A study to assess whether fixed-width beam walking provides sufficient challenge to assess balance ability across lower limb prosthesis users.

PubMed

Sawers, Andrew; Hafner, Brian J

2018-04-01

To evaluate the feasibility of fixed-width beam walking for assessing balance in lower limb prosthesis users. Cross-sectional. Laboratory. Lower limb prosthesis users. Participants attempted 10 walking trials on three fixed-width beams (18.6, 8.60, and 4.01 wide; 5.5 m long; 3.8 cm high). Beam-walking performance was quantified using the distance walked to balance failure. Heuristic rules applied to each participant's beam-walking distance to classify each beam as "too easy," "too hard," or "appropriately challenging" and determine whether any single beam provided an appropriate challenge to all participants. The number of trials needed to achieve stable beam-walking performance was quantified for appropriately challenging beams by identifying the last inflection point in the slope of each participant's trial-by-trial cumulative performance record. In all, 30 unilateral lower limb prosthesis users participated in the study. Each of the fixed-width beams was either too easy or too hard for at least 33% of the sample. Thus, no single beam was appropriately challenging for all participants. Beam-walking performance was stable by trial 8 for all participants and by trial 6 for 90% of participants. There was no significant difference in the number of trials needed to achieve stable performance among beams ( P = 0.74). Results suggest that a clinical beam-walking test would require multiple beams to evaluate balance across a range of lower limb prosthesis users, emphasizing the need for adaptive or progressively challenging balance tests. While the administrative burden of a multiple-beam balance test may limit clinical feasibility, alternatives to ease this administrative burden are proposed.

Reconsidering the Gatekeeper Paradigm for Percutaneous Coronary Intervention in Stable Coronary Disease Management.

PubMed

Schulman-Marcus, Joshua; Weintraub, William S; Boden, William E

2017-10-15

Major randomized clinical trials over the last decade support the role of optimal medical therapy for the initial management approach for patients with stable coronary artery disease (CAD), whereas percutaneous coronary intervention (PCI) ought to be reserved for patients with persistent symptoms despite optimal medical therapy. Likewise, several studies have continued to demonstrate the superiority of coronary artery bypass grafting surgery over PCI in many patients with extensive multivessel CAD, especially those with diabetes. Nevertheless, the decision-making paradigm for patients with stable CAD often continues to propagate the upfront use of "ad hoc PCI" and disadvantages alternative therapeutic approaches. In our editorial, we discuss how multiple systemic and interpersonal factors continue to favor early revascularization with PCI in stable patients. We discuss whether the interventional cardiologist can be an unbiased "gatekeeper" for the use of PCI or whether other physicians should also be involved with the patient in decision-making. Finally, we offer suggestions that can redefine the gatekeeper role to facilitate an evidence-based approach that embraces shared decision-making. Copyright © 2017 Elsevier Inc. All rights reserved.

Insight in stable schizophrenia: relations with psychopathology and cognition.

PubMed

Mingrone, Cinzia; Rocca, Paola; Castagna, Filomena; Montemagni, Cristiana; Sigaudo, Monica; Scalese, Mara; Rocca, Giuseppe; Bogetto, Filippo

2013-07-01

This study evaluated the relationship among insight, sociodemographic and clinical variables, symptoms and cognitive functions in a population of outpatients with stable schizophrenia, in order to identify possible contributing factors to awareness. Two-hundred and seventy-six consecutive outpatients with stable schizophrenia were enrolled in a cross-sectional study. All subjects were assessed by psychiatric scales and interview, and a wide neuropsychological battery. A factor analysis was performed to identify cognitive factors and multiple regression analyses were executed to test the contribution of variables considered to insight. Our results showed that positive and negative symptoms, executive functions, verbal memory-learning were contributors of awareness of mental illness; positive and negative symptoms explained variability in awareness of the need for treatment; positive symptoms and executive functions contributed to awareness of the social consequences of disorder. These results suggested that insight was partially influenced by positive and negative symptoms and by cognitive functions. A complex system of overlapping variables may underlie impaired insight, contributing to a different extent to specific dimensions of poor insight in patients with stable schizophrenia. Copyright © 2013 Elsevier Inc. All rights reserved.

Management of a rare case of idiopathic multiple unerupted impacted permanent teeth in an adult female patient

PubMed Central

Shetty, Karunakar; Kumar, Mahesh; Amanna, Susan; Sridharan, Srirangarajan; Reddy, Satyanarayan

2016-01-01

This clinical case report describes the multi-disciplinary approach in the management of an unusual presentation of idiopathic multiple unerupted impacted permanent teeth in a 20-year-old female patient. The case was unique in that, not only were there multiple missing permanent teeth, but also over retained deciduous teeth and attrited existing permanent teeth with loss of vertical dimension of occlusion. Since the patient was young, it was decided to retain all the erupted permanent teeth and extract the infected deciduous teeth with the objective of fabricating overlay complete dentures. This is a simple, reversible and an economical treatment modality, which satisfies both the esthetic and functional demands where the extraction of teeth is not generally indicated and, in addition, provides a stable occlusion. PMID:27621553

3T deep gray matter T2 hypointensity correlates with disability over time in stable relapsing-remitting multiple sclerosis: a 3-year pilot study.

PubMed

Zhang, Y; Metz, L M; Yong, V W; Mitchell, J R

2010-10-15

Abnormally decreased deep gray matter (GM) signal intensity on T2-weighted MRI (T2 hypointensity) is associated with brain atrophy and disability progression in patients with multiple sclerosis (MS) and is believed to represent excessive iron deposition. We investigated the time course of deep GM T2 hypointensity and its relationship with disability at 3T in 8 stable relapsing-remitting (RR) MS patients treated with minocycline over 3years. MRI and disability measurements were compared at baseline, 6, 12, 24, and 36months. Grand mean deep GM T2 hypointensity was negatively correlated with EDSS over time (r=-0.94, P=0.02). This correlation was strongest in the head of caudate (r=-0.95, P=0.01) and putamen (r=-0.89, P=0.04). Additionally, baseline grand mean deep GM T2 hypointensity appears to predict third year EDSS (r=-0.72, P=0.04). These results suggest that iron associated deep GM injury correlates with patient disability in stable RRMS. Measurements of deep GM T2 hypointensity at high field MRI may prove to be useful in monitoring individuals with MS. Further studies are required to confirm these results in a large sample and to determine if T2 hypointensity changes in clinically active MS patients. Copyright 2010 Elsevier B.V. All rights reserved.

Monoclonal protein reference change value as determined by gel-based serum protein electrophoresis.

PubMed

Salamatmanesh, Mina; McCudden, Christopher R; McCurdy, Arleigh; Booth, Ronald A

2018-01-01

The International Myeloma Working Group recommendations for monitoring disease progression or response include quantitation of the involved monoclonal immunoglobulin. They have defined the minimum change criteria of ≧25% with an absolute change of no <5g/L for either minimal response or progression. Limited evidence is available to accurately determine the magnitude of change in a monoclonal protein to reflect a true change in clinical status. Here we determined the analytical and biological variability of monoclonal proteins in stable monoclonal gammopathy of undetermined significance (MGUS) patients. Analytical variability (CVa) of normal protein fractions and monoclonal proteins were assessed agarose gel-based serum protein electrophoresis. Sixteen clinically stable MGUS patients were identified from our clinical hematology database. Individual biological variability (CVi) was determined and used to calculate a monoclonal protein reference change value (RCV). Analytical variability of the normal protein fractions (albumin, alpha-1, alpha-2, beta, total gamma) ranged from 1.3% for albumin to 5.8% for the alpha-1 globulins. CVa of low (5.6g/L) and high (32.2g/L) concentration monoclonal proteins were 3.1% and 22.2%, respectively. Individual CVi of stable patients ranged from 3.5% to 24.5% with a CVi of 12.9%. The reference change value (RCV) at a 95% probability was determined to be 36.7% (low) 39.6% (high) using our CVa and CVi. Serial monitoring of monoclonal protein concentration is important for MGUS and multiple myeloma patients. Accurate criteria for interpreting a change in monoclonal protein concentration are required for appropriate decision making. We used QC results and real-world conditions to assess imprecision of serum protein fractions including low and high monoclonal protein fractions and clinically stable MGUS patients to determine CVi and RCV. The calculated RCVs of 36.7% (low) and 39.6% (high) in this study were greater that reported previously and greater than the established criteria for relapse. Response criteria may be reassessed to increase sensitivity and specificity for detection of response. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Change in "resolved plans" and "suicidal ideation" factors of suicidality after participation in an intensive outpatient treatment program.

PubMed

Minnix, Jennifer A; Romero, Catherine; Joiner, Thomas E; Weinberg, Elizabeth F

2007-11-01

This study aims to investigate factors related to suicide in a unique clinical population with more chronic psychopathology than many outpatient samples. One hundred and five adult outpatients were included in the current study. We predicted that higher scores on the resolved plans and preparation (RPP) factor of the Beck Suicide Scale [Beck, A.T., Kovacs, M., Weissman, M., (1979). Assessment of suicidal intention: The scale for suicidal ideation. Journal of Consulting and Clinical Psychology 47, 343-352] would predict multiple attempter status even after accounting for co-morbid diagnoses and suicidal ideation (SI) factor scores. Additionally, we predicted that the scores on the RPP factor would decrease less over time than scores on the SI factor. Results were consistent with both hypotheses, suggesting that RPP factor scores were uniquely predictive of status as a multiple attempter and were more stable over time. Mental health diagnoses were rendered without the use of a structured interview and therefore no reliability data were collected.

Sleep habits in middle-aged, non-hospitalized men and women with schizophrenia: a comparison with healthy controls.

PubMed

Poulin, Julie; Chouinard, Sylvie; Pampoulova, Tania; Lecomte, Yves; Stip, Emmanuel; Godbout, Roger

2010-10-30

Patients with schizophrenia may have sleep disorders even when clinically stable under antipsychotic treatments. To better understand this issue, we measured sleep characteristics between 1999 and 2003 in 150 outpatients diagnosed with Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) schizophrenia or schizoaffective disorder and 80 healthy controls using a sleep habits questionnaire. Comparisons between both groups were performed and multiple comparisons were Bonferroni corrected. Compared to healthy controls, patients with schizophrenia reported significantly increased sleep latency, time in bed, total sleep time and frequency of naps during weekdays and weekends along with normal sleep efficiency, sleep satisfaction, and feeling of restfulness in the morning. In conclusion, sleep-onset insomnia is a major, enduring disorder in middle-aged, non-hospitalized patients with schizophrenia that are otherwise clinically stable under antipsychotic and adjuvant medications. Noteworthy, these patients do not complain of sleep-maintenance insomnia but report increased sleep propensity and normal sleep satisfaction. These results may reflect circadian disturbances in schizophrenia, but objective laboratory investigations are needed to confirm subjective sleep reports. Copyright © 2009 Elsevier Ltd. All rights reserved.

Using multi-ring structure for suppression of mode competition in stable single-longitudinal-mode erbium fiber laser

NASA Astrophysics Data System (ADS)

Yeh, Chien-Hung; Huang, Tzu-Jung; Yang, Zi-Qing; Chow, Chi-Wai

2017-12-01

In this demonstration, a stable and tunable single-longitudinal-mode (SLM) erbium-doped fiber (EDF) laser with multiple-ring configuration is proposed and investigated. The proposed compound-ring structure can create different free spectrum ranges (FSRs) to result in the mode-filter effect based on the Vernier effect for suppressing the other modes. Additionally, the output stabilization of power and wavelength in the proposed EDF multiple-ring laser are also discussed.

Development of a pharmacogenetic-guided warfarin dosing algorithm for Puerto Rican patients.

PubMed

Ramos, Alga S; Seip, Richard L; Rivera-Miranda, Giselle; Felici-Giovanini, Marcos E; Garcia-Berdecia, Rafael; Alejandro-Cowan, Yirelia; Kocherla, Mohan; Cruz, Iadelisse; Feliu, Juan F; Cadilla, Carmen L; Renta, Jessica Y; Gorowski, Krystyna; Vergara, Cunegundo; Ruaño, Gualberto; Duconge, Jorge

2012-12-01

This study was aimed at developing a pharmacogenetic-driven warfarin-dosing algorithm in 163 admixed Puerto Rican patients on stable warfarin therapy. A multiple linear-regression analysis was performed using log-transformed effective warfarin dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other relevant nongenetic clinical and demographic factors as independent predictors. The model explained more than two-thirds of the observed variance in the warfarin dose among Puerto Ricans, and also produced significantly better 'ideal dose' estimates than two pharmacogenetic models and clinical algorithms published previously, with the greatest benefit seen in patients ultimately requiring <7 mg/day. We also assessed the clinical validity of the model using an independent validation cohort of 55 Puerto Rican patients from Hartford, CT, USA (R(2) = 51%). Our findings provide the basis for planning prospective pharmacogenetic studies to demonstrate the clinical utility of genotyping warfarin-treated Puerto Rican patients.

Gene Therapy with the Sleeping Beauty Transposon System.

PubMed

Kebriaei, Partow; Izsvák, Zsuzsanna; Narayanavari, Suneel A; Singh, Harjeet; Ivics, Zoltán

2017-11-01

The widespread clinical implementation of gene therapy requires the ability to stably integrate genetic information through gene transfer vectors in a safe, effective, and economical manner. The latest generation of Sleeping Beauty (SB) transposon vectors fulfills these requirements, and may overcome limitations associated with viral gene transfer vectors and transient nonviral gene delivery approaches that are prevalent in ongoing clinical trials. The SB system enables high-level stable gene transfer and sustained transgene expression in multiple primary human somatic cell types, thereby representing a highly attractive gene transfer strategy for clinical use. Here, we review the most important aspects of using SB for gene therapy, including vectorization as well as genomic integration features. We also illustrate the path to successful clinical implementation by highlighting the application of chimeric antigen receptor (CAR)-modified T cells in cancer immunotherapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Large pneumothorax in blunt chest trauma: Is a chest drain always necessary in stable patients? A case report.

PubMed

Idris, Baig M; Hefny, Ashraf F

2016-01-01

Pneumothorax is the most common potentially life-threatening blunt chest injury. The management of pneumothorax depends upon the etiology, its size and hemodynamic stability of the patient. Most clinicians agree that chest drainage is essential for the management of traumatic large pneumothorax. Herein, we present a case of large pneumothorax in blunt chest trauma patient that resolved spontaneously without a chest drain. A 63- year- old man presented to the Emergency Department complaining of left lateral chest pain due to a fall on his chest at home. On examination, he was hemodynamically stable. An urgent chest X-ray showed evidence of left sided pneumothorax. CT scan of the chest showed pneumothorax of more than 30% of the left hemithorax (around 600ml of air) with multiple left ribs fracture. Patient refused tube thoracostomy and was admitted to surgical department for close observation. The patient was managed conservatively without chest tube insertion. A repeat CT scan of the chest has shown complete resolution of the pneumothorax. The clinical spectrum of pneumothorax varies from asymptomatic to life threatening tension pneumothorax. In stable patients, conservative management can be safe and effective for small pneumothorax. To the best of our knowledge, this is the second reported case in the English literature with large pneumothorax which resolved spontaneously without chest drain. Blunt traumatic large pneumothorax in a clinically stable patient can be managed conservatively. Current recommendations for tube placement may need to be reevaluated. This may reduce morbidity associated with chest tube thoracostomy. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Family Instability and Child Well-Being

ERIC Educational Resources Information Center

Fomby, Paula; Cherlin, Andrew J.

2007-01-01

Children who experience multiple transitions in family structure may face worse developmental outcomes than children raised in stable, two-parent families, and perhaps even worse than children raised in stable, single-parent families--a point denoted in much prior research. Multiple transitions and negative child outcomes, however, may be…

Breaking Away: The Role of Homeostatic Drive in Perpetuating Depression.

PubMed

Tory Toole, J; Rice, Mark A; Craddock, Travis J A; Nierenberg, Barry; Klimas, Nancy G; Fletcher, Mary Ann; Zysman, Joel; Morris, Mariana; Broderick, Gordon

2018-01-01

We propose that the complexity of regulatory interactions modulating brain neurochemistry and behavior is such that multiple stable responses may be supported, and that some of these alternate regulatory programs may play a role in perpetuating persistent psychological dysfunction. To explore this, we constructed a model network representing major neurotransmission and behavioral mechanisms reported in literature as discrete logic circuits. Connectivity and information flow through this biobehavioral circuitry supported two distinct and stable regulatory programs. One such program perpetuated a depressive state with a characteristic neurochemical signature including low serotonin. Further analysis suggested that small irregularities in glutamate levels may render this pathology more directly accessible. Computer simulations mimicking selective serotonin reuptake inhibitor (SSRI) therapy in the presence of everyday stressors predicted recidivism rates similar to those reported clinically and highlighted the potentially significant benefit of concurrent behavioral stress management therapy.

Armored DNA in recombinant Baculoviruses as controls in molecular genetic assays.

PubMed

Freystetter, Andrea; Paar, Christian; Stekel, Herbert; Berg, Jörg

2017-10-01

The widespread use of molecular PCR-based assays in analytical and clinical laboratories brings about the need for test-specific, stable, and reliable external controls (EC) as well as standards and internal amplification controls (IC), in order to arrive at consistent test results. In addition, there is also a growing need to produce and provide stable, well-characterized molecular controls for quality assurance programs. In this study, we describe a novel approach to generate armored double-stranded DNA controls, which are encapsulated in baculovirus (BV) particles of the species Autographa californica multiple nucleopolyhedrovirus. We used the well-known BacPAK™ Baculovirus Expression System (Takara-Clontech), removed the polyhedrin promoter used for protein expression, and generated recombinant BV-armored DNAs. The obtained BV-armored DNAs were readily extracted by standard clinical DNA extraction methods, showed favorable linearity and performance in our clinical PCR assays, were resistant to DNase I digestion, and exhibited marked stability in human plasma and serum. BV-armored DNA ought to be used as ECs, quantification standards, and ICs in molecular assays, with the latter application allowing for the entire monitoring of clinical molecular assays for sample adequacy. BV-armored DNA may also be used to produce double-stranded DNA reference materials for, e.g., quality assurance programs. The ease to produce BV-armored DNA should make this approach feasible for a broad spectrum of molecular applications. Finally, as BV-armored DNAs are non-infectious to mammals, they may be even more conveniently shipped than clinical specimen.

Long-term treatment with low dose naltrexone maintains stable health in patients with multiple sclerosis.

PubMed

Ludwig, Michael D; Turel, Anthony P; Zagon, Ian S; McLaughlin, Patricia J

2016-01-01

A retrospective study was conducted on patients at Penn State Hershey Medical Center diagnosed with relapsing-remitting multiple sclerosis between 2006 and 2015. Laboratory and clinical data collected over this 10-year period were reviewed. Two cohorts of patients were established based on their relapsing-remitting multiple sclerosis therapy at the time of their first visit to Penn State. One group of patients ( n  = 23) was initially prescribed low dose naltrexone at the time first seen at Hershey. This group was offered low dose naltrexone because of symptoms of fatigue or refusal to take an available disease-modifying therapy. The second group of patients ( n  = 31) was treated with the glatiramer acetate (Copaxone) and offered low dose naltrexone as an adjunct therapy to their disease-modifying therapy. Patient data from visits after 1-50 months post-diagnosis were evaluated in a retrospective manner. Data obtained from patient charts included clinical laboratory values from standard blood tests, timed 25-foot walking trials, and changes in magnetic resonance imaging reports. Statistical analyses between the groups and for each patient over time indicated no significant differences in clinical laboratory values, timed walking, or changes in magnetic resonance imaging. These data suggest that the apparently non-toxic, inexpensive, biotherapeutic is safe and if taken alone did not result in an exacerbation of disease symptoms.

Transient impairment of olfactory threshold in acute multiple sclerosis relapse.

PubMed

Bsteh, Gabriel; Hegen, Harald; Ladstätter, Felix; Berek, Klaus; Amprosi, Matthias; Wurth, Sebastian; Auer, Michael; Di Pauli, Franziska; Deisenhammer, Florian; Lutterotti, Andreas; Berger, Thomas

2018-05-18

Impairment of olfactory threshold is a feature of early and active relapsing remitting multiple sclerosis (RRMS). It predicts inflammatory disease activity and was reported to be transient. However, the timing of onset and resolve of olfactory threshold impairment remains unclear. To prospectively assess the development of olfactory threshold in acute MS relapse over time in comparison to stable MS patients. In a prospective observational design, we measured olfactory threshold by performing the Sniffin' Sticks test (minimum score 0, maximum score 16 reflecting optimal olfactory function) at baseline and after 4, 12 and 24 weeks. We included 30 RRMS patients with acute MS relapse and 30 clinically stable RRMS patients (defined as no relapse within the last 12 months) as a control group. Olfactory threshold was impaired in patients with acute MS relapse at baseline (median difference = -3.5; inter-quartile range [IQR] -4.5- - 2.5; p < 0.001), week 4 (-2.5; IQR -3.0 - -2.0; p < 0.001), week 12 (-1.5; IQR -2.0 - -0.5; p = 0.002) and week 24 (-0.5; IQR -1.0 - 0.0; p = 0.159) compared to stable MS patients. Of note, in relapsing patients in whom disease-modifying treatment was initiated or escalated after relapse, threshold did not differ anymore from stable patients at week 12 (-0.5; IQR -1.0 - 0.5; p = 0.247) and week 24 (0.0; IQR -1.0 - 1.0; p = 0.753). Olfactory threshold impairment seems to be a transient bystander feature of MS relapse. It may be correlated to the level of inflammation within the CNS and might be a useful biomarker in this regard. Copyright © 2018 Elsevier B.V. All rights reserved.

Urinary incontinence in multiple sclerosis: prevalence, severity and impact on patients' quality of life.

PubMed

Zecca, C; Riccitelli, G C; Disanto, G; Singh, A; Digesu, G A; Panicari, L; Puccini, F; Mattioli, M; Tubaro, A; Gobbi, C

2016-07-01

Lower urinary tract symptoms (LUTS) including frequent urination, nocturia and urge urinary incontinence negatively impact quality of life. This project aimed at characterizing the prevalence and severity of urinary incontinence in multiple sclerosis (MS) patients and its association with demographic and clinical features. In all, 403 consecutive clinically stable MS patients answered the International Consultation on Incontinence Questionnaire (ICIQ) and the Patient Perception of Bladder Condition (PPBC) questionnaire. Demographic and clinical parameters including the Expanded Disability Status Scale (EDSS) were collected. Statistical analyses were performed using univariate and multivariate linear regression models. Females represented 72%, relapsing-remitting patients 82%. The mean (SD) disease duration and EDSS were 11.8 (8.6) years and 3.1 (1.9) respectively. Approximately 35% of patients reported urine incontinence. ICIQ scores were positively associated with EDSS, female gender, presence of LUTS therapies and absence of disease modifying treatments (P < 0.001). PPBC scores were positively associated with EDSS and the presence of LUTS therapies (P < 0.001). Urinary incontinence is frequent in MS, prevailing in more disabled and female patients. Currently available LUTS therapies appear insufficient in the treatment of this symptom. The negative impact of urinary incontinence on quality of life is high and requires more attention in clinical management and research. © 2016 EAN.

A psychosocial profile of adolescent pregnancy termination patients.

PubMed

Ely, Gretchen E; Dulmus, Catherine N

2008-01-01

This study examined the psychosocial problems of a sample of adolescent women who presented for a pregnancy termination appointment at a family planning clinic located in the southeastern region of the United States. The sample consisted of 120 adolescent women, age 14-21 who were administered the Multidimensional Adolescent Assessment Scale (MAAS) while waiting for their pregnancy termination procedure. The MAAS is a self-administered instrument with multiple subscales that measure a variety of psychosocial problems. Results indicated that most subjects did not score in the clinical range on the various subscales, thus indicating respondents as overall being stable and healthy. This paper reviews the specific findings from the study and discusses implications for practice and future research directions on this understudied population.

Clinical and Radiologic Predictive Factors of Rib Fractures in Outpatients With Chest Pain.

PubMed

Zhang, Liang; McMahon, Colm J; Shah, Samir; Wu, Jim S; Eisenberg, Ronald L; Kung, Justin W

To identify the clinical and radiologic predictive factors of rib fractures in stable adult outpatients presenting with chest pain and to determine the utility of dedicated rib radiographs in this population of patients. Following Institutional Review Board approval, we performed a retrospective review of 339 consecutive cases in which a frontal chest radiograph and dedicated rib series had been obtained for chest pain in the outpatient setting. The frontal chest radiograph and dedicated rib series were sequentially reviewed in consensus by two fellowship-trained musculoskeletal radiologists blinded to the initial report. The consensus interpretation of the dedicated rib series was used as the gold standard. Multiple variable logistic regression analysis assessed clinical and radiological factors associated with rib fractures. Fisher exact test was used to assess differences in medical treatment between the 2 groups. Of the 339 patients, 53 (15.6%) had at least 1 rib fracture. Only 20 of the 53 (37.7%) patients' fractures could be identified on the frontal chest radiograph. The frontal chest radiograph had a sensitivity of 38% and specificity of 100% when using the rib series as the reference standard. No pneumothorax, new mediastinal widening or pulmonary contusion was identified. Multiple variable logistic regression analysis of clinical factors associated with the presence of rib fractures revealed a significant association of trauma history (odds ratio 5.7 [p < 0.05]) and age ≥40 (odds radio 3.1 [p < 0.05]). Multiple variable logistic regression analysis of radiographic factors associated with rib fractures in this population demonstrated a significant association of pleural effusion with rib fractures (odds ratio 18.9 [p < 0.05]). Patients with rib fractures received narcotic analgesia in 47.2% of the cases, significantly more than those without rib fractures (21.3%, p < 0.05). None of the patients required hospitalization. In the stable outpatient setting, rib fractures have a higher association with a history of minor trauma and age ≥40 in the adult population. Radiographic findings associated with rib fractures include pleural effusion. The frontal chest radiograph alone has low sensitivity in detecting rib fractures. The dedicated rib series detected a greater number of rib fractures. Although no patients required hospitalization, those with rib fractures were more likely to receive narcotic analgesia. Copyright © 2018 Elsevier Inc. All rights reserved.

Chronic periodontitis with multiple risk factor syndrome: a case report.

PubMed

Shimoe, Masayuki; Yamamoto, Tadashi; Iwamoto, Yoshihiro; Shiomi, Nobuyuki; Maeda, Hiroshi; Nishimura, Fusanori; Takashiba, Shogo

2011-07-01

Multiple risk factor syndrome is a clustering of cardiovascular risk factors, such as diabetes, dyslipidemia, hypertension, and obesity associated epidemiologically with insulin resistance. This report describes the clinical course of a patient suffering from severe periodontitis with multiple risk factor syndrome, and discusses the association between periodontal infection and systemic health. The patient had a history of type 2 diabetes, dyslipidemia, and hypertension for over 10 years. At baseline, her hemoglobin A1 c was 8.1%. However, she had no diabetic complications except periodontitis. The IgG antibody titers against Porphyromonas gingivalis FDC 381 and SU63 were elevated above the mean of healthy subjects +2 standard deviations. Intensive periodontal treatment, including periodontal surgery, was performed to reduce periodontal infection and bacteremia. Her systemic and periodontal conditions were evaluated longitudinally for 10 years. Following periodontal treatment, antibody titers against Porphyromonas gingivalis and hemoglobin A1c values were significantly improved. The other clinical data and medication for her systemic condition also remained stable during supportive periodontal therapy. However, she developed myocardial infarction, and showed continuous deterioration of hemoglobin A1 c level and periodontitis. The long-term clustering of risk factors, such as diabetes, dyslipidemia, hypertension, and periodontitis, are associated with the development of myocardial infarction. Treatment of systemic conditions in combination with comprehensive periodontal treatment is important in management of patients with multiple risk factor syndrome.

Idiopathic hypersomnia: a study of 77 cases.

PubMed

Anderson, Kirstie N; Pilsworth, Samantha; Sharples, Linda D; Smith, Ian E; Shneerson, John M

2007-10-01

To review the clinical and polysomnographic characteristics of idiopathic hypersomnia as well as the long-term response to treatment. The Respiratory Support and Sleep Centre at Papworth Hospital, Cambridge, UK. A large database of more than 6000 patients with sleep disorders was reviewed. A retrospective study of the clinical and polysomnographic characteristics of 77 patients with idiopathic hypersomnia was performed. Comparison with a similar group of patients with narcolepsy was performed. The response to drug treatment was assessed in 61 patients over a mean follow-up of 3.8 years. Idiopathic hypersomnia was 60% as prevalent as narcolepsy. Comparison with a similar group of patients with narcolepsy showed that those with idiopathic hypersomnia were more likely to have prolonged unrefreshing daytime naps, a positive family history, increased slow-wave sleep, and a longer sleep latency on the Multiple Sleep Latency Test. The results of the Multiple Sleep Latency Test were not helpful in predicting disease severity or treatment response. The clinical features were heterogeneous and of variable severity. The majority of patients with idiopathic hypersomnia had symptoms that remained stable over many years, but 11% had spontaneous remission, which was never seen in narcolepsy. Two thirds of patients with idiopathic hypersomnolence had a sustained improvement in daytime somnolence with medication, although a third needed high doses or combinations of drugs. Idiopathic hypersomnolence has characteristic clinical and polysomnographic features but the prolonged latency on the Multiple Sleep Latency Test raises doubt about the validity of this test within the current diagnostic criteria. The disease often responds well to treatment and a substantial minority of patients appear to spontaneously improve.

Synchronization within, and interactions between, the default mode and dorsal attention networks in relapsing-remitting multiple sclerosis.

PubMed

Huang, Muhua; Zhou, Fuqing; Wu, Lin; Wang, Bo; Wan, Hui; Li, Fangjun; Zeng, Xianjun; Gong, Honghan

2018-01-01

The effects of the interactions between the default mode network (DMN) and the dorsal attention network (DAN), which present anticorrelated behaviors, in relapsing-remitting multiple sclerosis (RRMS) are poorly understood. This study used resting-state functional connectivity (FC) and the Granger causality test (GCT) to examine changes in the undirected and effective functional network connectivity (FNC) between the two networks during the remitting phase in RRMS patients. Thirty-three patients experiencing a clinically diagnosed remitting phase of RRMS and 33 well-matched healthy control subjects participated in this study. First, an independent component (IC) analysis was performed to preprocess the functional magnetic resonance imaging data and select resting-state networks. Then, an FNC analysis and the GCT were combined to examine the temporal correlations between the ICs of the DMN and DAN and to identify correlations with clinical markers. Compared with the healthy subjects, the RRMS patients in the remitting phase showed the following: 1) significantly decreased FC within the DAN in the postcentral gyrus and decreased FC within the DMN in several regions except the parahippocampal gyrus, where increased FC was observed; 2) a relatively stable interaction between the two anticorrelated networks as well as a driving connectivity from the DAN to DMN (IC15); and 3) significantly positive correlations between the connectivity coefficient of the right superior temporal gyrus and the Modified Fatigue Impact Scale score ( ρ = 0.379, p = 0.036). Adaptive mechanisms that maintain stable interactions might occur between the DMN and DAN during the remitting phase in RRMS patients.

An In Situ One-Pot Synthetic Approach towards Multivariate Zirconium MOFs.

PubMed

Sun, Yujia; Sun, Lixian; Feng, Dawei; Zhou, Hong-Cai

2016-05-23

Chemically highly stable MOFs incorporating multiple functionalities are of great interest for applications under harsh environments. Herein, we presented a facile one-pot synthetic strategy to incorporate multiple functionalities into stable Zr-MOFs from mixed ligands of different geometry and connectivity. Via our strategy, tetratopic tetrakis(4-carboxyphenyl)porphyrin (TCPP) ligands were successfully integrated into UiO-66 while maintaining the crystal structure, morphology, and ultrahigh chemical stability of UiO-66. The amount of incorporated TCPP is controllable. Through various combinations of BDC derivatives and TCPP, 49 MOFs with multiple functionalities were obtained. Among them, MOFs modified with FeTCPPCl were demonstrated to be catalytically active for the oxidation of ABTS. We anticipate our strategy to provide a facile route to introduce multiple functionalities into stable Zr-MOFs for a wide variety of potential applications. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Central Field Index Versus Visual Field Index for Central Visual Function in Stable Glaucoma.

PubMed

Rao, Aparna; Padhy, Debananda; Mudunuri, Harika; Roy, Avik K; Sarangi, Sarada P; Das, Gopinath

2017-01-01

To compare the variability of central field index (CFI) versus visual field index (VFI) in stable glaucoma with central fixation involvement. For this retrospective study, we identified multiple visual fields (VFs) of patients with repeatable central fixation involvement on Humphrey VFs (24-2 and 10-2 program) which were stable (clinically and on VFs) over a very short period of 2 to 3 months. The VFI and CFI were calculated as described in earlier reports. We graded the fields as early [mean deviation (MD)>-6 dB], moderate (-6.1 to -12 dB), and severe glaucoma (<-12 dB) based on MD on 24-2 program. The variability of CFI and VFI between visits and across different severity of glaucoma was compared. Relation of the divergence to field indices and clinical parameters were assessed. The intervisit difference for VFI was greater than CFI ranging from -4% to 9% versus -1% to 8% in early (P=0.9), -13% to 18% versus -6% to 17% (P=0.056) in moderate, and -21% to 19% versus -9% to 9% (P<0.001) in severe glaucoma. The CFI within each group had narrower range than VFI with maximum range in severe glaucoma (33% to 95%). The divergence of CFI from VFI started at MD 24-2 beyond (worse) -10 dB. This difference between CFI and VFI was associated significantly with number of points with P<1% on 24-2 (R=80.3%). CFI is less variable than VFI in stable eyes with fixation involvement especially in severe glaucoma indicating need for incorporating CFI calculation for monitoring advanced disease in eyes with central defects.

Stability of Chimerism in Non-Obese Diabetic Mice Achieved By Rapid T Cell Depletion Is Associated With High Levels of Donor Cells Very Early After Transplant.

PubMed

Lin, Jiaxin; Chan, William F N; Boon, Louis; Anderson, Colin C

2018-01-01

Stable mixed hematopoietic chimerism is a robust method for inducing donor-specific tolerance with the potential to prevent rejection of donor islets in recipients with autoimmune type-1 diabetes. However, with reduced intensity conditioning, fully allogeneic chimerism in a tolerance resistant autoimmune-prone non-obese diabetic (NOD) recipient has rarely been successful. In this setting, successful multilineage chimerism has required either partial major histocompatability complex matching, mega doses of bone marrow, or conditioning approaches that are not currently clinically feasible. Irradiation free protocols with moderate bone marrow doses have not generated full tolerance; donor skin grafts were rejected. We tested whether more efficient recipient T cell depletion would generate a more robust tolerance. We show that a combination of donor-specific transfusion-cyclophosphamide and multiple T cell depleting antibodies could induce stable high levels of fully allogeneic chimerism in NOD recipients. Less effective T cell depletion was associated with instability of chimerism. Stable chimeras appeared fully donor-specific tolerant, with clonal deletion of allospecific T cells and acceptance of donor skin grafts, while recovering substantial immunocompetence. The loss of chimerism months after transplant was significantly associated with a lower level of chimerism and donor T cells within the first 2 weeks after transplant. Thus, rapid and robust recipient T cell depletion allows for stable high levels of fully allogeneic chimerism and robust donor-specific tolerance in the stringent NOD model while using a clinically feasible protocol. In addition, these findings open the possibility of identifying recipients whose chimerism will later fail, stratifying patients for early intervention.

Can interleukin-2 and interleukin-1β be specific biomarkers of negative symptoms in schizophrenia?

PubMed

González-Blanco, Leticia; García-Portilla, María P; García-Álvarez, Leticia; de la Fuente-Tomás, Lorena; Iglesias García, Celso; Sáiz, Pilar A; Rodríguez-González, Susana; Coto-Montes, Ana; Bobes, Julio

2018-04-30

Evidence suggests the existence of cytokine disturbances in patients with schizophrenia but their association with psychopathology is still unclear. The aim of the current study was to determine if pro-inflammatory cytokine levels (tumor necrosis factor-α, interleukin (IL)-6, IL-2, IL-1β, IL-1RA) are increased in stable outpatients compared with healthy subjects, and to analyze if they could be specific biomarkers of clinical dimensions in schizophrenia. We studied 73 stable outpatients with schizophrenia in their first 10 years of illness and 73 age- and sex-matched healthy controls. An accurate assessment of clinical dimensions (positive, negative, depressive, cognitive) was performed in patients. Only IL-6 levels were significantly increased in patients after controlling for body mass index, waist circumference, smoking, and psychopharmacological treatment, compared with healthy subjects. After adjusting for several confounders, multiple linear regression models identified that Positive and Negative Syndrome Scale negative symptoms, general psychopathology, and global severity are predicted by IL-1β concentrations, while motivation and pleasure domain of Clinical Assessment Interview for Negative Symptoms and Personal and Social Performance global functioning scores are predicted by IL-2 levels. Cognitive performance, positive, and depressive symptom severity did not correlate with any cytokine. Our findings suggested that IL-6 concentrations are elevated in stable patients with schizophrenia. Whereas IL-2 specifically marks severity of the motivation and pleasure domain of negative symptoms, IL-1β is not specific to this dimension as it also predicts severity of general and global symptomatology. Copyright © 2018 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.

The effect of time-of-day and chest physiotherapy on multiple breath washout measures in children with clinically stable cystic fibrosis.

PubMed

Voldby, Christian; Green, Kent; Rosthøj, Susanne; Kongstad, Thomas; Philipsen, Lue; Buchvald, Frederik; Skov, Marianne; Pressler, Tania; Gustafsson, Per; Nielsen, Kim G

2018-01-01

In this pilot study we investigated daytime variation of multiple breath nitrogen washout (N2MBW) measures in children with clinically stable cystic fibrosis. To our knowledge the effect of time-of-day on multiple breath washout measures in patients with cystic fibrosis has not previously been reported. Furthermore, we assessed the influence of chest physiotherapy on N2MBW measures. Ten school children with cystic fibrosis performed N2MBW followed by spirometry and plethysmography in the morning and afternoon at three visits that were one month apart. Chest physiotherapy was performed immediately before the afternoon measurements at visit 2 and immediately before morning and afternoon measurements at visit 3. The influence of time-of-day and chest physiotherapy on the measures was evaluated using linear mixed models. There were adequate quality data from 8 children with median age (range) 9.6 (6.0; 15.1) years. Baseline lung clearance index (LCI) (range) was 9.0 (7.1; 13.0) and baseline FEV1% predicted was 97.5 (78.5; 117.9). No N2MBW measures were significantly influenced by time-of-day or chest physiotherapy. LCI (95% confidence interval) decreased non-significantly 0.05 (-0.32; 0.22) during the day and increased non-significantly 0.08 (-0.26; 0.42) after chest physiotherapy. All spirometric measures were unaffected by time-of-day and chest physiotherapy. For plethysmographic measures FRCpleth decreased significantly (p<0.01) 110 mL during the day, whereas a borderline significant (p = 0.046) decrease in ΔFRCpleth-MBW during the day and a borderline significant (p = 0.03) increase in TLC after CPT were observed. This study demonstrated that the time-of-day as well as chest physiotherapy performed immediately prior to N2MBW had no consistent or significant influence on N2MBW measures. However, we emphasize that further studies of the effect of both daytime variation and the effect of chest physiotherapy on multiple breath washout measures are warranted.

Evaluation of helper-dependent canine adenovirus vectors in a 3D human CNS model

PubMed Central

Simão, Daniel; Pinto, Catarina; Fernandes, Paulo; Peddie, Christopher J.; Piersanti, Stefania; Collinson, Lucy M.; Salinas, Sara; Saggio, Isabella; Schiavo, Giampietro; Kremer, Eric J.; Brito, Catarina; Alves, Paula M.

2017-01-01

Gene therapy is a promising approach with enormous potential for treatment of neurodegenerative disorders. Viral vectors derived from canine adenovirus type 2 (CAV-2) present attractive features for gene delivery strategies in the human brain, by preferentially transducing neurons, are capable of efficient axonal transport to afferent brain structures, have a 30-kb cloning capacity and have low innate and induced immunogenicity in pre-clinical tests. For clinical translation, in-depth pre-clinical evaluation of efficacy and safety in a human setting is primordial. Stem cell-derived human neural cells have a great potential as complementary tools by bridging the gap between animal models, which often diverge considerably from human phenotype, and clinical trials. Herein, we explore helper-dependent CAV-2 (hd-CAV-2) efficacy and safety for gene delivery in a human stem cell-derived 3D neural in vitro model. Assessment of hd-CAV-2 vector efficacy was performed at different multiplicities of infection, by evaluating transgene expression and impact on cell viability, ultrastructural cellular organization and neuronal gene expression. Under optimized conditions, hd-CAV-2 transduction led to stable long-term transgene expression with minimal toxicity. hd-CAV-2 preferentially transduced neurons, while human adenovirus type 5 (HAdV5) showed increased tropism towards glial cells. This work demonstrates, in a physiologically relevant 3D model, that hd-CAV-2 vectors are efficient tools for gene delivery to human neurons, with stable long-term transgene expression and minimal cytotoxicity. PMID:26181626

Posttraumatic stress symptom trajectories among children exposed to violence.

PubMed

Miller-Graff, Laura E; Howell, Kathryn H

2015-02-01

Little research has examined the developmental course of posttraumatic stress symptoms (PTSS) in children. The current study aimed to identify developmental trajectories of PTSS in childhood and to examine predictors of symptom presentation in 1,178 children from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN) studies, a consortium of studies focusing on the causes and effects of child maltreatment. Most children had a history of documented reports with Child Protective Services (CPS) and all were identified as living in high-risk environments. Using group-based trajectory modeling, 3 unique developmental trajectories were identified: Resilient, Clinical-Improving (PTSS in the clinical range at baseline then declining over time), and Borderline-Stable (chronically subclinical PTSS). Children in the Clinical-Improving group were more likely than children in the Resilient group to have reports of physical abuse (RRR = 1.76), emotional abuse (RRR = 2.55), neglect (RRR = 1.57), and exposure to violence at home and in the community (RRR = 1.04). Children in the Borderline-Stable group were more likely than children in the Resilient group to have a CPS history of neglect (RRR = 2.44) and exposure to violence at home and in the community (RRR = 1.04). Many children living in high-risk environments exhibit resilience to PTSS, but exposure to witnessed violence and neglect appear to put children at chronic risk for poor adjustment. These children may require more intensive, integrated clinical services that attend to multiple adverse experiences. Copyright © 2015 International Society for Traumatic Stress Studies.

Immersion in altered experience: An investigation of the relationship between absorption and psychopathology

PubMed Central

Rosen, Cherise; Jones, Nev; Chase, Kayla A.; Melbourne, Jennifer K.; Grossman, Linda S.; Sharma, Rajiv P.

2017-01-01

Understanding alterations in perceptual experiences as a component of the basic symptom structure of psychosis may improve early detection and the identification of subtle shifts that can precede symptom exacerbation. We explored the phenomenological construct of absorption and psychotic experiences in both clinical (bipolar psychosis and schizophrenia spectrum) and non-clinical participants. Participants with psychosis endorsed significantly higher absorption compared to the non-clinical group. Absorption was positively correlated with all types of hallucinations and multiple types of delusions. The analysis yielded two distinct cluster groups that demarcated a distinction along the continuum of self-disturbance: on characterized by attenuated ego boundaries and the other stable ego boundaries. The study suggests that absorption is a potentially important but under-researched component of psychosis that overlaps with, but is not identical to the more heavily theorized constructs of aberrant salience and hyperreflexivity. PMID:28219788

Automated segmentation reveals silent radiographic progression in adult-onset vanishing white-matter disease.

PubMed

Huber, Thomas; Herwerth, Marina; Alberts, Esther; Kirschke, Jan S; Zimmer, Claus; Ilg, Ruediger

2017-02-01

Adult-onset vanishing white-matter disease (VWM) is a rare autosomal recessive disease with neurological symptoms such as ataxia and paraparesis, showing extensive white-matter hyperintensities (WMH) on magnetic resonance (MR) imaging. Besides symptom-specific scores like the International Cooperative Ataxia Rating Scale (ICARS), there is no established tool to monitor disease progression. Because of extensive WMH, visual comparison of MR images is challenging. Here, we report the results of an automated method of segmentation to detect alterations in T2-weighted fluid-attenuated-inversion-recovery (FLAIR) sequences in a one-year follow-up study of a clinically stable patient with genetically diagnosed VWM. Signal alterations in MR imaging were quantified with a recently published WMH segmentation method by means of extreme value distribution (EVD). Our analysis revealed progressive FLAIR alterations of 5.84% in the course of one year, whereas no significant WMH change could be detected in a stable multiple sclerosis (MS) control group. This result demonstrates that automated EVD-based segmentation allows a precise and rapid quantification of extensive FLAIR alterations like in VWM and might be a powerful tool for the clinical and scientific monitoring of degenerative white-matter diseases and potential therapeutic interventions.

Spiking Neural Network With Distributed Plasticity Reproduces Cerebellar Learning in Eye Blink Conditioning Paradigms.

PubMed

Antonietti, Alberto; Casellato, Claudia; Garrido, Jesús A; Luque, Niceto R; Naveros, Francisco; Ros, Eduardo; D' Angelo, Egidio; Pedrocchi, Alessandra

2016-01-01

In this study, we defined a realistic cerebellar model through the use of artificial spiking neural networks, testing it in computational simulations that reproduce associative motor tasks in multiple sessions of acquisition and extinction. By evolutionary algorithms, we tuned the cerebellar microcircuit to find out the near-optimal plasticity mechanism parameters that better reproduced human-like behavior in eye blink classical conditioning, one of the most extensively studied paradigms related to the cerebellum. We used two models: one with only the cortical plasticity and another including two additional plasticity sites at nuclear level. First, both spiking cerebellar models were able to well reproduce the real human behaviors, in terms of both "timing" and "amplitude", expressing rapid acquisition, stable late acquisition, rapid extinction, and faster reacquisition of an associative motor task. Even though the model with only the cortical plasticity site showed good learning capabilities, the model with distributed plasticity produced faster and more stable acquisition of conditioned responses in the reacquisition phase. This behavior is explained by the effect of the nuclear plasticities, which have slow dynamics and can express memory consolidation and saving. We showed how the spiking dynamics of multiple interactive neural mechanisms implicitly drive multiple essential components of complex learning processes.  This study presents a very advanced computational model, developed together by biomedical engineers, computer scientists, and neuroscientists. Since its realistic features, the proposed model can provide confirmations and suggestions about neurophysiological and pathological hypotheses and can be used in challenging clinical applications.

Molecular Dimensions of Gastric Cancer: Translational and Clinical Perspectives.

PubMed

Choi, Yoon Young; Noh, Sung Hoon; Cheong, Jae-Ho

2016-01-01

Gastric cancer is a global health burden and has the highest incidence in East Asia. This disease is complex in nature because it arises from multiple interactions of genetic, local environmental, and host factors, resulting in biological heterogeneity. This genetic intricacy converges on molecular characteristics reflecting the pathophysiology, tumor biology, and clinical outcome. Therefore, understanding the molecular characteristics at a genomic level is pivotal to improving the clinical care of patients with gastric cancer. A recent landmark study, The Cancer Genome Atlas (TCGA) project, showed the molecular landscape of gastric cancer through a comprehensive molecular evaluation of 295 primary gastric cancers. The proposed molecular classification divided gastric cancer into four subtypes: Epstein-Barr virus-positive, microsatellite unstable, genomic stable, and chromosomal instability. This information will be taken into account in future clinical trials and will be translated into clinical therapeutic decisions. To fully realize the clinical benefit, many challenges must be overcome. Rapid growth of high-throughput biology and functional validation of molecular targets will further deepen our knowledge of molecular dimensions of this cancer, allowing for personalized precision medicine.

Development of a pharmacogenetic-guided warfarin dosing algorithm for Puerto Rican patients

PubMed Central

Ramos, Alga S; Seip, Richard L; Rivera-Miranda, Giselle; Felici-Giovanini, Marcos E; Garcia-Berdecia, Rafael; Alejandro-Cowan, Yirelia; Kocherla, Mohan; Cruz, Iadelisse; Feliu, Juan F; Cadilla, Carmen L; Renta, Jessica Y; Gorowski, Krystyna; Vergara, Cunegundo; Ruaño, Gualberto; Duconge, Jorge

2012-01-01

Aim This study was aimed at developing a pharmacogenetic-driven warfarin-dosing algorithm in 163 admixed Puerto Rican patients on stable warfarin therapy. Patients & methods A multiple linear-regression analysis was performed using log-transformed effective warfarin dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other relevant nongenetic clinical and demographic factors as independent predictors. Results The model explained more than two-thirds of the observed variance in the warfarin dose among Puerto Ricans, and also produced significantly better ‘ideal dose’ estimates than two pharmacogenetic models and clinical algorithms published previously, with the greatest benefit seen in patients ultimately requiring <7 mg/day. We also assessed the clinical validity of the model using an independent validation cohort of 55 Puerto Rican patients from Hartford, CT, USA (R2 = 51%). Conclusion Our findings provide the basis for planning prospective pharmacogenetic studies to demonstrate the clinical utility of genotyping warfarin-treated Puerto Rican patients. PMID:23215886

[Choroidal neovascularization followed in a patient with "Multiple Evanescent White Dot Syndrome" (MEWDS) -- a case report].

PubMed

Löw, U; Palmowski, A M; Weich, C-M; Ruprecht, K W

2004-12-01

Since the description of the "multiple evanescent white dot syndrome" (MEWDS) by Jampol et al, choroiditis has been in the focus of interest. But the classical type of MEWDS was an exceptional case in clinical routine. A 48-year-old female presented to our hospital with a sudden unilateral visual acuity decrease and an extension of the blind spot. Ophthalmoscopy and fluorescein angiography revealed typical multiple grey-white chorioretinal patches of the same stage with lesion areas of about 100 - 200 microm compatible with the diagnose of MEWDS. Although visual acuity increased continuously the patient developed a classical choroidal neovascularization within 4 weeks. She was treated with PDT and visual acuity as well as the ophthalmoscopic diagnosis remained stable. In spite of visual improvement in MEWDS, regular control is recommended. In addition we propose to consider the diagnosis of MEWDS if an enlargement of the blind spot and CNV without lesions of the retinal pigment epithelium are diagnosed.

Prospective Analysis of Behavioral Economic Predictors of Stable Moderation Drinking Among Problem Drinkers Attempting Natural Recovery

PubMed Central

Tucker, Jalie A.; Cheong, JeeWon; Chandler, Susan D.; Lambert, Brice H.; Pietrzak, Brittney; Kwok, Heather; Davies, Susan L.

2016-01-01

Background As interventions have expanded beyond clinical treatment to include brief interventions for persons with less severe alcohol problems, predicting who can achieve stable moderation drinking has gained importance. Recent behavioral economic (BE) research on natural recovery has shown that active problem drinkers who allocate their monetary expenditures on alcohol and saving for the future over longer time horizons tend to have better subsequent recovery outcomes, including maintenance of stable moderation drinking. The present study compared the predictive utility of this money-based “Alcohol-Savings Discretionary Expenditure” (ASDE) index with multiple BE analogue measures of behavioral impulsivity and self-control, which have seldom been investigated together, to predict outcomes of natural recovery attempts. Methods Community-dwelling problem drinkers, enrolled shortly after stopping abusive drinking without treatment, were followed prospectively for up to a year (N = 175 [75.4% male], M age = 50.65 years). They completed baseline assessments of pre-resolution drinking practices and problems; analogue behavioral choice tasks (Delay Discounting, Melioration-Maximization, and Alcohol Purchase Tasks); and a Timeline Followback interview including expenditures on alcohol compared to voluntary savings (ASDE index) during the pre-resolution year. Results Multinomial logistic regression models showed that, among the BE measures, only the ASDE index predicted stable moderation drinking compared to stable abstinence or unstable resolutions involving relapse. As hypothesized, stable moderation was associated with more balanced pre-resolution allocations to drinking and savings (OR = 1.77, 95% CI = 1.02 ∼ 3.08, p < .05), suggesting it is associated with longer term behavior regulation processes than abstinence. Conclusions The ASDE's unique predictive utility may rest on its comprehensive representation of contextual elements to support this patterning of behavioral allocation. Stable low risk drinking, but not abstinence, requires such regulatory processes. PMID:27775161

Applications of stable isotopes in clinical pharmacology

PubMed Central

Schellekens, Reinout C A; Stellaard, Frans; Woerdenbag, Herman J; Frijlink, Henderik W; Kosterink, Jos G W

2011-01-01

This review aims to present an overview of the application of stable isotope technology in clinical pharmacology. Three main categories of stable isotope technology can be distinguished in clinical pharmacology. Firstly, it is applied in the assessment of drug pharmacology to determine the pharmacokinetic profile or mode of action of a drug substance. Secondly, stable isotopes may be used for the assessment of drug products or drug delivery systems by determination of parameters such as the bioavailability or the release profile. Thirdly, patients may be assessed in relation to patient-specific drug treatment; this concept is often called personalized medicine. In this article, the application of stable isotope technology in the aforementioned three areas is reviewed, with emphasis on developments over the past 25 years. The applications are illustrated with examples from clinical studies in humans. PMID:21801197

Use of modified lip repositioning technique associated with esthetic crown lengthening for treatment of excessive gingival display: A case report of multiple etiologies

PubMed Central

Mantovani, Matheus Bortoluzzi; Souza, Eduardo Clemente; Marson, Fabiano Carlos; Corrêa, Giovani Oliveira; Progiante, Patrícia Saram; Silva, Cléverson Oliveira

2016-01-01

Excessive gingival display during smile can result in compromised esthetics. This study aims to report a case of excessive gingival display with multiple etiologies treated by means of modified lip repositioning technique associated with esthetic crown lengthening. A 23-year-old female patient, with 5-mm gingival display during smile caused by altered passive eruption and hypermobility of the upper lip, underwent the modified lip repositioning technique associated with gingivectomy followed by flap elevation and ostectomy/osteoplasty. Seven months after the second procedure, the patient had her esthetic complaint solved appearing stable in the observation period. The modified lip repositioning technique is an effective procedure employed to reduce gingival display and when associated with esthetic clinical crown lengthening, can appropriately treat cases of gummy smile. PMID:27041845

A new surgical technique for traumatic dislocation of posterior tibial tendon with avulsion fracture of medial malleolus.

