kersten, Hannah M; Danesh-Meyer, Helen V; Kilfoyle, Dean H; Roxburgh, Richard H

    2015-11-01

    Previous reports of ocular abnormalities in Huntington's disease (HD) have detailed eye movement disorders. The objective of this case-control study was to investigate optic nerve and macular morphology in HD using optical coherence tomography (OCT). A total of 26 HD patients and 29 controls underwent a thorough ophthalmic examination including spectral domain OCT scans of the macula and peripapillary retinal nerve fibre layer (RNFL). Genetic testing results, disease duration, HD disease burden scores and Unified HD Rating Scale motor scores were acquired for HD patients. Temporal RNFL thickness was significantly reduced in the HD group (62.3 vs. 69.8 μm, p = 0.005), and there was a significant negative correlation between temporal RNFL thickness and disease duration (R (2) = -0.51, p = 0.04). Average peripapillary RNFL thickness was not significantly different between the HD and control groups. There was a significant negative correlation between macular volume and disease duration (R (2) = -0.71, p = 0.002), and motor scores (R (2) = -0.56, p = 0.01). Colour vision was significantly poorer in the HD group. Temporal RNFL is preferentially thinned in HD patients, possibly implicating mitochondrial dysfunction as the temporal RNFL is reduced in the patients with some mitochondrial disorders, including Leber's hereditary optic neuropathy. The correlation between the decrease in macular volume and temporal RNFL, and increasing disease severity suggests that OCT may be a useful biomarker for disease progression in HD. Larger, longitudinal studies are required.

  2. Do Positive Psychosocial Factors Predict Disease Progression in HIV-1? A Review of the Evidence

    PubMed Central

    Ironson, Gail H.; Hayward, H’sien

    2008-01-01

    Adding to a traditional stress perspective, behavioral medicine has been focusing increasingly on investigating the potential impact of positive psychosocial factors on disease course in HIV. Dispositional optimism, active coping, and spirituality show the most evidence for predicting slower disease progression, although the data are not entirely consistent. Findings for the role of social support are mixed, although indications are that it may be particularly helpful at later stages of illness. Many of the other constructs (positive affect, finding meaning, emotional expression/processing, openness, extraversion, conscientiousness, altruism, and self-efficacy) have only been examined in one or two studies; results are preliminary but suggestive of protective effects. Plausible behavioral and biological mechanisms are discussed (including health behaviors, neurohormones, and immune measures) as well as suggestions for clinicians, limitations, future directions, and a discussion of whether these constructs can be changed. In conclusion, investigating the importance and usefulness of positive psychosocial factors in predicting disease progression in HIV is in its beginning scientific stages and shows good initial evidence and future promise. PMID:18541905

  3. Hippocampal Plasticity During the Progression of Alzheimer’s disease

    PubMed Central

    Mufson, Elliott J.; Mahady, Laura; Waters, Diana; Counts, Scott E.; Perez, Sylvia E.; DeKosky, Steven; Ginsberg, Stephen D.; Ikonomovic, Milos D.; Scheff, Stephen; Binder, Lester

    2015-01-01

    Neuroplasticity involves molecular changes in central nervous system (CNS) synaptic structure and function throughout life. The concept of neural organization allows for synaptic remodeling as a compensatory mechanism to the early pathobiology of Alzheimer’s disease (AD) in an attempt to maintain brain function and cognition during the onset of dementia. The hippocampus, a crucial component of the medial temporal lobe memory circuit, is affected early in AD and displays synaptic and intraneuronal molecular remodeling against a pathological background of extracellular amyloid-beta (Aβ) deposition and intracellular neurofibrillary tangle (NFT) formation in the early stages of AD. Here we discuss human clinical pathological findings supporting the concept that the hippocampus is capable of neural plasticity during mild cognitive impairment (MCI), a prodromal stage of AD and early stage AD. PMID:25772787

  4. The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives.

    PubMed

    Swerdlow, Russell H; Burns, Jeffrey M; Khan, Shaharyar M

    2014-08-01

    Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains that gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (Aβ) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it. We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts that biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Aβ at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late-onset AD is and how to best treat it.

  5. How does smoking affect olfaction in Parkinson's disease?

    PubMed

    Moccia, Marcello; Picillo, Marina; Erro, Roberto; Vitale, Carmine; Amboni, Marianna; Palladino, Raffaele; Cioffi, Dante Luigi; Barone, Paolo; Pellecchia, Maria Teresa

    2014-05-15

    Smoke-induced upper airway damage and Parkinson's disease (PD) can be considered independent risk factors for smell impairment. Interestingly, cigarette smoking has been strongly associated with reduced risk of PD and, therefore, has been suggested to have neuroprotective effects. Our pilot study aimed to evaluate the relationship between smoking and olfaction in PD patients and matched controls. Sixty-eight PD patients and 61 healthy controls were categorized in relation to PD diagnosis and current smoking status, and evaluated by means of the Italian version of the University of Pennsylvania 40-item Smell Identification Test (UPSIT-40). ANOVA analysis with post-hoc Bonferroni correction showed that non-smoker controls presented a higher UPSIT-40 total score than smoker controls (p<0.001), non-smoker PD patients (p<0.001) and smoker PD patients (p<0.001). In this view, smoking seems to affect olfaction in controls but not in PD patients, and no significant differences were found when comparing smoker controls, smoker PD patients and non-smoker PD patients. Several epidemiological studies showed a negative effect of smoking on olfaction in the general population. Otherwise the sense of smell is similar in smoker and non-smoker PD patients. These results suggest that PD and smoking are not independent risk factors for impairment of sense of smell, but they might variably interact.

  6. Subthalamic nucleus stimulation affects incentive salience attribution in Parkinson's disease.

    PubMed

    Serranová, Tereza; Jech, Robert; Dušek, Petr; Sieger, Tomáš; Růžička, Filip; Urgošík, Dušan; Růžička, Evžen

    2011-10-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can induce nonmotor side effects such as behavioral and mood disturbances or body weight gain in Parkinson's disease (PD) patients. We hypothesized that some of these problems could be related to an altered attribution of incentive salience (ie, emotional relevance) to rewarding and aversive stimuli. Twenty PD patients (all men; mean age ± SD, 58.3 ± 6 years) in bilateral STN DBS switched ON and OFF conditions and 18 matched controls rated pictures selected from the International Affective Picture System according to emotional valence (unpleasantness/pleasantness) and arousal on 2 independent visual scales ranging from 1 to 9. Eighty-four pictures depicting primary rewarding (erotica and food) and aversive fearful (victims and threat) and neutral stimuli were selected for this study. In the STN DBS ON condition, the PD patients attributed lower valence scores to the aversive pictures compared with the OFF condition (P < .01) and compared with controls (P < .01). The difference between the OFF condition and controls was less pronounced (P < .05). Furthermore, postoperative weight gain correlated with arousal ratings from the food pictures in the STN DBS ON condition (P < .05 compensated for OFF condition). Our results suggest that STN DBS increases activation of the aversive motivational system so that more relevance is attributed to aversive fearful stimuli. In addition, STN DBS-related sensitivity to food reward stimuli cues might drive DBS-treated patients to higher food intake and subsequent weight gain.

  7. A Review of Factors Affecting Vaccine Preventable Disease in Japan

    PubMed Central

    Ching, Michael SL

    2014-01-01

    Japan is well known as a country with a strong health record. However its incidence rates of vaccine preventable diseases (VPD) such as hepatitis B, measles, mumps, rubella, and varicella remain higher than other developed countries. This article reviews the factors that contribute to the high rates of VPD in Japan. These include historical and political factors that delayed the introduction of several important vaccines until recently. Access has also been affected by vaccines being divided into government-funded “routine” (eg, polio, pertussis) and self-pay “voluntary” groups (eg, hepatitis A and B). Routine vaccines have higher rates of administration than voluntary vaccines. Administration factors include differences in well child care schedules, the approach to simultaneous vaccination, vaccination contraindication due to fever, and vaccination spacing. Parental factors include low intention to fully vaccinate their children and misperceptions about side effects and efficacy. There are also provider knowledge gaps regarding indications, adverse effects, interval, and simultaneous vaccination. These multifactorial issues combine to produce lower population immunization rates and a higher incidence of VPD than other developed countries. This article will provide insight into the current situation of Japanese vaccinations, the issues to be addressed and suggestions for public health promotion. PMID:25628969

  8. Saliva/Pathogen Biomarker Signatures and Periodontal Disease Progression

    PubMed Central

    Kinney, J.S.; Morelli, T.; Braun, T.; Ramseier, C.A.; Herr, A.E.; Sugai, J.V.; Shelburne, C.E.; Rayburn, L.A.; Singh, A.K.; Giannobile, W.V.

    2011-01-01

    The purpose of this study was to determine the role of saliva-derived biomarkers and periodontal pathogens during periodontal disease progression (PDP). One hundred human participants were recruited into a 12-month investigation. They were seen bi-monthly for saliva and clinical measures and bi-annually for subtraction radiography, serum and plaque biofilm assessments. Saliva and serum were analyzed with protein arrays for 14 pro-inflammatory and bone turnover markers, while qPCR was used for detection of biofilm. A hierarchical clustering algorithm was used to group study participants based on clinical, microbiological, salivary/serum biomarkers, and PDP. Eighty-three individuals completed the six-month monitoring phase, with 44 exhibiting PDP, while 39 demonstrated stability. Participants assembled into three clusters based on periodontal pathogens, serum and salivary biomarkers. Cluster 1 members displayed high salivary biomarkers and biofilm; 82% of these individuals were undergoing PDP. Cluster 2 members displayed low biofilm and biomarker levels; 78% of these individuals were stable. Cluster 3 members were not discriminated by PDP status; however, cluster stratification followed groups 1 and 2 based on thresholds of salivary biomarkers and biofilm pathogens. The association of cluster membership to PDP was highly significant (p < 0.0002). The use of salivary and biofilm biomarkers offers potential for the identification of PDP or stability (ClinicalTrials.gov number, CT00277745). PMID:21406610

  9. Disease progression in non-erosive reflux disease (NERD): impact of initial esophageal acid exposure.

    PubMed

    Chen, C L; Liu, T T; Yi, C H

    2010-11-01

    We investigated the 5-year clinical course in a cohort of patients with typical reflux symptoms and negative endoscopy. Prospective follow-up was conducted in patients with non-erosive reflux disease (NERD) for at least 5 years after initial evaluation with esophageal pH monitoring and upper gastrointestinal endoscopy. Within the last year of follow-up, reflux symptoms occurred in 27 of the 30 patients (90%). Twenty-five of twenty-seven symptomatic patients (93%) were on acid suppression therapy. The majority of our patients (70%) remained unchanged regarding their endoscopic status over 5 years. Progression to erosive esophagitis occurred in four patients with Los Angeles (LA) A (13%), three patients with LA B (10%), and two patients with LA C (7%). The presence of pathological acid exposure did not alter the presence of reflux symptoms over 5 years. Disease progression to erosive esophagitis occurred more frequently in patients with pathological acid exposure than those without pathological acid exposure (P= 0.025). Most NERD patients have symptoms and require acid suppression therapy 5 years after their initial diagnosis. Initial pathological acid exposure does not influence the use of acid suppression; however, it does influence the progression of NERD within 5 years of follow-up.

  10. Dietary magnesium and copper affect survival time and neuroinflammation in chronic wasting disease

    PubMed Central

    Nichols, Tracy A.; Spraker, Terry R.; Gidlewski, Thomas; Cummings, Bruce; Hill, Dana; Kong, Qingzhong; Balachandran, Aru; VerCauteren, Kurt C.; Zabel, Mark D.

    2016-01-01

    ABSTRACT Chronic wasting disease (CWD), the only known wildlife prion disease, affects deer, elk and moose. The disease is an ongoing and expanding problem in both wild and captive North American cervid populations and is difficult to control in part due to the extreme environmental persistence of prions, which can transmit disease years after initial contamination. The role of exogenous factors in CWD transmission and progression is largely unexplored. In an effort to understand the influence of environmental and dietary constituents on CWD, we collected and analyzed water and soil samples from CWD-negative and positive captive cervid facilities, as well as from wild CWD-endozootic areas. Our analysis revealed that, when compared with CWD-positive sites, CWD-negative sites had a significantly higher concentration of magnesium, and a higher magnesium/copper (Mg/Cu) ratio in the water than that from CWD-positive sites. When cevidized transgenic mice were fed a custom diet devoid of Mg and Cu and drinking water with varied Mg/Cu ratios, we found that higher Mg/Cu ratio resulted in significantly longer survival times after intracerebral CWD inoculation. We also detected reduced levels of inflammatory cytokine gene expression in mice fed a modified diet with a higher Mg/Cu ratio compared to those on a standard rodent diet. These findings indicate a role for dietary Mg and Cu in CWD pathogenesis through modulating inflammation in the brain. PMID:27216881

  11. Chronic Alcohol Abuse and HIV Disease Progression: Studies with the Non-Human Primate Model

    PubMed Central

    Amedee, Angela M.; Nichols, Whitney A.; Robichaux, Spencer; Bagby, Gregory J.; Nelson, Steve

    2015-01-01

    The populations at risk for HIV infection, as well as those living with HIV, overlap with populations that engage in heavy alcohol consumption. Alcohol use has been associated with high-risk sexual behavior and an increased likelihood of acquiring HIV, as well as poor outcome measures of disease such as increased viral loads and declines in CD4+ T lymphocytes among those living with HIV-infections. It is difficult to discern the biological mechanisms by which alcohol use affects the virus:host interaction in human populations due to the numerous variables introduced by human behavior. The rhesus macaque infected with simian immunodeficiency virus has served as an invaluable model for understanding HIV disease and transmission, and thus, provides an ideal model to evaluate the effects of chronic alcohol use on viral infection and disease progression in a controlled environment. In this review, we describe the different macaque models of chronic alcohol consumption and summarize the studies conducted with SIV and alcohol. Collectively, they have shown that chronic alcohol consumption results in higher levels of plasma virus and alterations in immune cell populations that potentiate SIV replication. They also demonstrate a significant impact of chronic alcohol use on SIV-disease progression and survival. These studies highlight the utility of the rhesus macaque in deciphering the biological effects of alcohol on HIV disease. Future studies with this well-established model will address the biological influence of alcohol use on susceptibility to HIV, as well as the efficacy of anti-retroviral therapy. PMID:25053367

  12. A possible mechanism for the progression of chronic renal disease and congestive heart failure.

    PubMed

    Re, Richard N

    2015-01-01

    Chronic neurologic diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as various forms of chronic renal disease and systolic congestive heart failure, are among the most common progressive degenerative disorders encountered in medicine. Each disease follows a nearly relentless course, albeit at varying rates, driven by progressive cell dysfunction and drop-out. The neurologic diseases are characterized by the progressive spread of disease-causing proteins (prion-like proteins) from cell to cell. Recent evidence indicates that cell autonomous renin angiotensin systems operate in heart and kidney, and it is known that functional intracrine proteins can also spread between cells. This then suggests that certain progressive degenerative cardiovascular disorders such as forms of chronic renal insufficiency and systolic congestive heart failure result from dysfunctional renin angiotensin system intracrine action spreading in kidney or myocardium.

  13. Impact of Depression and Inflammation on the Progression of HIV Disease

    PubMed Central

    Rivera-Rivera, Yainyrette; Vázquez-Santiago, Fabián J.; Albino, Elinette; Sánchez, María del C.; Rivera-Amill, Vanessa

    2016-01-01

    The human immunodeficiency virus type 1 (HIV-1) epidemic has negatively affected over 40 million people worldwide. Antiretroviral therapy (ART) has improved life expectancy and changed the outcome of HIV-1 infection, making it a chronic and manageable disease. However, AIDS and non-AIDS comorbid illnesses persist during the course of infection despite the use of ART. In addition, the development of neuropsychiatric comorbidities (including depression) by HIV-infected subjects significantly affects quality of life, medication adherence, and disease prognosis. The factors associated with depression during HIV-1 infection include altered immune response, the release of pro-inflammatory cytokines, and monoamine imbalance. Elevated plasma pro-inflammatory cytokine levels contribute to the development of depression and depressive-like behaviors in HIV+ subjects. In addition, comorbid depression influences the decline rates of CD4+ cell counts and increases plasma viral load. Depression can manifest in some subjects despite their adherence to ART. In addition, psychosocial factors related to stigma (negative attitudes, moral issues, and abuse of HIV+ subjects) are also associated with depression. Both neurobiological and psychosocial factors are important considerations for the effective clinical management of HIV and the prevention of HIV disease progression. PMID:27478681

  14. Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease

    PubMed Central

    Bax, Nathalie M.; Fakin, Ana; Groenewoud, Joannes M. M.; Klevering, B. Jeroen; Moore, Anthony T.; Michaelides, Michel; Webster, Andrew R.; van der Wilt, Gert Jan; Hoyng, Carel B.

    2017-01-01

    Background Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options—including gene therapy—are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration. Methods and findings We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30–0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33–0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients. Conclusions These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a

  15. Transmission and Progression to Disease of Mycobacterium tuberculosis Phylogenetic Lineages in The Netherlands.

    PubMed

    Nebenzahl-Guimaraes, Hanna; Verhagen, Lilly M; Borgdorff, Martien W; van Soolingen, Dick

    2015-10-01

    The aim of this study was to determine if mycobacterial lineages affect infection risk, clustering, and disease progression among Mycobacterium tuberculosis cases in The Netherlands. Multivariate negative binomial regression models adjusted for patient-related factors and stratified by patient ethnicity were used to determine the association between phylogenetic lineages and infectivity (mean number of positive contacts around each patient) and clustering (as defined by number of secondary cases within 2 years after diagnosis of an index case sharing the same fingerprint) indices. An estimate of progression to disease by each risk factor was calculated as a bootstrapped risk ratio of the clustering index by the infectivity index. Compared to the Euro-American reference, Mycobacterium africanum showed significantly lower infectivity and clustering indices in the foreign-born population, while Mycobacterium bovis showed significantly lower infectivity and clustering indices in the native population. Significantly lower infectivity was also observed for the East African Indian lineage in the foreign-born population. Smear positivity was a significant risk factor for increased infectivity and increased clustering. Estimates of progression to disease were significantly associated with age, sputum-smear status, and behavioral risk factors, such as alcohol and intravenous drug abuse, but not with phylogenetic lineages. In conclusion, we found evidence of a bacteriological factor influencing indicators of a strain's transmissibility, namely, a decreased ability to infect and a lower clustering index in ancient phylogenetic lineages compared to their modern counterparts. Confirmation of these findings via follow-up studies using tuberculin skin test conversion data should have important implications on M. tuberculosis control efforts.

  16. Transmission and Progression to Disease of Mycobacterium tuberculosis Phylogenetic Lineages in The Netherlands

    PubMed Central

    Verhagen, Lilly M.; Borgdorff, Martien W.; van Soolingen, Dick

    2015-01-01

    The aim of this study was to determine if mycobacterial lineages affect infection risk, clustering, and disease progression among Mycobacterium tuberculosis cases in The Netherlands. Multivariate negative binomial regression models adjusted for patient-related factors and stratified by patient ethnicity were used to determine the association between phylogenetic lineages and infectivity (mean number of positive contacts around each patient) and clustering (as defined by number of secondary cases within 2 years after diagnosis of an index case sharing the same fingerprint) indices. An estimate of progression to disease by each risk factor was calculated as a bootstrapped risk ratio of the clustering index by the infectivity index. Compared to the Euro-American reference, Mycobacterium africanum showed significantly lower infectivity and clustering indices in the foreign-born population, while Mycobacterium bovis showed significantly lower infectivity and clustering indices in the native population. Significantly lower infectivity was also observed for the East African Indian lineage in the foreign-born population. Smear positivity was a significant risk factor for increased infectivity and increased clustering. Estimates of progression to disease were significantly associated with age, sputum-smear status, and behavioral risk factors, such as alcohol and intravenous drug abuse, but not with phylogenetic lineages. In conclusion, we found evidence of a bacteriological factor influencing indicators of a strain's transmissibility, namely, a decreased ability to infect and a lower clustering index in ancient phylogenetic lineages compared to their modern counterparts. Confirmation of these findings via follow-up studies using tuberculin skin test conversion data should have important implications on M. tuberculosis control efforts. PMID:26224845

  17. Screening-detected rheumatic heart disease can progress to severe disease

    PubMed Central

    Wheaton, Gavin R; Mataika, Reapi L; Kado, Joseph H; Colquhoun, Samantha M; Remenyi, Bo; Steer, Andrew C

    2016-01-01

    Objectives Echocardiography is a sensitive test for rheumatic heart disease (RHD) screening; however the natural history of RHD detected on screening has not been established. We aimed to evaluate the progression of screening-detected RHD in Fiji. Methods All young people previously diagnosed with RHD through screening, with echocardiograms available for review, were eligible. All baseline echocardiograms were reported again. Participants underwent follow-up echocardiography. A paediatric cardiologist determined the diagnosis using the World Heart Federation criteria and assessed the severity of regurgitation and stenosis. Results Ninety-eight participants were recruited (mean age, 17 years; median duration of follow-up, 7.5 years). Two other children had died from severe RHD. Fourteen of 20 (70%) definite RHD cases persisted or progressed, including four (20%) requiring valve surgery. Four (20%) definite RHD cases improved to borderline RHD and two (10%) to normal. Four of 17 (24%) borderline cases progressed to definite RHD (moderate: 2; severe: 2) and two (12%) improved to normal. Four of the 55 cases reclassified as normal at baseline progressed to borderline RHD. Cases with a follow-up interval >5 years were more likely to improve (37% vs 6%, p=0.03). Conclusions The natural history of screening-detected RHD is not benign. Most definite RHD cases persist and others may require surgery or succumb. Progression of borderline cases to severe RHD demonstrates the need for monitoring and individualised consideration of prophylaxis. Robust health system structures are needed for follow-up and delivery of secondary prophylaxis if RHD screening is to be scaled up. PMID:27933106

  18. T1ρ Imaging in Premanifest Huntington Disease Reveals Changes Associated with Disease Progression

    PubMed Central

    Wassef, Shafik N.; Wemmie, John; Johnson, Casey P.; Johnson, Hans; Paulsen, Jane S.; Long, Jeffrey D.; Magnotta, Vincent A.

    2016-01-01

    Background Imaging biomarkers sensitive to Huntington’s disease (HD) during the premanifest phase preceding motor diagnosis may accelerate identification and evaluation of potential therapies. For this purpose, quantitative MRI sensitive to tissue microstructure and metabolism may hold great potential. We investigated the potential value of T1ρ relaxation to detect pathological changes in premanifest HD (preHD) relative to other quantitative relaxation parameters. Methods Quantitative MR parametric mapping was used to assess differences between 50 preHD subjects and 26 age- and sex-matched controls. Subjects with preHD were classified into two progression groups based on their CAG-age product (CAP) score; a high and a low/moderate CAP group. Voxel-wise and region-of-interest analyses were used to assess changes in the quantitative relaxation times. Results T1ρ showed a significant increase in the relaxation times in the high-CAP group, as compared to controls, largely in the striatum. The T1ρ changes in the preHD subjects showed a significant relationship with CAP score. No significant changes in T2 or T2* relaxation times were found in the striatum. T2* relaxation changes were found in the globus pallidus, but no significant changes with disease progression were found. Conclusion These data suggest that quantitative T1ρ mapping may provide a useful marker for assessing disease progression in HD. The absence of T2 changes suggests that the T1ρ abnormalities are unlikely owing to altered water content or tissue structure. The established sensitivity of T1ρ to pH and glucose suggests that these factors are altered in HD perhaps owing to abnormal mitochondrial function. PMID:25820773

  19. Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications

    PubMed Central

    Weidemann, F; Niemann, M; Störk, S; Breunig, F; Beer, M; Sommer, C; Herrmann, S; Ertl, G; Wanner, C

    2013-01-01

    Objective The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards ‘hard’ clinical end-points in comparison with the natural course of the disease. Methods A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain. Results During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min−1 per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry. Conclusion Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease. PMID:23586858

  20. Late-onset Tay-Sachs disease: the spectrum of peripheral neuropathy in 30 affected patients.

    PubMed

    Shapiro, Barbara E; Logigian, Eric L; Kolodny, Edwin H; Pastores, Gregory M

    2008-08-01

    Late-onset Tay-Sachs (LOTS) disease is a chronic, progressive, lysosomal storage disorder caused by a partial deficiency of beta-hexosaminidase A (HEXA) activity. Deficient levels of HEXA result in the intracellular accumulation of GM2-ganglioside, resulting in toxicity to nerve cells. Clinical manifestations primarily involve the central nervous system (CNS) and lower motor neurons, and include ataxia, weakness, spasticity, dysarthria, dysphagia, dystonia, seizures, psychosis, mania, depression, and cognitive decline. The prevalence of peripheral nervous system (PNS) involvement in LOTS has not been well documented, but it has traditionally been thought to be very low. We examined a cohort of 30 patients with LOTS who underwent clinical and electrophysiologic examination, and found evidence of a predominantly axon loss polyneuropathy affecting distal nerve segments in the lower and upper extremities in eight patients (27%).

  1. Ezrin Is Associated with Disease Progression in Ovarian Carcinoma

    PubMed Central

    Horwitz, Vered; Davidson, Ben; Stern, Dganit; Tropé, Claes G.; Tavor Re’em, Tali; Reich, Reuven

    2016-01-01

    Objective Ezrin and p130Cas are structural proteins with an important role in signaling pathways and have been shown to promote cancer dissemination. We previously reported on overexpression of both ezrin and p130Cas in breast carcinoma effusions compared to primary carcinomas. Since ovarian and breast carcinomas share the ability to disseminate by forming malignant effusions, we sought to study the role of these molecules in ovarian carcinoma (OC). Methods OC cell lines were cultured in two different 3-dimensional conditions, on alginate scaffolds and as spheroids, which served as models for solid tumor and malignant effusions, respectively. shRNA was used to reduce protein expression in the cells. The malignant potential was evaluated by chemo-invasion assay, branching capacity on Matrigel and rate of proliferation. Subsequently, clinical specimens of high-grade serous carcinoma effusions, ovarian tumors and solid metastases were analyzed for ezrin and p130Cas expression. Results Higher ezrin expression was found in cells composing the spheroids compared to their counterparts cultured on alginate scaffold and in clinical samples of malignant effusions compared to solid tumors. In addition, reduced Ezrin expression impaired the invasion ability and the branching capacity of OC cells to a greater extent than reduced p130Cas expression. However, ezrin and p130Cas expression in effusions was unrelated to clinical outcome. Conclusions The 3-dimensional cell cultures were found to mimic the different tumor sites and be applicable as a model. The in vitro results concur with the clinical specimen analysis, suggesting that in OC, the role of ezrin in disease progression is more pronounced than that of p130Cas. PMID:27622508

  2. An alternative medical approach for the neuroprotective therapy to slow the progression of Parkinson's disease.

    PubMed

    Muroyama, Akiko

    2013-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the core symptoms such as bradykinesia, resting tremor, rigidity and postural instability. Currently, pharmacotherapy and surgical approaches for the treatments of PD can only improve the neurological symptoms. Therefore, to search neuroprotective therapies using pharmacological and nonpharmacological approaches could be important to delay the progression of pathogenesis in PD. Coenzyme Q10 (CoQ10) is a component of the electron transport chain as well as an important antioxidant in mitochondrial and lipid membranes. The central role of CoQ10 in two areas implicated in the pathogenesis of PD, mitochondrial dysfunction and oxidative damages, suggest that it may be useful for treatment to slow the progression of PD. The neuroprotective effect of CoQ10 has been reported in several in vivo and in vitro models of neurodegenerative disorders. Although CoQ10 attenuated the toxin-induced reduction of dopamine content and tyrosine hydroxylase-immunoreactive neurons in the striatum of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, it is still unknown how this nutrition affects the mitochondrial function. We demonstrated that oral administration of CoQ10 significantly attenuated the loss of dopaminergic nerve terminals induced by MPTP treatment. Furthermore, our experimental data indicate that an inhibition of mitochondrial cytochrome c release is one of the primary targets for CoQ10 and may lead to a potent neuroprotection.

  3. Learning Biomarker Models for Progression Estimation of Alzheimer’s Disease

    PubMed Central

    Ledig, Christian; Guerrero, Ricardo; Molina-Abril, Helena; Frangi, Alejandro; Rueckert, Daniel

    2016-01-01

    Being able to estimate a patient’s progress in the course of Alzheimer’s disease and predicting future progression based on a number of observed biomarker values is of great interest for patients, clinicians and researchers alike. In this work, an approach for disease progress estimation is presented. Based on a set of subjects that convert to a more severe disease stage during the study, models that describe typical trajectories of biomarker values in the course of disease are learned using quantile regression. A novel probabilistic method is then derived to estimate the current disease progress as well as the rate of progression of an individual by fitting acquired biomarkers to the models. A particular strength of the method is its ability to naturally handle missing data. This means, it is applicable even if individual biomarker measurements are missing for a subject without requiring a retraining of the model. The functionality of the presented method is demonstrated using synthetic and—employing cognitive scores and image-based biomarkers—real data from the ADNI study. Further, three possible applications for progress estimation are demonstrated to underline the versatility of the approach: classification, construction of a spatio-temporal disease progression atlas and prediction of future disease progression. PMID:27096739

  4. The mouse mutation muscle deficient (mdf) is characterized by a progressive motoneuron disease.

    PubMed

    Blot, S; Poirier, C; Dreyfus, P A

    1995-11-01

    Muscle deficient (mdf) is an autosomal-recessive mutation mapped to mouse chromosome 19. The clinical phenotype and the muscle histopathology, briefly described in 1980, and the nervous system histopathology are detailed in the present study. Homozygotes develop a posterior waddle at 4 to 8 weeks of age. Soon thereafter, the hindlimbs become paralyzed and weakness appears in forelimbs, leading to a serious disability. The disease progresses slowly and the mean lifespan is reduced to 8 months. Skeletal muscles exhibit a neurogenic atrophy with signs of reinnervation. Peripheral nerves display axonal degeneration. Neurons within the spinal cord ventral horn, and some motor nuclei of the brain stem, are affected by a cytoplasmic vacuolar degeneration. Ascending and descending spinal cord tracts appear normal. An astrogliosis, restricted to the ventral horn of the spinal cord, occurs in mdf/mdf mice of 10 weeks of age. These clinical and histological features are indicative of a progressive motor neuronopathy. Among the murine spinal muscular atrophies, the programmed cell death of the mdf motoneurons is morphologically similar to wobbler. Because of the long time course, the mdf mutation may represent a valuable tool for understanding juvenile motoneuron diseases with chronic evolution, even though the murine locus is not syntenic with the human ones.

  5. Evidence for Angiogenesis in Parkinson’s disease, Incidental Lewy Body disease, and Progressive Supranuclear Palsy

    PubMed Central

    Bradaric, Brinda Desai; Patel, Aditiben; Schneider, Julie A.; Carvey, Paul M.; Hendey, Bill

    2012-01-01

    Angiogenesis has not been extensively studied in Parkinson’s disease (PD) despite being associated with other neurodegenerative disorders. Post-mortem human brain tissues were obtained from subjects with pathologically confirmed Parkinson’s disease (PD) and progressive supranuclear palsy (PSP), a rapidly progressing Parkinsonian-like disorder. Tissues were also obtained from subjects with incidental Lewy body disease (iLBD) who had Lewy bodies in the substantia nigra pars compacta (SNpc) but had not been diagnosed with PD and age-matched controls without Lewy body pathology. The SNpc, putamen, locus ceruleus (LC) and midfrontal cortex were examined for integrin αvβ3, a marker for angiogenesis, along with vessel number and activated microglia. All parkinsonian syndromes had greater αvβ3 in the LC and the SNpc, while only PD and PSP subjects had elevated αvβ3 in the putamen compared to controls. PD and PSP subjects also had increases in microglia number and activation in the SNpc suggesting a link between inflammation and clinical disease. Microglia activation in iLBD subjects was limited to the LC, an area involved at an early stage of PD. Likewise, iLBD subjects did not differ from controls in αvβ3 staining in the putamen, a late area of involvement in PD. The presence of αvβ3 reactive vessels in PD and its syndromes is indicative of newly created vessels that have not likely developed the restrictive properties of the blood brain barrier. Such angiogenic vessels could contribute to neuroinflammation by failing to protect the parenchyma from peripheral immune cells and inflammatory or toxic factors in the peripheral circulation. PMID:21748523

  6. Prevention studies in Alzheimer's disease: progress towards the development of new therapeutics.

    PubMed

    Coley, Nicola; Gallini, Adeline; Andrieu, Sandrine

    2015-07-01

    Alzheimer's disease (AD) is the most common form of dementia and is a major cause of disability and dependency amongst older people. AD drugs approved so far are symptomatic treatments and are not thought to affect the underlying disease process. Trials conducted with agents aiming to slow or stop disease progression in patients with AD have all failed, perhaps because they were tested too late in the disease process. Therefore, there has been a move towards prevention of AD. This paper presents an overview of trials testing pharmacological interventions for sporadic AD prevention. Those tested to date were initially developed for the treatment of AD or for the treatment of other conditions, rather than being specifically developed for AD prevention. Associated issues, such as evidence of 'proof-of-concept,' doses and safety, are discussed. A major shift has taken place in the methodology of AD prevention trials since the results of the first trials were published in the 1990s. New directions that are currently being considered in ongoing or future prevention trials are discussed, in terms of endpoints, target populations, and study design. The use of AD-specific drugs to prevent AD in high-risk individuals is currently limited by a lack of validated predictive and surrogate markers. Population approaches, such as lifestyle changes, are an alternative strategy that could be of public health interest, but may provide only limited benefits for individuals. The best chance of preventing AD may come from a combination of individual and population prevention approaches.

  7. Water, sanitation and hygiene for accelerating and sustaining progress on neglected tropical diseases: a new Global Strategy 2015-20.

    PubMed

    Boisson, Sophie; Engels, Dirk; Gordon, Bruce A; Medlicott, Kate O; Neira, Maria P; Montresor, Antonio; Solomon, Anthony W; Velleman, Yael

    2016-03-01

    Neglected tropical diseases (NTDs) affect over 1 billion people. Safe water, sanitation and hygiene (WASH) contribute to prevention and management of most NTDs. Linking WASH and NTD interventions has potential to impact on multiple NTDs and can help secure sustainable and equitable progress towards universal access to WASH. The need to address the determinants of NTDs has been acknowledged. In response, WHO has published a new Global Strategy: 'Water, Sanitation and Hygiene for accelerating and sustaining progress on Neglected Tropical Diseases'. The Strategy focuses on cross-cutting actions that benefit disease control and care efforts, and strengthen health systems. Implementation of the strategy and the accompanying action plan can help ensure that the health and development agenda leaves no one behind.

  8. Total Kidney Volume in Autosomal Dominant Polycystic Kidney Disease: A Biomarker of Disease Progression and Therapeutic Efficacy.

    PubMed

    Alam, Ahsan; Dahl, Neera K; Lipschutz, Joshua H; Rossetti, Sandro; Smith, Patricia; Sapir, Daniel; Weinstein, Jordan; McFarlane, Philip; Bichet, Daniel G

    2015-10-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially life-threatening monogenic disorder in humans, characterized by progressive development and expansion of fluid-filled cysts in the kidneys and other organs. Ongoing cyst growth leads to progressive kidney enlargement, whereas kidney function remains stable for decades as a result of hyperfiltration and compensation by unaffected nephrons. Kidney function irreversibly declines only in the late stages of the disease, when most of the parenchyma is lost to cystic and fibrotic tissue and the remaining compensatory capacity is overwhelmed. Hence, conventional kidney function measures, such as glomerular filtration rate, do not adequately assess disease progression in ADPKD, especially in its early stages. Given the recent development of potential targeted therapies in ADPKD, it has become critically important to identify relevant biomarkers that can be used to determine the degree of disease progression and evaluate the effects of therapeutic interventions on the course of the disease. We review the current evidence to provide an informed perspective on whether total kidney volume (TKV) is a suitable biomarker for disease progression and whether TKV can be used as an efficacy end point in clinical trials. We conclude that because cystogenesis is the central factor leading to kidney enlargement, TKV appears to be an appropriate biomarker and is gaining wider acceptance. Several studies have identified TKV as a relevant imaging biomarker for monitoring and predicting disease progression and support its use as a prognostic end point in clinical trials.

  9. Increasing concentrations of phenol progressively affect anaerobic digestion of cellulose and associated microbial communities.

    PubMed

    Chapleur, Olivier; Madigou, Céline; Civade, Raphaël; Rodolphe, Yohan; Mazéas, Laurent; Bouchez, Théodore

    2016-02-01

    Performance stability is a key issue when managing anaerobic digesters. However it can be affected by external disturbances caused by micropollutants. In this study the influence of phenol on the methanization of cellulose was evaluated through batch toxicity assays. Special attention was given to the dynamics of microbial communities by means of automated ribosomal intergenic spacer analysis. We observed that, as phenol concentrations increased, the different steps of anaerobic cellulose digestion were unevenly and progressively affected, methanogenesis being the most sensitive: specific methanogenic activity was half-inhibited at 1.40 g/L of phenol, whereas hydrolysis of cellulose and its fermentation to VFA were observed at up to 2.00 g/L. Depending on the level of phenol, microbial communities resisted either through physiological or structural adaptation. Thus, performances at 0.50 g/L were maintained in spite of the microbial community's shift. However, the communities' ability to adapt was limited and performances decreased drastically beyond 2.00 g/L of phenol.

  10. Induced pluripotent stem cells (iPSCs) and neurological disease modeling: progress and promises

    PubMed Central

    Marchetto, Maria C.; Brennand, Kristen J.; Boyer, Leah F.; Gage, Fred H.

    2011-01-01

    The systematic generation of neurons from patients with neurological disorders can provide important insights into disease pathology, progression and mechanism. This review will discuss recent progress in modeling neurodegenerative and neurodevelopmental diseases using induced pluripotent stem cells (iPSCs) and highlight some of the current challenges in the field. Combined with other technologies previously used to study brain disease, iPSC modeling has the promise to influence modern medicine on several fronts: early diagnosis, drug development and effective treatment. PMID:21828073

  11. Autoimmune BSEP disease: disease recurrence after liver transplantation for progressive familial intrahepatic cholestasis.

    PubMed

    Kubitz, Ralf; Dröge, Carola; Kluge, Stefanie; Stross, Claudia; Walter, Nathalie; Keitel, Verena; Häussinger, Dieter; Stindt, Jan

    2015-06-01

    Severe cholestasis may result in end-stage liver disease with the need of liver transplantation (LTX). In children, about 10 % of LTX are necessary because of cholestatic liver diseases. Apart from bile duct atresia, three types of progressive familial intrahepatic cholestasis (PFIC) are common causes of severe cholestasis in children. The three subtypes of PFIC are defined by the involved genes: PFIC-1, PFIC-2, and PFIC-3 are due to mutations of P-type ATPase ATP8B1 (familial intrahepatic cholestasis 1, FIC1), the ATP binding cassette transporter ABCB11 (bile salt export pump, BSEP), or ABCB4 (multidrug resistance protein 3, MDR3), respectively. All transporters are localized in the canalicular membrane of hepatocytes and together mediate bile salt and phospholipid transport. In some patients with PFIC-2 disease, recurrence has been observed after LTX, which mimics a PFIC phenotype. It could be shown by several groups that inhibitory anti-BSEP antibodies emerge, which most likely cause disease recurrence. The prevalence of severe BSEP mutations (e.g., splice site and premature stop codon mutations) is very high in this group of patients. These mutations often result in the complete absence of BSEP, which likely accounts for an insufficient auto-tolerance against BSEP. Although many aspects of this "new" disease are not fully elucidated, the possibility of anti-BSEP antibody formation has implications for the pre- and posttransplant management of PFIC-2 patients. This review will summarize the current knowledge including diagnosis, pathomechanisms, and management of "autoimmune BSEP disease."

  12. The impact of impaired macrophage functions in cystic fibrosis disease progression.

    PubMed

    Lévêque, Manuella; Le Trionnaire, Sophie; Del Porto, Paola; Martin-Chouly, Corinne

    2016-11-14

    The underlying cause of morbidity in cystic fibrosis (CF) is the decline in lung function, which results in part from chronic inflammation. Inflammation and infection occur early in infancy in CF and the role of innate immune defense in CF has been highlighted in the last years. Once thought simply to be consumers of bacteria, macrophages have emerged as highly sensitive immune cells that are located at the balance point between inflammation and resolution of this inflammation in CF pathophysiology. In order to assess the potential role of macrophage in CF, we review the evidence that: (1) CF macrophage has a dysregulated inflammatory phenotype; (2) CF macrophage presents altered phagocytosis capacity and bacterial killing; and (3) lipid disorders in CF macrophage affect its function. These alterations of macrophage weaken innate defense of CF patients and may be involved in CF disease progression and lung damage.

  13. Butyrylcholinesterase K and apolipoprotein ε4 affect cortical thickness and neuropsychiatric symptoms in Alzheimer's disease.

    PubMed

    Yoo, Hye B; Lee, Hae W; Shin, Sue; Park, Sun-Won; Choi, Jung S; Jung, Hee Y; Cha, Jungho; Lee, Jong-Min; Lee, Jun-Young

    2014-02-01

    Two major genotypes are known to affect the development and progression of Alzheimer's disease (AD) and its response to cholinesterase inhibitors: the apolipoprotein E (ApoE) and butyrylcholinesterase genes (BChE). This study analyzed the effects of the BChE and ApoE genotypes on the cortical thickness of patients with AD and examined how these genotypes affect the neuropsychiatric symptoms of AD. AD-drug-naïve patients who met the probable AD criteria proposed by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association were recruited. Of 96 patients with AD, 65 were eligible for cortical thickness analysis. 3D T1-weighted images were acquired, and the cortical regions were segmented using the constrained Laplacian-based automated segmentation with proximities (CLASP) algorithm. Neuropsychiatric symptoms were measured by Neuropsychiatric Inventory (NPI) scores. BChE wild-type carriers (BChE-W) showed more thinning in the left dorsolateral prefrontal cortex, including the lateral premotor regions and anterior cingulate cortex, than did BChE-K variant carriers (BChE-K). ApoE-ε4 carriers had a thinner left medial prefrontal cortex, left superior frontal cortex, and left posterior cingulate cortex than did ApoE-ε4 non-carriers. Statistical analyses revealed that BChE-K carriers showed significantly less severe aberrant motor behavioral symptoms and that ε4 non-carriers showed less severe anxiety and indifference symptoms. The current findings show that, similar to ApoE-ε4 non-carriers, BChE-K carriers are protected from the pathological detriments of AD that affect frontal cortical thickness and neuropsychiatric symptoms. This study visually demonstrated the effects of the BChE-K and ApoE genotypes on the structural degeneration and complex aspects of the symptoms of AD.

  14. Microbial translocation, the innate cytokine response, and HIV-1 disease progression in Africa

    PubMed Central

    Redd, Andrew D.; Dabitao, Djeneba; Bream, Jay H.; Charvat, Blake; Laeyendecker, Oliver; Kiwanuka, Noah; Lutalo, Tom; Kigozi, Godfrey; Tobian, Aaron A. R.; Gamiel, Jordyn; Neal, Jessica D.; Oliver, Amy E.; Margolick, Joseph B.; Sewankambo, Nelson; Reynolds, Steven J.; Wawer, Maria J.; Serwadda, David; Gray, Ronald H.; Quinn, Thomas C.

    2009-01-01

    Reports from the United States have demonstrated that elevated markers of microbial translocation from the gut may be found in chronic and advanced HIV-1 infection and are associated with an increase in immune activation. However, this phenomenon's role in HIV-1 disease in Africa is unknown. This study examined the longitudinal relationship between microbial translocation and circulating inflammatory cytokine responses in a cohort of people with varying rates of HIV-1 disease progression in Rakai, Uganda. Multiple markers for microbial translocation (lipopolysaccharide, endotoxin antibody, and sCD14) did not change significantly during HIV-1 disease progression. Moreover, circulating immunoreactive cytokine levels either decreased or remained virtually unchanged throughout disease progression. These data suggest that microbial translocation and its subsequent inflammatory immune response do not have a causal relationship with HIV-1 disease progression in Africa. PMID:19357303

  15. Progressive lung disease in a malt-worker.

    PubMed Central

    Ellis, M E; Friend, J A

    1981-01-01

    We described a malt-worker whose initial symptoms suggested extrinsic allergic alveolitis. The ensuing cavitating lung disease, Aspergillus fumigatus infection with mycetomata, vigorous immune response, and granulomatous liver disease are unusual features. Images PMID:7031969

  16. A Lipidomic Readout of Disease Progression in A Diet-Induced Mouse Model of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Sanyal, Arun J.; Pacana, Tommy

    2015-01-01

    Multiple changes in lipid metabolism occur in nonalcoholic fatty liver disease. However, it is not known which of these contribute to disease progression. The objective of this study was to define changes in hepatic lipid composition over time in a diet-induced model of nonalcoholic fatty liver disease to identify changes associated with disease progression. A lipidomic approach was used to quantify individual lipid species with lipid classes of interest including diacylglycerols (DAG), cholesterol, phospholipids, plasmalogens, sphingolipids, and eicosanoids. C57b/S129J mice fed a high-fat, high-cholesterol diet developed fatty liver, inflammation, and ballooning by 16 weeks and extensive fibrosis by week 52. There was a marked increase in monounsaturated fatty acid containing DAGs and cholesterol esters by week 16 which decreased by week 52. The changes in DAG were associated with a 500- to 600-fold increase in phosphatidic acid (< 0.001) and its downstream product phosphatidylglycerol (P <0.01) whereas phosphatidylethanolamine, phosphatidylcholine, and phsophatidylserine all decreased. Disease progression was associated with a significant further decrease in phosphatidylcholine and phosphatidylethanolamine while several lysolecithin species increased. Disease progression was associated with a significant increase in the plasmalogen PC-P 16:0/16:1. Saturated fatty acid (16:0 and 18:0) containing ceramides, sphingosine, sphingosine-1-phosphate, dihydrosphingosine, and dihydrophingosine-1-phosphate increased by week 16 after high-fat high-cholesterol diet. Globotrioseacylceramide (GB3) also increased significantly by week 16 and increased further with disease progression. 12-hydroxyeicosatetranoic acid decreased at week 16 but increased with disease progression. In conclusion, multiple lipids were associated with disease progression and provide clues regarding lipid drivers of nonalcoholic steatohepatitis. PMID:26330688

  17. Infectious diseases affect marine fisheries and aquaculture economics

    USGS Publications Warehouse

    Lafferty, Kevin D.; Harvell, C. Drew; Conrad, Jon M.; Friedman, Carolyn S.; Kent, Michael L.; Kuris, Armand M.; Powell, Eric N.; Rondeau, Daniel; Saksida, Sonja M.

    2015-01-01

    Seafood is a growing part of the economy, but its economic value is diminished by marine diseases. Infectious diseases are common in the ocean, and here we tabulate 67 examples that can reduce commercial species' growth and survivorship or decrease seafood quality. These impacts seem most problematic in the stressful and crowded conditions of aquaculture, which increasingly dominates seafood production as wild fishery production plateaus. For instance, marine diseases of farmed oysters, shrimp, abalone, and various fishes, particularly Atlantic salmon, cost billions of dollars each year. In comparison, it is often difficult to accurately estimate disease impacts on wild populations, especially those of pelagic and subtidal species. Farmed species often receive infectious diseases from wild species and can, in turn, export infectious agents to wild species. However, the impact of disease export on wild fisheries is controversial because there are few quantitative data demonstrating that wild species near farms suffer more from infectious diseases than those in other areas. The movement of exotic infectious agents to new areas continues to be the greatest concern.

  18. Infectious Diseases Affect Marine Fisheries and Aquaculture Economics

    NASA Astrophysics Data System (ADS)

    Lafferty, Kevin D.; Harvell, C. Drew; Conrad, Jon M.; Friedman, Carolyn S.; Kent, Michael L.; Kuris, Armand M.; Powell, Eric N.; Rondeau, Daniel; Saksida, Sonja M.

    2015-01-01

    Seafood is a growing part of the economy, but its economic value is diminished by marine diseases. Infectious diseases are common in the ocean, and here we tabulate 67 examples that can reduce commercial species' growth and survivorship or decrease seafood quality. These impacts seem most problematic in the stressful and crowded conditions of aquaculture, which increasingly dominates seafood production as wild fishery production plateaus. For instance, marine diseases of farmed oysters, shrimp, abalone, and various fishes, particularly Atlantic salmon, cost billions of dollars each year. In comparison, it is often difficult to accurately estimate disease impacts on wild populations, especially those of pelagic and subtidal species. Farmed species often receive infectious diseases from wild species and can, in turn, export infectious agents to wild species. However, the impact of disease export on wild fisheries is controversial because there are few quantitative data demonstrating that wild species near farms suffer more from infectious diseases than those in other areas. The movement of exotic infectious agents to new areas continues to be the greatest concern.

  19. Infectious diseases affect marine fisheries and aquaculture economics.

    PubMed

    Lafferty, Kevin D; Harvell, C Drew; Conrad, Jon M; Friedman, Carolyn S; Kent, Michael L; Kuris, Armand M; Powell, Eric N; Rondeau, Daniel; Saksida, Sonja M

    2015-01-01

    Seafood is a growing part of the economy, but its economic value is diminished by marine diseases. Infectious diseases are common in the ocean, and here we tabulate 67 examples that can reduce commercial species' growth and survivorship or decrease seafood quality. These impacts seem most problematic in the stressful and crowded conditions of aquaculture, which increasingly dominates seafood production as wild fishery production plateaus. For instance, marine diseases of farmed oysters, shrimp, abalone, and various fishes, particularly Atlantic salmon, cost billions of dollars each year. In comparison, it is often difficult to accurately estimate disease impacts on wild populations, especially those of pelagic and subtidal species. Farmed species often receive infectious diseases from wild species and can, in turn, export infectious agents to wild species. However, the impact of disease export on wild fisheries is controversial because there are few quantitative data demonstrating that wild species near farms suffer more from infectious diseases than those in other areas. The movement of exotic infectious agents to new areas continues to be the greatest concern.

  20. FACTORS AFFECTING SUSCEPTIBILITY OF THE CORAL MONTASTRAEA FAVEOLATE TO BLACK-BAND DISEASE

    EPA Science Inventory

    Black-band disease affects many species of tropical reef-building corals, but it is unclear what factors contribute to the disease-susceptibility of individual corals or how the disease is transmitted between colonies. Studies have suggested that the ability of black-band disease...

  1. Exploration of Anaemia as a Progression Factor in African Americans with Cardiovascular Disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Despite the higher incidence of end stage renal disease (ESRD) among African Americans, whites in the United States population have a higher prevalence of chronic kidney disease. This may be due, in part, to a faster rate of progression to ESRD among African Americans with kidney disease. Anemia i...

  2. Progression of polyvascular disease--is there any rule?

    PubMed

    Despotovic, N; Erceg, P; Brajovic, M; Sekularac, N; Milosevic, D; Davidovic, M

    2008-01-01

    The polyvascular disease (PVD) is presented by coexistence of ischemic heart disease (IHD),carotid disease (CD) and peripheral arterial disease (PAD). In the essence of this disease is atherosclerosis. The aim of the research was to learn what is the course of the worsening multiple arterial diseases during the two-year period considering the new cardiac, cerebrovascular and peripheral vascular events. Among 150 patients with clinical manifestations of obliterate vascular disease of at least two aforementioned vascular diseases, we investigated the incidence of new coronary, carotid and peripheral vascular events during the two-year period. New coronary events were the most common in PVD patients with preexisted IHD (88 persons, 58.7%, p < 0.01), in PVD patients with preexisted CD (51 persons, 34.0%, p < 0.01) and in PVD patients with preexisted PAD (61 persons, 40.7%, p < 0.01) as well. The second most common event is the worsening of the preexisting dominating vascular disease. Thus, whatever the predominant vascular disease was, in the further two-year course of polyvascular disease, the new coronary events are the most frequent.

  3. Human immunodeficiency virus type 1 gp120 envelope characteristics associated with disease progression differ in family members infected with genetically similar viruses.

    PubMed

    Baan, Elly; van der Sluis, Renée M; Bakker, Margreet E; Bekker, Vincent; Pajkrt, Dasja; Jurriaans, Suzanne; Kuijpers, Taco W; Berkhout, Ben; Wolthers, Katja C; Paxton, William A; Pollakis, Georgios

    2013-01-01

    The human immunodeficiency virus type 1 (HIV-1) envelope protein provides the primary contact between the virus and host, and is the main target of the adaptive humoral immune response. The length of gp120 variable loops and the number of N-linked glycosylation events are key determinants for virus infectivity and immune escape, while the V3 loop overall positive charge is known to affect co-receptor tropism. We selected two families in which both parents and two children had been infected with HIV-1 for nearly 10 years, but who demonstrated variable parameters of disease progression. We analysed the gp120 envelope sequence and compared individuals that progressed to those that did not in order to decipher evolutionary alterations that are associated with disease progression when individuals are infected with genetically related virus strains. The analysis of the V3-positive charge demonstrated an association between higher V3-positive charges with disease progression. The ratio between the amino acid length and the number of potential N-linked glycosylation sites was also shown to be associated with disease progression with the healthier family members having a lower ratio. In conclusion in individuals initially infected with genetically linked virus strains the V3-positive charges and N-linked glycosylation are associated with HIV-1 disease progression and follow varied evolutionary paths for individuals with varied disease progression.

  4. Local ASIC3 modulates pain and disease progression in a rat model of osteoarthritis

    PubMed Central

    2012-01-01

    Background Recent data have suggested a relationship between acute arthritic pain and acid sensing ion channel 3 (ASIC3) on primary afferent fibers innervating joints. The purpose of this study was to clarify the role of ASIC3 in a rat model of osteoarthritis (OA) which is considered a degenerative rather than an inflammatory disease. Methods We induced OA via intra-articular mono-iodoacetate (MIA) injection, and evaluated pain-related behaviors including weight bearing measured with an incapacitance tester and paw withdrawal threshold in a von Frey hair test, histology of affected knee joint, and immunohistochemistry of knee joint afferents. We also assessed the effect of ASIC3 selective peptide blocker (APETx2) on pain behavior, disease progression, and ASIC3 expression in knee joint afferents. Results OA rats showed not only weight-bearing pain but also mechanical hyperalgesia outside the knee joint (secondary hyperalgesia). ASIC3 expression in knee joint afferents was significantly upregulated approximately twofold at Day 14. Continuous intra-articular injections of APETx2 inhibited weight distribution asymmetry and secondary hyperalgesia by attenuating ASIC3 upregulation in knee joint afferents. Histology of ipsilateral knee joint showed APETx2 worked chondroprotectively if administered in the early, but not late phase. Conclusions Local ASIC3 immunoreactive nerve is strongly associated with weight-bearing pain and secondary hyperalgesia in MIA-induced OA model. APETx2 inhibited ASIC3 upregulation in knee joint afferents regardless of the time-point of administration. Furthermore, early administration of APETx2 prevented cartilage damage. APETx2 is a novel, promising drug for OA by relieving pain and inhibiting disease progression. PMID:22909215

  5. Biology of chronic graft-vs-host disease: Immune mechanisms and progress in biomarker discovery

    PubMed Central

    Presland, Richard B

    2016-01-01

    Chronic graft-vs-host disease (cGVHD) is the leading cause of long-term morbidity and mortality following allogeneic hematopoietic stem cell transplantation. It presents as a chronic inflammatory and sclerotic autoimmune-like condition that most frequently affects the skin, oral mucosa, liver, eyes and gastrointestinal tract. Both clinical and animal studies have shown that multiple T cell subsets including Th1, Th2, Th17, T follicular helper cells and regulatory T-cells play some role in cGVHD development and progression; B cells also play an important role in the disease including the production of antibodies to HY and nuclear antigens that can cause serious tissue damage. An array of cytokines and chemokines produced by different types of immune cells also mediate tissue inflammation and damage of cGVHD target tissues such as the skin and oral cavity. Many of these same immune regulators have been studied as candidate cGVHD biomarkers. Recent studies suggest that some of these biomarkers may be useful for determining disease prognosis and planning long-term clinical follow-up of cGVHD patients. PMID:28058210

  6. Chronic follicular bronchiolitis requires antigen-specific regulatory T cell control to prevent fatal disease progression

    PubMed Central

    Schmitt, Erica G.; Haribhai, Dipica; Jeschke, Jonathan C.; Co, Dominic O.; Ziegelbauer, Jennifer; Yan, Ke; Iwakura, Yoichiro; Mishra, Manoj K.; Simpson, Pippa; Salzman, Nita H.; Williams, Calvin B.

    2014-01-01

    In order to study regulatory T (Treg) cell control of chronic autoimmunity in a lymphoreplete host, we created and characterized a new model of autoimmune lung inflammation that targets the medium and small airways. We generated transgenic mice that express a chimeric membrane protein consisting of hen egg lysozyme (mHEL) and a hemoglobin (Hb) epitope tag under the control of the Clara cell secretory protein (CCSP) promoter, which largely limited transgene expression to the respiratory bronchioles. When CCSP-mHEL/Hb transgenic mice were crossed to N3.L2 TCR transgenic mice that recognize the Hb epitope, the bigenic progeny developed dense, pseudo-follicular lymphocytic peribronchiolar infiltrates that resembled the histological pattern of follicular bronchiolitis. Aggregates of activated IFN-γ- and IL-17A-secreting CD4+ T cells as well as B cells surrounded the airways. Lung pathology was similar in Ifng−/− and Il17a−/− mice, indicating that either cytokine is sufficient to establish chronic disease. A large number of antigen-specific Treg cells accumulated in the lesions and Treg cell-depletion in the affected mice led to an interstitial spread of the disease that ultimately proved fatal. Thus Treg cells act to restrain autoimmune responses, resulting in an organized and controlled chronic pathological process rather than a progressive disease. PMID:24163409

  7. Fibroblast cell interactions with human melanoma cells affect tumor cell growth as a function of tumor progression.

    PubMed Central

    Cornil, I; Theodorescu, D; Man, S; Herlyn, M; Jambrosic, J; Kerbel, R S

    1991-01-01

    It is known from a variety of experimental systems that the ability of tumor cells to grow locally and metastasize can be affected by the presence of adjacent normal tissues and cells, particularly mesenchymally derived stromal cells such as fibroblasts. However, the comparative influence of such normal cell-tumor cell interactions on tumor behavior has not been thoroughly investigated from the perspective of different stages of tumor progression. To address this question we assessed the influence of normal dermal fibroblasts on the growth of human melanoma cells obtained from different stages of tumor progression. We found that the in vitro growth of most (4 out of 5) melanoma cell lines derived from early-stage radial growth phase or vertical growth phase metastatically incompetent primary lesions is repressed by coculture with normal dermal fibroblasts, suggesting that negative homeostatic growth controls are still operative on melanoma cells from early stages of disease. On the other hand, 9 out of 11 melanoma cell lines derived from advanced metastatically competent vertical growth phase primary lesions, or from distant metastases, were found to be consistently stimulated to grow in the presence of dermal fibroblasts. Evidence was obtained to show that this discriminatory fibroblastic influence is mediated by soluble inhibitory and stimulatory growth factor(s). Taken together, these results indicate that fibroblast-derived signals can have antithetical growth effects on metastatic versus metastatically incompetent tumor subpopulations. This resultant conversion in responsiveness to host tissue environmental factors may confer upon small numbers of metastatically competent cells a growth advantage, allowing them to escape local growth constraints both in the primary tumor site and at distant ectopic tissue sites. PMID:2068080

  8. Impaired suppressor activity in children affected by coeliac disease.

    PubMed Central

    Pignata, C; Troncone, R; Monaco, G; Ciriaco, M; Farris, E; Carminati, G; Auricchio, S

    1985-01-01

    Immunoregulatory cells were enumerated in 19 coeliac disease children on a gluten free diet by means of monoclonal antibodies that define total T lymphocytes (T3), helper/inducer T cells (T4), suppressor/cytotoxic T cells (T8) and monocytes (M1), as well as by means of surface receptors for Fc fragments of IgM and IgG (T mu and T gamma, respectively). In addition, suppressor cell function was assessed in 17 coeliac disease patients by examining the ability of concanavalin-A (Con-A)-activated suppressor cells to inhibit autologous cell response to mitogenic stimulus as compared with age-matched controls. No statistically significant differences were found in the percentages of subsets defined by monoclonal antibodies between coeliac disease patients and age-matched controls, whereas coeliac disease patients had a significant decrease of the subpopulation bearing membrane receptor for Fc fragment of IgG. Mean value was 8.5% in coeliac patients versus 13.4% in age-matched controls. In the functional assay, mononuclear cells from 10 out of 17 coeliac disease patients either totally or partially failed to suppress responder cells after Con-A-activation. This defect is not related to HLA-DR status, because no difference was found between patients-HLA-matched and unmatched normal individuals. In this assay, mononuclear cells of three coeliac disease patients with low suppressor activity were able to inhibit responder cells to the same extent as controls, when indomethacin was used to block prostaglandin production in the induction phase of Con-A-activated suppressor cells. Our results suggest that an abnormality in immunoregulation may play a role in the pathogenesis of coeliac disease. PMID:3156076

  9. Periodontal disease's contribution to Alzheimer's disease progression in Down syndrome.

    PubMed

    Kamer, Angela R; Fortea, Juan O; Videla, Sebastià; Mayoral, Angela; Janal, Malvin; Carmona-Iragui, Maria; Benejam, Bessy; Craig, Ronald G; Saxena, Deepak; Corby, Patricia; Glodzik, Lidia; Annam, Kumar Raghava Chowdary; Robbins, Miriam; de Leon, Mony J

    2016-01-01

    People with Down syndrome (DS) are at an increased risk for Alzheimer's disease (AD). After 60 years of age, >50% of DS subjects acquire dementia. Nevertheless, the age of onset is highly variable possibly because of both genetic and environmental factors. Genetics cannot be modified, but environmental risk factors present a potentially relevant intervention for DS persons at risk for AD. Among them, inflammation, important in AD of DS type, is potential target. Consistent with this hypothesis, chronic peripheral inflammation and infections may contribute to AD pathogenesis in DS. People with DS have an aggressive form of periodontitis characterized by rapid progression, significant bacterial and inflammatory burden, and an onset as early as 6 years of age. This review offers a hypothetical mechanistic link between periodontitis and AD in the DS population. Because periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD.

  10. Different decision deficits impair response inhibition in progressive supranuclear palsy and Parkinson’s disease

    PubMed Central

    Rittman, Timothy; Nombela, Cristina; Fois, Alessandro; Coyle-Gilchrist, Ian; Barker, Roger A.; Hughes, Laura E.; Rowe, James B.

    2016-01-01

    Progressive supranuclear palsy and Parkinson’s disease have distinct underlying neuropathology, but both diseases affect cognitive function in addition to causing a movement disorder. They impair response inhibition and may lead to impulsivity, which can occur even in the presence of profound akinesia and rigidity. The current study examined the mechanisms of cognitive impairments underlying disinhibition, using horizontal saccadic latencies that obviate the impact of limb slowness on executing response decisions. Nineteen patients with clinically diagnosed progressive supranuclear palsy (Richardson’s syndrome), 24 patients with clinically diagnosed Parkinson’s disease and 26 healthy control subjects completed a saccadic Go/No-Go task with a head-mounted infrared saccadometer. Participants were cued on each trial to make a pro-saccade to a horizontal target or withhold their responses. Both patient groups had impaired behavioural performance, with more commission errors than controls. Mean saccadic latencies were similar between all three groups. We analysed behavioural responses as a binary decision between Go and No-Go choices. By using Bayesian parameter estimation, we fitted a hierarchical drift–diffusion model to individual participants’ single trial data. The model decomposes saccadic latencies into parameters for the decision process: decision boundary, drift rate of accumulation, decision bias, and non-decision time. In a leave-one-out three-way classification analysis, the model parameters provided better discrimination between patients and controls than raw behavioural measures. Furthermore, the model revealed disease-specific deficits in the Go/No-Go decision process. Both patient groups had slower drift rate of accumulation, and shorter non-decision time than controls. But patients with progressive supranuclear palsy were strongly biased towards a pro-saccade decision boundary compared to Parkinson’s patients and controls. This indicates a

  11. Different decision deficits impair response inhibition in progressive supranuclear palsy and Parkinson's disease.

    PubMed

    Zhang, Jiaxiang; Rittman, Timothy; Nombela, Cristina; Fois, Alessandro; Coyle-Gilchrist, Ian; Barker, Roger A; Hughes, Laura E; Rowe, James B

    2016-01-01

    Progressive supranuclear palsy and Parkinson's disease have distinct underlying neuropathology, but both diseases affect cognitive function in addition to causing a movement disorder. They impair response inhibition and may lead to impulsivity, which can occur even in the presence of profound akinesia and rigidity. The current study examined the mechanisms of cognitive impairments underlying disinhibition, using horizontal saccadic latencies that obviate the impact of limb slowness on executing response decisions. Nineteen patients with clinically diagnosed progressive supranuclear palsy (Richardson's syndrome), 24 patients with clinically diagnosed Parkinson's disease and 26 healthy control subjects completed a saccadic Go/No-Go task with a head-mounted infrared saccadometer. Participants were cued on each trial to make a pro-saccade to a horizontal target or withhold their responses. Both patient groups had impaired behavioural performance, with more commission errors than controls. Mean saccadic latencies were similar between all three groups. We analysed behavioural responses as a binary decision between Go and No-Go choices. By using Bayesian parameter estimation, we fitted a hierarchical drift-diffusion model to individual participants' single trial data. The model decomposes saccadic latencies into parameters for the decision process: decision boundary, drift rate of accumulation, decision bias, and non-decision time. In a leave-one-out three-way classification analysis, the model parameters provided better discrimination between patients and controls than raw behavioural measures. Furthermore, the model revealed disease-specific deficits in the Go/No-Go decision process. Both patient groups had slower drift rate of accumulation, and shorter non-decision time than controls. But patients with progressive supranuclear palsy were strongly biased towards a pro-saccade decision boundary compared to Parkinson's patients and controls. This indicates a prepotency of

  12. Oral muscles are progressively affected in Duchenne muscular dystrophy: implications for dysphagia treatment.

    PubMed

    van den Engel-Hoek, Lenie; Erasmus, Corrie E; Hendriks, Jan C M; Geurts, Alexander C H; Klein, Willemijn M; Pillen, Sigrid; Sie, Lilian T; de Swart, Bert J M; de Groot, Imelda J M

    2013-05-01

    Dysphagia is reported in advanced stages of Duchenne muscular dystrophy (DMD). The population of DMD is changing due to an increasing survival. We aimed to describe the dysphagia in consecutive stages and to assess the underlying mechanisms of dysphagia in DMD, in order to develop mechanism based recommendations for safe swallowing. In this cross-sectional study, participants were divided into: early and late ambulatory stage (AS, n = 6), early non-ambulatory stage (ENAS, n = 7), and late non-ambulatory stage (LNAS, n = 11). Quantitative oral muscle ultrasound was performed to quantify echo intensity. Swallowing was assessed with a video fluoroscopic swallow study, surface electromyography (sEMG) of the submental muscle group and tongue pressure. Differences in outcome parameters among the three DMD stages were tested with analysis of variance. Oral muscles related to swallowing were progressively affected, starting in the AS with the geniohyoid muscle. Tongue (pseudo) hypertrophy was found in 70 % of patients in the ENAS and LNAS. Oral phase problems and post-swallow residue were observed, mostly in the LNAS with solid food. sEMG and tongue pressure data of swallowing solid food revealed the lowest sEMG amplitude, the longest duration and lowest tongue pressure in the LNAS. In case of swallowing problems in DMD, based on the disturbed mechanisms of swallowing, it is suggested to (1) adjust meals in terms of less solid food, and (2) drink water after meals to clear the oropharyngeal area.

  13. CSF biomarkers associated with disease heterogeneity in early Parkinson's disease: the Parkinson's Progression Markers Initiative study.

    PubMed

    Kang, Ju-Hee; Mollenhauer, Brit; Coffey, Christopher S; Toledo, Jon B; Weintraub, Daniel; Galasko, Douglas R; Irwin, David J; Van Deerlin, Vivianna; Chen-Plotkin, Alice S; Caspell-Garcia, Chelsea; Waligórska, Teresa; Taylor, Peggy; Shah, Nirali; Pan, Sarah; Zero, Pawel; Frasier, Mark; Marek, Kenneth; Kieburtz, Karl; Jennings, Danna; Tanner, Caroline M; Simuni, Tanya; Singleton, Andrew; Toga, Arthur W; Chowdhury, Sohini; Trojanowski, John Q; Shaw, Leslie M

    2016-06-01

    The development of biomarkers to predict the progression of Parkinson's disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson's Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (α-syn), amyloid-beta1-42 (Aβ1-42), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF α-syn, t-tau and p-tau levels, but not Aβ1-42, were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of α-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest Aβ1-42, or highest t-tau/Aβ1-42 and t-tau/α-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower α-syn was significantly associated with worse cognitive test performance. APOE ε4 genotype was associated with lower levels of Aβ1-42, but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance.

  14. In vivo parahippocampal white matter pathology as a biomarker of disease progression to Alzheimer's disease.

    PubMed

    Solodkin, Ana; Chen, E Elinor; Van Hoesen, Gary W; Heimer, Lennart; Shereen, Ahmed; Kruggel, Frithjof; Mastrianni, James

    2013-12-15

    Noninvasive diagnostic tests for Alzheimer's disease (AD) are limited. Postmortem diagnosis is based on density and distribution of neurofibrillary tangles (NFTs) and amyloid-rich neuritic plaques. In preclinical stages of AD, the cells of origin for the perforant pathway within the entorhinal cortex are among the first to display NFTs, indicating its compromise in early stages of AD. We used diffusion tensor imaging (DTI) to assess the integrity of the parahippocampal white matter in mild cognitive impairment (MCI) and AD, as a first step in developing a noninvasive tool for early diagnosis. Subjects with AD (N = 9), MCI (N = 8), or no cognitive impairment (NCI; N = 20) underwent DTI-MRI. Fractional anisotropy (FA) and mean (MD) and radial (RD) diffusivity measured from the parahippocampal white matter in AD and NCI subjects differed greatly. Discriminant analysis in the MCI cases assigned statistical membership of 38% of MCI subjects to the AD group. Preliminary data 1 year later showed that all MCI cases assigned to the AD group either met the diagnostic criteria for probable AD or showed significant cognitive decline. Voxelwise analysis in the parahippocampal white matter revealed a progressive change in the DTI patterns in MCI and AD subjects: whereas converted MCI cases showed structural changes restricted to the anterior portions of this region, in AD the pathology was generalized along the entire anterior-posterior axis. The use of DTI for in vivo assessment of the parahippocampal white matter may be useful for identifying individuals with MCI at highest risk for conversion to AD and for assessing disease progression.

  15. How urbanization affects the epidemiology of emerging infectious diseases

    PubMed Central

    Neiderud, Carl-Johan

    2015-01-01

    The world is becoming more urban every day, and the process has been ongoing since the industrial revolution in the 18th century. The United Nations now estimates that 3.9 billion people live in urban centres. The rapid influx of residents is however not universal and the developed countries are already urban, but the big rise in urban population in the next 30 years is expected to be in Asia and Africa. Urbanization leads to many challenges for global health and the epidemiology of infectious diseases. New megacities can be incubators for new epidemics, and zoonotic diseases can spread in a more rapid manner and become worldwide threats. Adequate city planning and surveillance can be powerful tools to improve the global health and decrease the burden of communicable diseases. PMID:26112265

  16. Bile Acids in Polycystic Liver Diseases: Triggers of Disease Progression and Potential Solution for Treatment.

    PubMed

    Perugorria, Maria J; Labiano, Ibone; Esparza-Baquer, Aitor; Marzioni, Marco; Marin, Jose J G; Bujanda, Luis; Banales, Jesús M

    2017-01-01

    Polycystic liver diseases (PLDs) are a group of genetic hereditary cholangiopathies characterized by the development and progressive growth of cysts in the liver, which are the main cause of morbidity. Current therapies are based on surgical procedures and pharmacological strategies, which show short-term and modest beneficial effects. Therefore, the determination of the molecular mechanisms of pathogenesis appears to be crucial in order to find new potential targets for pharmacological therapy. Ductal plate malformation during embryogenesis and abnormal cystic cholangiocyte growth and secretion are some of the key mechanisms involved in the pathogenesis of PLDs. However, the discovery of the presence of bile acids in the fluid collected from human cysts and the intrahepatic accumulation of cytotoxic bile acids in an animal model of PLD (i.e. polycystic kidney (PCK) rat) suggest a potential role of impaired bile acid homeostasis in the pathogenesis of these diseases. On the other hand, ursodeoxycholic acid (UDCA) has emerged as a new potential therapeutic tool for PLDs by promoting the inhibition of cystic cholangiocyte growth in both PCK rats and highly symptomatic patients with autosomal dominant polycystic kidney disease (ADPKD: most common type of PLD), and improving symptoms. Chronic treatment with UDCA normalizes the decreased intracellular calcium levels in ADPKD human cholangiocytes in vitro, which results in the reduction of their baseline-stimulated proliferation. Moreover, UDCA decreases the liver concentration of cytotoxic bile acids in PCK rats and the bile acid-dependent enhanced proliferation of cystic cholangiocytes. Here, the role of bile acids in the pathogenesis of PLDs and the potential therapeutic value of UDCA for the treatment of these diseases are reviewed and future lines of investigation in this field are proposed.

  17. Postmortem Pittsburgh Compound B (PiB) binding increases with Alzheimer's disease progression.

    PubMed

    Beckett, Tina L; Webb, Robin L; Niedowicz, Dana M; Holler, Christopher J; Matveev, Sergey; Baig, Irfan; LeVine, Harry; Keller, Jeffrey N; Murphy, M Paul

    2012-01-01

    The development of imaging reagents is of considerable interest in the Alzheimer's disease (AD) field. Some of these, such as Pittsburgh Compound B (PiB), were designed to bind to the amyloid-β peptide (Aβ), the major component of amyloid deposits in the AD brain. Although these agents were designed for imaging amyloid deposits in vivo, a major avenue of evaluation relies on postmortem cross validation with established indices of AD pathology. In this study, we evaluated changes in the postmortem binding of PiB and its relationship to other aspects of Aβ-related pathology in a series of AD cases and age-matched controls. We also examined cases of preclinical AD (PCAD) and amnestic mild cognitive impairment (MCI), both considered early points in the AD continuum. PiB binding was found to increase with the progression of the disease and paralleled increases in the less soluble forms of Aβ, including SDS-stable Aβ oligomers. Increased PiB binding and its relationship to Aβ was only significant in a brain region vulnerable to the development of AD pathology (the superior and middle temporal gyri) but not in an unaffected region (cerebellum). This implies that the amyloid deposited in disease-affected regions may possess fundamental, brain region specific characteristics that may not as yet be fully appreciated. These data support the idea that PiB is a useful diagnostic tool for AD, particularly in the early stage of the disease, and also show that PiB could be a useful agent for the discovery of novel disease-related properties of amyloid.

  18. A Computational Neurodegenerative Disease Progression Score: Method and Results with the Alzheimer’s Disease Neuroimaging Initiative Cohort

    PubMed Central

    Jedynak, Bruno M.; Lang, Andrew; Liu, Bo; Katz, Elyse; Zhang, Yanwei; Wyman, Bradley T.; Raunig, David; Jedynak, C. Pierre; Caffo, Brian; Prince, Jerry L.

    2012-01-01

    While neurodegenerative diseases are characterized by steady degeneration over relatively long timelines, it is widely believed that the early stages are the most promising for therapeutic intervention, before irreversible neuronal loss occurs. Developing a therapeutic response requires a precise measure of disease progression. However, since the early stages are for the most part asymptomatic, obtaining accurate measures of disease progression is difficult. Longitudinal databases of hundreds of subjects observed during several years with tens of validated biomarkers are becoming available, allowing the use of computational methods. We propose a widely applicable statistical methodology for creating a disease progression score (DPS), using multiple biomarkers, for subjects with a neurodegenerative disease. The proposed methodology was evaluated for Alzheimer’s disease (AD) using the publicly available AD Neuroimaging Initiative (ADNI) database, yielding an Alzheimer’s DPS or ADPS score for each subject and each time-point in the database. In addition, a common description of biomarker changes was produced allowing for an ordering of the biomarkers. The Rey Auditory Verbal Learning Test delayed recall was found to be the earliest biomarker to become abnormal. The group of biomarkers comprising the volume of the hippocampus and the protein concentration amyloid beta and Tau were next in the timeline, and these were followed by three cognitive biomarkers. The proposed methodology thus has potential to stage individuals according to their state of disease progression relative to a population and to deduce common behaviors of biomarkers in the disease itself. PMID:22885136

  19. CDC Periodontal Disease Surveillance Project: background, objectives, and progress report.

    PubMed

    Eke, Paul I; Genco, Robert J

    2007-07-01

    This supplement contains papers presented at the 2006 International Association of Dental Research (IADR) symposium entitled "Development of Self-Reported Measures for Population-Based Surveillance of Periodontitis." These papers highlight activities of an independent periodontal disease surveillance workgroup convened by the Division of Oral Health (DOH), Centers for Disease Control and Prevention (CDC), in collaboration with the American Academy of Periodontology, to examine the feasibility of using self-reported measures for population-based surveillance of periodontal disease in the United States. This workgroup was convened in 2003 as part of a CDC periodontal disease surveillance project.

  20. Disease progresses more quickly in introverts. Shy, inhibited personalities may fare worse.

    PubMed

    2004-03-01

    Los Angeles researchers recently have discovered clinical evidence that HIV-positive people with shy and introverted personalities tend to have a faster disease progression and less optimal outcomes under antiretroviral treatment than do people with extroverted personalities.

  1. Weight preserving image registration for monitoring disease progression in lung CT.

    PubMed

    Gorbunova, Vladlena; Lol, Pechin; Ashraf, Haseem; Dirksen, Asger; Nielsen, Mads; de Bruijne, Marleen

    2008-01-01

    We present a new image registration based method for monitoring regional disease progression in longitudinal image studies of lung disease. A free-form image registration technique is used to match a baseline 3D CT lung scan onto a following scan. Areas with lower intensity in the following scan compared with intensities in the deformed baseline image indicate local loss of lung tissue that is associated with progression of emphysema. To account for differences in lung intensity owing to differences in the inspiration level in the two scans rather than disease progression, we propose to adjust the density of lung tissue with respect to local expansion or compression such that the total weight of the lungs is preserved during deformation. Our method provides a good estimation of regional destruction of lung tissue for subjects with a significant difference in inspiration level between CT scans and may result in a more sensitive measure of disease progression than standard quantitative CT measures.

  2. Association between IgG4-related disease and progressively transformed germinal centers of lymph nodes.

    PubMed

    Sato, Yasuharu; Inoue, Dai; Asano, Naoko; Takata, Katsuyoshi; Asaoku, Hideki; Maeda, Yoshinobu; Morito, Toshiaki; Okumura, Hirokazu; Ishizawa, Shin; Matsui, Shoko; Miyazono, Takayoshi; Takeuchi, Tamotsu; Kuroda, Naoto; Orita, Yorihisa; Takagawa, Kiyoshi; Kojima, Masaru; Yoshino, Tadashi

    2012-07-01

    Progressively transformed germinal centers is a benign condition of unknown pathogenesis characterized by a distinctive variant form of reactive follicular hyperplasia in lymph nodes. We recently reported Ig G4-related disease in progressively transformed germinal centers. However, no large case series has been reported and clinicopathologic findings remain unclear. Here, we report 40 Japanese patients (28 men, 12 women; median age, 56 years) with progressively transformed germinal centers of the lymph nodes who fulfilled the histological diagnostic criteria for IgG4-related disease (IgG4(+) progressively transformed germinal centers), with asymptomatic localized lymphadenopathy involving the submandibular nodes in 24, submandibular and cervical nodes in 14, cervical nodes only in 1, and cervical and supraclavicular nodes in 1. In all, 16 (52%) of 31 examined patients had allergic disease. Histologically, the lymph nodes demonstrated uniform histological findings, namely marked follicular hyperplasia with progressively transformed germinal centers, and localization of the majority of IgG4(+) plasma cells in the germinal centers. Serum IgG4, serum IgE and peripheral blood eosinophils were elevated in 87%, 92% and 53% of examined patients, respectively. Eighteen patients subsequently developed extranodal lesions (including five who developed systemic disease), which on histological examination were consistent with IgG4-related disease. IgG4(+) progressively transformed germinal centers presents with uniform clinicopathological features of asymptomatic localized submandibular lymphadenopathy, which persists and/or relapses, and sometimes progresses to extranodal lesions or systemic disease. Nine patients were administered steroid therapy when the lesions progressed, to which all responded well. We suggest that IgG4(+) progressively transformed germinal centers should be included in the IgG4-related disease spectrum.

  3. Concomitant gastroparesis negatively affects children with functional gallbladder disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The aim of the present study was to determine whether concomitant gastroparesis and biliary dyskinesia (BD) occur in children, and if so, to determine whether concomitant gastroparesis affects clinical outcome in children with BD. We conducted a retrospective chart review of children with BD (ejecti...

  4. 16th International Pathogenic Neisseria Conference: recent progress towards effective meningococcal disease vaccines.

    PubMed

    Gorringe, Andrew R; van Alphen, Loek

    2009-02-01

    The report describes developments in meningococcal disease vaccines presented at the 16th International Pathogenic Neisseria Conference, Rotterdam, 7-12 September 2008. Great progress has been made by the Meningitis Vaccine Project to provide an affordable and effective serogroup A conjugate vaccine for use in the meningitis belt of Sub-Saharan Africa. The vaccine has been shown to be safe and to produce excellent immune response in phase 2 clinical trials in India and Africa in the target populations and will be rolled out to the worst affected countries from 2009. This vaccine has the potential to make a huge impact on public health in this region. This conference heard that the use of an epidemic strain-specific outer membrane vesicle (OMV) vaccine in New Zealand has been discontinued. Views for and against this decision were presented. Several MenB vaccines have progressed to clinical evaluation. The most advanced are the Novartis five recombinant protein variants and the Wyeth vaccine based on two factor H binding protein variants. Promising results from both vaccines with genetically-detoxified lipooligosaccharide and overexpressed heterologous antigens, OMV's from Neisseria lactamica and recombinant Opa proteins.

  5. Factors Affecting the Efficacy of Recombinant Marek's Disease Vaccine Protection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Many factors have the potential to influence the efficacy of Marek's disease (MD) vaccination. Some of these factors include maternal antibody, vaccine dose, age of birds at vaccination or challenge, challenge virus strain and genetic background of chickens. The objective of this study was to evalua...

  6. Early Huntington's Disease Affects Movements in Transformed Sensorimotor Mappings

    ERIC Educational Resources Information Center

    Boulet, C.; Lemay, M.; Bedard, M.A.; Chouinard, M.J.; Chouinard, S.; Richer, F.

    2005-01-01

    This study examined the effect of transformed visual feedback on movement control in Huntington's disease (HD). Patients in the early stages of HD and controls performed aiming movements towards peripheral targets on a digitizing tablet and emphasizing precision. In a baseline condition, HD patients were slower but showed few precision problems in…

  7. Semantic Trouble Sources and Their Repair in Conversations Affected by Parkinson's Disease

    ERIC Educational Resources Information Center

    Saldert, Charlotta; Ferm, Ulrika; Bloch, Steven

    2014-01-01

    Background: It is known that dysarthria arising from Parkinson's disease may affect intelligibility in conversational interaction. Research has also shown that Parkinson's disease may affect cognition and cause word-retrieval difficulties and pragmatic problems in the use of language. However, it is not known whether or how these…

  8. Dietary modulation of the microbiome affects autoinflammatory disease

    PubMed Central

    Lukens, John R.; Gurung, Prajwal; Vogel, Peter; Johnson, Gordon R.; Carter, Robert A.; McGoldrick, Daniel J.; Bandi, Srinivasa R.A.O.; Calabrese, Christopher R.; Walle, Lieselotte Vande; Lamkanfi, Mohamed; Kanneganti, Thirumala-Devi

    2014-01-01

    The incidences of chronic inflammatory disorders have increased significantly over the past three decades1. Recent shifts in dietary consumption are believed to have contributed importantly to this surge, but how dietary consumption modulates inflammatory disease is poorly defined. Pstpip2cmo mice that express a homozygous L98P missense mutation in the Pombe Cdc15 homology (PCH) family proline-serine-threonine phosphatase interacting protein 2 (PSTPIP2) phosphatase spontaneously develop osteomyelitis that resembles chronic recurrent multifocal osteomyelitis (CRMO) in humans2-4. Recent reports demonstrated osteomyelitis to critically rely on IL-1β, but deletion of the inflammasome components caspase-1 and NLRP3 failed to rescue Pstpip2cmo mice from inflammatory bone disease5,6. Thus, the upstream mechanisms controlling IL-1β production in Pstpip2cmo mice remain to be identified. In addition, the environmental factors driving IL-1β-dependent inflammatory bone erosion are unknown. Here, we show that the intestinal microbiota of diseased Pstpip2cmo mice was characterized by an outgrowth of Prevotella. Notably, Pstpip2cmo mice that were fed a diet rich in fat and cholesterol maintained a normal body weight, but were markedly protected against inflammatory bone disease and bone erosion. Diet-induced protection against osteomyelitis was accompanied by marked reductions in intestinal Prevotella levels and significantly reduced proIL-1β expression in distant neutrophils. Furthermore, proIL-1β expression was also decreased in antibiotics-treated Pstpip2cmo mice, and in wildtype mice that were kept under germfree conditions. We further demonstrated that combined deletion of caspases 1 and 8 was required for protection against IL-1β-dependent inflammatory bone disease, whereas deletion of each caspase alone, elastase or neutrophil proteinase-3 failed to prevent inflammatory disease. Collectively, this work reveals diet-associated changes in the intestinal microbiome as a

  9. Assessment of definitions of sustained disease progression in relapsing-remitting multiple sclerosis.

    PubMed

    Healy, Brian C; Engler, David; Glanz, Bonnie; Musallam, Alexander; Chitnis, Tanuja

    2013-01-01

    Sustained progression on the expanded disability status scale (EDSS) is a common outcome measure of disease progression in clinical studies of MS. Unfortunately, this outcome may not accurately measure long-term and irreversible disease progression. To assess the performance of definitions of sustained progression, patients with relapsing-remitting MS (RRMS) or a clinically isolated syndrome with evidence of lesions on a brain MRI were included in our study. Fifteen definitions of sustained progression using both the EDSS and the functional system (FS) scales were investigated. The impact of both relapses and changes in provider on the probability of maintaining progression was also evaluated. Although the provider scoring the EDSS sometimes changed during followup, the provider had access to previous EDSS scores. Between 15.8% and 42.2% of patients experienced sustained progression based on the definitions using EDSS as the outcome, but nearly 50% of these patients failed to maintain sustained progression for the duration of followup. When FS scales were used, progression was most common on the pyramidal and sensory scales. Unfortunately, progression on specific FS scales failed to be more sensitive to irreversible disability. Relapses or changes in provider did not explain the poor performance of the measures. Short-term changes in the EDSS or FS scores may not be an accurate marker of irreversible change in RRMS.

  10. Issues affecting minority participation in research studies of Alzheimer disease.

    PubMed

    Welsh, Kathleen A; Ballard, Edna; Nash, Florence; Raiford, Kate; Harrell, Lindy

    1994-01-01

    Despite the need for minority subjects in research studies of Alzheimer disease (AD), the successful involvement of minority patients in such studies has been difficult. This report discusses the many societal, economic, logistical, and attitudinal barriers that have inhibited the participation of minority patients and their families in medical research programs of AD. Special consideration is given to the unique cultural issues that arise when conducting studies involving African-American elderly subjects. Methods are considered for overcoming the barriers to participation gleaned from the national study CERAD (Consortium to Establish a Registry of Alzheimer Disease) and other investigations of AD. Recommendations are made for future research programs targeted on the specific health care needs and concerns of the minority segments of our population.