PubMed

Jeong, Soon-Taek; Hwang, Sun-Chul; Kim, Dong-Hee; Nam, Dae-Cheol

2015-01-01

We introduce a case of traumatic dislocation of the posterior tibial tendon with avulsion fracture of the medial malleolus in a 52-year-old female patient who was treated surgically with periosteal flap and suture anchor fixation. Based in the posteromedial ridge of the distal tibia, a quadrilateral periosteal flap was created and folded over the tendon, followed by fixation on the lateral aspect of the groove by use of multiple suture anchors. Clinical and radiological findings 25 months postoperatively showed well-preserved function of the ankle joint with stable tendon gliding.

Change descriptors for determining nodule malignancy in national lung screening trial CT screening images

NASA Astrophysics Data System (ADS)

Geiger, Benjamin; Hawkins, Samuel; Hall, Lawrence O.; Goldgof, Dmitry B.; Balagurunathan, Yoganand; Gatenby, Robert A.; Gillies, Robert J.

2016-03-01

Pulmonary nodules are effectively diagnosed in CT scans, but determining their malignancy has been a challenge. The rate of change of the volume of a pulmonary nodule is known to be a prognostic factor for cancer development. In this study, we propose that other changes in imaging characteristics are similarly informative. We examined the combination of image features across multiple CT scans, taken from the National Lung Screening Trial, with individual scans of the same patient separated by approximately one year. By subtracting the values of existing features in multiple scans for the same patient, we were able to improve the ability of existing classification algorithms to determine whether a nodule will become malignant. We trained each classifier on 83 nodules determined to be malignant by biopsy and 172 nodules determined to be benign by their clinical stability through two years of no change; classifiers were tested on 77 malignant and 144 benign nodules, using a set of features that in a test-retest experiment were shown to be stable. An accuracy of 83.71% and AUC of 0.814 were achieved with the Random Forests classifier on a subset of features determined to be stable via test-retest reproducibility analysis, further reduced with the Correlation-based Feature Selection algorithm.

High mass accuracy assay for trimethylamine N-oxide using stable-isotope dilution with liquid chromatography coupled to orthogonal acceleration time of flight mass spectrometry with multiple reaction monitoring.

PubMed

Heaney, Liam M; Jones, Donald J L; Mbasu, Richard J; Ng, Leong L; Suzuki, Toru

2016-01-01

Trimethylamine N-oxide (TMAO) has attracted interest as circulating levels have reported prognostic value in patients with cardiovascular conditions, such as heart failure. With continual advances in accurate mass measurements, robust methods that can employ the capabilities of time of flight mass spectrometers would offer additional utility in the analysis of complex clinical samples. A Waters Acquity UPLC was coupled to a Waters Synapt G2-S high-resolution mass spectrometer. TMAO was measured in plasma by stable-isotope dilution-hydrophilic interaction liquid chromatography-time of flight mass spectrometry with multiple reaction monitoring (LC-ToF-MRM). Two transitions were monitored: m/z 76.1 to 58.066/59.073 and m/z 85.1 to 66.116/68.130. The method was assessed for linearity, lower limits of detection and quantitation, and reproducibility. A selected cohort of patients with systolic heart failure (SHF; n = 43) and healthy controls (n = 42) were measured to verify the assay is suitable for the analysis of clinical samples. Quantitative analysis of TMAO using LC-ToF-MRM enabled linearity to be established between 0.1 and 75 μmol/L, with a lower limit of detection of 0.05 μmol/L. Relative standard deviations reported an inter-day variation of ≤20.8% and an intra-day variation of ≤11.4% with an intra-study quality control variation of 2.7%. Run times were 2.5 min. Clinical application of the method reported that TMAO in SHF was elevated compared to that of healthy controls (p < 0.0005). LC-ToF-MRM offers a highly selective method for accurate mass measurement of TMAO with rapid and reproducible results. Applicability of the method was shown in a selected cohort of patient samples.

Efficacy of a Computer-Assisted Cognitive Rehabilitation Intervention in Relapsing-Remitting Multiple Sclerosis Patients: A Multicenter Randomized Controlled Trial

PubMed Central

Kosmidis, Mary H.; Zampakis, Petros; Malefaki, Sonia; Ntoskou, Katerina; Nousia, Anastasia; Bakirtzis, Christos; Papathanasopoulos, Panagiotis

2017-01-01

Cognitive impairment is frequently encountered in multiple sclerosis (MS) affecting between 40–65% of individuals, irrespective of disease duration and severity of physical disability. In the present multicenter randomized controlled trial, fifty-eight clinically stable RRMS patients with mild to moderate cognitive impairment and relatively low disability status were randomized to receive either computer-assisted (RehaCom) functional cognitive training with an emphasis on episodic memory, information processing speed/attention, and executive functions for 10 weeks (IG; n = 32) or standard clinical care (CG; n = 26). Outcome measures included a flexible comprehensive neuropsychological battery of tests sensitive to MS patient deficits and feedback regarding personal benefit gained from the intervention on four verbal questions. Only the IG group showed significant improvements in verbal and visuospatial episodic memory, processing speed/attention, and executive functioning from pre - to postassessment. Moreover, the improvement obtained on attention was retained over 6 months providing evidence on the long-term benefits of this intervention. Group by time interactions revealed significant improvements in composite cognitive domain scores in the IG relative to the demographically and clinically matched CG for verbal episodic memory, processing speed, verbal fluency, and attention. Treated patients rated the intervention positively and were more confident about their cognitive abilities following treatment. PMID:29463950

Changes in magnetic resonance imaging disease measures over 3 years in mildly disabled patients with relapsing-remitting multiple sclerosis receiving interferon β-1a in the COGnitive Impairment in MUltiple Sclerosis (COGIMUS) study

PubMed Central

2011-01-01

Background Conventional magnetic resonance imaging (MRI) has improved the diagnosis and monitoring of multiple sclerosis (MS). In clinical trials, MRI has been found to detect treatment effects with greater sensitivity than clinical measures; however, clinical and MRI outcomes tend to correlate poorly. Methods In this observational study, patients (n = 550; 18-50 years; relapsing-remitting MS [Expanded Disability Status Scale score ≤4.0]) receiving interferon (IFN) β-1a therapy (44 or 22 µg subcutaneously [sc] three times weekly [tiw]) underwent standardized MRI, neuropsychological and quality-of-life (QoL) assessments over 3 years. In this post hoc analysis, MRI outcomes and correlations between MRI parameters and clinical and functional outcomes were analysed. Results MRI data over 3 years were available for 164 patients. T2 lesion and T1 gadolinium-enhancing (Gd+) lesion volumes, but not black hole (BH) volumes, decreased significantly from baseline to Year 3 (P < 0.0001). Percentage decreases (baseline to Year 3) were greater with the 44 μg dose than with the 22 μg dose for T2 lesion volume (-10.2% vs -4.5%, P = 0.025) and T1 BH volumes (-7.8% vs +10.3%, P = 0.002). A decrease in T2 lesion volume over 3 years predicted stable QoL over the same time period. Treatment with IFN β-1a, 44 μg sc tiw, predicted an absence of cognitive impairment at Year 3. Conclusion Subcutaneous IFN β-1a significantly decreased MRI measures of disease, with a significant benefit shown for the 44 µg over the 22 µg dose; higher-dose treatment also predicted better cognitive outcomes over 3 years. PMID:21999142

Idiopathic Hypersomnia: A Study of 77 Cases

PubMed Central

Anderson, Kirstie N.; Pilsworth, Samantha; Sharples, Linda D.; Smith, Ian E.; Shneerson, John M.

2007-01-01

Study Objectives: To review the clinical and polysomnographic characteristics of idiopathic hypersomnia as well as the long-term response to treatment. Setting: The Respiratory Support and Sleep Centre at Papworth Hospital, Cambridge, UK. Patients and Design: A large database of more than 6000 patients with sleep disorders was reviewed. A retrospective study of the clinical and polysomnographic characteristics of 77 patients with idiopathic hypersomnia was performed. Comparison with a similar group of patients with narcolepsy was performed. The response to drug treatment was assessed in 61 patients over a mean follow-up of 3.8 years. Measurements and Results: Idiopathic hypersomnia was 60% as prevalent as narcolepsy. Comparison with a similar group of patients with narcolepsy showed that those with idiopathic hypersomnia were more likely to have prolonged unrefreshing daytime naps, a positive family history, increased slow-wave sleep, and a longer sleep latency on the Multiple Sleep Latency Test. The results of the Multiple Sleep Latency Test were not helpful in predicting disease severity or treatment response. The clinical features were heterogeneous and of variable severity. The majority of patients with idiopathic hypersomnia had symptoms that remained stable over many years, but 11% had spontaneous remission, which was never seen in narcolepsy. Two thirds of patients with idiopathic hypersomnolence had a sustained improvement in daytime somnolence with medication, although a third needed high doses or combinations of drugs. Conclusions: Idiopathic hypersomnolence has characteristic clinical and polysomnographic features but the prolonged latency on the Multiple Sleep Latency Test raises doubt about the validity of this test within the current diagnostic criteria. The disease often responds well to treatment and a substantial minority of patients appear to spontaneously improve. Citation: Anderson KN; Pilsworth S; Sharples LD; Smith IE; Shneerson JM. Idiopathic hypersomnia: a study of 77 cases. SLEEP 2007;30(10):1274-1281. PMID:17969461

Reduced Antiplatelet Effect of Aspirin Does Not Predict Cardiovascular Events in Patients With Stable Coronary Artery Disease.

PubMed

Larsen, Sanne Bøjet; Grove, Erik Lerkevang; Neergaard-Petersen, Søs; Würtz, Morten; Hvas, Anne-Mette; Kristensen, Steen Dalby

2017-08-05

Increased platelet aggregation during antiplatelet therapy may predict cardiovascular events in patients with coronary artery disease. The majority of these patients receive aspirin monotherapy. We aimed to investigate whether high platelet-aggregation levels predict cardiovascular events in stable coronary artery disease patients treated with aspirin. We included 900 stable coronary artery disease patients with either previous myocardial infarction, type 2 diabetes mellitus, or both. All patients received single antithrombotic therapy with 75 mg aspirin daily. Platelet aggregation was evaluated 1 hour after aspirin intake using the VerifyNow Aspirin Assay (Accriva Diagnostics) and Multiplate Analyzer (Roche; agonists: arachidonic acid and collagen). Adherence to aspirin was confirmed by serum thromboxane B 2 . The primary end point was the composite of nonfatal myocardial infarction, ischemic stroke, and cardiovascular death. At 3-year follow-up, 78 primary end points were registered. The primary end point did not occur more frequently in patients with high platelet-aggregation levels (first versus fourth quartile) assessed by VerifyNow (hazard ratio: 0.5 [95% CI, 0.3-1.1], P =0.08) or Multiplate using arachidonic acid (hazard ratio: 1.0 [95% CI, 0.5-2.1], P =0.92) or collagen (hazard ratio: 1.4 [95% CI, 0.7-2.8], P =0.38). Similar results were found for the composite secondary end point (nonfatal myocardial infarction, ischemic stroke, stent thrombosis, and all-cause death) and the single end points. Thromboxane B 2 levels did not predict any end points. Renal insufficiency was the only clinical risk factor predicting the primary and secondary end points. This study is the largest to investigate platelet aggregation in stable coronary artery disease patients receiving aspirin as single antithrombotic therapy. We found that high platelet-aggregation levels did not predict cardiovascular events. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Preparation, Purification, and Stability of Tuberculin

PubMed Central

Landi, S.

1963-01-01

The method used to produce “Connaught” tuberculin purified protein derivative (PPD) is described. The tuberculin PPD for the multiple-puncture method was shown to be stable for at least 24 months at 5 C; tuberculin PPD for the intracutaneous method was shown to be stable at 5 C and 24 C for a period of 18 months in the presence of Tween 80. Evans blue or brillant vital red was added to tuberculin PPD for improved testing by the multiple-puncture method. These tinted tuberculin preparations were found to be as stable as the Connaught tuberculin PPD preparations without dye at 5 C. Freeze-dried tuberculin PPD with Plasdone as an inert base was found to be remarkably stable for a period of at least 24 months at 5, 24, and 37 C. PMID:14063782

Safety and pharmacodynamics of venetoclax (ABT-199) in a randomized single and multiple ascending dose study in women with systemic lupus erythematosus.

PubMed

Lu, P; Fleischmann, R; Curtis, C; Ignatenko, S; Clarke, S H; Desai, M; Wong, S L; Grebe, K M; Black, K; Zeng, J; Stolzenbach, J; Medema, J K

2018-02-01

Objective The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) may contribute to the pathogenesis of systemic lupus erythematosus. The safety, tolerability, and pharmacodynamics of the selective Bcl-2 inhibitor venetoclax (ABT-199) were assessed in women with systemic lupus erythematosus. Methods A phase 1, double-blind, randomized, placebo controlled study evaluated single ascending doses (10, 30, 90, 180, 300, and 500 mg) and multiple ascending doses (2 cycles; 30, 60, 120, 240, 400, and 600 mg for 1 week, and then 3 weeks off per cycle) of orally administered venetoclax. Eligible participants were aged 18-65 years with a diagnosis of systemic lupus erythematosus for 6 months or more receiving stable therapy for systemic lupus erythematosus (which could have included corticosteroids and/or stable antimalarials). Results All patients (48/48) completed the single ascending dose, 25 continued into the multiple ascending dose, and 44/50 completed the multiple ascending dose; two of the withdrawals (venetoclax 60 mg and 600 mg cohorts) were due to adverse events. Adverse event incidences were slightly higher in the venetoclax groups compared with the placebo groups, with no dose dependence. There were no serious adverse events with venetoclax. The most common adverse events were headache, nausea, and fatigue. Venetoclax 600 mg multiple ascending dose treatment depleted total lymphocytes and B cells by approximately 50% and 80%, respectively. Naive, switched memory, and memory B-cell subsets enriched in autoreactive B cells exhibited dose-dependent reduction of up to approximately 80%. There were no consistent or marked changes in neutrophils, natural killer cells, hemoglobin, or platelets. Conclusions Venetoclax was generally well tolerated in women with systemic lupus erythematosus and reduced total lymphocytes and disease-relevant subsets of antigen-experienced B cells. Registration ClinicalTrials.gov: NCT01686555.

Cognitive burden of anticholinergic medications in psychotic disorders.

PubMed

Eum, Seenae; Hill, S Kristian; Rubin, Leah H; Carnahan, Ryan M; Reilly, James L; Ivleva, Elena I; Keedy, Sarah K; Tamminga, Carol A; Pearlson, Godfrey D; Clementz, Brett A; Gershon, Elliot S; Keshavan, Matcheri S; Keefe, Richard S E; Sweeney, John A; Bishop, Jeffrey R

2017-12-01

Patients with psychotic disorders are often treated with numerous medications, many of which have anticholinergic activity. We assessed cognition in relation to the cumulative anticholinergic burden of multiple drugs included in treatment regimens of participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Clinically stable participants with schizophrenia (n=206), schizoaffective disorder (n=131), and psychotic bipolar disorder (n=146) were examined. Anticholinergic properties of all scheduled drugs were quantified using the Anticholinergic Drug Scale (ADS). ADS scores were summed across individual drugs to create a total ADS burden score for each participant and examined in relation to the Brief Assessment of Cognition in Schizophrenia (BACS). Anticholinergic burden aggregated across all medications was inversely related to cognitive performance starting at ADS scores of 4 in participants with schizophrenia. Those with ADS scores ≥4 had lower composite BACS scores compared to those with ADS<4 (p=0.004). Among BACS subtests, Verbal Memory was the most adversely affected by high anticholinergic burden. Despite similar anticholinergic burden scores across groups, a significant threshold effect of anticholinergic burden was not detected in schizoaffective or psychotic bipolar disorder. We identified an adverse effect threshold of anticholinergic burden on cognition in clinically stable participants with schizophrenia. This relationship was not identified in affective psychoses. Examination of other medications, doses, and clinical measures did not account for these findings. Patients with schizophrenia may have increased cognitive susceptibility to anticholinergic medications and the aggregate effects of one's medication regimen may be important to consider in clinical practice. Copyright © 2017 Elsevier B.V. All rights reserved.

Heart rate variability is differentially altered in multiple sclerosis: implications for acute, worsening and progressive disability.

PubMed

Studer, Valeria; Rocchi, Camilla; Motta, Caterina; Lauretti, Benedetta; Perugini, Jacopo; Brambilla, Laura; Pareja-Gutierrez, Lorena; Camera, Giorgia; Barbieri, Francesca Romana; Marfia, Girolama A; Centonze, Diego; Rossi, Silvia

2017-01-01

Sympathovagal imbalance has been associated with poor prognosis in chronic diseases, but there is conflicting evidence in multiple sclerosis. The objective of this study was to investigate the autonomic nervous system dysfunction correlation with inflammation and progression in multiple sclerosis. Heart rate variability was analysed in 120 multiple sclerosis patients and 60 healthy controls during supine rest and head-up tilt test; the normalised units of low frequency and high frequency power were considered to assess sympathetic and vagal components, respectively. Correlation analyses with clinical and radiological markers of disease activity and progression were performed. Sympathetic dysfunction was closely related to the progression of disability in multiple sclerosis: progressive patients showed altered heart rate variability with respect to healthy controls and relapsing-remitting patients, with higher rest low frequency power and lacking the expected low frequency power increase during the head-up tilt test. In relapsing-remitting patients, disease activity, even subclinical, was associated with lower rest low frequency power, whereas stable relapsing-remitting patients did not differ from healthy controls. Less sympathetic reactivity and higher low frequency power at rest were associated with incomplete recovery from relapse. Autonomic balance appears to be intimately linked with both the inflammatory activity of multiple sclerosis, which is featured by an overall hypoactivity of the sympathetic nervous system, and its compensatory plastic processes, which appear inefficient in case of worsening and progressive multiple sclerosis.

Cognitive and Language Deficits in Multiple Sclerosis: Comparison of Relapsing Remitting and Secondary Progressive Subtypes

PubMed Central

Ntoskou, Katerina; Messinis, Lambros; Nasios, Grigorios; Martzoukou, Maria; Makris, Giorgos; Panagiotopoulos, Elias; Papathanasopoulos, Panagiotis

2018-01-01

Objective: The objective of this study was to investigate the pattern and severity of cognitive and language impairment in Greek patients with Relapsing-remitting (RRMS) and Secondary Progressive Multiple Sclerosis (SPMS), relative to control participants. Method: A prospective study was conducted in 27 patients with multiple sclerosis (PwMS), (N= 15) with RRMS, (N= 12) with SPMS, and (N= 12) healthy controls. All participants were assessed with a flexible comprehensive neuropsychological – language battery of tests that have been standardized in Greece and validated in Greek MS patients. They were also assessed on measures of disability (Expanded Disability Status Scale; EDSS), fatigue (Fatigue Severity Scale; FSS) and depression (Beck Depression Inventory - fast screen; BDI-FS). Results: Our results revealed that groups were well matched on baseline demographic and clinical characteristics. The two clinical groups (RRMS; SPMS) did not differ on overall global cognitive impairment but differed in the initial encoding of verbal material, mental processing speed, response inhibition and set-shifting. RRMS patients differed from controls in the initial encoding of verbal material, learning curve, delayed recall of verbal information, processing speed, and response inhibition. SPMS patients differed in all utilized measures compared to controls. Moreover, we noted increased impairment frequency on individualized measures in the progressive SPMS group. Conclusion: We conclude that MS patients, irrespective of clinical subtype, have cognitive deficits compared to healthy participants, which become increasingly worse when they convert from RRMS to SPMS.On the contrary,the pattern of impairment remains relatively stable. PMID:29576812

Stable Isotope Mixing Models as a Tool for Tracking Sources of Water and Water Pollutants

EPA Science Inventory

One goal of monitoring pollutants is to be able to trace the pollutant to its source. Here we review how mixing models using stable isotope information on water and water pollutants can help accomplish this goal. A number of elements exist in multiple stable (non-radioactive) i...

Toward highly efficient electrocatalyst for Li–O 2 batteries using biphasic N-doping cobalt@graphene multiple-capsule heterostructures

DOE PAGES

Tan, Guoqiang; Chong, Lina; Amine, Rachid; ...

2017-04-12

To promote lithium-oxygen batteries available for practical applications, the development of advanced cathode catalysts with low-cost, high activity and stable structural properties is demanded. Such development is rooted on certain intelligent catalyst-electrode design that fundamentally facilitates electronic and ionic transport, and improves oxygen diffusivity in a porous environment. Here we design a biphasic nitrogen-doped cobalt@graphene multiple-capsule heterostructure, combined with a flexible, stable porous electrode architecture, and apply it as promising cathodes for lithium-oxygen cells. The biphasic nitrogen-doping feature improves the electric conductivity and catalytic activity; the multiple-nanocapsule configuration makes high/uniform electro-active zones possible; furthermore, the colander-like porous electrode facilitates themore » oxygen diffusion, catalytic reaction, and stable deposition of discharge products. Finally, the electrode exhibits much improved electrocatalytic properties associated with unique morphologies of electrochemically grown lithium peroxides.« less

Toward Highly Efficient Electrocatalyst for Li–O 2 Batteries Using Biphasic N-Doping Cobalt@Graphene Multiple-Capsule Heterostructures

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

Tan, Guoqiang; Chong, Lina; Amine, Rachid

For the promotion of lithium oxygen batteries available for :practical applications, the development of advanced cathode catalysts with low-high activity, and stable structural properties is demanded. Such development is rooted on certain intelligent catalyst-electrode design that fundamentally facilitates electronic and ionic transport and improves oxygen diffusivity in a porous environment. Here we design a biphasic nitrogen-doped cobalt@grapbene Multiple-capsule heterostructure, combined with a flexible, stable porous electrode architecture, and apply it as promising cathodes for lithium oxygen cells. 'The biphasic nitrogen-doping feature improves the electric conductivity and catalytic activity; the multiple-nanocapsule configuration makes high/uniform electroactive zones possible; furthermore the colander-like porousmore » electrode facilitates the oxygen diffusion, catalytic reaction,and stable deposition of discharge products. As a result, the electrode exhibits much improved electrocatalytic properties associated with unique morphologies of electrochemically grown lithium peroxides.« less

Toward highly efficient electrocatalyst for Li–O 2 batteries using biphasic N-doping cobalt@graphene multiple-capsule heterostructures

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

Tan, Guoqiang; Chong, Lina; Amine, Rachid

To promote lithium-oxygen batteries available for practical applications, the development of advanced cathode catalysts with low-cost, high activity and stable structural properties is demanded. Such development is rooted on certain intelligent catalyst-electrode design that fundamentally facilitates electronic and ionic transport, and improves oxygen diffusivity in a porous environment. Here we design a biphasic nitrogen-doped cobalt@graphene multiple-capsule heterostructure, combined with a flexible, stable porous electrode architecture, and apply it as promising cathodes for lithium-oxygen cells. The biphasic nitrogen-doping feature improves the electric conductivity and catalytic activity; the multiple-nanocapsule configuration makes high/uniform electro-active zones possible; furthermore, the colander-like porous electrode facilitates themore » oxygen diffusion, catalytic reaction, and stable deposition of discharge products. Finally, the electrode exhibits much improved electrocatalytic properties associated with unique morphologies of electrochemically grown lithium peroxides.« less

Toward Highly Efficient Electrocatalyst for Li-O2 Batteries Using Biphasic N-Doping Cobalt@Graphene Multiple-Capsule Heterostructures.

PubMed

Tan, Guoqiang; Chong, Lina; Amine, Rachid; Lu, Jun; Liu, Cong; Yuan, Yifei; Wen, Jianguo; He, Kun; Bi, Xuanxuan; Guo, Yuanyuan; Wang, Hsien-Hau; Shahbazian-Yassar, Reza; Al Hallaj, Said; Miller, Dean J; Liu, Dijia; Amine, Khalil

2017-05-10

For the promotion of lithium-oxygen batteries available for practical applications, the development of advanced cathode catalysts with low-cost, high activity, and stable structural properties is demanded. Such development is rooted on certain intelligent catalyst-electrode design that fundamentally facilitates electronic and ionic transport and improves oxygen diffusivity in a porous environment. Here we design a biphasic nitrogen-doped cobalt@graphene multiple-capsule heterostructure, combined with a flexible, stable porous electrode architecture, and apply it as promising cathodes for lithium-oxygen cells. The biphasic nitrogen-doping feature improves the electric conductivity and catalytic activity; the multiple-nanocapsule configuration makes high/uniform electroactive zones possible; furthermore, the colander-like porous electrode facilitates the oxygen diffusion, catalytic reaction, and stable deposition of discharge products. As a result, the electrode exhibits much improved electrocatalytic properties associated with unique morphologies of electrochemically grown lithium peroxides.

Effects of a novel cytokine haemoadsorbtion system on inflammatory response in septic shock after cephalic pancreatectomy – a case report

PubMed Central

Tomescu, Dana; Dima, Simona O.; Tănăsescu, Sabina; Tănase, Cristiana Pistol; Năstase, Anca; Popescu, Mihai

2014-01-01

Severe sepsis and septic shock are associated with an inflammatory cascade that is primarily responsible for multiple organ dysfunction. To date, there are no specific treatments designed to modulate and rebalance inflammatory cytokines levels. We present a case of a 50 years old man with postoperative septic shock after undergoing cephalic pancreatectomy for a pancreatic cystic tumor. The use of a haemoadsorbtion device (CytoSorb®) in combination with continuous veno-venous haemofiltration was associated with a decrease in TNFα, IL-1β and IFNγ and an increase in IL-10 levels measured before and after two consecutive procedures. The effect of CytoSorb® on inflammatory cytokines translated into a more stable haemodynamic profile with a stable cardiac output and normalization of systemic vascular resistance index and decreased vasopressor requirements. Further prospective large clinical trials are required in order to determine the indications for CytoSorb® and to evaluate the overall outcome. PMID:28913446

Effects of a novel cytokine haemoadsorbtion system on inflammatory response in septic shock after cephalic pancreatectomy - a case report.

PubMed

Tomescu, Dana; Dima, Simona O; Tănăsescu, Sabina; Tănase, Cristiana Pistol; Năstase, Anca; Popescu, Mihai

2014-10-01

Severe sepsis and septic shock are associated with an inflammatory cascade that is primarily responsible for multiple organ dysfunction. To date, there are no specific treatments designed to modulate and rebalance inflammatory cytokines levels. We present a case of a 50 years old man with postoperative septic shock after undergoing cephalic pancreatectomy for a pancreatic cystic tumor. The use of a haemoadsorbtion device (CytoSorb ® ) in combination with continuous veno-venous haemofiltration was associated with a decrease in TNFα, IL-1β and IFNγ and an increase in IL-10 levels measured before and after two consecutive procedures. The effect of CytoSorb ® on inflammatory cytokines translated into a more stable haemodynamic profile with a stable cardiac output and normalization of systemic vascular resistance index and decreased vasopressor requirements. Further prospective large clinical trials are required in order to determine the indications for CytoSorb ® and to evaluate the overall outcome.

Clinical, biochemical, and hygiene assessment of stabled horses provided continuous or intermittent access to drinking water.

PubMed

Freeman, D A; Cymbaluk, N F; Schott, H C; Hinchcliff, K; McDonnell, S M; Kyle, B

1999-11-01

To compare health, hydration status, and management of stabled pregnant mares provided drinking water continuously or via 1 of 3 intermittent delivery systems. 22 Quarter Horse (QH) or QH-crossbred mares and 18 Belgian or Belgian-crossbred mares (study 1); 24 QH or QH-crossbred mares and 18 Belgian or Belgian-crossbred mares (study 2). Stabled horses were provided water continuously or via 1 of 3 intermittent water delivery systems in 2 study periods during a 2-year period. Body temperature, attitude, appetite, water intake, and urine output were recorded daily. Hygiene of each horse and the stable were assessed weekly. Clinical and biochemical measures of hydration were determined 3 times during each study. Clinical measures of hydration included skin turgor, gum moisture, capillary refill time, and fecal consistency. Biochemical measures of hydration included PCV, plasma total protein concentration, serum osmolality, plasma vasopressin concentration, urine specific gravity, and urine osmolality. All horses remained healthy. Stable hygiene was worse when horses had continuous access to water. Clinical and biochemical measures of hydration did not differ among water delivery systems. Various continuous and intermittent water delivery systems provided adequate amounts of water to stabled horses to maintain health and hydration status. Providing intermittent access to water may be preferable on the basis of stable hygiene.

Brain temperature and its fundamental properties: a review for clinical neuroscientists

PubMed Central

Wang, Huan; Wang, Bonnie; Normoyle, Kieran P.; Jackson, Kevin; Spitler, Kevin; Sharrock, Matthew F.; Miller, Claire M.; Best, Catherine; Llano, Daniel; Du, Rose

2014-01-01

Brain temperature, as an independent therapeutic target variable, has received increasingly intense clinical attention. To date, brain hypothermia represents the most potent neuroprotectant in laboratory studies. Although the impact of brain temperature is prevalent in a number of common human diseases including: head trauma, stroke, multiple sclerosis, epilepsy, mood disorders, headaches, and neurodegenerative disorders, it is evident and well recognized that the therapeutic application of induced hypothermia is limited to a few highly selected clinical conditions such as cardiac arrest and hypoxic ischemic neonatal encephalopathy. Efforts to understand the fundamental aspects of brain temperature regulation are therefore critical for the development of safe, effective, and pragmatic clinical treatments for patients with brain injuries. Although centrally-mediated mechanisms to maintain a stable body temperature are relatively well established, very little is clinically known about brain temperature's spatial and temporal distribution, its physiological and pathological fluctuations, and the mechanism underlying brain thermal homeostasis. The human brain, a metabolically “expensive” organ with intense heat production, is sensitive to fluctuations in temperature with regards to its functional activity and energy efficiency. In this review, we discuss several critical aspects concerning the fundamental properties of brain temperature from a clinical perspective. PMID:25339859

Body-force-driven multiplicity and stability of combined free and forced convection in rotating curved ducts: Coriolis force

NASA Astrophysics Data System (ADS)

Yang, T.; Wang, L.

A numerical study is made on the fully developed bifurcation structure and stability of forced convection in a rotating curved duct of square cross-section. Solution structure is determined as variation of a parameter that indicates the effect of rotation (Coriolis-force-driven multiplicity). Three solutions for the flows in a stationary curved duct obtained in the work of Yang and Wang [1] are used as initial solutions of continuation calculations to unfold the solution branches. Twenty-one solution branches are found comparing with five obtained by Selmi and Nandakumar [2]. Dynamic responses of the multiple solutions to finite random disturbances are examined by the direct transient computation. Results show that characteristics of physically realizable fully developed flows changes significantly with variation of effect of rotation. Fourteen sub-ranges are identified according to characteristics of physically realizable solutions. As rotation effect changes, possible physically realizable fully-developed flows can be stable steady 2-cell state, stable multi-cell state, temporal periodic oscillation between symmetric/asymmetric 2-cell/4-cell flows, temporal oscillation with intermittency, temporal chaotic oscillation and temporal oscillation with pseudo intermittency. Among these possible physically realizable fully developed flows, stable multi-cell state and stable steady 2-cell state exist as dual stable. And oscillation with pseudo intermittency is a new phenomenon. In addition to the temporal oscillation with intermittency, sudden shift from stationary stable solution to temporal chaotic oscillation is identified to be another way of onset of chaos.

Allergen-specific immunotherapy in horses with insect bite hypersensitivity: a double-blind, randomized, placebo-controlled study.

PubMed

Ginel, Pedro J; Hernández, Eduardo; Lucena, Rosario; Blanco, Beatriz; Novales, Manuel; Mozos, Elena

2014-02-01

Insect bite hypersensitivity (IBH) is a common cause of pruritus in horses, but there are few controlled studies on the efficacy of allergen-specific immunotherapy (ASIT). Atopic dermatitis and IBH can present with overlapping clinical signs; multiple insect and environmental allergens could be indicated in these horses to achieve effective hyposensitization. Although the success of ASIT using Culicoides spp. whole-body extracts is controversial, there are no controlled studies published that clearly show benefit from this form of therapy. The objective was to evaluate the efficacy of ASIT in horses with IBH using commercially available extracts and tests. Twenty horses with seasonal pruritus and positive intradermal reactions to a whole Culicoides extract. An enzyme-linked immunosorbent assay test (Allercept(®) ) was used to detect concurrent allergen-specific IgE for other insects and environmental allergens. The ASIT was formulated by adding the relevant serologically positive allergens to the Culicoides extract. After randomization, 10 horses received ASIT and the rest a placebo solution. Clinical response was assessed every 4 months during 1 year using a clinical scoring system based on the severity of four clinical signs at 10 different body regions. Horses were not stabled and, to minimize dropouts, an insect repellent was used weekly in both groups. Differences in clinical scores between groups were nonsignificant at any re-evaluation, while both groups improved to a similar extent, probably due to the insecticide treatment. Using commercially available extracts and tests, we could not demonstrate a beneficial effect of 1 year multiple ASIT in nonstabled horses with IBH. © 2013 ESVD and ACVD.

Robotic Colorectal Surgery

PubMed Central

2008-01-01

Robotic colorectal surgery has gradually been performed more with the help of the technological advantages of the da Vinci® system. Advanced technological advantages of the da Vinci® system compared with standard laparoscopic colorectal surgery have been reported. These are a stable camera platform, three-dimensional imaging, excellent ergonomics, tremor elimination, ambidextrous capability, motion scaling, and instruments with multiple degrees of freedom. However, despite these technological advantages, most studies did not report the clinical advantages of robotic colorectal surgery compared to standard laparoscopic colorectal surgery. Only one study recently implies the real benefits of robotic rectal cancer surgery. The purpose of this review article is to outline the early concerns of robotic colorectal surgery using the da Vinci® system, to present early clinical outcomes from the most current series, and to discuss not only the safety and the feasibility but also the real benefits of robotic colorectal surgery. Moreover, this article will comment on the possible future clinical advantages and limitations of the da Vinci® system in robotic colorectal surgery. PMID:19108010

On the structure of cellular solutions in Rayleigh-Benard-Marangoni flows in small-aspect-ratio containers

NASA Technical Reports Server (NTRS)

Dijkstra, Henk A.

1992-01-01

Multiple steady flow patterns occur in surface-tension/buoyancy-driven convection in a liquid layer heated from below (Rayleigh-Benard-Marangoni flows). Techniques of numerical bifurcation theory are used to study the multiplicity and stability of two-dimensional steady flow patterns (rolls) in rectangular small-aspect-ratio containers as the aspect ratio is varied. For pure Marangoni flows at moderate Biot and Prandtl number, the transitions occurring when paths of codimension 1 singularities intersect determine to a large extent the multiplicity of stable patterns. These transitions also lead, for example, to Hopf bifurcations and stable periodic flows for a small range in aspect ratio. The influence of the type of lateral walls on the multiplicity of steady states is considered. 'No-slip' lateral walls lead to hysteresis effects and typically restrict the number of stable flow patterns (with respect to 'slippery' sidewalls) through the occurrence of saddle node bifurcations. In this way 'no-slip' sidewalls induce a selection of certain patterns, which typically have the largest Nusselt number, through secondary bifurcation.

Wide Awake and Ready to Move: 20 Years of Non-Viral Therapeutic Genome Engineering with the Sleeping Beauty Transposon System.

PubMed

Hodge, Russ; Narayanavari, Suneel A; Izsvák, Zsuzsanna; Ivics, Zoltán

2017-10-01

Gene therapies will only become a widespread tool in the clinical treatment of human diseases with the advent of gene transfer vectors that integrate genetic information stably, safely, effectively, and economically. Two decades after the discovery of the Sleeping Beauty (SB) transposon, it has been transformed into a vector system that is fulfilling these requirements. SB may well overcome some of the limitations associated with viral gene transfer vectors and transient non-viral gene delivery approaches that are being used in the majority of ongoing clinical trials. The SB system has achieved a high level of stable gene transfer and sustained transgene expression in multiple primary human somatic cell types, representing crucial steps that may permit its clinical use in the near future. This article reviews the most important aspects of SB as a tool for gene therapy, including aspects of its vectorization and genomic integration. As an illustration, the clinical development of the SB system toward gene therapy of age-related macular degeneration and cancer immunotherapy is highlighted.

Comparing compound-specific and bulk stable nitrogen isotope trophic discrimination factors across multiple freshwater fish species and diets

USDA-ARS?s Scientific Manuscript database

The use of nitrogen stable isotopes for estimation of animal trophic position has become an indispensable approach in food web ecology. Compound-specific isotope analysis of amino acids is a new approach for estimating trophic position that may overcome key issues associated with nitrogen stable iso...

Fingolimod inhibits brain atrophy and promotes brain-derived neurotrophic factor in an animal model of multiple sclerosis.

PubMed

Smith, Paul A; Schmid, Cindy; Zurbruegg, Stefan; Jivkov, Magali; Doelemeyer, Arno; Theil, Diethilde; Dubost, Valérie; Beckmann, Nicolau

2018-05-15

Longitudinal brain atrophy quantification is a critical efficacy measurement in multiple sclerosis (MS) clinical trials and the determination of No Evidence of Disease Activity (NEDA). Utilising fingolimod as a clinically validated therapy we evaluated the use of repeated brain tissue volume measures during chronic experimental autoimmune encephalomyelitis (EAE) as a new preclinical efficacy measure. Brain volume changes were quantified using magnetic resonance imaging (MRI) at 7 Tesla and correlated to treatment-induced brain derived neurotrophic factor (BDNF) measured in blood, cerebrospinal fluid, spinal cord and brain. Serial brain MRI measurements revealed slow progressive brain volume loss in vehicle treated EAE mice despite a stable clinical score. Fingolimod (1 mg/kg) significantly ameliorated brain tissue atrophy in the cerebellum and striatum when administered from established EAE disease onwards. Fingolimod-dependent tissue preservation was associated with induction of BDNF specifically within the brain and co-localized with neuronal soma. In contrast, therapeutic teriflunomide (3 mg/kg) treatment failed to inhibit CNS autoimmune mediated brain degeneration. Finally, weekly anti-IL-17A antibody (15 mg/kg) treatment was highly efficacious and preserved whole brain, cerebellum and striatum volume. Fingolimod-mediated BDNF increases within the CNS may contribute to limiting progressive tissue loss during chronic neuroinflammation. Copyright © 2018 Elsevier B.V. All rights reserved.

Phase I Study of Anti-GM2 Ganglioside Monoclonal Antibody BIW-8962 as Monotherapy in Patients with Previously Treated Multiple Myeloma.

PubMed

Baz, Rachid C; Zonder, Jeffrey A; Gasparetto, Cristina; Reu, Frederic J; Strout, Vincent

2016-01-01

BIW-8962 is a monoclonal antibody to GM2 ganglioside that shows preclinical activity towards multiple myeloma (MM) cell lines and in animal models bearing MM xenografts. The objective of this study was to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, potential immunogenicity, and preliminary clinical efficacy of BIW-8962 in patients with heavily pretreated MM. Patients ( n  = 23) received escalating doses of BIW-8962 (0.03-3 mg/kg) intravenously every 2 weeks in phase Ia. The highest anticipated dose (10 mg/kg) was not tested and the study was discontinued without proceeding to phases Ib and II. The MTD of BIW-8962 was not established and BIW-8962 was relatively well tolerated. No pattern of consistent toxicity could be inferred from treatment-related AEs grade ≥3 and only two dose-limiting toxicities were recorded (atrial thrombosis + cardiomyopathy and chest pain, respectively). In the efficacy evaluable population ( n  = 22), no patient had a response (complete or partial) and 16 (72.7%) had a best response of stable disease, which was generally not durable. BIW-8962 did not show evidence of clinical activity. The study was therefore stopped and further development of BIW-8962 in MM was halted. This work was funded by Kyowa Kirin Pharmaceutical Development, Inc. ClinicalTrials.gov identifier, NCT00775502.

Multiple stable states of a periodically driven electron spin in a quantum dot using circularly polarized light

NASA Astrophysics Data System (ADS)

Korenev, V. L.

2011-06-01

The periodical modulation of circularly polarized light with a frequency close to the electron spin resonance frequency induces a sharp change of the single electron spin orientation. Hyperfine interaction provides a feedback, thus fixing the precession frequency of the electron spin in the external and the Overhauser field near the modulation frequency. The nuclear polarization is bidirectional and the electron-nuclear spin system (ENSS) possesses a few stable states. The same physics underlie the frequency-locking effect for two-color and mode-locked excitations. However, the pulsed excitation with mode-locked laser brings about the multitudes of stable states in ENSS in a quantum dot. The resulting precession frequencies of the electron spin differ in these states by the multiple of the modulation frequency. Under such conditions ENSS represents a digital frequency converter with more than 100 stable channels.

Prospective Analysis of Behavioral Economic Predictors of Stable Moderation Drinking Among Problem Drinkers Attempting Natural Recovery.

PubMed

Tucker, Jalie A; Cheong, JeeWon; Chandler, Susan D; Lambert, Brice H; Pietrzak, Brittney; Kwok, Heather; Davies, Susan L

2016-12-01

As interventions have expanded beyond clinical treatment to include brief interventions for persons with less severe alcohol problems, predicting who can achieve stable moderation drinking has gained importance. Recent behavioral economic (BE) research on natural recovery has shown that active problem drinkers who allocate their monetary expenditures on alcohol and saving for the future over longer time horizons tend to have better subsequent recovery outcomes, including maintenance of stable moderation drinking. This study compared the predictive utility of this money-based "Alcohol-Savings Discretionary Expenditure" (ASDE) index with multiple BE analogue measures of behavioral impulsivity and self-control, which have seldom been investigated together, to predict outcomes of natural recovery attempts. Community-dwelling problem drinkers, enrolled shortly after stopping abusive drinking without treatment, were followed prospectively for up to a year (N = 175 [75.4% male], M age = 50.65 years). They completed baseline assessments of preresolution drinking practices and problems, analogue behavioral choice tasks (Delay Discounting, Melioration-Maximization, and Alcohol Purchase Tasks), and a Timeline Followback interview including expenditures on alcohol compared to voluntary savings (ASDE index) during the preresolution year. Multinomial logistic regression models showed that, among the BE measures, only the ASDE index predicted stable moderation drinking compared to stable abstinence or unstable resolutions involving relapse. As hypothesized, stable moderation was associated with more balanced preresolution allocations to drinking and savings (odds ratio = 1.77, 95% confidence interval = 1.02 to 3.08, p < 0.05), suggesting it is associated with longer-term behavior regulation processes than abstinence. The ASDE's unique predictive utility may rest on its comprehensive representation of contextual elements to support this patterning of behavioral allocation. Stable low-risk drinking, but not abstinence, requires such regulatory processes. Copyright © 2016 by the Research Society on Alcoholism.

Cost-effectiveness of subdermal implantable buprenorphine versus sublingual buprenorphine to treat opioid use disorder.

PubMed

Carter, John A; Dammerman, Ryan; Frost, Michael

2017-08-01

Subdermal implantable buprenorphine (BSI) was recently approved to treat opioid use disorder (OUD) in clinically-stable adults. In the pivotal clinical trial, BSI was associated with a higher proportion of completely-abstinent patients (85.7% vs 71.9%; p = .03) vs sublingual buprenorphine (SL-BPN). Elsewhere, relapse to illicit drug use is associated with diminished treatment outcomes and increased costs. This study evaluated the cost-effectiveness of BSI vs SL-BPN from a US societal perspective. A Markov model simulated BSI and SL-BPN cohorts (clinically-stable adults) transiting through four mutually-exclusive health states for 12 months. Cohorts accumulated direct medical costs from drug acquisition/administration; treatment-diversion/abuse; newly-acquired hepatitis-C; emergency room, hospital, and rehabilitation services; and pediatric poisonings. Non-medical costs of criminality, lost wages/work-productivity, and out-of-pocket expenses were also included. Transition probabilities to a relapsed state were derived from the aforementioned trial. Other transition probabilities, costs, and health-state utilities were derived from observational studies and adjusted for trial characteristics. Outcomes included incremental cost per quality-adjusted-life-year (QALY) gained and incremental net-monetary-benefit (INMB). Uncertainty was assessed by univariate and probabilistic sensitivity analysis (PSA). BSI was associated with lower total costs (-$4,386), more QALYs (+0.031), and favorable INMB at all willingness-to-pay (WTP) thresholds considered. Higher drug acquisition costs for BSI (+$6,492) were outpaced, primarily by reductions in emergency room/hospital utilization (-$8,040) and criminality (-$1,212). BSI was cost-effective in 89% of PSA model replicates, and had a significantly higher NMB at $50,000/QALY ($20,783 vs $15,007; p < .05). BSI was preferred over SL-BPN from a health-economic perspective for treatment of OUD in clinically-stable adults. These findings should be interpreted carefully, due to some relationships having been modeled from inputs derived from multiple sources, and would benefit from comparison with outcomes from studies that employ administrative claims data or a naturalistic comparative design.

Coexistence of Multiple Attractors in an Active Diode Pair Based Chua’s Circuit

NASA Astrophysics Data System (ADS)

Bao, Bocheng; Wu, Huagan; Xu, Li; Chen, Mo; Hu, Wen

This paper focuses on the coexistence of multiple attractors in an active diode pair based Chua’s circuit with smooth nonlinearity. With dimensionless equations, dynamical properties, including boundness of system orbits and stability distributions of two nonzero equilibrium points, are investigated, and complex coexisting behaviors of multiple kinds of disconnected attractors of stable point attractors, limit cycles and chaotic attractors are numerically revealed. The results show that unlike the classical Chua’s circuit, the proposed circuit has two stable nonzero node-foci for the specified circuit parameters, thereby resulting in the emergence of multistability phenomenon. Based on two general impedance converters, the active diode pair based Chua’s circuit with an adjustable inductor and an adjustable capacitor is made in hardware, from which coexisting multiple attractors are conveniently captured.

Modest rise in chlamydia and gonorrhoea testing did not increase case detection in a clinical HIV cohort in Ontario, Canada

PubMed Central

Burchell, Ann N; Grewal, Ramandip; Allen, Vanessa G; Gardner, Sandra L; Moravan, Veronika; Bayoumi, Ahmed M; Kaul, Rupert; McGee, Frank; Millson, Margaret (Peggy) E; Remis, Robert S; Raboud, Janet; Mazzulli, Tony; Rourke, Sean B

2014-01-01

Objectives We described patterns of testing for chlamydia and gonorrhoea infection among persons in specialty HIV care in Ontario, Canada, from 2008 to 2011. Methods We analysed data from 3165 participants in the OHTN Cohort Study attending one of seven specialty HIV care clinics. We obtained chlamydia and gonorrhoea test results via record linkage with the provincial public health laboratory. We estimated the proportion of participants who underwent testing annually, the positivity rate among those tested and the proportion diagnosed with chlamydia or gonorrhoea among all under observation. We explored risk factors for testing and diagnosis using multiple logistic regression analysis. Results The proportion tested annually rose from 15.2% (95% CI 13.6% to 16.7%) in 2008 to 27.0% (95% CI 25.3% to 28.6%) in 2011 (p<0.0001). Virtually all were urine-based nucleic acid amplification tests. Testing was more common among men who have sex with men (MSM), younger adults, Toronto residents, persons attending primary care clinics and persons who had tested in the previous year or who had more clinic visits in the current year. We observed a decrease in test positivity rates over time. However, the annual proportion diagnosed remained stable and in 2011 this was 0.97% (95% CI 0.61% to 1.3%) and 0.79% (95% CI 0.46% to 1.1%) for chlamydia and gonorrhoea, respectively. Virtually all cases were among MSM. Conclusions Chlamydia and gonorrhoea testing increased over time while test positivity rates declined and the overall proportion diagnosed remained stable, suggesting that the modest increase in testing did not improve case detection. PMID:25178285

Measuring influenza RNA quantity after prolonged storage or multiple freeze/thaw cycles.

PubMed

Granados, Andrea; Petrich, Astrid; McGeer, Allison; Gubbay, Jonathan B

2017-09-01

In this study, we aim to determine what effects prolonged storage and repeated freeze/thaw cycles have on the stability of influenza A(H1N1)pdm09 (influenza A/H1N1)RNA. Cloned influenza A/H1N1 RNA transcripts were serially diluted from 8.0-1.0 log 10 copies/μl. RT-qPCR was used to measure RNA loss in transcripts stored at -80°C, -20°C, 4°C and 25°C for up to 84days or transcripts undergoing a total of 10 freeze/thaw cycles. Viral load was measured in clinical specimens stored at-80°C for three years (n=89 influenza A RNA extracts; n=35 primary specimens) and in 10 clinical specimens from the 2015/2016 influenza season that underwent 7 freeze/thaw cycles. RNA stored at -80°C, -20°C, 4°C and 25°C is stable for up to 56, 56, 21, and 7days respectively or up to 9 freeze/thaw cycles when stored at -80°C. There is no difference in viral load in clinical specimens that have been stored for up to three years at -80°C if they are re-extracted. Similarly, clinical specimens undergoing up to 7 freeze/thaw cycles are stable if they are re-extracted between cycles. Influenza specimens can be stored for up to three years at -80°C or undergo up to 7 freeze/thaw cycles without loss of RNA quantity if re-extracted. Copyright © 2017 Elsevier B.V. All rights reserved.

Long-Term Natural Course of Small Nonfunctional Pancreatic Neuroendocrine Tumors in MEN1-Results From the Dutch MEN1 Study Group.

PubMed

Pieterman, Carolina R C; de Laat, Joanne M; Twisk, Jos W R; van Leeuwaarde, Rachel S; de Herder, Wouter W; Dreijerink, Koen M A; Hermus, Ad R M M; Dekkers, Olaf M; van der Horst-Schrivers, Anouk N A; Drent, Madeleine L; Bisschop, Peter H; Havekes, Bastiaan; Borel Rinkes, Inne H M; Vriens, Menno R; Valk, Gerlof D

2017-10-01

Pancreatic neuroendocrine tumors (pNETs) are highly prevalent in patients with multiple endocrine neoplasia type 1 (MEN1), and metastatic disease is an important cause of MEN1-related mortality. Especially small nonfunctional (NF) pNETs pose a challenge to the treating physician and more information is needed regarding their natural course. We assessed long-term natural history of small NF-pNETs and its modifiers in the Dutch MEN1 population. Retrospective longitudinal observational cohort study of patients with small (<2 cm) NF-pNETs from the Dutch national MEN1 database, which includes >90% of the Dutch MEN1 population. Modifiers of long-term natural course were analyzed using linear mixed-models analysis. Growth rate of the 115 included small NF-pNETs from 99 patients was slow (0.4 mm/y; 95% confidence interval, 0.15 to 0.59). Seventy percent of the tumors was stable and a subgroup of 30% of the tumors was growing (1.6 mm/y; 95% confidence interval, 1.1 to 2.0). No differences in clinical characteristics were identified between growing and stable tumors. Within the subgroup of growing tumors, germline missense mutations were significantly associated with accelerated growth compared with nonsense and frameshift mutations. The majority of small NF-pNETs are stable at long-term follow-up, irrespective of the underlying MEN1 genotype. A subgroup of tumors is slowly growing but cannot be identified on clinical grounds. In this subgroup, tumors with missense mutations exhibited faster growth. Additional events appear necessary for pNETs to progress. Future studies should be aimed at identifying these molecular driving events, which could be used as potential biomarkers. Copyright © 2017 Endocrine Society

STABLE ISOTOPES IN ECOLOGICAL STUDIES: NEW DEVELOPMENTS IN MIXING MODELS

EPA Science Inventory

Stable isotopes are increasingly being used as tracers in ecological studies. One application uses isotopic ratios to quantify the proportional contributions of multiple sources to a mixture. Examples include food sources for animals, water sources for plants, pollution sources...

Pilot clinical study of boron neutron capture therapy for recurrent hepatic cancer involving the intra-arterial injection of a (10)BSH-containing WOW emulsion.

PubMed

Yanagie, Hironobu; Higashi, Syushi; Seguchi, Koji; Ikushima, Ichiro; Fujihara, Mituteru; Nonaka, Yasumasa; Oyama, Kazuyuki; Maruyama, Syoji; Hatae, Ryo; Suzuki, Minoru; Masunaga, Shin-ichiro; Kinashi, Tomoko; Sakurai, Yoshinori; Tanaka, Hiroki; Kondo, Natsuko; Narabayashi, Masaru; Kajiyama, Tetsuya; Maruhashi, Akira; Ono, Koji; Nakajima, Jun; Ono, Minoru; Takahashi, Hiroyuki; Eriguchi, Masazumi

2014-06-01

A 63-year-old man with multiple HCC in his left liver lobe was enrolled as the first patient in a pilot study of boron neutron capture therapy (BNCT) involving the selective intra-arterial infusion of a (10)BSH-containing water-in-oil-in-water emulsion ((10)BSH-WOW). The size of the tumorous region remained stable during the 3 months after the BNCT. No adverse effects of the BNCT were observed. The present results show that (10)BSH-WOW can be used as novel intra-arterial boron carriers during BNCT for HCC. Copyright © 2014 Elsevier Ltd. All rights reserved.

Computed Tomography (CT) Imaging of Injuries from Blunt Abdominal Trauma: A Pictorial Essay.

PubMed

Hassan, Radhiana; Abd Aziz, Azian

2010-04-01

Blunt abdominal trauma can cause multiple internal injuries. However, these injuries are often difficult to accurately evaluate, particularly in the presence of more obvious external injuries. Computed tomography (CT) imaging is currently used to assess clinically stable patients with blunt abdominal trauma. CT can provide a rapid and accurate appraisal of the abdominal viscera, retroperitoneum and abdominal wall, as well as a limited assessment of the lower thoracic region and bony pelvis. This paper presents examples of various injuries in trauma patients depicted in abdominal CT images. We hope these images provide a resource for radiologists, surgeons and medical officers, as well as a learning tool for medical students.

Three years of experience: the Italian registry and safety data update.

PubMed

Mancardi, G L; Tedeschi, G; Amato, M P; D'Alessandro, R; Drago, F; Milanese, C; Popoli, P; Rossi, P; Savettieri, G; Tola, M R; Comi, G; Pozzilli, C; Bertolotto, A; Marrosu, M G; Grimaldi, L M E; Laroni, A; Vanacore, N; Covezzoli, A; De Rosa, M; Piccinni, C; Montanaro, N; Periotto, L; Iommelli, R; Tomino, C; Provinciali, L

2011-01-01

At the end of 2006, a pharmacovigilance program on natalizumab was settled by the Italian Pharmaceutical Agency, and on January 2007, multiple sclerosis patients poorly responding to the immunomodulating therapies or with an aggressive clinical form of disease from onset initiated to be registered and to receive the medication. On February 2010, almost 3,000 cases have been treated with natalizumab. The drop-out rate is 10%. Almost 800 cases received cycles of natalizumab for more than 18 months. One case of PML was reported and other adverse events are similar to those described in phase III studies. The majority of cases remained stable, while in 25% of cases, an improvement of disability was documented.

Design and operation of a continuous 13C and 15N labeling chamber for uniform or differential, metabolic and structural, plant tissue isotope labeling

USDA-ARS?s Scientific Manuscript database

Tracing heavy stable isotopes from plant material through the ecosystem provides the most sensitive information about ecosystem processes; from CO2 fluxes and soil organic matter formation to small-scale stable-isotope biomarker probing. Coupling multiple stable isotopes such as 13C with 15N, 18O o...

Plaque disruption by coronary computed tomographic angiography in stable patients vs. acute coronary syndrome: a feasibility study.

PubMed

Bilolikar, Abhay N; Goldstein, James A; Madder, Ryan D; Chinnaiyan, Kavitha M

2016-03-01

This study was designed to determine whether coronary CT angiography (CTA) can detect features of plaque disruption in clinically stable patients and to compare lesion prevalence and features between stable patients and those with acute coronary syndrome (ACS). We retrospectively identified patients undergoing CTA, followed by invasive coronary angiography (ICA) within 60 days. Quantitative 3-vessel CTA lesion analysis was performed on all plaques ≥25% stenosis to assess total plaque volume, low attenuation plaque (LAP, <50 HU) volume, and remodelling index. Plaques were qualitatively assessed for CTA features of disruption, including ulceration and intra-plaque dye penetration (IDP). ICA was employed as a reference standard for disruption. A total of 145 (94 ACS and 51 stable) patients were identified. By CTA, plaque disruption was evident in 77.7% of ACS cases. Although more common among those with ACS, CTA also detected plaque disruption in 37.3% of clinically stable patients (P < 0.0001). Clinically stable patients commonly manifest plaques with features of disruption as determined by CTA. Though the prevalence of plaque disruption is less than patients with ACS, these findings support the concept that some clinically stable patients may harbour 'silent' disrupted plaques. These findings may have implications for detection of 'at risk' plaques and patients. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Disease modifying drugs modulate endogenous secretory receptor for advanced glycation end-products, a new biomarker of clinical relapse in multiple sclerosis.

PubMed

Sternberg, Zohara; Sternberg, Daniel; Drake, Allison; Chichelli, Trevor; Yu, Jinhee; Hojnacki, David

2014-09-15

This study is one in a series measuring RAGE axis (receptor for advanced glycation end products, its isoforms, and ligands) and its potential as a biomarker in multiple sclerosis (MS). We evaluated serum levels of the endogenous secretory RAGE (esRAGE) in MS patients and assessed the relationship between esRAGE levels and the use of disease modifying drugs (DMDs), and between esRAGE levels and indicators of MS disease severity. esRAGE serum levels were compared between 98 MS patients and 34 healthy controls (HCs) using ELISA. esRAGE serum levels were similar between MS and HCs. DMD-treated patients had higher esRAGE serum levels than DMD-naïve patients (395.7±38.6pg/ml vs. 299.2±20.1pg/ml, P=0.02). DMD-naïve, primary progressive (PP) patients had higher esRAGE serum levels, than relapsing remitting (RR) (P=0.02) and secondary progressive (SP) (P=0.04) patients; RRMS patients in clinical relapse had lower esRAGE serum levels than clinically stable patients (219.7±30.0pg/ml vs. 338.2±31.6pg/ml, P=0.02). In a univariate regression analysis of DMD-naïve MS patients, esRAGE serum levels inversely correlated with the rate of clinical relapse (r=-0.44, P=0.006), MS severity scale (MSSS) (r=-0.32, P=0.03), and expanded disability status scale (EDSS) (r=-0.251, P=0.07). esRAGE serum levels are modulated by DMDs. The serum levels may be a useful biomarker of MS clinical relapse. Published by Elsevier B.V.

Pharmacogenomics and Efficacy of Risperidone Long-Term Treatment in Thai Autistic Children and Adolescents.

PubMed

Nuntamool, Nopphadol; Ngamsamut, Nattawat; Vanwong, Natchaya; Puangpetch, Apichaya; Chamnanphon, Monpat; Hongkaew, Yaowaluck; Limsila, Penkhae; Suthisisang, Chuthamanee; Wilffert, Bob; Sukasem, Chonlaphat

2017-10-01

The purpose of this study was to evaluate the association of pharmacogenomic factors and clinical outcome in autistic children and adolescents who were treated with risperidone for long periods. Eighty-two autistic subjects diagnosed with DSM-IV and who were treated with risperidone for more than 1 year were recruited. Pharmacogenomics and clinical outcome (CGI-I, aggressive, overactivity and repetitive score) were evaluated. Almost all patients showed stable symptoms on aggressive behaviour (89.02%), overactivity (71.95%), repetitive (70.89%) behaviour and all clinical symptoms (81.71%). Only 4.48% of patients showed minimally worse CGI-I score. Patients in the non-stable symptom group had DRD2 Taq1A non-wild-type (TT and CT) frequencies higher than the clinically stable group (p = 0.04), whereas other gene polymorphisms showed no significant association. Haplotype ACCTCAT (rs6311, rs1045642, rs1128503, rs1800497, rs4436578, rs1799978, rs6280) showed a significant association with non-stable clinical outcome (χ 2  = 6.642, p = 0.010). Risperidone levels showed no association with any clinical outcome. On the other hand, risperidone dose, 9-OH risperidone levels and prolactin levels were significantly higher in the non-stable compared to the stable symptom group (p = 0.013, p = 0.044, p = 0.030). Increased appetite was the most common adverse drug reaction and associated with higher body-weight, whereas it was not significantly associated with genetic variations and non-genetic information. In conclusion, risperidone showed efficacy to control autism, especially aggressive symptoms in long-term treatment. However, Taq1A T - carrier of dopamine 2 receptor gene - is associated with non-stable response in risperidone-treated patients. This study supports pharmacogenomics testing for personalized therapy with risperidone in autistic children and adolescents. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Microcanonical molecular simulations of methane hydrate nucleation and growth: evidence that direct nucleation to sI hydrate is among the multiple nucleation pathways.

PubMed

Zhang, Zhengcai; Walsh, Matthew R; Guo, Guang-Jun

2015-04-14

The results of six high-precision constant energy molecular dynamics (MD) simulations initiated from methane-water systems equilibrated at 80 MPa and 250 K indicate that methane hydrates can nucleate via multiple pathways. Five trajectories nucleate to an amorphous solid. One trajectory nucleates to a structure-I hydrate template with long-range order which spans the simulation box across periodic boundaries despite the presence of several defects. While experimental and simulation data for hydrate nucleation with different time- and length-scales suggest that there may exist multiple pathways for nucleation, including metastable intermediates and the direct formation of the globally-stable phase, this work provides the most compelling evidence that direct formation to the globally stable crystalline phase is one of the multiple pathways available for hydrate nucleation.

STABLE ISOTOPES IN ECOLOGICAL STUDIES: NEW DEVELOPMENTS IN MIXING MODELS (URUGUAY)

EPA Science Inventory

Stable isotopes are increasingly being used as tracers in ecological studies. One application uses isotopic ratios to quantify the proportional contributions of multiple sources to a mixture. Examples include pollution sources for air or water bodies, food sources for animals, ...

STABLE ISOTOPES IN ECOLOGICAL STUDIES: NEW DEVELOPMENTS IN MIXING MODELS (BRAZIL)

EPA Science Inventory

Stable isotopes are increasingly being used as tracers in ecological studies. One application uses isotopic ratios to quantify the proportional contributions of multiple sources to a mixture. Examples include pollution sources for air or water bodies, food sources for animals, ...

Long-Term Survival in a Patient with Multiple Brain Metastases from Small-Cell Lung Cancer Treated with Gamma Knife Radiosurgery on Four Occasions: A Case Report

PubMed Central

Elaimy, Ameer L.; Thumma, Sudheer R.; Lamm, Andrew F.; Mackay, Alexander R.; Lamoreaux, Wayne T.; Fairbanks, Robert K.; Demakas, John J.; Cooke, Barton S.; Lee, Christopher M.

2012-01-01

Brain metastases are the most common cancerous neoplasm in the brain. The treatment of these lesions is challenging and often includes a multimodality management approach with whole-brain radiation therapy, stereotactic radiosurgery, and neurosurgery options. Although advances in biomedical imaging technologies and the treatment of extracranial cancer have led to the overall increase in the survival of brain metastases patients, the finding that select patients survive several years remains puzzling. For this reason, we present the case of a 70-year-old patient who was diagnosed with multiple brain metastases from small-cell lung cancer five years ago and is currently alive following treatment with chemotherapy for the primary cancer and whole-brain radiation therapy and Gamma Knife radiosurgery on four separate occasions for the neurological cancer. Since the diagnosis of brain metastases five years ago, the patient's primary cancer has remained controlled. Furthermore, multiple repeat GKRS procedures provided this patient with high levels of local tumor control, which in combination with a stable primary cancer led to an extended period of survival and a highly functional life. Further analysis and clinical research will be valuable in assessing the durability of multiple GKRS for brain metastases patients who experience long-term survival. PMID:23091748

Application of stable isotope tools for evaluating natural and stimulated biodegradation of organic pollutants in field studies.

PubMed

Fischer, Anko; Manefield, Mike; Bombach, Petra

2016-10-01

Stable isotope tools are increasingly applied for in-depth evaluation of biodegradation of organic pollutants at contaminated field sites. They can be divided into three methods i) determination of changes in natural abundance of stable isotopes using compound-specific stable isotope analysis (CSIA), ii) detection of incorporation of stable-isotope label from a stable-isotope labelled target compound into degradation and/or mineralisation products and iii) determination of stable-isotope label incorporation into biomarkers using stable isotope probing (SIP). Stable isotope tools have been applied as key monitoring tools for multiple-line-of-evidence-approaches (MLEA) for sensitive evaluation of pollutant biodegradation. This review highlights the application of CSIA, SIP and MLEA including stable isotope tools for assessing natural and stimulated biodegradation of organic pollutants in field studies dealing with soil and groundwater contaminations. Copyright © 2016 Elsevier Ltd. All rights reserved.

Comparing Multiple Criteria for Species Identification in Two Recently Diverged Seabirds

PubMed Central

Militão, Teresa; Gómez-Díaz, Elena; Kaliontzopoulou, Antigoni; González-Solís, Jacob

2014-01-01

Correct species identification is a crucial issue in systematics with key implications for prioritising conservation effort. However, it can be particularly challenging in recently diverged species due to their strong similarity and relatedness. In such cases, species identification requires multiple and integrative approaches. In this study we used multiple criteria, namely plumage colouration, biometric measurements, geometric morphometrics, stable isotopes analysis (SIA) and genetics (mtDNA), to identify the species of 107 bycatch birds from two closely related seabird species, the Balearic (Puffinus mauretanicus) and Yelkouan (P. yelkouan) shearwaters. Biometric measurements, stable isotopes and genetic data produced two stable clusters of bycatch birds matching the two study species, as indicated by reference birds of known origin. Geometric morphometrics was excluded as a species identification criterion since the two clusters were not stable. The combination of plumage colouration, linear biometrics, stable isotope and genetic criteria was crucial to infer the species of 103 of the bycatch specimens. In the present study, particularly SIA emerged as a powerful criterion for species identification, but temporal stability of the isotopic values is critical for this purpose. Indeed, we found some variability in stable isotope values over the years within each species, but species differences explained most of the variance in the isotopic data. Yet this result pinpoints the importance of examining sources of variability in the isotopic data in a case-by-case basis prior to the cross-application of the SIA approach to other species. Our findings illustrate how the integration of several methodological approaches can help to correctly identify individuals from recently diverged species, as each criterion measures different biological phenomena and species divergence is not expressed simultaneously in all biological traits. PMID:25541978

Deformable microparticles with multiple functions for drug delivery and device testing

NASA Astrophysics Data System (ADS)

Thula, Taili T.

Since the HIV epidemic of the 1990s, researchers have attempted to develop a red blood cell analog. Even though some of these substitutes are now in Phase III of clinical trials, their use is limited by side effects and short half-life in the human body. As a result, there is still a need for an effective erythrocyte analog with minimum immunogenic and side effects, so that it can be used for multiple applications. Finding new approaches to develop more efficient blood substitutes will not only bring valuable advances in the clinical approach, but also in the area of in vitro testing of medical devices. We examined the feasibility of creating a deformable multi-functional, biodegradable, biocompatible particle for applications in drug delivery and device testing. As a preliminary evaluation, we synthesized different types of microcapsules using natural and synthetic polymers, various cross-linking agents, and diverse manufacturing techniques. After fully characterizing of each system, we determined the most promising red blood cell analog in terms of deformability, stability and toxicity. We also examined the encapsulation and release of bovine serum albumin (BSA) within these deformable particles. After removal of cross-linkers, zinc- and copper-alginate microparticles surrounded by multiple polyelectrolyte layers of chitosan oligosaccharide and alginate were deformable and remained stable under physiological pressures applied by the micropipette technique. In addition, multiple coatings decreased toxicity of heavy-metal crosslinked particles. BSA encapsulation and release from chitosan-alginate microspheres were contingent on the crosslinker and number of polyelectrolyte coatings, respectively. Further rheological studies are needed to determine how closely these particles simulate the behavior of erythrocytes. Also, studies on the encapsulation and release of different proteins, including hemoglobin, are needed to establish the desired controlled release of bioactive agents for the proposed delivery system.

Passive band-gap reconfiguration born from bifurcation asymmetry.

PubMed

Bernard, Brian P; Mann, Brian P

2013-11-01

Current periodic structures are constrained to have fixed energy transmission behavior unless active control or component replacement is used to alter their wave propagation characteristics. The introduction of nonlinearity to generate multiple stable equilibria is an alternative strategy for realizing distinct energy propagation behaviors. We investigate the creation of a reconfigurable band-gap system by implementing passive switching between multiple stable states of equilibrium, to alter the level of energy attenuation in response to environmental stimuli. The ability to avoid potentially catastrophic loads is demonstrated by tailoring the bandpass and band-gap regions to coalesce for two stable equilibria and varying an external load parameter to trigger a bifurcation. The proposed phenomenon could be utilized in remote or autonomous applications where component modifications and active control are impractical.

Hemoglobin Threshold for Blood Transfusion in a Pediatric Intensive Care Unit.

PubMed

Chegondi, Madhuradhar; Sasaki, Jun; Raszynski, André; Totapally, Balagangadhar R

2016-07-01

To evaluate the hemoglobin threshold for red cell transfusion in children admitted to a pediatric intensive care unit (PICU). Retrospective chart review study. Tertiary care PICU. Critically ill pediatric patients requiring blood transfusion. No intervention. We analyzed the charts of all children between 1 month and 21 years of age who received packed red blood cell (PRBC) transfusions during a 2-year period. The target patients were identified from our blood bank database. For analysis, the patients were subdivided into four groups: acute blood loss (postsurgically, trauma, or acute gastrointestinal bleeding from other causes), hematologic (hematologic malignancies, bone marrow suppression, hemolytic anemia, or sickle cell disease), unstable (FiO 2 > 0.6 and/or on inotropic support), and stable groups. We also compared the pre-transfusion hemoglobin threshold in all unstable patients with that of all stable patients. A total of 571 transfusion episodes in 284 patients were analyzed. 28% (n = 160) of transfusions were administered to patients in the acute blood loss group, 36% (n = 206) to hematologic patients, 17% (n = 99) to unstable patients, and 18% (n = 106) to stable patients. The mean pre-transfusion hemoglobin (± SD) in all children as well as in the acute blood loss, hematologic, unstable and stable groups was 7.3 ± 1.20, 7.83 ± 1.32, 6.97 ± 1.31, 7.96 ± 1.37, 7.31 ± 1.09 g/dl, respectively. The transfusion threshold for acute blood loss and unstable groups was higher compared to hematologic and stable groups (p < 0.001; ANOVA with multiple comparisons). The mean pre-transfusion hemoglobin threshold for stable and unstable patients among all groups was 7.3 ± 1.3 and 7.9 ± 1.3 (p < 0.0001), respectively. The observed mortality rate was higher among children who received transfusion compared to other children admitted to PICU. The hemoglobin threshold for transfusion varied according to clinical conditions. Overall, the hemoglobin threshold for transfusion was 7.3 ± 1.20 g/dl.

Identifying employed multiple sclerosis patients at-risk for job loss: When do negative work events pose a threat?

PubMed

Kordovski, Victoria M; Frndak, Seth E; Fisher, Carrie S; Rodgers, Jonathan; Weinstock-Guttman, Bianca; Benedict, Ralph H B

2015-09-01

Physical disability and cognitive impairment are significant predictors of unemployment in multiple sclerosis (MS). However, little is known about the frequency of work problems in employed patients, in comparison to employed healthy persons. Use an online monitoring tool to compare the frequency of negative work events in MS patients and healthy controls, and determine a threshold at which the frequency of work problems is clinically meaningful. The sample comprised 138 MS patients and 62 healthy controls. All reported on recent negative work events and accommodations using an online survey. The clinical test battery measured depression, motor and cognitive function. Statistical tests compared the frequency of work problems in MS patients and healthy controls. Clinical neuro-performance scales were then assessed in at-risk patients with many work problems, versus those with no work problems. As a group, employed MS patients exhibited deficits in motor ability, verbal memory, and processing speed and were more likely than controls to report negative work events and accommodations. At-risk patients, that is, those reporting more than one negative work event, had more pronounced motor and cognitive deficits than their relatively stable counterparts. The data show that employed MS patients report more negative work events and accommodations than employed healthy persons. Those patients deemed at risk for job loss have more cognitive and motor impairment, suggesting the need for cognitive training and specific accommodation strategies in the work place. Copyright © 2015 Elsevier B.V. All rights reserved.

Photonic Shape Memory Polymer with Stable Multiple Colors

PubMed Central

2017-01-01

A photonic shape memory polymer film that shows large color response (∼155 nm) in a wide temperature range has been fabricated from a semi-interpenetrating network of a cholesteric polymer and poly(benzyl acrylate). The large color response is achieved by mechanical embossing of the photonic film above its broad glass transition temperature. The embossed film, as it recovers to its original shape on heating through the broad thermal transition, exhibits multiple structural colors ranging from blue to orange. The relaxation behavior of the embossed film can be fully described using a Kelvin–Voigt model, which reveals that the influence of temperature on the generation of colors is much stronger than that of time, thereby producing stable multiple colors. PMID:28840717

Hepatic trauma management in polytraumatised patients.

PubMed

Pop, P Axentii; Pop, M; Iovan, C; Boancã, C

2012-01-01

The specialty literature of the last decade presents the nonoperative management of the closed abdominal trauma as the treatment of choice. The purpose of this study is to highlight the importance of the optimal management of hepatic lesions considering the clinical, paraclinical and therapeutic approach. Our study is based on the analysis of the clinical and paraclinical data and also on the evaluation of the treatment results in 1671 patients with abdominal trauma affecting multiple organs who were treated at the Clinic of Surgery, County Hospital of Oradea from 2008 to 2011. The non-operative approach of the hepatic trauma, applied in 52% of the patients, was indicated in stable hemodynamic status, non-bleeding hepatic lesions on the abdominal CT, and the absence of other significant abdominal lesions. The remaining 48% were treated surgically. The postoperative evolution was free of complications in 72% of the patients while the rest of 28% presented one or more postoperative complications. CT = Computer Tomography; ISS= Injury Severity Score; AIS = Abbreviated Index of Severity; AAST = American Association for the Surgery of Trauma; ARDS = Adult Respiratory Distress Syndrome. RevistaChirurgia.

Molecular profiling of single cancer cells and clinical tissue specimens with semiconductor quantum dots

PubMed Central

Xing, Yun; Smith, Andrew M; Agrawal, Amit; Ruan, Gang; Nie, Shuming

2006-01-01

Semiconductor quantum dots (QDs) are a new class of fluorescent labels with broad applications in biomedical imaging, disease diagnostics, and molecular and cell biology. In comparison with organic dyes and fluorescent proteins, quantum dots have unique optical and electronic properties such as size-tunable light emission, improved signal brightness, resistance against photobleaching, and simultaneous excitation of multiple fluorescence colors. Recent advances have led to multifunctional nanoparticle probes that are highly bright and stable under complex in vitro and in vivo conditions. New designs involve encapsulating luminescent QDs with amphiphilic block copolymers, and linking the polymer coating to tumor-targeting ligands and drug-delivery functionalities. These improved QDs have opened new possibilities for real-time imaging and tracking of molecular targets in living cells, for multiplexed analysis of biomolecular markers in clinical tissue specimens, and for ultrasensitive imaging of malignant tumors in living animal models. In this article, we briefly discuss recent developments in bioaffinity QD probes and their applications in molecular profiling of individual cancer cells and clinical tissue specimens. PMID:17722280

INCORPORATING CONCENTRATION DEPENDENCE IN STABLE ISOTOPE MIXING MODELS

EPA Science Inventory

Stable isotopes are frequently used to quantify the contributions of multiple sources to a mixture; e.g., C and N isotopic signatures can be used to determine the fraction of three food sources in a consumer's diet. The standard dual isotope, three source linear mixing model ass...

INCORPORATING CONCENTRATION DEPENDENCE IN STABLE ISOTOPE MIXING MODELS

EPA Science Inventory

Stable isotopes are often used as natural labels to quantify the contributions of multiple sources to a mixture. For example, C and N isotopic signatures can be used to determine the fraction of three food sources in a consumer's diet. The standard dual isotope, three source li...

Analysis on clinical characteristics of intracranial Arachnoid Cysts in 488 pediatric cases

PubMed Central

Huang, Jian-Huang; Mei, Wen-Zhong; Chen, Yao; Chen, Jian-Wu; Lin, Zhi-Xiong

2015-01-01

To summarize the clinical characteristics of intracranial arachnoid cysts (IACs) in pediatric cases. A retrospective analysis was carried out on clinical characteristics of IACs in 488 pediatric cases who were treated at our hospital from January 2003 to September 2013. There were 342 males and 146 females (male-to-female ratio, 2.34:1), aged 5.61±3.25 years on average. 221 cases (45.29%) were diagnosed accidentally, 267 cases had clinical complaints (54.71%), among which relationships between clinical complaints and IACs were identified in 123 (46.07%). Simple IACs occurred in 364 cases (4.59%), and concurrent congenital abnormalities occurred in 124 cases (4.59%). In terms of location, 355 had IACs in middle cranial fossa (72.75%), 82 cases in posterior cranial fossa (16.80%), 20 cases in anterior cranial fossa (4.10%), 12 cases in dorsolateral surface (2.46%), 7 cases in suprasellar cistern (1.43%), 5 cases in cerebral ventricle (1.02%), 5 cases in quadrigeminal cistern (1.02%), and 2 cases in interhemispheric region (0.41%). There were 449 cases with single IAC (92.01%) and 39 cases with multiple IACs (7.99%). On MRI, the cysts produced tension in 127 cases (26.02%), but not in the remaining 361 cases (73.98%). Surgery was performed on 76 of 488 cases (15.57%), while conservative observation was accepted in 412 cases (84.43%). For the former, the symptoms and the cyst volume were improved to varying extent; for the latter, the follow-up lasting for 3-72 months (average 32.43±8.92 months) showed that the cyst volume remained stable in 407 cases (98.78%), enlarged with aggravated symptoms in 3 cases (0.73%), and shrank in 2 cases (0.49%). Clinical complaints of IACs varied in pediatric cases, and the relationships between clinical complaints and IACs were established only partially. Some pediatric cases were combined with other congenital abnormalities. The cyst volume largely remained stable during the disease course, and surgery was required for only a few IACs. PMID:26770437

[Lentivirus-mediated shRNA silencing of LAMP2A inhibits the proliferation of multiple myeloma cells].

PubMed

Li, Lixuan; Li, Jia

2015-05-01

To study the effects of lentivirus-mediated short hairpin RNA (shRNA) silencing of lysosome-associated membrane protein type 2A (LAMP2A) expression on the proliferation of multiple myeloma cells. The constructed shRNA lentiviral vector was applied to infect human multiple myeloma cell line MM.1S, and stable expression cell line was obtained by puromycin screening. Western blotting was used to verify the inhibitory effect on LAMP2A protein expression. MTT assay was conducted to detect the effect of knocked-down LAMP2A on MM.1S cell proliferation, and the anti-tumor potency of suberoylanilide hydroxamic acid (SAHA) against the obtained MM.1S LAMP2A(shRNA) stable cell line. Lactate assay was performed to observe the impact of low LAMP2A expression on cell glycolysis. The stable cell line with low LAMP2A expression were obtained with the constructed human LAMP2A-shRNA lentiviral vector. Down-regulation of LAMP2A expression significantly inhibited MM.1S cell proliferation and enhanced the anti-tumor activity of SAHA. Interestingly, decreased LAMP2A expression also inhibited MM.1S cell lactic acid secretion. Down-regulation of LAMP2A expression could inhibit cell proliferation in multiple myeloma cells.

Behavior of stabled horses provided continuous or intermittent access to drinking water.

PubMed

McDonnell, S M; Freeman, D A; Cymbaluk, N F; Schott, H C; Hinchcliff, K; Kyle, B

1999-11-01

To compare quantitative measures and clinical assessments of behavior as an indication of psychologic well-being of stabled horses provided drinking water continuously or via 1 of 3 intermittent delivery systems. 22 Quarter Horse (QH) or QH-crossbred mares and 17 Belgian or Belgian-crossbred mares (study 1) and 24 QH or QH-crossbred mares and 18 Belgian or Belgian-crossbred mares (study 2). Stabled horses were provided water continuously or via 1 of 3 intermittent water delivery systems in 2 study periods during a 2-year period. Continuous 24-hour videotaped samples were used to compare quantitative measures and clinical assessments of behavior among groups provided water by the various water delivery systems. All horses had clinically normal behavior. Significant differences in well being were not detected among groups provided water by the various delivery systems. Various continuous and intermittent water delivery systems can provide adequately for the psychologic well-being of stabled horses.

[Implantation of the paclitaxel-eluting stent Apollo in patients with stable angina pectoris: long-term angiographic and clinical results].

PubMed

Batyraliev, T A; Fettser, D V; Samko, A N; Sidorenko, B A

2010-01-01

to assess the long-term angiographic and clinical results of percutaneous coronary interventions (PCI) with implantation of the drug-eluting stent (DES) Apollo in patients with stable angina pectoris. The study enrolled 48 patients with stable angina who had been implanted with 59 stents. A follow-up of the patients lasted 12 months. The intervention was successful in 100% patients. Following 12 months, 81.3% of the patients underwent angiography that demonstrated that the vascular diameter decreased by 0.32 +/- 0.45 mm and the rate of restenosis was reduced by only 5.3%. The frequency of evident cardiac complications over 12 months was as high as 11.6%. The DES Apollo provides a way of safely performing PCI, by achieving a high of angiographic success rate. The application of this stent yields long-term good angiographic and clinical results in patients with stable angina pectoris.

Preliminary 1 month stability screening of cosmetic multiple emulsions (W/O/W) prepared using cetyl dimethicone copolyol and Polysorbate 80.

PubMed

Khan, H; Akhtar, N; Mahmood, T; Jameel, A; Mohsin, S

2015-02-01

The objective of this work was to develop W/O/W emulsions with different concentration of paraffin oil, lipophilic (cetyl dimethicone copolyol) and hydrophilic emulsifiers (polysorbate 80) and to check their stability at different storage conditions. Approximately, 20 formulations (W/O/W) multiple emulsions were prepared, and their stability was checked at different storage conditions for the period of 30 days. Stability of some multiple emulsions ME12, ME13, ME14, ME19 and ME20 was also checked with carbomer as viscosity-enhancing agent. Microscopic analysis for droplet size determination and rheological characterization of most stable multiple emulsions, that is, ME20 were also performed. It was observed that stability of multiple emulsion increases with the addition of gelling agent. Formulation (ME20) with 13.6% paraffin oil, 2.4% cetyl dimethicone copolyol and 0.8% polysorbate 80 was found more stable at 25°C and 40°C for the period of 30 days. Rheological analysis indicated a decrease in viscosity with the passage of time, while droplet size analysis indicated an increase in droplet size with the passage of time. As a conclusion of this work, a stable multiple emulsion with 13.6% paraffin oil, 2.4% cetyl dimethicone copolyol and 0.8% polysorbate 80 can be formulated and can be further studied for any active ingredient for cosmetic purposes. © 2014 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

MIXING MODELS IN ANALYSES OF DIET USING MULTIPLE STABLE ISOTOPES: A CRITIQUE

EPA Science Inventory

Stable isotopes have become widely used in ecology to quantify the importance of different sources based on their isotopic signature. One example of this has been the determination of food webs, where the isotopic signatures of a predator and various prey items can be used to de...

UNCERTAINTY IN SOURCE PARTITIONING USING STABLE ISOTOPES

EPA Science Inventory

Stable isotope analyses are often used to quantify the contribution of multiple sources to a mixture, such as proportions of food sources in an animal's diet, C3 vs. C4 plant inputs to soil organic carbon, etc. Linear mixing models can be used to partition two sources with a sin...

Application of stable isotope ratio analysis for biodegradation monitoring in groundwater

USGS Publications Warehouse

Hatzinger, Paul B.; Böhlke, John Karl; Sturchio, Neil C.

2013-01-01

Stable isotope ratio analysis is increasingly being applied as a tool to detect, understand, and quantify biodegradation of organic and inorganic contaminants in groundwater. An important feature of this approach is that it allows degradative losses of contaminants to be distinguished from those caused by non-destructive processes such as dilution, dispersion, and sorption. Recent advances in analytical techniques, and new approaches for interpreting stable isotope data, have expanded the utility of this method while also exposing complications and ambiguities that must be considered in data interpretations. Isotopic analyses of multiple elements in a compound, and multiple compounds in the environment, are being used to distinguish biodegradative pathways by their characteristic isotope effects. Numerical models of contaminant transport, degradation pathways, and isotopic composition are improving quantitative estimates of in situ contaminant degradation rates under realistic environmental conditions.

What is the benefit of treatment with multiple lines of chemotherapy for patients with metastatic breast cancer? A retrospective cohort study.

PubMed

Bakker, J L; Wever, K; van Waesberghe, J H; Beeker, A; Meijers-Heijboer, H; Konings, I R; Verheul, H M W

2015-12-01

Despite the extensive clinical experience, it is still under debate to what extent patients with metastatic breast cancer (MBC) benefit from multiple lines of chemotherapy beyond standard first or second line treatment. Selection of patients with MBC who will benefit from treatment is crucial to improve outcome and reduce unnecessary toxicity. In this retrospective study, systemic treatment outcome for patients with metastatic MBC is being evaluated. We evaluated to what extent the clinical benefit of prior chemotherapy can predict the success of a subsequent treatment line. Ninety-one patients treated with chemotherapy for MBC between January 2005 and January 2009 were included in this study. Clinical characteristics of patients, choices of chemotherapy and response at first evaluation of every treatment line was evaluated based on radiologic and clinical data. Patients received multiple systemic cytotoxic and biological (combination) therapies. 30% of these patients received more than five consecutive systemic (combination) treatments. First line chemotherapy was mostly anthracycline-based, followed by taxanes, capecitabine and vinorelbine. The response rate (RR, complete response plus partial response according to RECIST 1.1) decreased from 20% (95% CI 11-28%) upon first line of treatment to 0% upon the fourth line. The clinical benefit rate (combining RR and stable disease) decreased from 85% (95% CI 78-93%) in the first to 54% (95% CI 26-67) upon the fourth line. 24% of the patients with clinical benefit at first evaluation did not receive a subsequent line of treatment when progressive disease occurred, while sixty-one percent of the patients with progressive disease at first evaluation of a treatment did not receive a subsequent line of chemotherapy. When applied, the efficacy of a subsequent line of treatment was similar for patients independent of previous treatment benefit. The clinical benefit at first evaluation from systemic treatment in MBC does not predict for subsequent treatment benefit in this retrospective analysis. The fact that 61% of patients did not receive subsequent treatment after previous treatment failure suggests that either clinical judgement is of critical value in selection of patients to prevent them from unnecessary toxicity or, alternatively indicates that based on the assumption that prior treatment failure predicts for lack of benefit undertreatment of patients occurs. Therefore, a more adequate clinical judgement tool or predictive biomarkers for response are urgently needed to improve treatment outcome. Copyright © 2015. Published by Elsevier Ltd.

Congenital extrahepatic portosystemic shunt (Abernethy malformation) treated endovascularly with vascular plug shunt closure.

PubMed

Passalacqua, Matthew; Lie, Kevin T; Yarmohammadi, Hooman

2012-01-01

A 3-year-old boy, who presented with progressive cyanosis and hypoxia, was diagnosed with a large congenital extrahepatic portosystemic shunt, interrupted IVC with azygos continuation, and multiple congenital anomalies. Traditionally open and laparoscopic surgical techniques have been used to treat this malformation. Endovascular repair using a 16-mm Amplatzer vascular plug (AGA Medical Corporation, Golden Valley, Minnesota, USA) was used to occlude the shunt. Immediate post-placement venography demonstrated cessation of flow within the shunt and increased portal venous flow. The patient's hypoxia and cyanosis decreased significantly, and he was discharged on the 5th post-procedure day in stable clinical condition. Three months follow-up evaluation demonstrated the vascular plug in place, unchanged in position.

Early Tibiotalocalcaneal Arthrodesis Intramedullary Nail for Treatment of a Complex Tibial Pilon Fracture (AO/OTA 43-C).

PubMed

Hsu, Andrew R; Szatkowski, Jan P

2015-06-01

Management of severely comminuted, complete articular tibial pilon fractures (AO/OTA 43-C) remains a challenge, with few treatment options providing good clinical outcomes. Open reduction and internal fixation of the tibial plafond, tibiotalar arthrodesis, and salvage hindfoot reconstruction procedures are all associated with surgical complications and functional limitations. In this report, we present a case of a complex pilon fracture in a patient with multiple medical comorbidities and socioeconomic disadvantages that was successfully and acutely treated with a retrograde tibiotalocalcaneal hindfoot arthrodesis nail. At final follow-up examination, the patient had decreased pain, a stable plantigrade foot, and could ambulate with normal shoes without any assistive devices. Therapeutic, Level IV: Case series. © 2014 The Author(s).

Progression in disability and regional grey matter atrophy in relapsing-remitting multiple sclerosis.

PubMed

Hofstetter, Louis; Naegelin, Yvonne; Filli, Lukas; Kuster, Pascal; Traud, Stefan; Smieskova, Renata; Mueller-Lenke, Nicole; Kappos, Ludwig; Gass, Achim; Sprenger, Till; Penner, Iris-Katharina; Nichols, Thomas E; Vrenken, Hugo; Barkhof, Frederik; Polman, Chris; Radue, Ernst-Wilhelm; Borgwardt, Stefan J; Bendfeldt, Kerstin

2014-02-01

In multiple sclerosis (MS) regional grey matter (GM) atrophy has been associated with disability progression. The aim of this study was to compare regional GM volume changes in relapsing-remitting MS (RRMS) patients with progressive and stable disability, using voxel-based morphometry (VBM). We acquired baseline and 1-year follow-up 3-dimensional (3D) T1-weighted magnetic resonance imaging (MRI) data of RRMS patients, using two 1.5-Tesla scanners. Patients were matched pair-wise with respect to age, gender, disease duration, medication, scanner and baseline Expanded Disability Status Scale (EDSS) into 13 pairs, with either progressive EDSS (≥ 1 point change y(-1)) or stable EDSS, as well as into 29 pairs with either progressive Multiple Sclerosis Functional Composite (MSFC) at ≥ 0.25% decrease in y(-1) in any component, or stable MSFC. We analysed longitudinal regional differences in GM volumes in the progressive and stable EDSS and MSFC groups, respectively, using VBM. Significant GM volume reductions occurred in the right precuneus, in the progressive EDSS group. Differential between-group effects occurred in the right precuneus and in the postcentral gyrus. Further longitudinal GM volume reductions occurred in the right orbicular gyrus, in the progressive MSFC group, but no between-group differences were observed (non-stationary cluster-wise inference, all P(corrected) < 0.05). These results suggested a direct association of disability progression and regional GM atrophy in RRMS.

Real-time inextensible surgical thread simulation.

PubMed

Xu, Lang; Liu, Qian

2018-03-27

This paper discusses a real-time simulation method of inextensible surgical thread based on the Cosserat rod theory using position-based dynamics (PBD). The method realizes stable twining and knotting of surgical thread while including inextensibility, bending, twisting and coupling effects. The Cosserat rod theory is used to model the nonlinear elastic behavior of surgical thread. The surgical thread model is solved with PBD to achieve a real-time, extremely stable simulation. Due to the one-dimensional linear structure of surgical thread, the direct solution of the distance constraint based on tridiagonal matrix algorithm is used to enhance stretching resistance in every constraint projection iteration. In addition, continuous collision detection and collision response guarantee a large time step and high performance. Furthermore, friction is integrated into the constraint projection process to stabilize the twining of multiple threads and complex contact situations. Through comparisons with existing methods, the surgical thread maintains constant length under large deformation after applying the direct distance constraint in our method. The twining and knotting of multiple threads correspond to stable solutions to contact and friction forces. A surgical suture scene is also modeled to demonstrate the practicality and simplicity of our method. Our method achieves stable and fast simulation of inextensible surgical thread. Benefiting from the unified particle framework, the rigid body, elastic rod, and soft body can be simultaneously simulated. The method is appropriate for applications in virtual surgery that require multiple dynamic bodies.

Unified dead-time compensation structure for SISO processes with multiple dead times.

PubMed

Normey-Rico, Julio E; Flesch, Rodolfo C C; Santos, Tito L M

2014-11-01

This paper proposes a dead-time compensation structure for processes with multiple dead times. The controller is based on the filtered Smith predictor (FSP) dead-time compensator structure and it is able to control stable, integrating, and unstable processes with multiple input/output dead times. An equivalent model of the process is first computed in order to define the predictor structure. Using this equivalent model, the primary controller and the predictor filter are tuned to obtain an internally stable closed-loop system which also attempts some closed-loop specifications in terms of set-point tracking, disturbance rejection, and robustness. Some simulation case studies are used to illustrate the good properties of the proposed approach. Copyright © 2014 ISA. Published by Elsevier Ltd. All rights reserved.

Subclinical myocardial necrosis and cardiovascular risk in stable patients undergoing elective cardiac evaluation.

PubMed

Tang, W H Wilson; Wu, Yuping; Nicholls, Stephen J; Brennan, Danielle M; Pepoy, Michael; Mann, Shirley; Pratt, Alan; Van Lente, Frederick; Hazen, Stanley L

2010-03-01

The presence of subclinical myocardial necrosis as a prodrome to longer-term adverse cardiac event risk has been debated. The debate has focused predominantly within patients with acute coronary syndrome, and on issues of troponin assay variability and accuracy of detection, rather than on the clinical significance of the presence of subclinical myocardial necrosis (ie, "troponin leak") within stable cardiac patients. Herein, we examine the relationship between different degrees of subclinical myocardial necrosis and long-term adverse clinical outcomes within a stable cardiac patient population with essentially normal renal function. Sequential consenting patients (N=3828; median creatinine clearance, 100 mL/min/1.73m(2)) undergoing elective diagnostic coronary angiography with cardiac troponin I (cTnI) levels below the diagnostic cut-off for defining myocardial infarction (<0.03 ng/mL) were evaluated. The relationship of subclinical myocardial necrosis with incident major adverse cardiovascular events (defined as any death, myocardial infarction, or stroke) over 3-year follow-up was examined. "Probable" (cTnI 0.001-0.008 ng/mL) and "definite" (cTnI 0.009-0.029 ng/mL) subclinical myocardial necrosis were observed frequently within the cohort (34% and 18%, respectively). A linear relationship was observed between the magnitude of subclinical myocardial necrosis and risk of 3-year incident major adverse cardiovascular events, particularly in those with cTnI 0.009 ng/mL or higher (hazard ratio, 3.00; 95% confidence interval, 2.4-3.8), even after adjustment for traditional risk factors, C-reactive protein, and creatinine clearance. The presence of subclinical myocardial necrosis was associated with elevations in acute phase proteins (C-reactive protein, ceruloplasmin; P<0.01 each) and reduction in systemic antioxidant enzyme activities (arylesterase; P<0.01) but showed no significant associations with multiple specific measures of oxidant stress, and showed borderline associations with myeloperoxidase, a marker of leukocyte activation. In stable cardiology patients, prodromal subclinical myocardial necrosis is associated with substantially higher long-term risk for major adverse cardiovascular events. The underlying mechanisms contributing to this minimal troponin leak phenomenon warrants further investigation.

Aptamer-based hydrogel barcodes for the capture and detection of multiple types of pathogenic bacteria.

PubMed

Xu, Yueshuang; Wang, Huan; Luan, Chengxin; Liu, Yuxiao; Chen, Baoan; Zhao, Yuanjin

2018-02-15

Rapid and sensitive diagnosing hematological infections based on the separation and detection of pathogenic bacteria in the patient's blood is a significant challenge. To address this, we herein present a new barcodes technology that can simultaneously capture and detect multiple types of pathogenic bacteria from a complex sample. The barcodes are poly (ethylene glycol) (PEG) hydrogel inverse opal particles with characteristic reflection peak codes that remain stable during bacteria capture on their surfaces. As the spherical surface of the particles has ordered porous nanostructure, the barcodes can provide not only more surface area for probe immobilization and reaction, but also a nanopatterned platform for highly efficient bioreactions. In addition, the PEG hydrogel scaffold could decrease the non-specificity adsorption by its anti-adhesive effect, and the decorated aptamer probes in the scaffolds could increase the sensitivity, reliability, and specificity of the bacteria capture and detection. Moreover, the tagged magnetic nanoparticles in the PEG scaffold could impart the barcodes with controllable movement under magnetic fields, which can be used to significantly increase the reaction speed and simplify the processing of the bioassays. Based on the describe barcodes, it was demonstrated that the bacteria could be captured and identified even at low bacterial concentrations (100 CFU mL -1 ) within 2.5h, which is effectively shortened in comparison with the "gold standard" in clinic. These features make the barcodes ideal for capturing and detecting multiple bacteria from clinical samples for hematological infection diagnostics. Copyright © 2017 Elsevier B.V. All rights reserved.

Prescriptive Oriented Drug Analysis of Multiple Sclerosis Disease by LC-UV in Whole Human Blood.

PubMed

Suneetha, A; Rajeswari, Raja K

2016-02-01

As a polytherapy treatment, multiple sclerosis disease demands prescriptions with more than one drug. Polytherapy is sometimes rational for drug combinations chosen to minimize adverse effects. Estimation of drugs that are concomitantly administered in polytherapy is acceptable as it shortens the analytical timepoints and also the usage of biological matrices. In clinical phase trials, the withdrawal of biofluids is a critical issue for each analysis. Estimating all the coadminsitered drugs in a single shot will be more effective and economical for pharmaceuticals. A single, simple, rapid and sensitive high-performance liquid chromatography assay method has been developed with UV detection and fully validated for the quantification of 14 drugs (at random combinations) used in the treatment of multiple sclerosis disease. The set of combinations was based on prescriptions to patients. Separations were achieved on an X-Terra MS C18 (100 × 3.9 mm, 5 µm) column. The analytes were extracted from 50 µL aliquots of whole human blood with protein precipitation using acetonitrile. All the drugs were sufficiently stable during storage for 24 h at room temperature and for 23 days at 2-8°C. The percentage recoveries of all drugs were between 90 and 115%, with RSD values <10.6%. This method has been shown to be reproducible and sensitive and can be applied to clinical samples from pharmacokinetic studies and also a useful tool in studying the drug interaction studies. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Multiple degree of freedom optical pattern recognition

NASA Technical Reports Server (NTRS)

Casasent, D.

1987-01-01

Three general optical approaches to multiple degree of freedom object pattern recognition (where no stable object rest position exists) are advanced. These techniques include: feature extraction, correlation, and artificial intelligence. The details of the various processors are advanced together with initial results.

Expanding a First-Order Logic Mitigation Framework to Handle Multimorbid Patient Preferences

PubMed Central

Michalowski, Martin; Wilk, Szymon; Rosu, Daniela; Kezadri, Mounira; Michalowski, Wojtek; Carrier, Marc

2015-01-01

The increasing prevalence of multimorbidity is a challenge for physicians who have to manage a constantly growing number of patients with simultaneous diseases. Adding to this challenge is the need to incorporate patient preferences as key components of the care process, thanks in part to the emergence of personalized and participatory medicine. In our previous work we proposed a framework employing first order logic to represent clinical practice guidelines (CPGs) and to mitigate possible adverse interactions when concurrently applying multiple CPGs to a multimorbid patient. In this paper, we describe extensions to our methodological framework that (1) broaden our definition of revision operators to support required and desired types of revisions defined in secondary knowledge sources, and (2) expand the mitigation algorithm to apply revisions based on their type. We illustrate the capabilities of the expanded framework using a clinical case study of a multimorbid patient with stable cardiac artery disease who suffers a sudden onset of deep vein thrombosis. PMID:26958226

Treatment factors affecting longitudinal quality of life in new onset pediatric epilepsy.

PubMed

Modi, Avani C; Ingerski, Lisa M; Rausch, Joseph R; Glauser, Tracy A

2011-05-01

Recognizing the importance of patient-reported outcomes, this longitudinal, prospective study examined: Changes in health-related quality of life (HRQOL) over seven months following antiepileptic drug (AED) initiation and the relationship of seizures, AED side-effects, and AED type to HRQOL. Parents of 124 children with newly diagnosed epilepsy completed measures of HRQOL and side-effects at each clinic visit. Treatment information was also collected. HRQOL remained stable over time; however, seizures and AED side-effects significantly affected multiple HRQOL domains. Higher seizure activity was associated with decreased Physical HRQOL. Side-effects were negatively associated with all HRQOL domains. Children taking carbamazepine who experienced higher side-effects early in therapy demonstrated declining emotional functioning compared to children experiencing no/some side-effects. AED side-effects, AED type, and seizure frequency were associated with longitudinal HRQOL in children with newly-diagnosed epilepsy. Routine assessment of AED side-effects and HRQOL may be useful for clinical decision making.

Durable clinical remission of a skull metastasis under intralesional Viscum album extract therapy: Case report.

PubMed

Werthmann, Paul Georg; Huber, Roman; Kienle, Gunver Sophia

2018-06-09

Skull metastases are rare, they can eventually cause pain, and can invade the brain. Viscum album extracts (VAEs) are used as an adjuvant treatment in cancer. A 68-year-old patient with rectal cancer presented with lung metastases, and metastases to multiple bone sites, the chest wall, and the liver were later identified. Histological examination of one of the bone lesions revealed an additional thyroid carcinoma. An osteolytic parietal bone lesion progressed to a painful metastasis of the skull despite radiotherapy and chemotherapy. The VAEs were applied weekly into the metastasis, followed by pain relief and softening of the lesion. The lesion partially regressed (>50%) after 8 months of continued VAE treatment and remained stable for 2 years. This case shows a durable clinical remission of a skull metastasis under VAE. Further investigations of intratumoral VAE treatment seem worthwhile-especially in symptomatic skull metastases not responding to radiotherapy or systemic therapies. © 2018 The Authors Head & Neck Published by Wiley Periodicals, Inc.

Therapeutic potential of microRNAs in heart failure.

PubMed

Dorn, Gerald W

2010-05-01

There is an ongoing explosion of information about microRNAs (miRs) in cardiac disease. These small noncoding RNAs regulate protein expression by destabilization and translational inhibition of target mRNAs. Similar to mRNAs, miRs are regulated in cardiac hypertrophy and heart failure, but miR expression profiles appear to be more sensitive than mRNA signatures to changes in clinical status, suggesting that miR levels in myocardium or plasma could enhance clinical diagnostics. Single miRs can target dozens or hundreds of different mRNAs, complicating attempts to determine their individual physiologic effects. However, manipulating individual miRs by overexpression or gene ablation in experimental models has begun to unravel this conundrum: Single miRs tend to regulate numerous effectors within the same functional pathway, producing a coherent physiologic response via multiple parallel perturbations. miRs are attractive nodal therapeutic targets, and stable miR mimetics (agomiRs) and antagonists (antagomiRs) are being evaluated to prevent or reverse heart failure.

A new dimethyl labeling-based SID-MRM-MS method and its application to three proteases involved in insulin maturation.

PubMed

Cheng, Dongwan; Zheng, Li; Hou, Junjie; Wang, Jifeng; Xue, Peng; Yang, Fuquan; Xu, Tao

2015-01-01

The absolute quantification of target proteins in proteomics involves stable isotope dilution coupled with multiple reactions monitoring mass spectrometry (SID-MRM-MS). The successful preparation of stable isotope-labeled internal standard peptides is an important prerequisite for the SID-MRM absolute quantification methods. Dimethyl labeling has been widely used in relative quantitative proteomics and it is fast, simple, reliable, cost-effective, and applicable to any protein sample, making it an ideal candidate method for the preparation of stable isotope-labeled internal standards. MRM mass spectrometry is of high sensitivity, specificity, and throughput characteristics and can quantify multiple proteins simultaneously, including low-abundance proteins in precious samples such as pancreatic islets. In this study, a new method for the absolute quantification of three proteases involved in insulin maturation, namely PC1/3, PC2 and CPE, was developed by coupling a stable isotope dimethyl labeling strategy for internal standard peptide preparation with SID-MRM-MS quantitative technology. This method offers a new and effective approach for deep understanding of the functional status of pancreatic β cells and pathogenesis in diabetes.

Changes in the Neuropsychological Correlates of Clinical Dimensions between the Acute and Stable Phase of Schizophrenia

ERIC Educational Resources Information Center

Guillem, F.; Ganeva, E.; Pampoulova, T.; Stip, E.; Lalonde, P.; Sasseville, M.