  11. Major viral diseases affecting fish aquaculture in Spain.

    PubMed

    Pérez, S I; Rodríguez, S

    1997-06-01

    The number of viruses isolated from fish has grown in the last few years as a reflection of the increasing interest in fish diseases, particularly those occurring in aquaculture facilities. Of all the described viruses, only a few are considered to be of serious concern and economic importance; they are described in this review, drawing special attention to the four families of viruses (Birnaviridae, Rhabdoviridae, Iridoviridae and Reoviridae) that have been reported in Spanish aquaculture. Infectious pancreatic necrosis virus, a member of the first family, is the most spread virus with a prevalence of 39%. Viral diseases are untreatable and because effective and safe vaccines for fish are not yet commercially available, a great care needs to be exercised when moving fish or eggs from one site or country to another. Some fish health control regulations have been legislated in Europe and USA.

  12. Body side and predominant motor features at the onset of Parkinson's disease are linked to motor and nonmotor progression.

    PubMed

    Baumann, Christian R; Held, Ulrike; Valko, Philipp O; Wienecke, Miriam; Waldvogel, Daniel

    2014-02-01

    Patients with Parkinson's disease most often have asymmetric motor features at onset, and specific motor signs (ie, tremor versus bradykinesia and rigidity) frequently characterize the first few years of disease evolution. Some previous clinical evidence has suggested that body side and a predominance of motor manifestations at disease onset are linked to long-term evolution and disease progression. We prospectively analyzed 206 patients with Parkinson's disease according to the most affected side and predominant motor signs at onset. Patients were divided into left-side rigid-akinetic (n = 71), right-side rigid-akinetic (n = 59), left-side tremor (n = 41), and right-side tremor (n = 35) subgroups. These subgroups were compared in terms of motor and cognitive functions, mean motor deterioration per year (calculated as the motor score divided by disease duration), total equivalent doses of dopaminergic drugs, and the presence of hallucinations and rapid eye movement sleep behavior disorder. Disease duration was similar in all groups. Motor fluctuations were more likely to occur in rigid-akinetic patients. In a multiple model analysis adjusted for potential confounders, faster disease progression was associated with right-side (P = 0.045) and rigid-akinetic onset (P = 0.001). With respect to nonmotor symptoms, the rigid-akinetic type was associated with increased risk of cognitive decline (P = 0.004) compared with the tremor type. A trend was noticed toward an increased risk of developing visual hallucinations in rigid-akinetic patients and toward an increased frequency of rapid eye movement sleep behavior disorder in those who had left-sided onset of symptoms. Our findings corroborate that body side and type of motor signs at the time of diagnosis affect the evolution of motor severity and may also have an impact on some nonmotor manifestations.

  13. Plasma prion protein concentration and progression of Alzheimer disease

    PubMed Central

    Schmidt, Christian; Becker, Harry; Peter, Christoph; Lange, Katharina; Friede, Tim; Zerr, Inga

    2014-01-01

    Background/Objective: Recently, PrPc has been linked to AD pathogenesis. Second, a relation of PrPc plasma levels with cognitive status and decline of healthy elderly subjects has been reported. Therefore, we hypothesized baseline plasma levels of PrPc to be associated with AD progression in cognitive and functional domains. Materials and Methods: AD patients (n = 84) were included into an observational study at time of diagnosis. Baseline plasma PrPc levels were determined. Decline was assessed annually (mean follow-up time 3 years) with the aid of different standardized tests (MMSE, iADL, bADL, GDS, UPDRSIII). Multiple regression analyses were used to uncover potential associations between decline and PrPc levels. Results: No association of PrPc and decline could be established. Presence of diabetes mellitus was linked to slower deterioration. Intake of neuroleptic drugs or memantine was associated with faster progression. Conclusion: Plasma PrPc at baseline could not be shown to be related to AD progression in this study. An interesting association of diabetes mellitus and decline warrants further investigation. PMID:24549099

  14. Use of dynamic microsimulation to predict disease progression in patients with pneumonia-related sepsis

    PubMed Central

    Saka, Görkem; Kreke, Jennifer E; Schaefer, Andrew J; Chang, Chung-Chou H; Roberts, Mark S; Angus, Derek C

    2007-01-01

    Introduction Sepsis is the leading cause of death in critically ill patients and often affects individuals with community-acquired pneumonia. To overcome the limitations of earlier mathematical models used to describe sepsis and predict outcomes, we designed an empirically based Monte Carlo model that simulates the progression of sepsis in hospitalized patients over a 30-day period. Methods The model simulates changing health over time, as represented by the Sepsis-related Organ Failure Assessment (SOFA) score, as a function of a patient's previous health state and length of hospital stay. We used data from patients enrolled in the GenIMS (Genetic and Inflammatory Markers of Sepsis) study to calibrate the model, and tested the model's ability to predict deaths, discharges, and daily SOFA scores over time using different algorithms to estimate the natural history of sepsis. We evaluated the stability of the methods using bootstrap sampling techniques. Results Of the 1,888 patients originally enrolled, most were elderly (mean age 67.77 years) and white (80.72%). About half (47.98%) were female. Most were relatively ill, with a mean Acute Physiology and Chronic Health Evaluation III score of 56 and Pneumonia Severity Index score of 73.5. The model's estimates of the daily pattern of deaths, discharges, and SOFA scores over time were not statistically different from the actual pattern when information about how long patients had been ill was included in the model (P = 0.91 to 0.98 for discharges; P = 0.26 to 0.68 for deaths). However, model estimates of these patterns were different from the actual pattern when the model did not include data on the duration of illness (P < 0.001 for discharges; P = 0.001 to 0.040 for deaths). Model results were stable to bootstrap validation. Conclusion An empiric simulation model of sepsis can predict complex longitudinal patterns in the progression of sepsis, most accurately by models that contain data representing both organ

  15. Progress in Early Diagnosis of Sickle Cell Disease

    ERIC Educational Resources Information Center

    Pearson, Howard A.

    1971-01-01

    Discusses the basis of sickle cell Anemia, including: a description of the diseased blood, genetic implications, recognition of symptoms in infancy, the need for implementation of wide screening procedures, and the future prospects of a cure. (AJ)

  16. miR-181b is a biomarker of disease progression in chronic lymphocytic leukemia.

    PubMed

    Visone, Rosa; Veronese, Angelo; Rassenti, Laura Z; Balatti, Veronica; Pearl, Dennis K; Acunzo, Mario; Volinia, Stefano; Taccioli, Cristian; Kipps, Thomas J; Croce, Carlo M

    2011-09-15

    MicroRNAs play a crucial role in chronic lymphocytic leukemia. We investigated whether microRNAs can discriminate patients with a progressive disease from patients with a stable disease. We analyzed microRNA expression on leukemic cells isolated from 358 sequential samples of 114 patients with either stable or progressive disease. We found that during the course of the disease the expression values of miR-181b, the most dysregulated microRNA, decreased in samples of patients with a progressive (P < .001, training and validation sets) but not in samples of patients with a stable disease (P = .3, training set; P = .2, validation set) over time. A drop of ≥ 50% between sequential samples and/or a miR-181b value ≤ 0.005 at the starting time point were significant to differentiate progressive from stable disease (P = .004, training set; P < .001, validation set). These parameters were associated with high risk of requiring treatment (risk ratio, 5.8; 95% confidence interval, 2.5-14.9). We also observed that miR-181b targets Mcl-1 protein and that the decrease of its expression inversely correlated with increased protein levels of MCL1 and BCL2 target genes. We conclude that parameters defined on the basis of the miR-181b expression values specify disease progression in chronic lymphocytic leukemia and are associated with clinical outcome.

  17. Interleukin-33 promotes disease progression in patients with primary biliary cirrhosis.

    PubMed

    Sun, Yongqiang; Zhang, Ji-Yuan; Lv, Sa; Wang, Huan; Gong, Man; Du, Ning; Liu, Honghong; Zhang, Ning; Jing, Jing; Zhou, Chao; Zhang, Fan; Wang, Zongren

    2014-01-01

    Primary biliary cirrhosis (PBC) is a progressive autoimmune liver disease that can cause a series of complications, including cirrhosis, liver failure and hepatocellular carcinoma. Interleukin-33 (IL-33) is expressed in various non-hematopoietic cells and a certain population of immune cells, and exerts its biological effects by binding to the specific receptor, suppression of tumorigenicity 2 (ST2). A soluble form of ST2 (sST2) has been postulated to act as a decoy receptor for IL-33. In this study, we aimed to investigate the role of IL-33 in the pathogenesis of PBC. The study included 20 healthy controls and 68 patients with PBC. We thus found the increased serum IL-33 levels in PBC patients. Its elevated levels were positively correlated with serum alkaline phosphatase levels (a key parameter for the definition of PBC) and with Child-Pugh scores, which were used to determine the prognosis of liver cirrhosis. Moreover, the serum concentrations of sST2 were significantly higher in PBC patients compared with healthy subjects, irrespective of the disease severity. Importantly, the cells that express IL-33 and/or myeloperoxidase (a marker for neutrophils) were accumulated in the livers of PBC patients, and their number increased with the severity of liver lesions. Lastly, in vitro chemotaxis assays revealed that IL-33 enhanced the migration of neutrophils. These data suggest that IL-33 may affect the progress of PBC by recruiting neutrophils to the liver. This expanded knowledge of IL-33 in PBC patients is important for developing therapeutic strategies (e.g., neutralization of IL-33), selecting optimal clinical management, and predicting prognosis.

  18. Minichromosome maintenance 7 protein is a reliable biological marker for human cervical progressive disease

    PubMed Central

    Lobato, Soraya; Tafuri, Alexandre; Fernandes, Paula Ávila; Caliari, Marcelo Vidigal; Silva, Marcos Xavier; Xavier, Marcelo Antônio Pascoal

    2012-01-01

    Objective This study focused on comparing the expression levels of p16, Ki-67, and minichromosome maintenance 7 (MCM7) protein in normal and affected cervical epithelium to ascertain the biological significance of these markers in detecting progressive cervical disease. Methods A quantitative and based on-scanning-microscopy analysis of the three markers expression was performed in normal and cervical intraepithelial neoplasia (CIN) I, II, and III tissues. p16 area as well as p16, Ki-67, and MCM7 positive cells or nuclei were evaluated according to their distribution and extent through the cervical epithelium. Results A clear p16 over-expression was observed in all the dysplastic epithelium tissue samples. The quantitative analysis of p16 area as well as the number of p16 positive cells was able to better discriminate the CIN lesions grades than the usual semi-quantitative analysis. The average Ki-67 labeling indexes for the normal epithelium, CIN I, CIN II, and CIN III groups were 19.8%, 27.3%, 32.8%, and 37.1%, respectively, whereas the mean MCM7 labeling indexes for the correspondent grades were 27.0%, 30.4%, 50.5%, and 67.2%. The Ki-67 and MCM7 labeling indexes were closely correlated with the CIN histological grade, with higher labeling indexe values obtained from the more severe lesions (p<0.05), being the MCM7 labeling indexes the highest values in all the CIN categories (p<0.05). Conclusion We observed a good correlation among the p16, Ki-67, and MCM7 data. In addition, MCM7 demonstrated to be a more efficient and sensitive marker to assess disease progression in the uterine cervix. PMID:22355461

  19. Postnatal Infections and Immunology Affecting Chronic Lung Disease of Prematurity

    PubMed Central

    Pryhuber, Gloria S.

    2015-01-01

    Synopsis Premature infants suffer significant respiratory morbidity during infancy with long-term negative consequences on health, quality of life, and health care costs. Enhanced susceptibility to a variety of infections and inflammation play a large role in early and prolonged lung disease following premature birth, though the mechanisms of susceptibility and immune dysregulation are active areas of research. This chapter will review aspects of host-pathogen interactions and immune responses that are altered by preterm birth and that impact chronic respiratory morbidity in these children. PMID:26593074

  20. Vector-borne pathogens: New and emerging arboviral diseases affecting public health

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dengue and Zika have quickly become two of the most important vector-borne diseases affecting Public health around the world. This presentation will introduce vector-borne diseases and all the vectors implicated. A focus will be made on the most important arboviral diseases (Zika and dengue) describ...

  1. Distinct patterns of brain activity in progressive supranuclear palsy and Parkinson's disease

    PubMed Central

    Burciu, Roxana G.; Ofori, Edward; Shukla, Priyank; Planetta, Peggy J.; Snyder, Amy F.; Li, Hong; Hass, Chris J.; Okun, Michael S.; McFarland, Nikolaus R.; Vaillancourt, David E.

    2015-01-01

    Background The basal ganglia-thalamo-cortical and cerebello-thalamo-cortical circuits are important for motor control. As yet, it is not clear whether their functioning is affected in a similar or different way by progressive supranuclear palsy (PSP) and Parkinson's disease (PD). Methods A functional MRI force production paradigm and voxel-based morphometry were used to assess differences in brain activity and macrostructural volumes between PSP, PD, and healthy age-matched controls. Results We found that PSP and PD share reduced functional activity of the basal ganglia and cortical motor areas, but this is more pronounced in PSP than in PD. In PSP the frontal regions are underactive, whereas the posterior parietal and occipital regions are overactive as compared to controls and PD. Furthermore, lobules I-IV, V, and VI of the cerebellum are hypoactive in PSP and PD, while Crus I and lobule IX are hyperactive in PSP only. Reductions in gray and white matter volume are specific to PSP. Finally, the functional status of the caudate as well as the volume of the superior frontal gyrus predict clinical gait and posture measures in PSP. Conclusions PSP and PD share hypoactivity of the basal ganglia, motor cortex, and anterior cerebellum. PSP patients also display a unique pattern, such that anterior regions of the cortex are hypoactive and posterior regions of the cortex and cerebellum are hyperactive. Together, these findings suggest that specific structures within the basal ganglia, cortex, and cerebellum are affected differently in PSP relative to PD. PMID:26148135

  2. Distinct patterns of brain activity in progressive supranuclear palsy and Parkinson's disease.

    PubMed

    Burciu, Roxana G; Ofori, Edward; Shukla, Priyank; Planetta, Peggy J; Snyder, Amy F; Li, Hong; Hass, Chris J; Okun, Michael S; McFarland, Nikolaus R; Vaillancourt, David E

    2015-08-01

    The basal ganglia-thalamo-cortical and cerebello-thalamo-cortical circuits are important for motor control. Whether their functioning is affected in a similar or different way by progressive supranuclear palsy (PSP) and Parkinson's disease (PD) is not clear. A functional magnetic resonance imaging (fMRI) force production paradigm and voxel-based morphometry were used to assess differences in brain activity and macrostructural volumes between PSP, PD, and healthy age-matched controls. We found that PSP and PD share reduced functional activity of the basal ganglia and cortical motor areas, but this is more pronounced in PSP than in PD. In PSP the frontal regions are underactive, whereas the posterior parietal and occipital regions are overactive as compared with controls and PD. Furthermore, lobules I through IV, V, and VI of the cerebellum are hypoactive in PSP and PD, whereas Crus I and lobule IX are hyperactive in PSP only. Reductions in gray and white matter volume are specific to PSP. Finally, the functional status of the caudate as well as the volume of the superior frontal gyrus predict clinical gait and posture measures in PSP. PSP and PD share hypoactivity of the basal ganglia, motor cortex, and anterior cerebellum. These patients also display a unique pattern, such that anterior regions of the cortex are hypoactive and posterior regions of the cortex and cerebellum are hyperactive. Together, these findings suggest that specific structures within the basal ganglia, cortex, and cerebellum are affected differently in PSP relative to PD.

  3. Chronic Ischemic Heart Disease Affects Health Related Quality of Life

    PubMed Central

    Goreishi, Abolfazl; Shajari, Zahra; Mohammadi, Zeinab

    2012-01-01

    Background Chronic diseases endanger not only physical health but also psychological and social health of patient. Thus, evaluation of such patients for psychological treatment decisions is very important. Method This is a descriptive study that was performed with 50 chronic patients (ischemic heart disease) selected from Valiasr and Mousavi at cardiac wards in Zanjan Province. They were given three types of questionnaire: demographic, WHOQOL, and Zung depression and anxiety index. The information was statically analyzed by frequency chart, central indexes, dispersion, Chi-Square and t tests, Pearson’s correlation index (P < 0.05). Results The average of quality of life in all patients were calculated as was respectively 12.19, 11.98, 12.08, and 12.4 in physical, psychological, social and environmental domains respectively, 68 percent of total number of the patients had various degrees of anxiety and 78 percent of them had various degrees of depression. There was a significant relationship between the life quality average in all domains and anxiety intensity and depression intensity (P < 0.05) and there was a significant relationship between life quality average in all domains and income (P < 0.05). Conclusion As the level of depression and anxiety goes up, quality of life decreases pointing out that they have a reverse relationship. Depression and anxiety are one of the most significant factors of quality of life among other variables. Regarding specific conditions of the treatment, it is necessary to pay special attention to psychological aspects.

  4. Disease progression in patients with single, large-scale mitochondrial DNA deletions.

    PubMed

    Grady, John P; Campbell, Georgia; Ratnaike, Thiloka; Blakely, Emma L; Falkous, Gavin; Nesbitt, Victoria; Schaefer, Andrew M; McNally, Richard J; Gorman, Grainne S; Taylor, Robert W; Turnbull, Doug M; McFarland, Robert

    2014-02-01

    Single, large-scale deletions of mitochondrial DNA are a common cause of mitochondrial disease and cause a broad phenotypic spectrum ranging from mild myopathy to devastating multi-system syndromes such as Kearns-Sayre syndrome. Studies to date have been inconsistent on the value of putative predictors of clinical phenotype and disease progression such as mutation load and the size or location of the deletion. Using a cohort of 87 patients with single, large-scale mitochondrial DNA deletions we demonstrate that a variety of outcome measures such as COX-deficient fibre density, age-at-onset of symptoms and progression of disease burden, as measured by the Newcastle Mitochondrial Disease Adult Scale, are significantly (P < 0.05) correlated with the size of the deletion, the deletion heteroplasmy level in skeletal muscle, and the location of the deletion within the genome. We validate these findings with re-analysis of 256 cases from published data and clarify the previously conflicting information of the value of these predictors, identifying that multiple regression analysis is necessary to understand the effect of these interrelated predictors. Furthermore, we have used mixed modelling techniques to model the progression of disease according to these predictors, allowing a better understanding of the progression over time of this strikingly variable disease. In this way we have developed a new paradigm in clinical mitochondrial disease assessment and management that sidesteps the perennial difficulty of ascribing a discrete clinical phenotype to a broad multi-dimensional and progressive spectrum of disease, establishing a framework to allow better understanding of disease progression.

  5. Infectious, inflammatory, and metabolic diseases affecting the athlete's spine.

    PubMed

    Metz, Lionel N; Wustrack, Rosanna; Lovell, Alberto F; Sawyer, Aenor J

    2012-07-01

    Sports and weight-bearing activities can have a positive effect on bone health in the growing, mature, or aging athlete. However, certain athletic activities and training regimens may place the athlete at increased risk for stress fractures in the spine. In addition, some athletes have an underlying susceptibility to fracture due to either systemic or focal abnormalities. It is important to identify and treat these athletes in order to prevent stress fractures and reduce the risk of osteoporosis in late adulthood. Therefore, the pre-participation physical examination offers a unique opportunity to screen athletes for metabolic bone disease through the history and physical examination. Positive findings warrant a thorough workup including a metabolic bone laboratory panel, and possibly a DEXA scan, which includes a lateral spine view.

  6. Adaptive autophagy in Alexander disease-affected astrocytes.

    PubMed

    Tang, Guomei; Yue, Zhenyu; Tallóczy, Zsolt; Goldman, James E

    2008-07-01

    The ubiquitin-proteasome and autophagy-lysosomal pathways are the two main routes of protein and organelle clearance in eukaryotic cells. The proteasome system is responsible for unfolded, short-lived proteins, which precludes the clearance of oligomeric and aggregated proteins, whereas macroautophagy, a process generally referred to as autophagy, mediates mainly the bulk degradation of long-lived cytoplasmic proteins, large protein complexes or organelles.(1) Recently, the autophagy-lysosomal pathway has been implicated in neurodegenerative disorders as an important pathway for the clearance of abnormally accumulated intracellular proteins, such as huntingtin, tau, and mutant and modified α-synuclein.(1-6) Our recent study illustrated the induction of adaptive autophagy in response to mutant glial fibrillary acidic protein (GFAP) accumulation in astrocytes, in the brains of patients with Alexander disease (AxD), and in mutant GFAP knock-in mouse brains.(7) This autophagic response is negatively regulated by mammalian target of rapamycin (mTOR). The activation of p38 MAPK by GFAP accumulation is responsible for mTOR inactivation and the induction of autophagy. We also found that the accumulation of GFAP impairs proteasome activity.(8) In this commentary we discuss the potential compensatory relationship between an impaired proteasome and activated autophagy, and propose that the MLK-MAPK (mixed lineage kinase-mitogen-activated protein kinase) cascade is a regulator of this crosstalk. Addendum to: Tang G, Yue Z, Talloczy, Z, Hagemann T, Cho W, Sulzer D, Messing A, Goldman JE. Alexander disease-mutant GFAP accumulation stimulates autophagy through p38 MAPK and mTOR signaling pathways. Hum Mol Genetics 2008; In press.

  7. Progression of postural changes in Parkinson's disease: quantitative assessment.

    PubMed

    Khlebtovsky, Alexander; Djaldetti, Ruth; Rodity, Yaniv; Keret, Ofir; Tsvetov, Gloria; Slutzcki-Shraga, Ilana; Benninger, Felix

    2017-02-02

    Previous studies of posture in Parkinson's disease (PD) patients focused on the pathophysiology of severe deformities, using mainly subjective estimations or goniometric measures. The aim of this study was to investigate risk factors associated with flexed posture in PD and their effects on the course of posture variations. One hundred-ninety patients with definite PD were prospectively evaluated for angles of spinal inclination in upright position, extension, and flexion using a mechanical computer-assisted, hand-held device (SpinalMouse). Patients underwent clinical examination, including background data and bone mineral density. Motor function was evaluated with the UPDRS, and back pain with the RMDQ. Physical activity data were collected by self-report. Postural measurements were repeated after 10-17 months. Angle of upright inclination correlated with age (p = 0.0004), older age at disease onset (p = 0.0085), longer disease duration (p = 0.003), higher UPDRS motor and posture score (p = 0.0005 and 0.0001), the presence of back-pain (p = 0.0097), and osteoporosis (p = 0.027). There was no correlation between upright angle of inclination and gender, disease type, or side of disease onset. Re-evaluation of posture in 124 patients at 13.77 ± 4.4 months after the initial evaluation showed significant deterioration in forward bending (p < 0.0001) and was significantly associated with disease duration (p = 0.029), worsening of the UPDRS score (p = 0.016), right-side disease onset (p = 0.032), presence of vertebral fractures (p = 0.049), and the lack of physical activity (p = 0.0327). Older age, disease severity and duration, presence of back-pain and osteoporosis are associated with postural abnormalities in PD. Physical activity might slow the worsening of postural abnormalities in PD.

  8. Human Herpesviruses as Copathogens of HIV Infection, Their Role in HIV Transmission, and Disease Progression

    PubMed Central

    Munawwar, Arshi; Singh, Sarman

    2016-01-01

    Of eight human herpesviruses (HHVs), often, only herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) find mention in medical literature as both of these viruses are commonly associated with genital lesions and oral ulcers, commonly known as cold sores. However, role of human herpesviruses as copathogens and in aggravation and in the transmission of other human diseases, especially the Acquired immunodeficiency syndrome (HIV/AIDS) has only very recently been recognized. Therefore, screening and treating subclinical HHV infections may offer slowing of HIV infection, disease progression, and its transmission. Beside HSV-1 and HSV-2, HHV-3 a causative agent of herpes zoster remained one of the first manifestations of HIV disease before the era of highly active antiretroviral therapy (HAART). HHV-5 also known as human Cytomegalovirus infection remains a significant risk factor for HIV-associated mortality and morbidity even in HAART era. It is proposed that Cytomegalovirus viremia could be a better predictor of HIV disease progression than CD4+ T-lymphocyte count. The role of HHV-4 or Epstein–Burr virus and HHV-6, HHV-7, and HHV-8 is still being investigated in HIV disease progression. This review provides insight into the current understanding about these 8 HHVs, their co-pathogenesis, and role in HIV/AIDS disease progression. The review also covers recent literature in favor and against administering anti-HHV treatment along with HAART for slower AIDS progression and interrupted sexual transmission. PMID:27013807

  9. Progressive age-related changes in sleep and EEG profiles in the PLB1Triple mouse model of Alzheimer's disease.

    PubMed

    Jyoti, Amar; Plano, Andrea; Riedel, Gernot; Platt, Bettina

    2015-10-01

    Sleep disturbances are common in Alzheimer's disease (AD) and now assumed to contribute to disease onset and progression. Here, we investigated whether activity, sleep/wake pattern, and electroencephalogram (EEG) profiles are altered in the knock-in PLB1Triple mouse model from 5 to 21 months of age. PLB1Triple mice displayed a progressive increase in wakefulness and non-rapid eye movement sleep fragmentation from 9 months onward, whereas PLB1WT wild type controls showed such deterioration only at 21 months. Impaired habituation to spatial novelty was also detected in PLB1Triple mice. Hippocampal power spectra of transgenic mice revealed progressive, vigilance stage-, brain region-, and age-specific changes. Age had an impact on EEG spectra in both cohorts but led to accelerated genotype-dependent differences, ultimately affecting all bands at 21 months. Overall, although PLB1Triple animals display only subtle amyloid and tau pathologies, robust sleep-wake and EEG abnormalities emerged. We hypothesize that such endophenotypes are sensitive, noninvasive, and reliable biomarker to identify onset and progression of AD.

  10. Disseminated oligodendroglial-like leptomeningeal tumor with anaplastic progression and presumed extraneural disease: case report.

    PubMed

    Kessler, Brice A; Bookhout, Christine; Jaikumar, Sivakumar; Hipps, John; Lee, Yueh Z

    2015-01-01

    We report the neuroimaging and histopathologic findings of a 12-year-old female patient with a disseminated oligodendroglial-like leptomeningeal tumor with anaplastic progression and presumed extraneural metastatic disease. These tumors may represent distinct pathology primarily seen in pediatric patients. Neuroimaging demonstrates diffuse, progressive enhancement of the leptomeninges often with interval development of intraparenchymal lesions on follow-up. Disease is typically confined to the central nervous system, though diffuse peritoneal disease was seen in our case, possibly through metastatic seeding of the abdomen via ventriculoperitoneal shunt.

  11. Predicting Disease Progression in Scleroderma with Skin and Blood Biomarkers

    DTIC Science & Technology

    2015-10-01

    cytokines, DNA, RNA , skin biopsy 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON...scans. In the first year we have focused on patient recruitment, clinical characterization, specimen collection (DNA, RNA , skin biopsies, serum...Genes versus Environment in Scleroderma Outcome Study), Interstitial Lung Disease, cytokines, DNA, RNA , skin biopsy 3. Overall Project Summary

  12. Predicting Disease Progression in Scleroderma with Skin and Blood Biomarkers

    DTIC Science & Technology

    2014-10-01

    Scleroderma (Systemic Sclerosis , SSc) is a chronic, incurable autoimmune disease associated with high morbidity and mortality primarily due to SSc-lung...utilizing the biospecimens and longitudinal clinical data in the GENISOS cohort to perform an analysis combining data from multiple areas to develop...19, 2014 in Boston. 15. SUBJECT TERMS Scleroderma, Systemic Sclerosis , GENISOS (Genes versus Environment in Scleroderma Outcome Study

  13. THE ROLE OF STRESS IN PERIODONTAL DISEASE PROGRESSION IN OLDER ADULTS.

    PubMed

    Salazar, Christian R

    2013-11-01

    Periodontal disease is characterized by chronic inflammation of the gingiva (gum tissues) caused by infection with anaerobic bacteria. In older adults, progression of disease can lead to tooth loss, inadequate nutritional intake, and a higher risk of other chronic conditions such as cardiovascular disease and diabetes mellitus. As the proportion of older adults continues to grow over time and rates of tooth loss decline, prevalence and severity of periodontal disease will increase. While much is known about risk factors for disease onset, gaps remain in our understanding of factors that could influence disease progression. Over the past few decades, stress has been implicated as a contributory factor. This review critically examines the epidemiological and laboratory evidence and describes a conceptual framework that could help move the research forward.

  14. Does Parkinson's disease affect judgement about another person's action?

    PubMed

    Poliakoff, E; Galpin, A J; Dick, J P R; Tipper, S P

    2010-07-01

    The observer's motor system has been shown to be involved in observing the actions of another person. Recent findings suggest that people with Parkinson's disease do not show the same motor facilitatory effects when observing the actions of another person. We studied whether Parkinson's patients were able to make unspeeded judgements about another person's action. Participants were asked to watch video clips of an actor lifting a box containing different weights (100, 200, 300 or 400 g) and to guess the weight that was being lifted on a 9-point scale. We compared the performance of 16 patients with PD with 16 healthy age-matched controls. Both groups were able to do the task, showing a significant relationship between the real weight and the guessed weight, albeit with a tendency to overestimate the lowest weight and underestimate the heaviest weight. The PD patients, however, showed a reduced slope value. These results show that despite their own motor deficits, PD patients are still able to judge the weight being lifted by another person, albeit with a slight reduction in accuracy. Further research will be required to determine whether PD patients use a motor simulation or a visual compensatory strategy to achieve this.

  15. The Trail Making Test in Prodromal Huntington Disease: Contributions of Disease Progression to Test Performance

    PubMed Central

    O’Rourke, Justin J.F.; Beglinger, Leigh J.; Smith, Megan M.; Mills, James; Moser, David J.; Rowe, Kelly C.; Langbehn, Douglas R.; Duff, Kevin; Stout, Julie C.; Harrington, Deborah L.; Carlozzi, Noelle; Paulsen, Jane S.

    2011-01-01

    We examined the Trail Making Test (TMT) in a sample of 767 participants with prodromal Huntington disease (prodromal HD) and 217 healthy comparisons to determine the contributions of motor, psychiatric, and cognitive changes to TMT scores. Eight traditional and derived TMT scores were also evaluated for their ability to differentiate prodromal participants closer to estimated age of diagnosis from those farther away and prodromal individuals from healthy comparisons. Results indicate that motor signs only mildly affected part A, and psychiatric symptoms did not affect either part. Tests of perceptual processing, visual scanning, and attention were primarily associated with part A, and executive functioning (response inhibition, set-shifting), processing speed, and working memory were associated with part B. Additionally, TMT scores differentiated between healthy comparisons and prodromal HD individuals as far as 9–15 years before estimated diagnosis. In participants manifesting prodromal motor signs and psychiatric symptoms, the TMT primarily measures cognition and is able to discriminate between groups based on health status and estimated time to diagnosis. PMID:21302170

  16. Optical Assessment of Vascular Disease Progression and Treatment

    NASA Astrophysics Data System (ADS)

    Samuels, Joshua A.

    Vascular disease manifests itself in many different forms, including chronic ulcers which do not heal, impaired blood flow to the limbs, or damage to the natural reperfusion process. The current forms of assessing vascular disease are often subjective and provide incomplete knowledge about the tissue of interest. This work focused on developing non-invasive techniques to quantitatively evaluate three specific elements of vascular disease: diabetic ulcers, venous ulcers, and peripheral arterial disease. Diffuse Near Infrared Spectroscopy (DNIRS) was used to predict healing (82% positive predictive value) in diabetic ulcers after 4 weeks of assessment (sensitivity of 0.9 and specificity of 0.86; p<0.002), proving to be an alternative and superior method to wound size reduction alone (the current gold standard). A novel therapeutic ultrasound treatment for venous ulcers, using a low-frequency (20kHz), low intensity (<100mW/cm2 ISPTP), fully-wearable applicator, was assessed using DNIRS and Diffuse Correlation Spectroscopy (DCS), wherein it was established that capillary flow changes over time in healing venous ulcers compared to wounds which do not heal (p<0.01). It was also determined that the ultrasound therapy was successful at improving wound outcomes, specifically the rate of wound closure per week (p<0.05 for wound size, p<0.01 for optical data). Finally, DNIRS and DCS were used in conjunction to assess the reactive hyperemic response in patients with suspected Peripheral Arterial Disease (PAD). It was found that the time between the release of cuff occlusion in the diseased limb and the first peak of reperfusion (flow mediated dilatation) correlated to PAD severity, with longer times (>30 seconds) belonging to patients with PAD (p<0.05). Additionally, it was discovered that the magnitude of the reperfusion did not relate to PAD, but rather to tobacco use. Patients who smoked had reduced hyperemic responses (p<0.02), whether or not they had PAD. Overall, this

  17. Serum Metabolomics of Slow vs. Rapid Motor Progression Parkinson’s Disease: a Pilot Study

    PubMed Central

    Roede, James R.; Uppal, Karan; Park, Youngja; Lee, Kichun; Tran, Vilinh; Walker, Douglas; Strobel, Frederick H.; Rhodes, Shannon L.; Ritz, Beate; Jones, Dean P.

    2013-01-01

    Progression of Parkinson’s disease (PD) is highly variable, indicating that differences between slow and rapid progression forms could provide valuable information for improved early detection and management. Unfortunately, this represents a complex problem due to the heterogeneous nature of humans in regards to demographic characteristics, genetics, diet, environmental exposures and health behaviors. In this pilot study, we employed high resolution mass spectrometry-based metabolic profiling to investigate the metabolic signatures of slow versus rapidly progressing PD present in human serum. Archival serum samples from PD patients obtained within 3 years of disease onset were analyzed via dual chromatography-high resolution mass spectrometry, with data extraction by xMSanalyzer and used to predict rapid or slow motor progression of these patients during follow-up. Statistical analyses, such as false discovery rate analysis and partial least squares discriminant analysis, yielded a list of statistically significant metabolic features and further investigation revealed potential biomarkers. In particular, N8-acetyl spermidine was found to be significantly elevated in the rapid progressors compared to both control subjects and slow progressors. Our exploratory data indicate that a fast motor progression disease phenotype can be distinguished early in disease using high resolution mass spectrometry-based metabolic profiling and that altered polyamine metabolism may be a predictive marker of rapidly progressing PD. PMID:24167579

  18. Hypoxia response and VEGF-A expression in human proximal tubular epithelial cells in stable and progressive renal disease.

    PubMed

    Rudnicki, Michael; Perco, Paul; Enrich, Julia; Eder, Susanne; Heininger, Dorothea; Bernthaler, Andreas; Wiesinger, Martin; Sarközi, Rita; Noppert, Susie-Jane; Schramek, Herbert; Mayer, Bernd; Oberbauer, Rainer; Mayer, Gert

    2009-03-01

    Proteinuria, inflammation, chronic hypoxia, and rarefaction of peritubular capillaries contribute to the progression of renal disease by affecting proximal tubular epithelial cells (PTECs). To study the transcriptional response that separates patients with a stable course from those with a progressive course of disease, we isolated PTECs by laser capture microdissection from cryocut tissue sections of patients with proteinuric glomerulopathies (stable n=20, progressive n=11) with a median clinical follow-up of 26 months. Gene-expression profiling and a systems biology analysis identified activation of intracellular vascular endothelial growth factor (VEGF) signaling and hypoxia response pathways in progressive patients, which was associated with upregulation of hypoxia-inducible-factor (HIF)-1alpha and several HIF target genes, such as transferrin, transferrin-receptor, p21, and VEGF-receptor 1, but downregulation of VEGF-A. The inverse expression levels of HIF-1alpha and VEGF-A were significantly superior in predicting clinical outcome as compared with proteinuria, renal function, and degree of tubular atrophy and interstitial fibrosis at the time of biopsy. Interactome analysis showed the association of attenuated VEGF-A expression with the downregulation of genes that usually stimulate VEGF-A expression, such as epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and HIF-2alpha. In vitro experiments confirmed the positive regulatory effect of EGF and IGF-1 on VEGF-A transcription in human proximal tubular cells. Thus, in progressive but not in stable proteinuric kidney disease, human PTECs show an attenuated VEGF-A expression despite an activation of intracellular hypoxia response and VEGF signaling pathways, which might be due to a reduced expression of positive coregulators, such as EGF and IGF-1.

  19. Quantifying functional mobility progress for chronic disease management.

    PubMed

    Boyle, Justin; Karunanithi, Mohan; Wark, Tim; Chan, Wilbur; Colavitti, Christine

    2006-01-01

    A method for quantifying improvements in functional mobility is presented based on patient-worn accelerometer devices. For patients with cardiovascular, respiratory, or other chronic disease, increasing the amount of functional mobility is a large component of rehabilitation programs. We have conducted an observational trial on the use of accelerometers for quantifying mobility improvements in a small group of chronic disease patients (n=15, 48 - 86 yrs). Cognitive impairments precluded complex instrumentation of patients, and movement data was obtained from a single 2-axis accelerometer device worn at the hip. In our trial, movement data collected from accelerometer devices was classified into Lying vs Sitting/Standing vs Walking/Activity movements. This classification enabled the amount of walking to be quantified and graphically presented to clinicians and carers for feedback on exercise efficacy. Presenting long term trends in this data to patients also provides valuable feedback for self managed care and assisting with compliance.

  20. Self Antigen Prognostic for Human Immunodeficiency Virus Disease Progression

    PubMed Central

    Bristow, Cynthia L.; Patel, Hirenkumar; Arnold, Roland R.

    2001-01-01

    We have recently found that an extracellular protein, α1 proteinase inhibitor (α1PI; α1 antitrypsin), is required for in vitro human immunodeficiency virus (HIV) infectivity outcome. We show here in a study of HIV-seropositive patients that decreased viral load is significantly correlated with decreased circulating α1PI. In the asymptomatic category of HIV disease, 100% of patients manifest deficient levels of active α1PI, a condition known to lead to degenerative lung diseases and a dramatically reduced life span. Further, HIV-associated α1PI deficiency is correlated with circulating anti-α1PI immunoglobulin G. These results suggest that preventing HIV-associated α1PI deficiency may provide a strategic target for preventing HIV-associated pathophysiology. PMID:11527807

  1. Five-year follow-up of angiographic disease progression after medicine, angioplasty, or surgery

    PubMed Central

    2010-01-01

    Background Progression of atherosclerosis in coronary artery disease is observed through consecutive angiograms. Prognosis of this progression in patients randomized to different treatments has not been established. This study compared progression of coronary artery disease in native coronary arteries in patients undergoing surgery, angioplasty, or medical treatment. Methods Patients (611) with stable multivessel coronary artery disease and preserved ventricular function were randomly assigned to CABG, PCI, or medical treatment alone (MT). After 5-year follow-up, 392 patients (64%) underwent new angiography. Progression was considered a new stenosis of ≥ 50% in an arterial segment previously considered normal or an increased grade of previous stenosis > 20% in nontreated vessels. Results Of the 392 patients, 136 underwent CABG, 146 PCI, and 110 MT. Baseline characteristics were similar among treatment groups, except for more smokers and statin users in the MT group, more hypertensives and lower LDL-cholesterol levels in the CABG group, and more angina in the PCI group at study entry. Analysis showed greater progression in at least one native vessel in PCI patients (84%) compared with CABG (57%) and MT (74%) patients (p < 0.001). LAD coronary territory had higher progression compared with LCX and RCA (P < 0.001). PCI treatment, hypertension, male sex, and previous MI were independent risk factors for progression. No statistical difference existed between coronary events and the development of progression. Conclusion The angioplasty treatment conferred greater progression in native coronary arteries, especially in the left anterior descending territories and treated vessels. The progression was independently associated with hypertension, male sex, and previous myocardial infarction. PMID:20977758

  2. Mutations in TJP2 cause progressive cholestatic liver disease

    PubMed Central

    Sambrotta, Melissa; Strautnieks, Sandra; Papouli, Efterpi; Rushton, Peter; Clark, Barnaby E.; Parry, David A.; Logan, Clare V.; Newbury, Lucy J.; Kamath, Binita M.; Ling, Simon; Grammatikopoulos, Tassos; Wagner, Bart E.; Magee, John C.; Sokol, Ronald J.; Mieli-Vergani, Giorgina; Smith, Joshua D.; Johnson, Colin A.; McClean, Patricia; Simpson, Michael A.; Knisely, A.S.; Bull, Laura N.; Thompson, Richard J.

    2014-01-01

    The elucidation of genetic causes of cholestasis has proved to be important in understanding the physiology and pathophysiology of the liver. Protein-truncating mutations in the tight junction protein 2 gene (TJP2) are shown to cause failure of protein localisation, with disruption of tight-junction structure leading to severe cholestatic liver disease. This contrasts with the embryonic-lethal knockout mouse, highlighting differences in redundancy in junctional complexes between organs and species. PMID:24614073

  3. Hepatitis C Virus Infection: Mechanisms of Disease Progression

    DTIC Science & Technology

    2005-10-01

    complications and approximately 1,000 will require liver transplantation. The United States military have rates of HCV infection similar to the general US...population (1.6%). However, it is a younger population and its natural history of HCV infection has not been studied. Therefore, the clinical outcome of HCV ...regarding optimal management and prevention of the disease. This study focuses on active duty military subjects infected with HCV , who will be enrolled and

  4. Hepatitis C. Virus Infection: Mechanisms of Disease Progression

    DTIC Science & Technology

    2006-10-01

    military have rates of HCV infection similar to the general US population (1.6%). However, it is a younger population and its natural history of HCV ...infection has not been studied. Therefore, the clinical outcome of HCV -infected military subjects and risk factors contributing to disease...active duty military subjects infected with HCV , who will be enrolled and observed prospectively over four years (48 months). Liver biopsies are to

  5. Hepatitis C. Virus Infection: Mechanism of Disease Progression

    DTIC Science & Technology

    2004-10-01

    approximately 1,000 will require liver transplantation. The United States military have rates of HCV infection similar to the general US population (1.6...However, it is a younger population and its natural history of HCV infection has not been studied. Therefore, the clinical outcome of HCV -infected...management and prevention of the disease. This study focuses on active duty military subjects infected with HCV , who will be enrolled and observed

  6. Calprotectin as a Biomarker for Melioidosis Disease Progression and Management.

    PubMed

    Natesan, Mohan; Corea, Enoka; Krishnananthasivam, Shivankari; Sathkumara, Harindra Darshana; Dankmeyer, Jennifer L; Dyas, Beverly K; Amemiya, Kei; De Silva, Aruna Dharshan; Ulrich, Robert G

    2017-04-01

    Melioidosis is a neglected tropical disease that is caused by the bacterium Burkholderia pseudomallei and is underreported in many countries where the disease is endemic. A long and costly administration of antibiotics is needed to clear infections, and there is an unmet need for biomarkers to guide antibiotic treatment and increase the number of patients that complete therapy. We identified calprotectin as a lead biomarker of B. pseudomallei infections and examined correlations between this serum protein and the antibiotic treatment outcomes of patients with melioidosis. Serum levels of calprotectin and C-reactive protein were significantly higher in patients with melioidosis and nonmelioidosis sepsis than in healthy controls. Median calprotectin levels were higher in patients with melioidosis than in those with nonmelioidosis sepsis, whereas C-reactive protein levels were similar in both groups. Notably, intensive intravenous antibiotic treatment of patients with melioidosis resulted in lower levels of calprotectin and C-reactive protein (P < 0.0001), coinciding with recovery. The median percent reduction of calprotectin and C-reactive protein was 71% for both biomarkers after antibacterial therapy. In contrast, we found no significant differences in calreticulin levels between the two melioidosis treatment phases. Thus, reductions in serum calprotectin levels were linked to therapeutic responses to antibiotics. Our results suggest that calprotectin may be a sensitive indicator of melioidosis disease activity and illustrate the potential utility of this biomarker in guiding the duration of antibiotic therapy.