2005-01-01

This study was designed to investigate whether the neuropsychological correlates of the symptom dimensions of schizophrenia vary with the clinical state in patients followed from the acute to stable the phase of the illness. Fifteen patients were assessed for symptoms (SAPS-SANS) and undergone a complete neuropsychological assessment at two…

Evaluation of helper-dependent canine adenovirus vectors in a 3D human CNS model.

PubMed

Simão, D; Pinto, C; Fernandes, P; Peddie, C J; Piersanti, S; Collinson, L M; Salinas, S; Saggio, I; Schiavo, G; Kremer, E J; Brito, C; Alves, P M

2016-01-01

Gene therapy is a promising approach with enormous potential for treatment of neurodegenerative disorders. Viral vectors derived from canine adenovirus type 2 (CAV-2) present attractive features for gene delivery strategies in the human brain, by preferentially transducing neurons, are capable of efficient axonal transport to afferent brain structures, have a 30-kb cloning capacity and have low innate and induced immunogenicity in preclinical tests. For clinical translation, in-depth preclinical evaluation of efficacy and safety in a human setting is primordial. Stem cell-derived human neural cells have a great potential as complementary tools by bridging the gap between animal models, which often diverge considerably from human phenotype, and clinical trials. Herein, we explore helper-dependent CAV-2 (hd-CAV-2) efficacy and safety for gene delivery in a human stem cell-derived 3D neural in vitro model. Assessment of hd-CAV-2 vector efficacy was performed at different multiplicities of infection, by evaluating transgene expression and impact on cell viability, ultrastructural cellular organization and neuronal gene expression. Under optimized conditions, hd-CAV-2 transduction led to stable long-term transgene expression with minimal toxicity. hd-CAV-2 preferentially transduced neurons, whereas human adenovirus type 5 (HAdV5) showed increased tropism toward glial cells. This work demonstrates, in a physiologically relevant 3D model, that hd-CAV-2 vectors are efficient tools for gene delivery to human neurons, with stable long-term transgene expression and minimal cytotoxicity.

Vitamin K Nutrition, Metabolism, and Requirements: Current Concepts and Future Research12

PubMed Central

Shearer, Martin J.; Fu, Xueyan; Booth, Sarah L.

2012-01-01

In 2001, the US Food and Nutrition Board concluded that there were insufficient data with which to establish a RDA for vitamin K, in large part because of a lack of robust endpoints that reflected adequacy of intake. Knowledge of the relative bioavailability of multiple vitamin K forms was also poor. Since then, stable isotope methodologies have been applied to the assessment of the bioavailability of the major dietary form of vitamin K in its free state and when incorporated into a plant matrix. There is a need for stable isotope studies with enhanced sensitivity to expand knowledge of the bioavailability, absorption, disposition, and metabolism of different molecular forms of vitamin K. Another area for future research stems from evidence that common polymorphisms or haplotypes in certain key genes implicated in vitamin K metabolism might affect nutritional requirements. Thus far, much of this evidence is indirect via effects on warfarin dose requirements. In terms of clinical endpoints, vitamin K deficiency in early infancy continues to be a leading cause of intracranial bleeding even in developed countries and the reasons for its higher prevalence in certain Asian countries has not been solved. There is universal consensus for the need for vitamin K prophylaxis in newborns, but the effectiveness of any vitamin K prophylactic regimen needs to be based on sound nutritional principles. In contrast, there is still a lack of suitable biomarkers or clinical endpoints that can be used to determine vitamin K requirements among adults. PMID:22516726

[Study on differences between pharmacokinetics and chromatopharmacodynamics for Chinese materia medica formulae].

PubMed

He, Fuyuan; Deng, Kaiwen; Zou, Huan; Qiu, Yun; Chen, Feng; Zhou, Honghao

2011-01-01

To study on the differences between chromatopharmacokinetics (pharmacokinetics with fingerprint chromatography) and chromatopharmacodynamics (pharmacodynamics with fingerprint chromatography) of Chinese materia medica formulae to answer the question whether the pharmacokinetic parameters of multiple composites can be utilized to guide the medication of multiple composites. On the base of established four chromatopharmacology (pharmacology with chromatographic fingerprint), the pharmacokinetics, and pharmacodynamics were analyzed comparably on their mathematical model and parameter definition. On the basis of quantitative pharmacology, the function expressions and total statistical parameters, such as total zero moment, total first moment, total second moment of the pharmacokinetics, and pharmacodynamics were analyzed to the common expressions and elucidated results for single and multiple components in Chinese materia medica formulae. Total quantitative pharmacokinetic, i.e., chromatopharmacokinetic parameter were decided by each component pharmacokinetic parameters, whereas the total quantitative pharmacodynamic, i.e., chromatopharmacodynamic parameter were decided by both of pharmacokinetic and pharmacodynamic parameters of each components. The pharmacokinetic parameters were corresponded to pharmacodynamic parameters with an existing stable effective coefficient when the constitutive ratio of each composite was a constant. The effects of Chinese materia medica were all controlled by pharmacokinetic and pharmacodynamic coefficient. It is a special case that the pharmacokinetic parameter could independently guide the clinical medication for single component whereas the chromatopharmacokinetic parameters are not applied to the multiple drug combination system, and not be used to solve problems of chromatopharmacokinetic of Chinese materia medica formulae.

Global stability of a multiple infected compartments model for waterborne diseases

NASA Astrophysics Data System (ADS)

Wang, Yi; Cao, Jinde

2014-10-01

In this paper, mathematical analysis is carried out for a multiple infected compartments model for waterborne diseases, such as cholera, giardia, and rotavirus. The model accounts for both person-to-person and water-to-person transmission routes. Global stability of the equilibria is studied. In terms of the basic reproduction number R0, we prove that, if R0⩽1, then the disease-free equilibrium is globally asymptotically stable and the infection always disappears; whereas if R0>1, there exists a unique endemic equilibrium which is globally asymptotically stable for the corresponding fast-slow system. Numerical simulations verify our theoretical results and present that the decay rate of waterborne pathogens has a significant impact on the epidemic growth rate. Also, we observe numerically that the unique endemic equilibrium is globally asymptotically stable for the whole system. This statement indicates that the present method need to be improved by other techniques.

Interfacial film stabilized W/O/W nano multiple emulsions loaded with green tea and lotus extracts: systematic characterization of physicochemical properties and shelf-storage stability.

PubMed

Mahmood, Tariq; Akhtar, Naveed; Manickam, Sivakumar

2014-05-12

Multiple emulsions have excellent encapsulating potential and this investigation has been aimed to encapsulate two different plant extracts as functional cosmetic agents in the W/O/W multiple emulsions and the resultant system's long term stability has been determined in the presence of a thickener, hydroxypropyl methylcellulose (HPMC). Multiple W/O/W emulsions have been generated using cetyl dimethicone copolyol as lipophilic emulsifier and a blend of polyoxyethylene (20) cetyl ether and cetomacrogol 1000® as hydrophilic emulsifiers. The generated multiple emulsions have been characterized with conductivity, pH, microscopic analysis, phase separation and rheology for a period of 30 days. Moreover, long term shelf-storage stability has been tested to understand the shelf-life by keeping the generated multiple emulsion formulations at 25 ± 10°C and at 40 ± 10% relative humidity for a period of 12 months. It has been observed that the hydrophilic emulsifiers and HPMC have considerably improved the stability of multiple emulsions for the followed period of 12 months at different storage conditions. These multiple emulsions have shown improved entrapment efficiencies concluded on the release rate of conductometric tracer entrapped in the inner aqueous phase of the multiple emulsions. Multiple emulsions have been found to be stable for a longer period of time with promising characteristics. Hence, stable multiple emulsions loaded with green tea and lotus extracts could be explored for their cosmetic benefits.

Experimental confirmation of multiple community states in a marine ecosystem.

PubMed

Petraitis, Peter S; Methratta, Elizabeth T; Rhile, Erika C; Vidargas, Nicholas A; Dudgeon, Steve R

2009-08-01

Small changes in environmental conditions can unexpectedly tip an ecosystem from one community type to another, and these often irreversible shifts have been observed in semi-arid grasslands, freshwater lakes and ponds, coral reefs, and kelp forests. A commonly accepted explanation is that these ecosystems contain multiple stable points, but experimental tests confirming multiple stable states have proven elusive. Here we present a novel approach and show that mussel beds and rockweed stands are multiple stable states on intertidal shores in the Gulf of Maine, USA. Using broad-scale observational data and long-term data from experimental clearings, we show that the removal of rockweed by winter ice scour can tip persistent rockweed stands to mussel beds. The observational data were analyzed with Anderson's discriminant analysis of principal coordinates, which provided an objective function to separate mussel beds from rockweed stands. The function was then applied to 55 experimental plots, which had been established in rockweed stands in 1996. Based on 2005 data, all uncleared controls and all but one of the small clearings were classified as rockweed stands; 37% of the large clearings were classified as mussel beds. Our results address the establishment of mussels versus rockweeds and complement rather than refute the current paradigm that mussel beds and rockweed stands, once established, are maintained by site-specific differences in strong consumer control.

Optimization and development of stable w/o/w cosmetic multiple emulsions by means of the Quality by Design approach.

PubMed

Kovács, A; Erős, I; Csóka, I

2016-04-01

The aim of our present work was to develop stable water-in-oil-in-water (w/o/w) cosmetic multiple emulsions that are proper for cosmetic use and can also be applied on the skin as pharmaceutical vehicles by means of Quality by Design (QbD) concept. This product design concept consists of a risk assessment step and also the 'predetermination' of the critical material attributes and process parameters of a stable multiple emulsion system. We have set up the hypothesis that the stability of multiple emulsions can be improved by the development based on such systematic planning - making a map of critical product parameters - so their industrial usage can be increased. The risk assessment and the determination of critical physical-chemical stability parameters of w/o/w multiple emulsions to define critical control points were performed by means of quality tools and the leanqbd(™) (QbD Works LLC, Fremont, CA, U.S.A.) software. Critical materials and process parameters: Based on the results of preformulation experiments, three factors, namely entrapped active agent, preparation methodology and shear rate, were found to be highly critical factors for critical quality attributes (CQAs) and for stability, whereas the nature of oil was found a medium level risk factor. The results of the risk assessment are the following: (i) droplet structure and size distribution should be evaluated together to be able to predict the stability issues, (ii) the presence of entrapped active agents had a great impact on droplet structure, (iii) the viscosity curves represent the structural changes during storage, if the decrease in relative viscosity is >15% the emulsion disintegrates, and (iv) it is enough to use the shear rate between 34g and 116g relative centrifugal force (RCF). CQAs: By risk assessment, we discovered that four factors should be considered to be high-risk variables as compared to others: droplet size, droplet structure, viscosity and multiple character were found to be highly critical attributes. The preformulation experiment is the part of a development plan. On the basis of these results, the control strategy can be defined and a stable multiple emulsion can be ensured that meets the relevant stakeholders' quality expectations. © 2015 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Modest rise in chlamydia and gonorrhoea testing did not increase case detection in a clinical HIV cohort in Ontario, Canada.

PubMed

Burchell, Ann N; Grewal, Ramandip; Allen, Vanessa G; Gardner, Sandra L; Moravan, Veronika; Bayoumi, Ahmed M; Kaul, Rupert; McGee, Frank; Millson, Margaret Peggy E; Remis, Robert S; Raboud, Janet; Mazzulli, Tony; Rourke, Sean B

2014-12-01

We described patterns of testing for chlamydia and gonorrhoea infection among persons in specialty HIV care in Ontario, Canada, from 2008 to 2011. We analysed data from 3165 participants in the OHTN Cohort Study attending one of seven specialty HIV care clinics. We obtained chlamydia and gonorrhoea test results via record linkage with the provincial public health laboratory. We estimated the proportion of participants who underwent testing annually, the positivity rate among those tested and the proportion diagnosed with chlamydia or gonorrhoea among all under observation. We explored risk factors for testing and diagnosis using multiple logistic regression analysis. The proportion tested annually rose from 15.2% (95% CI 13.6% to 16.7%) in 2008 to 27.0% (95% CI 25.3% to 28.6%) in 2011 (p<0.0001). Virtually all were urine-based nucleic acid amplification tests. Testing was more common among men who have sex with men (MSM), younger adults, Toronto residents, persons attending primary care clinics and persons who had tested in the previous year or who had more clinic visits in the current year. We observed a decrease in test positivity rates over time. However, the annual proportion diagnosed remained stable and in 2011 this was 0.97% (95% CI 0.61% to 1.3%) and 0.79% (95% CI 0.46% to 1.1%) for chlamydia and gonorrhoea, respectively. Virtually all cases were among MSM. Chlamydia and gonorrhoea testing increased over time while test positivity rates declined and the overall proportion diagnosed remained stable, suggesting that the modest increase in testing did not improve case detection. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Multiple spatially localized dynamical states in friction-excited oscillator chains

NASA Astrophysics Data System (ADS)

Papangelo, A.; Hoffmann, N.; Grolet, A.; Stender, M.; Ciavarella, M.

2018-03-01

Friction-induced vibrations are known to affect many engineering applications. Here, we study a chain of friction-excited oscillators with nearest neighbor elastic coupling. The excitation is provided by a moving belt which moves at a certain velocity vd while friction is modelled with an exponentially decaying friction law. It is shown that in a certain range of driving velocities, multiple stable spatially localized solutions exist whose dynamical behavior (i.e. regular or irregular) depends on the number of oscillators involved in the vibration. The classical non-repeatability of friction-induced vibration problems can be interpreted in light of those multiple stable dynamical states. These states are found within a "snaking-like" bifurcation pattern. Contrary to the classical Anderson localization phenomenon, here the underlying linear system is perfectly homogeneous and localization is solely triggered by the friction nonlinearity.

Use of the piggyBac transposon to create stable packaging cell lines for the production of clinical-grade self-inactivating γ-retroviral vectors.

PubMed

Feldman, Steven A; Xu, Hui; Black, Mary A; Park, Tristen S; Robbins, Paul F; Kochenderfer, James N; Morgan, Richard A; Rosenberg, Steven A

2014-08-01

Efforts to improve the biosafety of γ-retroviral-mediated gene therapy have resulted in a shift toward the use of self-inactivating (SIN) γ-retroviral vectors. However, scale-up and manufacturing of such vectors requires significant optimization of transient transfection-based processes or development of novel platforms for the generation of stable producer cell clones. To that end, we describe the use of the piggybac transposon to generate stable producer cell clones for the production of SIN γ-retroviral vectors. The piggybac transposon is a universal tool allowing for the stable integration of SIN γ-retroviral constructs into murine (PG13) and human 293-based Phoenix (GALV and RD114, respectively) packaging cell lines without reverse transcription. Following transposition, a high-titer clone is selected for manufacture of a master cell bank and subsequent γ-retroviral vector supernatant production. Packaging cell clones created using the piggybac transposon have comparable titers to non-SIN vectors generated via conventional methods. We describe herein the use of the piggybac transposon for the production of stable packaging cell clones for the manufacture of clinical-grade SIN γ-retroviral vectors for ex vivo gene therapy clinical trials.

Stochastic maps, continuous approximation, and stable distribution

NASA Astrophysics Data System (ADS)

Kessler, David A.; Burov, Stanislav

2017-10-01

A continuous approximation framework for general nonlinear stochastic as well as deterministic discrete maps is developed. For the stochastic map with uncorelated Gaussian noise, by successively applying the Itô lemma, we obtain a Langevin type of equation. Specifically, we show how nonlinear maps give rise to a Langevin description that involves multiplicative noise. The multiplicative nature of the noise induces an additional effective force, not present in the absence of noise. We further exploit the continuum description and provide an explicit formula for the stable distribution of the stochastic map and conditions for its existence. Our results are in good agreement with numerical simulations of several maps.

Multi-stability in folded shells: non-Euclidean origami

NASA Astrophysics Data System (ADS)

Evans, Arthur

2015-03-01

Both natural and man-made structures benefit from having multiple mechanically stable states, from the quick snapping motion of hummingbird beaks to micro-textured surfaces with tunable roughness. Rather than discuss special fabrication techniques for creating bi-stability through material anisotropy, in this talk I will present several examples of how folding a structure can modify the energy landscape and thus lead to multiple stable states. Using ideas from origami and differential geometry, I will discuss how deforming a non-Euclidean surface can be done either continuously or discontinuously, and explore the effects that global constraints have on the ultimate stability of the surface.

Brain reserve against physical disability progression over 5 years in multiple sclerosis.

PubMed

Sumowski, James F; Rocca, Maria A; Leavitt, Victoria M; Meani, Alessandro; Mesaros, Sarlota; Drulovic, Jelena; Preziosa, Paolo; Habeck, Christian G; Filippi, Massimo

2016-05-24

The brain reserve hypothesis links larger maximal lifetime brain growth (MLBG, estimated with intracranial volume [ICV]) with lower risk for cognitive decline/dementia. We examined whether larger MLBG is also linked to less physical disability progression over 5 years in a prospective sample of treatment-naive patients with multiple sclerosis (MS). Physical disability was measured with the Expanded Disability Status Scale (EDSS) at baseline and 5-year follow-up in 52 treatment-naive Serbian patients with MS. MRI measured disease burden (cerebral atrophy, T2 lesion volume) and MLBG: a genetically determined, premorbid (established during adolescence, stable thereafter) patient characteristic estimated with ICV (adjusted for sex). Logistic regression tested whether MLBG (smaller vs larger) predicts disability progression (stable vs worsened) independently of disease burden. Disability progression was observed in 29 (55.8%) patients. Larger MLBG predicted lower risk for progression (odds ratio 0.13, 95% confidence interval 0.02-0.78), independently of disease burden. We also calculated absolute change in EDSS scores, and observed that patients with smaller MLBG showed worse EDSS change (0.91 ± 0.71) than patients with larger MLBG (0.42 ± 0.87). Larger MLBG was linked to lower risk for disability progression in patients with MS over 5 years, which is the first extension of the brain reserve hypothesis to physical disability. MLBG (ICV) represents a clinically available metric that may help gauge risk for future disability in patients with MS, which may advance the science and practice of early intervention. Potential avenues for future research are discussed. © 2016 American Academy of Neurology.

Optimized protocol for quantitative multiple reaction monitoring-based proteomic analysis of formalin-fixed, paraffin embedded tissues

PubMed Central

Kennedy, Jacob J.; Whiteaker, Jeffrey R.; Schoenherr, Regine M.; Yan, Ping; Allison, Kimberly; Shipley, Melissa; Lerch, Melissa; Hoofnagle, Andrew N.; Baird, Geoffrey Stuart; Paulovich, Amanda G.

2016-01-01

Despite a clinical, economic, and regulatory imperative to develop companion diagnostics, precious few new biomarkers have been successfully translated into clinical use, due in part to inadequate protein assay technologies to support large-scale testing of hundreds of candidate biomarkers in formalin-fixed paraffin embedded (FFPE) tissues. While the feasibility of using targeted, multiple reaction monitoring-mass spectrometry (MRM-MS) for quantitative analyses of FFPE tissues has been demonstrated, protocols have not been systematically optimized for robust quantification across a large number of analytes, nor has the performance of peptide immuno-MRM been evaluated. To address this gap, we used a test battery approach coupled to MRM-MS with the addition of stable isotope labeled standard peptides (targeting 512 analytes) to quantitatively evaluate the performance of three extraction protocols in combination with three trypsin digestion protocols (i.e. 9 processes). A process based on RapiGest buffer extraction and urea-based digestion was identified to enable similar quantitation results from FFPE and frozen tissues. Using the optimized protocols for MRM-based analysis of FFPE tissues, median precision was 11.4% (across 249 analytes). There was excellent correlation between measurements made on matched FFPE and frozen tissues, both for direct MRM analysis (R2 = 0.94) and immuno-MRM (R2 = 0.89). The optimized process enables highly reproducible, multiplex, standardizable, quantitative MRM in archival tissue specimens. PMID:27462933

Virally delivered Channelrhodopsin-2 Safely and Effectively Restores Visual Function in Multiple Mouse Models of Blindness

PubMed Central

Doroudchi, M Mehdi; Greenberg, Kenneth P; Liu, Jianwen; Silka, Kimberly A; Boyden, Edward S; Lockridge, Jennifer A; Arman, A Cyrus; Janani, Ramesh; Boye, Shannon E; Boye, Sanford L; Gordon, Gabriel M; Matteo, Benjamin C; Sampath, Alapakkam P; Hauswirth, William W; Horsager, Alan

2011-01-01

Previous work established retinal expression of channelrhodopsin-2 (ChR2), an algal cation channel gated by light, restored physiological and behavioral visual responses in otherwise blind rd1 mice. However, a viable ChR2-based human therapy must meet several key criteria: (i) ChR2 expression must be targeted, robust, and long-term, (ii) ChR2 must provide long-term and continuous therapeutic efficacy, and (iii) both viral vector delivery and ChR2 expression must be safe. Here, we demonstrate the development of a clinically relevant therapy for late stage retinal degeneration using ChR2. We achieved specific and stable expression of ChR2 in ON bipolar cells using a recombinant adeno-associated viral vector (rAAV) packaged in a tyrosine-mutated capsid. Targeted expression led to ChR2-driven electrophysiological ON responses in postsynaptic retinal ganglion cells and significant improvement in visually guided behavior for multiple models of blindness up to 10 months postinjection. Light levels to elicit visually guided behavioral responses were within the physiological range of cone photoreceptors. Finally, chronic ChR2 expression was nontoxic, with transgene biodistribution limited to the eye. No measurable immune or inflammatory response was observed following intraocular vector administration. Together, these data indicate that virally delivered ChR2 can provide a viable and efficacious clinical therapy for photoreceptor disease-related blindness. PMID:21505421

Association Between Cognitive Complaints and Vulnerability to Environmental Distraction in Multiple Sclerosis.

PubMed

Randolph, John J; Randolph, Jennifer S; Wishart, Heather A

2017-02-01

Individuals with multiple sclerosis (MS) often report cognitive dysfunction, although neuropsychological evaluation findings may not correlate with subjective concerns. One factor that may explain this lack of correspondence is the controlled testing environment, which differs from busier settings where cognitive lapses are noted to occur. This study used a novel environmental manipulation to determine whether individuals with MS who report cognitive dysfunction are more vulnerable to the effects of auditory distraction during neuropsychological testing. Twenty-four individuals with clinically definite MS or clinically isolated syndrome were administered a cognitive battery during two counterbalanced auditory conditions: quiet/standard condition, and distraction condition with random office background noise. Participants were divided into high versus low cognitive complaint groups using a median split analysis of Perceived Deficits Questionnaire responses. Participants with more cognitive complaints showed a decrement in performance on the oral Symbol Digit Modalities Test during the distraction condition while those with fewer cognitive complaints demonstrated stable performance across conditions. These findings remained significant after controlling for education, premorbid intellect, fatigue, and depressed mood. These results suggest that individuals with MS with more cognitive complaints are vulnerable to environmental distraction, particularly regarding processing speed. Incorporating random environmental noise or other distraction conditions during selected measures may enhance the ecological validity of neuropsychological evaluation results in MS. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A new approach for generating bispecific antibodies based on a common light chain format and the stable architecture of human immunoglobulin G1.

PubMed

De Nardis, Camilla; Hendriks, Linda J A; Poirier, Emilie; Arvinte, Tudor; Gros, Piet; Bakker, Alexander B H; de Kruif, John

2017-09-01

Bispecific antibodies combine two different antigen-binding sites in a single molecule, enabling more specific targeting, novel mechanisms of action, and higher clinical efficacies. Although they have the potential to outperform conventional monoclonal antibodies, many bispecific antibodies have issues regarding production, stability, and pharmacokinetic properties. Here, we describe a new approach for generating bispecific antibodies using a common light chain format and exploiting the stable architecture of human immunoglobulin G 1 We used iterative experimental validation and computational modeling to identify multiple Fc variant pairs that drive efficient heterodimerization of the antibody heavy chains. Accelerated stability studies enabled selection of one Fc variant pair dubbed "DEKK" consisting of substitutions L351D and L368E in one heavy chain combined with L351K and T366K in the other. Solving the crystal structure of the DEKK Fc region at a resolution of 2.3 Å enabled detailed analysis of the interactions inducing CH3 interface heterodimerization. Local shifts in the IgG backbone accommodate the introduction of lysine side chains that form stabilizing salt-bridge interactions with substituted and native residues in the opposite chain. Overall, the CH3 domain adapted to these shifts at the interface, yielding a stable Fc conformation very similar to that in wild-type IgG. Using the DEKK format, we generated the bispecific antibody MCLA-128, targeting human EGF receptors 2 and 3. MCLA-128 could be readily produced and purified at industrial scale with a standard mammalian cell culture platform and a routine purification protocol. Long-term accelerated stability assays confirmed that MCLA-128 is highly stable and has excellent biophysical characteristics. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

A new approach for generating bispecific antibodies based on a common light chain format and the stable architecture of human immunoglobulin G1

PubMed Central

De Nardis, Camilla; Hendriks, Linda J. A.; Poirier, Emilie; Arvinte, Tudor; Gros, Piet; Bakker, Alexander B. H.; de Kruif, John

2017-01-01

Bispecific antibodies combine two different antigen-binding sites in a single molecule, enabling more specific targeting, novel mechanisms of action, and higher clinical efficacies. Although they have the potential to outperform conventional monoclonal antibodies, many bispecific antibodies have issues regarding production, stability, and pharmacokinetic properties. Here, we describe a new approach for generating bispecific antibodies using a common light chain format and exploiting the stable architecture of human immunoglobulin G1. We used iterative experimental validation and computational modeling to identify multiple Fc variant pairs that drive efficient heterodimerization of the antibody heavy chains. Accelerated stability studies enabled selection of one Fc variant pair dubbed “DEKK” consisting of substitutions L351D and L368E in one heavy chain combined with L351K and T366K in the other. Solving the crystal structure of the DEKK Fc region at a resolution of 2.3 Å enabled detailed analysis of the interactions inducing CH3 interface heterodimerization. Local shifts in the IgG backbone accommodate the introduction of lysine side chains that form stabilizing salt-bridge interactions with substituted and native residues in the opposite chain. Overall, the CH3 domain adapted to these shifts at the interface, yielding a stable Fc conformation very similar to that in wild-type IgG. Using the DEKK format, we generated the bispecific antibody MCLA-128, targeting human EGF receptors 2 and 3. MCLA-128 could be readily produced and purified at industrial scale with a standard mammalian cell culture platform and a routine purification protocol. Long-term accelerated stability assays confirmed that MCLA-128 is highly stable and has excellent biophysical characteristics. PMID:28655766

A phase I study of combination vaccine treatment of five therapeutic epitope-peptides for metastatic colorectal cancer; safety, immunological response, and clinical outcome.

PubMed

Hazama, Shoichi; Nakamura, Yusuke; Takenouchi, Hiroko; Suzuki, Nobuaki; Tsunedomi, Ryouichi; Inoue, Yuka; Tokuhisa, Yoshihiro; Iizuka, Norio; Yoshino, Shigefumi; Takeda, Kazuyoshi; Shinozaki, Hirokazu; Kamiya, Akira; Furukawa, Hiroyuki; Oka, Masaaki

2014-03-10

To evaluate the safety of combination vaccine treatment of multiple peptides, phase I clinical trial was conducted for patients with advanced colorectal cancer using five novel HLA-A*2402-restricted peptides, three peptides derived from oncoantigens, ring finger protein 43 (RNF43), 34 kDa-translocase of the outer mitochondrial membrane (TOMM34), and insulin-like growth factor-II mRNA binding protein 3 (KOC1), and the remaining two from angiogenesis factors, vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2. Eighteen HLA- A*2402-positive colorectal cancer patients who had failed to standard therapy were enrolled in this study. 0.5 mg, 1.0 mg or 3.0 mg each of the peptides was mixed with incomplete Freund's adjuvant and then subcutaneously injected at five separated sites once a week. We also examined possible effect of a single site injection of "the cocktail of 5 peptides" on the immunological responses. ELISPOT assay was performed before and after vaccinations in the schedule of every 4 weeks. The vaccine treatment using multiple peptides was well tolerated without any severe treatment-associated systemic adverse events. Dose-dependent induction of peptide-specific cytotoxic T lymphocytes was observed. The single injection of "peptides cocktail" did not diminish the immunological responses. Regarding the clinical outcome, one patient achieved complete response and 6 patients revealed stable disease for 4 to 7 months. The median overall survival time (MST) was 13.5 months. Patients, in which we detected induction of cytotoxic T lymphocytes specific to 3 or more peptides, revealed significantly better prognosis (MST; 27.8 months) than those with poorer immune responses (MST; 3.7 months) (p = 0.032). Our cancer vaccine treatment using multiple peptides is a promising approach for advanced colorectal cancer with the minimum risk of systemic adverse reactions. UMIN-CTR number UMIN000004948.

Diabetes mellitus and cardiovascular clinical characteristics of Spanish women with stable ischaemic heart disease: Data from the SIRENA study.

PubMed

Gámez, José M; Masmiquel, Luis; Ripoll, Tomás; Barrios, Vivencio; Anguita, Manuel

2017-01-01

The relationship between diabetes and the cardiovascular clinical characteristics of Spanish women with stable ischaemic heart disease was studied in a nationwide cross-sectional study. Diabetes was related to a higher burden of risk factors, comorbidity, multivessel disease and coronary surgery. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Beta-Blockers and Nitrates: Pharmacotherapy and Indications.

PubMed

Facchini, Emanuela; Degiovanni, Anna; Cavallino, Chiara; Lupi, Alessandro; Rognoni, Andrea; Bongo, Angelo S

2015-01-01

Many clinically important differences exist between beta blockers. B1-selectivity is of clinical interest because at clinically used doses, b1- selective agents block cardiac b-receptors while having minor effects on bronchial and vascular b-receptors. Beta-adrenergic blocking agents significantly decrease the frequency and duration of angina pectoris, instead the prognostic benefit of beta-blockers in stable angina has been extrapolated from studies of post myocardial infarction but has not yet been documented without left ventricular disfunction or previous myocardial infarction. Organic nitrates are among the oldest drugs, but they still remain a widely used adjuvant in the treatment of symptomatic coronary artery disease. While their efficacy in relieving angina pectoris symptoms in acute settings and in preventing angina before physical or emotional stress is undisputed, the chronic use of nitrates has been associated with potentially important side effects such as tolerance and endothelial dysfunction. B-blockers are the firstline anti-anginal therapy in stable stable angina patients without contraindications, while nitrates are the secondline anti-anginal therapy. Despite 150 years of clinical practice, they remain fascinating drugs, which in a chronic setting still deserve investigation. This review evaluated pharmacotherapy and indications of Beta-blockers and nitrates in stable angina.

Biomarker-Based Risk Model to Predict Cardiovascular Mortality in Patients With Stable Coronary Disease.

PubMed

Lindholm, Daniel; Lindbäck, Johan; Armstrong, Paul W; Budaj, Andrzej; Cannon, Christopher P; Granger, Christopher B; Hagström, Emil; Held, Claes; Koenig, Wolfgang; Östlund, Ollie; Stewart, Ralph A H; Soffer, Joseph; White, Harvey D; de Winter, Robbert J; Steg, Philippe Gabriel; Siegbahn, Agneta; Kleber, Marcus E; Dressel, Alexander; Grammer, Tanja B; März, Winfried; Wallentin, Lars

2017-08-15

Currently, there is no generally accepted model to predict outcomes in stable coronary heart disease (CHD). This study evaluated and compared the prognostic value of biomarkers and clinical variables to develop a biomarker-based prediction model in patients with stable CHD. In a prospective, randomized trial cohort of 13,164 patients with stable CHD, we analyzed several candidate biomarkers and clinical variables and used multivariable Cox regression to develop a clinical prediction model based on the most important markers. The primary outcome was cardiovascular (CV) death, but model performance was also explored for other key outcomes. It was internally bootstrap validated, and externally validated in 1,547 patients in another study. During a median follow-up of 3.7 years, there were 591 cases of CV death. The 3 most important biomarkers were N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and low-density lipoprotein cholesterol, where NT-proBNP and hs-cTnT had greater prognostic value than any other biomarker or clinical variable. The final prediction model included age (A), biomarkers (B) (NT-proBNP, hs-cTnT, and low-density lipoprotein cholesterol), and clinical variables (C) (smoking, diabetes mellitus, and peripheral arterial disease). This "ABC-CHD" model had high discriminatory ability for CV death (c-index 0.81 in derivation cohort, 0.78 in validation cohort), with adequate calibration in both cohorts. This model provided a robust tool for the prediction of CV death in patients with stable CHD. As it is based on a small number of readily available biomarkers and clinical factors, it can be widely employed to complement clinical assessment and guide management based on CV risk. (The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial [STABILITY]; NCT00799903). Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Development and Application of a High-Performance Liquid Chromatography Stability-Indicating Assay for Beyond-Use Date Determination of Compounded Topical Gels Containing Multiple Active Drugs.

PubMed

Gorman, Gregory; Sokom, Simara; Coward, Lori; Arnold, John J

2017-01-01

Topical gels compounded by pharmacists are important clinical tools for the management of pain. Nevertheless, there is often a dearth of information about the chemical stability of drugs included in these topical formulations, complicating the assignment of beyond-use dating. The purpose of this study was to develop a high-performance liquid chromatography photodiode array-based stability-indicating assay that could simultaneously resolve six drugs (amitriptyline, baclofen, clonidine, gabapentin, ketoprofen, lidocaine) commonly included in topical gels for pain management and their potential degradation products. Furthermore, this method was applied to the determination of beyond-use dating of combinations of these drugs prepared in commonly utilized bases (Lipobase, Lipoderm, Pluronic organogel). Gabapentin was determined to be the least stable component in all formulations tested. Measured stability ranged between 7 to 49 days depending on the base and other active drugs present in the formulation. In the absence of gabapentin, baclofen was the next least stable component, lasting for 120 days, regardless of the type of formulating base used. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Application of Machine-Learning Models to Predict Tacrolimus Stable Dose in Renal Transplant Recipients

NASA Astrophysics Data System (ADS)

Tang, Jie; Liu, Rong; Zhang, Yue-Li; Liu, Mou-Ze; Hu, Yong-Fang; Shao, Ming-Jie; Zhu, Li-Jun; Xin, Hua-Wen; Feng, Gui-Wen; Shang, Wen-Jun; Meng, Xiang-Guang; Zhang, Li-Rong; Ming, Ying-Zi; Zhang, Wei

2017-02-01

Tacrolimus has a narrow therapeutic window and considerable variability in clinical use. Our goal was to compare the performance of multiple linear regression (MLR) and eight machine learning techniques in pharmacogenetic algorithm-based prediction of tacrolimus stable dose (TSD) in a large Chinese cohort. A total of 1,045 renal transplant patients were recruited, 80% of which were randomly selected as the “derivation cohort” to develop dose-prediction algorithm, while the remaining 20% constituted the “validation cohort” to test the final selected algorithm. MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied and their performances were compared in this work. Among all the machine learning models, RT performed best in both derivation [0.71 (0.67-0.76)] and validation cohorts [0.73 (0.63-0.82)]. In addition, the ideal rate of RT was 4% higher than that of MLR. To our knowledge, this is the first study to use machine learning models to predict TSD, which will further facilitate personalized medicine in tacrolimus administration in the future.

Using stable isotopes and models to explore estuarine linkages at multiple scales

EPA Science Inventory

Estuarine managers need tools to respond to dynamic stressors that occur in three linked environments – coastal ocean, estuaries and watersheds. Models have been the tool of choice for examining these dynamic systems because they simplify processes and integrate over multiple sc...

Functional impacts of exoskeleton-based rehabilitation in chronic stroke: multi-joint versus single-joint robotic training

PubMed Central

2013-01-01

Stroke is a major cause of disability in the world. The activities of upper limb segments are often compromised following a stroke, impairing most daily tasks. Robotic training is now considered amongst the rehabilitation methods applied to promote functional recovery. However, the implementation of robotic devices remains a major challenge for the bioengineering and clinical community. Latest exoskeletons with multiple degrees of freedom (DOF) may become particularly attractive, because of their low apparent inertia, the multiple actuators generating large torques, and the fact that patients can move the arm in the normal wide workspace. A recent study published in JNER by Milot and colleagues underlines that training with a 6-DOF exoskeleton impacts positively on motor function in patients being in stable phase of recovery after a stroke. Also, multi-joint robotic training was not found to be superior to single-joint robotic training. Although it is often considered that rehabilitation should start from simple movements to complex functional movements as the recovery evolves, this study challenges this widespread notion whose scientific basis has remained uncertain. PMID:24354518

Multiple imputation strategies for zero-inflated cost data in economic evaluations: which method works best?

PubMed

MacNeil Vroomen, Janet; Eekhout, Iris; Dijkgraaf, Marcel G; van Hout, Hein; de Rooij, Sophia E; Heymans, Martijn W; Bosmans, Judith E

2016-11-01

Cost and effect data often have missing data because economic evaluations are frequently added onto clinical studies where cost data are rarely the primary outcome. The objective of this article was to investigate which multiple imputation strategy is most appropriate to use for missing cost-effectiveness data in a randomized controlled trial. Three incomplete data sets were generated from a complete reference data set with 17, 35 and 50 % missing data in effects and costs. The strategies evaluated included complete case analysis (CCA), multiple imputation with predictive mean matching (MI-PMM), MI-PMM on log-transformed costs (log MI-PMM), and a two-step MI. Mean cost and effect estimates, standard errors and incremental net benefits were compared with the results of the analyses on the complete reference data set. The CCA, MI-PMM, and the two-step MI strategy diverged from the results for the reference data set when the amount of missing data increased. In contrast, the estimates of the Log MI-PMM strategy remained stable irrespective of the amount of missing data. MI provided better estimates than CCA in all scenarios. With low amounts of missing data the MI strategies appeared equivalent but we recommend using the log MI-PMM with missing data greater than 35 %.

No evidence of disease activity in patients receiving fingolimod at private or academic centers in clinical practice: a retrospective analysis of the multiple sclerosis, clinical, and magnetic resonance imaging outcomes in the USA (MS-MRIUS) study.

PubMed

Zivadinov, Robert; Khan, Nasreen; Korn, Jonathan R; Lathi, Ellen; Silversteen, Jason; Calkwood, Jonathan; Kolodny, Scott; Silva, Diego; Medin, Jennie; Weinstock-Guttman, Bianca

2018-04-12

The impact of multiple sclerosis (MS) center type on outcomes has not been investigated. This study aimed to evaluate baseline characteristics and clinical and magnetic resonance imaging (MRI) outcomes in patients with MS receiving fingolimod over 16 months' follow-up at private or academic centers in the USA. Clinical and MRI data collected in clinical practice from patients initiating fingolimod were stratified by center type and retrospectively analyzed. No evidence of disease activity (NEDA-3) was defined as patients with no new/enlarged T2/gadolinium-enhancing lesions, no relapses, and no disability progression (Expanded Disability Status Scale scores). Data were collected for 398 patients from 25 private centers and 192 patients from eight academic centers. Patients were older (median age = 43 vs 41 years; p = .0047) and had a numerically shorter median disease duration (7.0 vs 8.5 years; p = .0985) at private vs academic centers. Annualized relapse rate (ARR) was higher in patients at private than academic centers in the pre-index (0.40 vs 0.29; p = .0127) and post-index (0.16 vs 0.08; p = .0334) periods. The opposite was true for T2 lesion volume in the pre-index (2.86 vs 5.23 mL; p = .0002) and post-index (2.86 vs 5.11 mL; p = .0016) periods; other MRI outcomes were similar between center types. After initiating fingolimod, ARRs were reduced, disability and most MRI outcomes remained stable, and a similar proportion of patients achieved NEDA-3 at private and academic centers (64.1% vs 56.1%; p = .0659). Patient characteristics differ between private and academic centers. Over 55% of patients achieved NEDA-3 during fingolimod treatment at both center types.

Basic design of MRM assays for peptide quantification.

PubMed

James, Andrew; Jorgensen, Claus

2010-01-01

With the recent availability and accessibility of mass spectrometry for basic and clinical research, the requirement for stable, sensitive, and reproducible assays to specifically detect proteins of interest has increased. Multiple reaction monitoring (MRM) or selective reaction monitoring (SRM) is a highly selective, sensitive, and robust assay to monitor the presence and amount of biomolecules. Until recently, MRM was typically used for the detection of drugs and other biomolecules from body fluids. With increased focus on biomarkers and systems biology approaches, researchers in the proteomics field have taken advantage of this approach. In this chapter, we will introduce the reader to the basic principle of designing and optimizing an MRM workflow. We provide examples of MRM workflows for standard proteomic samples and provide suggestions for the reader who is interested in using MRM for quantification.

The domestication of the probiotic bacterium Lactobacillus acidophilus

PubMed Central

Bull, Matthew J.; Jolley, Keith A.; Bray, James E.; Aerts, Maarten; Vandamme, Peter; Maiden, Martin C. J.; Marchesi, Julian R.; Mahenthiralingam, Eshwar

2014-01-01

Lactobacillus acidophilus is a Gram-positive lactic acid bacterium that has had widespread historical use in the dairy industry and more recently as a probiotic. Although L. acidophilus has been designated as safe for human consumption, increasing commercial regulation and clinical demands for probiotic validation has resulted in a need to understand its genetic diversity. By drawing on large, well-characterised collections of lactic acid bacteria, we examined L. acidophilus isolates spanning 92 years and including multiple strains in current commercial use. Analysis of the whole genome sequence data set (34 isolate genomes) demonstrated L. acidophilus was a low diversity, monophyletic species with commercial isolates essentially identical at the sequence level. Our results indicate that commercial use has domesticated L. acidophilus with genetically stable, invariant strains being consumed globally by the human population. PMID:25425319

The domestication of the probiotic bacterium Lactobacillus acidophilus.

PubMed

Bull, Matthew J; Jolley, Keith A; Bray, James E; Aerts, Maarten; Vandamme, Peter; Maiden, Martin C J; Marchesi, Julian R; Mahenthiralingam, Eshwar

2014-11-26

Lactobacillus acidophilus is a Gram-positive lactic acid bacterium that has had widespread historical use in the dairy industry and more recently as a probiotic. Although L. acidophilus has been designated as safe for human consumption, increasing commercial regulation and clinical demands for probiotic validation has resulted in a need to understand its genetic diversity. By drawing on large, well-characterised collections of lactic acid bacteria, we examined L. acidophilus isolates spanning 92 years and including multiple strains in current commercial use. Analysis of the whole genome sequence data set (34 isolate genomes) demonstrated L. acidophilus was a low diversity, monophyletic species with commercial isolates essentially identical at the sequence level. Our results indicate that commercial use has domesticated L. acidophilus with genetically stable, invariant strains being consumed globally by the human population.

Peptide-based biosensors: From self-assembled interfaces to molecular probes in electrochemical assays.

PubMed

Puiu, Mihaela; Bala, Camelia

2018-04-01

Redox-tagged peptides have emerged as functional materials with multiple applications in the area of sensing and biosensing applications due to their high stability, excellent redox properties and versatility of biomolecular interactions. They allow direct observation of molecular interactions in a wide range of affinity and enzymatic assays and act as electron mediators. Short helical peptides possess the ability to self-assemble in specific configurations with the possibility to develop in highly-ordered, stable 1D, 2D and 3D architectures in a hierarchical controlled manner. We provide here a brief overview of the electrochemical techniques available to study the electron transfer in peptide films with particular interest in developing biosensors with immobilized peptide motifs, for biological and clinical applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Interfacial film stabilized W/O/W nano multiple emulsions loaded with green tea and lotus extracts: systematic characterization of physicochemical properties and shelf-storage stability

PubMed Central

2014-01-01

Background and aims Multiple emulsions have excellent encapsulating potential and this investigation has been aimed to encapsulate two different plant extracts as functional cosmetic agents in the W/O/W multiple emulsions and the resultant system’s long term stability has been determined in the presence of a thickener, hydroxypropyl methylcellulose (HPMC). Methods Multiple W/O/W emulsions have been generated using cetyl dimethicone copolyol as lipophilic emulsifier and a blend of polyoxyethylene (20) cetyl ether and cetomacrogol 1000® as hydrophilic emulsifiers. The generated multiple emulsions have been characterized with conductivity, pH, microscopic analysis, phase separation and rheology for a period of 30 days. Moreover, long term shelf-storage stability has been tested to understand the shelf-life by keeping the generated multiple emulsion formulations at 25 ± 10°C and at 40 ± 10% relative humidity for a period of 12 months. Results It has been observed that the hydrophilic emulsifiers and HPMC have considerably improved the stability of multiple emulsions for the followed period of 12 months at different storage conditions. These multiple emulsions have shown improved entrapment efficiencies concluded on the release rate of conductometric tracer entrapped in the inner aqueous phase of the multiple emulsions. Conclusion Multiple emulsions have been found to be stable for a longer period of time with promising characteristics. Hence, stable multiple emulsions loaded with green tea and lotus extracts could be explored for their cosmetic benefits. PMID:24885994

Response Strength in Extreme Multiple Schedules

ERIC Educational Resources Information Center

McLean, Anthony P.; Grace, Randolph C.; Nevin, John A.

2012-01-01

Four pigeons were trained in a series of two-component multiple schedules. Reinforcers were scheduled with random-interval schedules. The ratio of arranged reinforcer rates in the two components was varied over 4 log units, a much wider range than previously studied. When performance appeared stable, prefeeding tests were conducted to assess…

Verification across Multiple Identities: The Role of Status

ERIC Educational Resources Information Center

Stets, Jan E.; Harrod, Michael M.

2004-01-01

We explore how the external social structure influences internal self-processes by examining whether one's status in the social structure influences one's ability to self-verify across multiple identities. We also examine whether greater verification is related to positive self-feelings (higher self-esteem and mastery) in a stable manner, across…

Multiplicities and thermal runaway of current leads for superconducting magnets

NASA Astrophysics Data System (ADS)

Krikkis, Rizos N.

2017-04-01

The multiple solutions of conduction and vapor cooled copper leads modeling current delivery to a superconducting magnet have been numerically calculated. Both ideal convection and convection with a finite heat transfer coefficient for an imposed coolant mass flow rate have been considered. Because of the nonlinearities introduced by the temperature dependent material properties, two solutions exist, one stable and one unstable regardless of the cooling method. The limit points separating the stable form the unstable steady states form the blow-up threshold beyond which, any further increase in the operating current results in a thermal runway. An interesting finding is that the multiplicity persists even when the cold end temperature is raised above the liquid nitrogen temperature. The effect of various parameters such as the residual resistivity ratio, the overcurrent and the variable conductor cross section on the bifurcation structure and their stabilization effect on the blow-up threshold is also evaluated.

Graphene oxide selectively targets cancer stem cells, across multiple tumor types: Implications for non-toxic cancer treatment, via “differentiation-based nano-therapy”

PubMed Central

Fiorillo, Marco; Verre, Andrea F.; Iliut, Maria; Peiris-Pagés, Maria; Ozsvari, Bela; Gandara, Ricardo; Cappello, Anna Rita; Sotgia, Federica; Vijayaraghavan, Aravind; Lisanti, Michael P.

2015-01-01

Tumor-initiating cells (TICs), a.k.a. cancer stem cells (CSCs), are difficult to eradicate with conventional approaches to cancer treatment, such as chemo-therapy and radiation. As a consequence, the survival of residual CSCs is thought to drive the onset of tumor recurrence, distant metastasis, and drug-resistance, which is a significant clinical problem for the effective treatment of cancer. Thus, novel approaches to cancer therapy are needed urgently, to address this clinical need. Towards this end, here we have investigated the therapeutic potential of graphene oxide to target cancer stem cells. Graphene and its derivatives are well-known, relatively inert and potentially non-toxic nano-materials that form stable dispersions in a variety of solvents. Here, we show that graphene oxide (of both big and small flake sizes) can be used to selectively inhibit the proliferative expansion of cancer stem cells, across multiple tumor types. For this purpose, we employed the tumor-sphere assay, which functionally measures the clonal expansion of single cancer stem cells under anchorage-independent conditions. More specifically, we show that graphene oxide effectively inhibits tumor-sphere formation in multiple cell lines, across 6 different cancer types, including breast, ovarian, prostate, lung and pancreatic cancers, as well as glioblastoma (brain). In striking contrast, graphene oxide is non-toxic for “bulk” cancer cells (non-stem) and normal fibroblasts. Mechanistically, we present evidence that GO exerts its striking effects on CSCs by inhibiting several key signal transduction pathways (WNT, Notch and STAT-signaling) and thereby inducing CSC differentiation. Thus, graphene oxide may be an effective non-toxic therapeutic strategy for the eradication of cancer stem cells, via differentiation-based nano-therapy. PMID:25708684

The Changing Lifeworld of Young People: Risk, Resume-Padding, and Civic Engagement. Circle Working Paper 40

ERIC Educational Resources Information Center

Friedland, Lewis A.; Morimoto, Shauna

2005-01-01

This research assumes a relatively stable lifeworld for young people. For example, it assumes that the meaning of volunteering or service is sufficiently similar across multiple contexts to remain a valid and stable indicator. By extension, it also assumes that the lifeworld of young people today is not undergoing a period of rapid, and perhaps…

Stable scalable control of soliton propagation in broadband nonlinear optical waveguides

NASA Astrophysics Data System (ADS)

Peleg, Avner; Nguyen, Quan M.; Huynh, Toan T.

2017-02-01

We develop a method for achieving scalable transmission stabilization and switching of N colliding soliton sequences in optical waveguides with broadband delayed Raman response and narrowband nonlinear gain-loss. We show that dynamics of soliton amplitudes in N-sequence transmission is described by a generalized N-dimensional predator-prey model. Stability and bifurcation analysis for the predator-prey model are used to obtain simple conditions on the physical parameters for robust transmission stabilization as well as on-off and off-on switching of M out of N soliton sequences. Numerical simulations for single-waveguide transmission with a system of N coupled nonlinear Schrödinger equations with 2 ≤ N ≤ 4 show excellent agreement with the predator-prey model's predictions and stable propagation over significantly larger distances compared with other broadband nonlinear single-waveguide systems. Moreover, stable on-off and off-on switching of multiple soliton sequences and stable multiple transmission switching events are demonstrated by the simulations. We discuss the reasons for the robustness and scalability of transmission stabilization and switching in waveguides with broadband delayed Raman response and narrowband nonlinear gain-loss, and explain their advantages compared with other broadband nonlinear waveguides.

The Absence of a Mature Cell Wall Sacculus in Stable Listeria monocytogenes L-Form Cells Is Independent of Peptidoglycan Synthesis.

PubMed

Studer, Patrick; Borisova, Marina; Schneider, Alexander; Ayala, Juan A; Mayer, Christoph; Schuppler, Markus; Loessner, Martin J; Briers, Yves

2016-01-01

L-forms are cell wall-deficient variants of otherwise walled bacteria that maintain the ability to survive and proliferate in absence of the surrounding peptidoglycan sacculus. While transient or unstable L-forms can revert to the walled state and may still rely on residual peptidoglycan synthesis for multiplication, stable L-forms cannot revert to the walled form and are believed to propagate in the complete absence of peptidoglycan. L-forms are increasingly studied as a fundamental biological model system for cell wall synthesis. Here, we show that a stable L-form of the intracellular pathogen Listeria monocytogenes features a surprisingly intact peptidoglycan synthesis pathway including glycosyl transfer, in spite of the accumulation of multiple mutations during prolonged passage in the cell wall-deficient state. Microscopic and biochemical analysis revealed the presence of peptidoglycan precursors and functional glycosyl transferases, resulting in the formation of peptidoglycan polymers but without the synthesis of a mature cell wall sacculus. In conclusion, we found that stable, non-reverting L-forms, which do not require active PG synthesis for proliferation, may still continue to produce aberrant peptidoglycan.

Neurocognitive function in clinically stable individuals with long-term bipolar I disorder: Comparisons with schizophrenia patients and controls.

PubMed

Lin, Pei-Yun; Wang, Peng-Wei; Chen, Cheng-Sheng; Yen, Cheng-Fang

2017-05-01

This study compared the levels of the five domains of neurocognitive function-executive function, attention, memory, verbal comprehension, and perceptual organization-among clinically stable individuals with long-term bipolar I disorder, individuals with long-term schizophrenia, and a group of controls. We recruited a total of 93 clinically stable individuals with bipolar I disorder, 94 individuals with schizophrenia, and 106 controls in this study. Their neurocognitive function was measured using a series of neurocognitive function tests: the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III), Line Cancellation Test, Visual Form Discrimination, Controlled Oral Word Association Test, Wisconsin Card Sorting Test, Continuous Performance Task, and Wechsler Memory Scale-Third Edition. Neurocognitive function was compared among the three groups through a multivariate analysis of variance. The results indicated that when the effect of age was controlled, clinically stable individuals with bipolar I disorder and those with schizophrenia demonstrated poor neurocognitive function on all tests except for the WAIS-III Similarity and Information and the Line Cancellation Test. The individuals with bipolar I disorder had similar levels of neurocognitive function compared with the schizophrenia group, but higher levels of neurocognitive function on the WAIS-III Comprehension, Controlled Oral Word Association Test, and Wechsler Memory Scale-Third Edition Auditory Immediate and Delayed Index and Visual Immediate and Delayed Index. The conclusions of this study suggest that compared with controls, individuals with long-term bipolar I disorder and those with long-term schizophrenia have poorer neurocognitive function, even when clinically stable. Individuals with long-term bipolar I disorder and those with long-term schizophrenia have similar levels of deficits in several domains of neurocognitive function. Copyright © 2017. Published by Elsevier Taiwan.