  7. Progress in gene therapy of dystrophic heart disease.

    PubMed

    Lai, Y; Duan, D

    2012-06-01

    The heart is frequently afflicted in muscular dystrophy. In severe cases, cardiac lesion may directly result in death. Over the years, pharmacological and/or surgical interventions have been the mainstay to alleviate cardiac symptoms in muscular dystrophy patients. Although these traditional modalities remain useful, the emerging field of gene therapy has now provided an unprecedented opportunity to transform our thinking/approach in the treatment of dystrophic heart disease. In fact, the premise is already in place for genetic correction. Gene mutations have been identified and animal models are available for several types of muscular dystrophy. Most importantly, innovative strategies have been developed to effectively deliver therapeutic genes to the heart. Dystrophin-deficient Duchenne cardiomyopathy is associated with Duchenne muscular dystrophy (DMD), the most common lethal muscular dystrophy. Considering its high incidence, there has been a considerable interest and significant input in the development of Duchenne cardiomyopathy gene therapy. Using Duchenne cardiomyopathy as an example, here we illustrate the struggles and successes experienced in the burgeoning field of dystrophic heart disease gene therapy. In light of abundant and highly promising data with the adeno-associated virus (AAV) vector, we have specially emphasized on AAV-mediated gene therapy. Besides DMD, we have also discussed gene therapy for treating cardiac diseases in other muscular dystrophies such as limb-girdle muscular dystrophy.

  8. Progress in the Diagnosis and Control of Ebola Disease.

    PubMed

    Woźniak-Kosek, Agnieszka; Kosek, Jarosław; Mierzejewski, Jerzy; Rapiejko, Piotr

    2015-01-01

    Ebola hemorrhagic fever is one of numerous viral hemorrhagic fevers. It is a severe, often fatal disease in humans and nonhuman primates (gorillas and chimpanzees). This article discusses the history of Ebola disease, already known routes of infection together with defining prevention methods and treatment trials. The importance of increasing awareness of the risk of disease among people who do not inhabit endemic regions is emphasized. This risk is associated especially with the increasing popularity of tourism to African countries, even to those where the virus is endemic. The research conducted over the years shows that three species of frugivorous bats are subjected to contamination by Ebola, but the infection is asymptomatic in them. It is believed that the saliva of these mammals and other body fluids may be a potential source of infection for primates and humans. In the laboratory, infection through small-particle aerosols has been demonstrated in primates, and airborne spread among humans is strongly suspected, although it has not yet been conclusively demonstrated. The importance of this route of transmission remains unclear. Poor hygienic conditions can aid the spread of the virus. These observations suggest approaches to the study of routes of transmission to and among humans.

  9. [Research Progress of Pathogenesis and Treatment of Parkinsons Disease].

    PubMed

    Liu, Jia; Duan, Chun-li; Yang, Hui

    2015-06-01

    Parkinson's disease (PD) is the second most common neurodegenerative disease. The most prominent pathological features are the loss of dopaminergic neurons in the substantia nigra pars compacta and the deposition of intraneuronal inclusions named Lewy bodies in most cases. The most prominent symptom of PD is the impairment of motor behavior due to the loss of dopaminergic neurons and the consequent loss of the dopamine signaling in the basal ganglia. So DA replacement (including L-dopa, the gold standard treatment) still remains to be the best treatment for the disease due to its ability of relieving most of the motor symptoms. Growing evidence suggests that a combination of environmental, genetic factors and aging may contribute to PD. Mitochondrial dysfunction, oxidative stress, neuroinflammation, and excitability toxicity contribute to the pathogensis of PD. Currently available treatments for PD, including drug therapy, surgical treatment, cell and tissue transplantation and gene therapy, but their efficacy was unsatisfactory. Here we review the most recent findings and developments about pathogenesis and treatment of PD, and hope to offer some clues for clinical drug development and novel alternative therapies.

  10. History and progression of Fat cadherins in health and disease

    PubMed Central

    Zhang, Xiaofeng; Liu, Jinghua; Liang, Xiao; Chen, Jiang; Hong, Junjie; Li, Libo; He, Qiang; Cai, Xiujun

    2016-01-01

    Intercellular adhesions are vital hubs for signaling pathways during multicellular development and animal morphogenesis. In eukaryotes, under aberrant intracellular conditions, cadherins are abnormally regulated, which can result in cellular pathologies such as carcinoma, kidney disease, and autoimmune diseases. As a member of the Ca2+-dependent adhesion super-family, Fat proteins were first described in the 1920s as an inheritable lethal mutant phenotype in Drosophila, consisting of four member proteins, FAT1, FAT2, FAT3, and FAT4, all of which are highly conserved in structure. Functionally, FAT1 was found to regulate cell migration and growth control through specific protein–protein interactions of its cytoplasmic tail. FAT2 and FAT3 are relatively less studied and are thought to participate in the development of human cancer through a pathway similar to that of the Ena/VASP proteins. In contrast, FAT4 has been widely studied in the context of biological functions and tumor mechanisms and has been shown to regulate the planar cell polarity pathway, the Hippo signaling pathway, the canonical Wnt signaling cascade, and the expression of YAP1. Overall, Fat cadherins may be useful as emerging disease biomarkers and as novel therapeutic targets. PMID:27942226

  11. Ca2+ dysregulation in the endoplasmic reticulum related to Alzheimer's disease: A review on experimental progress and computational modeling.

    PubMed

    Liang, Jingyi; Kulasiri, Don; Samarasinghe, Sandhya

    2015-08-01

    Alzheimer's disease (AD) is a devastating, incurable neurodegenerative disease affecting millions of people worldwide. Dysregulation of intracellular Ca(2+) signaling has been observed as an early event prior to the presence of clinical symptoms of AD and is believed to be a crucial factor contributing to its pathogenesis. The progressive and sustaining increase in the resting level of cytosolic Ca(2+) will affect downstream activities and neural functions. This review focuses on the issues relating to the increasing Ca(2+) release from the endoplasmic reticulum (ER) observed in AD neurons. Numerous research papers have suggested that the dysregulation of ER Ca(2+) homeostasis is associated with mutations in the presenilin genes and amyloid-β oligomers. These disturbances could happen at many different points in the signaling process, directly affecting ER Ca(2+) channels or interfering with related pathways, which makes it harder to reveal the underlying mechanisms. This review paper also shows that computational modeling is a powerful tool in Ca(2+) signaling studies and discusses the progress in modeling related to Ca(2+) dysregulation in AD research.

  12. Inflammatory Leukocyte Phenotypes Correlate with Disease Progression in Idiopathic Pulmonary Fibrosis

    PubMed Central

    Moore, Bethany B.; Fry, Chris; Zhou, Yueren; Murray, Susan; Han, MeiLan K.; Martinez, Fernando J.; Flaherty, Kevin R.

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by progressive deposition of extracellular matrix, worsening dyspnea, and eventual mortality. Pathogenesis of IPF is poorly understood and the role inflammation and activated leukocytes play in the disease process is controversial. Previous studies demonstrated that activated leukocyte subsets characterize IPF patients. We sought to validate this observation in a well-defined cohort of 35 IPF patients and to correlate the observed leukocyte phenotypes with robust parameters of disease progression. We demonstrate that in univariate and multivariate analyses, increases in the CD14hi, CD16hi subset of monocytes measured at baseline correlated with disease progression, with a threshold value >0.5% of the total peripheral blood mononuclear cells being a significant predictor for worse outcome. In addition, several T cell subsets, including CD25 expressing CD4 cells, and CXCR3 expressing CD4 and CD8 subsets correlated with disease progression when found in increased percentages in the peripheral blood of IPF patients when sampled at baseline. Somewhat surprising in comparison to previous literature, the CD4 T cells did not appear to have lost expression of the co-stimulatory molecule, CD28, but the CD8 T cells did. Taken together, these results are consistent with the presence of an inflammatory process in IPF patients who eventually progress. However, when longitudinal measurements of these same markers were examined, there was significant heterogeneity of expression and these biomarkers did not necessarily remain elevated in IPF patients with progressive disease. We interpret this heterogeneity to suggest that IPF patients experience episodic inflammatory events that once triggered, may lead to disease progression. This longitudinal heterogeneity in biomarker analyses may explain why such markers are not consistently measured in all IPF cohorts. PMID:25580363

  13. BDNF and VEGF in the pathogenesis of stress-induced affective diseases: an insight from experimental studies.

    PubMed

    Nowacka, Marta; Obuchowicz, Ewa

    2013-01-01

    Stress is known to play an important role in etiology, development and progression of affective diseases. Especially, chronic stress, by initiating changes in the hypothalamic-pituitary-adrenal axis (HPA), neurotransmission and the immune system, acts as a trigger for affective diseases. It has been reported that the rise in the concentration of pro-inflammatory cytokines and persistent up-regulation of glucocorticoid expression in the brain and periphery increases the excitotoxic effect on CA3 pyramidal neurons in the hippocampus resulting in dendritic atrophy, apoptosis of neurons and possibly inhibition of neurogenesis in adult brain. Stress was observed to disrupt neuroplasticity in the brain, and growing evidence demonstrates its role in the pathomechanism of affective disorders. Experimental studies indicate that a well-known brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) which have recently focused increasing attention of neuroscientists, promote cell survival, positively modulate neuroplasticity and hippocampal neurogenesis. In this paper, we review the alterations in BDNF and VEGF pathways induced by chronic and acute stress, and their relationships with HPA axis activity. Moreover, behavioral effects evoked in rodents by both above-mentioned factors and the effects consequent to their deficit are presented. Biochemical as well as behavioral findings suggest that BDNF and VEGF play an important role as components of cascade of changes in the pathomechanism of stress-induced affective diseases. Further studies on the mechanisms regulating their expression in stress conditions are needed to better understand the significance of trophic hypothesis of stress-induced affective diseases.

  14. Making choices—how stochastic decisions determine disease progression

    PubMed Central

    Park, Ki-Sun; Pfeifer, Karl

    2016-01-01

    In this issue of Genes & Development, Ginart and colleagues (pp. 567–578) study a mouse model for Russell-Silver syndrome (RSS) and show that similar cells within one individual can display distinct gene expression patterns because of epigenetic marks that are established stochastically during early development. Their results provide an excellent explanation for phenotypes seen in RSS and other imprinting disorders and especially help us understand how patients with similar or even identical genetic mutations can display distinct disease profiles. PMID:26944674

  15. Disease Severity and Progression in Progressive Supranuclear Palsy and Multiple System Atrophy: Validation of the NNIPPS – PARKINSON PLUS SCALE

    PubMed Central

    Payan, Christine A. M.; Viallet, François; Landwehrmeyer, Bernhard G.; Bonnet, Anne-Marie; Borg, Michel; Durif, Franck; Lacomblez, Lucette; Bloch, Frédéric; Verny, Marc; Fermanian, Jacques; Agid, Yves; Ludolph, Albert C.

    2011-01-01

    Background The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS) study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = 362) and Multiple System Atrophy (MSA, n = 398). To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study. Methods and Findings Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116), validity (n = 760), and responsiveness (n = 642). Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α≥0.70). Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94) and 9 dimensions (Intra-class coefficient = 0.80–0.93), and moderate (Intra-class coefficient = 0.54–0.77) for 6. Correlations of the total score with other clinical measures of severity were good (rho≥0.70). The total score was significantly and linearly related to survival (p<0.0001). Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10), though higher in PSP (SRM = 1.25) than in MSA (SRM = 1.0), indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall

  16. Electrostimulation to reduce synaptic scaling driven progression of Alzheimer's disease.

    PubMed

    Rowan, Mark S; Neymotin, Samuel A; Lytton, William W

    2014-01-01

    Cell death and synapse dysfunction are two likely causes of cognitive decline in AD. As cells die and synapses lose their drive, remaining cells suffer an initial decrease in activity. Neuronal homeostatic synaptic scaling then provides a feedback mechanism to restore activity. This homeostatic mechanism is believed to sense levels of activity-dependent cytosolic calcium within the cell and to adjust neuronal firing activity by increasing the density of AMPA synapses at remaining synapses to achieve balance. The scaling mechanism increases the firing rates of remaining cells in the network to compensate for decreases in network activity. However, this effect can itself become a pathology, as it produces increased imbalance between excitatory and inhibitory circuits, leading to greater susceptibility to further cell loss via calcium-mediated excitotoxicity. Here, we present a mechanistic explanation of how directed brain stimulation might be expected to slow AD progression based on computational simulations in a 470-neuron biomimetic model of a neocortical column. The simulations demonstrate that the addition of low-intensity electrostimulation (neuroprosthesis) to a network undergoing AD-like cell death can raise global activity and break this homeostatic-excitotoxic cascade. The increase in activity within the remaining cells in the column results in lower scaling-driven AMPAR upregulation, reduced imbalances in excitatory and inhibitory circuits, and lower susceptibility to ongoing damage.

  17. Podoplanin Expression Correlates with Disease Progression in Mycosis Fungoides.

    PubMed

    Jankowska-Konsur, Alina; Kobierzycki, Christopher; Grzegrzółka, Jędrzej; Piotrowska, Aleksandra; Gomulkiewicz, Agnieszka; Glatzel-Plucinska, Natalia; Reich, Adam; Podhorska-Okołów, Marzenna; Dzięgiel, Piotr; Szepietowski, Jacek C

    2017-02-08

    The aim of this study was to investigate the role of lymphangiogenesis in the clinical progression and outcome of mycosis fungoides. Immunohistochemistry and Western blot techniques were used to assess the expression of podoplanin and vascular endothelial growth factor C in mycosis fungoides. Expression of vascular endothelial growth factor C measured by immunohistochemistry was significantly higher in mycosis fungoides samples in comparison with control cases (chronic benign dermatoses) (p = 0.0012). Increased expression of podoplanin was found in advanced vs. early mycosis fungoides (p < 0.0001), and was positively correlated with cutaneous and nodal involvement (p < 0.001, p < 0.0001; respectively). Higher podoplanin expression was also significantly associated with shorter survival (p < 0.001). Strong positive correlation was observed between expression of podoplanin analysed by immunohistochemistry and Western blot (r = 0.75, p < 0.0001). A similar association was shown regarding expression of vascular endothelial growth factor C (r = 0.68, p = 0.0007). In conclusion, these results suggest that increased expression of podoplanin is associated with poor clinical course, as well as shorter survival, of patients with mycosis fungoides.

  18. Electrostimulation to reduce synaptic scaling driven progression of Alzheimer's disease

    PubMed Central

    Rowan, Mark S.; Neymotin, Samuel A.; Lytton, William W.

    2014-01-01

    Cell death and synapse dysfunction are two likely causes of cognitive decline in AD. As cells die and synapses lose their drive, remaining cells suffer an initial decrease in activity. Neuronal homeostatic synaptic scaling then provides a feedback mechanism to restore activity. This homeostatic mechanism is believed to sense levels of activity-dependent cytosolic calcium within the cell and to adjust neuronal firing activity by increasing the density of AMPA synapses at remaining synapses to achieve balance. The scaling mechanism increases the firing rates of remaining cells in the network to compensate for decreases in network activity. However, this effect can itself become a pathology, as it produces increased imbalance between excitatory and inhibitory circuits, leading to greater susceptibility to further cell loss via calcium-mediated excitotoxicity. Here, we present a mechanistic explanation of how directed brain stimulation might be expected to slow AD progression based on computational simulations in a 470-neuron biomimetic model of a neocortical column. The simulations demonstrate that the addition of low-intensity electrostimulation (neuroprosthesis) to a network undergoing AD-like cell death can raise global activity and break this homeostatic-excitotoxic cascade. The increase in activity within the remaining cells in the column results in lower scaling-driven AMPAR upregulation, reduced imbalances in excitatory and inhibitory circuits, and lower susceptibility to ongoing damage. PMID:24765074

  19. Parkinson's disease progression at 30 years: a study of subthalamic deep brain-stimulated patients.

    PubMed

    Merola, Aristide; Zibetti, Maurizio; Angrisano, Serena; Rizzi, Laura; Ricchi, Valeria; Artusi, Carlo A; Lanotte, Michele; Rizzone, Mario G; Lopiano, Leonardo

    2011-07-01

    Clinical findings in Parkinson's disease suggest that most patients progressively develop disabling non-levodopa-responsive symptoms during the course of the disease. Nevertheless, several heterogeneous factors, such as clinical phenotype, age at onset and genetic aspects may influence the long-term clinical picture. In order to investigate the main features of long-term Parkinson's disease progression, we studied a cohort of 19 subjects treated with subthalamic nucleus deep brain stimulation after >20 years of disease, reporting clinical and neuropsychological data up to a mean of 30 years from disease onset. This group of patients was characterized by an early onset of disease, with a mean age of 38.63 years at Parkinson's disease onset, which was significantly lower than in the other long-term subthalamic nucleus deep brain stimulation follow-up cohorts reported in the literature. All subjects were regularly evaluated by a complete Unified Parkinson's Disease Rating Scale, a battery of neuropsychological tests and a clinical interview, intended to assess the rate of non-levodopa-responsive symptom progression. Clinical data were available for all patients at presurgical baseline and at 1, 3 and 5 years from the subthalamic nucleus deep brain stimulation surgical procedure, while follow-up data after >7 years were additionally reported in a subgroup of 14 patients. The clinical and neuropsychological performance progressively worsened during the course of follow-up; 64% of patients gradually developed falls, 86% dysphagia, 57% urinary incontinence and 43% dementia. A progressive worsening of motor symptoms was observed both in 'medication-ON' condition and in 'stimulation-ON' condition, with a parallel reduction in the synergistic effect of 'medication-ON/stimulation-ON' condition. Neuropsychological data also showed a gradual decline in the performances of all main cognitive domains, with an initial involvement of executive functions, followed by the impairment

  20. 4-hydroxynonenal in the pathogenesis and progression of human diseases

    PubMed Central

    Shoeb, Mohammad; Ansari, Naseem H; Srivastava, Satish K; Ramana, Kota V

    2014-01-01

    Metastable aldehydes produced by lipid peroxidation act as 'toxic second messengers' that extend the injurious potential of free radicals. 4-hydroxy 2-nonenal (HNE), a highly toxic and most abundant stable end product of lipid peroxidation, has been implicated in the tissue damage, dysfunction, injury associated with aging and other pathological states such as cancer, Alzheimer, diabetes, cardiovascular and inflammatory complications. Further, HNE has been considered as a oxidative stress marker and it act as a secondary signaling molecule to regulates a number of cell signaling pathways. Biological activity of HNE depends on its intracellular concentration, which can differentially modulate cell death, growth and differentiation. Therefore, the mechanisms responsible for maintaining the intracellular levels of HNE are most important, not only in the defense against oxidative stress but also in the pathophysiology of a number of disease processes. In this review, we discusse the significance of HNE in mediating various disease processes and how regulation of its metabolism could be therapeutically effective. PMID:23848536

  1. Body mass index, weight change, and clinical progression in mild cognitive impairment and Alzheimer disease.

    PubMed

    Besser, Lilah M; Gill, Dawn P; Monsell, Sarah E; Brenowitz, Willa; Meranus, Dana H; Kukull, Walter; Gustafson, Deborah R

    2014-01-01

    The speed and severity of clinical progression after Alzheimer disease (AD) diagnosis varies and depends on multiple factors, most not well elucidated. We assessed whether body mass index (BMI) and 1-year weight change (WC) are associated with clinical progression in amnestic mild cognitive impairment (aMCI) and early-stage AD. Longitudinal data comprising 2268 aMCI and 1506 AD participants in the National Alzheimer's Coordinating Center's Uniform Data Set were used to examine nuances of clinical progression by BMI and WC, as well as potential variations in associations by age, sex, BMI (WC model), or apolipoprotein E genotype. In aMCI, high BMI (vs. moderate BMI) was associated with slower progression; weight loss (vs. no WC) was associated with faster progression. In AD, no significant differences were observed in clinical progression by BMI or WC. The association between BMI and clinical progression varied significantly by apolipoprotein E genotype in AD, and the association between WC and clinical progression varied significantly by sex and BMI in aMCI. Baseline BMI and 1-year WC in late life may serve as early prognostic indicators in aMCI and early-stage AD. If replicated, these results may help in counseling patients on anticipated clinical progression and suggest windows of opportunity for intervention.

  2. The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis

    PubMed Central

    Sharma, Mithun; Mitnala, Shasikala; Vishnubhotla, Ravi K.; Mukherjee, Rathin; Reddy, Duvvur N.; Rao, Padaki N.

    2015-01-01

    Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed. PMID:26155043

  3. The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis.

    PubMed

    Sharma, Mithun; Mitnala, Shasikala; Vishnubhotla, Ravi K; Mukherjee, Rathin; Reddy, Duvvur N; Rao, Padaki N

    2015-06-01

    Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed.

  4. Neurophysiological assessment of neural network plasticity and connectivity: Progress towards early functional biomarkers for disease interception therapies in Alzheimer's disease.

    PubMed

    Walsh, C; Drinkenburg, W H I M; Ahnaou, A

    2017-02-01

    Despite a great deal of research into Alzheimer's disease (AD) over the last 20 years, an effective treatment to halt or slow its progression has yet to be developed. With many aspects of the disease progression still to be elucidated, focus has shifted from reducing levels of amyloid β (Aβ) in the brains of AD patients towards tau, another pathology, which initiates much earlier in deeper brainstem networks and is thought to propagate via cell-to-cell processes prior to the onset of amyloid pathology and cognitive impairments. In-vitro, ex-vivo molecular biology/biochemistry read-outs, and various transgenic animal models have been developed, yet clinical failures have highlighted a clear disconnect and inadequate use of such animal models in translational research across species. AD pathology is now estimated to begin at least 10-20 years before clinical symptoms, and imaging and cerebrospinal fluid biomarkers are leading the way in assessing the disease progression at a stage where neuronal damage has already occurred. Here, we emphasize the relevance of assessing early disruptions in network connectivity and plasticity that occur before neuropathological damage and progressive memory dysfunction, which can have high translational value for discovery of pre-symptomatic AD biomarkers and early mechanism-based disease interception therapeutics.

  5. Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function.

    PubMed

    Ontaneda, Daniel; Thompson, Alan J; Fox, Robert J; Cohen, Jeffrey A

    2017-04-01

    Multiple sclerosis is a major cause of neurological disability, which accrues predominantly during progressive forms of the disease. Although development of multifocal inflammatory lesions is the underlying pathological process in relapsing-remitting multiple sclerosis, the gradual accumulation of disability that characterises progressive multiple sclerosis seems to result more from diffuse immune mechanisms and neurodegeneration. As a result, the 14 anti-inflammatory drugs that have regulatory approval for treatment of relapsing-remitting multiple sclerosis have little or no efficacy in progressive multiple sclerosis without inflammatory lesion activity. Effective therapies for progressive multiple sclerosis that prevent worsening, reverse damage, and restore function are a major unmet need. In this Series paper we summarise the current status of therapy for progressive multiple sclerosis and outline prospects for the future.

  6. Serum Antibodies to Melanocytes in Patients With Vitiligo Are Predictors of Disease Progression.

    PubMed

    Jimenez-Brito, Gustavo; Garza-de-La-Peña, Eduardo; Pérez-Romano, Beatriz; Ruiz-Argüelles, Alejandro

    2016-01-01

    The aim of this study was to investigate whether the amount of serum antibodies to melanocyte antigens could predict clinical activity or disease progression in patients with vitiligo. A solid-phase enzyme immunoassay was developed to semiquantitate serum antibodies to a human melanocyte extract and was used in 127 patients, 93 of whom showed clinical progression of the disease, while the remaining 34 were quiescent. Results showed different values for clinical sensitivity and specificity depending on the cutoff level for decision, but the overall performance of the test was adequate and supported statistical significance to predict clinical activity/progression or quietness of the disease process. The test might prove useful in deciding the indication and aggressiveness of immunosuppressive therapy in patients with vitiligo. Previous findings suggest that melanocyte-specific antibodies might play a pathogenetic role in the depletion of melanocytes, which characterizes this disorder, and that this depletion might be due to apoptosis following antibody internalization.

  7. Theory of Mind and social reserve: Alternative hypothesis of progressive Theory of Mind decay during different stages of Alzheimer's disease.

    PubMed

    Fliss, Rafika; Le Gall, Didier; Etcharry-Bouyx, Frédérique; Chauviré, Valérie; Desgranges, Béatrice; Allain, Philippe

    2016-01-01

    Although Theory of Mind (ToM) is thought to be impaired in Alzheimer's disease (AD), it remains unclear whether this impairment is linked to the level of task complexity, the heterogeneity of the studied patients, or the implication of executive dysfunctions. To elucidate this point, 42 AD patients, divided into two subgroups [moderate AD (mAD) patients (n = 19) and early AD (eAD) patients (n = 23)], and 23 matched healthy older subjects (HO) were enrolled. All participants were given (1) a false-belief task (cognitive ToM), (2) a revised version of the "Reading the Mind in the Eyes" test (affective ToM), and (3) a composite task designed to assess ToM abilities with minimal cognitive demands. Participants were also given executive tasks assessing inhibition, shifting, and updating processes. We observed a significant impairment of cognitive and composite ToM abilities in eAD patients compared with mAD patients. There was no impairment of affective ToM. Stepwise regression revealed that measures of global efficiency and executive functions (EFs) were the best predictors of progressive decay of ToM scores. These results indicate that cognitive aspects of ToM are more sensitive to AD progression than affective tasks. They also show that ToM abilities are more affected by dementia severity than by task complexity. One explanation of our results is the presence of compensatory mechanisms (social reserve) in AD.

  8. Vitamin D Status Does Not Affect Disability Progression of Patients with Multiple Sclerosis over Three Year Follow-Up

    PubMed Central

    Smolders, Joost; Rolf, Linda; Klinkenberg, Lieke J. J.; van der Linden, Noreen; Meex, Steven; Damoiseaux, Jan; Hupperts, Raymond

    2016-01-01

    Background and Objective The risk of developing multiple sclerosis (MS) as well as MS disease activity is associated with vitamin D (25(OH)D) status. The relationship between the main functional disability hallmark of MS, disability progression, and 25(OH)D status is less well established though, especially not in MS patients with progressive disease. Methods This retrospective follow-up study included 554 MS patients with a serum baseline 25(OH)D level and Expanded Disability Status Scale (EDSS) with a minimum follow-up of three years. Logistic regressions were performed to assess the effect of baseline 25(OH)D status on relapse rate. Repeated measures linear regression analyses were performed to assess the effect on disability and disability progression. Results Baseline deseasonalized 25(OH)D status was associated with subsequent relapse risk (yes/no), but only in the younger MS patients (≤ 37.5 years; OR = 0.872, per 10 nmol/L 25(OH)D, p = 0.041). Baseline 25(OH)D status was not significantly associated with either disability or disability progression, irrespective of MS phenotype. Conclusion Within the physiological range, 25(OH)D status is just significantly associated with the occurrence of relapses in younger MS patients, but is not associated with disability or disability progression over three years follow-up. Whether high dose supplementation to supra physiological 25(OH)D levels prevents disability progression in MS should become clear from long term follow-up of supplementation studies. PMID:27276080

  9. Apoptosis as a Mechanism for Liver Disease Progression

    PubMed Central

    Guicciardi, Maria Eugenia; Gores, Gregory J.

    2011-01-01

    Hepatocyte injury is ubiquitous in clinical practice, and the mode of cell death associated with this injury is often apoptosis, especially by death receptors. Information from experimental systems demonstrates that hepatocyte apoptosis is sufficient to cause liver hepatic fibrogenesis. The mechanisms linking hepatocyte apoptosis to hepatic fibrosis remain incompletely understood, but likely relate to engulfment of apoptotic bodies by professional phagocytic cells and stellate cells, and release of mediators by cells undergoing apoptosis. Inhibition of apoptosis with caspase inhibitors has demonstrated beneficial effects in murine models of hepatic fibrosis. Recent studies implicating Toll-like receptor 9 (TLR9) in liver injury and fibrosis are also of particular interest. Engulfment of apoptotic bodies is one mechanism by which the TLR9 ligand (CpG DNA motifs) could be delivered to this intracellular receptor. These concepts suggest therapy focused on interrupting the cellular mechanisms linking apoptosis to fibrosis would be useful in human liver diseases. PMID:20960379

  10. PHD2: from hypoxia regulation to disease progression.

    PubMed

    Meneses, Ana M; Wielockx, Ben

    2016-01-01

    Oxygen represents one of the major molecules required for the development and maintenance of life. An adequate response to hypoxia is therefore required for the functioning of the majority of living organisms and relies on the activation of the hypoxia-inducible factor (HIF) pathway. HIF prolyl hydroxylase domain-2 (PHD2) has long been recognized as the major regulator of this response, controlling a myriad of outcomes that range from cell death to proliferation. However, this enzyme has been associated with more pathways, making the role of this protein remarkably complex under distinct pathologies. While a protective role seems to exist in physiological conditions such as erythropoiesis; the picture is more complex during pathologies such as cancer. Since the regulation of this enzyme and its closest family members is currently considered as a possible therapy for various diseases, understanding the different particular roles of this protein is essential.

  11. PHD2: from hypoxia regulation to disease progression

    PubMed Central

    Meneses, Ana M; Wielockx, Ben

    2016-01-01

    Oxygen represents one of the major molecules required for the development and maintenance of life. An adequate response to hypoxia is therefore required for the functioning of the majority of living organisms and relies on the activation of the hypoxia-inducible factor (HIF) pathway. HIF prolyl hydroxylase domain-2 (PHD2) has long been recognized as the major regulator of this response, controlling a myriad of outcomes that range from cell death to proliferation. However, this enzyme has been associated with more pathways, making the role of this protein remarkably complex under distinct pathologies. While a protective role seems to exist in physiological conditions such as erythropoiesis; the picture is more complex during pathologies such as cancer. Since the regulation of this enzyme and its closest family members is currently considered as a possible therapy for various diseases, understanding the different particular roles of this protein is essential. PMID:27800508

  12. Progress update: Pharmacological treatment of Alzheimer’s disease

    PubMed Central

    Hogan, David B

    2007-01-01

    A number of drugs have been approved for the treatment of Alzheimer’s disease (AD) and a larger number are being studied as possible therapies. The current mainstays of the pharmacotherapy of AD are the cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine. They collectively have acceptable tolerability and proven but modest efficacy. The agents being studied include dietary supplements (eg, vitamin E), herbal preparations (eg, Ginkgo biloba), medications approved for other indications (eg, HMG-CoA reductase enzyme inhibitors) and research drugs. In this review we discuss in detail the approved agents and review a number of the unapproved therapies that are currently available to the practitioner. While our era offers much more in the way of therapeutics for AD, it is clear that more work still needs to be done. PMID:19300586

  13. Progress on conformal microwave array applicators for heating chestwall disease

    NASA Astrophysics Data System (ADS)

    Stauffer, P. R.; Maccarini, P. F.; Juang, T.; Jacobsen, S. K.; Gaeta, C. J.; Schlorff, J. L.; Milligan, A. J.

    2007-02-01

    Previous studies have reported the computer modeling, CAD design, and theoretical performance of single and multiple antenna arrays of Dual Concentric Conductor (DCC) square slot radiators driven at 915 and 433 MHz. Subsequently, practical CAD designs of microstrip antenna arrays constructed on thin and flexible printed circuit board (PCB) material were reported which evolved into large Conformal Microwave Array (CMA) sheets that could wrap around the surface of the human torso for delivering microwave energy to large areas of superficial tissue. Although uniform and adjustable radiation patterns have been demonstrated from multiple element applicators radiating into simple homogeneous phantom loads, the contoured and heterogeneous tissue loads typical of chestwall recurrent breast cancer have required additional design efforts to achieve good coupling and efficient heating from the increasingly larger conformal array applicators used to treat large area contoured patient anatomy. Thus recent work has extended the theoretical optimization of DCC antennas to improve radiation efficiency of each individual aperture and reduce mismatch reflections, radiation losses, noise, and cross coupling of the feedline distribution network of large array configurations. Design improvements have also been incorporated into the supporting bolus structure to maintain effective coupling of DCC antennas into contoured anatomy and to monitor and control surface temperatures under the entire array. New approaches for non-invasive monitoring of surface and sub-surface tissue temperatures under each independent heat source are described that make use of microwave radiometry and flexible sheet grid arrays of thermal sensors. Efforts to optimize the clinical patient interface and move from planar rectangular shapes to contoured vest applicators that accommodate entire disease in a larger number of patients are summarized. By applying heat more uniformly to large areas of contoured anatomy

  14. Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

    PubMed Central

    Ferenczy, Michael W.; Marshall, Leslie J.; Nelson, Christian D. S.; Atwood, Walter J.; Nath, Avindra; Khalili, Kamel

    2012-01-01

    Summary: Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies. PMID:22763635

  15. Associations of hormonal contraceptive use with measures of HIV disease progression and antiretroviral therapy effectiveness☆

    PubMed Central

    Whiteman, Maura K.; Jeng, Gary; Samarina, Anna; Akatova, Natalia; Martirosyan, Margarita; Kissin, Dmitry M.; Curtis, Kathryn M.; Marchbanks, Polly A.; Hillis, Susan D.; Mandel, Michele G.; Jamieson, Denise J.

    2015-01-01

    Objective To examine the associations between hormonal contraceptive use and measures of HIV disease progression and antiretroviral treatment (ART) effectiveness. Study design A prospective cohort study of women with prevalent HIV infection in St. Petersburg, Russia, was conducted. After contraceptive counseling, participants chose to use combined oral contraceptives (COCs), depot-medroxyprogesterone acetate (DMPA), a copper intrauterine device (IUD) or male condoms for pregnancy prevention. Among participants not using ART at enrollment, we used multivariate Cox regression to assess the association between current (time-varying) contraceptive use and disease progression, measured by the primary composite outcome of CD4 decline to <350 cells/mm3, ART initiation or death. Among participants using ART at enrollment, we used linear mixed models to estimate the predicted mean CD4 change at select time points by contraceptive method. Results During a total of 5233 months follow-up among participants not using ART with enrollment CD4 ≥ 350 cells/mm3 (n=315), 97 experienced disease progression. Neither current use of COCs [adjusted hazard ratio (aHR) 0.91, 95% confidence interval (CI) 0.56–1.48] nor DMPA (aHR 1.28, 95% CI 0.71–2.31) was associated with a statistically significant increased risk for disease progression compared with use of nonhormonal methods (IUD or condoms). Among participants using ART at enrollment (n=77), we found no statistically significant differences in the predicted mean changes in CD4 cell count comparing current use of COCs (p=.1) or DMPA (p=.3) with nonhormonal methods. Conclusion Hormonal contraceptive use was not significantly associated with measures of HIV disease progression or ART effectiveness among women with prevalent HIV infection. Implications Hormonal contraceptive use was not significantly associated with measures of HIV disease progression or ART effectiveness among women with prevalent HIV infection. PMID:26197261

  16. Progressive disease in glioblastoma: Benefits and limitations of semi-automated volumetry

    PubMed Central

    Alber, Georgina; Bette, Stefanie; Kaesmacher, Johannes; Boeckh-Behrens, Tobias; Gempt, Jens; Ringel, Florian; Specht, Hanno M.; Meyer, Bernhard; Zimmer, Claus

    2017-01-01

    Purpose Unambiguous evaluation of glioblastoma (GB) progression is crucial, both for clinical trials as well as day by day routine management of GB patients. 3D-volumetry in the follow-up of GB provides quantitative data on tumor extent and growth, and therefore has the potential to facilitate objective disease assessment. The present study investigated the utility of absolute changes in volume (delta) or regional, segmentation-based subtractions for detecting disease progression in longitudinal MRI follow-ups. Methods 165 high resolution 3-Tesla MRIs of 30 GB patients (23m, mean age 60.2y) were retrospectively included in this single center study. Contrast enhancement (CV) and tumor-related signal alterations in FLAIR images (FV) were semi-automatically segmented. Delta volume (dCV, dFV) and regional subtractions (sCV, sFV) were calculated. Disease progression was classified for every follow-up according to histopathologic results, decisions of the local multidisciplinary CNS tumor board and a consensus rating of the neuro-radiologic report. Results A generalized logistic mixed model for disease progression (yes / no) with dCV, dFV, sCV and sFV as input variables revealed that only dCV was significantly associated with prediction of disease progression (P = .005). Delta volume had a better accuracy than regional, segmentation-based subtractions (79% versus 72%) and a higher area under the curve by trend in ROC curves (.83 versus .75). Conclusion Absolute volume changes of the contrast enhancing tumor part were the most accurate volumetric determinant to detect progressive disease in assessment of GB and outweighed FLAIR changes as well as regional, segmentation-based image subtractions. This parameter might be useful in upcoming objective response criteria for glioblastoma. PMID:28245291

  17. Multivariate clustering of progression profiles reveals different depression patterns in prodromal Huntington disease

    PubMed Central

    Kim, Ji-in; Long, Jeffrey D.; Mills, James A.; McCusker, Elizabeth; Paulsen, Jane S.

    2015-01-01

    Objective Although Huntington disease (HD) is caused by an autosomal dominant mutation, its phenotypic presentation differs widely. Variability in clinical phenotypes of HD may reflect the existence of disease subtypes. This hypothesis was tested in prodromal participants from the longitudinal Neurobiological Predictors of Huntington's Disease (PREDICT-HD) study. Method We performed clustering using longitudinal data assessing motor, cognitive, and depression symptoms. Using data from 521 participants with 2716 data points, we fit growth mixture models (GMM) that identify groups based on multivariate trajectories. Results In various GMM, different phases of disease progression were partitioned by progression trajectories of motor and cognitive signs, and by overall level of depression symptoms. More progressed motor signs were accompanied by more progressed cognitive signs, but not always by higher levels of depressive symptoms. In several models, there were at least two groups with similar trajectories for motor and cognitive signs that showed different levels for depression symptoms - one with a very low level of depression and the other with a higher level of depression. Conclusions Findings indicate that at least intermediate HD progression might be associated with different levels of depression. Depression is one of the few symptoms that is treatable in HD and has implications for clinical care. Identification of potential depression subtypes may also help to select appropriate patients for clinical trials. PMID:26011117

  18. Dyspnoea assessed by visual analogue scale in patients with chronic obstructive lung disease during progressive and high intensity exercise.

    PubMed Central

    Noseda, A; Carpiaux, J P; Schmerber, J; Yernault, J C

    1992-01-01

    BACKGROUND: A study was carried out to determine whether rating of dyspnoea by means of a visual analogue scale during a progressive exercise test is affected by the subject's awareness of the progressive nature of the protocol. METHODS: Nineteen patients with chronic obstructive lung disease (FEV1 mean (SE) 1.06 (0.07) 1) were studied. A preliminary incremental test was carried out with a work rate increasing by 10 watts every minute until the subject could no longer exercise, to determine the maximum work load (Wmax) and to anchor the upper end of the visual analogue scale. This was followed by two exercise tests performed one day apart in randomised sequence, with two different protocols. One was a 12 minute protocol that included two sudden bursts of three minute high intensity exercise, up to the subject's Wmax, each preceded by three minutes of low level exercise. The other test was a conventional three minute incremental test lasting 12 minutes. On both study days the only information given to the subject about the temporal profile of load was that a change would be made every three minutes. The relation between dyspnoea, as assessed by the visual analogue scale, and ventilation, measured during high intensity or progressive exercise, was studied. RESULTS: The mean (SE) rates of increase of dyspnoea with increasing ventilation (% of line length 1(-1) min) obtained by linear regression analysis were similar for the two tests (2.86 (0.20) for progressive exercise and 2.87 (0.25) for high intensity exercise); it was 2.59 (0.25) for the initial burst of high intensity exercise when the data on this were analysed separately. In six subjects with stable disease studied again two months later the reproducibility of the rating of dyspnoea was reasonably good for both protocols. CONCLUSION: The results suggest that in most patients with chronic obstructive lung disease the assessment of exercise induced dyspnoea by means of a visual analogue scale during a

  19. Quantitative EEG parameters correlate with the progression of human prion diseases

    PubMed Central

    Wehner, Tim; Lowe, Jessica; Porter, Marie-Claire; Kenny, Joanna; Thompson, Andrew; Rudge, Peter; Collinge, John; Mead, Simon

    2016-01-01

    Background Prion diseases are universally fatal and often rapidly progressive neurodegenerative diseases. EEG has long been used in the diagnosis of sporadic Creutzfeldt-Jakob disease; however, the characteristic waveforms do not occur in all types of prion diseases. Here, we re-evaluate the utility of EEG by focusing on the development of biomarkers. We test whether abnormal quantitative EEG parameters can be used to measure disease progression in prion diseases or predict disease onset in healthy individuals at risk of disease. Methods In the National Prion Monitoring Cohort study, we did quantitative encephalography on 301 occasions in 29 healthy controls and 67 patients with prion disease. The patients had either inherited prion disease or sporadic Creutzfeldt-Jakob disease. We computed the main background frequency, the α and θ power and the α/θ power ratio, then averaged these within 5 electrode groups. These measurements were then compared among participant groups and correlated with functional and cognitive scores cross-sectionally and longitudinally. Results We found lower main background frequency, α power and α/θ power ratio and higher θ power in patients compared to control participants. The main background frequency, the power in the α band and the α/θ power ratio also differed in a consistent way among the patient groups. Moreover, the main background frequency and the α/θ power ratio correlated significantly with functional and cognitive scores. Longitudinally, change in these parameters also showed significant correlation with the change in clinical and cognitive scores. Conclusions Our findings support the use of quantitative EEG to follow the progression of prion disease, with potential to help evaluate the treatment effects in future clinical-trials. PMID:27413165

  20. Effects of daily pain intensity, positive affect, and individual differences in pain acceptance on work goal interference and progress.

    PubMed

    Mun, Chung Jung; Karoly, Paul; Okun, Morris A

    2015-11-01

    Multilevel modeling was used to examine the effects of morning pain intensity and morning positive and negative affect on pain's interference with afternoon work goal pursuit and with evening work goal progress in a community sample of 132 adults who completed a 21-day diary. The moderating effects of pain acceptance and pain catastrophizing on the associations between morning pain intensity and afternoon work goal interference were also tested. Results revealed that the positive relationship between morning pain intensity and pain's interference with work goal pursuit was significantly moderated by pain acceptance, but not by pain catastrophizing. Both morning pain intensity and positive affect exerted significant indirect effects on evening work goal progress through the perception of pain's interference with work goal pursuit in the afternoon. Furthermore, the mediated effect of morning pain on evening work goal progress was significant when pain acceptance was at the grand mean and 1 SD below the grand mean, but not when pain acceptance was 1 SD above the grand mean. Thus, it appears that high pain acceptance significantly attenuates pain's capacity to disrupt work goal pursuit. Moreover, morning positive affect appears to operate as a protective factor. Additional interpretations and potential explanations for some inconsistent outcomes are discussed along with limitations, clinical implications, and suggestions for future studies.

  1. Chronic temporal lobe epilepsy: a neurodevelopmental or progressively dementing disease?

    PubMed

    Helmstaedter, C; Elger, C E

    2009-10-01

    To what degree does the so-called 'initial hit' of the brain versus chronic epilepsy contribute towards the memory impairment observed in chronic temporal lobe epilepsy (TLE) patients? We examined cross-sectional comparisons of age-related regressions of verbal learning and memory in 1156 patients with chronic TLE (age range 6-68 years, mean epilepsy onset 14 +/- 11 years) versus 1000 healthy control subjects (age range 6-80 years) and tested the hypothesis that deviations of age regressions (i.e. slowed rise, accelerated decline) will reveal critical phases during which epilepsy interferes with cognitive development. Patients were recruited over a 20-year period at the Department of Epileptology, University of Bonn. Healthy subjects were drawn from an updated normative population of the Verbaler Lern- und Merkfähigkeitstest, the German pendant to the Rey Auditory Verbal learning Test. A significant divergence of age regressions indicates that patients fail to build up adequate learning and memory performance during childhood and particularly during adolescence. The learning peak (i.e. crossover into decline) is seen earlier in patients (at about the age of 16-17 years) than for controls (at about the age of 23-24 years). Decline in performance with ageing in patients and controls runs in parallel, but due to the initial distance between the groups, patients reach very poor performance levels much earlier than controls. Patients with left and right TLEs performed worse in verbal memory than controls. In addition, patients with left TLE performed worse than those with right TLE. However, laterality differences were evident only in adolescent and adult patients, and not (or less so) in children and older patients. Independent of age, hippocampal sclerosis was associated with poorer performance than other pathologies. The results indicate developmental hindrance plus a negative interaction of cognitive impairment with mental ageing, rather than a progressively

  2. Effect of Paget's disease of bone (osteitis deformans) on the progression of prostate cancer bone metastasis

    PubMed Central

    Tu, S-M; Som, A; Tu, B; Logothetis, C J; Lee, M-H; Yeung, S-CJ

    2012-01-01

    Background: Patients with prostate cancer tend to die from bone metastases. Until now, no evidence has shown that Paget's disease of bone (PDB) affects the progression of bone metastasis or overall survival of patients with prostate cancer. Methods: We searched our patient database for men who had presented with prostate cancer and PDB between June 1993 and March 2009, and identified best-matched control patients according to stage, grade, age, date of diagnosis, treatment, and race. Results: Among 1346 consecutive patients with prostate cancer diagnosed before 2008, 15 were confirmed to have comorbid PDB. Twenty-six more were identified from the institutional billing search. Including the 41 best-matched controls, our total study population was 82 patients. In the Kaplan–Meier analysis, we estimated median times from diagnosis of prostate cancer to bone metastasis to be 21.5 years for those with PDB and 9.4 years for those without PDB (P=0.044). Median overall survival times were 11.8 and 9.2 years for the two groups, respectively (P=0.008). Conclusion: For the first time, we have obtained evidence that patients with prostate cancer and PDB have delayed time to bone metastases and improved overall survival than do patients with prostate cancer alone. PMID:22805323

  3. Decision Aids for Multiple-Decision Disease Management as Affected by Weather Input Errors

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Many disease management decision support systems (DSS) rely, exclusively or in part, on weather inputs to calculate an indicator for disease hazard. Error in the weather inputs, typically due to forecasting, interpolation or estimation from off-site sources, may affect model calculations and manage...