Performance metric comparison study for non-magnetic bi-stable energy harvesters

NASA Astrophysics Data System (ADS)

Udani, Janav P.; Wrigley, Cailin; Arrieta, Andres F.

2017-04-01

Energy harvesting employing non-linear systems offers considerable advantages over linear systems given the broadband resonant response which is favorable for applications involving diverse input vibrations. In this respect, the rich dynamics of bi-stable systems present a promising means for harvesting vibrational energy from ambient sources. Harvesters deriving their bi-stability from thermally induced stresses as opposed to magnetic forces are receiving significant attention as it reduces the need for ancillary components and allows for bio- compatible constructions. However, the design of these bi-stable harvesters still requires further optimization to completely exploit the dynamic behavior of these systems. This study presents a comparison of the harvesting capabilities of non-magnetic, bi-stable composite laminates under variations in the design parameters as evaluated utilizing established power metrics. Energy output characteristics of two bi-stable composite laminate plates with a piezoelectric patch bonded on the top surface are experimentally investigated for variations in the thickness ratio and inertial mass positions for multiple load conditions. A particular design configuration is found to perform better over the entire range of testing conditions which include single and multiple frequency excitation, thus indicating that design optimization over the geometry of the harvester yields robust performance. The experimental analysis further highlights the need for appropriate design guidelines for optimization and holistic performance metrics to account for the range of operational conditions.

Two competing species in super-diffusive dynamical regimes

NASA Astrophysics Data System (ADS)

La Cognata, A.; Valenti, D.; Spagnolo, B.; Dubkov, A. A.

2010-09-01

The dynamics of two competing species within the framework of the generalized Lotka-Volterra equations, in the presence of multiplicative α-stable Lévy noise sources and a random time dependent interaction parameter, is studied. The species dynamics is characterized by two different dynamical regimes, exclusion of one species and coexistence of both, depending on the values of the interaction parameter, which obeys a Langevin equation with a periodically fluctuating bistable potential and an additive α-stable Lévy noise. The stochastic resonance phenomenon is analyzed for noise sources asymmetrically distributed. Finally, the effects of statistical dependence between multiplicative noise and additive noise on the dynamics of the two species are studied.

Oxidative stress biomarkers and clinical dimensions in first 10 years of schizophrenia.

PubMed

González-Blanco, Leticia; García-Portilla, María Paz; García-Álvarez, Leticia; de la Fuente-Tomás, Lorena; Iglesias García, Celso; Sáiz, Pilar A; Rodríguez-González, Susana; Coto-Montes, Ana; Bobes, Julio

2018-04-21

Several studies have described increased oxidative stress parameters in patients with schizophrenia. The objectives of the current study were to identify potential oxidative stress biomarkers in stable patients during first 10 years of schizophrenia and determine if they are associated with specific clinical dimensions. Seventy-three clinically stable outpatients with schizophrenia and 73 sex and age-matched healthy controls were recruited. Sociodemographic, clinical and biological data were collected at enrollment. Blood biomarkers included homocysteine, the percentage of hemolysis, lipid peroxidation subproducts, and as an antioxidant biomarker, catalase activity in erythrocytes. Comparative analyses after controlling for smoking and metabolic syndrome evidenced a significant increase in catalase activity in patients. Also, lower lipid peroxidation levels showed an association with negative symptoms. In conclusion, compensatory antioxidant mechanisms might be increased in stable patients with schizophrenia at early stages. Furthermore, there may be an inverse relationship between oxidative stress and negative dimension. Copyright © 2018 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.

Pattern formation of Rayleigh-Bénard convection of cold water near its density maximum in a vertical cylindrical container.

PubMed

Li, You-Rong; Ouyang, Yu-Qing; Hu, Yu-Peng

2012-10-01

In order to understand the onset of convective instability and multiple stable convection patterns of buoyancy-driven convection of cold water near its density maximum in a vertical cylindrical container heated from below, a series of three-dimensional numerical simulations were performed. The aspect ratio of the container was 2 and Prandtl number of cold water was 11.57. The sidewall was considered to be perfectly adiabatic, and the density inversion parameter was fixed at 0.3. The result shows that the density inversion phenomenon in cold water has an important effect on the critical Rayleigh number for the onset of convection and the pattern formation at higher Rayleigh numbers. When the Rayleigh number varies from 3×10(3) to 1.2×10(5), eight stable, steady convection patterns are obtained under different initial conditions. The coexistence of multiple stable steady flow patterns is also observed within some specific ranges of the Rayleigh number.

Washout and non-washout solutions of a system describing microbial fermentation process under the influence of growth inhibitions and maximal concentration of yeast cells.

PubMed

Kasbawati; Gunawan, Agus Yodi; Sidarto, Kuntjoro Adjie

2017-07-01

An unstructured model for the growth of yeast cell on glucose due to growth inhibitions by substrate, products, and cell density is discussed. The proposed model describes the dynamical behavior of fermentation system that shows multiple steady states for a certain regime of operating parameters such as inlet glucose and dilution rate. Two types of steady state solutions are found, namely washout and non-washout solutions. Furthermore, different numerical impositions to the two parameters put in evidence three results regarding non-washout solution: a unique locally stable non-washout solution, a unique locally stable non-washout solution towards which other nearby solutions exhibit damped oscillations, and multiple non-washout solutions where one is locally stable while the other is unstable. It is also found an optimal inlet glucose which produces the highest cell and ethanol concentration. Copyright © 2017 Elsevier Inc. All rights reserved.

Design and methodology of the NorthStar Study: NT-proBNP stratified follow-up in outpatient heart failure clinics -- a randomized Danish multicenter study.

PubMed

Schou, Morten; Gustafsson, Finn; Videbaek, Lars; Markenvard, John; Ulriksen, Hans; Ryde, Henrik; Jensen, Jens C H; Nielsen, Tonny; Knudsen, Anne S; Tuxen, Christian D; Handberg, Jens; Sørensen, Per J; Espersen, Geert; Lind-Rasmussen, Søren; Keller, Niels; Egstrup, Kenneth; Nielsen, Olav W; Abdulla, Jawdat; Nyvad, Ole; Toft, Jens; Hildebrandt, Per R

2008-10-01

Randomized clinical trials have shown that newly discharged and symptomatic patients with chronic heart failure (CHF) benefit from follow-up in a specialized heart failure clinic (HFC). Clinical stable and educated patients are usually discharged from the HFC when on optimal therapy. It is unknown if risk stratification using natriuretic peptides could identify patients who would benefit from longer-term follow-up. Furthermore, data on the use of natriuretic peptides for monitoring of stable patients with CHF are sparse. The aims of this study are to test the hypothesis that clinical stable, educated, and medical optimized patients with CHF with N-terminal pro-brain natriuretic peptide (NT-proBNP) levels > or = 1,000 pg/mL benefit from long-term follow-up in an HFC and to assess the efficacy of NT-proBNP monitoring. A total of 1,250 clinically stable, medically optimized, and educated patients with CHF will be enrolled from 18 HFCs in Denmark. The patients will be randomized to treatment in general practice, to a standard follow-up program in the HFC, or to NT-proBNP monitoring in the HFC. The patients will be followed for 30 months (median). Data will be collected from 2006 to 2009. At present (March 2008), 720 patients are randomized. Results expect to be presented in the second half of 2010. This article outlines the design of the NorthStar study. If our hypotheses are confirmed, the results will help cardiologists and nurses in HFCs to identify patients who may benefit from long-term follow-up. Our results may also indicate whether patients with CHF will benefit from adding serial NT-proBNP measurements to usual clinical monitoring.

Domiciliary pulse-oximetry at exacerbation of chronic obstructive pulmonary disease: prospective pilot study

PubMed Central

2010-01-01

Background The ability to objectively differentiate exacerbations of chronic obstructive pulmonary disease (COPD) from day-to-day symptom variations would be an important development in clinical practice and research. We assessed the ability of domiciliary pulse oximetry to achieve this. Methods 40 patients with moderate-severe COPD collected daily data on changes in symptoms, heart-rate (HR), oxygen saturation (SpO2) and peak-expiratory flow (PEF) over a total of 2705 days. 31 patients had data suitable for baseline analysis, and 13 patients experienced an exacerbation. Data were expressed as multiples of the standard deviation (SD) observed from each patient when stable. Results In stable COPD, the SD for HR, SpO2 and PEF were approximately 5 min-1, 1% and 10l min-1. There were detectable changes in all three variables just prior to exacerbation onset, greatest 2-3 days following symptom onset. A composite Oximetry Score (mean magnitude of SpO2 fall and HR rise) distinguished exacerbation onset from symptom variation (area under receiver-operating characteristic curve, AUC = 0.832, 95%CI 0.735-0.929, p = 0.003). In the presence of symptoms, a change in Score of ≥1 (average of ≥1SD change in both HR and SpO2) was 71% sensitive and 74% specific for exacerbation onset. Conclusion We have defined normal variation of pulse oximetry variables in a small sample of patients with COPD. A composite HR and SpO2 score distinguished exacerbation onset from symptom variation, potentially facilitating prompt therapy and providing validation of such events in clinical trials. PMID:20961450

Outcome definitions and clinical predictors influence pharmacogenetic associations between HTR3A gene polymorphisms and response to clozapine in patients with schizophrenia.

PubMed

Rajkumar, A P; Poonkuzhali, B; Kuruvilla, A; Srivastava, A; Jacob, M; Jacob, K S

2012-12-01

Pharmacogenetics of schizophrenia has not yet delivered anticipated clinical dividends. Clinical heterogeneity of schizophrenia contributes to the poor replication of the findings of pharmacogenetic association studies. Functionally important HTR3A gene single-nucleotide polymorphisms (SNPs) were reported to be associated with response to clozapine. The aim of this study was to investigate how the association between HTR3A gene SNP and response to clozapine is influenced by various clinical predictors and by differing outcome definitions in patients with treatment-resistant schizophrenia (TRS). We recruited 101 consecutive patients with TRS, on stable doses of clozapine, and evaluated their HTR3A gene SNP (rs1062613 and rs2276302), psychopathology, and serum clozapine levels. We assessed their socio-demographic and clinical profiles, premorbid adjustment, traumatic events, cognition, and disability using standard assessment schedules. We evaluated their response to clozapine, by employing six differing outcome definitions. We employed appropriate multivariate statistics to calculate allelic and genotypic association, accounting for the effects of various clinical variables. T allele of rs1062613 and G allele of rs2276302 were significantly associated with good clinical response to clozapine (p = 0.02). However, varying outcome definitions make these associations inconsistent. rs1062613 and rs2276302 could explain only 13.8 % variability in the responses to clozapine, while combined clinical predictors and HTR3A pharmacogenetic association model could explain 38 % variability. We demonstrated that the results of pharmacogenetic studies in schizophrenia depend heavily on their outcome definitions and that combined clinical and pharmacogenetic models have better predictive values. Future pharmacogenetic studies should employ multiple outcome definitions and should evaluate associated clinical variables.

The Face-Processing Network Is Resilient to Focal Resection of Human Visual Cortex

PubMed Central

Jonas, Jacques; Gomez, Jesse; Maillard, Louis; Brissart, Hélène; Hossu, Gabriela; Jacques, Corentin; Loftus, David; Colnat-Coulbois, Sophie; Stigliani, Anthony; Barnett, Michael A.; Grill-Spector, Kalanit; Rossion, Bruno

2016-01-01

Human face perception requires a network of brain regions distributed throughout the occipital and temporal lobes with a right hemisphere advantage. Present theories consider this network as either a processing hierarchy beginning with the inferior occipital gyrus (occipital face area; IOG-faces/OFA) or a multiple-route network with nonhierarchical components. The former predicts that removing IOG-faces/OFA will detrimentally affect downstream stages, whereas the latter does not. We tested this prediction in a human patient (Patient S.P.) requiring removal of the right inferior occipital cortex, including IOG-faces/OFA. We acquired multiple fMRI measurements in Patient S.P. before and after a preplanned surgery and multiple measurements in typical controls, enabling both within-subject/across-session comparisons (Patient S.P. before resection vs Patient S.P. after resection) and between-subject/across-session comparisons (Patient S.P. vs controls). We found that the spatial topology and selectivity of downstream ipsilateral face-selective regions were stable 1 and 8 month(s) after surgery. Additionally, the reliability of distributed patterns of face selectivity in Patient S.P. before versus after resection was not different from across-session reliability in controls. Nevertheless, postoperatively, representations of visual space were typical in dorsal face-selective regions but atypical in ventral face-selective regions and V1 of the resected hemisphere. Diffusion weighted imaging in Patient S.P. and controls identifies white matter tracts connecting retinotopic areas to downstream face-selective regions, which may contribute to the stable and plastic features of the face network in Patient S.P. after surgery. Together, our results support a multiple-route network of face processing with nonhierarchical components and shed light on stable and plastic features of high-level visual cortex following focal brain damage. SIGNIFICANCE STATEMENT Brain networks consist of interconnected functional regions commonly organized in processing hierarchies. Prevailing theories predict that damage to the input of the hierarchy will detrimentally affect later stages. We tested this prediction with multiple brain measurements in a rare human patient requiring surgical removal of the putative input to a network processing faces. Surprisingly, the spatial topology and selectivity of downstream face-selective regions are stable after surgery. Nevertheless, representations of visual space were typical in dorsal face-selective regions but atypical in ventral face-selective regions and V1. White matter connections from outside the face network may support these stable and plastic features. As processing hierarchies are ubiquitous in biological and nonbiological systems, our results have pervasive implications for understanding the construction of resilient networks. PMID:27511014

Improvements in cognition, quality of life, and physical performance with clinical Pilates in multiple sclerosis: a randomized controlled trial

PubMed Central

Küçük, Fadime; Kara, Bilge; Poyraz, Esra Çoşkuner; İdiman, Egemen

2016-01-01

[Purpose] The aim of this study was to determine the effects of clinical Pilates in multiple sclerosis patients. [Subjects and Methods] Twenty multiple sclerosis patients were enrolled in this study. The participants were divided into two groups as the clinical Pilates and control groups. Cognition (Multiple Sclerosis Functional Composite), balance (Berg Balance Scale), physical performance (timed performance tests, Timed up and go test), tiredness (Modified Fatigue Impact scale), depression (Beck Depression Inventory), and quality of life (Multiple Sclerosis International Quality of Life Questionnaire) were measured before and after treatment in all participants. [Results] There were statistically significant differences in balance, timed performance, tiredness and Multiple Sclerosis Functional Composite tests between before and after treatment in the clinical Pilates group. We also found significant differences in timed performance tests, the Timed up and go test and the Multiple Sclerosis Functional Composite between before and after treatment in the control group. According to the difference analyses, there were significant differences in Multiple Sclerosis Functional Composite and Multiple Sclerosis International Quality of Life Questionnaire scores between the two groups in favor of the clinical Pilates group. There were statistically significant clinical differences in favor of the clinical Pilates group in comparison of measurements between the groups. Clinical Pilates improved cognitive functions and quality of life compared with traditional exercise. [Conclusion] In Multiple Sclerosis treatment, clinical Pilates should be used as a holistic approach by physical therapists. PMID:27134355

Improvements in cognition, quality of life, and physical performance with clinical Pilates in multiple sclerosis: a randomized controlled trial.

PubMed

Küçük, Fadime; Kara, Bilge; Poyraz, Esra Çoşkuner; İdiman, Egemen

2016-03-01

[Purpose] The aim of this study was to determine the effects of clinical Pilates in multiple sclerosis patients. [Subjects and Methods] Twenty multiple sclerosis patients were enrolled in this study. The participants were divided into two groups as the clinical Pilates and control groups. Cognition (Multiple Sclerosis Functional Composite), balance (Berg Balance Scale), physical performance (timed performance tests, Timed up and go test), tiredness (Modified Fatigue Impact scale), depression (Beck Depression Inventory), and quality of life (Multiple Sclerosis International Quality of Life Questionnaire) were measured before and after treatment in all participants. [Results] There were statistically significant differences in balance, timed performance, tiredness and Multiple Sclerosis Functional Composite tests between before and after treatment in the clinical Pilates group. We also found significant differences in timed performance tests, the Timed up and go test and the Multiple Sclerosis Functional Composite between before and after treatment in the control group. According to the difference analyses, there were significant differences in Multiple Sclerosis Functional Composite and Multiple Sclerosis International Quality of Life Questionnaire scores between the two groups in favor of the clinical Pilates group. There were statistically significant clinical differences in favor of the clinical Pilates group in comparison of measurements between the groups. Clinical Pilates improved cognitive functions and quality of life compared with traditional exercise. [Conclusion] In Multiple Sclerosis treatment, clinical Pilates should be used as a holistic approach by physical therapists.

Safety and tolerability profile of daclizumab in patients with relapsing-remitting multiple sclerosis: An integrated analysis of clinical studies.

PubMed

Giovannoni, Gavin; Kappos, Ludwig; Gold, Ralf; Khatri, Bhupendra O; Selmaj, Krzysztof; Umans, Kimberly; Greenberg, Steven J; Sweetser, Marianne; Elkins, Jacob; McCroskery, Peter

2016-09-01

Daclizumab has been evaluated in multicentre, randomised, double-blind studies for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). Safety and tolerability are key considerations in MS treatment selection, as they influence adherence to medication. Evaluate the safety of daclizumab in patients with RRMS from an integrated analysis of six clinical studies. Patients treated with at least one dose of subcutaneous daclizumab 150mg or 300mg monthly in three completed and three ongoing clinical studies were included in this integrated analysis. Cumulative incidence of treatment-emergent adverse events (AEs) was the primary endpoint. This analysis included 2236 patients with 5214 patient-years of exposure to daclizumab. The cumulative incidence of any AE was 84% and of any serious AE excluding MS relapse was 16%. The incidences of AEs when evaluated by 6-month intervals remained stable over the 6.5 years of maximum follow-up. Most AEs were mild or moderate in severity. An important safety concern associated with daclizumab therapy involved hepatic AEs (16%) and serum transaminase elevations at least three times the upper limit of normal (10%), most of which were asymptomatic, self-limiting, and non-recurring. Cumulative incidences of cutaneous, infectious, and gastrointestinal AEs were 33%, 59%, and 25%, respectively; most events either resolved spontaneously or were treated successfully with standard medical interventions and did not result in discontinuation of treatment. This integrated analysis demonstrates that treatment of RRMS with daclizumab for periods of up to 6.5 years is associated with an acceptable safety profile with no evidence of cumulative toxicity over time. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Cerebral palsy rates by birth weight, gestation and severity in North of England, 1991-2000 singleton births.

PubMed

Glinianaia, Svetlana V; Rankin, Judith; Colver, Allan

2011-02-01

To investigate changes in rates of cerebral palsy (CP) by birth weight, gestational age, severity of disability, clinical subtype and maternal age in the North of England, 1991-2000. Data on 908 cases of CP (816 singletons, 92 multiples) were analysed from the prospective population-based North of England Collaborative Cerebral Palsy Survey. Severity of disability, measured as a Lifestyle Assessment Score (LAS), was derived from the lifestyle assessment questionnaire. CP rates by birth weight, gestational age, birth weight standardised for gestational age and sex, severity of disability and maternal age were compared between 1991-1995 and 1996-2000 using rate ratios (RR). The prevalence of CP in singletons was 2.46 (95% CI 2.29 to 2.63) per 1000 neonatal survivors compared to 11.06 per 1000 (95% CI 8.81 to 13.3) in multiples (RR 4.49, 95% CI 3.62 to 5.57), with no significant change between quinquennia. The singleton CP rates were higher for lower birth weight groups than birth weight ≥2500 g; and there were no significant changes for any birth weight group between quinquennia. There were also no changes in rates of more severe disability (LAS≥30%) by birth weight, gestation or clinical subtype. For preterm and term births the patterns of Z-score of birth weight-for-gestation are similar, with CP rates increasing as Z-score deviates from the optimal weight-for-gestation, which is about 1 SD above the mean. In contrast to increasing rates in previous years, rates of CP and more severe CP were stable by birth weight, gestational age and clinical subtype for 1991-2000.

Clinical application of inert gas Multiple Breath Washout in children and adolescents with asthma.

PubMed

Zwitserloot, Annelies; Fuchs, Susanne I; Müller, Christina; Bisdorf, Kornelia; Gappa, Monika

2014-09-01

Children with asthma often have normal spirometry despite significant disease. The pathology of the small airways in asthma may be assessed using Multiple Breath Washout (MBW) and calculating the Lung Clearance Index (LCI). There are only few studies using MBW in children with asthma and existing data regarding bronchodilator effect are contradictory. The aim of the present pilot study was to compare LCI in asthma and controls and assess the effect of salbutamol in children with asthma on the LCI. Unselected patients with a diagnosis of asthma visiting the outpatient department of our hospital between 04-2010 and 03-2011 were recruited and compared to a healthy control group. MBW was performed as inert gas MBW using sulfurhexafluorid (SF6) as the tracer gas. Clinical data were documented and spirometry and MBW (EasyOne Pro, MBW module, NDD Switzerland) were performed before and after the use of salbutamol (200-400 μg). Healthy controls performed baseline MBW only. 32 children diagnosed with asthma (4.7-17.4 years) and 42 controls (5.3-20.8) were included in the analysis. LCI differed between patients and controls, with a mean LCI (SD) of 6.48 (0.48) and 6.21 (0.38) (P = 0.008). Use of salbutamol had no significant effect on LCI for the group. These pilot data show that clinically stable asthma patients and controls both have a LCI in the normal range. However, in patients the LCI is significantly higher indicating that MBW may have a role in assessing small airways disease in asthma. Copyright © 2014 Elsevier Ltd. All rights reserved.

PHYSICAL AND CHEMICAL STABILITY ANALYSIS OF COSMETIC MULTI- PLE EMULSIONS LOADED WITH ASCORBYL PALMITATE AND SODIUM ASCORBYL PHOSPHATE SALTS.

PubMed

Khan, Hira; Akhtar, Naveed; Ali, Atif; Khan, Haji M Shoaib; Sohail, Muhammad; Naeem, Muhammad; Nawaz, Zarqa

2016-09-01

Stability of hydrophilic and lipophilic vitamin C derivatives for quenching synergistic antioxidant activities and to treat oxidative related diseases is a major issue. This study was aimed to encapsulate hydrophilic and lipophilic vitamin C derivatives (ascorbyl palmitate and sodium ascorbyl phosphate) as functional ingredients in a newly formulated multiple emulsion of the W//W type to attain the synergistic antioxidant effects and the resultant system's long term physical and chemical stability. Several multiple emulsions using the same concentration of emulsifiers but different concentrations of ascorbyl palmitate and sodium ascorbyl phosphate were developed. Three finally selected multiple emulsions (ME₁, ME₂ and ME₃) were evaluated for physical stability in terms of rheology, microscopy, conductivity, pH, and organoleptic characteristics under different storage conditions for 3 months. Chemical stability was determined by HPLC on Sykam GmbH HPLC system (Germany), equipped with a variable UV detector. Results showed that at accelerated storage conditions all the three multiple emulsions had shear thinning behavior of varying shear stress with no influence of location of functional ingredients in a carrier system. Conductivity values increased and pH values remained within the skin pH range for 3 months. Microscopic analysis showed an increase in globule size with the passage of time, especially at higher temperatures while decreased at low temperatures. Centrifugation test did not cause phase separation till the 45th day, but little effects after 2 months. Chemical stability analysis by HPLC at the end of 3 months showed that ascorbyl palmitate and sodium ascorbyl phosphate were almost stable in all multiple emulsions with no influence of their location in a carrier system. Multiple emulsions were found a stable carrier for hydrophilic and lipophilic vitamin C derivatives to enhance their desired effects. Considering that many topical formulations contain simple vitamin C it is suggested that present study may contribute to the development of more stable formulations with a combination of vitamin C derivatives to enhance their cosmetic benefits.

Impact of osmotic pressure and gelling in the generation of highly stable single core water-in-oil-in-water (W/O/W) nano multiple emulsions of aspirin assisted by two-stage ultrasonic cavitational emulsification.

PubMed

Tang, Siah Ying; Sivakumar, Manickam; Nashiru, Billa

2013-02-01

The present investigation focuses in investigating the effect of osmotic pressure, gelling on the mean droplet diameter, polydispersity index, droplet size stability of the developed novel Aspirin containing water-in-oil-in-water (W/O/W) nano multiple emulsion. The aspirin-loaded nano multiple emulsion formulation was successfully generated using two-stage ultrasonic cavitational emulsification which had been reported in author's previous study. The osmotic behavior of ultrasonically prepared nano multiple emulsions were also examined with different glucose concentrations both in the inner and outer aqueous phases. In addition, introducing gelatin into the formulation also observed to play an important role in preventing the interdroplet coalescence via the formation of interfacial rigid film. Detailed studies were also made on the possible mechanisms of water migration under osmotic gradient which primarily caused by the permeation of glucose. Besides, the experimental results have shown that the interfacial tension between the two immiscible phases decreases with varying the composition of organic phase. Although the W/O/W emulsion prepared with the inner/outer glucose weight ratio of 1-0.5% (w/w) showed an excellent droplet stability, the formulation containing 0.5% (w/w) glucose in the inner aqueous phase appeared to be the most stable with minimum change in the mean droplet size upon one-week storage period. Based on the optimization, nano multiple emulsion droplets with the mean droplet diameter of around 400 nm were produced using 1.25% (w/w) Span 80 and 0.5% Cremophore EL. Overall, our investigation makes a pathway in proving that the use of ultrasound cavitation is an efficient yet promising approach in the generation of stable and uniform nano multiple emulsions and could be used in the encapsulation of various active pharmaceutical ingredients in the near future. Copyright © 2012 Elsevier B.V. All rights reserved.

Analysis of practical backoff protocols for contention resolution with multiple servers

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

Goldberg, L.A.; MacKenzie, P.D.

Backoff protocols are probably the most widely used protocols for contention resolution in multiple access channels. In this paper, we analyze the stochastic behavior of backoff protocols for contention resolution among a set of clients and servers, each server being a multiple access channel that deals with contention like an Ethernet channel. We use the standard model in which each client generates requests for a given server according to a Bemoulli distribution with a specified mean. The client-server request rate of a system is the maximum over all client-server pairs (i, j) of the sum of all request rates associatedmore » with either client i or server j. Our main result is that any superlinear polynomial backoff protocol is stable for any multiple-server system with a sub-unit client-server request rate. We confirm the practical relevance of our result by demonstrating experimentally that the average waiting time of requests is very small when such a system is run with reasonably few clients and reasonably small request rates such as those that occur in actual ethernets. Our result is the first proof of stability for any backoff protocol for contention resolution with multiple servers. Our result is also the first proof that any weakly acknowledgment based protocol is stable for contention resolution with multiple servers and such high request rates. Two special cases of our result are of interest. Hastad, Leighton and Rogoff have shown that for a single-server system with a sub-unit client-server request rate any modified superlinear polynomial backoff protocol is stable. These modified backoff protocols are similar to standard backoff protocols but require more random bits to implement. The special case of our result in which there is only one server extends the result of Hastad, Leighton and Rogoff to standard (practical) backoff protocols. Finally, our result applies to dynamic routing in optical networks.« less

Risk Factors for Sexually Transmitted Disease Among Rural-to-Urban Migrants in China: Implications for HIV/Sexually Transmitted Disease Prevention

PubMed Central

LIU, HONGJIE; LI, XIAOMING; STANTON, BONITA; LIU, HUI; LIANG, GUOJUN; CHEN, XINGUANG; YANG, HONGMEI; HONG, YAN

2007-01-01

The objective of the study was to identify risk factors associated with sexually transmitted diseases (STDs) among rural-to-urban migrants in Beijing in 2002. Migrants with STDs consisted of 432 migrants who sought STD care in two public STD clinics. Migrants without STDs included 892 migrants recruited from 10 occupational clusters. Multiple logistic regression was used for data analysis. Compared to migrants without STDs, migrants with STDs were more likely to report having engaged in commercial sex (selling or buying sex) (odds ratio [OR] = 2.70, 95% confidence interval [CI]: 1.71–4.25), multiple sex partners in the previous month (OR = 6.50, 95% CI: 3.73–11.32) and higher perceived HIV-related stigma (OR = 1.89, 95% CI: 1.30–2.75). Being a migrant with an STD was also associated with female gender (OR = 4.10, 95% CI: 2.89–5.82), higher education (OR = 2.92, 95% CI: 1.40–6.06), and higher monthly salary (OR = 1.68. 95% CI: 1.23–2.29). Migrants with STDs visited their hometowns more frequently and had more stable jobs than migrants without STDs. Approximately 10% of the migrants with STDs and 7.7% of the migrants without STDs always used condoms. This study suggests that among migrants, acquisition of an STD is associated with higher participation in risk behaviors as would be expected, but also with higher perceived stigma, education, stable jobs, salary, and with female gender. Appropriate behavioral intervention programs are advocated to reduce the risk and stigma among the special population. PMID:15665635

Induction of broad immunity by thermostabilised vaccines incorporated in dissolvable microneedles using novel fabrication methods.

PubMed

Vrdoljak, Anto; Allen, Evin A; Ferrara, Francesca; Temperton, Nigel J; Crean, Abina M; Moore, Anne C

2016-03-10

Dissolvable microneedle (DMN) patches for immunization have multiple benefits, including vaccine stability and ease-of-use. However, conventional DMN fabrication methods have several drawbacks. Here we describe a novel, microfluidic, drop dispensing-based dissolvable microneedle production method that overcomes these issues. Uniquely, heterogeneous arrays, consisting of microneedles of diverse composition, can be easily produced on the same patch. Robustness of the process was demonstrated by incorporating and stabilizing adenovirus and MVA vaccines. Clinically-available trivalent inactivated influenza vaccine (TIV) in DMN patches is fully stable for greater than 6months at 40°C. Immunization using low dose TIV-loaded DMN patches induced significantly higher antibody responses compared to intramuscular-based immunization in mice. TIV-loaded patches also induced a broader, heterosubtypic neutralizing antibody response. By addressing issues that will be faced in large-scale fill-finish DMN fabrication processes and demonstrating superior thermostable characteristics and immunogenicity, this study progresses the translation of this microneedle platform to eventual clinical deployment. Copyright © 2016 Elsevier B.V. All rights reserved.

A case of neurosarcoidosis secondary to treatment of etanercept and review of the literature.

PubMed

Berrios, Idanis; Jun-O'Connell, Adalia; Ghiran, Sorina; Ionete, Carolina

2015-07-06

There are only three cases in the literature that describe development of neurosarcoidosis in a patient who is on tumour necrosis factor α inhibitors. We describe a case of a 33-year-old woman with a history of juvenile rheumatoid arthritis and refractory uveitis (with previous treatment trials of adalimumab, infliximab, mycophenolate, methotrexate) who had been stable for 2 years on etanercept. She was diagnosed with biopsy-proven systemic sarcoidosis with meningeal and parenchymal neurosarcoidosis. She was switched to infliximab and methotrexate, with clinical and imaging improvements. This is a case that demonstrates the difficulty of choosing tumour necrosis factor α (TNF-α) inhibitors when treating patients with multiple clinical autoimmune entities. It is also a case where a change in the mechanism of TNF-α inhibition pathway can still be used to treat refractory sarcoidoisis and rheumatoid arthritis. It is still unclear what the exact difference between the TNF-α blockers and their neurological complications is, and who the patients at risk of developing neurological complications are. 2015 BMJ Publishing Group Ltd.

Estimating individual glomerular volume in the human kidney: clinical perspectives.

PubMed

Puelles, Victor G; Zimanyi, Monika A; Samuel, Terence; Hughson, Michael D; Douglas-Denton, Rebecca N; Bertram, John F; Armitage, James A

2012-05-01

Measurement of individual glomerular volumes (IGV) has allowed the identification of drivers of glomerular hypertrophy in subjects without overt renal pathology. This study aims to highlight the relevance of IGV measurements with possible clinical implications and determine how many profiles must be measured in order to achieve stable size distribution estimates. We re-analysed 2250 IGV estimates obtained using the disector/Cavalieri method in 41 African and 34 Caucasian Americans. Pooled IGV analysis of mean and variance was conducted. Monte-Carlo (Jackknife) simulations determined the effect of the number of sampled glomeruli on mean IGV. Lin's concordance coefficient (R(C)), coefficient of variation (CV) and coefficient of error (CE) measured reliability. IGV mean and variance increased with overweight and hypertensive status. Superficial glomeruli were significantly smaller than juxtamedullary glomeruli in all subjects (P < 0.01), by race (P < 0.05) and in obese individuals (P < 0.01). Subjects with multiple chronic kidney disease (CKD) comorbidities showed significant increases in IGV mean and variability. Overall, mean IGV was particularly reliable with nine or more sampled glomeruli (R(C) > 0.95, <5% difference in CV and CE). These observations were not affected by a reduced sample size and did not disrupt the inverse linear correlation between mean IGV and estimated total glomerular number. Multiple comorbidities for CKD are associated with increased IGV mean and variance within subjects, including overweight, obesity and hypertension. Zonal selection and the number of sampled glomeruli do not represent drawbacks for future longitudinal biopsy-based studies of glomerular size and distribution.

From Coordination Cages to a Stable Crystalline Porous Hydrogen-Bonded Framework

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

Ju, Zhanfeng; Liu, Guoliang; Chen, Yu-Sheng

2017-03-20

A stable framework has been constructed through multiple charge-assisted H-bonds between cationic coordination cages and chloride ions. The framework maintained its original structure upon desolvation, which has been established by single-crystal structure analysis. This is the first fully characterized stable porous framework based on coordination cages after desolvation, with a moderately high Brunauer–Emmett–Teller (BET) surface area of 1201 m2 g-1. This work will not only give a light to construct stable porous frameworks based on coordination cages and thus broaden their applications, but will also provide a new avenue to the assembly of other porous materials such as porous organicmore » cages and hydrogen-bonded organic frameworks (HOFs) through non covalent bonds.« less

Unilateral facial palsy in an infant: an unusual presentation of familial multiple cerebral cavernous malformation

PubMed Central

Zakaria, Zaitun; Kaliaperumal, Chandrasekaran; Caird, John; Sattar, Mohammad

2012-01-01

Cerebral cavernous malformation (CCM) in infants tends to have genetic predisposition. These cavernomas have a progressive course of events and associated neurological symptoms with increase in age. They most commonly present with seizure and syndrome of increased intracranial pressure comprising of headache, vomiting and focal neurological signs. We describe a case of a 7-month-old infant who presented with an acute onset of right facial paralysis with a background of familial CCM. The CT and MRI scan revealed fresh haemorrhage in the right cerebellar and pontine cavernomas with surrounding oedema and no evidence of obstructive hydrocephalus. These two cavernomas re-bled in a week duration causing episodes of incessant crying and irritability. After discussing the pros and cons of treatment, owing to stable clinical status, the patient is currently been managed conservatively. PMID:23203183

A gastrointestinal anti-infectious biotherapeutic agent: the heat-treated Lactobacillus LB

PubMed Central

Liévin-Le Moal, Vanessa

2016-01-01

Experimental in vitro and in vivo studies support the hypothesis that heat-treated, lyophilized Lactobacillus acidophilus LB cells and concentrated, neutralized spent culture medium conserve the variety of pharmacological, antimicrobial activities of the live probiotic strain against several infectious agents involved in well-established acute and persistent watery diarrhoea and gastritis. Heat-treated cells and heat-stable secreted molecules trigger multiple strain-specific activities explaining the therapeutic efficacy of L. acidophilus LB. This review discusses the current body of knowledge on the antimicrobial mechanisms of action exerted by L. acidophilus LB demonstrated in in vitro and in vivo experimental studies, and the evidence for the therapeutic efficacy of this anti-infectious biotherapeutic agent proved in randomized clinical trials for the treatment of acute and persistent watery diarrhoea associated with several intestinal infectious diseases in humans. PMID:26770268

Genomic and epigenomic heterogeneity in molecular subtypes of gastric cancer.

PubMed

Lim, Byungho; Kim, Jong-Hwan; Kim, Mirang; Kim, Seon-Young

2016-01-21

Gastric cancer is a complex disease that is affected by multiple genetic and environmental factors. For the precise diagnosis and effective treatment of gastric cancer, the heterogeneity of the disease must be simplified; one way to achieve this is by dividing the disease into subgroups. Toward this effort, recent advances in high-throughput sequencing technology have revealed four molecular subtypes of gastric cancer, which are classified as Epstein-Barr virus-positive, microsatellite instability, genomically stable, and chromosomal instability subtypes. We anticipate that this molecular subtyping will help to extend our knowledge for basic research purposes and will be valuable for clinical use. Here, we review the genomic and epigenomic heterogeneity of the four molecular subtypes of gastric cancer. We also describe a mutational meta-analysis and a reanalysis of DNA methylation that were performed using previously reported gastric cancer datasets.

Treatment of Gingival Recessions Associated to Cervical Abrasion Lesions with Subepithelial Connective Tissue Graft: A Case Report

PubMed Central

Deliberador, Tatiana M.; Bosco, Alvaro F.; Martins, Thiago M.; Nagata, Maria J. H.

2009-01-01

Extensive gingival recessions associated with cervical abrasions are common among the population. Several different surgical and/or restorative therapies have been proposed to correct these lesions. This manuscript reports the treatment of multiple gingival recessions associated to cervical abrasions. The procedure involved the utilization of subepithelial connective tissue graft (SCTG) combined with coronally advanced flap onto a previously restored root surface. At the postoperative follow-up visits, the success of the restorative/surgical approach was confirmed by the absence of bleeding to probing and periodontal pockets as well as presence of gingival tissue with normal color, texture and contouring. After 18 months of follow-up, the clinical conditions are stable with satisfactory root coverage and periodontal health. An excellent esthetical outcome was achieved and the patient is satisfied with case resolution. PMID:19826605

Using d15 N in Fish Larvae as an Indicator of Watershed Sources of Anthropogenic Nitrogen: Response at Multiple Spatial Scales

EPA Science Inventory

The nitrogen stable isotope, 15N, is an effective tool to track anthropogenic N sources to aquatic ecosystems. It may be difficult to identify potential N sources, however, where 15N responds similarly to multiple, concurrent activities in the watershed that cause higher nutrient...

Highly scalable multichannel mesh electronics for stable chronic brain electrophysiology

PubMed Central

Fu, Tian-Ming; Hong, Guosong; Viveros, Robert D.; Zhou, Tao

2017-01-01

Implantable electrical probes have led to advances in neuroscience, brain−machine interfaces, and treatment of neurological diseases, yet they remain limited in several key aspects. Ideally, an electrical probe should be capable of recording from large numbers of neurons across multiple local circuits and, importantly, allow stable tracking of the evolution of these neurons over the entire course of study. Silicon probes based on microfabrication can yield large-scale, high-density recording but face challenges of chronic gliosis and instability due to mechanical and structural mismatch with the brain. Ultraflexible mesh electronics, on the other hand, have demonstrated negligible chronic immune response and stable long-term brain monitoring at single-neuron level, although, to date, it has been limited to 16 channels. Here, we present a scalable scheme for highly multiplexed mesh electronics probes to bridge the gap between scalability and flexibility, where 32 to 128 channels per probe were implemented while the crucial brain-like structure and mechanics were maintained. Combining this mesh design with multisite injection, we demonstrate stable 128-channel local field potential and single-unit recordings from multiple brain regions in awake restrained mice over 4 mo. In addition, the newly integrated mesh is used to validate stable chronic recordings in freely behaving mice. This scalable scheme for mesh electronics together with demonstrated long-term stability represent important progress toward the realization of ideal implantable electrical probes allowing for mapping and tracking single-neuron level circuit changes associated with learning, aging, and neurodegenerative diseases. PMID:29109247

Plasmon-mediated binding forces on gold or silver homodimer and heterodimer

NASA Astrophysics Data System (ADS)

Liaw, Jiunn-Woei; Kuo, Ting-Yu; Kuo, Mao-Kuen

2016-02-01

This study theoretically investigates plasmon-mediated optical binding forces, which are exerted on metal homo or heterodimers, induced by the normal illumination of a linearly polarized plane wave or Gaussian beam. Using the multiple multipole method, we analyzed the optical force in terms of Maxwell's stress tensor for various interparticle distance at some specific wavelengths. Numerical results show that for a given wavelength there are several stable equilibrium distances between two nanoparticles (NPs) of a homodimer, which are slightly shorter than some integer multiples of the wavelength in medium, such that metal dimer acts as bonded together. At these specific interparticle distances, the optical force between dimer is null and serves a restoring force, which is repulsive and attractive, respectively, as the two NPs are moving closer to and away from each other. The spring constant of the restoring force at the first stable equilibrium is always the largest, indicating that the first stable equilibrium distance is the most stable one. Moreover, the central line (orientation) of a dimer tends to be perpendicular to the polarization of light. For the cases of heterodimers, the phenomenon of stable equilibrium interparticle distance still exists, except there is an extra net photophoretic force drifting the heterodimer as one. Moreover, gradient force provided by a Gaussian beam may reduce the stability of these equilibriums, so larger NPs are preferred to stabilize a dimer under illumination of Gaussian beam. The finding may pave the way for using optical manipulation on the gold or silver colloidal self-assembly.

Detection of social group instability among captive rhesus macaques using joint network modeling

PubMed Central

Beisner, Brianne A.; Jin, Jian; Fushing, Hsieh; Mccowan, Brenda

2015-01-01

Social stability in group-living animals is an emergent property which arises from the interaction amongst multiple behavioral networks. However, pinpointing when a social group is at risk of collapse is difficult. We used a joint network modeling approach to examine the interdependencies between two behavioral networks, aggression and status signaling, from four stable and three unstable groups of rhesus macaques in order to identify characteristic patterns of network interdependence in stable groups that are readily distinguishable from unstable groups. Our results showed that the most prominent source of aggression-status network interdependence in stable social groups came from more frequent dyads than expected with opposite direction status-aggression (i.e. A threatens B and B signals acceptance of subordinate status). In contrast, unstable groups showed a decrease in opposite direction aggression-status dyads (but remained higher than expected) as well as more frequent than expected dyads with bidirectional aggression. These results demonstrate that not only was the stable joint relationship between aggression and status networks readily distinguishable from unstable time points, social instability manifested in at least two different ways. In sum, our joint modeling approach may prove useful in quantifying and monitoring the complex social dynamics of any wild or captive social system, as all social systems are composed of multiple interconnected networks PMID:26052339

Revealing stable processing products from ribosome-associated small RNAs by deep-sequencing data analysis.

PubMed

Zywicki, Marek; Bakowska-Zywicka, Kamilla; Polacek, Norbert

2012-05-01

The exploration of the non-protein-coding RNA (ncRNA) transcriptome is currently focused on profiling of microRNA expression and detection of novel ncRNA transcription units. However, recent studies suggest that RNA processing can be a multi-layer process leading to the generation of ncRNAs of diverse functions from a single primary transcript. Up to date no methodology has been presented to distinguish stable functional RNA species from rapidly degraded side products of nucleases. Thus the correct assessment of widespread RNA processing events is one of the major obstacles in transcriptome research. Here, we present a novel automated computational pipeline, named APART, providing a complete workflow for the reliable detection of RNA processing products from next-generation-sequencing data. The major features include efficient handling of non-unique reads, detection of novel stable ncRNA transcripts and processing products and annotation of known transcripts based on multiple sources of information. To disclose the potential of APART, we have analyzed a cDNA library derived from small ribosome-associated RNAs in Saccharomyces cerevisiae. By employing the APART pipeline, we were able to detect and confirm by independent experimental methods multiple novel stable RNA molecules differentially processed from well known ncRNAs, like rRNAs, tRNAs or snoRNAs, in a stress-dependent manner.

The 11-year long-term follow-up study from the randomized BENEFIT CIS trial

PubMed Central

Edan, Gilles; Freedman, Mark S.; Montalbán, Xavier; Hartung, Hans-Peter; Hemmer, Bernhard; Fox, Edward J.; Barkhof, Frederik; Schippling, Sven; Schulze, Andrea; Pleimes, Dirk; Pohl, Christoph; Sandbrink, Rupert; Suarez, Gustavo; Wicklein, Eva-Maria

2016-01-01

Objective: To assess outcomes for patients treated with interferon beta-1b immediately after clinically isolated syndrome (CIS) or after a short delay. Methods: Participants in BENEFIT (Betaferon/Betaseron in Newly Emerging MS for Initial Treatment) were randomly assigned to receive interferon beta-1b (early treatment) or placebo (delayed treatment). After conversion to clinically definite multiple sclerosis (CDMS) or 2 years, patients on placebo could switch to interferon beta-1b or another treatment. Eleven years after randomization, patients were reassessed. Results: Two hundred seventy-eight (59.4%) of the original 468 patients (71.3% of those eligible at participating sites) were enrolled (early: 167 [57.2%]; delayed: 111 [63.1%]). After 11 years, risk of CDMS remained lower in the early-treatment arm compared with the delayed-treatment arm (p = 0.0012), with longer time to first relapse (median [Q1, Q3] days: 1,888 [540, not reached] vs 931 [253, 3,296]; p = 0.0005) and lower overall annualized relapse rate (0.21 vs 0.26; p = 0.0018). Only 25 patients (5.9%, overall; early, 4.5%; delayed, 8.3%) converted to secondary progressive multiple sclerosis. Expanded Disability Status Scale scores remained low and stable, with no difference between treatment arms (median [Q1, Q3]: 2.0 [1.0, 3.0]). The early-treatment group had better Paced Auditory Serial Addition Task–3 total scores (p = 0.0070). Employment rates remained high, and health resource utilization tended to be low in both groups. MRI metrics did not differ between groups. Conclusions: Although the delay in treatment was relatively short, several clinical outcomes favored earlier treatment. Along with low rates of disability and disease progression in both groups, this supports the value of treatment at CIS. ClinicalTrials.gov identifier: NCT01795872. Classification of evidence: This study provides Class IV evidence that early compared to delayed treatment prolongs time to CDMS in CIS after 11 years. PMID:27511182

Clinical and Demographic Profile of Patients Receiving Fingolimod in Clinical Practice in Germany and the Benefit-Risk Profile of Fingolimod After 1 Year of Treatment: Initial Results From the Observational, Noninterventional Study PANGAEA.

PubMed

Ziemssen, Tjalf; Lang, Michael; Tackenberg, Björn; Schmidt, Stephan; Albrecht, Holger; Klotz, Luisa; Haas, Judith; Lassek, Christoph; Medin, Jennie; Cornelissen, Christian

2018-01-01

The population with multiple sclerosis receiving treatment in clinical practice differs from that in randomized controlled trials (RCTs). An assessment of the real-world benefit-risk profile of therapies is needed. This analysis used data from the large, noninterventional, observational German study Post-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA) to assess prospectively baseline characteristics and outcomes after 12 months (± 90 days) of fingolimod treatment. Patients were divided into 2 cohorts: fingolimod starter [first received fingolimod in PANGAEA (n = 3315)] and previous study [received fingolimod before enrollment in PANGAEA in RCTs (n = 875), some of whom also had baseline data at entry into RCTs (n = 505)]. At PANGAEA baseline, patients in the fingolimod starter versus the previous study cohort had a higher annualized relapse rate [ARR (95% confidence interval): 1.79 (1.75-1.83) vs 1.32 (1.25-1.40)] and Expanded Disability Status Scale score [3.11 (3.04-3.17) vs 2.55 (2.44-2.66)]. A greater proportion in the fingolimod starter versus previous study cohort had diabetes (2.0% vs 0.7%). After 12 months of fingolimod, ARRs were lower than in the 12 months before PANGAEA enrollment in the fingolimod starter [0.386 (0.360-0.414)] and previous study [0.276 (0.238-0.320)] cohorts. Expanded Disability Status Scale scores were stable versus baseline. Adverse events were experienced by similar proportions in both cohorts during fingolimod treatment. Relevant differences exist in disease activity and comorbidities between patients receiving fingolimod in clinical practice versus RCTs. Irrespective of baseline differences indicating a higher proportion at an advanced stage of multiple sclerosis in the real world versus RCTs, fingolimod remains effective, with a manageable safety profile.

Multiple emulsions controlled by stimuli-responsive polymers.

PubMed

Besnard, Lucie; Marchal, Frédéric; Paredes, Jose F; Daillant, Jean; Pantoustier, Nadège; Perrin, Patrick; Guenoun, Patrick

2013-05-28

The phase inversion of water-toluene emulsions stabilized with a single thermo- and pH-sensitive copolymer occurs through the formation of multiple emulsions. At low pH and ambient temperature, oil in water emulsions are formed which transform into highly stable multiple emulsions at pHs immediately lower than the inversion border. At higher pHs, the emulsion turns into a water in oil one. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Prediction of serious complications in patients with seemingly stable febrile neutropenia: validation of the Clinical Index of Stable Febrile Neutropenia in a prospective cohort of patients from the FINITE study.

PubMed

Carmona-Bayonas, Alberto; Jiménez-Fonseca, Paula; Virizuela Echaburu, Juan; Antonio, Maite; Font, Carme; Biosca, Mercè; Ramchandani, Avinash; Martínez, Jerónimo; Hernando Cubero, Jorge; Espinosa, Javier; Martínez de Castro, Eva; Ghanem, Ismael; Beato, Carmen; Blasco, Ana; Garrido, Marcelo; Bonilla, Yaiza; Mondéjar, Rebeca; Arcusa Lanza, María Ángeles; Aragón Manrique, Isabel; Manzano, Aránzazu; Sevillano, Elena; Castañón, Eduardo; Cardona, Mercé; Gallardo Martín, Elena; Pérez Armillas, Quionia; Sánchez Lasheras, Fernando; Ayala de la Peña, Francisco

2015-02-10

To validate a prognostic score predicting major complications in patients with solid tumors and seemingly stable episodes of febrile neutropenia (FN). The definition of clinical stability implies the absence of organ dysfunction, abnormalities in vital signs, and major infections. We developed the Clinical Index of Stable Febrile Neutropenia (CISNE), with six explanatory variables associated with serious complications: Eastern Cooperative Oncology Group performance status ≥ 2 (2 points), chronic obstructive pulmonary disease (1 point), chronic cardiovascular disease (1 point), mucositis of grade ≥ 2 (National Cancer Institute Common Toxicity Criteria; 1 point), monocytes < 200 per μL (1 point), and stress-induced hyperglycemia (2 points). We integrated these factors into a score ranging from 0 to 8, which classifies patients into three prognostic classes: low (0 points), intermediate (1 to 2 points), and high risk (≥ 3 points). We present a multicenter validation of CISNE. We prospectively recruited 1,133 patients with seemingly stable FN from 25 hospitals. Complication rates in the training and validation subsets, respectively, were 1.1% and 1.1% in low-, 6.1% and 6.2% in intermediate-, and 32.5% and 36% in high-risk patients; mortality rates within each class were 0% in low-, 1.6% and 0% in intermediate-, and 4.3% and 3.1% in high-risk patients. Areas under the receiver operating characteristic curves in the validation subset were 0.652 (95% CI, 0.598 to 0.703) for Talcott, 0.721 (95% CI, 0.669 to 0.768) for Multinational Association for Supportive Care in Cancer (MASCC), and 0.868 (95% CI, 0.827 to 0.903) for CISNE (P = .002 for comparison between CISNE and MASCC). CISNE is a valid model for accurately classifying patients with cancer with seemingly stable FN episodes. © 2015 by American Society of Clinical Oncology.

Multiple μ-stability of neural networks with unbounded time-varying delays.

PubMed

Wang, Lili; Chen, Tianping

2014-05-01

In this paper, we are concerned with a class of recurrent neural networks with unbounded time-varying delays. Based on the geometrical configuration of activation functions, the phase space R(n) can be divided into several Φη-type subsets. Accordingly, a new set of regions Ωη are proposed, and rigorous mathematical analysis is provided to derive the existence of equilibrium point and its local μ-stability in each Ωη. It concludes that the n-dimensional neural networks can exhibit at least 3(n) equilibrium points and 2(n) of them are μ-stable. Furthermore, due to the compatible property, a set of new conditions are presented to address the dynamics in the remaining 3(n)-2(n) subset regions. As direct applications of these results, we can get some criteria on the multiple exponential stability, multiple power stability, multiple log-stability, multiple log-log-stability and so on. In addition, the approach and results can also be extended to the neural networks with K-level nonlinear activation functions and unbounded time-varying delays, in which there can store (2K+1)(n) equilibrium points, (K+1)(n) of them are locally μ-stable. Numerical examples are given to illustrate the effectiveness of our results. Copyright © 2014 Elsevier Ltd. All rights reserved.