  4. The Ecology of Technological Progress: How Symbiosis and Competition Affect the Growth of Technology Domains

    ERIC Educational Resources Information Center

    Carnabuci, Gianluca

    2010-01-01

    We show that the progress of technological knowledge is an inherently ecological process, wherein the growth rate of each technology domain depends on dynamics occurring in "other" technology domains. We identify two sources of ecological interdependence among technology domains. First, there are symbiotic interdependencies, implying…

  5. Caregiver-recipient closeness and symptom progression in Alzheimer disease. The Cache County Dementia Progression Study.

    PubMed

    Norton, Maria C; Piercy, Kathleen W; Rabins, Peter V; Green, Robert C; Breitner, John C S; Ostbye, Truls; Corcoran, Christopher; Welsh-Bohmer, Kathleen A; Lyketsos, Constantine G; Tschanz, Joann T

    2009-09-01

    Applying Rusbult's investment model of dyadic relationships, we examined the effect of caregiver-care recipient relationship closeness (RC) on cognitive and functional decline in Alzheimer's disease. After diagnosis, 167 participants completed up to six visits, observed over an average of 20 months. Participants were 64% women, had a mean age of 86 years, and mean dementia duration of 4 years. Caregiver-rated closeness was measured using a six-item scale. In mixed models adjusted for dementia severity, dyads with higher levels of closeness (p < .05) and with spouse caregivers (p = .01) had slower cognitive decline. Effect of higher RC on functional decline was greater with spouse caregivers (p = .007). These findings of attenuated Alzheimer's dementia (AD) decline with closer relationships, particularly with spouse caregivers, are consistent with investment theory. Future interventions designed to enhance the caregiving dyadic relationship may help slow decline in AD.

  6. Estimating Premorbid Functioning in Huntington's Disease: The Relationship between Disease Progression and the Wide Range Achievement Test Reading Subtest

    PubMed Central

    O'Rourke, Justin J.F.; Adams, William H.; Duff, Kevin; Byars, Joanne; Nopoulos, Peg; Paulsen, Jane S.; Beglinger, Leigh J.

    2011-01-01

    The estimation of premorbid abilities is an essential part of a neuropsychological evaluation, especially in neurodegenerative conditions. Although word pronunciation tests are one standard method for estimating the premorbid level, research suggests that these tests may not be valid in neurodegenerative diseases. Therefore, the current study sought to examine two estimates of premorbid intellect, the Wide Range Achievement Test (WRAT) Reading subtest and the Barona formula, in 93 patients with mild to moderate Huntington's disease (HD) to determine their utility and to investigate how these measures relate to signs and symptoms of disease progression. In 89% of participants, WRAT estimates were below the Barona estimates. WRAT estimates were related to worsening memory and motor functioning, whereas the Barona estimates had weaker relationships. Neither estimate was related to depression or functional capacity. Irregular word reading tests appear to decline with HD progression, whereas estimation methods based on demographic factors may be more robust but overestimate premorbid functioning. PMID:21147861

  7. Ebolavirus Vaccines: Progress in the Fight Against Ebola Virus Disease.

    PubMed

    Wu, Xiao-Xin; Yao, Hang-Ping; Wu, Nan-Ping; Gao, Hai-Nv; Wu, Hai-Bo; Jin, Chang-Zhong; Lu, Xiang-Yun; Xie, Tian-Shen; Li, Lan-Juan

    2015-01-01

    Ebolaviruses are highly infectious pathogens that cause lethal Ebola virus disease (EVD) in humans and non-human primates (NHPs). Due to their high pathogenicity and transmissibility, as well as the potential to be misused as a bioterrorism agent, ebolaviruses would threaten the health of global populations if not controlled. In this review, we describe the origin and structure of ebolaviruses and the development of vaccines from the beginning of the 1980s, including conventional ebolavirus vaccines, DNA vaccines, Ebola virus-like particles (VLPs), vaccinia virus-based vaccines, Venezuelan equine encephalitis virus (VEEV)-like replicon particles, Kunjin virus-based vaccine, recombinant Zaire Ebolavirusx2206;VP30, recombinant cytomegalovirus (CMV)-based vaccines, recombinant rabies virus (RABV)-based vaccines, recombinant paramyxovirus-based vaccines, adenovirus-based vaccines and vesicular stomatitis virus (VSV)-based vaccines. No licensed vaccine or specific treatment is currently available to counteract ebolavirus infection, although DNA plasmids and several viral vector approaches have been evaluated as promising vaccine platforms. These vaccine candidates have been confirmed to be successful in protecting NHPs against lethal infection. Moreover, these vaccine candidates were successfully advanced to clinical trials. The present review provides an update of the current research on Ebola vaccines, with the aim of providing an overview on current prospects in the fight against EVD.

  8. Quantitative Micro-Computed Tomography Imaging of Vascular Dysfunction in Progressive Kidney Diseases.

    PubMed

    Ehling, Josef; Bábíčková, Janka; Gremse, Felix; Klinkhammer, Barbara M; Baetke, Sarah; Knuechel, Ruth; Kiessling, Fabian; Floege, Jürgen; Lammers, Twan; Boor, Peter

    2016-02-01

    Progressive kidney diseases and renal fibrosis are associated with endothelial injury and capillary rarefaction. However, our understanding of these processes has been hampered by the lack of tools enabling the quantitative and noninvasive monitoring of vessel functionality. Here, we used micro-computed tomography (µCT) for anatomical and functional imaging of vascular alterations in three murine models with distinct mechanisms of progressive kidney injury: ischemia-reperfusion (I/R, days 1-56), unilateral ureteral obstruction (UUO, days 1-10), and Alport mice (6-8 weeks old). Contrast-enhanced in vivo µCT enabled robust, noninvasive, and longitudinal monitoring of vessel functionality and revealed a progressive decline of the renal relative blood volume in all models. This reduction ranged from -20% in early disease stages to -61% in late disease stages and preceded fibrosis. Upon Microfil perfusion, high-resolution ex vivo µCT allowed quantitative analyses of three-dimensional vascular networks in all three models. These analyses revealed significant and previously unrecognized alterations of preglomerular arteries: a reduction in vessel diameter, a prominent reduction in vessel branching, and increased vessel tortuosity. In summary, using µCT methodology, we revealed insights into macro-to-microvascular alterations in progressive renal disease and provide a platform that may serve as the basis to evaluate vascular therapeutics in renal disease.

  9. Dietary flax oil during pregnancy and lactation retards disease progression in rat offspring with inherited kidney disease.

    PubMed

    Sankaran, Deepa; Bankovic-Calic, Neda; Peng, Claudia Yu-Chen; Ogborn, Malcolm R; Aukema, Harold M

    2006-12-01

    Dietary flax oil (FO) retards disease progression in growing or adult animal models of kidney disease. To determine whether dietary flax oil during the perinatal period would alter renal disease progression in offspring, Han-SPRD-cy rats with inherited cystic kidney disease were given diets with either 7% FO or corn oil (CO), throughout pregnancy and lactation. At 3 wk of age, offspring were then given either the same or the alternate diet for 7 wk. Rats given FO during the maternal period had 15% less renal cyst growth compared with rats given FO only in the postweaning period. Dietary FO, compared with CO, in the maternal period also resulted in 12% lower cell proliferation and 15% less oxidant injury in diseased kidneys of offspring. Including FO in both the maternal and postweaning period resulted in 29-34% less renal interstitial fibrosis and 22-23% lower glomerular hypertrophy. Along with improved histology, these rats exhibited 13% less proteinuria and 30% lower creatinine clearance when dietary FO was given in the maternal period. The potential for dietary FO during pregnancy and lactation to positively modulate adult renal disease has significant implications for the 1 in 1000 individuals with congenital cystic kidney disease.

  10. Serum microRNA-125a-5p, a useful biomarker in liver diseases, correlates with disease progression.

    PubMed

    Zheng, Jianjian; Zhou, Zhenxu; Xu, Ziqiang; Li, Guojun; Dong, Peihong; Chen, Zhanguo; Lin, Dezhao; Chen, Bicheng; Yu, Fujun

    2015-07-01

    It has been demonstrated that liver microRNA-125a-5p (miR-125a-5p) is correlated with disease progression in different liver diseases, including liver fibrosis and hepatocellular carcinoma (HCC). The present study investigated whether serum miR-125a-5p correlated with the progression of different liver diseases. Serum samples were obtained from healthy individuals, patients with chronic hepatitis B who had undergone a liver biopsy, and patients with HCC and were analyzed for the levels of miR-125a-5p. Compared with the healthy controls, the serum levels of miR-125a-5p were significantly higher in the liver fibrosis serum, and were reduced in HCC. With the development of liver fibrosis, there was a significant increase in the expression of miR-125a-5p (P<0.05). In comparing histological activity index (HAI) scores, higher expression levels of miR125a-5p were observed in the high HAI score group (P<0.05). Furthermore, correlation between serum miR-125a-5p and viral replication (P<0.001) was observed. Notably, miR-125a-5p demonstrated significant correlation with other markers in the liver fibrosis group (P<0.001). In the patients with HCC, lower serum levels of miR-125a-5p were correlated with a poor prognosis, determined by Kaplan-Meier curve analysis (P=0.009). In the liver fibrosis and HCC groups, different expression levels of serum miR-125a-5p were observed, and were correlated with disease progression. The results of the present study suggested that serum miR-125a-5p may be used as a non-invasive biomarker for monitoring disease progression in liver diseases.

  11. The utility of cerebral blood flow imaging in patients with the unique syndrome of progressive dementia with motor neuron disease

    SciTech Connect

    Ohnishi, T.; Hoshi, H.; Jinnouchi, S.; Nagamachi, S.; Watanabe, K.; Mituyama, Y. )

    1990-05-01

    Two patients presenting with progressive dementia coupled with motor neuron disease underwent brain SPECT using N-isopropyl-p iodine-123-iodoamphetamine (({sup 123}I)IMP). The characteristic clinical features of progressive dementia and motor neuron disease were noted. IMP SPECT also revealed reduced uptake in the bilateral frontal and temporal regions, with no reduction of uptake in the parietal, parietal-occipital regions. We conclude that IMP SPECT has potential for the evaluation of progressive dementia with motor neuron disease.

  12. An economic model of Parkinson's disease: implications for slowing progression in the United States.

    PubMed

    Johnson, Scott J; Diener, Melissa D; Kaltenboeck, Anna; Birnbaum, Howard G; Siderowf, Andrew D

    2013-03-01

    Multiple studies describe progression, dementia rates, direct and indirect costs, and health utility by Hoehn and Yahr (H&Y) stage, but research has not incorporated these data into a model to evaluate possible economic consequences of slowing progression. This study aimed to model the course of Parkinson's disease (PD) and describe the economic consequences of slower rates of progression. A Markov model was developed to show the net monetary benefits of slower rates of progression. Four scenarios assuming hypothetical slower rates of progression were compared to a base case scenario. A systematic literature review identified published longitudinal H&Y progression rates. Direct and indirect excess costs (i.e., healthcare costs beyond what similar patients without PD would incur), mortality rates, dementia rates, and health utility were derived from the literature. Ten publications (N = 3,318) were used to model longitudinal H&Y progression. Base case results indicate average excess direct costs of $303,754, life-years of 12.8 years and quality-adjusted life-years of 6.96. A scenario where PD progressed 20% slower than the base case resulted in net monetary benefits of $60,657 ($75,891 including lost income) per patient. The net monetary benefit comes from a $37,927 decrease in direct medical costs, 0.45 increase in quality-adjusted life-years, and $15,235 decrease in lost income. The scenario where PD progression was arrested resulted in net monetary benefits of $442,429 per patient. Reducing progression rates could produce significant economic benefit. This benefit is strongly dependent on the degree to which progression is slowed.

  13. Minimally Invasive Early Operative Treatment of Progressive Foot and Ankle Deformity Associated With Charcot-Marie-Tooth Disease.

    PubMed

    Boffeli, Troy J; Tabatt, Jessica A

    2015-01-01

    Charcot-Marie-Tooth disease is a neuromuscular disorder that commonly results in a predictable pattern of progressive bilateral lower extremity weakness, numbness, contracture, and deformity, including drop foot, loss of ankle eversion strength, dislocated hammertoes, and severe cavus foot deformity. Late stage reconstructive surgery will be often necessary if the deformity becomes unbraceable or when neuropathic ulcers have developed. Reconstructive surgery for Charcot-Marie-Tooth deformity is generally extensive and sometimes staged. Traditional reconstructive surgery involves a combination of procedures, including tendon lengthening or transfer, osteotomy, and arthrodesis. The described technique highlights our early surgical approach, which involves limited intervention before the deformity becomes rigid, severe, or disabling. We present 2 cases to contrast our early minimally invasive technique with traditional late stage reconstruction. Charcot-Marie-Tooth disease affects different muscles at various stages of disease progression. As 1 muscle becomes weak, the antagonist will overpower it and cause progressive deformity. The focus of the early minimally invasive approach is to decrease the forces that cause progressive deformity yet maintain function, where possible. Our goal has been to maintain a functional and braceable foot and ankle, with the hope of avoiding or limiting the extent of future major reconstructive surgery. The presented cases highlight the patient selection criteria, the ideal timing of early surgical intervention, the procedure selection criteria, and operative pearls. The early minimally invasive approach includes plantar fasciotomy, Achilles tendon lengthening, transfer of the peroneus longus to the fifth metatarsal, Hibbs and Jones tendon transfer, and hammertoe repair of digits 1 to 5.

  14. Impacts of neglected tropical disease on incidence and progression of HIV/AIDS, tuberculosis, and malaria: scientific links.

    PubMed

    Simon, G G

    2016-01-01

    The neglected tropical diseases (NTDs) are the most common infections of humans in Sub-Saharan Africa. Virtually all of the population living below the World Bank poverty figure is affected by one or more NTDs. New evidence indicates a high degree of geographic overlap between the highest-prevalence NTDs (soil-transmitted helminths, schistosomiasis, onchocerciasis, lymphatic filariasis, and trachoma) and malaria and HIV, exhibiting a high degree of co-infection. Recent research suggests that NTDs can affect HIV and AIDS, tuberculosis (TB), and malaria disease progression. A combination of immunological, epidemiological, and clinical factors can contribute to these interactions and add to a worsening prognosis for people affected by HIV/AIDS, TB, and malaria. Together these results point to the impacts of the highest-prevalence NTDs on the health outcomes of malaria, HIV/AIDS, and TB and present new opportunities to design innovative public health interventions and strategies for these 'big three' diseases. This analysis describes the current findings of research and what research is still needed to strengthen the knowledge base of the impacts NTDs have on the big three.

  15. Microgeodic Disease Affecting the Fingers and Toes in Childhood: A Case Report

    PubMed Central

    Tetsunaga, Tomonori; Endo, Hirosuke; Fujiwara, Kazuo; Tetsunaga, Tomoko; Ozaki, Toshifumi

    2016-01-01

    Microgeodic disease is a disease of unknown etiology that affects the fingers and toes of children, with ≥ 90% of cases involving the fingers alone. We present a rare case of microgeodic disease affecting an index finger and two toes simultaneously in a 7-year-old girl. X-ray and magnetic resonance imaging (MRI) showed multiple small areas of osteolysis in the middle phalanges of the left index finger, hallux, and second toe. Microgeodic disease was diagnosed from X-ray and MRI findings, and conservative therapy involving rest and avoidance of cold stimuli was provided. Although pathological fractures occurred in the course of conservative treatment, the affected finger healed under splinting without any deformity of the finger. PMID:27843512

  16. The cellular stress response of the scleractinian coral Goniopora columna during the progression of the black band disease.

    PubMed

    Seveso, Davide; Montano, Simone; Reggente, Melissa Amanda Ljubica; Maggioni, Davide; Orlandi, Ivan; Galli, Paolo; Vai, Marina

    2017-03-01

    Black band disease (BBD) is a widespread coral pathology caused by a microbial consortium dominated by cyanobacteria, which is significantly contributing to the loss of coral cover and diversity worldwide. Since the effects of the BBD pathogens on the physiology and cellular stress response of coral polyps appear almost unknown, the expression of some molecular biomarkers, such as Hsp70, Hsp60, HO-1, and MnSOD, was analyzed in the apparently healthy tissues of Goniopora columna located at different distances from the infection and during two disease development stages. All the biomarkers displayed different levels of expression between healthy and diseased colonies. In the healthy corals, low basal levels were found stable over time in different parts of the same colony. On the contrary, in the diseased colonies, a strong up-regulation of all the biomarkers was observed in all the tissues surrounding the infection, which suffered an oxidative stress probably generated by the alternation, at the progression front of the disease, of conditions of oxygen supersaturation and hypoxia/anoxia, and by the production of the cyanotoxin microcystin by the BBD cyanobacteria. Furthermore, in the infected colonies, the expression of all the biomarkers appeared significantly affected by the development stage of the disease. In conclusion, our approach may constitute a useful diagnostic tool, since the cellular stress response of corals is activated before the pathogens colonize the tissues, and expands the current knowledge of the mechanisms controlling the host responses to infection in corals.

  17. Progress in reading and spelling of dyslexic children is not affected by executive functioning.

    PubMed

    Walda, Sietske A E; van Weerdenburg, Marjolijn; Wijnants, Maarten L; Bosman, Anna M T

    2014-12-01

    Although poor reading and spelling skills have been associated with weak skills of executive functioning (EF), its role in literacy is not undisputed. Because EF has different theoretical underpinnings, methods of analysis and of assessing, it has led to varying and often contrasting results in its effects in children with dyslexia. The present study has two goals. The first goal is to establish the relationship between a large number of EF tasks and reading and spelling skills in a large number of Dutch dyslexic children (n = 229). More interesting, however, is the second aim. To what extent do EF skills predict progress in reading and spelling in dyslexic children who attended a remediation programme? The results revealed small, but significant relationships between EF and reading and spelling skills, but no relationships between EF and progress in reading and spelling. It is concluded that training EF skills is unlikely to enhance reading and spelling skills.

  18.  PARK2 polymorphisms predict disease progression in patients infected with hepatitis C virus.

    PubMed

    Al-Qahtani, Ahmed A; Al-Anazi, Mashael R; Al-Zoghaibi, Fahad A; Abdo, Ayman A; Sanai, Faisal M; Al-Hamoudi, Waleed K; Alswat, Khalid A; Al-Ashgar, Hamad I; Khan, Mohammed Q; Albenmousa, Ali; Khalak, Hanif; Al-Ahdal, Mohammed N

     Background. The protein encoded by PARK2 gene is a component of the ubiquitin-proteasome system that mediates targeting of proteins for the degradation pathway. Genetic variations at PARK2 gene were linked to various diseases including leprosy, typhoid and cancer. The present study investigated the association of single nucleotide polymorphisms (SNPs) in the PARK2 gene with the development of hepatitis C virus (HCV) infection and its progression to severe liver diseases.

  19. Early HLA-B*57-Restricted CD8+ T Lymphocyte Responses Predict HIV-1 Disease Progression

    PubMed Central

    Ibarrondo, F. Javier; Sugar, Catherine A.; Hausner, Mary Ann; Shih, Roger; Ng, Hwee L.; Detels, Roger; Margolick, Joseph B.; Rinaldo, Charles R.; Phair, John; Jacobson, Lisa P.; Yang, Otto O.

    2012-01-01

    Although HLA-B*57 (B57) is associated with slow progression to disease following HIV-1 infection, B57 heterozygotes display a wide spectrum of outcomes, including rapid progression, viremic slow progression, and elite control. Efforts to identify differences between B57-positive (B57+) slow progressors and B57+ rapid progressors have largely focused on cytotoxic T lymphocyte (CTL) phenotypes and specificities during chronic stages of infection. Although CTL responses in the early months of infection are likely to be the most important for the long-term rate of HIV-1 disease progression, few data on the early CTL responses of eventual slow progressors have been available. Utilizing the Multicenter AIDS Cohort Study (MACS), we retrospectively examined the early HIV-1-specific CTL responses of 14 B57+ individuals whose time to development of disease ranged from 3.5 years to longer than 25 years after infection. In general, a greater breadth of targeting of epitopes from structural proteins, especially Gag, as well as of highly conserved epitopes from any HIV-1 protein, correlated with longer times until disease. The single elite controller in the cohort was an outlier on several correlations of CTL targeting and time until disease, consistent with reports that elite control is typically not achieved solely by protective HLA-mediated CTLs. When targeting of individual epitopes was analyzed, we found that early CTL responses to the IW9 (ISPRTLNAW) epitope of Gag, while generally subdominant, correlated with delayed progression to disease. This is the first study to identify early CTL responses to IW9 as a correlate of protection in persons with HLA-B*57. PMID:22811521

  20. Iron homeostasis and progression to pulmonary tuberculosis disease among household contacts.

    PubMed

    Minchella, Peter A; Donkor, Simon; McDermid, Joann M; Sutherland, Jayne S

    2015-05-01

    Early identification of individuals at risk for progressing to active tuberculosis (TB) disease may limit new transmission and improve clinical outcomes. Evidence indicates altered iron homeostasis may identify those at greater risk of disease progression in HIV co-infection. We aimed to investigate iron homeostasis biomarkers as risk factors for progression to TB. Archived plasma samples were analyzed from household contacts of pulmonary TB index cases in The Gambia. Contacts were classified as asymptomatic non-progressors (n = 17) or TB-progressors (n = 10), which included two HIV-infected participants. Iron homeostasis (hemoglobin, ferritin, hepcidin, soluble transferrin receptor, transferrin) was assessed in all contacts at study recruitment. Plasma was collected a median of 910 days prior to TB diagnosis. Low transferrin around the time of known exposure to infectious TB was a disease progression risk factor among all TB-progressors (Poisson incidence rate ratio: 0.55; 95% CI: 0.35-0.89). Iron homeostasis also differed between early and delayed TB-progressors, with higher ferritin and hepcidin concentrations observed among early TB-progressors (mean ferritin 50.2 vs. 26.2 ng/ml; P = 0.027; mean hepcidin 37.7 vs. 5.6 ng/ml; P = 0.036). Iron homeostasis is associated with progression to TB among household contacts. Further studies are needed to elucidate mechanisms and determine the clinical utility of monitoring iron homeostasis biomarkers.

  1. Genetic Deficiency of Complement Component 3 Does Not Alter Disease Progression in a Mouse Model of Huntington's Disease.

    PubMed

    Larkin, Paul B; Muchowski, Paul J

    2012-01-01

    Several genes and proteins of the complement cascade are present at elevated levels in brains of patients with Huntington's disease (HD). The complement cascade is well characterized as an effector arm of the immune system, and in the brain it is important for developmental synapse elimination. We hypothesized that increased levels of complement in HD brains contributes to disease progression, perhaps by contributing to synapse elimination or inflammatory signaling. We tested this hypothesis in the R6/2 mouse model of HD by crossing mice deficient in complement component 3 (C3), a crucial complement protein found at increased levels in HD brains, to R6/2 mice and monitoring behavioral and neuropathological disease progression. We found no alterations in multiple behavioral assays, weight or survival in R6/2 mice lacking C3. We also quantified the expression of several complement cascade genes in R6/2 brains and found that the large scale upregulation of complement genes observed in HD brains is not mirrored in R6/2 brains. These data show that C3 deficiency does not alter disease progression in the R6/2 mouse model of HD.

  2. Neurofilament Light Chain in Blood and CSF as Marker of Disease Progression in Mouse Models and in Neurodegenerative Diseases.

    PubMed

    Bacioglu, Mehtap; Maia, Luis F; Preische, Oliver; Schelle, Juliane; Apel, Anja; Kaeser, Stephan A; Schweighauser, Manuel; Eninger, Timo; Lambert, Marius; Pilotto, Andrea; Shimshek, Derya R; Neumann, Ulf; Kahle, Philipp J; Staufenbiel, Matthias; Neumann, Manuela; Maetzler, Walter; Kuhle, Jens; Jucker, Mathias

    2016-07-06

    A majority of current disease-modifying therapeutic approaches for age-related neurodegenerative diseases target their characteristic proteopathic lesions (α-synuclein, Tau, Aβ). To monitor such treatments, fluid biomarkers reflecting the underlying disease process are crucial. We found robust increases of neurofilament light chain (NfL) in CSF and blood in murine models of α-synucleinopathies, tauopathy, and β-amyloidosis. Blood and CSF NfL levels were strongly correlated, and NfL increases coincided with the onset and progression of the corresponding proteopathic lesions in brain. Experimental induction of α-synuclein lesions increased CSF and blood NfL levels, while blocking Aβ lesions attenuated the NfL increase. Consistently, we also found NfL increases in CSF and blood of human α-synucleinopathies, tauopathies, and Alzheimer's disease. Our results suggest that CSF and particularly blood NfL can serve as a reliable and easily accessible biomarker to monitor disease progression and treatment response in mouse models and potentially in human proteopathic neurodegenerative diseases.

  3. [McArdle disease or glycogen storage disease type v: Should it affect anaesthetic management?].

    PubMed

    Ayerza-Casas, V; Ferreira-Laso, L; Alloza-Fortun, M C; Fraile-Jimenez, A E

    2015-02-01

    McArdle disease is a metabolic myopathy that can may lead to severe perioperative problems. A case is reported of a woman with a history of McArdle disease, who was scheduled for a mastectomy. An understanding of the physiology and pathology, and the application of appropriate preventive measures can avoid complications. A overview of the complications and the management are described.

  4. Advance care discussions with young people affected by life-limiting neuromuscular diseases: A systematic literature review and narrative synthesis.

    PubMed

    Hiscock, Andy; Kuhn, Isla; Barclay, Stephen

    2017-02-01

    End of life care policy in the UK advocates open discussions between health professionals and patients as the end of life approaches. Despite well documented understanding of the progression of life-limiting neuromuscular diseases, the majority of patients affected by such conditions die without a formal end of life plan in place. We performed a systematic review to investigate conversations regarding end of life care between healthcare professionals and younger adult patients with life-limiting neuromuscular diseases. The search strategy included terms that focused on death and dying along with other factors that could impact length of life. The review found a very limited body of literature regarding end of life care conversations between young people affected by neuromuscular diseases and health professionals. The views and preferences of patients themselves have not been investigated. There is a shared reluctance of patients, family carers and healthcare professionals to initiate end of life care discussions. There are many factors that need to be investigated further in order to develop a consensus that would allow healthcare professionals to engage patients in end of life care conversations allowing them to face the end of their lives with appropriate plans in place.

  5. CD24 expression does not affect dopamine neuronal survival in a mouse model of Parkinson's disease

    PubMed Central

    Hayat, Shaista; Carnwath, Tom; Garas, Shaady; Sleeman, Jonathan P.; Barker, Roger A.

    2017-01-01

    Parkinson’s disease (PD) is a progressive neurodegenerative condition that is characterised by the loss of specific populations of neurons in the brain. The mechanisms underlying this selective cell death are unknown but by using laser capture microdissection, the glycoprotein, CD24 has been identified as a potential marker of the populations of cells that are affected in PD. Using in situ hybridization and immunohistochemistry on sections of mouse brain, we confirmed that CD24 is robustly expressed by many of these subsets of cells. To determine if CD24 may have a functional role in PD, we modelled the dopamine cell loss of PD in Cd24 mutant mice using striatal delivery of the neurotoxin 6-OHDA. We found that Cd24 mutant mice have an anatomically normal dopamine system and that this glycoprotein does not modulate the lesion effects of 6-OHDA delivered into the striatum. We then undertook in situ hybridization studies on sections of human brain and found—as in the mouse brain—that CD24 is expressed by many of the subsets of the cells that are vulnerable in PD, but not those of the midbrain dopamine system. Finally, we sought to determine if CD24 is required for the neuroprotective effect of Glial cell-derived neurotrophic factor (GDNF) on the dopaminergic nigrostriatal pathway. Our results indicate that in the absence of CD24, there is a reduction in the protective effects of GDNF on the dopaminergic fibres in the striatum, but no difference in the survival of the cell bodies in the midbrain. While we found no obvious role for CD24 in the normal development and maintenance of the dopaminergic nigrostriatal system in mice, it may have a role in mediating the neuroprotective aspects of GDNF in this system. PMID:28182766

  6. Category and Letter Fluency in Semantic Dementia, Primary Progressive Aphasia, and Alzheimer's Disease

    ERIC Educational Resources Information Center

    Marczinski, Cecile A.; Kertesz, Andrew

    2006-01-01

    This study examined the impact of various degenerative dementias on access to semantic knowledge and the status of semantic representations. Patients with semantic dementia, primary progressive aphasia, and Alzheimer's disease were compared with elderly controls on tasks of category and letter fluency, with number of words generated, mean lexical…

  7. Physical therapy assessment tools to evaluate disease progression and phenotype variability in Golden Retriever muscular dystrophy.

    PubMed

    Gaiad, T P; Silva, M B; Silva, G C A; Caromano, F A; Miglino, M A; Ambrósio, C E

    2011-10-01

    Dogs suffering from Golden Retriever muscular dystrophy (GRMD) present symptoms that are similar to human patients with Duchenne muscular dystrophy (DMD). Phenotypic variability is common in both cases and correlates with disease progression and response to therapy. Physical therapy assessment tools were used to study disease progression and assess phenotypic variability in dogs with GRMD. At 5 (T0), 9 (T1), 13 (T2) and 17 (T3)months of age, the physical features, joint ranges of motion (ROM), limb and thorax circumferences, weight and creatine kinase (CK) levels were assessed in 11 dogs with GRMD. Alterations of physical features were higher at 13 months, and different disease progression rates were observed. Passive ROM decreased until 1 year old, which was followed by a decline of elbow and tarsal ROM. Limb and thorax circumferences, which were corrected for body weight, decreased significantly between T0 and T3. These measurements can be used to evaluate disease progression in dogs with GRMD and to help discover new therapies for DMD patients.

  8. The Functional Transitions Model: Maximizing Ability in the Context of Progressive Disability Associated with Alzheimer's Disease

    ERIC Educational Resources Information Center

    Slaughter, Susan; Bankes, Jane

    2007-01-01

    The Functional Transitions Model (FTM) integrates the theoretical notions of progressive functional decline associated with Alzheimer's disease (AD), excess disability, and transitions occurring intermittently along the trajectory of functional decline. Application of the Functional Transitions Model to clinical practice encompasses the paradox of…

  9. Brain Substrates of Learning and Retention in Mild Cognitive Impairment Diagnosis and Progression to Alzheimer's Disease

    ERIC Educational Resources Information Center

    Chang, Yu-Ling; Bondi, Mark W.; Fennema-Notestine, Christine; McEvoy, Linda K.; Hagler, Donald J., Jr.; Jacobson, Mark W.; Dale, Anders M.

    2010-01-01

    Understanding the underlying qualitative features of memory deficits in mild cognitive impairment (MCI) can provide critical information for early detection of Alzheimer's disease (AD). This study sought to investigate the utility of both learning and retention measures in (a) the diagnosis of MCI, (b) predicting progression to AD, and (c)…

  10. Brain iron deposition fingerprints in Parkinson's disease and progressive supranuclear palsy.

    PubMed

    Boelmans, Kai; Holst, Brigitte; Hackius, Marc; Finsterbusch, Jürgen; Gerloff, Christian; Fiehler, Jens; Münchau, Alexander

    2012-03-01

    It can be difficult to clinically distinguish between classical Parkinson's disease (PD) and progressive supranuclear palsy. Previously, there have been no biomarkers that reliably allow this distinction to be made. We report that an abnormal brain iron accumulation is a marker for ongoing neurodegeneration in both conditions, but the conditions differ with respect to the anatomical distribution of these accumulations. We analyzed quantitative T2' maps as markers of regional brain iron content from PD and progressive supranuclear palsy patients and compared them to age-matched control subjects. T2-weighted and T2*-weighted images were acquired in 30 PD patients, 12 progressive supranuclear palsy patients, and 24 control subjects at 1.5 Tesla. Mean T2' values were determined in regions-of-interest in the basal ganglia, thalamus, and white matter within each hemisphere. The main findings were shortened T2' values in the caudate nucleus, globus pallidus, and putamen in progressive supranuclear palsy compared to PD patients and controls. A stepwise linear discriminant analysis allowed progressive supranuclear palsy patients to be distinguished from PD patients and the healthy controls. All progressive supranuclear palsy patients were correctly classified. No progressive supranuclear palsy patient was classified as a healthy control, no healthy controls were incorrectly classified as having progressive supranuclear palsy, and only 6.7% of the PD patients were incorrectly classified as progressive supranuclear palsy. Regional decreases of T2' relaxation times in parts of the basal ganglia reflecting increased brain iron load in these areas are characteristic for progressive supranuclear palsy but not PD patients.

  11. Nuclear localization of γ-tubulin affects E2F transcriptional activity and S-phase progression

    PubMed Central

    Höög, Greta; Zarrizi, Reihaneh; von Stedingk, Kristoffer; Jonsson, Kristina; Alvarado-Kristensson, Maria

    2011-01-01

    We show that the centrosome- and microtubule-regulating protein γ-tubulin interacts with E2 promoter binding factors (E2Fs) to modulate E2F transcriptional activity and thereby control cell cycle progression. γ-Tubulin contains a C-terminal signal that results in its translocation to the nucleus during late G1 to early S phase. γ-Tubulin mutants showed that the C terminus interacts with the transcription factor E2F1 and that the E2F1–γ-tubulin complex is formed during the G1/S transition, when E2F1 is transcriptionally active. Furthermore, E2F transcriptional activity is altered by reduced expression of γ-tubulin or by complex formation between γ-tubulin and E2F1, E2F2, or E2F3, but not E2F6. In addition, the γ-tubulin C terminus encodes a DNA-binding domain that interacts with E2F-regulated promoters, resulting in γ-tubulin-mediated transient activation of E2Fs. Thus, we report a novel mechanism regulating the activity of E2Fs, which can help explain how these proteins affect cell cycle progression in mammalian cells.—Höög, G., Zarrizi, R., von Stedingk, K., Jonsson, K., Alvarado-Kristensson, M. Nuclear localization of γ-tubulin affects E2F transcriptional activity and S-phase progression. PMID:21788450

  12. Rapid Disease Progression With Delay in Treatment of Non-Small-Cell Lung Cancer

    SciTech Connect

    Mohammed, Nasiruddin; Kestin, Larry Llyn; Grills, Inga Siiner; Battu, Madhu; Fitch, Dwight Lamar; Wong, Ching-yee Oliver; Margolis, Jeffrey Harold; Chmielewski, Gary William; Welsh, Robert James

    2011-02-01

    Purpose: To assess rate of disease progression from diagnosis to initiation of treatment for Stage I-IIIB non-small-cell lung cancer (NSCLC). Methods and Materials: Forty patients with NSCLC underwent at least two sets of computed tomography (CT) and 18-fluorodeoxyglucose positron emission tomography (PET) scans at various time intervals before treatment. Progression was defined as development of any new lymph node involvement, site of disease, or stage change. Results: Median time interval between first and second CT scans was 13.4 weeks, and between first and second PET scans was 9.0 weeks. Median initial primary maximum tumor dimension (MTD) was 3.5 cm (0.6-8.5 cm) with a median standardized uptake value (SUV) of 13.0 (1.7-38.5). The median MTD increased by a median of 1.0 cm (mean, 1.6 cm) between scans for a median relative MTD increase of 35% (mean, 59%). Nineteen patients (48%) progressed between scans. Rate of any progression was 13%, 31%, and 46% at 4, 8, and 16 weeks, respectively. Upstaging occurred in 3%, 13%, and 21% at these intervals. Distant metastasis became evident in 3%, 13%, and 13% after 4, 8, and 16 weeks, respectively. T and N stage were associated with progression, whereas histology, grade, sex, age, and maximum SUV were not. At 3 years, overall survival for Stage III patients with vs. without progression was 18% vs. 67%, p = 0.05. Conclusions: With NSCLC, treatment delay can lead to disease progression. Diagnosis, staging, and treatment initiation should be expedited. After 4-8 weeks of delay, complete restaging should be strongly considered.

  13. [Ocular fundus disease in China: the current situation, progression, and issues to be resolved].

    PubMed

    Xu, Xun

    2014-11-01

    Ocular fundus disease is an important cause of blindness in China today. It has been a serious threat to people's health and quality of life. After unremitting efforts of generations, we have made remarkable achievements in the prevention, diagnosis, and treatment of ocular fundus disease. We have achieved many breakthroughs and progressions in the investigations of diabetic retinopathy, choroidal neovascularization, pediatric fundus disease, and other major diseases. And weare gradually standardizing imaging data management, new drug development procedures, and multi-center clinical trials. In the future, we need to further standardize the clinical diagnosis and treatment, to accelerate the basic research of serious and rare diseases, and to improve the overall level in the field of ocular fundus disease in China, so as to enhance our international influence in ophthalmology.

  14. Unveiling Clusters of RNA Transcript Pairs Associated with Markers of Alzheimer’s Disease Progression

    PubMed Central

    Arefin, Ahmed Shamsul; Mathieson, Luke; Johnstone, Daniel; Berretta, Regina; Moscato, Pablo

    2012-01-01

    Background One primary goal of transcriptomic studies is identifying gene expression patterns correlating with disease progression. This is usually achieved by considering transcripts that independently pass an arbitrary threshold (e.g. p<0.05). In diseases involving severe perturbations of multiple molecular systems, such as Alzheimer’s disease (AD), this univariate approach often results in a large list of seemingly unrelated transcripts. We utilised a powerful multivariate clustering approach to identify clusters of RNA biomarkers strongly associated with markers of AD progression. We discuss the value of considering pairs of transcripts which, in contrast to individual transcripts, helps avoid natural human transcriptome variation that can overshadow disease-related changes. Methodology/Principal Findings We re-analysed a dataset of hippocampal transcript levels in nine controls and 22 patients with varying degrees of AD. A large-scale clustering approach determined groups of transcript probe sets that correlate strongly with measures of AD progression, including both clinical and neuropathological measures and quantifiers of the characteristic transcriptome shift from control to severe AD. This enabled identification of restricted groups of highly correlated probe sets from an initial list of 1,372 previously published by our group. We repeated this analysis on an expanded dataset that included all pair-wise combinations of the 1,372 probe sets. As clustering of this massive dataset is unfeasible using standard computational tools, we adapted and re-implemented a clustering algorithm that uses external memory algorithmic approach. This identified various pairs that strongly correlated with markers of AD progression and highlighted important biological pathways potentially involved in AD pathogenesis. Conclusions/Significance Our analyses demonstrate that, although there exists a relatively large molecular signature of AD progression, only a small number of

  15. CRP Polymorphisms and Progression of Chronic Kidney Disease in African Americans

    PubMed Central

    Crawford, Dana C.; Griffin, Marie R.; Brown-Gentry, Kristin; Lipkowitz, Michael S.; Siew, Edward D.; Cavanaugh, Kerri; Lewis, Julia B.; Ikizler, T. Alp

    2010-01-01

    Background and objectives: Chronic inflammation may play a role in chronic kidney disease (CKD) progression. CRP gene polymorphisms are associated with serum C-reactive protein (CRP) concentrations. It is unknown if CRP polymorphisms are associated with CKD progression or modify the effectiveness of anti-hypertensive therapy in delaying CKD progression. Design, setting, participants, & measurements: We genotyped 642 participants with CKD from the African American Study of Kidney Disease and Hypertension (AASK), selecting five tag polymorphisms: rs2808630, rs1205, rs3093066, rs1417938, and rs3093058. We compared the minor allele frequencies (MAF) of single nucleotide polymorphisms (SNPs) in AASK to MAFs of African Americans from NHANES III. Among AASK participants, we evaluated the association of SNPs with CRP levels and prospectively with a composite: halving the GFR, ESRD, or death. Results: The MAF was higher for the rs2808630_G allele (P = 0.03) and lower for the rs1205_A allele (P = 0.03) in the AASK compared with NHANES III. Among AASK participants, the rs3093058_T allele predicted higher CRP concentrations (P < 0.0001) but not CKD progression. The rs2808630_GG genotype was associated with higher risk of the composite endpoint compared with the AA genotype (P = 0.002). Participants with the rs2808630_GG genotype on angiotensin converting enzyme inhibitors (ACEIs) versus β blockers had increased risk of progression (P = 0.03). Conclusion: CRP SNPs that were associated with higher levels of CRP did not predict CKD progression. The rs2808630_GG genotype was associated with higher risk of CKD progression, and in patients with this genotype, ACEIs did not slow progression. PMID:19965533

  16. Immune responses in rapidly progressive dementia: a comparative study of neuroinflammatory markers in Creutzfeldt-Jakob disease, Alzheimer's disease and multiple sclerosis.

    PubMed

    Stoeck, Katharina; Schmitz, Matthias; Ebert, Elisabeth; Schmidt, Christian; Zerr, Inga

    2014-10-15

    Immunological responses may contribute to disease progression and clinical heterogeneity in neurodegenerative dementia, for example, Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD). Recently, a rapidly progressive form of AD (rpAD) has been described. On neuropathological grounds classical AD and rpAD are not distinguishable at present. All those protein aggregopathies show a state of chronic inflammation with microglia activation and production of proinflammatory cytokines. In this context, it is hypothesized that the severity of the surrounding inflammation substantially contributes to disease progression and accelerated disease courses as seen in rpAD.