21 CFR 862.2150 - Continuous flow sequential multiple chemistry analyzer for clinical use.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Continuous flow sequential multiple chemistry..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Laboratory Instruments § 862.2150 Continuous flow sequential multiple chemistry...

21 CFR 862.2150 - Continuous flow sequential multiple chemistry analyzer for clinical use.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Continuous flow sequential multiple chemistry..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Laboratory Instruments § 862.2150 Continuous flow sequential multiple chemistry...

21 CFR 862.2150 - Continuous flow sequential multiple chemistry analyzer for clinical use.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Continuous flow sequential multiple chemistry..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Laboratory Instruments § 862.2150 Continuous flow sequential multiple chemistry...

21 CFR 862.2150 - Continuous flow sequential multiple chemistry analyzer for clinical use.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Continuous flow sequential multiple chemistry..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Laboratory Instruments § 862.2150 Continuous flow sequential multiple chemistry...

21 CFR 862.2150 - Continuous flow sequential multiple chemistry analyzer for clinical use.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Continuous flow sequential multiple chemistry..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Laboratory Instruments § 862.2150 Continuous flow sequential multiple chemistry...

Spontaneous switching among multiple spatio-temporal patterns in three-oscillator systems constructed with oscillatory cells of true slime mold

NASA Astrophysics Data System (ADS)

Takamatsu, Atsuko

2006-11-01

Three-oscillator systems with plasmodia of true slime mold, Physarum polycephalum, which is an oscillatory amoeba-like unicellular organism, were experimentally constructed and their spatio-temporal patterns were investigated. Three typical spatio-temporal patterns were found: rotation ( R), partial in-phase ( PI), and partial anti-phase with double frequency ( PA). In pattern R, phase differences between adjacent oscillators were almost 120 ∘. In pattern PI, two oscillators were in-phase and the third oscillator showed anti-phase against the two oscillators. In pattern PA, two oscillators showed anti-phase and the third oscillator showed frequency doubling oscillation with small amplitude. Actually each pattern is not perfectly stable but quasi-stable. Interestingly, the system shows spontaneous switching among the multiple quasi-stable patterns. Statistical analyses revealed a characteristic in the residence time of each pattern: the histograms seem to have Gamma-like distribution form but with a sharp peak and a tail on the side of long period. That suggests the attractor of this system has complex structure composed of at least three types of sub-attractors: a “Gamma attractor”-involved with several Poisson processes, a “deterministic attractor”-the residence time is deterministic, and a “stable attractor”-each pattern is stable. When the coupling strength was small, only the Gamma attractor was observed and switching behavior among patterns R, PI, and PA almost always via an asynchronous pattern named O. A conjecture is as follows: Internal/external noise exposes each pattern of R, PI, and PA coexisting around bifurcation points: That is observed as the Gamma attractor. As coupling strength increases, the deterministic attractor appears then followed by the stable attractor, always accompanied with the Gamma attractor. Switching behavior could be caused by regular existence of the Gamma attractor.

A modified precise integration method for transient dynamic analysis in structural systems with multiple damping models

NASA Astrophysics Data System (ADS)

Ding, Zhe; Li, Li; Hu, Yujin

2018-01-01

Sophisticated engineering systems are usually assembled by subcomponents with significantly different levels of energy dissipation. Therefore, these damping systems often contain multiple damping models and lead to great difficulties in analyzing. This paper aims at developing a time integration method for structural systems with multiple damping models. The dynamical system is first represented by a generally damped model. Based on this, a new extended state-space method for the damped system is derived. A modified precise integration method with Gauss-Legendre quadrature is then proposed. The numerical stability and accuracy of the proposed integration method are discussed in detail. It is verified that the method is conditionally stable and has inherent algorithmic damping, period error and amplitude decay. Numerical examples are provided to assess the performance of the proposed method compared with other methods. It is demonstrated that the method is more accurate than other methods with rather good efficiency and the stable condition is easy to be satisfied in practice.

Temporal Stability of Multiple Response Systems to 7.5% Carbon Dioxide Challenge

PubMed Central

Roberson-Nay, Roxann; Gorlin, Eugenia I.; Beadel, Jessica R.; Cash, Therese; Vrana, Scott; Teachman, Bethany A.

2017-01-01

Self-reported anxiety, and potentially physiological response, to maintained inhalation of carbon dioxide (CO2) enriched air shows promise as a putative marker of panic reactivity and vulnerability. Temporal stability of response systems during low-dose, steady-state CO2 breathing challenge is lacking. Outcomes on multiple levels were measured two times, one week apart, in 93 individuals. Stability was highest during the CO2 breathing phase compared to pre-CO2 and recovery phases, with anxiety ratings, respiratory rate, skin conductance level, and heart rate demonstrating good to excellent temporal stability (ICCs ≥ 0.71). Cognitive symptoms tied to panic were somewhat less stable (ICC = 0.58) than physical symptoms (ICC = 0.74) during CO2 breathing. Escape/avoidance behaviors and DSM-5 panic attacks were not stable. Large effect sizes between task phases also were observed. Overall, results suggest good-excellent levels of temporal stability for multiple outcomes during respiratory stimulation via 7.5% CO2. PMID:28163046

Laboratory observation of multiple double layer resembling space plasma double layer

NASA Astrophysics Data System (ADS)

Alex, Prince; Arumugam, Saravanan; Sinha, Suraj

2017-10-01

Perceptible double layer consisting of more than one layers were produced in laboratory using a double discharge plasma setup. The confinement of oppositely charged particles in each layer with sharply defined luminous boarder is attributed to the self-organization scenario. This structure is generated in front of a positively biased electrode when the electron drift velocity (νd) exceeds 1.3 times the electron thermal velocity (νte) . Stable multiple double layer structures were observed only between 1.3 νte <=νd <= 3 νte. At νd = 1.3 νte, oscillations were excited in the form of large amplitude burst followed by a high frequency stable oscillation. Beyond νd = 3 νte, multiple double layer begins to collapse which is characterized by an emergence in turbulence. Long range dependence in the corresponding electrostatic potential fluctuations indicates the role of self-organized criticality in the emergence of turbulence. The algebraic decaying tale of the autocorrelation function and power law behavior in the power spectrum are consistent with the observation.

Impacts of education level and employment status on health-related quality of life in multiple sclerosis patients.

PubMed

Šabanagić-Hajrić, Selma; Alajbegović, Azra

2015-02-01

To evaluate the impacts of education level and employment status on health-related quality of life (HRQoL) in multiple sclerosis patients. This study included 100 multiple sclerosis patients treated at the Department of Neurology, Clinical Center of the University of Sarajevo. Inclusion criteria were the Expanded Disability Status Scale (EDSS) score between 1.0 and 6.5, age between 18 and 65 years, stable disease on enrollment. Quality of life (QoL) was evaluated by the Multiple Sclerosis Quality of Life-54 questionnaire (MSQoL-54). Mann-Whitney and Kruskal-Wallis test were used for comparisons. Linear regression analyses were performed to evaluate prediction value of educational level and employment status in predicting MSQOL-54 physical and mental composite scores. Full employment status had positive impact on physical health (54.85 vs. 37.90; p les than 0.001) and mental health (59.55 vs. 45.90; p les than 0.001) composite scores. Employment status retained its independent predictability for both physical (r(2)=0.105) and mental (r(2)=0.076) composite scores in linear regression analysis. Patients with college degree had slightly higher median value of physical (49.36 vs. 45.30) and mental health composite score (66.74 vs. 55.62) comparing to others, without statistically significant difference. Employment proved to be an important factor in predicting quality of life in multiple sclerosis patients. Higher education level may determine better QOL but without significant predictive value. Sustained employment and development of vocational rehabilitation programs for MS patients living in the country with high unemployment level is an important factor in improving both physical and mental health outcomes in MS patients.

Peptide vaccine immunotherapy biomarkers and response patterns in pediatric gliomas

PubMed Central

Müller, Sören; Agnihotri, Sameer; Shoger, Karsen E.; Myers, Max I.; Chaparala, Srilakshmi; Villanueva, Clarence R.; Chattopadhyay, Ansuman; Butterfield, Lisa H.; Okada, Hideho; Pollack, Ian F.

2018-01-01

Low-grade gliomas (LGGs) are the most common brain tumor affecting children. We recently reported an early phase clinical trial of a peptide-based vaccine, which elicited consistent antigen-specific T cell responses in pediatric LGG patients. Additionally, we observed radiologic responses of stable disease (SD), partial response (PR), and near-complete/complete response (CR) following therapy. To identify biomarkers of clinical response in peripheral blood, we performed RNA sequencing on PBMC samples collected at multiple time points. Patients who showed CR demonstrated elevated levels of T cell activation markers, accompanied by a cytotoxic T cell response shortly after treatment initiation. At week 34, patients with CR demonstrated both IFN signaling and Poly-IC:LC adjuvant response patterns. Patients with PR demonstrated a unique, late monocyte response signature. Interestingly, HLA-V expression, before or during therapy, and an early monocytic hematopoietic response were strongly associated with SD. Finally, low IDO1 and PD-L1 expression before treatment and early elevated levels of T cell activation markers were associated with prolonged progression-free survival. Overall, our data support the presence of unique peripheral immune patterns in LGG patients associated with different radiographic responses to our peptide vaccine immunotherapy. Future clinical trials, including our ongoing phase II LGG vaccine immunotherapy, should monitor these response patterns. PMID:29618666

[Clinical applications of dosing algorithm in the predication of warfarin maintenance dose].

PubMed

Huang, Sheng-wen; Xiang, Dao-kang; An, Bang-quan; Li, Gui-fang; Huang, Ling; Wu, Hai-li

2011-12-27

To evaluate the feasibility of clinical application for genetic based dosing algorithm in the predication of warfarin maintenance dose in Chinese population. The clinical data were collected and blood samples harvested from a total of 126 patients undergoing heart valve replacement. The genotypes of VKORC1 and CYP2C9 were determined by melting curve analysis after PCR. They were divided randomly into the study and control groups. In the study group, the first three doses of warfarin were prescribed according to the predicted warfarin maintenance dose while warfarin was initiated at 2.5 mg/d in the control group. The warfarin doses were adjusted according to the measured international normalized ratio (INR) values. And all subjects were followed for 50 days after an initiation of warfarin therapy. At the end of a 50-day follow-up period, the proportions of the patients on a stable dose were 82.4% (42/51) and 62.5% (30/48) for the study and control groups respectively. The mean durations of reaching a stable dose of warfarin were (27.5 ± 1.8) and (34.7 ± 1.8) days and the median durations were (24.0 ± 1.7) and (33.0 ± 4.5) days in the study and control groups respectively. Significant differences existed in the durations of reaching a stable dose between the two groups (P = 0.012). Compared with the control group, the hazard ratio (HR) for the duration of reaching a stable dose was 1.786 in the study group (95%CI 1.088 - 2.875, P = 0.026). The predicted dosing algorithm incorporating genetic and non-genetic factors may shorten the duration of achieving efficiently a stable dose of warfarin. And the present study validates the feasibility of its clinical application.

Safety of stable isotope use.

PubMed

Koletzko, B; Sauerwald, T; Demmelmair, H

1997-08-01

The increased employment of stable isotope tracers for diagnostic and research purposes frequently raises questions on potential risks associated with their use, which is of particular importance in the paediatric age group. Biological effects and the potential of adverse events has been evaluated in a large number of animal and, in part, also human studies. Possible differences in physical, chemical and biochemical behaviour resulting in kinetic and thermodynamic isotope effects between stable isotopes of the same element are related to the relative differences in atomic weight. Deuterium (2H), which differs markedly in mass from the predominant hydrogen isotope 1H, may induce serious side-effects at high concentrations in body fluids. The threshold dose for the occurrence of side-effects lies well above the usual tracer dosages for clinical use. In contrast to deuterium, heavier stable isotopes such as 13C, 15N or 18O that differ relatively little in mass from the predominant isotopes such as 12C, does not show any adverse biological effects even at highest enrichments. The doses of stable isotope tracer substances that are used for clinical diagnostic and research purposes appear safe and without any adverse effects. Stable isotope tracers should only be used in children if the trace is safe at the doses applied, and tracer is chemically pure and stable. In the case of intravenous application, the tracer preparation must also be sterile and pyrogen free.

Protocol biopsy of the stable renal transplant: a multicenter study of methods and complication rates.

PubMed

Furness, Peter N; Philpott, Carl M; Chorbadjian, Mary T; Nicholson, Michael L; Bosmans, Jean-Louis; Corthouts, Bob L; Bogers, Johannes J P M; Schwarz, Anke; Gwinner, Wilfried; Haller, Hermann; Mengel, Michael; Seron, Daniel; Moreso, Francesc; Cañas, Conception

2003-09-27

Clinical trials in renal transplantation must use surrogate markers of long-term graft survival if conclusions are to be drawn at acceptable speed and cost. Morphologic changes in transplant biopsies provide the earliest available evidence of damage, and "protocol" biopsies from stable grafts can be used to reduce the number of patients needed in clinical trials. This approach has been inhibited by concerns over safety, but the risk of biopsy of a stable kidney, with no active inflammation or acute functional impairment, has never been formally estimated. In accordance with a predefined set of questions, a retrospective audit of a sequential series of protocol biopsies was performed in four major transplant centers. A total of 2,127 biopsy events were assessed for major complications, and 1,486 were assessed for minor ones. There were no deaths. One graft was lost, under circumstances indicating that the loss should have been prevented. Three episodes of hemorrhage required direct intervention. Three further patients required transfusion. There were two episodes of peritonitis, but one was arguably an unrelated event. All serious complications presented within 4 hr of biopsy. The incidence of clinically significant complications after protocol biopsy of a stable renal transplant is low. Direct benefits to the patients concerned (irrespective of the benefit that may accrue in clinical trials) were not formally assessed but seem likely to outweigh the risk of the procedure. We believe that it is ethically justifiable to ask renal transplant recipients to undergo protocol biopsies in clinical trials and routine care.

An in-advance stable isotope labeling strategy for relative analysis of multiple acidic plant hormones in sub-milligram Arabidopsis thaliana seedling and a single seed.

PubMed

Sun, Xiaohong; Ouyang, Yue; Chu, Jinfang; Yan, Jing; Yu, Yan; Li, Xiaoqiang; Yang, Jun; Yan, Cunyu

2014-04-18

A sensitive and reliable in-advance stable isotope labeling strategy was developed for simultaneous relative quantification of 8 acidic plant hormones in sub-milligram amount of plant materials. Bromocholine bromide (BETA) and its deuterated counterpart D9-BETA were used to in-advance derivatize control and sample extracts individually, which were then combined and subjected to solid-phase extraction (SPE) purification followed by UPLC-MS/MS analysis. Relative quantification of target compounds was obtained by calculation of the peak area ratios of BETA/D9-BETA labeled plant hormones. The in-advance stable isotope labeling strategy realized internal standard-based relative quantification of multiple kinds of plant hormones independent of availability of internal standard of every analyte with enhanced sensitivity of 1-3 orders of magnitude. Meanwhile, the in-advance labeling contributes to higher sample throughput and more reliability. The method was successfully applied to determine 8 plant hormones in 0.8mg DW (dry weight) of seedlings and 4 plant hormones from single seed of Arabidopsis thaliana. The results show the potential of the method in relative quantification of multiple plant hormones in tiny plant tissues or organs, which will advance the knowledge of the crosstalk mechanism of plant hormones. Copyright © 2014 Elsevier B.V. All rights reserved.

Multiple myeloma: a clinical overview.

PubMed

Anderson, Kenneth C

2011-11-15

Multiple myeloma (MM) is the second most common hematologic malignancy in the United States, affecting slightly more men than women and twice as many African Americans as Caucasians. Older age is the primary risk factor for MM, but obesity also increases risk. MM is incurable, but treatment advances in the past decade have more than doubled the duration of survival. MM is a progressive plasma cell tumor in which an initially stable clone becomes malignant via a multistep process. Causative factors implicated in this process include radiation, environmental toxins, chronic antigen stimulation, and genetics. The malignant plasma cells interact with other hematopoietic and stromal cells within the bone marrow microenvironment to disrupt homeostasis among cells and within the extracellular matrix. These tumor-host interactions lead to MM cell proliferation and migration, angiogenesis, osteolysis, immunodeficiency, and anemia. As a result, patients often present with osteolytic bone lesions, recurrent infections, renal insufficiency, and fatigue. The Durie-Salmon and International Staging Systems are used to stage MM, with the latter providing prognostic information based on readily available laboratory data. However, a number of cytogenetic markers are emerging as prognostic indicators, introducing the possibility of more refined disease staging systems and tailored treatment strategies based on genetic profiles.

Ultrasound internal tattooing.

PubMed

Couture, Olivier; Faivre, Magalie; Pannacci, Nicolas; Babataheri, Avin; Servois, Vincent; Tabeling, Patrick; Tanter, Mickael

2011-02-01

The ability of remotely tagging tissues in a controlled and three-dimensional manner during preoperative imaging could greatly help surgeons to identify targets for resection. The authors' objective is to selectively and noninvasively deposit markers under image guidance for such internal tattooing. This study describes the production of new ultrasound-inducible droplets carrying large payloads of fluorescent markers and the in vivo proof of concept of their remote and controlled deposition via focused ultrasound. The droplets are monodispersed multiple emulsions produced in a microfluidic system, consisting of aqueous fluorescein in perfluorocarbon in water. Their conversion (either by vaporization or cavitation) is performed remotely using a clinical ultrasonic imaging probe. When submitted to 5 MHz imaging pulses, the droplets vaporize in vitro at 1.4 MPa peak-negative pressure and eject their content. After several seconds, a brightly fluorescent spot (0.5 mm diameter) is observed at the focus of the transducer. Experiments in the chorioallantoique membrane of chicken eggs and chicken embryo demonstrate that the spot is stable and is easily seen by naked eye. These ultrasound-inducible multiple emulsions could be used to deliver large amounts of contrast agents, chemotherapy, and genetic materials in vivo using a conventional ultrasound scanner.

Long-term Stability of Urinary Biomarkers of Acute Kidney Injury in Children.

PubMed

Schuh, Meredith P; Nehus, Edward; Ma, Qing; Haffner, Christopher; Bennett, Michael; Krawczeski, Catherine D; Devarajan, Prasad

2016-01-01

Recent meta-analyses support the utility of urinary biomarkers for the diagnosis and prognosis of acute kidney injury. It is critical to establish optimal sample handling conditions for short-term processing and long-term urinary storage prior to widespread clinical deployment and meaningful use in prospective clinical trials. Prospective study. 80 children (median age, 1.1 [IQR, 0.5-4.2] years) undergoing cardiac surgery with cardiopulmonary bypass at our center. 50% of patients had acute kidney injury (defined as ≥50% increase in serum creatinine from baseline). We tested the effect on biomarker concentrations of short-term urine storage in ambient, refrigerator, and freezer conditions. We also tested the effects of multiple freeze-thaw cycles, as well as prolonged storage for 5 years. Urine concentrations of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), and interleukin 18 (IL-18). All biomarkers were measured using commercially available kits. All 3 biomarkers were stable in urine stored at 4°C for 24 hours, but showed significant degradation (5.6%-10.1% from baseline) when stored at 25°C. All 3 biomarkers showed only a small although significant decrease in concentration (0.77%-2.9% from baseline) after 3 freeze-thaw cycles. Similarly, all 3 biomarkers displayed only a small but significant decrease in concentration (0.84%-3.2%) after storage for 5 years. Only the 3 most widely studied biomarkers were tested. Protease inhibitors were not evaluated. Short-term storage of urine samples for measurement of NGAL, KIM-1, and IL-18 may be performed at 4°C for up to 24 hours, but not at room temperature. These urinary biomarkers are stable at -80°C for up to 5 years of storage. Our results are reassuring for the deployment of these assays as biomarkers in clinical practice, as well as in prospective clinical studies requiring long-term urine storage. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

The effects of competition on assisted reproductive technology outcomes.

PubMed

Henne, Melinda B; Bundorf, M Kate

2010-04-01

To evaluate the relationship between competition among fertility clinics and assisted reproductive technology (ART) treatment outcomes, particularly multiple births. Using clinic-level data from 1995 to 2001, we examined the relationship between competition and clinic-level ART outcomes and practice patterns. National database registry. Clinics performing ART. The number of clinics within a 20-mile (32.19-km) radius of a given clinic. Clinic-level births, singleton births, and multiple births per ART cycle; multiple births per ART birth; average number of embryos transferred per cycle; and the proportion of cycles for women under age 35 years. The number of competing clinics is not strongly associated with ART birth and multiple birth rates. Relative to clinics with no competitors, the rate of multiple births per cycle is lower (-0.03 percentage points) only for clinics with more than 15 competitors. Embryo transfer practices are not statistically significantly associated with the number of competitors. Clinic-level competition is strongly associated with patient mix. The proportion of cycles for patients under 35 years old is 6.4 percentage points lower for clinics with more than 15 competitors than for those with no competitors. Competition among fertility clinics does not appear to increase rates of multiple births from ART by promoting more aggressive embryo transfer decisions. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.Published by Elsevier Inc.

Uniform, stable supply of medium for in vitro cell culture using a robust chamber

NASA Astrophysics Data System (ADS)

Wei, Juan; Liu, Chong; Jiang, Yang; Liu, Tao; Chen, Li; Liu, Bo; Li, Jingmin

2018-06-01

A uniform, stable supply of medium is important for in vitro cell culture. In this paper, a microfluidic device is presented for culturing cells inside a robust chamber with continuous perfusion of medium. The device consists of a main channel, two bifurcated channels and a culture chamber. The culture chamber connects to the bifurcated channels via multiple paths, and distributes symmetrically on the main channel, to improve the efficiency of medium exchange. Furthermore, regular polygonal chambers with various numbers of edges have been designed, to study the effects of chamber shape on flow fields. The finite element method has been employed to predict the effects of multiple paths on the uniformity and stability of flow fields in the culture chamber. Particle tracking technology has been used to evaluate the flow fields in the chambers, and PC-12 cells have been cultured using the microfluidic device, to test its validity. The results of simulation and experiment indicate that the microfluidic design could provide a continuous interstitial-like flow microenvironment, with a relatively stable and uniform supply of medium.

Design of Multistable Origami Structures

NASA Astrophysics Data System (ADS)

Gillman, Andrew; Fuchi, Kazuko; Bazzan, Giorgio; Reich, Gregory; Alyanak, Edward; Buskohl, Philip

Origami is being transformed from an art to a mathematically robust method for device design in a variety of scientific applications. These structures often require multiple stable configurations, e.g. efficient well-controlled deployment. However, the discovery of origami structures with mechanical instabilities is challenging given the complex geometric nonlinearities and the large design space to investigate. To address this challenge, we have developed a topology optimization framework for discovering origami fold patterns that realize stable and metastable positions. The objective function targets both the desired stable positions and nonlinear loading profiles of specific vertices in the origami structure. Multistable compliant structures have been shown to offer advantages in their stability and efficiency, and certain origami fold patterns exhibit multistable behavior. Building on this previous work of single vertex multistability analysis, e.g. waterbomb origami pattern, we are expanding the solution set of multistable mechanisms to include multiple vertices and a broader set of reference configurations. Collectively, these results enable an initial classification of geometry-induced mechanical instabilities that can be programmed into active material systems. This work was supported by the Air Force Office of Scientific Research.

Quadratures with multiple nodes, power orthogonality, and moment-preserving spline approximation

NASA Astrophysics Data System (ADS)

Milovanovic, Gradimir V.

2001-01-01

Quadrature formulas with multiple nodes, power orthogonality, and some applications of such quadratures to moment-preserving approximation by defective splines are considered. An account on power orthogonality (s- and [sigma]-orthogonal polynomials) and generalized Gaussian quadratures with multiple nodes, including stable algorithms for numerical construction of the corresponding polynomials and Cotes numbers, are given. In particular, the important case of Chebyshev weight is analyzed. Finally, some applications in moment-preserving approximation of functions by defective splines are discussed.

Concentration of stable elements in food products

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

Montford, M.A.; Shank, K.E.; Hendricks, C.

1980-01-01

Food samples were taken from commercial markets and analyzed for stable element content. The concentrations of most stable elements (Ag, Al, As, Au, Ba, Br, Ca, Ce, Cl, Co, Cr, Cs, Cu, Fe, Hf, I, K, La, Mg, Mn, Mo, Na, Rb, Sb, Sc, Se, Sr, Ta, Th, Ti, V, Zn, Zr) were determined using multiple-element neutron activation analysis, while the concentrations of other elements (Cd, Hg, Ni, Pb) were determined using atomic absorption. The relevance of the concentrations found are noted in relation to other literature values. An earlier study was extended to include the determination of the concentrationmore » of stable elements in home-grown products in the vicinity of the Oak Ridge National Laboratory. Comparisons between the commercial and local food-stuff values are discussed.« less

Effective search for stable segregation configurations at grain boundaries with data-mining techniques

NASA Astrophysics Data System (ADS)

Kiyohara, Shin; Mizoguchi, Teruyasu

2018-03-01

Grain boundary segregation of dopants plays a crucial role in materials properties. To investigate the dopant segregation behavior at the grain boundary, an enormous number of combinations have to be considered in the segregation of multiple dopants at the complex grain boundary structures. Here, two data mining techniques, the random-forests regression and the genetic algorithm, were applied to determine stable segregation sites at grain boundaries efficiently. Using the random-forests method, a predictive model was constructed from 2% of the segregation configurations and it has been shown that this model could determine the stable segregation configurations. Furthermore, the genetic algorithm also successfully determined the most stable segregation configuration with great efficiency. We demonstrate that these approaches are quite effective to investigate the dopant segregation behaviors at grain boundaries.

Qualitative analysis of Cohen-Grossberg neural networks with multiple delays

NASA Astrophysics Data System (ADS)

Ye, Hui; Michel, Anthony N.; Wang, Kaining

1995-03-01

It is well known that a class of artificial neural networks with symmetric interconnections and without transmission delays, known as Cohen-Grossberg neural networks, possesses global stability (i.e., all trajectories tend to some equilibrium). We demonstrate in the present paper that many of the qualitative properties of Cohen-Grossberg networks will not be affected by the introduction of sufficiently small delays. Specifically, we establish some bound conditions for the time delays under which a given Cohen-Grossberg network with multiple delays is globally stable and possesses the same asymptotically stable equilibria as the corresponding network without delays. An effective method of determining the asymptotic stability of an equilibrium of a Cohen-Grossberg network with multiple delays is also presented. The present results are motivated by some of the authors earlier work [Phys. Rev. E 50, 4206 (1994)] and by some of the work of Marcus and Westervelt [Phys. Rev. A 39, 347 (1989)]. These works address qualitative analyses of Hopfield neural networks with one time delay. The present work generalizes these results to Cohen-Grossberg neural networks with multiple time delays. Hopfield neural networks constitute special cases of Cohen-Grossberg neural networks.

Design, implementation and multisite evaluation of a system suitability protocol for the quantitative assessment of instrument performance in liquid chromatography-multiple reaction monitoring-MS (LC-MRM-MS).

PubMed

Abbatiello, Susan E; Mani, D R; Schilling, Birgit; Maclean, Brendan; Zimmerman, Lisa J; Feng, Xingdong; Cusack, Michael P; Sedransk, Nell; Hall, Steven C; Addona, Terri; Allen, Simon; Dodder, Nathan G; Ghosh, Mousumi; Held, Jason M; Hedrick, Victoria; Inerowicz, H Dorota; Jackson, Angela; Keshishian, Hasmik; Kim, Jong Won; Lyssand, John S; Riley, C Paige; Rudnick, Paul; Sadowski, Pawel; Shaddox, Kent; Smith, Derek; Tomazela, Daniela; Wahlander, Asa; Waldemarson, Sofia; Whitwell, Corbin A; You, Jinsam; Zhang, Shucha; Kinsinger, Christopher R; Mesri, Mehdi; Rodriguez, Henry; Borchers, Christoph H; Buck, Charles; Fisher, Susan J; Gibson, Bradford W; Liebler, Daniel; Maccoss, Michael; Neubert, Thomas A; Paulovich, Amanda; Regnier, Fred; Skates, Steven J; Tempst, Paul; Wang, Mu; Carr, Steven A

2013-09-01

Multiple reaction monitoring (MRM) mass spectrometry coupled with stable isotope dilution (SID) and liquid chromatography (LC) is increasingly used in biological and clinical studies for precise and reproducible quantification of peptides and proteins in complex sample matrices. Robust LC-SID-MRM-MS-based assays that can be replicated across laboratories and ultimately in clinical laboratory settings require standardized protocols to demonstrate that the analysis platforms are performing adequately. We developed a system suitability protocol (SSP), which employs a predigested mixture of six proteins, to facilitate performance evaluation of LC-SID-MRM-MS instrument platforms, configured with nanoflow-LC systems interfaced to triple quadrupole mass spectrometers. The SSP was designed for use with low multiplex analyses as well as high multiplex approaches when software-driven scheduling of data acquisition is required. Performance was assessed by monitoring of a range of chromatographic and mass spectrometric metrics including peak width, chromatographic resolution, peak capacity, and the variability in peak area and analyte retention time (RT) stability. The SSP, which was evaluated in 11 laboratories on a total of 15 different instruments, enabled early diagnoses of LC and MS anomalies that indicated suboptimal LC-MRM-MS performance. The observed range in variation of each of the metrics scrutinized serves to define the criteria for optimized LC-SID-MRM-MS platforms for routine use, with pass/fail criteria for system suitability performance measures defined as peak area coefficient of variation <0.15, peak width coefficient of variation <0.15, standard deviation of RT <0.15 min (9 s), and the RT drift <0.5min (30 s). The deleterious effect of a marginally performing LC-SID-MRM-MS system on the limit of quantification (LOQ) in targeted quantitative assays illustrates the use and need for a SSP to establish robust and reliable system performance. Use of a SSP helps to ensure that analyte quantification measurements can be replicated with good precision within and across multiple laboratories and should facilitate more widespread use of MRM-MS technology by the basic biomedical and clinical laboratory research communities.

Design, Implementation and Multisite Evaluation of a System Suitability Protocol for the Quantitative Assessment of Instrument Performance in Liquid Chromatography-Multiple Reaction Monitoring-MS (LC-MRM-MS)*

PubMed Central

Abbatiello, Susan E.; Mani, D. R.; Schilling, Birgit; MacLean, Brendan; Zimmerman, Lisa J.; Feng, Xingdong; Cusack, Michael P.; Sedransk, Nell; Hall, Steven C.; Addona, Terri; Allen, Simon; Dodder, Nathan G.; Ghosh, Mousumi; Held, Jason M.; Hedrick, Victoria; Inerowicz, H. Dorota; Jackson, Angela; Keshishian, Hasmik; Kim, Jong Won; Lyssand, John S.; Riley, C. Paige; Rudnick, Paul; Sadowski, Pawel; Shaddox, Kent; Smith, Derek; Tomazela, Daniela; Wahlander, Asa; Waldemarson, Sofia; Whitwell, Corbin A.; You, Jinsam; Zhang, Shucha; Kinsinger, Christopher R.; Mesri, Mehdi; Rodriguez, Henry; Borchers, Christoph H.; Buck, Charles; Fisher, Susan J.; Gibson, Bradford W.; Liebler, Daniel; MacCoss, Michael; Neubert, Thomas A.; Paulovich, Amanda; Regnier, Fred; Skates, Steven J.; Tempst, Paul; Wang, Mu; Carr, Steven A.

2013-01-01

Multiple reaction monitoring (MRM) mass spectrometry coupled with stable isotope dilution (SID) and liquid chromatography (LC) is increasingly used in biological and clinical studies for precise and reproducible quantification of peptides and proteins in complex sample matrices. Robust LC-SID-MRM-MS-based assays that can be replicated across laboratories and ultimately in clinical laboratory settings require standardized protocols to demonstrate that the analysis platforms are performing adequately. We developed a system suitability protocol (SSP), which employs a predigested mixture of six proteins, to facilitate performance evaluation of LC-SID-MRM-MS instrument platforms, configured with nanoflow-LC systems interfaced to triple quadrupole mass spectrometers. The SSP was designed for use with low multiplex analyses as well as high multiplex approaches when software-driven scheduling of data acquisition is required. Performance was assessed by monitoring of a range of chromatographic and mass spectrometric metrics including peak width, chromatographic resolution, peak capacity, and the variability in peak area and analyte retention time (RT) stability. The SSP, which was evaluated in 11 laboratories on a total of 15 different instruments, enabled early diagnoses of LC and MS anomalies that indicated suboptimal LC-MRM-MS performance. The observed range in variation of each of the metrics scrutinized serves to define the criteria for optimized LC-SID-MRM-MS platforms for routine use, with pass/fail criteria for system suitability performance measures defined as peak area coefficient of variation <0.15, peak width coefficient of variation <0.15, standard deviation of RT <0.15 min (9 s), and the RT drift <0.5min (30 s). The deleterious effect of a marginally performing LC-SID-MRM-MS system on the limit of quantification (LOQ) in targeted quantitative assays illustrates the use and need for a SSP to establish robust and reliable system performance. Use of a SSP helps to ensure that analyte quantification measurements can be replicated with good precision within and across multiple laboratories and should facilitate more widespread use of MRM-MS technology by the basic biomedical and clinical laboratory research communities. PMID:23689285

Fiber Optic Cable Thermal Preparation to Ensure Stable Operation

NASA Technical Reports Server (NTRS)

Thoames Jr, William J.; Chuska, Rick F.; LaRocca, Frank V.; Switzer, Robert C.; Macmurphy, Shawn L.; Ott, Melanie N.

2008-01-01

Fiber optic cables are widely used in modern systems that must provide stable operation during exposure to changing environmental conditions. For example, a fiber optic cable on a satellite may have to reliably function over a temperature range of -50 C up to 125 C. While the system requirements for a particular application will dictate the exact method by which the fibers should be prepared, this work will examine multiple ruggedized fibers prepared in different fashions and subjected to thermal qualification testing. The data show that if properly conditioned the fiber cables can provide stable operation, but if done incorrectly, they will have large fluctuations in transmission.

Transition of spiral calcium waves between multiple stable patterns can be triggered by a single calcium spark in a fire-diffuse-fire model

PubMed Central

Tang, Ai-Hui; Wang, Shi-Qiang

2009-01-01

Spiral patterns have been found in various nonequilibrium systems. The Ca2+-induced Ca2+ release system in single cardiac cells is unique for highly discrete reaction elements, each giving rise to a Ca2+ spark upon excitation. We imaged the spiral Ca2+ waves in isolated cardiac cells and numerically studied the effect of system excitability on spiral patterns using a two-dimensional fire-diffuse-fire model. We found that under certain conditions, the system was able to display multiple stable patterns of spiral waves, each exhibiting different periods and distinct routines of spiral tips. Transition between these different patterns could be triggered by an internal fluctuation in the form of a single Ca2+ spark. PMID:19792039

Transition of spiral calcium waves between multiple stable patterns can be triggered by a single calcium spark in a fire-diffuse-fire model.

PubMed

Tang, Ai-Hui; Wang, Shi-Qiang

2009-09-01

Spiral patterns have been found in various nonequilibrium systems. The Ca(2+)-induced Ca(2+) release system in single cardiac cells is unique for highly discrete reaction elements, each giving rise to a Ca(2+) spark upon excitation. We imaged the spiral Ca(2+) waves in isolated cardiac cells and numerically studied the effect of system excitability on spiral patterns using a two-dimensional fire-diffuse-fire model. We found that under certain conditions, the system was able to display multiple stable patterns of spiral waves, each exhibiting different periods and distinct routines of spiral tips. Transition between these different patterns could be triggered by an internal fluctuation in the form of a single Ca(2+) spark.

Menogaril in the treatment of relapsed multiple myeloma. A phase II trial of the Cancer Center of Wake Forest University.

PubMed

Cruz, J M; Case, L D; Dalton, H B; Ramseur, W L; Richards, F; Jackson, D V; Muss, H B; Zekan, P J; Brodkin, R A; Brown, R C

1992-04-01

Fifteen patients with relapsed multiple myeloma (MM) were treated with menogaril 160 mg/m2 intravenously (IV) every 28 days. No responses were seen: 8 patients had stable disease, 4 progressed after one course of therapy, and 3 patients were removed from study after 1 course for other reasons. Four of the 8 patients with stable disease had an improved performance status, and 3 had a decrease in analgesic use. The major toxicity was myelosuppression. The median progression-free interval was 3.0 months with a range of 0.7 to 22 months and median survival was 11.3 months with a range of 0.7 to 39+ months. Menogaril displays little activity in patients with previously treated MM.

Endovascular treatment of chronic cerebro spinal venous insufficiency in patients with multiple sclerosis modifies circulating markers of endothelial dysfunction and coagulation activation: a prospective study.

PubMed

Napolitano, Mariasanta; Bruno, Aldo; Mastrangelo, Diego; De Vizia, Marcella; Bernardo, Benedetto; Rosa, Buonagura; De Lucia, Domenico

2014-10-01

We performed a monocentric observational prospective study to evaluate coagulation activation and endothelial dysfunction parameters in patients with multiple sclerosis undergoing endovascular treatment for cerebro-spinal-venous insufficiency. Between February 2011 and July 2012, 144 endovascular procedures in 110 patients with multiple sclerosis and chronical cerebro-spinal venous insufficiency were performed and they were prospectively analyzed. Each patient was included in the study according to previously published criteria, assessed by the investigators before enrollment. Endothelial dysfunction and coagulation activation parameters were determined before the procedure and during follow-up at 1, 3, 6, 9, 12, 15 and 18 months after treatment, respectively. After the endovascular procedure, patients were treated with standard therapies, with the addition of mesoglycan. Fifty-five percent of patients experienced a favorable outcome of multiple sclerosis within 1 month after treatment, 25% regressed in the following 3 months, 24.9% did not experience any benefit. In only 0.1% patients, acute recurrence was observed and it was treated with high-dose immunosuppressive therapy. No major complications were observed. Coagulation activation and endothelial dysfunction parameters were shown to be reduced at 1 month and stable up to 12-month follow-up, and they were furthermore associated with a good clinical outcome. Endovascular procedures performed by a qualified staff are well tolerated; they can be associated with other currently adopted treatments. Correlations between inflammation, coagulation activation and neurodegenerative disorders are here supported by the observed variations in plasma levels of markers of coagulation activation and endothelial dysfunction.

Stable 293 T and CHO cell lines expressing cleaved, stable HIV-1 envelope glycoprotein trimers for structural and vaccine studies.

PubMed

Chung, Nancy P Y; Matthews, Katie; Kim, Helen J; Ketas, Thomas J; Golabek, Michael; de Los Reyes, Kevin; Korzun, Jacob; Yasmeen, Anila; Sanders, Rogier W; Klasse, Per Johan; Wilson, Ian A; Ward, Andrew B; Marozsan, Andre J; Moore, John P; Cupo, Albert

2014-04-25

Recombinant soluble, cleaved HIV-1 envelope glycoprotein SOSIP.664 gp140 trimers based on the subtype A BG505 sequence are being studied structurally and tested as immunogens in animals. For these trimers to become a vaccine candidate for human trials, they would need to be made in appropriate amounts at an acceptable quality. Accomplishing such tasks by transient transfection is likely to be challenging. The traditional way to express recombinant proteins in large amounts is via a permanent cell line, usually of mammalian origin. Making cell lines that produce BG505 SOSIP.664 trimers requires the co-expression of the Furin protease to ensure that the cleavage site between the gp120 and gp41 subunits is fully utilized. We designed a vector capable of expressing Env and Furin, and used it to create Stable 293 T and CHO Flp-In™ cell lines through site-specific recombination. Both lines produce high quality, cleaved trimers at yields of up to 12-15 mg per 1 × 109 cells. Trimer expression at such levels was maintained for up to 30 days (10 passages) after initial seeding and was consistently superior to what could be achieved by transient transfection. Electron microscopy studies confirm that the purified trimers have the same native-like appearance as those derived by transient transfection and used to generate high-resolution structures. They also have appropriate antigenic properties, including the presentation of the quaternary epitope for the broadly neutralizing antibody PGT145. The BG505 SOSIP.664 trimer-expressing cell lines yield proteins of an appropriate quality for structural studies and animal immunogenicity experiments. The methodology is suitable for making similar lines under Good Manufacturing Practice conditions, to produce trimers for human clinical trials. Moreover, any env gene can be incorporated into this vector system, allowing the manufacture of SOSIP trimers from multiple genotypes, either by transient transfection or from stable cell lines.

Interesting images: Multiple coronary artery aneurysms.

PubMed

Howard, Jonathon M; Viswanath, Omar; Armas, Alfredo; Santana, Orlando; Rosen, Gerald P

2017-01-01

We present the case of a 65-year-old male who presented with stable angina and dyspnea on exertion. His initial workup yielded a positive treadmill stress test for reversible apical ischemia, and transthoracic echocardiogram demonstrated impaired systolic function. Cardiac catheterization was then performed, revealing severe atherosclerotic disease including multiple coronary artery aneurysms. As a result, the patient was advised to and subsequently underwent a coronary artery bypass graft. This case highlights the presence of multiple coronary artery aneurysms and the ability to appreciate these pathologic findings on multiple imaging modalities, including coronary angiogram, transesophageal echocardiography, and direct visualization through the surgical field.

Interesting Images: Multiple Coronary Artery Aneurysms

PubMed Central

Howard, Jonathon M; Viswanath, Omar; Armas, Alfredo; Santana, Orlando; Rosen, Gerald P

2017-01-01

We present the case of a 65-year-old male who presented with stable angina and dyspnea on exertion. His initial workup yielded a positive treadmill stress test for reversible apical ischemia, and transthoracic echocardiogram demonstrated impaired systolic function. Cardiac catheterization was then performed, revealing severe atherosclerotic disease including multiple coronary artery aneurysms. As a result, the patient was advised to and subsequently underwent a coronary artery bypass graft. This case highlights the presence of multiple coronary artery aneurysms and the ability to appreciate these pathologic findings on multiple imaging modalities, including coronary angiogram, transesophageal echocardiography, and direct visualization through the surgical field. PMID:28701599

Effects of Arnica comp.-Heel® on reducing cardiovascular events in patients with stable coronary disease.

PubMed

Fioranelli, Massimo; Bianchi, Maria; Roccia, Maria G; Di Nardo, Veronica

2016-02-01

The purpose of the study was to evaluate the effectiveness of the treatment with one tablet a day of a low dose multicomponent medication (Arnica comp.-Heel® tablets) with anti-inflammatory properties in order to reduce the risk of cardiovascular events in patients with clinically stable coronary disease. The presence of inflammatory cells in atherosclerotic plaques of patients with stable coronary disease indicates the possibility to act by inhibiting the inflammatory phenomenon with Arnica comp.-Heel® tablets reducing the risk of instability of the plaque and, consequently, improving the clinical outcome in patients with stable coronary disease. Within this retrospective observational spontaneous clinical study 44 patients (31 males and 13 females) all presenting stable coronary artery disease were evaluated; 25 subjects were treated with only acetylsalicylic acid and/or clopidogrel in association with statins (standard therapeutic protocol) while for the other 18 subjects the standard therapeutic protocol was integrated with Arnica comp.-Heel® (one sublingual tablet/day). The primary outcome was to evaluate the incidence of acute coronary syndrome, out-of-hospital cardiac arrest, or non-cardioembolic ischemic stroke. The evaluation of the primary outcome showed that in the group of patients (18) who received the standard therapeutic protocol plus Arnica comp.-Heel® only one cardiovascular event was registered (5.6%) while in the group treated only with standard therapy 4 events were recorded in 25 patients (16%). The treatment with Arnica comp.-Heel® (one tablet/day) in combination with standard therapies for secondary prevention is effective in reducing the incidence of cardiovascular events in patients with stable coronary artery disease.

Evolving biomarkers improve prediction of long-term mortality in patients with stable coronary artery disease: the BIO-VILCAD score.

PubMed

Kleber, M E; Goliasch, G; Grammer, T B; Pilz, S; Tomaschitz, A; Silbernagel, G; Maurer, G; März, W; Niessner, A

2014-08-01

Algorithms to predict the future long-term risk of patients with stable coronary artery disease (CAD) are rare. The VIenna and Ludwigshafen CAD (VILCAD) risk score was one of the first scores specifically tailored for this clinically important patient population. The aim of this study was to refine risk prediction in stable CAD creating a new prediction model encompassing various pathophysiological pathways. Therefore, we assessed the predictive power of 135 novel biomarkers for long-term mortality in patients with stable CAD. We included 1275 patients with stable CAD from the LUdwigshafen RIsk and Cardiovascular health study with a median follow-up of 9.8 years to investigate whether the predictive power of the VILCAD score could be improved by the addition of novel biomarkers. Additional biomarkers were selected in a bootstrapping procedure based on Cox regression to determine the most informative predictors of mortality. The final multivariable model encompassed nine clinical and biochemical markers: age, sex, left ventricular ejection fraction (LVEF), heart rate, N-terminal pro-brain natriuretic peptide, cystatin C, renin, 25OH-vitamin D3 and haemoglobin A1c. The extended VILCAD biomarker score achieved a significantly improved C-statistic (0.78 vs. 0.73; P = 0.035) and net reclassification index (14.9%; P < 0.001) compared to the original VILCAD score. Omitting LVEF, which might not be readily measureable in clinical practice, slightly reduced the accuracy of the new BIO-VILCAD score but still significantly improved risk classification (net reclassification improvement 12.5%; P < 0.001). The VILCAD biomarker score based on routine parameters complemented by novel biomarkers outperforms previous risk algorithms and allows more accurate classification of patients with stable CAD, enabling physicians to choose more personalized treatment regimens for their patients.

Smoking in asthma is associated with elevated levels of corticosteroid resistant sputum cytokines-an exploratory study.

PubMed

Spears, Mark; McSharry, Charles; Chaudhuri, Rekha; Weir, Christopher J; de Wet, Carl; Thomson, Neil C

2013-01-01

Current cigarette smoking is associated with reduced acute responses to corticosteroids and worse clinical outcomes in stable chronic asthma. The mechanism by which current smoking promotes this altered behavior is currently unclear. Whilst cytokines can induce corticosteroid insensitivity in-vitro, how current and former smoking affects airway cytokine concentrations and their responses to oral corticosteroids in stable chronic asthma is unclear. To examine blood and sputum cytokine concentrations in never, ex and current smokers with asthma before and after oral corticosteroids. Exploratory study utilizing two weeks of oral dexamethasone (equivalent to 40 mg/day prednisolone) in 22 current, 21 never and 10 ex-smokers with asthma. Induced sputum supernatant and plasma was obtained before and after oral dexamethasone. 25 cytokines were measured by multiplex microbead system (Invitrogen, UK) on a Luminex platform. Smokers with asthma had elevated sputum cytokine interleukin (IL) -6, -7, and -12 concentrations compared to never smokers with asthma. Few sputum cytokine concentrations changed in response to dexamethasone IL-17 and IFNα increased in smokers, CCL4 increased in never smokers and CCL5 and CXCL10 reduced in ex-smokers with asthma. Ex-smokers with asthma appeared to have evidence of an ongoing corticosteroid resistant elevation of cytokines despite smoking cessation. Several plasma cytokines were lower in smokers with asthma compared to never smokers with asthma. Cigarette smoking in asthma is associated with a corticosteroid insensitive increase in multiple airway cytokines. Distinct airway cytokine profiles are present in current smokers and never smokers with asthma and could provide an explanatory mechanism for the altered clinical behavior observed in smokers with asthma.

[Clinical observation of apatinib mesylate for the treatment of multi-drug resistant advanced breast cancer].

PubMed

Lü, H M; Zhang, M W; Niu, L M; Zeng, H A; Yan, M

2018-04-24

Objective: To assess the clinical efficacy and adverse outcomes of apatinib mesylate for the treatment of multi-drug resistant advanced breast cancer. Methods: A total of 24 patients with multi-drug-resistant advanced breast cancer who underwent apatinib mesylate treatment were retrospectively analyzed at the Diagnosis and Treatment Center for Breast Cancer of Henan Cancer Hospital. Patients were reviewed every 4 weeks after initial treatment and then every 8 weeks after stable disease. Objective response rate (ORR), progression free survival (PFS), overall survival (OS) , toxicity and adverse outcomes of apatinib mesylate treatment were evaluated by imaging examinations. Results: Totally, 24 patients received apatinib mesylate at a dose of 500 mg QD. Out of the 24 patients treated, complete remission (CR) occurred in none of the patients, partial remission (PR) in 10 cases, stable disease (SD) in 10 cases, progressive disease (PD) in 4 cases, and drug with drawal in 2 cases due to adverse outcomes. Treatment with apatinib mesylate resulted in an ORR of 41.7% (10/24), disease control rate (DCR) of 83.3%, PFS of 4.7 months, and OS of 8.0 months. Adverse outcomes included proteinuria, high blood pressure, fatigue, hand-foot skin reaction (HFSR), hyperbilirubinemia, leukopenia, hair/skin pigmentation decreased. Most of the adverse events were tolerable and can be controlled after symptomatic management. Conclusions: Single-agent apatinib mesylate demonstrated the good short-term efficacy for multi-drug resistant advanced breast cancer in patients who previously underwent multiple line treatment failures. Adverse effects were controllable after symptomatic management. Treatment with apatinib mesylate maybe a viable option when other treatment modalities failed.

Prevalence and associated factors for decreased appetite among patients with stable heart failure.

PubMed

Andreae, Christina; Strömberg, Anna; Årestedt, Kristofer

2016-06-01

To explore the prevalence of decreased appetite and factors associated with appetite among patients with stable heart failure. Decreased appetite is an important factor for the development of undernutrition among patients with heart failure, but there are knowledge gaps about prevalence and the factors related to appetite in this patient group. Observational, cross-sectional study. A total of 186 patients with mild to severe heart failure were consecutively recruited from three heart failure outpatient clinics. Data were obtained from medical records (heart failure diagnosis, comorbidity and medical treatment) and self-rated questionnaires (demographics, appetite, self-perceived health, symptoms of depression and sleep). Blood samples were taken to determine myocardial stress and nutrition status. Heart failure symptoms and cognitive function were assessed by clinical examinations. The Council on Nutrition Appetite Questionnaire was used to assess self-reported appetite. Bivariate correlations and multivariate linear regression analyses were conducted to explore factors associated with appetite. Seventy-one patients (38%) experienced a loss of appetite with a significant risk of developing weight loss. The final multiple regression model showed that age, symptoms of depression, insomnia, cognitive function and pharmacological treatment were associated with appetite, explaining 27% of the total variance. In this cross-sectional study, a large share of patients with heart failure was affected by decreased appetite, associated with demographic, psychosocial and medical factors. Loss of appetite is a prevalent problem among patients with heart failure that may lead to undernutrition. Health care professionals should routinely assess appetite and discuss patients' experiences of appetite, nutrition intake and body weight and give appropriate nutritional advice with respect to individual needs. © 2016 John Wiley & Sons Ltd.

Clinical commentary on "Paroxysmal kinesigenic dyskinesia-like phenotype in multiple sclerosis" and "Secondary paroxysmal dyskinesia in multiple sclerosis: Clinical-radiological features and treatment. Case report of seven patients".

PubMed

Pareés, Isabel

2017-11-01

This clinical commentary discusses the phenomenology and treatment of paroxysmal dyskinesia in patients with multiple sclerosis. It calls for a consensus on the definition as well as for larger studies to better understand this unusual clinical association.

The Effects of Clinically Relevant Multiple-Choice Items on the Statistical Discrimination of Physician Clinical Competence.

ERIC Educational Resources Information Center

Downing, Steven M.; Maatsch, Jack L.

To test the effect of clinically relevant multiple-choice item content on the validity of statistical discriminations of physicians' clinical competence, data were collected from a field test of the Emergency Medicine Examination, test items for the certification of specialists in emergency medicine. Two 91-item multiple-choice subscales were…

The Face-Processing Network Is Resilient to Focal Resection of Human Visual Cortex.