  17. Association of serum carotenoid, retinol, and tocopherol concentrations with the progression of Parkinson's Disease

    PubMed Central

    Kim, Ji Hyun; Hwang, Jinah; Shim, Eugene; Chung, Eun-Jung; Jang, Sung Hee

    2017-01-01

    BACKGROUND/OBJECTIVES A pivotal role of oxidative stress has been emphasized in the pathogenesis as well as in the disease progression of Parkinson's disease (PD). We aimed at investigating serum levels of antioxidant vitamins and elucidating whether they could be associated with the pathogenesis and progression of PD. MATERIALS/METHODS Serum levels of retinol, α- and γ-tocopherols, α- and β-carotenes, lutein, lycopene, zeaxanthin and β-cryptoxanthin were measured and compared between 104 patients with idiopathic PD and 52 healthy controls matched for age and gender. In order to examine the relationship between antioxidant vitamins and the disease progression, multiple group comparisons were performed among the early PD (Hoehn and Yahr stage I and II, N = 47), advanced PD (stage III and IV, N = 57) and control groups. Separate correlation analyses were performed between the measured antioxidant vitamins and clinical variables, such as Hoehn and Yahr stage and Unified Parkinson's Disease Rating Scale (UPDRS) motor score. RESULTS Compared to controls, PD patients had lower levels of α- and β-carotenes and lycopene. α-carotene, β-carotene and lycopene levels were significantly reduced in advanced PD patients relative to early PD patients and were negatively correlated with Hoehn and Yahr stage and UPDRS motor score in PD patients. No significant differences were found in serum levels of retinol, α- and γ-tocopherols, and other carotenoids between PD patients and controls. No significant correlations were found between these vitamin levels and clinical variables in PD patients. CONCLUSIONS We found that serum levels of some carotenoids, α-carotene, β-carotene and lycopene, were lower in PD patients, and that these carotenoids inversely correlated with clinical variables representing disease progression. Our findings suggest that decreases in serum α-carotene, β-carotene and lycopene may be associated with the pathogenesis as well as progression of PD

  18. Differential phenolic production in leaves of Vitis vinifera cv. Alvarinho affected with esca disease.

    PubMed

    Lima, Marta R M; Felgueiras, Mafalda L; Cunha, Ana; Chicau, Gisela; Ferreres, Federico; Dias, Alberto C P

    2017-03-01

    Esca is a destructive disease of complex etiology affecting grapevines worldwide. A major constraint to the study and control of esca is that the disease is not diagnosed until external leaf and/or fruit symptoms are visible; however external symptoms usually appear several years after infection onset. We studied the phenolic content of V. vinifera cv. Alvarinho leaves using high performance liquid chromatography-diode array detection-mass spectrometry (HPLC-DAD-MS)/LC-MS. Leaves from affected cordons with and without visible symptoms (diseased and apparently healthy leaves, respectively) and leaves from asymptomatic cordons (healthy leaves) were analyzed. Application of principal components analysis (PCA) to HPLC data showed a clear separation between diseased, apparently healthy, and healthy leaves, with the apparently healthy leaves clustered in a medial position. Several compounds were highly correlated with diseased leaves indicating a differential phenolic production due to esca disease in V. vinifera cv. Alvarinho leaves. Total phenolic production was shown to significantly increase in diseased leaves, compared to healthy leaves, with apparently healthy leaves containing a medial amount. Trans-caffeoyltartaric acid, trans-coumaroyl-tartaric acid, quercetin-3-O-glucoside, quercetin-3-O-galactoside, kaempferol-3-glucoside and myricetin were identified among the compounds associated with disease and their content shown to change similarly to total phenolic production. This study shows that it is possible to discriminate between diseased, healthy and apparently healthy leaves by applying PCA to HPLC data.

  19. A Case of Sarcoidosis with Interstitial Lung Disease Mimicking Clinically Amyopathic Dermatomyositis and Rapidly Progressive Interstitial Lung Disease

    PubMed Central

    Nogi, Shinichi; Sasaki, Noriko; Chinen, Naofumi; Honda, Kiri; Saito, Eiko; Wakabayashi, Takayuki; Yamada, Chiho; Suzuki, Yasuo

    2014-01-01

    Here, we report a patient with sarcoidosis who developed edematous erythema and interstitial lung disease. At the initial visit, clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP-ILD) was suspected because he had progressive dyspnea but no muscle weakness. The presence of anti-CADM-140/MDA5 autoantibodies was immediately assessed to facilitate a precise diagnosis, with negative results. Thereafter, skin and transbronchial lung biopsies revealed noncaseating granuloma with Langhans giant cells in both specimens, leading to a diagnosis of sarcoidosis. In this case, clinical features of skin and lung were unable to distinguish DM (including CADM) from sarcoidosis, but the lack of anti-CADM-140/MDA5 antibody was useful for differentiating CADM with RP-ILD mimicking sarcoidosis from bona fide sarcoidosis. PMID:25431723

  20. Utility of quantitative ultrasound for tracking the progression of polycystic kidney disease

    NASA Astrophysics Data System (ADS)

    Hall, Timothy J.; Khant, Htet A.; Insana, Michael F.; Wood, John G.; Zhu, Yanning; Preston, David; Cowley, Benjamin D.

    2000-04-01

    We are combining techniques of quantitative ultrasonic imaging to study polycystic kidney disease (PKD) as the disease progresses to renal failure. Our goal is to use ultrasound noninvasively to detect morphological changes early in the disease process when interventions are most likely to be successful and prior to a significant loss in renal function. We are examining the kidneys of normal rats and those with PKD at various ages with several techniques to obtain comprehensive knowledge of the disease progression. The Han:SPRD rat inherits PKD as an autosomal dominant trait (ADPKD) that closely mimics ADPKD in humans. Changes in renal function are assessed using tracer kinetics (DTPA) and IOH clearance). Ultrasonic techniques, based on measurements of acoustic backscatter coefficients and parameters derived from these measurements, are sensitive to microscopic changes in the tissue morphology. Elasticity imaging is used to study the changes in the tissue macrostructure. All acoustic measurements are made using a state-of-the-art clinical imaging system (Siemens Elegra). Our results show that ultrasonic techniques are very sensitive to early changes in renal microstructure and macrostructure. Ultrasound can be used to detect changes in the renal cortex long before there is a measurable loss of renal function. These techniques are also useful for monitoring the progression of the disease. Most importantly, these techniques are noninvasive and directly applicable to humans.

  1. The Alzheimer’s Disease Neuroimaging Initiative 2 Biomarker Core: A review of progress and plans

    PubMed Central

    Kang, Ju-Hee; Korecka, Magdalena; Figurski, Michal J.; Toledo, Jon B.; Blennow, Kaj; Zetterberg, Henrik; Waligorska, Teresa; Brylska, Magdalena; Fields, Leona; Shah, Nirali; Soares, Holly; Dean, Robert A.; Vanderstichele, Hugo; Petersen, Ronald C.; Aisen, Paul S.; Saykin, Andrew J.; Weiner, Michael W.; Trojanowski, John Q.; Shaw, Leslie M.

    2016-01-01

    Introduction We describe Alzheimer’s Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (Aβ1–42), t-tau, and p-tau181 analytical performance, definition of Alzheimer’s disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids. Methods Review publications authored or coauthored by ADNI Biomarker core faculty and selected non-ADNI studies to deepen the understanding and interpretation of CSF Aβ1–42, t-tau, and p-tau181 data. Results CSFAD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in non-ADNI living subjects followed by the autopsy confirmation of AD. Collaboration across ADNI cores generated the temporal ordering model of AD biomarkers varying across individuals because of genetic/environmental factors that increase/decrease resilience to AD pathologies. Discussion Further studies will refine this model and enable the use of biomarkers studied in ADNI clinically and in disease-modifying therapeutic trials. PMID:26194312

  2. PARKINSON'S DISEASE PATIENTS WITH DOMINANT HEMIBODY AFFECTED BY THE DISEASE RELY MORE ON VISION TO MAINTAIN UPRIGHT POSTURAL CONTROL.

    PubMed

    Lahr, Juliana; Pereira, Marcelo Pinto; Pelicioni, Paulo Henrique Silva; De Morais, Luana Carolina; Gobbi, Lilian Teresa Bucken

    2015-12-01

    This study assesses the association between disease onset side (dominant or non-dominant) and vision on postural control of Parkinson's disease patients. Patient volunteers composed two groups, according to the onset side affected: Dominant group (n=9; M age=66.1 yr., SD=7.2; 6 women, 3 men) and Non-dominant group (n=9; M age=67.4 yr., SD=6.4; 6 women, 3 men). The groups' postural control was assessed by posturography during quiet upright stance in two conditions, Eyes open and Eyes closed. Two-way analyses of variance (ANOVAs; group×condition) with repeated measures for the second factor assessed the differences associated with affected hemibody and vision on postural control. Analyses indicated that patients with the dominant side affected also presented significantly greater variation in center of pressure than those with the non-dominant side affected, mainly in the Eyes closed condition. The results demonstrate a higher reliance on vision in the dominant side, possibly to compensate somatosensory system impairments. These results also highlight the importance of analyzing the hemibody affected by the disease when postural control is assessed in this population.

  3. RIPK3-Mediated Necroptosis and Apoptosis Contributes to Renal Tubular Cell Progressive Loss and Chronic Kidney Disease Progression in Rats

    PubMed Central

    Zhu, Yongjun; Cui, Hongwang; Xia, Yunfeng; Gan, Hua

    2016-01-01

    Tubulointerstitial fibrosis (TIF) is caused by the progressive loss of renal tubular cells and the consequent replacement of the extracellular matrix. The progressive depletion of renal tubular cells results from apoptosis and necroptosis; however, the relative significance of each of these cell death mechanisms at different stages during the progression of chronic kidney disease (CKD) remains unclear. We sought to explore the mechanisms of renal tubular cell death during the early and intermediate stages of chronic renal damage of subtotal nephrectomied (SNx) rats. The results of tissue histological assays indicated that the numbers of necrotic dying cells and apoptotic cells were significantly higher in kidney tissues derived from a rat model of CKD. In addition, there was a significant increase in necroptosis observed by transmission electron microscopy (TEM) and an increase in the proportion of TUNEL-positive cells in kidney tissues from SNx rats compared with control rats, and necrostatin-1 (Nec-1) could inhibit necroptosis and reduce the proportion of TUNEL-positive cells. More importantly, we observed a significant increase in the incidence of necroptosis compared with apoptosis by TEM in vivo and in vitro and a significant increase in the proportion of TUNEL-positive tubular epithelial cells that did not express caspase-3 compared with those expressing cleaved caspase-3 in vitro. Furthermore, treatment with Nec-1 and zVAD strongly reduced necroptosis- and apoptosis-mediated renal tubular cell death and decreased the levels of blood urea nitrogen and serum creatinine and tubular damage scores of SNx rats. These results suggest that necroptotic cell death plays a more significant role than apoptosis in mediating the loss of renal tubular cells in SNx rats and that effectively blocking both necroptosis and apoptosis improves renal function and tubular damage at early and intermediate stages of CKD. PMID:27281190

  4. Transgenic over-expression of mammalian heparanase delays prion disease onset and progression

    PubMed Central

    Kovalchuk Ben-Zaken, O; Nissan, I; Tzaban, S; Taraboulos, A; Zcharia, E; Matzger, S; Shafat, I; Vlodavsky, I; Tal, Y.

    2015-01-01

    Cellular heparan sulfate (HS) has a dual role in scrapie pathogenesis; it is required for PrPSc (scrapie prion protein) formation and facilitates infection of cells, mediating cellular uptake of prions. We examined the involvement of heparanase, a mammalian endoglycosidase degrading HS, in scrapie infection. In cultured cells, heparanase treatment or over-expression resulted in a profound decrease in PrPSc. Moreover, disease onset and progression were dramatically delayed in scrapie infected transgenic mice over-expressing heparanase. Together, our results provide direct in vivo evidence for the involvement of intact HS in the pathogenesis of prion disease and the protective role of heparanase both in terms of susceptibility to infection and disease progression. PMID:26168721

  5. Neuropsychological pattern of striatonigral degeneration: comparison with Parkinson's disease and progressive supranuclear palsy.

    PubMed Central

    Pillon, B; Gouider-Khouja, N; Deweer, B; Vidailhet, M; Malapani, C; Dubois, B; Agid, Y

    1995-01-01

    To study the neuropsychological pattern of striatonigral degeneration (SND), 14 consecutive patients with probable SND were submitted to an extensive battery of neuropsychological tests. Compared with controls the performance of patients with SND was impaired on category and phonemic fluency, frontal behaviours, trail making test A and B, and free recall of the Grober and Buschke test, but normal on the revised WAIS verbal scale, Raven 47 coloured progressive matrices, Wechsler memory scale, California verbal learning test, Wisconsin card sorting test, and the Stroop interference condition. The performance of patients with SND was also compared with that of 14 patients with Parkinson's disease and 14 patients with progressive supranuclear palsy (PSP) matched for age at onset, duration of disease, severity of intellectual deterioration, and depression. The results showed that the dysexecutive syndrome of SND is similar to that of Parkinson's disease and less severe than in PSP. PMID:7876847

  6. Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment.

    PubMed

    Clapper, Jason R; Hendricks, Michelle D; Gu, Guibao; Wittmer, Carrie; Dolman, Carrie S; Herich, John; Athanacio, Jennifer; Villescaz, Christiane; Ghosh, Soumitra S; Heilig, Joseph S; Lowe, Carolyn; Roth, Jonathan D

    2013-10-01

    Shortcomings of previously reported preclinical models of nonalcoholic steatohepatitis (NASH) include inadequate methods used to induce disease and assess liver pathology. We have developed a dietary model of NASH displaying features observed clinically and methods for objectively assessing disease progression. Mice fed a diet containing 40% fat (of which ∼18% was trans fat), 22% fructose, and 2% cholesterol developed three stages of nonalcoholic fatty liver disease (steatosis, steatohepatitis with fibrosis, and cirrhosis) as assessed by histological and biochemical methods. Using digital pathology to reconstruct the left lateral and right medial lobes of the liver, we made comparisons between and within lobes to determine the uniformity of collagen deposition, which in turn informed experimental sampling methods for histological, biochemical, and gene expression analyses. Gene expression analyses conducted with animals stratified by disease severity led to the identification of several genes for which expression highly correlated with the histological assessment of fibrosis. Importantly, we have established a biopsy method allowing assessment of disease progression. Mice subjected to liver biopsy recovered well from the procedure compared with sham-operated controls with no apparent effect on liver function. Tissue obtained by biopsy was sufficient for gene and protein expression analyses, providing the opportunity to establish an objective method of assessing liver pathology before subjecting animals to treatment. The improved assessment techniques and the observation that mice fed the high-fat diet exhibit many clinically relevant characteristics of NASH establish a preclinical model for identifying pharmacological interventions with greater likelihood of translating to the clinic.

  7. An Unrecognized Rash Progressing to Lyme Carditis: Important Features and Recommendations Regarding Lyme Disease.

    PubMed

    Lee, Shawn; Singla, Montish

    2016-01-01

    We present a case report of 46-year-old man with no medical history, who complained of extreme fatigue, near-syncope, and palpitations. He initially presented in complete heart block. A transvenous pacemaker was placed in the emergency department, and he was started empirically on Ceftriaxone for Lyme disease. He was admitted and over the course of the next few days, his rhythm regressed to Mobitz type I first-degree atrioventricular block and then to normal sinus rhythm. This case report highlights some important features regarding Lyme carditis, a rare presentation of early disseminated Lyme disease (seen in a few weeks to months after the initial tick bite). In 25%-30% of patients, the characteristic targetoid rash may not be seen, a likely culprit of the disease not being detected early and progressing to disseminated disease. The most common cardiac complaint of Lyme disease is palpitations, occurring in 6.6% of patients, which may not accurately reflect progression into disseminated Lyme disease because it is a nonspecific finding. Conduction abnormality, occurring in 1.8% of patients, is a more specific finding of Borrelia invading cardiac tissue. Finally, this case report highlights a recommendation that patients with confirmed Lyme disease or those presenting with cardiac abnormalities or symptoms who have an atypical profile for a cardiac event should be screened with a 12-lead electrocardiogram, Lyme serology, and be considered for antibiotic therapy with the possibility of temporary pacing.

  8. Huntington's disease biomarker progression profile identified by transcriptome sequencing in peripheral blood.

    PubMed

    Mastrokolias, Anastasios; Ariyurek, Yavuz; Goeman, Jelle J; van Duijn, Erik; Roos, Raymund A C; van der Mast, Roos C; van Ommen, GertJan B; den Dunnen, Johan T; 't Hoen, Peter A C; van Roon-Mom, Willeke M C

    2015-10-01

    With several therapeutic approaches in development for Huntington's disease, there is a need for easily accessible biomarkers to monitor disease progression and therapy response. We performed next-generation sequencing-based transcriptome analysis of total RNA from peripheral blood of 91 mutation carriers (27 presymptomatic and, 64 symptomatic) and 33 controls. Transcriptome analysis by DeepSAGE identified 167 genes significantly associated with clinical total motor score in Huntington's disease patients. Relative to previous studies, this yielded novel genes and confirmed previously identified genes, such as H2AFY, an overlap in results that has proven difficult in the past. Pathway analysis showed enrichment of genes of the immune system and target genes of miRNAs, which are downregulated in Huntington's disease models. Using a highly parallelized microfluidics array chip (Fluidigm), we validated 12 of the top 20 significant genes in our discovery cohort and 7 in a second independent cohort. The five genes (PROK2, ZNF238, AQP9, CYSTM1 and ANXA3) that were validated independently in both cohorts present a candidate biomarker panel for stage determination and therapeutic readout in Huntington's disease. Finally we suggest a first empiric formula predicting total motor score from the expression levels of our biomarker panel. Our data support the view that peripheral blood is a useful source to identify biomarkers for Huntington's disease and monitor disease progression in future clinical trials.

  9. Heterogeneity of neuroanatomical patterns in prodromal Alzheimer's disease: links to cognition, progression and biomarkers.

    PubMed

    Dong, Aoyan; Toledo, Jon B; Honnorat, Nicolas; Doshi, Jimit; Varol, Erdem; Sotiras, Aristeidis; Wolk, David; Trojanowski, John Q; Davatzikos, Christos

    2016-12-20

    Individuals with mild cognitive impairment and Alzheimer's disease clinical diagnoses can display significant phenotypic heterogeneity. This variability likely reflects underlying genetic, environmental and neuropathological differences. Characterizing this heterogeneity is important for precision diagnostics, personalized predictions, and recruitment of relatively homogeneous sets of patients into clinical trials. In this study, we apply state-of-the-art semi-supervised machine learning methods to the Alzheimer's disease Neuroimaging cohort (ADNI) to elucidate the heterogeneity of neuroanatomical differences between subjects with mild cognitive impairment (n = 530) and Alzheimer's disease (n = 314) and cognitively normal individuals (n = 399), thereby adding to an increasing literature aiming to establish neuroanatomical and neuropathological (e.g. amyloid and tau deposition) dimensions in Alzheimer's disease and its prodromal stages. These dimensional approaches aim to provide surrogate measures of heterogeneous underlying pathologic processes leading to cognitive impairment. We relate these neuroimaging patterns to cerebrospinal fluid biomarkers, white matter hyperintensities, cognitive and clinical measures, and longitudinal trajectories. We identified four such atrophy patterns: (i) individuals with largely normal neuroanatomical profiles, who also turned out to have the least abnormal cognitive and cerebrospinal fluid biomarker profiles and the slowest clinical progression during follow-up; (ii) individuals with classical Alzheimer's disease neuroanatomical, cognitive, cerebrospinal fluid biomarkers and clinical profile, who presented the fastest clinical progression; (iii) individuals with a diffuse pattern of atrophy with relatively less pronounced involvement of the medial temporal lobe, abnormal cerebrospinal fluid amyloid-β1-42 values, and proportionally greater executive impairment; and (iv) individuals with notably focal involvement of the medial

  10. Cyclooxygenase product inhibition with acetylsalicylic acid slows disease progression in the Han:SPRD-Cy rat model of polycystic kidney disease.

    PubMed

    Ibrahim, Naser H M; Gregoire, Melanie; Devassy, Jessay G; Wu, Yinhong; Yoshihara, Daisuke; Yamaguchi, Tamio; Nagao, Shizuko; Aukema, Harold M

    2015-01-01

    Renal cyclooxygenase (COX) derived eicosanoids are elevated and lipoxygenase (LOX) products are reduced in the Han:SPRD-Cy rat model of polycystic kidney disease (PKD). Selective COX2 inhibition reduces kidney disease progression, but COX1 levels also are elevated in this model. Since the effect of reducing the products of both COX isoforms and the role of LOX products is not known, weanling normal and diseased Han:SPRD-cy littermates were given either low dose acetylsalicylic acid (ASA), nordihydroguaiaretic (NDGA) or no treatment for eight weeks. Renal eicosanoids were altered in the diseased compared to normal cortex, with COX products being higher and LOX products being lower. ASA reduced COX products, cyst growth and kidney water content, while NDGA reduced LOX products without altering disease progression or kidney function. Hence, a human equivalent ASA dose equal to less than one regular strength aspirin per day slowed disease progression, while further reduction of LOX products did not worsen disease progression.

  11. 18F-AV-1451 positron emission tomography in Alzheimer's disease and progressive supranuclear palsy.

    PubMed

    Passamonti, Luca; Vázquez Rodríguez, Patricia; Hong, Young T; Allinson, Kieren S J; Williamson, David; Borchert, Robin J; Sami, Saber; Cope, Thomas E; Bevan-Jones, W Richard; Jones, P Simon; Arnold, Robert; Surendranathan, Ajenthan; Mak, Elijah; Su, Li; Fryer, Tim D; Aigbirhio, Franklin I; O'Brien, John T; Rowe, James B

    2017-03-01

    The ability to assess the distribution and extent of tau pathology in Alzheimer's disease and progressive supranuclear palsy in vivo would help to develop biomarkers for these tauopathies and clinical trials of disease-modifying therapies. New radioligands for positron emission tomography have generated considerable interest, and controversy, in their potential as tau biomarkers. We assessed the radiotracer 18F-AV-1451 with positron emission tomography imaging to compare the distribution and intensity of tau pathology in 15 patients with Alzheimer's pathology (including amyloid-positive mild cognitive impairment), 19 patients with progressive supranuclear palsy, and 13 age- and sex-matched controls. Regional analysis of variance and a support vector machine were used to compare and discriminate the clinical groups, respectively. We also examined the 18F-AV-1451 autoradiographic binding in post-mortem tissue from patients with Alzheimer's disease, progressive supranuclear palsy, and a control case to assess the 18F-AV-1451 binding specificity to Alzheimer's and non-Alzheimer's tau pathology. There was increased 18F-AV-1451 binding in multiple regions in living patients with Alzheimer's disease and progressive supranuclear palsy relative to controls [main effect of group, F(2,41) = 17.5, P < 0.0001; region of interest × group interaction, F(2,68) = 7.5, P < 0.00001]. More specifically, 18F-AV-1451 binding was significantly increased in patients with Alzheimer's disease, relative to patients with progressive supranuclear palsy and with control subjects, in the hippocampus and in occipital, parietal, temporal, and frontal cortices (t's > 2.2, P's < 0.04). Conversely, in patients with progressive supranuclear palsy, relative to patients with Alzheimer's disease, 18F-AV-1451 binding was elevated in the midbrain (t = 2.1, P < 0.04); while patients with progressive supranuclear palsy showed, relative to controls, increased 18F-AV-1451 uptake in the putamen, pallidum

  12. Analysis of Mycobacterium ulcerans-specific T-cell cytokines for diagnosis of Buruli ulcer disease and as potential indicator for disease progression

    PubMed Central

    Antwi-Berko, Daniel; Mubarik, Yusif; Abass, Kabiru Mohammed; Owusu, Wellington; Owusu-Dabo, Ellis; Debrah, Linda Batsa; Debrah, Alexander Yaw; Jacobsen, Marc; Phillips, Richard O.

    2017-01-01

    Background Buruli ulcer disease (BUD), caused by Mycobacterium (M.) ulcerans, is the third most common mycobacterial disease after tuberculosis and leprosy. BUD causes necrotic skin lesions and is a significant problem for health care in the affected countries. As for other mycobacterial infections, T cell mediated immune responses are important for protection and recovery during treatment, but detailed studies investigating these immune responses in BUD patients are scarce. In this study, we aimed to characterise M. ulcerans-specific CD4+ T cell responses in BUD patients and to analyse specific cytokine-producing T cells in the context of disease severity and progression. Methodology/Principal findings For this case-control study, whole blood samples of BUD patients (N = 36, 1.5–17 years of age) and healthy contacts (N = 22, 3–15 years of age) were stimulated with antigen prepared from M. ulcerans and CD4+ T cells were analysed for the expression of TNFα, IFNγ and CD40L by flow cytometry. The proportions and profile of cytokine producing CD4+ T cells was compared between the two study groups and correlated with disease progression and severity. Proportions of cytokine double-positive IFNγ+TNFα+, TNFα+CD40L+, IFNγ+CD40L+ (p = 0.014, p = 0.010, p = 0.002, respectively) and triple positive IFNγ+TNFα+CD40L+ (p = 0.010) producing CD4+ T cell subsets were increased in BUD patients. In addition, TNFα+CD40L-IFNγ- CD4+ T cells differed between patients and controls (p = 0.034). TNFα+CD40L-IFNγ- CD4+ T cells were correlated with lesion size (p = 0.010) and proportion were higher in ‘slow’ healers compared to ‘fast healers’ (p = 0.030). Conclusions We were able to identify M. ulcerans-specific CD4+ T cell subsets with specific cytokine profiles. In particular a CD4+ T cell subset, producing TNFα but not IFNγ and CD40L, showed association with lesion size and healing progress. Further studies are required to investigate, if the identified CD4+ T cell

  13. Elevated depressive affect is associated with adverse cardiovascular outcomes among African Americans with chronic kidney disease.

    PubMed

    Fischer, Michael J; Kimmel, Paul L; Greene, Tom; Gassman, Jennifer J; Wang, Xuelei; Brooks, Deborah H; Charleston, Jeanne; Dowie, Donna; Thornley-Brown, Denyse; Cooper, Lisa A; Bruce, Marino A; Kusek, John W; Norris, Keith C; Lash, James P

    2011-09-01

    This study was designed to examine the impact of elevated depressive affect on health outcomes among participants with hypertensive chronic kidney disease in the African-American Study of Kidney Disease and Hypertension (AASK) Cohort Study. Elevated depressive affect was defined by Beck Depression Inventory II (BDI-II) thresholds of 11 or more, above 14, and by 5-Unit increments in the score. Cox regression analyses were used to relate cardiovascular death/hospitalization, doubling of serum creatinine/end-stage renal disease, overall hospitalization, and all-cause death to depressive affect evaluated at baseline, the most recent annual visit (time-varying), or average from baseline to the most recent visit (cumulative). Among 628 participants at baseline, 42% had BDI-II scores of 11 or more and 26% had a score above 14. During a 5-year follow-up, the cumulative incidence of cardiovascular death/hospitalization was significantly greater for participants with baseline BDI-II scores of 11 or more compared with those with scores <11. The baseline, time-varying, and cumulative elevated depressive affect were each associated with a significant higher risk of cardiovascular death/hospitalization, especially with a time-varying BDI-II score over 14 (adjusted HR 1.63) but not with the other outcomes. Thus, elevated depressive affect is associated with unfavorable cardiovascular outcomes in African Americans with hypertensive chronic kidney disease.

  14. Responses of horses affected with chronic obstructive pulmonary disease to inhalation challenges with mould antigens.

    PubMed

    McGorum, B C; Dixon, P M; Halliwell, R E

    1993-07-01

    Eight control and 8 asymptomatic COPD-affected horses were given, on separate occasions, inhalation challenges with extracts of Micropolyspora faeni, Aspergillus fumigatus and Thermoactinomyces vulgaris. All horses were also given nebulised phosphate-buffered saline (PBS) challenges and 'natural challenges' (NCs), i.e. exposure to hay and straw, as control challenges. Responses were assessed by clinical, pulmonary mechanics, arterial blood gas tensions, arterial blood pH and bronchoalveolar lavage fluid cytological examinations. PBS challenges had no effect on control or COPD-affected horses, while NC induced COPD only in the COPD-affected horses. Pulmonary disease, similar to naturally occurring COPD, was induced, only in the COPD-affected horses, by M. faeni and A. fumigatus challenges, thus implicating these organisms in the aetiology of equine COPD. The role of T. vulgaris in the aetiology of equine COPD could not, however, be determined because the T. vulgaris challenges, in addition to inducing pulmonary disease in 4 COPD-affected horses, induced pulmonary disease in 2 control horses which had been unaffected by NC. The absence of pulmonary disease in control horses after M. faeni, A. fumigatus and NC challenges suggests that equine COPD is a pulmonary hypersensitivity, rather than a non-specific toxic response.

  15. Passage of human T-cell leukemia virus type-1 during progression to cutaneous T-cell lymphoma results in myelopathic disease in an HTLV-1 infection model.

    PubMed

    Kindt, T J; Said, W A; Bowers, F S; Mahana, W; Zhao, T M; Simpson, R M

    2000-08-01

    Studies comparing functional differences in human T-cell leukemia virus type 1 (HTLV-1) clones that mediate distinct outcomes in experimentally infected rabbits, resulted in a dermatopathic smoldering adult T-cell leukemia/lymphoma following chronic infection with HTLV-1 strain RH/K34. During the 3.5 years' follow-up, HTLV-1 skin disease progressed to cutaneous T-cell lymphoma. When infection was passed to several naive rabbits, progressive paraparesis due to myelopathic neurodegeneration, analogous to HTLV-associated myelopathy, resulted in one of 4 transfusion recipients. Similar proviral loads were detected in the two diseases, regardless of stage of progression or tissue compartment of infection. Complete proviral sequences obtained from the donor and affected recipient aligned identically with each other and with the inoculated virus clone. Existence of disparate pathogenic outcomes following infectious transmission further extends the analogy of using rabbits to model human infection and disease. Although the experimental outcomes shown are limited by numbers of animals affected, they mimic the infrequency of HTLV-1 disease and authenticate epidemiological evidence of virus sequence stability regardless of disease phenotype. The findings suggest that further investigation of a possible role for HTLV-1 in some forms of cutaneous T-cell lymphoma is warranted.

  16. Does Vitamin D Affect Risk of Developing Autoimmune Disease?: A Systematic Review

    PubMed Central

    Kriegel, Martin A.; Manson, JoAnn E.; Costenbader, Karen H.

    2010-01-01

    Objectives We evaluated the epidemiologic evidence that vitamin D may be related to human autoimmune disease risk. Methods PubMed limited to English from inception through April 2010 was searched using keywords: “vitamin D”, “autoimmune” and autoimmune disease names. We summarized in vitro, animal, and genetic association studies of vitamin D in autoimmune disease pathogenesis. We sorted studies by design and disease and performed a systematic review of: a) cross-sectional data concerning vitamin D level and autoimmune disease; b) interventional data on vitamin D supplementation in autoimmune diseases and c) prospective data linking vitamin D level or intake to autoimmune disease risk. Results Vitamin D has effects on innate and acquired immune systems and vitamin D receptor polymorphisms have been associated with various autoimmune diseases. In experimental animal models, vitamin D supplementation can prevent or forestall autoimmune disease. We identified 76 studies in which vitamin D levels were studied in autoimmune disease patients, particularly with active disease, and compared to controls. Nineteen observational or interventional studies assessed the effect of vitamin D supplementation as therapy for various autoimmune diseases (excluding psoriasis and vitiligo) with a range of study approaches and results. The few prospective human studies performed conflict as to whether vitamin D level or intake is associated with autoimmune disease risk. No interventional trials have investigated whether vitamin D affects human autoimmune disease risk. Conclusions Cross-sectional data point to a potential role of vitamin D in autoimmune disease prevention, but prospective interventional evidence in humans is still lacking. PMID:21047669

  17. The Progressive BSSG Rat Model of Parkinson's: Recapitulating Multiple Key Features of the Human Disease.

    PubMed

    Van Kampen, Jackalina M; Baranowski, David C; Robertson, Harold A; Shaw, Christopher A; Kay, Denis G

    2015-01-01

    The development of effective neuroprotective therapies for Parkinson's disease (PD) has been severely hindered by the notable lack of an appropriate animal model for preclinical screening. Indeed, most models currently available are either acute in nature or fail to recapitulate all characteristic features of the disease. Here, we present a novel progressive model of PD, with behavioural and cellular features that closely approximate those observed in patients. Chronic exposure to dietary phytosterol glucosides has been found to be neurotoxic. When fed to rats, β-sitosterol β-d-glucoside (BSSG) triggers the progressive development of parkinsonism, with clinical signs and histopathology beginning to appear following cessation of exposure to the neurotoxic insult and continuing to develop over several months. Here, we characterize the progressive nature of this model, its non-motor features, the anatomical spread of synucleinopathy, and response to levodopa administration. In Sprague Dawley rats, chronic BSSG feeding for 4 months triggered the progressive development of a parkinsonian phenotype and pathological events that evolved slowly over time, with neuronal loss beginning only after toxin exposure was terminated. At approximately 3 months following initiation of BSSG exposure, animals displayed the early emergence of an olfactory deficit, in the absence of significant dopaminergic nigral cell loss or locomotor deficits. Locomotor deficits developed gradually over time, initially appearing as locomotor asymmetry and developing into akinesia/bradykinesia, which was reversed by levodopa treatment. Late-stage cognitive impairment was observed in the form of spatial working memory deficits, as assessed by the radial arm maze. In addition to the progressive loss of TH+ cells in the substantia nigra, the appearance of proteinase K-resistant intracellular α-synuclein aggregates was also observed to develop progressively, appearing first in the olfactory bulb, then

  18. ETS-Associated Genomic Alterations including ETS2 Loss Markedly Affect Prostate Cancer Progression

    DTIC Science & Technology

    2015-10-01

    suffering prior to death. Current investigations study the molecular and genetic basis of the disease, to identify potential new drug targets and therapies...interplay between RAS/MAPK pathway and screen hits via drugs such as MEK inhibitor PD98059 is potentially interesting, but such pathway analysis has...it lays the foundation for future investigations to identify novel drug targets. PUBLICATIONS, ABSTRACTS, AND PRESENTATIONS Presentations include

  19. [Contribution of genetics to knowledge and management of hereditary kidney diseases progressing to renal failure].

    PubMed

    Levy, M; Gubler, M C; Feingold, J

    2001-10-01

    Genes of most of the hereditary renal diseases progressing to renal insufficiency are now identified. In the first part of this paper we describe their multi-faceted genetics. Genetic heterogeneity has been demonstrated in many of these diseases, such as Alport's syndrome and nephronophtisis. In some of them an allelic heterogeneity is present as in the X-linked form of Alport's syndrome (more than 300 different mutations have been described along the COL4A5 gene). Besides these classical mendelian diseases, mendelian subentities have been isolated within common diseases such as cortico-resistant nephrosis. Many diseases also demonstrate a variability of their phenotype resulting from allelic and/or genetic heterogeneity, or from modifier genes. In the second part of the paper we discuss the consequences of this explosion of knowledge with respect to epidemiology, genetic diagnosis, prenatal diagnosis and treatment.

  20. Progress with anti-tumor necrosis factor therapeutics for the treatment of inflammatory bowel disease.

    PubMed

    Fernandes, Carlos; Allocca, Mariangela; Danese, Silvio; Fiorino, Gionata

    2015-01-01

    Anti-tumor necrosis factor (TNF) therapy is a valid, effective and increasingly used option in inflammatory bowel disease management. Nevertheless, further knowledge and therapeutic indications regarding these drugs are still evolving. Anti-TNF therapy may be essential to achieve recently proposed end points, namely mucosal healing, prevention of bowel damage and prevention of patient's disability. Anti-TNF drugs are also suggested to be more effective in early disease, particularly in early Crohn's disease. Moreover, its efficacy for prevention of postoperative recurrence in Crohn's disease is still debated. Costs and adverse effects, the relevance of drug monitoring and the possibility of anti-TNF therapy withdrawal in selected patients are still debated issues. This review aimed to describe and discuss the most relevant data about the progress with anti-TNF therapy for the management of inflammatory bowel disease.

  1. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    SciTech Connect

    Lake, April D.; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D.; Lu, Zhenqiang; Lehman-McKeeman, Lois D.; Cherrington, Nathan J.

    2013-04-15

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile acids

  2. MAPPING THE PROGRESSION OF ATROPHY IN EARLY AND LATE ONSET ALZHEIMER’S DISEASE

    PubMed Central

    Migliaccio, R; Agosta, F; Possin, KL; Canu, E; Filippi, M; Rabinovici, GD; Rosen, HJ; Miller, BL; Gorno-Tempini, ML

    2015-01-01

    The term early age-of-onset Alzheimer’s disease (EOAD) identifies patients who meet criteria for AD, but show onset of symptoms before the age of 65. We map progression of gray matter (GM) atrophy in EOAD patients compared to late onset AD (LOAD). T1-weighted MRI scans were obtained at diagnosis and one-year follow-up from 15 EOAD, 10 LOAD, and 38 age-matched controls. Voxel-based and tensor-based morphometry were used, respectively, to assess the baseline and progression of atrophy. At baseline, EOAD patients already showed a widespread atrophy in temporal, parietal, occipital and frontal cortices. After one year, EOAD had atrophy progression in medial temporal and medial parietal cortices. At baseline, LOAD patients showed atrophy in the medial temporal regions only, and, after one year, an extensive pattern of atrophy progression in the same neocortical cortices of EOAD. Although atrophy mainly involved different lateral neocortical or medial temporal hubs at baseline, it eventually progressed along the same brain default-network regions in both groups. The cortical region showing a significant progression in both groups was the medial precuneus/posterior cingulate. PMID:25737041

  3. Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms

    PubMed Central

    Ishibashi, Hidetoshi; Minakawa, Eiko N.; Motohashi, Hideyuki H.; Takayama, Osamu; Popiel, H. Akiko; Puentes, Sandra; Owari, Kensuke; Nakatani, Terumi; Nogami, Naotake; Yamamoto, Kazuhiro; Yonekawa, Takahiro; Tanaka, Yoko; Fujita, Naoko; Suzuki, Hikaru; Aizawa, Shu; Nagano, Seiichi; Yamada, Daisuke; Wada, Keiji; Kohsaka, Shinichi

    2017-01-01

    Abstract Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases. PMID:28374014

  4. Candidate blood proteome markers of Alzheimer's disease onset and progression: a systematic review and replication study.

    PubMed

    Kiddle, Steven J; Sattlecker, Martina; Proitsi, Petroula; Simmons, Andrew; Westman, Eric; Bazenet, Chantal; Nelson, Sally K; Williams, Stephen; Hodges, Angela; Johnston, Caroline; Soininen, Hilkka; Kłoszewska, Iwona; Mecocci, Patrizia; Tsolaki, Magda; Vellas, Bruno; Newhouse, Stephen; Lovestone, Simon; Dobson, Richard J B

    2014-01-01

    A blood-based protein biomarker, or set of protein biomarkers, that could predict onset and progression of Alzheimer's disease (AD) would have great utility; potentially clinically, but also for clinical trials and especially in the selection of subjects for preventative trials. We reviewed a comprehensive list of 21 published discovery or panel-based (> 100 proteins) blood proteomics studies of AD, which had identified a total of 163 candidate biomarkers. Few putative blood-based protein biomarkers replicate in independent studies but we found that some proteins do appear in multiple studies; for example, four candidate biomarkers are found to associate with AD-related phenotypes in five independent research cohorts in these 21 studies: α-1-antitrypsin, α-2-macroglobulin, apolipoprotein E, and complement C3. Using SomaLogic's SOMAscan proteomics technology, we were able to conduct a large-scale replication study for 94 of the 163 candidate biomarkers from these 21 published studies in plasma samples from 677 subjects from the AddNeuroMed (ANM) and the Alzheimer's Research UK/Maudsley BRC Dementia Case Registry at King's Health Partners (ARUK/DCR) research cohorts. Nine of the 94 previously reported candidates were found to associate with AD-related phenotypes (False Discovery Rate (FDR) q-value < 0.1). These proteins show sufficient replication to be considered for further investigation as a biomarker set. Overall, we show that there are some signs of a replicable signal in the range of proteins identified in previous studies and we are able to further replicate some of these. This suggests that AD pathology does affect the blood proteome with some consistency.

  5. Disease progression subtype discovery from longitudinal EMR data with a majority of missing values and unknown initial time points

    PubMed Central

    Huopaniemi, Ilkka; Nadkarni, Girish; Nadukuru, Rajiv; Lotay, Vaneet; Ellis, Steve; Gottesman, Omri; Bottinger, Erwin P

    2014-01-01

    Electronic medical records (EMR) contain a longitudinal collection of laboratory data that contains valuable phenotypic information on disease progression of a large collection of patients. These data can be potentially used in medical research or patient care; finding disease progression subtypes is a particularly important application. There are, however, two significant difficulties in utilizing this data for statistical analysis: (a) a large proportion of data is missing and (b) patients are in very different stages of disease progression and there are no well-defined start points of the time series. We present a Bayesian machine learning model that overcomes these difficulties. The method can use highly incomplete time-series measurement of varying lengths, it aligns together similar trajectories in different phases and is capable of finding consistent disease progression subtypes. We demonstrate the method on finding chronic kidney disease progression subtypes. PMID:25954377

  6. Does study partner type impact the rate of Alzheimer's disease progression?

    PubMed

    Grill, Joshua D; Zhou, Yan; Karlawish, Jason; Elashoff, David

    2014-01-01

    Most patients with Alzheimer's disease (AD) do not have a spouse. Despite this, the majority of AD research participants enroll with a spouse study partner. It remains unclear if differences between AD patients who do and do not have a spouse may bias study results. In this study, we examined whether AD patients with different study partner types (spouse versus adult child) demonstrate different rates of disease progression over two years on three outcome measures commonly used in AD research, including clinical trials. We used data from the National Alzheimer's Coordinating Center Uniform Data Set to examine disease progression in participants age 55-90 with probable AD dementia. We examined disease progression as measured by the Clinical Dementia Rating Scale-Sum of the Boxes score, the Mini Mental Status Examination, and the Functional Assessment Questionnaire. Analyses were performed on data for all available eligible participants from the NACC UDS and after performing a propensity-matching model to better account for inherent differences between the populations of interest. Propensity matching was successful only when models did not include age and gender. For both propensity-matched analyses and those of all available data, we did not observe any differences between the study partner populations for any outcome measure. These results suggest that if investigators can improve in recruiting AD patients with adult child caregivers to research, the implications to study results may be minimal.

  7. Chronic Progressive Neurodegeneration in a Transgenic Mouse Model of Prion Disease

    PubMed Central

    Fainstein, Nina; Dori, Dvir; Frid, Kati; Fritz, Alexa T.; Shapiro, Ilona; Gabizon, Ruth; Ben-Hur, Tamir

    2016-01-01

    Neurodegenerative diseases present pathologically with progressive structural destruction of neurons and accumulation of mis-folded proteins specific for each condition leading to brain atrophy and functional disability. Many animal models exert deposition of pathogenic proteins without an accompanying neurodegeneration pattern. The lack of a comprehensive model hinders efforts to develop treatment. We performed longitudinal quantification of cellular, neuronal and synaptic density, as well as of neurogenesis in brains of mice mimicking for genetic Creutzfeldt-Jacob disease as compared to age-matched wild-type mice. Mice exhibited a neurodegenerative process of progressive reduction in cortical neurons and synapses starting at age of 4–6 months, in accord with neurologic disability. This was accompanied by significant decrease in subventricular/subependymal zone neurogenesis. Although increased hippocampal neurogenesis was detected in mice, a neurodegenerative process of CA1 and CA3 regions associated with impaired hippocampal-dependent memory function was observed. In conclusion, mice exhibit pathological neurodegeneration concomitant with neurological disease progression, indicating these mice can serve as a model for neurodegenerative diseases. PMID:27891071

  8. View of God as benevolent and forgiving or punishing and judgmental predicts HIV disease progression.

    PubMed

    Ironson, Gail; Stuetzle, Rick; Ironson, Dale; Balbin, Elizabeth; Kremer, Heidemarie; George, Annie; Schneiderman, Neil; Fletcher, Mary Ann

    2011-12-01

    This study assessed the predictive relationship between View of God beliefs and change in CD4-cell and Viral Load (VL) in HIV positive people over an extended period. A diverse sample of HIVseropositive participants (N = 101) undergoing comprehensive psychological assessment and blood draws over the course of 4 years completed the View of God Inventory with subscales measuring Positive View (benevolent/forgiving) and Negative View of God (harsh/judgmental/punishing). Adjusting for initial disease status, age, gender, ethnicity, education, and antiretroviral medication (at every 6-month visit), a Positive View of God predicted significantly slower disease-progression (better preservation of CD4-cells, better control of VL), whereas a Negative View of God predicted faster disease-progression over 4 years. Effect sizes were greater than those previously demonstrated for psychosocial variables known to predict HIV-disease-progression, such as depression and coping. Results remained significant even after adjusting for church attendance and psychosocial variables (health behaviors, mood, and coping). These results provide good initial evidence that spiritual beliefs may predict health outcomes.

  9. Cyclooxygenase and Alzheimer's disease: implications for preventive initiatives to slow the progression of clinical dementia.

    PubMed

    Pasinetti, G M.

    2001-08-01

    Industry and academia are devoting a tremendous amount of resources to the testing of anti-inflammatory drugs for the treatment of Alzheimer's disease (AD). This trend is the result of the growing consensus supporting the inflammatory hypothesis of AD. If anti-inflammatory strategies succeed in slowing the rate of disease progression, the impact on patients and families could be enormous. However, given the large number of candidates in the pool of anti-inflammatory drugs and given their widely divergent activities, it is essential to use methods which optimizes drug selection and study design. Pilot studies of anti-inflammatory regimens are useful in determining tolerability. However, these studies have limited value in estimating effective size since disease-modification, rather than symptomatic improvement, is the ultimate goal. Better understanding of the influence of inflammatory activity and the specific mechanisms which play an early role in the progression of the disease, will improve the likelihood of successfully identifying an effective anti-inflammatory treatment strategy. This review outlines directions in research that address possible contributions of cyclooxygenase (COX)-2, COX-1 and other inflammatory mediators to AD neurodegeneration. Finally, this article addresses potential interventions designed to control segments of classical inflammatory cascades in the brain in which cyclooxygenase is highly implicated. These considerations are critical to understand the role of cyclooxygenase in the clinical progression of AD.

  10. Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer's type.

    PubMed

    Popp, Julius; Wolfsgruber, Steffen; Heuser, Isabella; Peters, Oliver; Hüll, Michael; Schröder, Johannes; Möller, Hans-Jürgen; Lewczuk, Piotr; Schneider, Anja; Jahn, Holger; Luckhaus, Christian; Perneczky, Robert; Frölich, Lutz; Wagner, Michael; Maier, Wolfgang; Wiltfang, Jens; Kornhuber, Johannes; Jessen, Frank

    2015-02-01

    Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer's disease (AD) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis. However, brain exposure to high cortisol concentrations may also accelerate disease progression and cognitive decline. The objectives of this study were to investigate whether HPA-axis dysregulation occurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associated with clinical disease progression. Morning plasma and CSF cortisol concentrations were obtained from the subjects with AD dementia, mild cognitive impairment of AD type (MCI-AD), MCI of other type (MCI-O), and controls with normal cognition included in a multicenter study from the German Dementia Competence Network. A clinical and neuropsychological follow-up was performed in a subgroup of participants with MCI-AD, MCI-O, and AD dementia. CSF cortisol concentrations were increased in the subjects with AD dementia or MCI-AD compared with subjects with MCI-O or normal cognition. After controlling for possible confounders including CSF measures of amyloid beta1-42 and total tau, higher baseline CSF cortisol levels were associated with faster clinical worsening and cognitive decline in MCI-AD. The findings suggest that HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline.

  11. Pregnancy and HIV Disease Progression in an Early Infection Cohort from Five African Countries

    PubMed Central

    Rida, Wasima; Haddad, Lisa B.; Kamali, Anatoli; Karita, Etienne; Lakhi, Shabir; Kilembe, William; Allen, Susan; Inambao, Mubiana; Yang, Annie H.; Latka, Mary H.; Anzala, Omu; Sanders, Eduard J.; Bekker, Linda-Gail; Edward, Vinodh A.; Price, Matt A.

    2017-01-01

    Background: Understanding associations between pregnancy and HIV disease progression is critical to provide appropriate counseling and care to HIV-positive women. Methods: From 2006 to 2011, women less than age 40 with incident HIV infection were enrolled in an early HIV infection cohort in Kenya, Rwanda, South Africa, Uganda, and Zambia. Time-dependent Cox models evaluated associations between pregnancy and HIV disease progression. Clinical progression was defined as a single CD4 measurement <200 cells/μl, percent CD4 <14%, or category C event, with censoring at antiretroviral (ART) initiation for reasons other than prevention of mother-to-child transmission (PMTCT). Immunologic progression was defined as two consecutive CD4s ≤350 cells/μl or a single CD4 ≤350 cells/μl followed by non-PMTCT ART initiation. Generalized estimating equations assessed changes in CD4 before and after pregnancy. Results: Among 222 women, 63 experienced clinical progression during 783.5 person-years at risk (8.0/100). Among 205 women, 87 experienced immunologic progression during 680.1 person-years at risk (12.8/100). The association between pregnancy and clinical progression was adjusted hazard ratio [aHR] = 0.7; 95% confidence interval (CI): 0.2, 1.8. The association between pregnancy and immunologic progression was aHR = 1.7; 95% CI: 0.9, 3.3. Models controlled for age; human leukocyte antigen alleles A*03:01, B*45, B*57; CD4 set point; and HIV-1 subtype. CD4 measurements before versus after pregnancies were not different. Conclusions: In this cohort, pregnancy was not associated with increased clinical or immunologic HIV progression. Similarly, we did not observe meaningful deleterious associations of pregnancy with CD4s. Our findings suggest that HIV-positive women may become pregnant without harmful health effects occurring during the pregnancy. Evaluation of longer-term impact of pregnancy on progression is warranted. PMID:27893488

  12. Can focusing on UPDRS Part II make assessments of Parkinson disease progression more efficient?

    PubMed

    Sampaio, Cristina

    2009-03-01

    Harrison et al. have attempted to validate Part II of the Unified Parkinson's Disease Rating Scale (UPDRS II) as a medication-independent measure of disease progression. The authors collected cross-sectional data from a cohort of 888 patients with idiopathic Parkinson disease, and they found a robust association between UPDRS II scores and disease duration. Other variables considered were the patients' levodopa status, age at disease onset, and scores on UPDRS I, II and III. The results suggest that a single UPDRS II measurement might be a good indicator of progression at a given time point, irrespective of the current disease-related circumstances. This concept is attractive in its simplicity and patient-centeredness. However, this evidence came from a single-center, retrospective study, the statistical model was constructed using a nonvalidated surrogate as an independent variable, and no external replication was conducted. Until further confirmation, therefore, Harrison et al.'s proposal can only be considered to be a working hypothesis.

  13. Rating competitors before tournament starts: How it's affecting team progression in a soccer tournament

    NASA Astrophysics Data System (ADS)

    Yusof, Muhammad Mat; Sulaiman, Tajularipin; Khalid, Ruzelan; Hamid, Mohamad Shukri Abdul; Mansor, Rosnalini

    2014-12-01

    In professional sporting events, rating competitors before tournament start is a well-known approach to distinguish the favorite team and the weaker teams. Various methodologies are used to rate competitors. In this paper, we explore four ways to rate competitors; least squares rating, maximum likelihood strength ratio, standing points in large round robin simulation and previous league rank position. The tournament metric we used to evaluate different types of rating approach is tournament outcome characteristics measure. The tournament outcome characteristics measure is defined by the probability that a particular team in the top 100q pre-tournament rank percentile progress beyond round R, for all q and R. Based on simulation result, we found that different rating approach produces different effect to the team. Our simulation result shows that from eight teams participate in knockout standard seeding, Perak has highest probability to win for tournament that use the least squares rating approach, PKNS has highest probability to win using the maximum likelihood strength ratio and the large round robin simulation approach, while Perak has the highest probability to win a tournament using previous league season approach.

  14. Factors affecting mutational specificity induced by ionizing radiation and oxidizing radicals. Progress report

    SciTech Connect

    Strauss, B.

    1992-07-01

    We propose to analyze the factors affecting the specificity of mutational change as induced by ionizing radiation and oxidizing radicals. We want to understand not only the rules the affect base substitution but also the mechanisms(s) by which additions and deletions are produced, since deletions are a common consequence of radiation. We wish to carry out this analysis in an in vitro mutation system that permits us to analyze the role of base sequence, of polymerase and of mutagenic agent. Our system is designed to screen out most direct breaks as a cause of mutation and should indicate the changes resulting from base damage to the DNA. Questions addressed include: 1. What types of base substitution mutations are induced by ionizing radiation and oxidizing radicals? 2. Are deletions and/or additions produced? 3. Is there a difference in type of mutation produced dependent on the polymerase used? Do mammalian polymerase plus their accessory factors result in different patterns of mutation. 4. What is the mechanism by which base damage is converted to mutation. Our proposal was based on utilization of an in vitro system in which mutations generated by the in vitro copying of a reporter gene sequence could be readily scored.

  15. Evidence that the APOE locus influences rate of disease progression in late onset familial Alzheimer`s disease but is not causative

    SciTech Connect

    Bennett, C.; Crawford, F.; Osborne, A.; Diaz, P.

    1995-02-27

    An association has been observed in several independent data sets between late onset Alzheimer`s Disease (AD) and the APOE locus on chromosome 19. We have examined the genotype in family history positive (FHP) and family history negative (FHN) cases and find a distortion of the APOE allele frequencies in accord with previous studies. However, when we examined the allele distribution of the at-risk siblings of the FHP group we found an excess of the {epsilon}4 allele which also differs significantly from historic controls but not from the affected siblings. The age distribution of the affected and unaffected siblings was similar, suggesting that the allelic frequency distortion in the unaffected siblings was not due to their being below the mean age of onset. Lod score linkage analysis, with age dependent onset and non-stringent specification of the genetic parameters, did not suggest linkage to the APOE locus. Furthermore, an analysis of variance of the age of disease free survival suggested that APOE genotype contributes a small fraction of the total variance indicating that the APOE locus is a poor predictor of disease free survival age within late onset families. One explanation for the age dependent association reported by other groups, and our results, is that the APOE locus enhances the rate of progression of the disease process in otherwise predisposed individuals and that variation at this locus is not able in and of itself to cause the disease. We suggest this hypothesis is compatible with the current literature regarding APOE and AD. 19 refs., 1 fig., 2 tabs.

  16. Activity of Crohn's disease assessed by colour Doppler ultrasound analysis of the affected loops.

    PubMed

    Esteban, J M; Maldonado, L; Sanchiz, V; Minguez, M; Benages, A

    2001-01-01

    The aim of this study was to evaluate with colour Doppler ultrasound the vascular changes in the wall of the loops affected by Crohn's disease, and to establish whether these changes reflects clinical or biochemical activity of Crohn's disease. Seventy-nine patients with Crohn's disease (44 with active disease and 35 inactive patients) were studied with frequency- and amplitude-encoded duplex Doppler sonography. A group of 35 healthy volunteers were also included. The exam consisted of the search for colour signals in the walls of the loops affected by Crohn's disease, classifying the degree of vascularity with a simple scoring system into three groups: absence of colour signal (score of 0); weak or scattered colour signals (score of 1); and multiple colour signals or clear identification of vessels in the loops walls (score of 2). Doppler curves were obtained of the detected vessels with measurement of the resistive index (RI). There was a visible increase in the gut walls' vascularity in the active patients compared with those with inactive disease. The mean RI was statistically significantly lower in the gut wall vessels of the patients with active illness than that obtained in the inactive patients. Colour Doppler ultrasound is a useful tool in the assessment of activity in Crohn's disease.

  17. Mutant Huntingtin Does Not Affect the Intrinsic Phenotype of Human Huntington's Disease T Lymphocytes.

    PubMed

    Miller, James R C; Träger, Ulrike; Andre, Ralph; Tabrizi, Sarah J

    2015-01-01

    Huntington's disease is a fatal neurodegenerative condition caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system is dysregulated in Huntington's disease and may contribute to its pathogenesis. However, it is not clear whether or to what extent the adaptive immune system is also involved. Here, we carry out the first comprehensive investigation of human ex vivo T lymphocytes in Huntington's disease, focusing on the frequency of a range of T lymphocyte subsets, as well as analysis of proliferation, cytokine production and gene transcription. In contrast to the innate immune system, the intrinsic phenotype of T lymphocytes does not appear to be affected by the presence of mutant huntingtin, with Huntington's disease T lymphocytes exhibiting no significant functional differences compared to control cells. The transcriptional profile of T lymphocytes also does not appear to be significantly affected, suggesting that peripheral immune dysfunction in Huntington's disease is likely to be mediated primarily by the innate rather than the adaptive immune system. This study increases our understanding of the effects of Huntington's disease on peripheral tissues, while further demonstrating the differential effects of the mutant protein on different but related cell types. Finally, this study suggests that the potential use of novel therapeutics aimed at modulating the Huntington's disease innate immune system should not be extended to include the adaptive immune system.

  18. Visual and Ocular Manifestations of Alzheimer’s Disease and Their Use as Biomarkers for Diagnosis and Progression

    PubMed Central

    Javaid, Fatimah Zara; Brenton, Jonathan; Guo, Li; Cordeiro, Maria F.

    2016-01-01

    Alzheimer’s disease (AD) is the most common form of dementia affecting the growing aging population today, with prevalence expected to rise over the next 35 years. Clinically, patients exhibit a progressive decline in cognition, memory, and social functioning due to deposition of amyloid β (Aβ) protein and intracellular hyperphosphorylated tau protein. These pathological hallmarks of AD are measured either through neuroimaging, cerebrospinal fluid analysis, or diagnosed post-mortem. Importantly, neuropathological progression occurs in the eye as well as the brain, and multiple visual changes have been noted in both human and animal models of AD. The eye offers itself as a transparent medium to cerebral pathology and has thus potentiated the development of ocular biomarkers for AD. The use of non-invasive screening, such as retinal imaging and visual testing, may enable earlier diagnosis in the clinical setting, minimizing invasive and expensive investigations. It also potentially improves disease management and quality of life for AD patients, as an earlier diagnosis allows initiation of medication and treatment. In this review, we explore the evidence surrounding ocular changes in AD and consider the biomarkers currently in development for early diagnosis. PMID:27148157

  19. Association Between Lung Microbiome and Disease Progression in IPF: A Prospective Cohort Study

    PubMed Central

    Han, MeiLan K.; Zhou, Yueren; Murray, Susan; Tayob, Nabihah; Noth, Imre; Lama, Vibha N.; Moore, Bethany B.; White, Eric S.; Flaherty, Kevin R.; Huffnagle, Gary B.; Martinez, Fernando J.

    2014-01-01

    Background The lung microbiome’s contribution to IPF pathogenesisis unknown. Using COMET-IPF (Correlating Outcomes with biochemical Markers to Estimate Time-progression in Idiopathic Pulmonary Fibrosis), the goal of this study was to determine whether unique microbial signatures would associate with disease progression. Methods IPF subjects within four years of diagnosis aged 35–80 were eligible for inclusion. Subjects were followed for up to a maximum of 80 weeks. This completed observational study is registered with ClinicalTrials.gov, number NCT01071707. Progression-free survival was defined as death, acute exacerbation, lung transplant, or decline in FVC of 10% or DLCO of 15%.DNA was isolated from 55 bronchoscopic alveolar lavage (BAL) samples. 454 pyrosequencing was used to assign operational taxonomic units (OTUs) based on a 3% sequence divergence. Adjusted Cox models identified OTUs significantly associated with progression-free survival at a p<0·10 level. These OTUs were then used in principal components (PC) analysis. The association between PCs and microbes with high factor loadings from the PC analysis and progression-free survival were examined via Cox regression analyses. Findings Mean FVC was 70·1% and mean DLCO 42·3 %predicted. Significant associations with disease progression were noted with increased % relative abundance of two OTUs identified by PC analysis, a Streptococcus OTU. (p<0·0009) and a Staphylococcus OTU(p=0·01). Strength of associations using PCs versus two OTUs alone was similar. Threshold analysis helped define a cut point for % relative abundance for each OTU associated with progression-free survival, >3·9% for the Streptococcus OTU, HR 10·19 (95% CI 2·94, 35·35; p=0·0002) and >1·8% for the Staphylococcus OTU, HR 5·06 (1·71, 14·93; p=0·003). Interpretation These preliminary data suggest IPF disease progression is associated with presence of specific members within the Staphylococcus and Streptococcus genera. PMID

  20. The affect of infectious bursal disease virus on avian influenza virus vaccine efficacy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Immunosuppressive viruses are known to affect vaccinal immunity, however the impact of virally induced immunosuppression on avian influenza vaccine efficacy has not been quantified. In order to determine the effect of exposure to infectious bursal disease virus (IBDV) on vaccinal immunity to highly ...

  1. Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

    PubMed Central

    Lasorsa, Vito Alessandro; Formicola, Daniela; Pignataro, Piero; Cimmino, Flora; Calabrese, Francesco Maria; Mora, Jaume; Esposito, Maria Rosaria; Pantile, Marcella; Zanon, Carlo; De Mariano, Marilena; Longo, Luca; Hogarty, Michael D.; de Torres, Carmen; Tonini, Gian Paolo; Iolascon, Achille; Capasso, Mario

    2016-01-01

    The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma. Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines. We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9, a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK. Other genes (PTK2, NAV3, NAV1, FZD1 and ATRX), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%. Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression. Notably BARD1, CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants. In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression. PMID:27009842

  2. Disease progression by infecting HIV-1 subtype in a seroconverter cohort in sub-Saharan Africa

    PubMed Central

    Amornkul, Pauli N.; Karita, Etienne; Kamali, Anatoli; Rida, Wasima N.; Sanders, Eduard J.; Lakhi, Shabir; Price, Matt A.; Kilembe, William; Cormier, Emmanuel; Anzala, Omu; Latka, Mary H.; Bekker, Linda-Gail; Allen, Susan A.; Gilmour, Jill; Fast, Patricia E.

    2013-01-01

    Objective: To describe immunologic, virologic, and clinical HIV disease progression by HIV-1 subtype among Africans with well documented estimated dates of HIV infection (EDIs). Design: Prospective cohort. Methods: Adults and youth with documented HIV-1 infection in the past 12 months were recruited from seroincidence cohorts in East and Southern Africa and followed at 3–6 month intervals. Blood for lymphocyte subset and viral load determination was collected at each visit. Pol was sequenced from the first positive specimen to ascertain subtype. Preantiretroviral therapy disease progression was measured by three time-to-event endpoints: CD4+ cell count 350 cells/μl or less, viral load measurement at least 1 × 105 copies/ml, and clinical AIDS. Results: From 2006 to 2011, 615 participants were enrolled at nine research centers in Kenya, Rwanda, South Africa, Uganda, and Zambia; 579 (94.1%) had viral subtyping completed. Predominant subtypes were C (256, 44.2%), A (209, 36.1%), and D (84, 14.5%). After adjustment for age, sex, and human leukocyte antigen alleles in Cox regression analyses, subtype C-infected participants progressed faster than subtype A to all three endpoints [CD4+ hazard ratio 1.60, 95% (confidence interval) CI 1.16, 2.20; viral load hazard ratio 1.59, 95% CI 1.12, 2.25; and AIDS hazard ratio 1.60, 95% CI 1.11, 2.31). Subtype D-infected participants reached high viral load more rapidly (hazard ratio 1.61, 95% CI 1.01, 2.57) and progressed nearly twice as fast to AIDS compared to subtype A (hazard ratio 1.93, 95% CI 1.21, 3.09). Conclusion: Subtype-specific differences in HIV disease progression suggest that the local subtype distribution be considered when planning HIV programs and designing and defining clinical endpoints for HIV prevention trials. PMID:24113395

  3. Long-term course and mechanisms of progression of renal disease in hemolytic uremic syndrome.

    PubMed

    Repetto, Horatio A

    2005-08-01

    In the classic form of hemolytic uremic syndrome associated with toxins of gram-negative enterobacteria, mortality in the acute stage has been lower than 5% since 1978 (data from the Nephrology Committee, Argentine Society of Pediatrics). Children usually die because of severe involvement of the central nervous system, intestine, or myocardium and its complications, or because of intercurrent infection. Treatment in this phase is supportive, and efforts should be put into prevention of infection by Shiga-like toxin-producing enterohemorrhagic Escherichia coli. Of the 95% who survive, approximately one third is at risk for having chronic sequelae. Motor, sensory, or intellectual deficits, intestinal strictures, myocardial infarctions, or diabetes are infrequent. The more-frequent chronic renal lesion is characterized by the hyperfunction of nephrons remaining after the acute necrotizing lesion, which leads to progressive scarring, and not by persistence or recurrence of the microangiopathic process. Three courses of progression to end-stage renal failure have been described. Children with most severe forms do not recover from acute renal failure and enter directly into a dialysis and transplantation program. A second group recovers renal function partially, with persistent proteinuria and frequently hypertension; progression to end-stage renal failure occurs in 2 to 5 years. The third group may recover normal serum creatinine and creatinine clearance, with persistent proteinuria. They are at risk of progressing to chronic renal failure and end-stage renal disease after more than 5 years, and sometimes as late as 20 years, after the acute disease. Treatment should aim at preventing the mechanisms associated with progressive renal scarring. Transplantation is indicated in this form of hemolytic uremic syndrome, because there is little, if any, risk of recurrence, and the prognosis is similar to that of transplantation for other diseases.

  4. Evaluation of Vascular Disease Progression in Retinopathy of Prematurity using Static and Dynamic Retinal Images

    PubMed Central

    Myung, Jane S.; Gelman, Rony; Aaker, Grant D.; Radcliffe, Nathan M.; Chan, R.V. Paul; Chiang, Michael F.

    2011-01-01

    Purpose To measure accuracy and speed for detection of vascular progression in retinopathy of prematurity (ROP) from serial images. Two strategies are compared: static side-by-side presentation vs. dynamic flickering of superimposed image pairs. Design Prospective comparative study. Methods Fifteen de-identified, wide-angle retinal image pairs were taken from infants who eventually developed plus disease. Image pairs representing vascular disease progression were taken ≥1 week apart, and control images without progression were taken on same day. Dynamic flickering pairs were created by digital image registration. Ten experts independently reviewed each image pair on a secure website using both strategies, and were asked to identify progression or state that images were identical. Accuracy and speed were measured, using examination date and ophthalmoscopic findings as a reference standard. Results Using static images, experts were accurate in a mean (%) ± standard deviation (SD) of 11.4/15 (76%) ± 1.7 image pairs. Using dynamic flickering images, experts were accurate in a mean (%) ± SD of 11.3/15 (75%) ± 1.7 image pairs. There was no significant difference in accuracy between these strategies (p=0.420). Diagnostic speed was faster using dynamic flickering (24.7±8.3 seconds) versus static side-by-side images (40.3±18.3 seconds) (p=0.002). Experts reported higher confidence when interpreting dynamic flickering images (p=0.001). Conclusions Retinal imaging provides objective documentation of vascular appearance, with potentially improved ability to recognize ROP progression compared to standard ophthalmoscopy. Speed of identifying vascular progression was faster by review of dynamic flickering image pairs than by static side-by-side images, although there was no difference in accuracy. PMID:22019222

  5. [The White man's burden - a case study caught between bipolar affective disorder and Huntington's disease].

    PubMed

    Nowidi, K; Kunisch, R; Bouna-Pyrrou, P; Meißner, D; Hennig-Fast, K; Weindl, A; Förster, S; Neuhann, T M; Falkai, P; Berger, M; Musil, R

    2013-06-01

    We report upon a case of a 55 year old patient with a bipolar affective disorder, presenting herself with a depressive symptomatology in addition to a severe motor perturbation. The main emphasis upon admittance was perfecting and improving her latest medication. Four weeks prior to her stay at our clinic a thorough neurological examination had taken place in terms of an invalidity pension trial which did not result in any diagnostic findings. Therefore a neurological disease seemed at first highly unlikely. Even though the prior testing was negative, the ensuing neurological examination at our clinic resulted in movement disorders very much indicative of Huntington's Disease. A detailed investigation in regards to the particular family history of the patient was positive for Huntington's Disease. However, whether the patient's mother had also been a genetic carrier of Huntington's Disease was still unknown at the time the patient was admitted to our clinic. It was nevertheless discovered that her mother had also suffered from a bipolar affective disorder. A genetic testing that followed the neurological examination of the patient proved positive for Huntington's Disease. Neuro-imaging resulted in a bicaudate-index of 2.4 (the critical value is 1.8). In a clinical psychological test battery the ensuing results were highly uncommon for patients with solely a bipolar affective disorder people. Under the medical regimen of Quetiapine, Citalopram and Tiaprid the patient's mood could be stabilized and there was some improvement of her motor pertubation.

  6. Gut Microbiota in HIV Infection: Implication for Disease Progression and Management

    PubMed Central

    Nwosu, Felix Chinweije; Avershina, Ekaterina; Wilson, Robert; Rudi, Knut

    2014-01-01

    Survival rates among HIV patients have significantly improved since the introduction of antiretroviral therapy (ART) in HIV management. However, persistent disease progression and clinical complications in virally suppressed individuals point to additional contributing factors other than HIV replication; microbial translocation is one such factor. The role of underlying commensal microbes and microbial products that traverse the intestinal lumen into systemic circulation in the absence of overt bacteraemia is under current investigation. This review focuses on current knowledge of the complex microbial communities and microbial markers involved in the disruption of mucosal immune T-cells in the promotion of inflammatory processes in HIV infections. Unanswered questions and aims for future studies are addressed. We provide perspective for discussing potential future therapeutic strategies focused on modulating the gut microbiota to abate HIV disease progression. PMID:25024700

  7. Atypical presentation of Creutzfeldt-Jakob disease: a rare but important cause of rapidly progressive dementia.

    PubMed

    Taillefer, Marguerite S; Tangarorang, Glendo L; Kuchel, George A; Menkes, Daniel L

    2011-09-01

    We report an atypical presentation of sporadic Creutzfeldt-Jakob disease (CJD) in a 74-year-old woman that illustrates the difficulty in diagnosing this rare, but important, cause of rapidly progressive dementia. Despite well-established criteria, this diagnosis is often missed or substantially delayed (Table 1). In this case, a precipitous cognitive decline associated with a urinary tract infection initiallysuggested delirium. Although atypical CJD was considered as a cause when symptoms persisted, a definitive diagnosis was established postmortem when the cerebrospinal fluid (CSF) prion protein 14-3-3 tested positive. Creutzfeldt-Jakob disease must be considered in the differential diagnosis of rapidly progressive dementia as Connecticut accounts for approximately three of the more than 200 cases diagnosed nationally.

  8. Genetic, Immune-Inflammatory, and Oxidative Stress Biomarkers as Predictors for Disability and Disease Progression in Multiple Sclerosis.

    PubMed

    Kallaur, Ana Paula; Reiche, Edna Maria Vissoci; Oliveira, Sayonara Rangel; Simão, Andrea Name Colado; Pereira, Wildea Lice de Carvalho Jennings; Alfieri, Daniela Frizon; Flauzino, Tamires; Proença, Caio de Meleck; Lozovoy, Marcell Alysson Batisti; Kaimen-Maciel, Damacio Ramón; Maes, Michael

    2017-01-01

    The aim of this study was to evaluate the TNFβ NcoI polymorphism (rs909253) and immune-inflammatory, oxidative, and nitrosative stress (IO&NS) biomarkers as predictors of disease progression in multiple sclerosis (MS). We included 212 MS patients (150 female, 62 male, mean (±standard deviation (SD)) age = 42.7 ± 13.8 years) and 249 healthy controls (177 female, 72 male, 36.8 ± 11 years). The disability was measured the Expanded Disability Status Scale (EDSS) in 2006 and 2011. We determined the TNFβ NcoI polymorphism and serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-4, IL-10, and IL-17, albumin, ferritin, and plasma levels of lipid hydroperoxides (CL-LOOH), carbonyl protein, advanced oxidation protein products (AOPPs), nitric oxide metabolites (NOx), and total radical-trapping antioxidant parameter (TRAP). The mean EDSS (±SD) in 2006 was 1.62 ± 2.01 and in 2011 3.16 ± 2.29, and disease duration was 7.34 ± 7.0 years. IL-10, TNF-α, IFN-γ, AOPP, and NOx levels were significantly higher and IL-4 lower in MS patients with a higher 2011 EDSS scores (≥3) as compared with those with EDSS < 3. The actual increases in EDSS from 2006 to 2011 were positively associated with TNF-α and IFN-γ. Increased IFN-γ values were associated with higher pyramidal symptoms and increased IL-6 with sensitive symptoms. Increased carbonyl protein and IL-10 but lowered albumin levels predicted cerebellar symptoms. The TNFB1/B2 genotype decreased risk towards progression of pyramidal symptoms. Treatments with IFN-β and glatiramer acetate significantly reduced TNF-α but did not affect the other IO&NS biomarkers or disease progression. Taken together, IO&NS biomarkers and NcoI TNFβ genotypes predict high disability in MS and are associated with different aspects of disease progression. New drugs to treat MS should also target oxidative stress pathways.

  9. 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.

  10. 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

  11. Effect of statin therapy on disease progression in pediatric ADPKD: design and baseline characteristics of participants.

    PubMed

    Cadnapaphornchai, Melissa A; George, Diana M; Masoumi, Amirali; McFann, Kim; Strain, John D; Schrier, Robert W

    2011-05-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney condition and is associated with important renal and cardiovascular manifestations in childhood. Renal cystic disease can be documented in some cases as early as in utero. Early intervention is critical if the long-term complications of this condition, including end-stage renal disease, are to be ameliorated. Here we describe our ongoing randomized double-blind placebo-controlled phase III clinical trial to assess the effect of pravastatin treatment on renal and cardiovascular disease progression in 107 children and young adults age 8-22 years with ADPKD who are receiving the angiotensin converting enzyme inhibitor lisinopril. Baseline demographic and laboratory data are provided. Results of this study could markedly impact the standard of care for evaluation and treatment of ADPKD in this population.

  12. Rapid progression to cardiac tamponade in Erdheim-Chester disease despite treatment with interferon alpha.

    PubMed

    Nakhleh, Afif; Slobodin, Gleb; Elias, Nizar; Bejar, Jacob; Odeh, Majed

    2016-07-01

    Erdheim-Chester disease (ECD) is a rare form of non-Langerhans histiocytosis with heterogeneous clinical manifestations. The most common presentation is bone pains typically involving the long bones. Approximately 75% of the patients develop extraskeletal involvement. Cardiac involvement is seen in up to 45% of the patients, and although, pericardial involvement is the most common cardiac pathology of this rare disease, cardiac tamponade due to ECD has been very rarely reported. We describe a case of a patient found to have ECD with multi-organ involvement and small pericardial effusion, which progressed to cardiac tamponade despite treatment with interferon alpha.

  13. Bilateral dissemination of malignant pleural mesothelioma via iatrogenic buffalo chest: a rare route of disease progression.

    PubMed

    Ikezoe, Kohei; Tanaka, Eisaku; Tanizawa, Kiminobu; Hashimoto, Seishu; Shindo, Toru; Noma, Satoshi; Kobashi, Yoichiro; Taguchi, Yoshio

    2012-09-01

    Buffalo chest refers to the pleuro-pleural communication that results in a single pleural cavity. Iatrogenic buffalo chest can occur following heart or heart-lung transplantation and other major thoracic surgeries. We present the case of malignant pleural mesothelioma in which iatrogenic buffalo chest after extended thymectomy caused bilateral pneumothoraces and contralateral dissemination of the disease. The free communication between bilateral pleural cavities had facilitated the rapid progression of tumor and the consequent bilateral malignant pleural effusions had made the management of disease much more difficult, leading to the early fatal outcome. To our knowledge, this is the first case of buffalo chest that was associated with bilateral malignant pleural effusions.

  14. [Progress in research on pathogenic genes and gene therapy for inherited retinal diseases].

    PubMed

    Zhu, Ling; Cao, Cong; Sun, Jiji; Gao, Tao; Liang, Xiaoyang; Nie, Zhipeng; Ji, Yanchun; Jiang, Pingping; Guan, Minxin

    2017-02-10

    Inherited retinal diseases (IRDs), including retinitis pigmentosa, Usher syndrome, Cone-Rod degenerations, inherited macular dystrophy, Leber's congenital amaurosis, Leber's hereditary optic neuropathy are the most common and severe types of hereditary ocular diseases. So far more than 200 pathogenic genes have been identified. With the growing knowledge of the genetics and mechanisms of IRDs, a number of gene therapeutic strategies have been developed in the laboratory or even entered clinical trials. Here the progress of IRD research on the pathogenic genes and therapeutic strategies, particularly gene therapy, are reviewed.

  15. [Research progress on multiple myeloma immunophenotyping and minimal residual disease detected by flow cytometry].

    PubMed

    Li, Han-Qing; Zhai, Yong-Ping

    2015-02-01

    Multiple myeloma (MM) is a haematological malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow and remained incurable. Flow cytometry has been widely used in the detection of immunophenotype and minimal residual disease, diagnosis, monitoring and prognosis of MM. Normal plasma cells and malignant plasma cells can be distinguished according to different cell surface antigen expression. The clinical significane of many immune markes has been elucidated. However, the clinical significance of some phenotype remains controversial, the detection scheme and gating strategy are not unified. This review discusses the recent research progress on detection of MM immunophenotype and minimal residual disease by flow cytovetry.

  16. Progress and prospects: gene therapy for genetic diseases with helper-dependent adenoviral vectors.

    PubMed

    Brunetti-Pierri, N; Ng, P

    2008-04-01

    Preclinical studies in small and large animal models using helper-dependent adenoviral vectors (HDAds) have generated promising results for the treatment of genetic diseases. However, clinical translation is complicated by the dose-dependent, capsid-mediated acute toxic response following systemic vector injection. With the advancements in vectorology, a better understanding of vector-mediated toxicity, and improved delivery methods, HDAds may emerge as an important vector for gene therapy of genetic diseases and this report highlights recent progress and prospects in this field.

  17. Current Progress in Nanotechnology Applications for Diagnosis and Treatment of Kidney Diseases

    PubMed Central

    Lee, Sue Hyun; Lee, Jung Bok; Bae, Min Soo; Balikov, Daniel A.; Hwang, Amy; Boire, Timothy C.; Kwon, Il Keun; Sung, Hak-Joon

    2016-01-01

    Significant progress has been made in nanomedicine, primarily in the form of nanoparticles, for theranostic applications to various diseases. A variety of materials, both organic and inorganic, have been used to develop nanoparticles with promise to achieve improved efficacy in medical applications as well as reduced systemic side effects compared to current standard of care medical practices. In particular, this article highlights the recent development and application of nanoparticles for diagnosing and treating nephropathologies. PMID:26121684

  18. Current progress in nanotechnology applications for diagnosis and treatment of kidney diseases.

    PubMed

    Lee, Sue Hyun; Lee, Jung Bok; Bae, Min Soo; Balikov, Daniel A; Hwang, Amy; Boire, Timothy C; Kwon, Il Keun; Sung, Hak-Joon; Yang, Jae Won

    2015-09-16

    Significant progress has been made in nanomedicine, primarily in the form of nanoparticles, for theranostic applications to various diseases. A variety of materials, both organic and inorganic, have been used to develop nanoparticles with promise to achieve improved efficacy in medical applications as well as reduced systemic side effects compared to current standard of care medical practices. In particular, this article highlights the recent development and application of nanoparticles for diagnosing and treating nephropathologies.

  19. Disease progression in Chinese patients with hepatitis C virus RNA-positive infection via blood transfusion

    PubMed Central

    Pan, Yan-Feng; Zheng, Yan; Qin, Tao; Feng, Lei; Zhang, Qian; Ping, Xiao-Gong; Pan, Yan-Ting; Wang, Xiao-Ping; Bai, Li; Li, Hua-Hua

    2016-01-01

    The majority of patients with hepatitis C virus (HCV) in China were infected via blood transfusion prior to the year 1996. In this systematic retrospective cohort study, disease progression in 804 consecutive patients with transfusion-acquired HCV is investigated. In addition, the occurrence of compensated cirrhosis, decompensated cirrhosis and hepatocellular carcinoma (HCC) is analyzed among these patients, along with the risk factors for disease progression. Patients with cirrhosis or HCC were classified as the serious development group (SD group) and the remaining patients with chronic hepatitis were classified as the hepatitis group (H group). Significant differences were found between the two groups in age at the time of infection, duration of infection and age at the time of observation. SD group patients were significantly older at the time of transfusion (33.73 vs. 23.56 years; P<0.001), with a significantly longer mean duration of HCV infection (21.88 vs. 21.15 years; P=0.029) compared with that in the H group. Male gender and age at the time of transfusion were significant risk factors for HCC (OR=2.48, P=0.031 and OR=1.07, P=0.002, respectively). Age was a significant risk factor for disease progression in older Chinese patients with transfusion-acquired HCV, and there were significant differences in the prevalence of compensated cirrhosis, decompensated cirrhosis and HCC between the age groups (P<0.001), suggesting that more patients with HCV may develop cirrhosis or HCC in their third and fourth decades of infection. Results of the present study will be helpful for predicting disease progression in Chinese patients with HCV infected via blood transfusion. PMID:27882182

  20. Pazopanib treatment slows progression and stabilizes disease in patients with taxane-resistant cutaneous angiosarcoma.

    PubMed

    Ogata, Dai; Yanagisawa, Hiroto; Suzuki, Kenji; Oashi, Kohei; Yamazaki, Naoya; Tsuchida, Tetsuya

    2016-10-01

    Although cutaneous angiosarcoma (cAS) has one of the worst prognoses among malignant skin tumors, few effective drug options for secondary treatment have been discovered to date because of the limited number of cases. Therefore, this study was aimed at determining pazopanib's potential as a new cAS treatment option. We retrospectively evaluated five patients with taxane-resistant unresectable cAS treated with pazopanib at a university hospital. Their characteristics and treatment outcomes were retrieved from their records. Progression-free survival (PFS), overall survival (OS), disease progression, and toxicity were evaluated; furthermore, the response to pazopanib was assessed in relation to the expression of vascular endothelial growth factor receptor 2 (VEGFR-2). The median PFS from the time of pazopanib initiation was 94 days. Two patients showed partial response, two showed stable disease, and one had progressive disease in the case of the best overall response. VEGFR-2 expression was positive in all cases, and patients with high expression had improved median OS compared to that in those with low expression. VEGFR-2 expression was correlated with a longer OS. The most common toxicities were hypertension and anorexia followed by myelosuppression. This is the largest case series reported wherein pazopanib was used for taxane-resistant cAS. Although the cytoreductive effect and survival benefits were not significant in this small sample, we consider pazopanib a valid treatment option for preserving patients' quality of life. Our results suggest pazopanib treatment slows the progression of disease and stabilizes it in patients with taxane-resistant cAS.

  1. Localized severe aggressive periodontitis. Disease progression and tooth preservation: a short case report over 14 years.

    PubMed

    Pelka, Matthias; Petschelt, Anselm

    2009-04-01

    A case of a 31-year-old female with aggressive periodontitis over 14 years is presented. From 1993 to 2000, no periodontal therapy occurred; disease development and progression could be reconstructed upon radiographic findings. In 2000, full-mouth disinfection therapy and antibiotic therapy was performed, as well as regenerative surgical treatments. Seven years after surgical treatment, stable periodontal conditions and clear bone regeneration in the surgical areas was evident.

  2. Genetic factors that affect nonalcoholic fatty liver disease: A systematic clinical review

    PubMed Central

    Severson, Tyler J; Besur, Siddesh; Bonkovsky, Herbert L

    2016-01-01

    AIM: To investigate roles of genetic polymorphisms in non-alcoholic fatty liver disease (NAFLD) onset, severity, and outcome through systematic literature review. METHODS: The authors conducted both systematic and specific searches of PubMed through December 2015 with special emphasis on more recent data (from 2012 onward) while still drawing from more historical data for background. We identified several specific genetic polymorphisms that have been most researched and, at this time, appear to have the greatest clinical significance on NAFLD and similar hepatic diseases. These were further investigated to assess their specific effects on disease onset and progression and the mechanisms by which these effects occur. RESULTS: We focus particularly on genetic polymorphisms of the following genes: PNPLA3, particularly the p. I148M variant, TM6SF2, particularly the p. E167K variant, and on variants in FTO, LIPA, IFNλ4, and iron metabolism, specifically focusing on HFE, and HMOX-1. We discuss the effect of these genetic variations and their resultant protein variants on the onset of fatty liver disease and its severity, including the effect on likelihood of progression to cirrhosis and hepatocellular carcinoma. While our principal focus is on NAFLD, we also discuss briefly effects of some of the variants on development and severity of other hepatic diseases, including hepatitis C and alcoholic liver disease. These results are briefly discussed in terms of clinical application and future potential for personalized medicine. CONCLUSION: Polymorphisms and genetic factors of several genes contribute to NAFLD and its end results. These genes hold keys to future improvements in diagnosis and management. PMID:27547017

  3. Effects of HMG-CoA reductase inhibitors (statins) on progression of kidney disease.

    PubMed

    Fried, Linda F

    2008-09-01

    Chronic kidney disease, especially in the setting of proteinuria, is characterized by hyperlipidemia. In animal models, hyperlipidemia causes glomerular foam cells and glomerulosclerosis. Treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) ameliorates kidney disease in these models. The data of the role of hyperlipidemia in progression of human kidney disease are less clear. Data from small studies in glomerular disease suggest that statins decrease proteinuria. Data mainly from cardiovascular studies suggest that statins decrease the loss of glomerular filtration. The benefit of statins may derive from their lipid lowering effects. More recently, data suggest that the benefit of statins is greater than lipid lowering alone. The pleiotropic effects of statins may derive from inhibition of other downstream targets (isoprenoids) of the mevalonic acid pathway that are separate from cholesterol synthesis. Statins inhibits isoprenylation of Ras and Rho GTPases. These effects may lead to decreased monocyte/macrophage infiltration in the glomerulus, decreased mesangial proliferation and decreased accumulation of extracellular matrix and fibrosis. In addition, inhibition of RhoA and Ras may decrease inflammation and increase eNOS activity. These effects could lead to improvement in the progression of kidney disease.

  4. Neo-epitope Peptides as Biomarkers of Disease Progression for Muscular Dystrophies and Other Myopathies

    PubMed Central

    Arvanitidis, A.; Henriksen, K.; Karsdal, M.A.; Nedergaard, A.

    2016-01-01

    For several decades, serological biomarkers of neuromuscular diseases as dystrophies, myopathies and myositis have been limited to routine clinical biochemistry panels. Gauging the pathological progression is a prerequisite for proper treatment and therefore identifying accessible, easy to monitor biomarkers that can predict the disease progression would be an important advancement. Most muscle diseases involve accelerated muscle fiber degradation, inflammation, fatty tissue substitution and/or fibrosis. All these pathological traits have been shown to give rise to serological peptide biomarkers in other tissues, underlining the potential application of existing biomarkers of such traits in muscle disorders. A significant quantity of tissue is involved in these pathological mechanisms alongside with qualitative changes in protein turnover in myofibrillar, extra-cellular matrix and immunological cell protein fractions accompanied by alterations in body fluids. We propose that protein and peptides can leak out of the afflicted muscles and can be of use in diagnosis, prediction of pathology trajectory and treatment efficacy. Proteolytic cleavage systems are especially modulated during a range of muscle pathologies, thereby giving rise to peptides that are differentially released during disease manifestation. Therefore, we believe that pathology-specific post-translational modifications like cleavages can give rise to neoepitope peptides that may represent a promising class of peptides for discovery of biomarkers pertaining to neuromuscular diseases. PMID:27854226

  5. Real-time progressive hyperspectral remote sensing detection methods for crop pest and diseases

    NASA Astrophysics Data System (ADS)

    Wu, Taixia; Zhang, Lifu; Peng, Bo; Zhang, Hongming; Chen, Zhengfu; Gao, Min

    2016-05-01

    Crop pests and diseases is one of major agricultural disasters, which have caused heavy losses in agricultural production each year. Hyperspectral remote sensing technology is one of the most advanced and effective method for monitoring crop pests and diseases. However, Hyperspectral facing serial problems such as low degree of automation of data processing and poor timeliness of information extraction. It resulting we cannot respond quickly to crop pests and diseases in a critical period, and missed the best time for quantitative spraying control on a fixed point. In this study, we take the crop pests and diseases as research point and breakthrough, using a self-development line scanning VNIR field imaging spectrometer. Take the advantage of the progressive obtain image characteristics of the push-broom hyperspectral remote sensor, a synchronous real-time progressive hyperspectral algorithms and models will development. Namely, the object's information will get row by row just after the data obtained. It will greatly improve operating time and efficiency under the same detection accuracy. This may solve the poor timeliness problem when we using hyperspectral remote sensing for crop pests and diseases detection. Furthermore, this method will provide a common way for time-sensitive industrial applications, such as environment, disaster. It may providing methods and technical reserves for the development of real-time detection satellite technology.

  6. Optical Coherence Tomography as a Biomarker for Diagnosis, Progression, and Prognosis of Neurodegenerative Diseases

    PubMed Central

    Otin, Sofia; Fuertes, Maria I.; Vilades, Elisa; Gracia, Hector; Ara, Jose R.; Alarcia, Raquel; Polo, Vicente; Larrosa, Jose M.; Pablo, Luis E.