PubMed

Weiner, Kevin S; Jonas, Jacques; Gomez, Jesse; Maillard, Louis; Brissart, Hélène; Hossu, Gabriela; Jacques, Corentin; Loftus, David; Colnat-Coulbois, Sophie; Stigliani, Anthony; Barnett, Michael A; Grill-Spector, Kalanit; Rossion, Bruno

2016-08-10

Human face perception requires a network of brain regions distributed throughout the occipital and temporal lobes with a right hemisphere advantage. Present theories consider this network as either a processing hierarchy beginning with the inferior occipital gyrus (occipital face area; IOG-faces/OFA) or a multiple-route network with nonhierarchical components. The former predicts that removing IOG-faces/OFA will detrimentally affect downstream stages, whereas the latter does not. We tested this prediction in a human patient (Patient S.P.) requiring removal of the right inferior occipital cortex, including IOG-faces/OFA. We acquired multiple fMRI measurements in Patient S.P. before and after a preplanned surgery and multiple measurements in typical controls, enabling both within-subject/across-session comparisons (Patient S.P. before resection vs Patient S.P. after resection) and between-subject/across-session comparisons (Patient S.P. vs controls). We found that the spatial topology and selectivity of downstream ipsilateral face-selective regions were stable 1 and 8 month(s) after surgery. Additionally, the reliability of distributed patterns of face selectivity in Patient S.P. before versus after resection was not different from across-session reliability in controls. Nevertheless, postoperatively, representations of visual space were typical in dorsal face-selective regions but atypical in ventral face-selective regions and V1 of the resected hemisphere. Diffusion weighted imaging in Patient S.P. and controls identifies white matter tracts connecting retinotopic areas to downstream face-selective regions, which may contribute to the stable and plastic features of the face network in Patient S.P. after surgery. Together, our results support a multiple-route network of face processing with nonhierarchical components and shed light on stable and plastic features of high-level visual cortex following focal brain damage. Brain networks consist of interconnected functional regions commonly organized in processing hierarchies. Prevailing theories predict that damage to the input of the hierarchy will detrimentally affect later stages. We tested this prediction with multiple brain measurements in a rare human patient requiring surgical removal of the putative input to a network processing faces. Surprisingly, the spatial topology and selectivity of downstream face-selective regions are stable after surgery. Nevertheless, representations of visual space were typical in dorsal face-selective regions but atypical in ventral face-selective regions and V1. White matter connections from outside the face network may support these stable and plastic features. As processing hierarchies are ubiquitous in biological and nonbiological systems, our results have pervasive implications for understanding the construction of resilient networks. Copyright © 2016 the authors 0270-6474/16/368426-16$15.00/0.

Bleeding complications with dual antiplatelet therapy among patients with stable vascular disease or risk factors for vascular disease: results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial.

PubMed

Berger, Peter B; Bhatt, Deepak L; Fuster, Valentin; Steg, P Gabriel; Fox, Keith A A; Shao, Mingyuan; Brennan, Danielle M; Hacke, Werner; Montalescot, Gilles; Steinhubl, Steven R; Topol, Eric J

2010-06-15

Uncertainty exists about the frequency, correlates, and clinical significance of bleeding with dual antiplatelet therapy (DAPT), particularly over an extended period in a stable population. We sought to determine the frequency and time course of bleeding with DAPT in patients with established vascular disease or risk factors only; identify correlates of bleeding; and determine whether bleeding is associated with mortality. We analyzed 15 603 patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, a double-blind, placebo-controlled, randomized trial comparing long-term clopidogrel 75 mg/d versus placebo; all patients received aspirin (75 to 162 mg) daily. Patients had either established stable vascular disease or multiple risk factors for vascular disease without established disease. Median follow-up was 28 months. Bleeding was assessed with the use of the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) criteria. Severe bleeding occurred in 1.7% of the clopidogrel group versus 1.3% on placebo (P=0.087); moderate bleeding occurred in 2.1% versus 1.3%, respectively (P<0.001). The risk of bleeding was greatest the first year. Patients without moderate or severe bleeding during the first year were no more likely than placebo-treated patients to have bleeding thereafter. The frequency of bleeding was similar in patients with established disease and risk factors only. In multivariable analysis, the relationship between moderate bleeding and all-cause mortality was strong (hazard ratio, 2.55; 95% confidence interval, 1.71 to 3.80; P<0.0001), along with myocardial infarction (hazard ratio, 2.92; 95% confidence interval, 2.04 to 4.18; P<0.0001) and stroke (hazard ratio, 4.20; 95% confidence interval, 3.05 to 5.77; P<0.0001). In CHARISMA, there was an increased risk of bleeding with long-term clopidogrel. The incremental risk of bleeding was greatest in the first year and similar thereafter. Moderate bleeding was strongly associated with mortality. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00050817.

Validation of a Quality of Life Questionnaire for Bronchiectasis: psychometric analyses of the Spanish QOL-B-V3.0.

PubMed

Olveira, Casilda; Olveira, Gabriel; Espildora, Francisco; Giron, Rosa-Maria; Muñoz, Gerard; Quittner, Alexandra L; Martinez-Garcia, Miguel-Angel

2014-05-01

Bronchiectasis is a chronic disease, leading to worsening of health-related quality of life. This study evaluated the psychometric properties of a new patient-reported outcome for non-cystic fibrosis bronchiectasis, the Quality of Life Questionnaire Bronchiectasis, translated into Spanish (QOL-B-Sp-V3.0). This prospective study recruited clinically stable patients with non-cystic fibrosis bronchiectasis at 4 Spanish centers. Health status was assessed with multiple indicators (dyspnea, exacerbations, bronchorrhea, etc.), microbiological, radiological, spirometric, and anthropometric parameters plus St-George Respiratory Questionnaire (SGRQ). Psychometric analyses included internal consistency, test-retest reliability, convergent validity, predictive validity, and responsivity to change. The 207 stable patients (mean age 57.2 years) had a Bhalla score of 11.53 ± 7.39 and FEV1% of 68.3 ± 22.2 %. One hundred and sixty-one stable patients repeated the test 2 weeks later, and 80 patients who had an exacerbation within 6 months of the assessment also repeated it. Internal consistency was high across all scales (Cronbach's alpha >0.70). Thirty-six of 37 items correlated more strongly with their assigned scale than a competing scale. Test-retest coefficients were strong (intraclass correlations r = 0.68-0.88). All scales, except Treatment Burden, discriminated significantly between patients with mild, moderate, and severe disease according to FEV1% and other respiratory parameters. Strong convergence was found between the QOL-B-Sp-V3.0 and SGRQ. Significant correlations were found between QOL-B-Sp-V3.0 and various clinical, spirometric, radiological, and anthropometric variables. Significant differences were found on all QOL-B-Sp-V3.0 scales, except emotional functioning, between the baseline responses and onset of an exacerbation; robust sensitivity to change was observed on the Respiratory Symptoms scale. The QOL-B-Sp-V3.0 questionnaire demonstrated strong reliability and validity. Scores were reproducible after 2 weeks, and it discriminated between patients who varied in severity and was responsive to changes related to exacerbation.

Ultrasound Findings in Tension Pneumothorax: A Case Report.

PubMed

Inocencio, Maxine; Childs, Jeannine; Chilstrom, Mikaela L; Berona, Kristin

2017-06-01

Delayed recognition of tension pneumothorax can lead to a mortality of 31% to 91%. However, the classic physical examination findings of tracheal deviation and distended neck veins are poorly sensitive in the diagnosis of tension pneumothorax. Point-of-care ultrasound is accurate in identifying the presence of pneumothorax, but sonographic findings of tension pneumothorax are less well described. We report the case of a 21-year-old man with sudden-onset left-sided chest pain. He was clinically stable without hypoxia or hypotension, and the initial chest x-ray study showed a large pneumothorax without mediastinal shift. While the patient was awaiting tube thoracostomy, a point-of-care ultrasound demonstrated findings of mediastinal shift and a dilated inferior vena cava (IVC) concerning for tension physiology, even though the patient remained hemodynamically stable. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case demonstrates a unique clinical scenario of ultrasound evidence of tension physiology in a clinically stable patient. Although this patient was well appearing without hypotension, respiratory distress, tracheal deviation, or distended neck veins, point-of-care ultrasound revealed mediastinal shift and a plethoric IVC. Given that the classic clinical signs of tension pneumothorax are not uniformly present, this case shows how point-of-care ultrasound may diagnose tension pneumothorax before clinical decompensation. Published by Elsevier Inc.

Comparative genome analysis of 19 Ureaplasma urealyticum and Ureaplasma parvum strains

PubMed Central

2012-01-01

Background Ureaplasma urealyticum (UUR) and Ureaplasma parvum (UPA) are sexually transmitted bacteria among humans implicated in a variety of disease states including but not limited to: nongonococcal urethritis, infertility, adverse pregnancy outcomes, chorioamnionitis, and bronchopulmonary dysplasia in neonates. There are 10 distinct serotypes of UUR and 4 of UPA. Efforts to determine whether difference in pathogenic potential exists at the ureaplasma serovar level have been hampered by limitations of antibody-based typing methods, multiple cross-reactions and poor discriminating capacity in clinical samples containing two or more serovars. Results We determined the genome sequences of the American Type Culture Collection (ATCC) type strains of all UUR and UPA serovars as well as four clinical isolates of UUR for which we were not able to determine serovar designation. UPA serovars had 0.75−0.78 Mbp genomes and UUR serovars were 0.84−0.95 Mbp. The original classification of ureaplasma isolates into distinct serovars was largely based on differences in the major ureaplasma surface antigen called the multiple banded antigen (MBA) and reactions of human and animal sera to the organisms. Whole genome analysis of the 14 serovars and the 4 clinical isolates showed the mba gene was part of a large superfamily, which is a phase variable gene system, and that some serovars have identical sets of mba genes. Most of the differences among serovars are hypothetical genes, and in general the two species and 14 serovars are extremely similar at the genome level. Conclusions Comparative genome analysis suggests UUR is more capable of acquiring genes horizontally, which may contribute to its greater virulence for some conditions. The overwhelming evidence of extensive horizontal gene transfer among these organisms from our previous studies combined with our comparative analysis indicates that ureaplasmas exist as quasi-species rather than as stable serovars in their native environment. Therefore, differential pathogenicity and clinical outcome of a ureaplasmal infection is most likely not on the serovar level, but rather may be due to the presence or absence of potential pathogenicity factors in an individual ureaplasma clinical isolate and/or patient to patient differences in terms of autoimmunity and microbiome. PMID:22646228

Comparative genome analysis of 19 Ureaplasma urealyticum and Ureaplasma parvum strains.

PubMed

Paralanov, Vanya; Lu, Jin; Duffy, Lynn B; Crabb, Donna M; Shrivastava, Susmita; Methé, Barbara A; Inman, Jason; Yooseph, Shibu; Xiao, Li; Cassell, Gail H; Waites, Ken B; Glass, John I

2012-05-30

Ureaplasma urealyticum (UUR) and Ureaplasma parvum (UPA) are sexually transmitted bacteria among humans implicated in a variety of disease states including but not limited to: nongonococcal urethritis, infertility, adverse pregnancy outcomes, chorioamnionitis, and bronchopulmonary dysplasia in neonates. There are 10 distinct serotypes of UUR and 4 of UPA. Efforts to determine whether difference in pathogenic potential exists at the ureaplasma serovar level have been hampered by limitations of antibody-based typing methods, multiple cross-reactions and poor discriminating capacity in clinical samples containing two or more serovars. We determined the genome sequences of the American Type Culture Collection (ATCC) type strains of all UUR and UPA serovars as well as four clinical isolates of UUR for which we were not able to determine serovar designation. UPA serovars had 0.75-0.78 Mbp genomes and UUR serovars were 0.84-0.95 Mbp. The original classification of ureaplasma isolates into distinct serovars was largely based on differences in the major ureaplasma surface antigen called the multiple banded antigen (MBA) and reactions of human and animal sera to the organisms. Whole genome analysis of the 14 serovars and the 4 clinical isolates showed the mba gene was part of a large superfamily, which is a phase variable gene system, and that some serovars have identical sets of mba genes. Most of the differences among serovars are hypothetical genes, and in general the two species and 14 serovars are extremely similar at the genome level. Comparative genome analysis suggests UUR is more capable of acquiring genes horizontally, which may contribute to its greater virulence for some conditions. The overwhelming evidence of extensive horizontal gene transfer among these organisms from our previous studies combined with our comparative analysis indicates that ureaplasmas exist as quasi-species rather than as stable serovars in their native environment. Therefore, differential pathogenicity and clinical outcome of a ureaplasmal infection is most likely not on the serovar level, but rather may be due to the presence or absence of potential pathogenicity factors in an individual ureaplasma clinical isolate and/or patient to patient differences in terms of autoimmunity and microbiome.

Evaluating CollaboRATE in a clinical setting: analysis of mode effects on scores, response rates and costs of data collection.

PubMed

Barr, Paul J; Forcino, Rachel C; Thompson, Rachel; Ozanne, Elissa M; Arend, Roger; Castaldo, Molly Ganger; O'Malley, A James; Elwyn, Glyn

2017-03-24

Shared decision-making (SDM) has become a policy priority, yet its implementation is not routinely assessed. To address this gap we tested the delivery of CollaboRATE, a 3-item patient reported experience measure of SDM, via multiple survey modes. To assess CollaboRATE response rates and respondent characteristics across different modes of administration, impact of mode and patient characteristics on SDM performance and cost of administration per response in a real-world primary care practice. Observational study design, with repeated assessment of SDM performance using CollaboRATE in a primary care clinic over 15 months of data collection. Different modes of administration were introduced sequentially including paper, patient portal, interactive voice response (IVR) call, text message and tablet computer. Consecutive patients ≥18 years, or parents/guardians of patients <18 years, visiting participating primary care clinicians. CollaboRATE assesses three core SDM tasks: (1) explanation about health issues, (2) elicitation of patient preferences and (3) integration of patient preferences into decisions. Responses to each item range from 0 (no effort was made) to 9 (every effort was made). CollaboRATE scores are calculated as the proportion of participants who report a score of nine on each of the three CollaboRATE questions. Scores were sensitive to mode effects: the paper mode had the highest average score (81%) and IVR had the lowest (61%). However, relative clinician performance rankings were stable across the different data collection modes used. Tablet computers administered by research staff had the highest response rate (41%), although this approach was costly. Clinic staff giving paper surveys to patients as they left the clinic had the lowest response rate (12%). CollaboRATE can be introduced using multiple modes of survey delivery while producing consistent clinician rankings. This may allow routine assessment and benchmarking of clinician and clinic SDM performance. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

21 CFR 880.2900 - Clinical color change thermometer.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Clinical color change thermometer. 880.2900... Monitoring Devices § 880.2900 Clinical color change thermometer. (a) Identification. A clinical color change... end of a plastic or metal strip. Body heat causes a stable color change in the heat sensitive...

Highly scalable multichannel mesh electronics for stable chronic brain electrophysiology.

PubMed

Fu, Tian-Ming; Hong, Guosong; Viveros, Robert D; Zhou, Tao; Lieber, Charles M

2017-11-21

Implantable electrical probes have led to advances in neuroscience, brain-machine interfaces, and treatment of neurological diseases, yet they remain limited in several key aspects. Ideally, an electrical probe should be capable of recording from large numbers of neurons across multiple local circuits and, importantly, allow stable tracking of the evolution of these neurons over the entire course of study. Silicon probes based on microfabrication can yield large-scale, high-density recording but face challenges of chronic gliosis and instability due to mechanical and structural mismatch with the brain. Ultraflexible mesh electronics, on the other hand, have demonstrated negligible chronic immune response and stable long-term brain monitoring at single-neuron level, although, to date, it has been limited to 16 channels. Here, we present a scalable scheme for highly multiplexed mesh electronics probes to bridge the gap between scalability and flexibility, where 32 to 128 channels per probe were implemented while the crucial brain-like structure and mechanics were maintained. Combining this mesh design with multisite injection, we demonstrate stable 128-channel local field potential and single-unit recordings from multiple brain regions in awake restrained mice over 4 mo. In addition, the newly integrated mesh is used to validate stable chronic recordings in freely behaving mice. This scalable scheme for mesh electronics together with demonstrated long-term stability represent important progress toward the realization of ideal implantable electrical probes allowing for mapping and tracking single-neuron level circuit changes associated with learning, aging, and neurodegenerative diseases. Copyright © 2017 the Author(s). Published by PNAS.

A distinct section of the Early Bronze Age society? Stable isotope investigations of burials in settlement pits and multiple inhumations of the Únětice culture in central Germany.

PubMed

Knipper, Corina; Fragata, Matthias; Nicklisch, Nicole; Siebert, Angelina; Szécsényi-Nagy, Anna; Hubensack, Vera; Metzner-Nebelsick, Carola; Meller, Harald; Alt, Kurt W

2016-03-01

Inhumations in so-called settlement pits and multiple interments are subordinate burial practices of the Early Bronze Age Únětice culture in central Germany (2200-1700/1650 BC). The majority of the Únětice population was entombed as single inhumations in rectangular grave pits with a normative position of the body. The goal of the study was to test archaeological hypotheses that the deviant burials may represent socially distinct or nonlocal individuals. The study comprised up to two teeth and one bone each of 74 human individuals from eight sites and faunal comparative samples. The inhumations included regular, deviant burials in so-called settlement or storage pits, and multiple burials. We investigated radiogenic strontium isotope compositions of tooth enamel ((87) Sr/(86) Sr) and light stable isotope ratios of carbon and nitrogen of bone collagen (δ(13) C, δ(15) N) aiming at the disclosure of residential changes and dietary patterns. Site-specific strontium isotope data ranges mirror different geological properties including calcareous bedrock, loess, and glacial till. Independent from burial types, they disclose low portions of nonlocal individuals of up to some 20% at the individual sites. The light stable isotope ratios of burials in settlement pits and rectangular graves overlap widely and indicate highly similar dietary habits. The analytical results let to conclude that inhumations in settlement pits and multiple burials were two of the manifold burial practices of the Early Bronze Age. The selection criteria of the individuals for the different forms of inhumation remained undisclosed. © 2015 Wiley Periodicals, Inc.

Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives

PubMed Central

Ontaneda, Daniel; Fox, Robert J.; Chataway, Jeremy

2015-01-01

Progressive multiple sclerosis is characterized by the gradual accrual of disability independent of relapses and can occur with disease onset (primary progressive) or preceded by a relapsing disease course (secondary progressive). An effective disease modifying treatment for progressive multiple sclerosis has not been identified, and the results of clinical trials to date have been generally disappointing. Ongoing advances in our understanding of pathogenesis, identification of novel targets for neuro-protection, and improved outcome measures have the potential to lead to effective treatments for progressive multiple sclerosis. In this review lessons learned from previous clinical trials and perspectives from current trials in progressive multiple sclerosis are summarized. Promising clinical, imaging, and biological markers will also be reviewed, along with novel clinical trial designs. PMID:25772899

Rapid and effective processing of blood specimens for diagnostic PCR using filter paper and Chelex-100.

PubMed Central

Polski, J M; Kimzey, S; Percival, R W; Grosso, L E

1998-01-01

AIM: To provide a more efficient method for isolating DNA from peripheral blood for use in diagnostic DNA mutation analysis. METHODS: The use of blood impregnated filter paper and Chelex-100 in DNA isolation was evaluated and compared with standard DNA isolation techniques. RESULTS: In polymerase chain reaction (PCR) based assays of five point mutations, identical results were obtained with DNA isolated routinely from peripheral blood and isolated using the filter paper and Chelex-100 method. CONCLUSION: In the clinical setting, this method provides a useful alternative to conventional DNA isolation. It is easily implemented and inexpensive, and provides sufficient, stable DNA for multiple assays. The potential for specimen contamination is reduced because most of the steps are performed in a single microcentrifuge tube. In addition, this method provides for easy storage and transport of samples from the point of acquisition. PMID:9893748

Rapid and effective processing of blood specimens for diagnostic PCR using filter paper and Chelex-100.

PubMed

Polski, J M; Kimzey, S; Percival, R W; Grosso, L E

1998-08-01

To provide a more efficient method for isolating DNA from peripheral blood for use in diagnostic DNA mutation analysis. The use of blood impregnated filter paper and Chelex-100 in DNA isolation was evaluated and compared with standard DNA isolation techniques. In polymerase chain reaction (PCR) based assays of five point mutations, identical results were obtained with DNA isolated routinely from peripheral blood and isolated using the filter paper and Chelex-100 method. In the clinical setting, this method provides a useful alternative to conventional DNA isolation. It is easily implemented and inexpensive, and provides sufficient, stable DNA for multiple assays. The potential for specimen contamination is reduced because most of the steps are performed in a single microcentrifuge tube. In addition, this method provides for easy storage and transport of samples from the point of acquisition.

The pharmacovigilance program on natalizumab in Italy: 2 years of experience.

PubMed

Tedeschi, G; Amato, M P; D'Alessandro, R; Drago, F; Milanese, C; Popoli, P; Rossi, P; Savettieri, G; Tola, M R; Vanacore, N; Covezzoli, A; De Rosa, M; Comi, G; Pozzilli, Carlo; Bertolotto, Antonio; Marrosu, Maria Giovanna; Grimaldi, Luigi M E; Piccinni, C; Montanaro, N; Periotto, Laura; Iommelli, Rosamaria; Addis, Antonio; Martini, Nello; Provinciali, L; Mancardi, G L

2009-10-01

At the end of 2006 a country-based surveillance program on natalizumab therapy in multiple sclerosis was settled in Italy by a collaborative effort of the Italian Drug Agency (AIFA) and a group of experts and neurologists appointed by the National Society of Neurology (SIN). After 2 years, 1,818 patients are registered in the database. The majority of cases (88.6%) failed the therapy with beta interferon or glatiramer acetate and had relapses or accumulated disability during immunomodulating treatment, while 11.4% of patients enrolled in the surveillance study were not previously treated with immunomodulating therapies and had a rapidly evolving clinical course. Almost 10% of the patients treated with natalizumab interrupted, for various different reasons, the therapy. Treatment was well tolerated and side effects were similar to those reported in the registrative studies. The majority of treated cases are stable or ameliorated.

Laserthermia: a new computer-controlled contact Nd: YAG system for interstitial local hyperthermia.

PubMed

Daikuzono, N; Suzuki, S; Tajiri, H; Tsunekawa, H; Ohyama, M; Joffe, S N

1988-01-01

Contact Nd:YAG laser surgery is assuming a greater importance in endoscopic and open surgery, allowing coagulation, cutting, and vaporization with greater precision and safety. A new contact probe allows a wider angle of irradiation and diffusion of low-power laser energy (less than 5 watts), using the interstitial technique for producing local hyperthermia. Temperature sensors that monitor continuously can be placed directly into the surrounding tissue or tumor. Using a computer program interfaced with the laser and sensors, a controlled and stable temperature (e.g., 42 degrees C) can be produced in a known volume of tissue over a prolonged period of time (e.g., 20-40 min). This new laserthermia system, using a single low-power Nd:YAG laser for interstitial local hyperthermia, may offer many new advantages in the experimental treatment and clinical management of carcinoma. A multiple system is now being developed.

Achieving Consistent Multiple Daily Low-Dose Bacillus anthracis Spore Inhalation Exposures in the Rabbit Model

DTIC Science & Technology

2012-06-13

plethysmography. Overall, the presented results show that the animal aerosol system was stable and highly reproducible between different studies and over...develop and deliver low-doses of B. anthracis spores via inhalation in a reproducible manner. The pilot feasibility study (see Table 1 for results) enabled...results presented in Figure 3 show that exposures produced by the aerosol system were stable and reproducible from day-to-day. In all testing, the

Clinical and MRI outcomes after stopping or switching disease-modifying therapy in stable MS patients: a case series report.

PubMed

Berkovich, Regina

2017-10-01

To evaluate clinical and MRI outcomes after stopping or switching disease-modifying therapy in patients with stable MS. A retrospective chart review was conducted of stable MS patients who discontinued or switched their DMT from 2011 to 2015. Clinical and MRI outcomes were obtained at baseline and 1-year follow-up. For the DMT discontinuation group, 15 patients were included, with 67% female, 53% Caucasian, mean age of 45.3 ± 12.2 years, disease duration of 9.1 ± 4.3 years, MS type (80% RRMS, 20% SPMS), and EDSS of 3.7 ± 1.6. The average duration of stable MS course was 5.5 ± 3.7 years. Within a mean of 6.4 ± 2.2 months after DMT discontinuation, all 15 patients experienced worsening of MS disease. After re-evaluation of MS treatment options, all 15 patients were restarted on DMT, of which, 6 (40%) restarted on their prior DMT, 4 (26.7%) switched to another DMT due to adverse events on prior DMT, and 5 (33.3%) switched to a more potent DMT due to worsening of MS activity. One year follow-up showed 2 patients (13.3%) who were restarted on their prior DMT experienced a relapse and the remaining 13 patients (86.7%) had no clinical or MRI activities. For the DMT switch group, 23 patients were included, with 65% female, 61% Caucasian, a mean age of 46.9 ± 11.6 years, disease duration of 11.7 ± 5.1 years, MS Type (83% RRMS, 17% SPMS), and EDSS of 3.5 ± 0.9. After switching DMT, 9 (39.1%) patients experienced worsening of clinical or MRI outcomes at the 1-year follow-up. Of the 9 switch failures, the majority (N = 6) were due to switching to dimethyl fumarate. DMT discontinuation in stable MS patients resulted in worsening of MS disease course for all patients, which improved upon DMT restart or switch. In contrast, 39% of MS stable patients experienced worsening of MS disease course when switched to another DMT, with DMT selection potentially impacting switch outcomes. Copyright © 2017 Elsevier B.V. All rights reserved.

Insight in Chinese schizophrenia patients: a 12-month follow-up.

PubMed

Wang, Y; Xiang, Y-T; Wang, C-Y; Chiu, H F K; Zhao, J-P; Chen, Q; Chan, S S M; Lee, E H M; Tang, W-K; Ungvari, G S

2011-11-01

This study aimed to assess insight in Chinese schizophrenia patients and to identify its relationship with socio-demographic and clinical factors, executive functions and quality of life (QOL). A cohort of 139 clinically stable schizophrenia patients was selected by consecutively screening patients diagnosed with schizophrenia who were attending the outpatient department of a university-affiliated psychiatric hospital in China. Participants' socio-demographic and clinical characteristics, including psychotic symptoms, depression and insight, as well as QOL and executive functions, were periodically assessed with standardized rating instruments. Patients received standard psychiatric care and were followed up for 1 year. Impaired insight was found to be common in stable Chinese schizophrenia patients (76.3%), with merely 5% showing improvement over the 1-year follow-up. Insight was inversely correlated with positive and negative symptoms at all but the 12-month assessment and with both the physical and mental components of QOL at baseline and the 12-month assessment. Insight was not associated with depressive symptoms or executive functions. Standard psychiatric care does not improve the level of insight in clinically stable Chinese schizophrenia outpatients, which warrants the introduction of specific therapeutic interventions that enhance insight. © 2011 Blackwell Publishing.

Evaluation of the 95% limits of agreement of the volumes of 5-year clinically stable solid nodules for the development of a follow-up system for indeterminate solid nodules in CT lung cancer screening

PubMed Central

Muramatsu, Yukio; Yamamichi, Junta; Gomi, Shiho; Oubel, Estanislao; Moriyama, Noriyuki

2018-01-01

Background This study sought to evaluate the 95% limits of agreement of the volumes of 5-year clinically stable solid nodules for the development of a follow-up system for indeterminate solid nodules. Methods The volumes of 226 solid nodules that had been clinically stable for 5 years were measured in 186 patients (53 female never-smokers, 36 male never-smokers, 51 males with <30 pack-years, and 46 males with ≥30 pack-years) using a three-dimensional semiautomated method. Volume changes were evaluated using three methods: percent change, proportional change and growth rate. The 95% limits of agreement were evaluated using the Bland-Altman method. Results The 95% limits of agreement were as follows: range of percent change, from ±34.5% to ±37.8%; range of proportional change, from ±34.1% to ±36.8%; and range of growth rate, from ±39.2% to ±47.4%. Percent change-based, proportional change-based, and growth rate-based diagnoses of an increase or decrease in ten solid nodules were made at a mean of 302±402, 367±455, and 329±496 days, respectively, compared with a clinical diagnosis made at 809±616 days (P<0.05). Conclusions The 95% limits of agreement for volume change in 5-year stable solid nodules may enable the detection of an increase or decrease in the solid nodule at an earlier stage than that enabled by a clinical diagnosis, possibly contributing to the development of a follow-up system for reducing the number of additional Computed tomography (CT) scans performed during the follow-up period. PMID:29600047

Evaluation of the 95% limits of agreement of the volumes of 5-year clinically stable solid nodules for the development of a follow-up system for indeterminate solid nodules in CT lung cancer screening.

PubMed

Kakinuma, Ryutaro; Muramatsu, Yukio; Yamamichi, Junta; Gomi, Shiho; Oubel, Estanislao; Moriyama, Noriyuki

2018-01-01

This study sought to evaluate the 95% limits of agreement of the volumes of 5-year clinically stable solid nodules for the development of a follow-up system for indeterminate solid nodules. The volumes of 226 solid nodules that had been clinically stable for 5 years were measured in 186 patients (53 female never-smokers, 36 male never-smokers, 51 males with <30 pack-years, and 46 males with ≥30 pack-years) using a three-dimensional semiautomated method. Volume changes were evaluated using three methods: percent change, proportional change and growth rate. The 95% limits of agreement were evaluated using the Bland-Altman method. The 95% limits of agreement were as follows: range of percent change, from ±34.5% to ±37.8%; range of proportional change, from ±34.1% to ±36.8%; and range of growth rate, from ±39.2% to ±47.4%. Percent change-based, proportional change-based, and growth rate-based diagnoses of an increase or decrease in ten solid nodules were made at a mean of 302±402, 367±455, and 329±496 days, respectively, compared with a clinical diagnosis made at 809±616 days (P<0.05). The 95% limits of agreement for volume change in 5-year stable solid nodules may enable the detection of an increase or decrease in the solid nodule at an earlier stage than that enabled by a clinical diagnosis, possibly contributing to the development of a follow-up system for reducing the number of additional Computed tomography (CT) scans performed during the follow-up period.

Regulatory issues with multiplicity in drug approval: Principles and controversies in a changing landscape.

PubMed

Benda, Norbert; Brandt, Andreas

2018-01-01

Recently, new draft guidelines on multiplicity issues in clinical trials have been issued by European Medicine Agency (EMA) and Food and Drug Administration (FDA), respectively. Multiplicity is an issue in clinical trials, if the probability of a false-positive decision is increased by insufficiently accounting for testing multiple hypotheses. We outline the regulatory principles related to multiplicity issues in confirmatory clinical trials intended to support a marketing authorization application in the EU, describe the reasons for an increasing complexity regarding multiple hypotheses testing and discuss the specific multiplicity issues emerging within the regulatory context and being relevant for drug approval.

Physician compensation for industry-sponsored clinical trials in multiple sclerosis influences patient trust.

PubMed

Klein, E; Solomon, A J; Corboy, J; Bernat, J

2016-07-01

Perceived physician financial conflicts of interest of can affect patient trust. Payment to physicians for industry sponsored clinical trials in multiple sclerosis is a relatively new potential source of physician conflict of interest. There is limited available data on how physician payment for trial involvement in multiple sclerosis clinical trials may influence patient trust. To understand how patient trust is influenced by information about physician payment for multiple sclerosis clinical trials. An anonymous online instrument was developed. 597 people with multiple sclerosis participated in the study. The study found that 61% of patients who had not previously participated in a clinical trial estimated that they would have lower levels of trust in their physician if the physician was paid for involvement in their clinical trial. Among former clinical trial participants, 38% self-reported a lower level of trust. Other potential physician-industry relationships, such as industry consulting or giving industry-sponsored talks, also adversely affected trust, though to a lesser extent than physician payment for subject participation in clinical trials. Results of this study demonstrate that physician payment for study participation in multiple sclerosis clinical trials is a potential conflict that can adversely affect patient trust. Copyright © 2016 Elsevier B.V. All rights reserved.

Individual Morphological Brain Network Construction Based on Multivariate Euclidean Distances Between Brain Regions.

PubMed

Yu, Kaixin; Wang, Xuetong; Li, Qiongling; Zhang, Xiaohui; Li, Xinwei; Li, Shuyu

2018-01-01

Morphological brain network plays a key role in investigating abnormalities in neurological diseases such as mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, most of the morphological brain network construction methods only considered a single morphological feature. Each type of morphological feature has specific neurological and genetic underpinnings. A combination of morphological features has been proven to have better diagnostic performance compared with a single feature, which suggests that an individual morphological brain network based on multiple morphological features would be beneficial in disease diagnosis. Here, we proposed a novel method to construct individual morphological brain networks for two datasets by calculating the exponential function of multivariate Euclidean distance as the evaluation of similarity between two regions. The first dataset included 24 healthy subjects who were scanned twice within a 3-month period. The topological properties of these brain networks were analyzed and compared with previous studies that used different methods and modalities. Small world property was observed in all of the subjects, and the high reproducibility indicated the robustness of our method. The second dataset included 170 patients with MCI (86 stable MCI and 84 progressive MCI cases) and 169 normal controls (NC). The edge features extracted from the individual morphological brain networks were used to distinguish MCI from NC and separate MCI subgroups (progressive vs. stable) through the support vector machine in order to validate our method. The results showed that our method achieved an accuracy of 79.65% (MCI vs. NC) and 70.59% (stable MCI vs. progressive MCI) in a one-dimension situation. In a multiple-dimension situation, our method improved the classification performance with an accuracy of 80.53% (MCI vs. NC) and 77.06% (stable MCI vs. progressive MCI) compared with the method using a single feature. The results indicated that our method could effectively construct an individual morphological brain network based on multiple morphological features and could accurately discriminate MCI from NC and stable MCI from progressive MCI, and may provide a valuable tool for the investigation of individual morphological brain networks.

Proximal design for a multimodality endoscope with multiphoton microscopy, optical coherence microscopy and visual modalities

NASA Astrophysics Data System (ADS)

Kiekens, Kelli C.; Talarico, Olivia; Barton, Jennifer K.

2018-02-01

A multimodality endoscope system has been designed for early detection of ovarian cancer. Multiple illumination and detection systems must be integrated in a compact, stable, transportable configuration to meet the requirements of a clinical setting. The proximal configuration presented here supports visible light navigation with a large field of view and low resolution, high resolution multiphoton microscopy (MPM), and high resolution optical coherence microscopy (OCM). All modalities are integrated into a single optical system in the endoscope. The system requires two light sources: a green laser for visible light navigation and a compact fiber based femtosecond laser for MPM and OCM. Using an inline wavelength division multiplexer, the two sources are combined into a single mode fiber. To accomplish OCM, a fiber coupler is used to separate the femtosecond laser into a reference arm and signal arm. The reflected reference arm and the signal from the sample are interfered and wavelength separated by a reflection grating and detected using a linear array. The MPM signal is collimated and goes through a series of filters to separate the 2nd and 3rd harmonics as well as twophoton excitation florescence (2PEF) and 3PEF. Each signal is independently detected on a photo multiplier tube and amplified. The visible light is collected by multiple high numerical aperture fibers at the endoscope tip which are bundled into one SMA adapter at the proximal end and connected to a photodetector. This integrated system design is compact, efficient and meets both optical and mechanical requirements for clinical applications.

Estimating individual glomerular volume in the human kidney: clinical perspectives

PubMed Central

Puelles, Victor G.; Zimanyi, Monika A.; Samuel, Terence; Hughson, Michael D.; Douglas-Denton, Rebecca N.; Bertram, John F.

2012-01-01

Background. Measurement of individual glomerular volumes (IGV) has allowed the identification of drivers of glomerular hypertrophy in subjects without overt renal pathology. This study aims to highlight the relevance of IGV measurements with possible clinical implications and determine how many profiles must be measured in order to achieve stable size distribution estimates. Methods. We re-analysed 2250 IGV estimates obtained using the disector/Cavalieri method in 41 African and 34 Caucasian Americans. Pooled IGV analysis of mean and variance was conducted. Monte-Carlo (Jackknife) simulations determined the effect of the number of sampled glomeruli on mean IGV. Lin’s concordance coefficient (RC), coefficient of variation (CV) and coefficient of error (CE) measured reliability. Results. IGV mean and variance increased with overweight and hypertensive status. Superficial glomeruli were significantly smaller than juxtamedullary glomeruli in all subjects (P < 0.01), by race (P < 0.05) and in obese individuals (P < 0.01). Subjects with multiple chronic kidney disease (CKD) comorbidities showed significant increases in IGV mean and variability. Overall, mean IGV was particularly reliable with nine or more sampled glomeruli (RC > 0.95, <5% difference in CV and CE). These observations were not affected by a reduced sample size and did not disrupt the inverse linear correlation between mean IGV and estimated total glomerular number. Conclusions. Multiple comorbidities for CKD are associated with increased IGV mean and variance within subjects, including overweight, obesity and hypertension. Zonal selection and the number of sampled glomeruli do not represent drawbacks for future longitudinal biopsy-based studies of glomerular size and distribution. PMID:21984554

Isolation of Separate Ureaplasma Species From Endotracheal Secretions of Twin Patients.

PubMed

Beeton, Michael L; Maxwell, Nicola C; Chalker, Victoria J; Brown, Rebecca J; Aboklaish, Ali F; Spiller, O Brad

2016-08-01

Isolation of Ureaplasma spp. from preterm neonates and the association with development of bronchopulmonary dysplasia has been previously investigated. However, few studies have contrasted the nature of infection in twins. In this article, we report that dizygotic twins (1 girl, 1 boy) born at 24 weeks gestation both yielded culturable Ureaplasma from endotracheal secretions. The samples were part of a serial blind collection cohort of ventilated premature neonates, and analysis of repeat cultures showed stable, separate infections over a period of 17 and 21 days, respectively. Immunoblot and probe-specific quantitative polymerase chain reaction analysis determined that Twin 1 was solely infected with Ureaplasma parvum (specifically, serovar 6 by gene sequencing), whereas Twin 2 was solely infected with Ureaplasma urealyticum (specifically, genotype A- serovars 2, 5, and 8 by gene sequencing). Immunoblot analysis found that the major surface antigen (multiple-banded antigen) altered relative mass for both strains during the course of infection. Quantitative polymerase chain reaction analysis of extracted endotracheal aspirates confirmed no evidence of mixed infection for either twin. Failure of sentinel ventilated preterm infants on the same ward to acquire Ureaplasma infection after the first week of birth suggests no cot-to-cot transfer of Ureaplasma infection occurred. This study demonstrated not only a contrasting clinical outcome for a set of twins infected with 2 separate species of Ureaplasma, but also the first real-time demonstration of multiple-banded antigen alteration and evolution of Ureaplasma over the course of a clinical infection. Copyright © 2016 by the American Academy of Pediatrics.

Multiple myeloma.

PubMed Central

MacLennan, I. C.; Drayson, M.; Dunn, J.

1994-01-01

Multiple myeloma occurs in over 2000 new patients in England and Wales each year. It presents most frequently as bone pain and patients tend to become dehydrated and may develop renal failure. No available treatment is curative, but about two thirds of patients achieve a stable response with low dose combination chemotherapy. Combination chemotherapy including doxorubicin and carmustine with the alkylating agents cyclophosphamide and melphalan achieve a higher stable response rate than conventional treatment with melphalan and prednisone without additional haematological toxicity. These responses are associated with loss of bone pain and patients remain symptom free for months without further treatment. Relapse occurs on average in a little under two years and, though second responses are frequently obtained, the disease eventually becomes refractory. This paper looks at who should be treated and the benefits that may be expected from the treatments available. PMID:8068084

A randomised phase II study of sialyl-Tn and DETOX-B adjuvant with or without cyclophosphamide pretreatment for the active specific immunotherapy of breast cancer.

PubMed

Miles, D W; Towlson, K E; Graham, R; Reddish, M; Longenecker, B M; Taylor-Papadimitriou, J; Rubens, R D

1996-10-01

Studies in animal models of mouse mammary carcinoma have shown that ovine submaxillary mucin, which carries multiple sialyl-Tn (STn) epitopes, is effective in stimulating an immune response and inhibiting tumour growth. In similar studies using carbohydrate antigens, pretreatment with low-dose cyclophosphamide has been shown to be important in modulating the immune response to antigen possibly by inhibiting suppresser T-cell activity. In a clinical trial assessing the efficacy and toxicity of synthetic STn, patients with metastatic breast cancer were randomised to receive 100 micrograms STn linked to keyhole limpet haemocyanin (KLH) with DETOX-B adjuvant given by subcutaneous injection at weeks 0, 2, 5 and 9 with or without low-dose cyclophosphamide (CTX, 300 mg m-2) pretreatment, 3 days before the start of immunotherapy. Patients with responding or stable disease after the first four injections were eligible to receive STn-KLH at 4 week intervals. The main toxicity noted was the development of subcutaneous granulomata at injection sites. Of 23 patients randomised, 18 received four injections, 5 patients having developed progressive disease during the initial 12 week period. Two minor responses were noted in the 18 patients who received four active specific immunotherapy (ASI) injections and a further five patients had stable disease. Six patients continued ASI at 4 week intervals and a partial response was noted in a patient who had previously had stable disease. All patients developed IgG and IgM responses to sialyl-Tn and levels of IgM antibodies were significantly higher in those patients who were pretreated with CTX. Measurable tumour responses have been recorded following ASI with STn-KLH plus DETOX and the immunomodulatory properties of low-dose CTX have been confirmed.

A randomised phase II study of sialyl-Tn and DETOX-B adjuvant with or without cyclophosphamide pretreatment for the active specific immunotherapy of breast cancer.

PubMed Central

Miles, D. W.; Towlson, K. E.; Graham, R.; Reddish, M.; Longenecker, B. M.; Taylor-Papadimitriou, J.; Rubens, R. D.

1996-01-01

Studies in animal models of mouse mammary carcinoma have shown that ovine submaxillary mucin, which carries multiple sialyl-Tn (STn) epitopes, is effective in stimulating an immune response and inhibiting tumour growth. In similar studies using carbohydrate antigens, pretreatment with low-dose cyclophosphamide has been shown to be important in modulating the immune response to antigen possibly by inhibiting suppresser T-cell activity. In a clinical trial assessing the efficacy and toxicity of synthetic STn, patients with metastatic breast cancer were randomised to receive 100 micrograms STn linked to keyhole limpet haemocyanin (KLH) with DETOX-B adjuvant given by subcutaneous injection at weeks 0, 2, 5 and 9 with or without low-dose cyclophosphamide (CTX, 300 mg m-2) pretreatment, 3 days before the start of immunotherapy. Patients with responding or stable disease after the first four injections were eligible to receive STn-KLH at 4 week intervals. The main toxicity noted was the development of subcutaneous granulomata at injection sites. Of 23 patients randomised, 18 received four injections, 5 patients having developed progressive disease during the initial 12 week period. Two minor responses were noted in the 18 patients who received four active specific immunotherapy (ASI) injections and a further five patients had stable disease. Six patients continued ASI at 4 week intervals and a partial response was noted in a patient who had previously had stable disease. All patients developed IgG and IgM responses to sialyl-Tn and levels of IgM antibodies were significantly higher in those patients who were pretreated with CTX. Measurable tumour responses have been recorded following ASI with STn-KLH plus DETOX and the immunomodulatory properties of low-dose CTX have been confirmed. PMID:8883420

Increased calcium absorption from synthetic stable amorphous calcium carbonate: Double-blind randomized crossover clinical trial in post-menopausal women

USDA-ARS?s Scientific Manuscript database

Calcium supplementation is a widely recognized strategy for achieving adequate calcium intake. We designed this blinded, randomized, crossover interventional trial to compare the bioavailability of a new stable synthetic amorphous calcium carbonate (ACC) with that of crystalline calcium carbonate (C...

TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia.

PubMed

Ghobrial, Irene M; Siegel, David S; Vij, Ravi; Berdeja, Jesus G; Richardson, Paul G; Neuwirth, Rachel; Patel, Chirag G; Zohren, Fabian; Wolf, Jeffrey L

2016-06-01

The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Waldenström's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK-228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty-nine patients received TAK-228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28-day cycles. The overall median age was 61.0 years (range 46-85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty-six patients (92%) reported at least one drug-related toxicity; the most common grade ≥3 drug-related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK-228 exhibited a dose-dependent increase in plasma exposure and no appreciable accumulation with repeat dosing; mean plasma elimination half-life was 6-8 hr. Of the 33 response-evaluable patients, one MM patient had a minimal response, one WM patient achieved partial response, one WM patient had a minor response, and 18 patients (14 MM, two NHL, and two WM) had stable disease. These findings encourage further studies including combination strategies. © 2016 Wiley Periodicals, Inc.

Technique of nonvascularized toe phalangeal transfer and distraction lengthening in the treatment of multiple digit symbrachydactyly.

PubMed

Netscher, David T; Lewis, Eric V

2008-06-01

A combination of nonvascularized multiple toe phalangeal transfers, web space deepening, and distraction lengthening may provide excellent function in the child born with the oligodactylous type of symbrachydactyly. These techniques may reconstruct multiple digits, maintaining a wide and stable grip span with good prehension to the thumb. We detail the techniques of each of these 3 stages in reconstruction and describe appropriate patient selection. Potential complications are discussed. However, with strict attention to technical details, these complications can be minimized.

Heart rate variability in idiopathic dilated cardiomyopathy: relation to disease severity and prognosis.

PubMed Central

Yi, G.; Goldman, J. H.; Keeling, P. J.; Reardon, M.; McKenna, W. J.; Malik, M.

1997-01-01

OBJECTIVE: To assess the clinical importance of heart rate variability (HRV) in patients with idiopathic dilated cardiomyopathy (DCM). PATIENTS AND METHODS: Time domain analysis of 24 hour HRV was performed in 64 patients with DCM, 19 of their relatives with left ventricular enlargement (possible early DCM), and 33 healthy control subjects. RESULTS: Measures of HRV were reduced in patients with DCM compared with controls (P < 0.05). HRV parameters were similar in relatives and controls. Measures of HRV were lower in DCM patients in whom progressive heart failure developed (n = 28) than in those who remained clinically stable (n = 36) during a follow up of 24 (20) months (P = 0.0001). Reduced HRV was associated with NYHA functional class, left ventricular end diastolic dimension, reduced left ventricular ejection fraction, and peak exercise oxygen consumption (P < 0.05) in all patients. DCM patients with standard deviation of normal to normal RR intervals calculated over the 24 hour period (SDNN) < 50 ms had a significantly lower survival rate free of progressive heart failure than those with SDNN > 50 ms (P = 0.0002, at 12 months; P = 0.0001, during overall follow up). Stepwise multiple regression analysis showed that SDNN < 50 ms identified, independently of other clinical variables, patients who were at increased risk of developing progressive heart failure (P = 0.0004). CONCLUSIONS: HRV is reduced in patients with DCM and related to disease severity. HRV is clinically useful as an early non-invasive marker of DCM deterioration. PMID:9068391

Manufacture of Clinical-Grade CD19-Specific T Cells Stably Expressing Chimeric Antigen Receptor Using Sleeping Beauty System and Artificial Antigen Presenting Cells

PubMed Central

Singh, Harjeet; Figliola, Matthew J.; Dawson, Margaret J.; Olivares, Simon; Zhang, Ling; Yang, Ge; Maiti, Sourindra; Manuri, Pallavi; Senyukov, Vladimir; Jena, Bipulendu; Kebriaei, Partow; Champlin, Richard E.; Huls, Helen; Cooper, Laurence J. N.

2013-01-01

Adoptive transfer of T cells expressing a CD19-specific chimeric antigen receptor (CAR) is being evaluated in multiple clinical trials. Our current approach to adoptive immunotherapy is based on a second generation CAR (designated CD19RCD28) that signals through a CD28 and CD3-ζ endodomain. T cells are electroporated with DNA plasmids from the Sleeping Beauty (SB) transposon/transposase system to express this CAR. Stable integrants of genetically modified T cells can then be retrieved when co-cultured with designer artificial antigen presenting cells (aAPC) in the presence of interleukin (IL)-2 and 21. Here, we reveal how the platform technologies of SB-mediated transposition and CAR-dependent propagation on aAPC were adapted for human application. Indeed, we have initiated clinical trials in patients with high-risk B-lineage malignancies undergoing autologous and allogeneic hematopoietic stem-cell transplantation (HSCT). We describe the process to manufacture clinical grade CD19-specific T cells derived from healthy donors. Three validation runs were completed in compliance with current good manufacturing practice for Phase I/II trials demonstrating that by 28 days of co-culture on γ-irradiated aAPC ∼1010 T cells were produced of which >95% expressed CAR. These genetically modified and propagated T cells met all quality control testing and release criteria in support of infusion. PMID:23741305

Investigational Antibody-Drug Conjugates for Treatment of B-lineage Malignancies.

PubMed

Herrera, Alex F; Molina, Arturo

2018-05-10

Antibody-drug conjugates (ADCs) are tripartite molecules consisting of a monoclonal antibody, a covalent linker, and a cytotoxic payload. ADC development has aimed to target the specificity inherent in antigen-antibody interactions to deliver potent cytotoxins preferentially to tumor cells and maximize antitumor activity and simultaneously minimize off-target toxicity. The earliest ADCs provided disappointing results in the clinic; however, the lessons learned regarding the need for human or humanized antibodies, more stable linkers, and greater potency payloads led to improved ADCs. Three ADCs, gemtuzumab ozogamicin, brentuximab vedotin (BV), and inotuzumab ozogamicin, have been approved for hematologic malignancies. Site-specific conjugation methods have now resulted in a new generation of more uniform, molecularly defined ADCs. These are expected to display improved in vivo properties and have recently entered the clinic. We reviewed investigational ADCs currently in clinical testing for the treatment of B-cell lineage malignancies, including leukemias, lymphomas, and multiple myeloma. The rationales for antigen targeting, data reported to date, current trial status, and preclinical results for several newer ADCs expected to enter first-in-human studies are presented. Owing to the large number of ongoing and reported BV clinical studies, only the studies of BV for diffuse large B-cell lymphoma and those combining BV with checkpoint inhibitors in B-lineage malignancies have been reviewed. With > 40 ongoing clinical trials and 7 investigational ADCs already having advanced to phase II studies, the role of ADCs in the armamentarium for the treatment of B-lineage malignancies continues to be elucidated. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Translational phases of evidence in a prognostic biomarker: a systematic review and meta-analysis of natriuretic peptides and the prognosis of stable coronary disease.

PubMed

Sutaria, Shailen; Philipson, Peter; Fitzpatrick, Natalie K; Abrams, Keith; Moreno, Santiago G; Timmis, Adam; Hingorani, Aroon D; Hemingway, Harry

2012-04-01

Translational phases of study are important in evaluating whether a prognostic biomarker is likely to have impact on clinical practice but systematic evaluations of such evidence are lacking. To systematically evaluate the clinical usefulness of the published literature on the association of natriuretic peptides (NP) and prognosis in stable coronary disease. MEDLINE and EMBASE until the end of July 2009, without restrictions. Prospective studies measuring NP in people with stable coronary disease who were followed-up for all cause mortality, coronary or cardiovascular events. Two independent reviewers categorised studies according to the American Heart Association phase of study, and extracted data according to the study reporting guidelines from the American Heart Association and REMARK. Systematic review of 19 studies found 17 which were phase 2, reporting an association between NP and events, two phase 3 studies, statistically examining the incremental prognostic value of NP, but no studies assessing whether NP predicted risk sufficiently to change management (phase 4), improve clinical outcomes (phase 5) or cost effectiveness (phase 6). No study referred to a statistical analytic protocol. Meta-analysis of 14 studies, reporting 18,841 patients and 1655 outcome events, found an RR for events of 3.28 (95% CI 2.45 to 4.38) comparing top versus bottom third of NP. This effect was 26% lower among the five studies which adjusted for a priori confounders (age, sex, renal function and left ventricular function) and 38% lower when adjusting for publication bias (Egger's p=0.001). The unbiased strength of association of NP with prognosis in stable coronary disease is unclear, and there is a lack of reports of clinically useful measures of prediction and discrimination or studies relating NP levels to clinical decision making. The available literature is confined to early phases and is of limited clinical usefulness.

Stable tearing behavior of a thin-sheet material with multiple cracks

NASA Technical Reports Server (NTRS)

Dawicke, D. S.; Newman, J. C., Jr.; Sutton, M. A.; Amstutz, B. E.

1994-01-01

Fracture tests were conducted on 2.3mm thick, 305mm wide sheets of 2024-T3 aluminum alloy with 1-5 collinear cracks. The cracks were introduced (crack history) into the specimens by three methods: (1) saw cutting; (2) fatigue precracking at a low stress range; and (3) fatigue precracking at a high stress range. For the single crack tests, the initial crack history influenced the stress required for the onset of stable crack growth and the first 10mm of crack growth. The effect on failure stress was about 4 percent or less. For the multiple crack tests, the initial crack history was shown to cause differences of more than 20 percent in the link-up stress and 13 percent in failure stress. An elastic-plastic finite element analysis employing the Crack Tip Opening Angle (CTOA) fracture criterion was used to predict the fracture behavior of the single and multiple crack tests. The numerical predictions were within 7 percent of the observed link-up and failure stress in all the tests.

Influence of crack history on the stable tearing behavior of a thin-sheet material with multiple cracks

NASA Technical Reports Server (NTRS)

Dawicke, D. S.; Newman, J. C., Jr.; Sutton, M. A.; Amstutz, B. E.

1994-01-01

Fracture tests were conducted on 2.3mm thick, 305mm wide sheets of 2024-T3 aluminum alloy with from one to five collinear cracks. The cracks were introduced (crack history) into the specimens by three methods: saw cutting, fatigue precracking at a low stress range, and fatigue precracking at a high stress range. For the single crack tests, the initial crack history influenced the stress required for the onset of stable crack growth and the first 10mm of crack growth. The effect on failure stress was about 4 percent or less. For the multiple crack tests, the initial crack history was shown to cause differences of more than 20 percent in the link-up stress and 13 percent in failure stress. An elastic-plastic finite element analysis employing the CTOA fracture criterion was used to predict the fracture behavior of the single and multiple crack tests. The numerical predictions were within 7 percent of the observed link-up and failure stress in all the tests.