    2016-01-01

    Neurodegenerative diseases present a current challenge for accurate diagnosis and for providing precise prognostic information. Developing imaging biomarkers for multiple sclerosis (MS), Parkinson disease (PD), and Alzheimer's disease (AD) will improve the clinical management of these patients and may be useful for monitoring treatment effectiveness. Recent research using optical coherence tomography (OCT) has demonstrated that parameters provided by this technology may be used as potential biomarkers for MS, PD, and AD. Retinal thinning has been observed in these patients and new segmentation software for the analysis of the different retinal layers may provide accurate information on disease progression and prognosis. In this review we analyze the application of retinal evaluation using OCT technology to provide better understanding of the possible role of the retinal layers thickness as biomarker for the detection of these neurodegenerative pathologies. Current OCT analysis of the retinal nerve fiber layer and, specially, the ganglion cell layer thickness may be considered as a good biomarker for disease diagnosis, severity, and progression. PMID:27840739

  7. Effects of Progressive Body Weight Support Treadmill Forward and Backward Walking Training on Stroke Patients’ Affected Side Lower Extremity’s Walking Ability

    PubMed Central

    Kim, Kyunghoon; Lee, Sukmin; Lee, Kyoungbo

    2014-01-01

    [Purpose] The purpose of the present study was to examine the effects of progressive body weight supported treadmill forward and backward walking training (PBWSTFBWT), progressive body weight supported treadmill forward walking training (PBWSTFWT), progressive body weight supported treadmill backward walking training (PBWSTBWT), on stroke patients’ affected side lower extremity’s walking ability. [Subjects and Methods] A total of 36 chronic stroke patients were divided into three groups with 12 subjects in each group. Each of the groups performed one of the progressive body weight supported treadmill training methods for 30 minute, six times per week for three weeks, and then received general physical therapy without any other intervention until the follow-up tests. For the assessment of the affected side lower extremity’s walking ability, step length of the affected side, stance phase of the affected side, swing phase of the affected side, single support of the affected side, and step time of the affected side were measured using optogait and the symmetry index. [Results] In the within group comparisons, all the three groups showed significant differences between before and after the intervention and in the comparison of the three groups, the PBWSTFBWT group showed more significant differences in all of the assessed items than the other two groups. [Conclusion] In the present study progressive body weight supported treadmill training was performed in an environment in which the subjects were actually walked, and PBWSTFBWT was more effective at efficiently training stroke patients’ affected side lower extremity’s walking ability. PMID:25540499

  8. Impact of Depression on Progression of Impairment and Disability in Early Parkinson’s Disease

    PubMed Central

    Bega, Danny; Luo, Sheng; Fernandez, Hubert; Chou, Kelvin; Aminoff, Michael; Parashos, Sotirios; Walker, Harrison; Russell, David S.; Christine, Chadwick W.; Dhall, Rohit; Singer, Carlos; Bodis-Wollner, Ivan; Hamill, Robert; Truong, Daniel; Mari, Zoltan; Glazmann, Sofya; Huang, Meilin; Houston, Emily; Simuni, Tanya

    2016-01-01

    Background Depression is one of the most common nonmotor symptoms associated with Parkinson’s disease (PD), yet the impact of depression on progression of disease is unclear. Objective The aim of this study was to prospectively characterize the relationship between depressive symptoms and measures of disease progression in a large sample of patients with early, medically treated PD. Methods Baseline and longitudinal Beck Depression Inventory (BDI) scores from participants in the NINDS Exploratory Trials in PD Long Term Study 1 were correlated with changes in multiple measures of disease severity over 5 years. Multivariate analysis of predictors of change in BDI was performed. Results Of 1,741 participants, 746 completed 5-year assessments and were included. Mean age was 62.00 years (standard deviation [SD]: 9.22) and mean disease duration was 1.69 years (SD, 1.16). Mean BDI score was 6.24 (SD, 5.02) at baseline and 8.57 (SD, 6.60) at 5 years. Baseline BDI score was strongly associated with rate of change in all examined measures of disease severity. In multivariate analysis, BDI 5-year change was associated with change in UPDRS Part I (excluding depression item; P < 0.01), 33-item Parkinson’s Disease Questionnaire (P < 0.01), EuroQOL Five Dimensional Questionnaire (P = 0.02), and Total Functional Capacity (P < 0.01), but was not associated with motor or cognitive measures. This model explained 68.8% of the variance 5-year change of the BDI score. Conclusions Worse baseline BDI scores are associated with a decline in multiple measures of disease severity in PD. Worsening of BDI at 5 years was associated with worsening in UPDRS Part I and quality-of-life measures, but not with motor or cognitive measures.

  9. Lumbar Facet Joint Motion in Patients with Degenerative Disc Disease at Affected and Adjacent Levels

    PubMed Central

    Li, Weishi; Wang, Shaobai; Xia, Qun; Passias, Peter; Kozanek, Michal; Wood, Kirkham; Li, Guoan

    2013-01-01

    Study Design Controlled laboratory study. Objective To evaluate the effect of lumbar degenerative disc diseases (DDDs) on motion of the facet joints during functional weight-bearing activities. Summary of Background Data It has been suggested that DDD adversely affects the biomechanical behavior of the facet joints. Altered facet joint motion, in turn, has been thought to associate with various types of lumbar spine pathology including facet degeneration, neural impingement, and DDD progression. However, to date, no data have been reported on the motion patterns of the lumbar facet joint in DDD patients. Methods Ten symptomatic patients of DDD at L4–S1 were studied. Each participant underwent magnetic resonance images to obtain three-dimensional models of the lumbar vertebrae (L2–S1) and dual fluoroscopic imaging during three characteristic trunk motions: left-right torsion, left-right bending, and flexion-extension. In vivo positions of the vertebrae were reproduced by matching the three-dimensional models of the vertebrae to their outlines on the fluoroscopic images. The kinematics of the facet joints and the ranges of motion (ROMs) were compared with a group of healthy participants reported in a previous study. Results In facet joints of the DDD patients, there was no predominant axis of rotation and no difference in ROMs was found between the different levels. During left-right torsion, the ROMs were similar between the DDD patients and the healthy participants. During left-right bending, the rotation around mediolateral axis at L4–L5, in the DDD patients, was significantly larger than that of the healthy participants. During flexion-extension, the rotations around anterioposterior axis at L4–L5 and around craniocaudal axis at the adjacent level (L3–L4), in the DDD patients, were also significantly larger, whereas the rotation around mediolateral axis at both L2–L3 and L3–L4 levels in the DDD patients were significantly smaller than those of the

  10. Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression.

    PubMed

    Davis, Albert A; Andruska, Kristin M; Benitez, Bruno A; Racette, Brad A; Perlmutter, Joel S; Cruchaga, Carlos

    2016-01-01

    Multiple genetic variants have been linked to risk of Parkinson disease (PD), but known mutations do not explain a large proportion of the total PD cases. Similarly, multiple loci have been associated with PD risk by genome-wide association studies (GWAS). The influence that genetic factors confer on phenotypic diversity remains unclear. Few studies have been performed to determine whether the GWAS loci are also associated with age at onset (AAO) or motor progression. We used 2 PD case-control data sets (Washington University and the Parkinson's Progression Markers Initiative) to determine whether polymorphisms located at the GWAS top hits (GBA, ACMSD/TMEM163, STK39, MCCC1/LAMP3, GAK/TMEM175, SNCA, and MAPT) show association with AAO or motor progression. We found associations between single nucleotide polymorphisms at the GBA and MAPT loci and PD AAO and progression. These findings reinforce the complex genetic basis of PD and suggest that distinct genes and variants explain the genetic architecture of PD risk, onset, and progression.

  11. Failed Tubule Recovery, AKI-CKD Transition, and Kidney Disease Progression

    PubMed Central

    Weinberg, Joel M.; Kriz, Wilhelm; Bidani, Anil K.

    2015-01-01

    The transition of AKI to CKD has major clinical significance. As reviewed here, recent studies show that a subpopulation of dedifferentiated, proliferating tubules recovering from AKI undergo pathologic growth arrest, fail to redifferentiate, and become atrophic. These abnormal tubules exhibit persistent, unregulated, and progressively increasing profibrotic signaling along multiple pathways. Paracrine products derived therefrom perturb normal interactions between peritubular capillary endothelium and pericyte-like fibroblasts, leading to myofibroblast transformation, proliferation, and fibrosis as well as capillary disintegration and rarefaction. Although signals from injured endothelium and inflammatory/immune cells also contribute, tubule injury alone is sufficient to produce the interstitial pathology required for fibrosis. Localized hypoxia produced by microvascular pathology may also prevent tubule recovery. However, fibrosis is not intrinsically progressive, and microvascular pathology develops strictly around damaged tubules; thus, additional deterioration of kidney structure after the transition of AKI to CKD requires new acute injury or other mechanisms of progression. Indeed, experiments using an acute-on-chronic injury model suggest that additional loss of parenchyma caused by failed repair of AKI in kidneys with prior renal mass reduction triggers hemodynamically mediated processes that damage glomeruli to cause progression. Continued investigation of these pathologic mechanisms should reveal options for preventing renal disease progression after AKI. PMID:25810494

  12. UCHL1 is a biomarker of aggressive multiple myeloma required for disease progression

    PubMed Central

    Hussain, Sajjad; Bedekovics, Tibor; Chesi, Marta; Bergsagel, P. Leif; Galardy, Paul J.

    2015-01-01

    The success of proteasome inhibition in multiple myeloma highlights the critical role for the ubiquitin-proteasome system (UPS) in this disease. However, there has been little progress in finding more specific targets within the UPS involved in myeloma pathogenesis. We previously found the ubiquitin hydrolase UCH-L1 to be frequently over-expressed in B-cell malignancies, including myeloma, and showed it to be a potent oncogene in mice. Here we show that UCH-L1 is a poor prognostic factor that is essential for the progression of myeloma. We found high levels of UCHL1 to predict early progression in newly diagnosed patients; a finding reversed by the inclusion of bortezomib. We also found high UCHL1 levels to be a critical factor in the superiority of bortezomib over high-dose dexamethasone in relapsed patients. High UCHL1 partially overlaps with, but is distinct from, known genetic risks including 4p16 rearrangement and 1q21 amplification. Using an orthotopic mouse model, we found UCH-L1 depletion delays myeloma dissemination and causes regression of established disease. We conclude that UCH-L1 is a biomarker of aggressive myeloma that may be an important marker of bortezomib response, and may itself be an effective target in disseminated disease. PMID:26513019

  13. Progression of carotid-artery disease in type 2 diabetic patients: a cohort prospective study

    PubMed Central

    Bosevski, Marijan; Stojanovska, Lily

    2015-01-01

    In order to assess the progression of carotid-artery disease in type 2 diabetic cohort (n=207 patients), the dynamic change in carotid intima-media thickness (CIMT) and the occurrence of plaques were followed for a period of 31.35±10.59 months. The mean CIMT at the beginning of the study was 0.9178±0.1447 mm, with a maximal value of 1.1210±0.2366 mm. The maximal value of CIMT changed by 0.07 mm/year. Progression of CIMT was noted in 86.8% and its regression in 7.8% of patients. The occurrence of carotid plaques was detected in 41.8% of patients. Multiple regression analysis revealed the maximal value of CIMT to be associated with diastolic blood pressure, despite mean CIMT being predicted by body mass index. The presence of peripheral arterial disease and hypo-high-density lipoproteinemia were found to be predictors for the occurrence of carotid plaques. Our data have clinical implications in predicting risk factors for the progression of carotid-artery disease in type 2 diabetic patients for their appropriate management. PMID:26527880

  14. Female gender lost protective effect against disease progression in elderly patients with chronic hepatitis B

    PubMed Central

    You, Hong; Kong, Yuanyuan; Hou, Jinlin; Wei, Lai; Zhang, Yuexin; Niu, Junqi; Han, Tao; Ou, Xiaojuan; Dou, Xiaoguang; Shang, Jia; Tang, Hong; Xie, Qing; Ding, Huiguo; Ren, Hong; Xu, Xiaoyuan; Xie, Wen; Liu, Xiaoqing; Xu, Youqing; Li, Yujie; Li, Jie; Chow, Shein-Chung; Zhuang, Hui; Jia, Jidong

    2016-01-01

    Female gender and younger age are protective factors against disease progression in chronic hepatitis B (CHB). However, it is not clear whether the disease progression still remains slow in elderly females. This study investigated the interaction of female gender and older age on the development of cirrhosis in patients recorded in China Registry of Hepatitis B. A total of 17,809 CHB patients were enrolled in this multi-center cross-sectional study. The prevalence of cirrhosis in female CHB patients increased faster than that in male CHB patients over 50 years old. Multivariate analysis showed that the increase of adjusted ORs for developing cirrhosis in females started to accelerate after 50 years old: 11.19 (95% CI: 5.93–21.11) in women versus 14.75 (95% CI: 8.35–26.07) in men at ages of 50–59 years, 21.67 (95% CI: 11.05–42.47) versus 24.4 (95% CI: 13.00–45.80) at ages 60–69 years, and 18.78 (95% CI: 6.61–53.36) versus 12.09 (95% CI: 4.35–33.61) in those over 70 years. In conclusion, the protective effect of female gender against cirrhosis gradually lost with increasing age, therefore disease progression should be monitored more closely in elderly women with CHB. PMID:27892487

  15. The genetics of human autoimmune disease: A perspective on progress in the field and future directions.

    PubMed

    Seldin, Michael F

    2015-11-01

    Progress in defining the genetics of autoimmune disease has been dramatically enhanced by large scale genetic studies. Genome-wide approaches, examining hundreds or for some diseases thousands of cases and controls, have been implemented using high throughput genotyping and appropriate algorithms to provide a wealth of data over the last decade. These studies have identified hundreds of non-HLA loci as well as further defining HLA variations that predispose to different autoimmune diseases. These studies to identify genetic risk loci are also complemented by progress in gene expression studies including definition of expression quantitative trait loci (eQTL), various alterations in chromatin structure including histone marks, DNase I sensitivity, repressed chromatin regions as well as transcript factor binding sites. Integration of this information can partially explain why particular variations can alter proclivity to autoimmune phenotypes. Despite our incomplete knowledge base with only partial definition of hereditary factors and possible functional connections, this progress has and will continue to facilitate a better understanding of critical pathways and critical changes in immunoregulation. Advances in defining and understanding functional variants potentially can lead to both novel therapeutics and personalized medicine in which therapeutic approaches are chosen based on particular molecular phenotypes and genomic alterations.

  16. Chronic and progressive Parkinson's disease MPTP model in adult and aged mice.

    PubMed

    Muñoz-Manchado, Ana B; Villadiego, Javier; Romo-Madero, Sonia; Suárez-Luna, Nela; Bermejo-Navas, Alfonso; Rodríguez-Gómez, José A; Garrido-Gil, Pablo; Labandeira-García, José L; Echevarría, Miriam; López-Barneo, José; Toledo-Aral, Juan J

    2016-01-01

    Despite the different animal models of Parkinson's disease developed during the last years, they still present limitations modelling the slow and progressive process of neurodegeneration. Here, we undertook a histological, neurochemical and behavioural analysis of a new chronic parkinsonian mouse model generated by the subcutaneous administration of low doses of MPTP (20 mg/kg, 3 times per week) for 3 months, using both young adult and aged mice. The MPTP-induced nigrostriatal neurodegeneration was progressive and was accompanied by a decrease in striatal dopamine levels and motor impairment. We also demonstrated the characteristic neuroinflammatory changes (microglial activation and astrogliosis) associated with the neurodegenerative process. Aged animals showed both a faster time course of neurodegeneration and an altered neuroinflammatory response. The long-term systemic application of low MPTP doses did not induce any increase in mortality in either young adult or aged mice and better resembles the slow evolution of the neurodegenerative process. This treatment could be useful to model different stages of Parkinson's disease, providing a better understanding of the pathophysiology of the disease and facilitating the testing of both protective and restorative treatments. Here, we show a new chronic and progressive parkinsonian mouse model, in young and aged mice. This model produces a stable degeneration of the dopaminergic nigrostriatal pathway, continuous neuroinflammatory reaction and motor deficits. Aged animals showed a faster neurodegeneration and an altered neuroinflammatory response. This treatment could be useful to model different stages of PD and to test both protective and restorative therapeutic approaches.

  17. Aquaporin-1 plays important role in proliferation by affecting cell cycle progression.

    PubMed

    Galán-Cobo, Ana; Ramírez-Lorca, Reposo; Toledo-Aral, Juan José; Echevarría, Miriam

    2016-01-01

    Aquaporin-1 (AQP1) has been associated with tumor development. Here, we investigated how AQP1 may affect cell proliferation. The proliferative rate of adult carotid body (CB) cells, known to proliferate under chronic hypoxia, was analyzed in wild-type (AQP1(+/+) ) and knock out (AQP1(-/-) ) mice, maintained in normoxia or exposed to hypoxia while BrdU was administered. Fewer numbers of total BrdU(+) and TH-BrdU(+) cells were observed in AQP1(-/-) mice, indicating a role for AQP1 in CB proliferation. Then, by flow cytometry, cell cycle state and proliferation of cells overexpressing AQP1 were compared to those of wild-type cells. In the AQP1-overexpressing cells, we observed higher cell proliferation and percentages of cells in phases S and G2/M and fewer apoptotic cells after nocodazole treatment were detected by annexin V staining. Also in these cells, proteomic assays showed higher expression of cyclin D1 and E1 and microarray analysis revealed changes in many cell proliferation-related molecules, including, Zeb 2, Jun, NF-kβ, Cxcl9, Cxcl10, TNF, and the TNF receptor. Overall, our results indicate that the presence of AQP1 modifies the expression of key cell cycle proteins apparently related to increases in cell proliferation. This contributes to explaining the presence of AQP1 in many different tumors.

  18. Ecosystem screening approach for pathogen-associated microorganisms affecting host disease.

    PubMed

    Galiana, Eric; Marais, Antoine; Mura, Catherine; Industri, Benoît; Arbiol, Gilles; Ponchet, Michel

    2011-09-01

    The microbial community in which a pathogen evolves is fundamental to disease outcome. Species interacting with a pathogen on the host surface shape the distribution, density, and genetic diversity of the inoculum, but the role of these species is rarely determined. The screening method developed here can be used to characterize pathogen-associated species affecting disease. This strategy involves three steps: (i) constitution of the microbial community, using the pathogen as a trap; (ii) community selection, using extracts from the pathogen as the sole nutrient source; and (iii) molecular identification and the screening of isolates focusing on their effects on the growth of the pathogen in vitro and host disease. This approach was applied to a soilborne plant pathogen, Phytophthora parasitica, structured in a biofilm, for screening the microbial community from the rhizosphere of Nicotiana tabacum (the host). Two of the characterized eukaryotes interfered with the oomycete cycle and may affect the host disease. A Vorticella species acted through a mutualistic interaction with P. parasitica, disseminating pathogenic material by leaving the biofilm. A Phoma species established an amensal interaction with P. parasitica, strongly suppressing disease by inhibiting P. parasitica germination. This screening method is appropriate for all nonobligate pathogens. It allows the definition of microbial species as promoters or suppressors of a disease for a given biotope. It should also help to identify important microbial relationships for ecology and evolution of pathogens.

  19. The fundamental role of mechanical properties in the progression of cancer disease and inflammation

    NASA Astrophysics Data System (ADS)

    Mierke, Claudia Tanja

    2014-07-01

    The role of mechanical properties in cancer disease and inflammation is still underinvestigated and even ignored in many oncological and immunological reviews. In particular, eight classical hallmarks of cancer have been proposed, but they still ignore the mechanics behind the processes that facilitate cancer progression. To define the malignant transformation of neoplasms and finally reveal the functional pathway that enables cancer cells to promote cancer progression, these classical hallmarks of cancer require the inclusion of specific mechanical properties of cancer cells and their microenvironment such as the extracellular matrix as well as embedded cells such as fibroblasts, macrophages or endothelial cells. Thus, this review will present current cancer research from a biophysical point of view and will therefore focus on novel physical aspects and biophysical methods to investigate the aggressiveness of cancer cells and the process of inflammation. As cancer or immune cells are embedded in a certain microenvironment such as the extracellular matrix, the mechanical properties of this microenvironment cannot be neglected, and alterations of the microenvironment may have an impact on the mechanical properties of the cancer or immune cells. Here, it is highlighted how biophysical approaches, both experimental and theoretical, have an impact on the classical hallmarks of cancer and inflammation. It is even pointed out how these biophysical approaches contribute to the understanding of the regulation of cancer disease and inflammatory responses after tissue injury through physical microenvironmental property sensing mechanisms. The recognized physical signals are transduced into biochemical signaling events that guide cellular responses, such as malignant tumor progression, after the transition of cancer cells from an epithelial to a mesenchymal phenotype or an inflammatory response due to tissue injury. Moreover, cell adaptation to mechanical alterations, in

  20. Differential virulence and disease progression following Mycobacterium tuberculosis complex infection of the common marmoset (Callithrix jacchus).

    PubMed

    Via, Laura E; Weiner, Danielle M; Schimel, Daniel; Lin, Philana Ling; Dayao, Emmanuel; Tankersley, Sarah L; Cai, Ying; Coleman, M Teresa; Tomko, Jaime; Paripati, Praveen; Orandle, Marlene; Kastenmayer, Robin J; Tartakovsky, Michael; Rosenthal, Alexander; Portevin, Damien; Eum, Seok Yong; Lahouar, Saher; Gagneux, Sebastien; Young, Douglas B; Flynn, Joanne L; Barry, Clifton E

    2013-08-01

    Existing small-animal models of tuberculosis (TB) rarely develop cavitary disease, limiting their value for assessing the biology and dynamics of this highly important feature of human disease. To develop a smaller primate model with pathology similar to that seen in humans, we experimentally infected the common marmoset (Callithrix jacchus) with diverse strains of Mycobacterium tuberculosis of various pathogenic potentials. These included recent isolates of the modern Beijing lineage, the Euro-American X lineage, and M. africanum. All three strains produced fulminant disease in this animal with a spectrum of progression rates and clinical sequelae that could be monitored in real time using 2-deoxy-2-[(18)F]fluoro-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT). Lesion pathology at sacrifice revealed the entire spectrum of lesions observed in human TB patients. The three strains produced different rates of progression to disease, various extents of extrapulmonary dissemination, and various degrees of cavitation. The majority of live births in this species are twins, and comparison of results from siblings with different infecting strains allowed us to establish that the infection was highly reproducible and that the differential virulence of strains was not simply host variation. Quantitative assessment of disease burden by FDG-PET/CT provided an accurate reflection of the pathology findings at necropsy. These results suggest that the marmoset offers an attractive small-animal model of human disease that recapitulates both the complex pathology and spectrum of disease observed in humans infected with various M. tuberculosis strain clades.

  1. Demography, disease and the devil: life-history changes in a disease-affected population of Tasmanian devils (Sarcophilus harrisii).

    PubMed

    Lachish, Shelly; McCallum, Hamish; Jones, Menna

    2009-03-01

    1. Examining the demographic responses of populations to disease epidemics and the nature of compensatory responses to perturbation from epidemics is critical to our understanding of the processes affecting population dynamics and our ability to conserve threatened species. Such knowledge is currently available for few systems. 2. We examined changes to the demography and life-history traits of a population of Tasmanian devils (Sarcophilus harrisii) following the arrival of a debilitating infectious disease, devil facial tumour disease (DFTD), and investigated the population's ability to compensate for the severe population perturbation caused by this epizootic. 3. There was a significant change to the age structure following the arrival of DFTD to the Freycinet Peninsula. This shift to a younger population was caused by the loss of older individuals from the population as a direct consequence of DFTD-driven declines in adult survival rates. 4. Offspring sex ratios of disease mothers were more female biased than those of healthy mothers, indicating that devils may facultatively adjust offspring sex ratios in response to disease-induced changes in maternal condition. 5. We detected evidence of reproductive compensation in response to disease impacts via a reduction in the age of sexual maturity of females (an increase in precocial breeding) over time. 6. The strength of this compensatory response appeared to be limited by factors that constrain the ability of individuals to reach a critical size for sexual maturity in their first year, because of the time limit dictated by the annual breeding season. 7. The ongoing devastating impacts of this disease for adult survival and the apparent reliance of precocial breeding on rapid early growth provide the opportunity for evolution to favour of this new life-history pattern, highlighting the potential for novel infectious diseases to be strong selective forces on life-history evolution.

  2. [Periodontitis determining the onset and progression of Huntington's disease: review of the literature].

    PubMed

    Rodríguez Coyago, María Lourdes; Sánchez Temiño, Victoria Emilia

    2015-10-27

    Huntington's disease is a neurodegenerative disorder caused by the expansion of a CAG triplet in the huntingtin gene. It presents with physical, cognitive and psychiatric impairment at different ages in the adult, and has a fatal prognosis. Other than the number of triplet repetitions, there seem to be other factors that explain the onset of this disease at an earlier age. It is well known that neuroinflammation has a key role in neurodegenerative disorders; Huntington's disease is not an exception to that rule. Neuroinflammation exacerbates neuronal damage produced by mutation, by initiating aberrant activation of microglia cell, as well as astrocyte and dendritic cell dysfunction; also compromising the blood-brain barrier and activating the complement cascade. The latter as a direct and indirect effect of the mutation and other stimuli such as chronic infections. In this study, periodontitis is presented as a model of chronic oral infection and a systemic inflammation source. We hypothesize the potential role of periodontitis in Huntington's disease, and the mechanisms by which it contributes to the early onset and progress of the disease. We considered experimental studies, systematic reviews, meta-analyses, published in both Spanish and English, obtained from the PubMed and SciELO databases. There are various mechanisms that generate brain inflammation in these patients; mechanisms of innate immunity being especially prominent. Chronic oral-dental infections, such as periodontal disease, may be an exacerbating factor that adds to the neuroinflammation of Huntington'’s disease.

  3. Progress in improving state and local disease surveillance--United States, 2000-2005.

    PubMed

    2005-08-26

    In September 2000, states began receiving federal funding to plan and implement integrated electronic systems for disease surveillance. CDC and state and local health departments had recognized the importance of such systems and of uniform standards to improve the usefulness of public health surveillance and the timeliness of response to outbreaks of disease. Previously, state health departments received most case-report forms by mail and then entered the data into computer systems, sometimes weeks after the cases of notifiable disease had occurred, including cases that warranted immediate public health investigation or intervention. In addition, depending on the disease, only 10%-85% of cases were reported, and more than 100 different systems were used to transmit these reports from the states to CDC (CDC, unpublished data, 2005). This report summarizes progress since the initial funding in 2000 in improving state and local disease surveillance through secure, Internet-based data entry and automated electronic laboratory results (ELR) reporting. Both are components of the National Electronic Disease Surveillance System (NEDSS), the surveillance and monitoring component of the broader Public Health Information Network (PHIN) initiative. Local, state, and national public health officials should continue to improve the timeliness and completeness of disease surveillance.

  4. Chronic kidney disease and the involvement of estrogen hormones in its pathogenesis and progression.

    PubMed

    Gluhovschi, Gh; Gluhovschi, A; Anastasiu, D; Petrica, Ligia; Gluhovschi, Cristina; Velciov, Silvia

    2012-01-01

    The kidney is under the influence of sexual hormones. Estrogens have a favourable role in the progression of some chronic renal diseases. Estrogen hormones act upon the nephron component cells, regulating several processes going on at this level. One of the most important actions of the estrogens is represented by the protective effect on the kidneys, estrogens attenuating glomerulosclerosis and tubulo-interstitial fibrosis. Thus, estrogens have nephroprotective effects. Phosphorus-calcium metabolism disturbances during chronic kidney disease are influenced by numerous regulatory factors: parathormone, vitamin D fibroblast growth factor, 23. Estrogens play an important part in disturbances of the phosphorus-calcium metabolism, co-operating with these factors. They exert favourable effects on renal osteodystrophy, the main consequence of phosphorus-calcium disturbances. Hormonal dysfunction in chronic kidney disease is clinically accompanied by sexual dysfunction that influences the life quality of these patients. In advanced stages of chronic kidney disease, especially in dialysed patients, these sexual dysfunctions can be more evident. Hormonal replacement therapy and estrogen therapy- receptor modulating therapy have an important role in correcting hormonal dysfunctions manifest in chronic kidney disease. Caution is necessary in case of a would-be pregnancy in patients with chronic kidney disease, given its risks and the complexity of the problem. Renal transplantation corrects to a great extent hormonal dysfunctions in chronic kidney disease.

  5. Postural Sway as a Marker of Progression in Parkinson's disease: a Pilot Longitudinal Study

    PubMed Central

    Carlson-Kuhta, Patricia; Zampieri, Cris; Nutt, John G.; Chiari, Lorenzo; Horak, Fay B.

    2013-01-01

    Objective measures of postural control that are sensitive to Parkinson's Disease (PD) progression would improve patient care and accelerate clinical trials. Although measures of postural sway during quiet stance in untreated PD have been shown to differ from age-matched control subjects, it is not known if sway measures change with disease progression in early PD. In this pilot study, we asked whether accelerometer-based metrics of sway could provide a practical tool for monitoring progression of postural dyscontrol in people with untreated or newly treated PD. We examined 13 subjects with PD and 12 healthy, age-matched control subjects. The PD subjects had been recently diagnosed and had not started any antiparkinsonian medications at the baseline session. All subjects were tested 3-to-6 months and 12 months after the baseline session. Subjects were asked to stand quietly for two minutes while wearing an inertial sensor on their posterior trunk that measured trunk linear acceleration. Our results suggested that objective sway measures deteriorated over one year despite minimal changes in UPDRS motor scores. Medio-lateral (ML) sway measures were more sensitive than antero-posterior sway measures in detecting progression. The ML JERK was larger in the PD group than the control group across all three testing sessions. The ML sway dispersion and ML sway velocity were also significantly higher in PD compared to control subjects by the 12-month evaluation. It is feasible to measure progression of PD prior to onset of treatment using accelerometer-based measures of quiet standing. PMID:22750016

  6. How do economic crises affect migrants’ risk of infectious disease? A systematic-narrative review

    PubMed Central

    Karanikolos, Marina; Williams, Gemma; Mladovsky, Philipa; King, Lawrence; Pharris, Anastasia; Suk, Jonathan E.; Hatzakis, Angelos; McKee, Martin; Noori, Teymur; Stuckler, David

    2015-01-01

    Background: It is not well understood how economic crises affect infectious disease incidence and prevalence, particularly among vulnerable groups. Using a susceptible-infected-recovered framework, we systematically reviewed literature on the impact of the economic crises on infectious disease risks in migrants in Europe, focusing principally on HIV, TB, hepatitis and other STIs. Methods: We conducted two searches in PubMed/Medline, Web of Science, Cochrane Library, Google Scholar, websites of key organizations and grey literature to identify how economic changes affect migrant populations and infectious disease. We perform a narrative synthesis in order to map critical pathways and identify hypotheses for subsequent research. Results: The systematic review on links between economic crises and migrant health identified 653 studies through database searching; only seven met the inclusion criteria. Fourteen items were identified through further searches. The systematic review on links between economic crises and infectious disease identified 480 studies through database searching; 19 met the inclusion criteria. Eight items were identified through further searches. The reviews show that migrant populations in Europe appear disproportionately at risk of specific infectious diseases, and that economic crises and subsequent responses have tended to exacerbate such risks. Recessions lead to unemployment, impoverishment and other risk factors that can be linked to the transmissibility of disease among migrants. Austerity measures that lead to cuts in prevention and treatment programmes further exacerbate infectious disease risks among migrants. Non-governmental health service providers occasionally stepped in to cater to specific populations that include migrants. Conclusions: There is evidence that migrants are especially vulnerable to infectious disease during economic crises. Ring-fenced funding of prevention programs, including screening and treatment, is important for

  7. Urinary Biomarkers for Monitoring Disease Progression in the Han:SPRD-cy Rat Model of Autosomal-Dominant Polycystic Kidney Disease

    PubMed Central

    Wiedmeyer, Charles E; Royal, Angela B

    2010-01-01

    The Han:SRPD-cy rat is a well-recognized model of human autosomal-dominant polycystic kidney disease. The disease is characterized by the development of progressive renal cysts, leading to declining renal function. Disease progression typically is monitored by measurement of plasma urea concentration. Although plasma urea may be an adequate measure of overall renal function, urinary biomarkers capable of accurately monitoring disease progression may be equally useful. The goal of this study was to assess several urinary biomarkers as potential markers of disease progression in male and female Han:SPRD-cy rats. These biomarkers were compared with changes in plasma urea concentration and morphometric changes as the disease progressed. Urinary activity of N-acetyl-β-D-glucosaminidase and concentration of α-glutathione S-transferase were measured as markers of proximal tubular dysfunction, glutathione S-transferase Yb1 as a distal tubular marker, and collagen IV as a biomarker for glomerular lesions. Urinary albumin was used as biomarker of glomerular or proximal tubular lesions. Albuminuria increased in male rats as the disease progressed, correlating with increasing plasma urea and morphologic changes. Urine concentrations of α-glutathione S-transferase decreased significantly in the male heterozygotic compared with wildtype rats in the later stages of the disease. Urinary concentrations of glutathione S-transferase Yb1 and collagen IV and activity of N-acetyl-β-D-glucosaminidase did not change during disease progression. Measurement of urinary albumin and concentrations of α-glutathione S-transferase may be useful for monitoring disease progression in the male Han:SPRD-cy rat model in future experiments. PMID:21262131

  8. Progressive resistance training in Parkinson's disease: a systematic review and meta-analysis

    PubMed Central

    Saltychev, Mikhail; Bärlund, Esa; Paltamaa, Jaana; Katajapuu, Niina; Laimi, Katri

    2016-01-01

    Objectives To investigate if there is evidence on effectiveness of progressive resistance training in rehabilitation of Parkinson disease. Design Systematic review and meta-analysis. Data sources: Central, Medline, Embase, Cinahl, Web of Science, Pedro until May 2014. Randomised controlled or controlled clinical trials. The methodological quality of studies was assessed according to the Cochrane Collaboration's domain-based evaluation framework. Data synthesis: random effects meta-analysis with test for heterogeneity using the I² and pooled estimate as the raw mean difference. Participants Adults with primary/idiopathic Parkinson's disease of any severity, excluding other concurrent neurological condition. Interventions Progressive resistance training defined as training consisting of a small number of repetitions until fatigue, allowing sufficient rest between exercises for recovery, and increasing the resistance as the ability to generate force improves. Comparison Progressive resistance training versus no treatment, placebo or other treatment in randomised controlled or controlled clinical trials. Primary and secondary outcome measures Any outcome. Results Of 516 records, 12 were considered relevant. Nine of them had low risk of bias. All studies were randomised controlled trials conducted on small samples with none or 1 month follow-up after the end of intervention. Of them, six were included in quantitative analysis. Pooled effect sizes of meta-analyses on fast and comfortable walking speed, the 6 min walking test, Timed Up and Go test and maximal oxygen consumption were below the level of minimal clinical significance. Conclusions There is so far no evidence on the superiority of progressive resistance training compared with other physical training to support the use of this technique in rehabilitation of Parkinson's disease. Systematic review registration number PROSPERO 2014:CRD42014009844. PMID:26743698

  9. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism.

    PubMed

    Vujkovic-Cvijin, Ivan; Dunham, Richard M; Iwai, Shoko; Maher, Michael C; Albright, Rebecca G; Broadhurst, Mara J; Hernandez, Ryan D; Lederman, Michael M; Huang, Yong; Somsouk, Ma; Deeks, Steven G; Hunt, Peter W; Lynch, Susan V; McCune, Joseph M

    2013-07-10

    Progressive HIV infection is characterized by dysregulation of the intestinal immune barrier, translocation of immunostimulatory microbial products, and chronic systemic inflammation that is thought to drive progression of disease to AIDS. Elements of this pathologic process persist despite viral suppression during highly active antiretroviral therapy (HAART), and drivers of these phenomena remain poorly understood. Disrupted intestinal immunity can precipitate dysbiosis that induces chronic inflammation in the mucosa and periphery of mice. However, putative microbial drivers of HIV-associated immunopathology versus recovery have not been identified in humans. Using high-resolution bacterial community profiling, we identified a dysbiotic mucosal-adherent community enriched in Proteobacteria and depleted of Bacteroidia members that was associated with markers of mucosal immune disruption, T cell activation, and chronic inflammation in HIV-infected subjects. Furthermore, this dysbiosis was evident among HIV-infected subjects undergoing HAART, and the extent of dysbiosis correlated with activity of the kynurenine pathway of tryptophan catabolism and plasma concentrations of the inflammatory cytokine interleukin-6 (IL-6), two established markers of disease progression. Gut-resident bacteria with capacity to catabolize tryptophan through the kynurenine pathway were found to be enriched in HIV-infected subjects, strongly correlated with kynurenine levels in HIV-infected subjects, and capable of kynurenine production in vitro. These observations demonstrate a link between mucosal-adherent colonic bacteria and immunopathogenesis during progressive HIV infection that is apparent even in the setting of viral suppression during HAART. This link suggests that gut-resident microbial populations may influence intestinal homeostasis during HIV disease.

  10. External Knee Adduction and Flexion Moments during Gait and Medial Tibiofemoral Disease Progression in Knee Osteoarthritis

    PubMed Central

    Chang, Alison H.; Moisio, Kirsten C.; Chmiel, Joan S.; Eckstein, Felix; Guermazi, Ali; Prasad, Pottumarthi V.; Zhang, Yunhui; Almagor, Orit; Belisle, Laura; Hayes, Karen; Sharma, Leena

    2015-01-01

    Objective Test the hypothesis that greater baseline peak external knee adduction moment (KAM), KAM impulse, and peak external knee flexion moment (KFM) during the stance phase of gait are associated with baseline-to-2-year medial tibiofemoral cartilage damage and bone marrow lesion progression, and cartilage thickness loss. Methods Participants all had knee OA in at least one knee. Baseline peak KAM, KAM impulse, and peak KFM (normalized to body weight and height) were captured and computed using a motion analysis system and 6 force plates. Participants underwent MRI of both knees at baseline and two years later. To assess the association between baseline moments and baseline-to-2-year semiquantitative cartilage damage and bone marrow lesion progression and quantitative cartilage thickness loss, we used logistic regression with generalized estimating equations (GEE), adjusting for gait speed, age, gender, disease severity, knee pain severity, and medication use. Results The sample consisted of 391 knees (204 persons): mean age 64.2 years (SD 10.0); BMI 28.4 kg/m2 (5.7); 156 (76.5%) women. Greater baseline peak KAM and KAM impulse were each associated with worsening of medial bone marrow lesions, but not cartilage damage. Higher baseline KAM impulse was associated with 2-year medial cartilage thickness loss assessed both as % loss and as a threshold of loss, whereas peak KAM was related only to % loss. There was no relationship between baseline peak KFM and any medial disease progression outcome measures. Conclusion Findings support targeting KAM parameters in an effort to delay medial OA disease progression. PMID:25677110

  11. An estrogen-induced endometrial hyperplasia mouse model recapitulating human disease progression and genetic aberrations.

    PubMed

    Yang, Chieh-Hsiang; Almomen, Aliyah; Wee, Yin Shen; Jarboe, Elke A; Peterson, C Matthew; Janát-Amsbury, Margit M

    2015-07-01

    Endometrial hyperplasia (EH) is a condition originating from uterine endometrial glands undergoing disordered proliferation including the risk to progress to endometrial adenocarcinoma. In recent years, a steady increase in EH cases among younger women of reproductive age accentuates the demand of therapeutic alternatives, which emphasizes that an improved disease model for therapeutic agents evaluation is concurrently desired. Here, a new hormone-induced EH mouse model was developed using a subcutaneous estradiol (E2)-sustained releasing pellet, which elevates the serum E2 level in mice, closely mimicking the effect known as estrogen dominance with underlying, pathological E2 levels in patients. The onset and progression of EH generated within this model recapitulate a clinically relevant, pathological transformation, beginning with disordered proliferation developing to simple EH, advancing to atypical EH, and then progressing to precancerous stages, all following a chronologic manner. Although a general increase in nuclear progesterone receptor (PR) expression occurred after E2 expression, a total loss in PR was noted in some endometrial glands as disease advanced to simple EH. Furthermore, estrogen receptor (ER) expression in the nucleus of endometrial cells was reduced in disordered proliferation and increased when EH progressed to atypical EH and precancerous stages. This EH model also resembles other pathological patterns found in human disease such as leukocytic infiltration, genetic aberrations in β-catenin, and joint phosphatase and tensin homolog/paired box gene 2 (PTEN/PAX2) silencing. In summary, this new and comprehensively characterized EH model is cost-effective, easily reproducible, and may serve as a tool for preclinical testing of therapeutic agents and facilitate further investigation of EH.

  12. Progressive heart disease in mucopolysaccharidosis type I mice may be mediated by increased cathepsin B activity.

    PubMed

    Baldo, Guilherme; Tavares, Angela Maria Vicente; Gonzalez, Esteban; Poletto, Edina; Mayer, Fabiana Quoos; Matte, Ursula da Silveira; Giugliani, Roberto

    Mucopolysaccharidosis type I (MPS I) is a lysosomal disorder characterized by a deficiency of alpha-L-iduronidase and storage of undegraded glycosaminoglycans (GAGs). Clinical findings of the disease include heart failure, and patients often need valve replacement. It has been shown that, later in life, MPS I mice develop those abnormalities, but to date, there have not been studies on the progression and pathogenesis of the disease. Therefore, in the present study, we evaluated heart function in normal and MPS I male mice from 2 to 8 months of age. Echocardiographic analysis showed left ventricular enlargement with progressive reduction in ejection fraction, fractional area change, and left ventricular fractional shortening in the MPS I hearts at 6 and 8 months of age and a reduction in acceleration time/ejection time ratio of the pulmonary artery starting at 6 months of age, which suggests pulmonary vascular resistance. Histological and biochemical analysis confirmed progressive GAG storage from 2 months of age and onwards in the myocardium and heart valves, which had also increased in thickness. Additionally, macrophages were present in the MPS I heart tissue. Collagen content was reduced in the MPS I mouse valves. Cathepsin B, an enzyme that is known to be able to degrade collagen and is involved in heart dilatation, displayed a marked elevation in activity in the MPS I mice and could be responsible for the heart dilatation and valves alterations observed. Our results suggest that the MPS I mice have progressive heart failure and valve disease, which may be caused by cathepsin B overexpression.

  13. Disease progression in young patients with COPD: rethinking the Fletcher and Peto model.

    PubMed

    Sanchez-Salcedo, Pablo; Divo, Miguel; Casanova, Ciro; Pinto-Plata, Victor; de-Torres, Juan P; Cote, Claudia; Cabrera, Carlos; Zagaceta, Jorge; Rodriguez-Roisin, Roberto; Zulueta, Javier J; Marin, Jose Maria; Celli, Bartolome

    2014-08-01

    Chronic obstructive pulmonary disease (COPD), although frequent in older individuals, can also occur at younger age; this latter population has not been well described. We reviewed the functional progression of 1708 patients with COPD attending pulmonary clinics. Those with three or more annual spirometries were divided into those who, at enrolment, were ≤ 55 (n = 103) or ≥ 65 (n = 463) years of age (younger and older COPD, respectively). Baseline and annual changes in lung function (forced expiratory volume in 1 s (FEV1)) and BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) score were recorded and compared between both groups. Severity distribution by Global Initiative for Chronic Obstructive Lung Disease and BODE scores were similar in both groups, except for mild obstruction, which was higher in the younger group. Mean FEV1 decline was 38.8 and 40.6 mL · year(-1), while BODE scores increased 0.19 and 0.23 units per year, for younger and older COPD, respectively. Both groups had similar proportion of FEV1 rapid decliners (42% and 46%, respectively). The severity distribution and progression of disease in younger patients with COPD is similar to that of patients of older age. This observation suggests that younger individuals presenting with COPD develop the disease from an already compromised pulmonary and systemic status, complementing the model of steeper decline of lung function proposed by Fletcher and Peto.

  14. Transient lactose malabsorption in patients affected by symptomatic uncomplicated diverticular