Multi-template tensor-based morphometry: Application to analysis of Alzheimer's disease

PubMed Central

Koikkalainen, Juha; Lötjönen, Jyrki; Thurfjell, Lennart; Rueckert, Daniel; Waldemar, Gunhild; Soininen, Hilkka

2012-01-01

In this paper methods for using multiple templates in tensor-based morphometry (TBM) are presented and comparedtothe conventional single-template approach. TBM analysis requires non-rigid registrations which are often subject to registration errors. When using multiple templates and, therefore, multiple registrations, it can be assumed that the registration errors are averaged and eventually compensated. Four different methods are proposed for multi-template TBM. The methods were evaluated using magnetic resonance (MR) images of healthy controls, patients with stable or progressive mild cognitive impairment (MCI), and patients with Alzheimer's disease (AD) from the ADNI database (N=772). The performance of TBM features in classifying images was evaluated both quantitatively and qualitatively. Classification results show that the multi-template methods are statistically significantly better than the single-template method. The overall classification accuracy was 86.0% for the classification of control and AD subjects, and 72.1%for the classification of stable and progressive MCI subjects. The statistical group-level difference maps produced using multi-template TBM were smoother, formed larger continuous regions, and had larger t-values than the maps obtained with single-template TBM. PMID:21419228

Pickering-type water-in-oil-in-water multiple emulsions toward multihollow nanocomposite microspheres.

PubMed

Maeda, Hayata; Okada, Masahiro; Fujii, Syuji; Nakamura, Yoshinobu; Furuzono, Tsutomu

2010-09-07

Multihollow hydroxyapatite (HAp)/poly(L-lactic acid) (PLLA) nanocomposite microspheres were readily fabricated by solvent evaporation from a "Pickering-type" water-in-(dichloromethane solution of PLLA)-in-water multiple emulsion stabilized with HAp nanoparticles. The multiple emulsion was stabilized with the aid of PLLA molecules used as a wettability modifier for HAp nanoparticles, although HAp nanoparticles did not work solely as particulate emulsifiers for Pickering-type emulsions consisting of pure dichloromethane and water. The interaction between PLLA and HAp nanoparticles at the oil-water interfaces plays a crucial role toward the preparation of stable multiple emulsion and multihollow microspheres.

MRMPlus: an open source quality control and assessment tool for SRM/MRM assay development.

PubMed

Aiyetan, Paul; Thomas, Stefani N; Zhang, Zhen; Zhang, Hui

2015-12-12

Selected and multiple reaction monitoring involves monitoring a multiplexed assay of proteotypic peptides and associated transitions in mass spectrometry runs. To describe peptide and associated transitions as stable, quantifiable, and reproducible representatives of proteins of interest, experimental and analytical validation is required. However, inadequate and disparate analytical tools and validation methods predispose assay performance measures to errors and inconsistencies. Implemented as a freely available, open-source tool in the platform independent Java programing language, MRMPlus computes analytical measures as recommended recently by the Clinical Proteomics Tumor Analysis Consortium Assay Development Working Group for "Tier 2" assays - that is, non-clinical assays sufficient enough to measure changes due to both biological and experimental perturbations. Computed measures include; limit of detection, lower limit of quantification, linearity, carry-over, partial validation of specificity, and upper limit of quantification. MRMPlus streamlines assay development analytical workflow and therefore minimizes error predisposition. MRMPlus may also be used for performance estimation for targeted assays not described by the Assay Development Working Group. MRMPlus' source codes and compiled binaries can be freely downloaded from https://bitbucket.org/paiyetan/mrmplusgui and https://bitbucket.org/paiyetan/mrmplusgui/downloads respectively.

Human hepatocytes derived from pluripotent stem cells: a promising cell model for drug hepatotoxicity screening.

PubMed

Gómez-Lechón, María José; Tolosa, Laia

2016-09-01

Drug-induced liver injury (DILI) is a frequent cause of failure in both clinical and post-approval stages of drug development, and poses a key challenge to the pharmaceutical industry. Current animal models offer poor prediction of human DILI. Although several human cell-based models have been proposed for the detection of human DILI, human primary hepatocytes remain the gold standard for preclinical toxicological screening. However, their use is hindered by their limited availability, variability and phenotypic instability. In contrast, pluripotent stem cells, which include embryonic and induced pluripotent stem cells (iPSCs), proliferate extensively in vitro and can be differentiated into hepatocytes by the addition of soluble factors. This provides a stable source of hepatocytes for multiple applications, including early preclinical hepatotoxicity screening. In addition, iPSCs also have the potential to establish genotype-specific cells from different individuals, which would increase the predictivity of toxicity assays allowing more successful clinical trials. Therefore, the generation of human hepatocyte-like cells derived from pluripotent stem cells seems to be promising for overcoming limitations of hepatocyte preparations, and it is expected to have a substantial repercussion in preclinical hepatotoxicity risk assessment in early drug development stages.

Quality of life in Chinese patients with schizophrenia treated in primary care.

PubMed

Li, Yan; Hou, Cai-Lan; Ma, Xin-Rong; Zhong, Bao-Liang; Zang, Yu; Jia, Fu-Jun; Lin, Yong-Qiang; Lai, Kelly Y C; Chiu, Helen F K; Ungvari, Gabor S; Hall, Brian J; Cai, Mei-Ying; Ng, Chee H; Xiang, Yu-Tao

2017-08-01

In China, maintenance treatment for clinically stable patients with schizophrenia is usually provided by primary care physicians. This study examined the quality of life (QOL) in patients with schizophrenia treated in primary care and explored the demographic and clinical characteristics associated with QOL. Altogether, 612 patients with schizophrenia treated in 22 randomly selected primary care services in China formed the study sample. QOL, psychotic and depressive symptoms, extra-pyramidal symptoms and insight were assessed using standardized instruments. Data analyses were conducted with the one sample t-test and multiple linear regression analyses. Compared with the normative data for the Chinese general population, significantly lower scores in physical and mental QOL domains were found in the patient group. Older age, being unemployed, major medical conditions, no smoking, more severe depressive and negative symptoms, more frequent insomnia, and suicidality were independently associated with poor physical QOL. Male gender, more severe depressive and anxiety symptoms, more frequent insomnia, and suicidality were independently associated with poor mental QOL. Patients with schizophrenia treated in primary care had lower level of QOL in comparison with general population. Effective measures need to be implemented to improve their QOL. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Prospects for Therapeutic Tolerance in Humans

PubMed Central

Baker, Kenneth F; Isaacs, John D

2015-01-01

Purpose of review To provide an overview of recent advances and future possibilities for therapeutic tolerance. Recent findings Allograft survival despite complete immunosuppressant withdrawal has been demonstrated in selected renal transplant recipients with haematopoietic chimerism. Early clinical trials of mesenchymal stromal cell therapy have shown promising results in several autoimmune diseases. Regulatory T-cells show potential benefit in graft versus host disease, although challenges to ex vivo expansion remain. Targeted modulation of T-cell function in vivo with monoclonal antibodies have shown beneficial effects in phase II/III trials of multiple sclerosis (alemtuzumab) and type I diabetes mellitus (teplizumab, otelixizumab). Emerging data from animal models suggests an important role for the commensal microbiome in the maintenance and disruption of immune tolerance with parallels in human studies. Summary After years of slow progress, recent research has reduced the translational gap between animal models and clinical therapeutic tolerance. Early detection of autoimmunity, potentially at preclinical stages, offers a window of opportunity for tolerogenic therapy. Reliable biomarkers of tolerance are urgently needed to provide objective measurements of the effectiveness of tolerogenic therapies, and to allow for intelligent immunosuppressant withdrawal in patients whose autoimmune disease is stable. Video Abstract PMID:24378931

The relation of illness perceptions to stress, depression, and fatigue in patients with chronic lymphocytic leukaemia.

PubMed

Westbrook, Travis D; Maddocks, Kami; Andersen, Barbara L

2016-07-01

Chronic lymphocytic leukaemia (CLL) is the most prevalent adult leukaemia and is incurable. The course and treatment of CLL is unique and characterised by repeated cycles of treatment, stable disease and relapse. Utilising a Self-Regulatory Model framework, we examined the relationship between patients' illness perceptions and cancer-specific stress, depressive symptoms and fatigue. Our aim was to test illness perceptions as predictors of these outcomes when variance due to disease and treatment variables was controlled. Data were collected on 147 patients with relapsed/refractory CLL as they entered a phase II clinical trial of an investigational medication at a university affiliated, National Cancer Institute designated comprehensive cancer center. Cancer-specific stress, depressive symptoms and fatigue interference. . Hierarchical multiple regression was used. Consequences and emotional representation were related to all outcomes (ps < .01). Illness concern was related to cancer-specific stress (p < .01), and identity was related to fatigue interference (p < .01). All relationships were observed while controlling for number of previous CLL therapies received. Illness perceptions are related to cancer-specific stress, depressive symptoms and fatigue interference in relapsed/refractory CLL. Interventions targeted at restructuring maladaptive illness perceptions may have clinical benefit in this population.

Trends and factors in human immunodeficiency virus and/or hepatitis C virus testing and infection among injection drug users newly entering methadone maintenance treatment in Guangdong Province, China 2006-2013: a consecutive cross sectional study.

PubMed

Liu, Yin; Liu, Yu; Zou, Xia; Chen, Wen; Ling, Li

2017-07-13

To assess trends and related factors in HIV and/or hepatitis C virus (HCV) antibody testing and infection among injection drug users (IDUs) newly entering methadone maintenance treatment (MMT) in Guangdong Province, China. Consecutive cross sectional surveys were conducted in 14 MMT clinics from July 2006 to December 2013 in Guangdong Province, China. IDUs were excluded if they were re-enrolled or referred from other MMT clinics. Trend tests were used to examine HIV and/or HCV testing and infection, sociodemographic characteristics, drug use related behaviours and the past 3 month sexual behaviours on enrolment. Multivariate logistic regression was used to identify correlates of HIV and/or HCV testing and infection. 7539 IDUs with an average age of 35.6±6.2 years were newly enrolled with a history of injection for an average of 11.8±4.9 years. The average frequency of injection before enrolment had been increasing. HIV, HCV and HIV/HCV dual testing increased from 2006 to 2013 (p trend <0.001). However, all three types of infections remained stable (p trend >0.05) until reaching a peak in 2011, excluding the first year. Associating with fellow drug users 1-4 times during the past month, injecting for 15+ years and having multiple sexual partners during the past 3 months predicted higher percentages for HIV and/or HCV testing (p<0.05), while those injecting 4+ times per day in the past month and those who had ever shared needles were less likely to take both tests (p<0.05). Having multiple sexual partners, a longer duration of injection drug use and sharing needles or sharing more frequently were major risk factors for HIV, HCV and HIV/HCV co-infection (p<0.05). The prevalence of HIV and HCV were high and quite stable among new IDU entrants in MMT. Publicising MMT, routine screening, and behavioural and structural interventions is needed. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Thrombolysis in myocardial infarction frame count in coronary arteries without visible atherosclerosis in coronary angiography of patients with stable coronary artery disease.

PubMed

Tacoy, Gulten A; Yazici, Guliz E; Kocaman, Sinan A; Ozdemir, Murat H

2009-06-01

To investigate the thrombolysis in myocardial infarction (TIMI) frame count (TFC) in the coronary arteries without visible atherosclerosis in coronary angiography of patients with stable coronary artery disease (CAD). Eighty-three patients (mean age 58+/-10, 31 [37%] males), who underwent coronary angiographic evaluation for stable angina in Gazi University, Ankara, Turkey, Cardiology clinic between 2006-2007 were enrolled. Forty patients with normal coronary arteries were defined as group I. Group II consisted of 43 patients, who have one normal coronary artery in the setting of stable CAD defined as stenoses 50% or greater in at least one major coronary artery. Coronary blood flow and microvascular perfusion was evaluated by TFC. In group II, the TFC of left anterior descending artery (LAD) in 15 patients, TFC of circumflex artery (CX) in 18 patient, and TFC of right coronary artery (RCA) in 10 patients were evaluated. In group II, the TFC of LAD (37+/-12 versus 29+/-12, p=0.015) and CX (22+/-8 versus 18+/-9, p=0.035) were significantly higher than those in group I. The TFC of RCA was similar between groups (17+/-9 versus 17+/-8, p=0.990). After the adjustment of the risk factors by multivariate regression analyses, the association between TFC and clinical characteristic was statistically non-significant. The TFC decreased in angiographically normal LAD and CX arteries in the setting of stable angina pectoris. The important predictor was CAD alone, irrespective of the clinical parameters.

An extractive removal step optimized for a high-throughput α-cellulose extraction method for δ 13 C and δ 18 O stable isotope ratio analysis in conifer tree rings

Treesearch

Wen Lin; Asko Noormets; John S. King; Ge Sun; Steve McNulty; Jean-Christophe Domec; Lucas Cernusak

2017-01-01

Stable isotope ratios (δ13C and δ18O) of tree-ring α-cellulose are important tools in paleoclimatology, ecology, plant physiology and genetics. The Multiple Sample Isolation System for Solids (MSISS) was a major advance in the tree-ring α-cellulose extraction methods, offering greater throughput and reduced labor input compared to traditional alternatives. However, the...

Microwave Comb Generator

NASA Technical Reports Server (NTRS)

Sigman, E. H.

1989-01-01

Stable reference tones aid testing and calibration of microwave receivers. Signal generator puts out stable tones in frequency range of 2 to 10 GHz at all multiples of reference input frequency, at any frequency up to 1 MHz. Called "comb generator" because spectral plot resembles comb. DC reverse-bias current switched on and off at 1 MHz to generate sharp pulses in step-recovery diode. Microwave components mounted on back of special connector containing built-in attenuator. Used in testing microwave and spread-spectrum wide-band receivers.

ANMCO/GICR-IACPR/SICI-GISE Consensus Document: the clinical management of chronic ischaemic cardiomyopathy

PubMed Central

Gulizia, Michele Massimo; Colivicchi, Furio; Di Lenarda, Andrea; Musumeci, Giuseppe; Faggiano, Pompilio Massimo; Abrignani, Maurizio Giuseppe; Rossini, Roberta; Fattirolli, Francesco; Valente, Serafina; Mureddu, Gian Francesco; Temporelli, Pier Luigi; Olivari, Zoran; Amico, Antonio Francesco; Casolo, Giancarlo; Fresco, Claudio; Menozzi, Alberto; Nardi, Federico

2017-01-01

Stable coronary artery disease (CAD) is a clinical entity of great epidemiological importance. It is becoming increasingly common due to the longer life expectancy, being strictly related to age and to advances in diagnostic techniques and pharmacological and non-pharmacological interventions. Stable CAD encompasses a variety of clinical and anatomic presentations, making the identification of its clinical and anatomical features challenging. Therapeutic interventions should be defined on an individual basis according to the patient’s risk profile. To this aim, management flow charts have been reviewed based on sustainability and appropriateness derived from recent evidence. Special emphasis has been placed on non-pharmacological interventions, stressing the importance of lifestyle changes, including smoking cessation, regular physical activity, and diet. Adherence to therapy as an emerging risk factor is also discussed. PMID:28533729

Recapitulating the clinical scenario of BRCA-associated pancreatic cancer in pre-clinical models.

PubMed

Golan, Talia; Stossel, Chani; Atias, Dikla; Buzhor, Ella; Halperin, Sharon; Cohen, Keren; Raitses-Gurevich, Maria; Glick, Yulia; Raskin, Stephen; Yehuda, Daniel; Feldman, Anna; Schvimer, Michael; Friedman, Eitan; Karni, Rotem; Wilson, Julie M; Denroche, Robert E; Lungu, Ilinca; Bartlett, John M S; Mbabaali, Faridah; Gallinger, Steven; Berger, Raanan

2018-07-01

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. BRCA-associated PDAC comprises a clinically relevant subtype. A portion of these patients are highly susceptible to DNA damaging therapeutics, however, responses are heterogeneous and clinical resistance evolves. We have developed unique patient-derived xenograft (PDX) models from metastatic lesions of germline BRCA-mutated patients obtained at distinct time points; before treatment and at progression. Thus, closely mimicking clinical scenarios, to further investigate treatment naïve and resistant patients. DNA was isolated from six BRCA-mutated PDXs and classified by whole-genome sequencing to stable-genome or homologous recombination deficient (HRD)-genome. The sensitivity to DNA-damaging agents was evaluated in vivo in three BRCA-associated PDAC PDXs models: (1) HRD-genome naïve to treatments; (2) stable-genome naïve to treatment; (3) HRD-genome resistant to treatment. Correlation between disease course at tissue acquisition and response to PARP inhibitor (PARPi)/platinum was demonstrated in PDXs in vivo. Only the HRD-genome PDX, naïve to treatment, was sensitive to PARP inhibitor/cisplatin treatments. Our results demonstrate heterogeneous responses to DNA damaging agents/PARPi in BRCA-associated PDX thus reflecting the wide clinical spectrum. An HRD-genome PDX generated from a naïve to treatment biopsy was sensitive to platinum/PARPi whereas no benefit was observed in treating a HRD-genome PDXs generated from a patient that had acquired resistance nor stable-genome PDXs. © 2018 UICC.

Feasibility of extended use of an electromagnetic lithotripter beyond the manufacturer's recommended maintenance schedule.

PubMed

Chen, Tony Y H; Ponsot, Yves; Brouillette, Martin; Tétrault, Jean-Píerre; Tu, Le Mai

2007-06-01

The study evaluates the effect of chronic usage, beyond the recommended maintenance schedule, on the efficacy of electromagnetic lithotripter. To our knowledge, there is no publication investigating the effect of chronic usage on the electromagnetic lithotripter, despite the maintenance schedule established by the manufacturers. Our goal is to verify if the acoustic parameters of the shock wave changed with usage, and if this change could be associated with change in clinical efficacy. This study lasted 18 months. Every 6 months the lithotripter's efficacy was evaluated in two ways: objectively and clinically. Objective efficacy was measured using a piezoelectric hydrophone and artificial stones to capture the acoustic parameters and the crater of fragmentation, respectively. Clinical efficacy data was collected by studying the rate of successful extracorporeal shock wave lithotripsy treatment in patients with urolithiasis. The changes in clinical efficacy, acoustic parameters, and craters of fragmentation were compared and analyzed with appropriate statistical methods. Five hundred twenty five patients participated in the study. The clinical efficacy remained stable throughout the three observation periods (55.7%, 66.2% and 55.5%; p = 0.11). The focal head of the lithotripter was used three times the recommended schedule. There was no obvious change in the acoustic parameters of the shock waves, and the focal zone remained stable. The clinical efficacy of the electromagnetic lithotripter appears to be stable despite usage beyond the recommended maintenance schedule. More studies are needed to validate the safety of this practice.

Combined action of time-delay and colored cross-associated multiplicative and additive noises on stability and stochastic resonance for a stochastic metapopulation system

NASA Astrophysics Data System (ADS)

Wang, Kang-Kang; Zong, De-Cai; Wang, Ya-Jun; Li, Sheng-Hong

2016-05-01

In this paper, the transition between the stable state of a big density and the extinction state and stochastic resonance (SR) for a time-delayed metapopulation system disturbed by colored cross-correlated noises are investigated. By applying the fast descent method, the small time-delay approximation and McNamara and Wiesenfeld's SR theory, we investigate the impacts of time-delay, the multiplicative, additive noises and colored cross-correlated noise on the SNR and the shift between the two states of the system. Numerical results show that the multiplicative, additive noises and time-delay can all speed up the transition from the stable state to the extinction state, while the correlation noise and its correlation time can slow down the extinction process of the population system. With respect to SNR, the multiplicative noise always weakens the SR effect, while noise correlation time plays a dual role in motivating the SR phenomenon. Meanwhile, time-delay mainly plays a negative role in stimulating the SR phenomenon. Conversely, it could motivate the SR effect to increase the strength of the cross-correlation noise in the SNR-β plot, while the increase of additive noise intensity will firstly excite SR, and then suppress the SR effect.

Ruptured Abdominal Aortic Aneurysm: Prediction of Mortality From Clinical Presentation and Glasgow Aneurysm Score.

PubMed

Weingarten, Toby N; Thompson, Lauren T; Licatino, Lauren K; Bailey, Christopher H; Schroeder, Darrell R; Sprung, Juraj

2016-04-01

To examine association of presenting clinical acuity and Glasgow Aneurysm Score (GAS) with perioperative and 1-year mortality. Retrospective chart review. Major tertiary care facility. Patients with ruptured abdominal aortic aneurysm (rAAA) from 2003 through 2013. Emergency repair of rAAA. The authors reviewed outcomes after stable versus unstable presentation and by GAS. Unstable presentation included hypotension, cardiac arrest, loss of consciousness, and preoperative tracheal intubation. In total, 125 patients (40 stable) underwent repair. Perioperative mortality rates were 41% and 12% in unstable and stable patients, respectively (p<0.001). Unstable status had 88% sensitivity and 41% specificity for predicting perioperative mortality. Using logistic regression, higher GAS was associated with perioperative mortality (p<0.001). Using receiver operating characteristic analysis, the area under the curve was 0.72 (95% CI, 0.62-0.82) and cutoff GAS≥96 had 63% and 72% sensitivity and specificity, respectively. Perioperative mortality for GAS≥96 was 51% (25/49), whereas it was 20% (15/76) for GAS≤95. The estimated 1-year survival (95% CI) was 75% (62%-91%) for stable patients and 48% (38%-60%) for unstable patients. Estimated 1-year survival (95% CI) was 23% (13%-40%) for GAS≥96 and 77% (67%-87%) for GAS≤95. Clinical presentation and GAS identified patients with rAAA who were likely to have a poor surgical outcome. GAS≥96 was associated with poor long-term survival, but>20% of these patients survived 1 year. Thus, neither clinical presentation nor GAS provided reliable guidance for decisions regarding futility of surgery. Copyright © 2016 Elsevier Inc. All rights reserved.

Construct the stable vendor managed inventory partnership through a profit-sharing approach

NASA Astrophysics Data System (ADS)

Li, S.; Yu, Z.; Dong, M.

2015-01-01

In real life, the vendor managed inventory (VMI) model is not always a stable supply chain partnership. This paper proposes a cooperative game based profit-sharing method to stabilize the VMI partnership. Specifically, in a B2C setting, we consider a VMI program including a manufacturer and multiple online retailers. The manufacturer provides the finished product at the equal wholesale price to multiple online retailers. The online retailers face the same customer demand information. We offer the model to compute the increased profits generated by information sharing for total possible VMI coalitions. Using the solution concept of Shapley value, the profit-sharing scheme is produced to fairly divide the total increased profits among the VMI members. We find that under a fair allocation scheme, the higher inventory cost of one VMI member increases the surplus of the other members. Furthermore, the manufacturer is glad to increase the size of VMI coalition, whereas, the retailers are delighted to limit the size of the alliance. Finally, the manufacturer can select the appropriate retailer to boost its surplus, which has no effect on the surplus of the other retailers. The numerical examples indicate that the grand coalition is stable under the proposed allocation scheme.

Vegetation engineers marsh morphology through multiple competing stable states

NASA Astrophysics Data System (ADS)

Marani, Marco; Da Lio, Cristina; D'Alpaos, Andrea

2013-02-01

Marshes display impressive biogeomorphic features, such as zonation, a mosaic of extensive vegetation patches of rather uniform composition, exhibiting sharp transitions in the presence of extremely small topographic gradients. Although generally associated with the accretion processes necessary for marshes to keep up with relative sea level rise, competing environmental constraints, and ecologic controls, zonation is still poorly understood in terms of the underlying biogeomorphic mechanisms. Here we find, through observations and modeling interpretation, that zonation is the result of coupled geomorphological-biological dynamics and that it stems from the ability of vegetation to actively engineer the landscape by tuning soil elevation within preferential ranges of optimal adaptation. We find multiple peaks in the frequency distribution of observed topographic elevation and identify them as the signature of biologic controls on geomorphodynamics through competing stable states modulated by the interplay of inorganic and organic deposition. Interestingly, the stable biogeomorphic equilibria correspond to suboptimal rates of biomass production, a result coherent with recent observations. The emerging biogeomorphic structures may display varying degrees of robustness to changes in the rate of sea level rise and sediment availability, with implications for the overall resilience of marsh ecosystems to climatic changes.

Vegetation engineers marsh morphology through multiple competing stable states

PubMed Central

Marani, Marco; Da Lio, Cristina; D’Alpaos, Andrea

2013-01-01

Marshes display impressive biogeomorphic features, such as zonation, a mosaic of extensive vegetation patches of rather uniform composition, exhibiting sharp transitions in the presence of extremely small topographic gradients. Although generally associated with the accretion processes necessary for marshes to keep up with relative sea level rise, competing environmental constraints, and ecologic controls, zonation is still poorly understood in terms of the underlying biogeomorphic mechanisms. Here we find, through observations and modeling interpretation, that zonation is the result of coupled geomorphological–biological dynamics and that it stems from the ability of vegetation to actively engineer the landscape by tuning soil elevation within preferential ranges of optimal adaptation. We find multiple peaks in the frequency distribution of observed topographic elevation and identify them as the signature of biologic controls on geomorphodynamics through competing stable states modulated by the interplay of inorganic and organic deposition. Interestingly, the stable biogeomorphic equilibria correspond to suboptimal rates of biomass production, a result coherent with recent observations. The emerging biogeomorphic structures may display varying degrees of robustness to changes in the rate of sea level rise and sediment availability, with implications for the overall resilience of marsh ecosystems to climatic changes. PMID:23401529

Intraoperative use of remifentanil and opioid induced hyperalgesia/acute opioid tolerance: systematic review.

PubMed

Kim, Sang Hun; Stoicea, Nicoleta; Soghomonyan, Suren; Bergese, Sergio D

2014-01-01

The use of opioids has been increasing in operating room and intensive care unit to provide perioperative analgesia as well as stable hemodynamics. However, many authors have suggested that the use of opioids is associated with the expression of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH) in experimental studies and clinical observations in dose and/or time dependent exposure even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management during anesthesia as well as in the intensive care units because of its rapid onset and offset. Search of the available literature to assess remifentanil AOT and OIH based on available published data. We reviewed articles analyzing remifentanil AOT and OIH, and focused our literature search on evidence based information. Experimental and clinical studies were identified using electronic searches of Medline (PubMed, Ovid, Springer, and Elsevier, ClinicalKey). Our results showed that the development of remifentanil AOT and OIH is a clinically significant phenomenon requiring further research. AOT - defined as an increase in the required opioid dose to maintain adequate analgesia, and OIH - defined as decreased pain threshold after chronic opioid treatment, should be suspected with any unexplained pain report unassociated with the disease progression. The clinical significance of these findings was evaluated taking into account multiple methodological issues including the dose and duration of opioids administration, the different infusion mode, the co-administrated anesthetic drug's effect, method assessing pain sensitivity, and the repetitive and potentially tissue damaging nature of the stimuli used to determine the threshold during opioid infusion. Future studies need to investigate the contribution of remifentanil induced hyperalgesia to chronic pain and the role of pharmacological modulation to reverse this process.

Stabilized polyacrylic saccharide protein conjugates

DOEpatents

Callstrom, M.R.; Bednarski, M.D.; Gruber, P.R.

1996-02-20

This invention is directed to water soluble protein polymer conjugates which are stable in hostile environments. The conjugate comprises a protein which is linked to an acrylic polymer at multiple points through saccharide linker groups. 16 figs.

Population variation in isotopic composition of shorebird feathers: Implications for determining molting grounds

USGS Publications Warehouse

Torres-Dowdall, J.; Farmer, A.H.; Bucher, E.H.; Rye, R.O.; Landis, G.

2009-01-01

Stable isotope analyses have revolutionized the study of migratory connectivity. However, as with all tools, their limitations must be understood in order to derive the maximum benefit of a particular application. The goal of this study was to evaluate the efficacy of stable isotopes of C, N, H, O and S for assigning known-origin feathers to the molting sites of migrant shorebird species wintering and breeding in Argentina. Specific objectives were to: 1) compare the efficacy of the technique for studying shorebird species with different migration patterns, life histories and habitat-use patterns; 2) evaluate the grouping of species with similar migration and habitat use patterns in a single analysis to potentially improve prediction accuracy; and 3) evaluate the potential gains in prediction accuracy that might be achieved from using multiple stable isotopes. The efficacy of stable isotope ratios to determine origin was found to vary with species. While one species (White-rumped Sandpiper, Calidris fuscicollis) had high levels of accuracy assigning samples to known origin (91% of samples correctly assigned), another (Collared Plover, Charadrius collaris) showed low levels of accuracy (52% of samples correctly assigned). Intra-individual variability may account for this difference in efficacy. The prediction model for three species with similar migration and habitat-use patterns performed poorly compared with the model for just one of the species (71% versus 91% of samples correctly assigned). Thus, combining multiple sympatric species may not improve model prediction accuracy. Increasing the number of stable isotopes in the analyses increased the accuracy of assigning shorebirds to their molting origin, but the best combination - involving a subset of all the isotopes analyzed - varied among species.

[Circular RNA in human disease and their potential clinic significance].

PubMed

Chen, Yonghua; Li, Cheng; Tan, Chunlu; Mai, Gang; Liu, Xubao

2017-02-10

Circular RNAs (circ RNAs) are a novel type of RNA that, unlike linear RNAs, form a covalently closed continuous loop and are highly represented in the eukaryotic transcriptome. They share a stable structure, high expression and often exhibit tissue/developmental-stage-specific expression. Emerging evidence indicates that circRNAs might play important roles in human disease, such as cancer, neurological disorders and atherosclerotic vascular disease risk. The huge potentials of circRNAs are recently being discovered from the laboratory to the clinic. CircRNAs might be developed as a potential novel and stable biomarker and potential drugs used in disease diagnosis and treatment. Here, we review the current understanding of the roles of circRNAs in human disease and their potential clinic significance in disease.

Production of lentiviral vectors

PubMed Central

Merten, Otto-Wilhelm; Hebben, Matthias; Bovolenta, Chiara

2016-01-01

Lentiviral vectors (LV) have seen considerably increase in use as gene therapy vectors for the treatment of acquired and inherited diseases. This review presents the state of the art of the production of these vectors with particular emphasis on their large-scale production for clinical purposes. In contrast to oncoretroviral vectors, which are produced using stable producer cell lines, clinical-grade LV are in most of the cases produced by transient transfection of 293 or 293T cells grown in cell factories. However, more recent developments, also, tend to use hollow fiber reactor, suspension culture processes, and the implementation of stable producer cell lines. As is customary for the biotech industry, rather sophisticated downstream processing protocols have been established to remove any undesirable process-derived contaminant, such as plasmid or host cell DNA or host cell proteins. This review compares published large-scale production and purification processes of LV and presents their process performances. Furthermore, developments in the domain of stable cell lines and their way to the use of production vehicles of clinical material will be presented. PMID:27110581

Identification of a B cell signature associated with renal transplant tolerance in humans

PubMed Central

Newell, Kenneth A.; Asare, Adam; Kirk, Allan D.; Gisler, Trang D.; Bourcier, Kasia; Suthanthiran, Manikkam; Burlingham, William J.; Marks, William H.; Sanz, Ignacio; Lechler, Robert I.; Hernandez-Fuentes, Maria P.; Turka, Laurence A.; Seyfert-Margolis, Vicki L.

2010-01-01

Establishing long-term allograft acceptance without the requirement for continuous immunosuppression, a condition known as allograft tolerance, is a highly desirable therapeutic goal in solid organ transplantation. Determining which recipients would benefit from withdrawal or minimization of immunosuppression would be greatly facilitated by biomarkers predictive of tolerance. In this study, we identified the largest reported cohort to our knowledge of tolerant renal transplant recipients, as defined by stable graft function and receiving no immunosuppression for more than 1 year, and compared their gene expression profiles and peripheral blood lymphocyte subsets with those of subjects with stable graft function who are receiving immunosuppressive drugs as well as healthy controls. In addition to being associated with clinical and phenotypic parameters, renal allograft tolerance was strongly associated with a B cell signature using several assays. Tolerant subjects showed increased expression of multiple B cell differentiation genes, and a set of just 3 of these genes distinguished tolerant from nontolerant recipients in a unique test set of samples. This B cell signature was associated with upregulation of CD20 mRNA in urine sediment cells and elevated numbers of peripheral blood naive and transitional B cells in tolerant participants compared with those receiving immunosuppression. These results point to a critical role for B cells in regulating alloimmunity and provide a candidate set of genes for wider-scale screening of renal transplant recipients. PMID:20501946

Preanalytical variables in measurement of free (ionized) calcium in lithium heparin-containing blood collection tubes.

PubMed

Haverstick, Doris M; Brill, Louis B; Scott, Mitchell G; Bruns, David E

2009-05-01

Measurements of free (ionized) calcium (iCa) are increasingly requested in patient care locations where immediate analysis is unavailable. Evacuated blood collection tubes containing lithium heparin and gel separator material are widely used in clinical laboratories, but little information is available on the effects of these tubes or of delay prior to analysis on the concentration or stability of iCa. We collected blood from volunteers into lithium-heparin tubes (PST, Vacutainer PST, BD Pre-Analytic Systems) of multiple lots and into electrolyte-balanced heparin syringes (Portex Dry Heparin, Smiths Medical). iCa was measured (Siemens 1265 blood gas analyzers) immediately and, in PST, at 0-7 h with or without transportation of the tubes from remote sites. The mean difference of free calcium results in the PST tubes and electrolyte-balanced syringes was -0.08 (95% confidence interval -0.17 to 0.012) mmol/l, and the SD of the residuals (Sy, x) of the regression was 0.03 mmol/l. There was no detectable lot-to-lot variation in results. Free calcium was stable in tubes at room temperature and at 4 degrees C for at least 7 h with or without transportation. iCa measured in the examined blood collection tubes is stable and unaffected by lot-to-lot variation of tubes, but results are slightly lower than with special blood gas syringes.

Computed Tomography Angiography Evaluation of Risk Factors for Unstable Intracranial Aneurysms.

PubMed

Wang, Guang-Xian; Gong, Ming-Fu; Wen, Li; Liu, Lan-Lan; Yin, Jin-Bo; Duan, Chun-Mei; Zhang, Dong

2018-03-19

To evaluate risk factors for instability in intracranial aneurysms (IAs) using computed tomography angiography (CTA). A total of 614 consecutive patients diagnosed with 661 IAs between August 2011 and February 2016 were reviewed. Patients and IAs were divided into stable and unstable groups. Along with clinical characteristics, IA characteristics were evaluated by CTA. Multiple logistic regression analysis was used to identify the independent risk factors associated with unstable IAs. Receiver operating characteristic (ROC) curve analysis was performed on the final model, and optimal thresholds were obtained. Patient age (odds ratio [OR], 0.946), cerebral atherosclerosis (CA; OR, 0.525), and IAs located at the middle cerebral artery (OR, 0.473) or internal carotid artery (OR, 0.512) were negatively correlated with instability, whereas IAs with irregular shape (OR, 2.157), deep depth (OR, 1.557), or large flow angle (FA; OR, 1.015) were more likely to be unstable. ROC analysis revealed threshold values of age, depth, and FA of 59.5 years, 4.25 mm, and 87.8°, respectively. The stability of IAs is significantly affected by several factors, including patient age and the presence of CA. IA shape and location also have an impact on the stability of IAs. Growth into an irregular shape, with a deep depth, and a large FA are risk factors for a change in IAs from stable to unstable. Copyright © 2018 Elsevier Inc. All rights reserved.

Lumican Peptides: Rational Design Targeting ALK5/TGFBRI

NASA Astrophysics Data System (ADS)

Gesteira, Tarsis Ferreira; Coulson-Thomas, Vivien J.; Yuan, Yong; Zhang, Jianhua; Nader, Helena B.; Kao, Winston W.-Y.

2017-02-01

Lumican, a small leucine rich proteoglycan (SLRP), is a component of extracellular matrix which also functions as a matrikine regulating multiple cell activities. In the cornea, lumican maintains corneal transparency by regulating collagen fibrillogenesis, promoting corneal epithelial wound healing, regulating gene expression and maintaining corneal homeostasis. We have recently shown that a peptide designed from the 13 C-terminal amino acids of lumican (LumC13) binds to ALK5/TGFBR1 (type1 receptor of TGFβ) to promote wound healing. Herein we evaluate the mechanism by which this synthetic C-terminal amphiphilic peptide (LumC13), binds to ALK5. These studies clearly reveal that LumC13-ALK5 form a stable complex. In order to determine the minimal amino acids required for the formation of a stable lumican/ALK5 complex derivatives of LumC13 were designed and their binding to ALK5 investigated in silico. These LumC13 derivatives were tested both in vitro and in vivo to evaluate their ability to promote corneal epithelial cell migration and corneal wound healing, respectively. These validations add to the therapeutic value of LumC13 (Lumikine) and aid its clinical relevance of promoting the healing of corneal epithelium debridement. Moreover, our data validates the efficacy of our computational approach to design active peptides based on interactions of receptor and chemokine/ligand.

Stable-isotope analysis: a neglected tool for placing parasites in food webs.

PubMed

Sabadel, A J M; Stumbo, A D; MacLeod, C D

2018-02-28

Parasites are often overlooked in the construction of food webs, despite their ubiquitous presence in almost every type of ecosystem. Researchers who do recognize their importance often struggle to include parasites using classical food-web theory, mainly due to the parasites' multiple hosts and life stages. A novel approach using compound-specific stable-isotope analysis promises to provide considerable insight into the energetic exchanges of parasite and host, which may solve some of the issues inherent in incorporating parasites using a classical approach. Understanding the role of parasites within food webs, and tracing the associated biomass transfers, are crucial to constructing new models that will expand our knowledge of food webs. This mini-review focuses on stable-isotope studies published in the past decade, and introduces compound-specific stable-isotope analysis as a powerful, but underutilized, newly developed tool that may answer many unresolved questions regarding the role of parasites in food webs.

Stable Isotope Ratios as Biomarkers of Diet for Health Research

PubMed Central

O’Brien, Diane M.

2016-01-01

Diet is a leading modifiable risk factor for chronic disease, but it remains difficult to measure accurately due to the error and bias inherent in self-reported methods of diet assessment. Consequently there is a pressing need for more objective biomarkers of diet for use in health research. The stable isotope ratios of light elements are a promising set of candidate biomarkers because they vary naturally and reproducibly among foods, and those variations are captured in molecules and tissues with high fidelity. Recent studies have identified valid isotopic measures of short and long-term sugar intake, meat intake, and fish intake in specific populations. These studies provide a strong foundation for validating stable isotopic biomarkers in the general United States population. Approaches to improve specificity for specific foods are needed, for example, by modeling intake using multiple stable isotope ratios, or by isolating and measuring specific molecules linked to foods of interest. PMID:26048703

Transarterial Embolization of Type II Endoleaks after EVAR: The Role of Ethylene Vinyl Alcohol Copolymer (Onyx)

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

Mueller-Wille, Rene, E-mail: rene.mueller-wille@ukr.de; Wohlgemuth, Walter A., E-mail: walter.wohlgemuth@ukr.de; Heiss, Peter, E-mail: peter.heiss@ukr.de

2013-10-15

Purpose: To determine the feasibility and efficacy of transarterial endoleak embolization using the liquid embolic agent ethylene vinyl alcohol copolymer (Onyx). Methods: Over a 7-year period eleven patients (6 women, 5 men; mean age 68 years, range 37-83 years) underwent transarterial embolization of a type II endoleak after endovascular aortic aneurysm repair using the liquid embolic agent Onyx. Two patients (18 %) had a simple type II endoleak with only one artery in communication with the aneurysm sac, whereas 9 patients (82 %) had a complex type II endoleak with multiple communicating vessels. We retrospectively analyzed the technical and clinicalmore » success of transarterial type II endoleak embolization with Onyx. Complete embolization of the nidus was defined as technical success. Embolization was considered clinically successful when volume of the aneurysm sac was stable or decreased on follow-up CT scans. Result: Mean follow-up time was 26.0 (range 6-50) months. Clinical success was achieved in 8 of 11 patients (73 %). Transarterial nidus embolization with Onyx was technically successful in 6 of 11 patients (55 %). In three cases the nidus was embolized without direct catheterization from a more distal access through the network of collateral vessels. Conclusion: Onyx is a favorable embolic agent for transarterial endoleak embolization. To achieve the best clinical results, complete occlusion of the nidus is mandatory.« less

A piezo surgery with corticotomies and implant placement as part of a multidisciplinary approach to treat malocclusion disorder in an adult patient: clinical report.

PubMed

Gelpi, Federico; De Santis, Daniele; Marconcini, Simone; Briguglio, Francesco; Finotti, Marco

2015-12-01

This clinical report illustrates a multidisciplinary approach for the rehabilitation of a young adult patient affected by a bilateral edentulous space and an anterior deep bite. The patient required orthodontics and surgical corticotomy and implantology (both performed with a piezo device). A multidisciplinary planning approach, including orthodontics, oral and periodontic surgery, and restorative dentistry, has an important role in the final outcome of treatment. In fact a dental class I occlusion has been established only on the right side. The left side could not be restored to an ideal class I relationship due to the pontic prosthesis. The original collapsed right posterior occlusion was corrected. A stable posterior occlusion was established, and the balancing interference was eliminated. Centric relation and centric occlusion were established at the same vertical dimension of occlusion. The cephalometric analysis and clinical aspect at the end of treatment showed that the patient had improvements in overbite and overjet.Multidisciplinary management, including endodontic and restorative dentistry, periodontics, corticotomy-assisted orthodontics, implants, and prosthetics, was used for a young female patient with multiple missing teeth, anterior deep bite, and a malocclusion with cant of the occlusal plane. The interaction of interdisciplinary specialties and careful treatment planning were required. The patient also benefited esthetically from our effort.

[Geographical differences in clinical characteristics and management of stable outpatients with coronary artery disease: comparison between the Italian and international population included in the Worldwide CLARIFY registry].

PubMed

Pozzoli, Massimo; Tavazzi, Luigi

2014-04-01

Limited data are available regarding specific differences among countries in demographic and clinical characteristics and treatment of patients with stable coronary artery disease. CLARIFY is an international, prospective and longitudinal registry including more than 33 000 patients with stable coronary artery disease enrolled in 45 countries worldwide. Data were used to compare the characteristics of patients enrolled in Italy with those enrolled in Europe and in the rest of the world. Baseline data were available for 33 283 patients, 2112 of whom from Italy and 12 614 from the remaining western European countries. Italian patients were found to be older, more frequently smoker, hypertensive and with sedentary habits. In addition, they presented more frequently a history of myocardial infarction, carotid arterial disease and chronic obstructive pulmonary disease. In addition, when compared with patients of both European and international cohorts, more Italian patients had undergone coronary angiography and angioplasty. As far as treatment was concerned, a greater number of Italian patients were taking ivabradine, angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers, nitrates, thienopyridines, while those taking beta-blockers, calcium antagonists and other antianginal medications were fewer. Among ambulatory patients with stable coronary artery disease, there are important geographic differences in terms of risk factors, clinical characteristics, surgical and pharmacological treatment.

Diagnosis of stable ischemic heart disease: summary of a clinical practice guideline from the American College of Physicians/American College of Cardiology Foundation/American Heart Association/American Association for Thoracic Surgery/Preventive Cardiovascular Nurses Association/Society of Thoracic Surgeons.

PubMed

Qaseem, Amir; Fihn, Stephan D; Williams, Sankey; Dallas, Paul; Owens, Douglas K; Shekelle, Paul

2012-11-20

The American College of Physicians (ACP) developed this guideline in collaboration with the American College of Cardiology Foundation (ACCF), American Heart Association (AHA), American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, and Society of Thoracic Surgeons to help clinicians diagnose known or suspected stable ischemic heart disease. Literature on this topic published before November 2011 was identified by using MEDLINE, Embase, Cochrane CENTRAL, PsychINFO, AMED, and SCOPUS. Searches were limited to human studies published in English. This guideline grades the evidence and recommendations according to a translation of the ACCF/AHA grading system into ACP's clinical practice guidelines grading system. This guideline includes 28 recommendations that address the following issues: the initial diagnosis of the patient who might have stable ischemic heart disease, cardiac stress testing to assess the risk for death or myocardial infarction in patients diagnosed with stable ischemic heart disease, and coronary angiography for risk assessment.

The Subfascial Approach to Primary and Secondary Breast Augmentation with Autologous Fat Grafting and Form-Stable Implants.

PubMed

Sampaio Goes, João Carlos; Munhoz, Alexandre Mendonça; Gemperli, Rolf

2015-10-01

This article presents an overview of the subfascial approach to primary and secondary breast augmentation with form-stable implants associated with autologous fat grafting. Although breast augmentation is a well-studied procedure, there are few previous reports concerning the subfascial technique and, especially, this technique associated with lipofilling. Consequently, the authors present their experience with a form-stable, anatomically shaped silicone gel breast implant, which has recently been approved in the United States following FDA clinical trials. Primary and secondary breast augmentations using form-stable implants resulted in satisfactory outcomes. Copyright © 2015 Elsevier Inc. All rights reserved.

LentiPro26: novel stable cell lines for constitutive lentiviral vector production.

PubMed

Tomás, H A; Rodrigues, A F; Carrondo, M J T; Coroadinha, A S

2018-03-27

Lentiviral vectors (LVs) are excellent tools to promote gene transfer and stable gene expression. Their potential has been already demonstrated in gene therapy clinical trials for the treatment of diverse disorders. For large scale LV production, a stable producer system is desirable since it allows scalable and cost-effective viral productions, with increased reproducibility and safety. However, the development of stable systems has been challenging and time-consuming, being the selection of cells presenting high expression levels of Gag-Pro-Pol polyprotein and the cytotoxicity associated with some viral components, the main limitations. Hereby is described the establishment of a new LV producer cell line using a mutated less active viral protease to overcome potential cytotoxic limitations. The stable transfection of bicistronic expression cassettes with re-initiation of the translation mechanism enabled the generation of LentiPro26 packaging populations supporting high titers. Additionally, by skipping intermediate clone screening steps and performing only one final clone screening, it was possible to save time and generate LentiPro26-A59 cell line, that constitutively produces titers above 10 6 TU.mL -1 .day -1 , in less than six months. This work constitutes a step forward towards the development of improved LV producer cell lines, aiming to efficiently supply the clinical expanding gene therapy applications.

Lessons learned: Infrastructure development and financial management for large, publically funded, international trials

PubMed Central

Larson, Gregg S; Carey, Cate; Grarup, Jesper; Hudson, Fleur; Sachi, Karen; Vjecha, Michael J; Gordin, Fred

2015-01-01

Background/Aims Randomized clinical trials are widely recognized as essential to address world-wide clinical and public health research questions. However, for many conditions, their size and duration can overwhelm available public and private resources. To remain competitive in international research settings, advocates and practitioners of clinical trials must implement practices that reduce their cost. We identify approaches and practices for large, publicly-funded, international trials that reduce cost without compromising data integrity, and recommend an approach to cost reporting that permits comparison of clinical trials. Methods We describe the organizational and financial characteristics of INSIGHT, an infectious disease research network that conducts multiple, large, long-term, international trials, and examine challenges associated with simple and streamlined governance and an infrastructure and financial management model that is based on performance, transparency, and accountability. Results It is possible to reduce costs of participant follow-up and not compromise clinical trial quality or integrity. The INSIGHT network has successfully completed four large HIV trials using cost-efficient practices that have not adversely affected investigator enthusiasm, accrual rates, loss-to-follow-up, adherence to the protocol, and completion of data collection. This experience is relevant to the conduct of large, publically funded trials in other disease areas, particularly trials dependent on international collaborations. Conclusion New approaches, or creative adaption of traditional clinical trial infrastructure and financial management tools, can render large, international clinical trials more cost-efficient by emphasizing structural simplicity; minimal up-front costs; payments for performance; and uniform algorithms and fees-for-service, irrespective of location. However, challenges remain. They include institutional resistance to financial change, growing trial complexity, and the difficulty of sustaining network infrastructure absent stable research work. There is also a need for more central monitoring, improved and harmonized regulations, and a widely-applied metric for measuring and comparing cost efficiency in clinical trials. ClinicalTrials.gov is recommended as a location where standardized trial cost information could be made publicly accessible. PMID:26908541

Narrowing beam-walking is a clinically feasible approach for assessing balance ability in lower-limb prosthesis users.

PubMed

Sawers, Andrew; Hafner, Brian J

2018-05-08

Challenging clinical balance tests are needed to expose balance deficits in lower-limb prost-hesis users. This study examined whether narrowing beam-walking could overcome conceptual and practical limitations identified in fixed-width beam-walking. Cross-sectional. Unilateral lower-limb prosthesis users. Participants walked 10 times along a low, narrowing beam. Performance was quantified using the normalized distance walked. Heuristic rules were applied to determine whether the narrowing beam task was "too easy," "too hard," or "appropriately challenging" for each participant. Linear regression and Bland-Altman plots were used to determine whether combinations of the first 5 trials could predict participants' stable beam-walking performance. Forty unilateral lower-limb prosthesis users participated. Narrowing beam-walking was appropriately challenging for 98% of participants. Performance stabilized for 93% of participants within 5 trials, while 62% were stable across all trials. The mean of trials 3-5 accurately predicted stable performance. A clinical narrowing beam-walking test is likely to challenge a range of lower-limb prosthesis users, have minimal administrative burden, and exhibit no floor or ceiling effects. Narrowing beam-walking is therefore a clinically viable method to evaluate lower-limb prosthesis users' balance ability, but requires psychometric testing before it is used to assess fall risk.

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

Intrathecal Baclofen Dosing Regimens: A Retrospective Chart Review.

PubMed

Clearfield, Jacob S; Nelson, Mary Elizabeth S; McGuire, John; Rein, Lisa E; Tarima, Sergey

2016-08-01

To examine dosing patterns in patients receiving baclofen via intrathecal baclofen pumps to assess for common patterns by diagnosis, ambulation ability, and affected limbs distribution. This trial study included 25 patients with baclofen pumps selected from the 356 patients enrolled in our center's baclofen pump program. Selection was done by splitting all patients into diagnostic categories of stroke, multiple sclerosis, traumatic/anoxic brain injury, cerebral palsy, and spinal cord injury, and then, five patients were randomly selected from each diagnosis.A systematic chart review was then conducted for each patient from Jan 1, 2008, through September 16, 2013, to look at factors including mean daily dose at end of study, and among those implanted during the study mean initial stable dose and time to initial stable dose. Analysis of mean daily dose across diagnoses found significant differences, with brain injury, cerebral palsy, and spinal cord injury patients having higher doses while multiple sclerosis and stroke patients required lower doses. Nonambulatory patients strongly trended to have higher daily doses than ambulatory patients. Similar trends of mean initial stable dose being higher in a similar pattern as that of end mean daily dose were seen according to diagnoses and ambulatory status, although statistical significance could not be achieved with the small sample size. Significant differences in dosing were found between diagnoses and trended to differ by ambulatory status at the end of the study, and similar trends could be observed in achieving initial stable dose. © 2015 International Neuromodulation Society.

Multiple Climate States of Habitable Exoplanets: The Role of Obliquity and Irradiance

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

Kilic, C.; Raible, C. C.; Stocker, T. F., E-mail: stocker@climate.unibe.ch

Stable, steady climate states on an Earth-size planet with no continents are determined as a function of the tilt of the planet’s rotation axis (obliquity) and stellar irradiance. Using a general circulation model of the atmosphere coupled to a slab ocean and a thermodynamic sea ice model, two states, the Aquaplanet and the Cryoplanet, are found for high and low stellar irradiance, respectively. In addition, four stable states with seasonally and perennially open water are discovered if comprehensively exploring a parameter space of obliquity from 0° to 90° and stellar irradiance from 70% to 135% of the present-day solar constant.more » Within 11% of today’s solar irradiance, we find a rich structure of stable states that extends the area of habitability considerably. For the same set of parameters, different stable states result if simulations are initialized from an aquaplanet or a cryoplanet state. This demonstrates the possibility of multiple equilibria, hysteresis, and potentially rapid climate change in response to small changes in the orbital parameters. The dynamics of the atmosphere of an aquaplanet or a cryoplanet state is investigated for similar values of obliquity and stellar irradiance. The atmospheric circulation substantially differs in the two states owing to the relative strength of the primary drivers of the meridional transport of heat and momentum. At 90° obliquity and present-day solar constant, the atmospheric dynamics of an Aquaplanet state and one with an equatorial ice cover is analyzed.« less

Multiple Climate States of Habitable Exoplanets: The Role of Obliquity and Irradiance

NASA Astrophysics Data System (ADS)

Kilic, C.; Raible, C. C.; Stocker, T. F.

2017-08-01

Stable, steady climate states on an Earth-size planet with no continents are determined as a function of the tilt of the planet’s rotation axis (obliquity) and stellar irradiance. Using a general circulation model of the atmosphere coupled to a slab ocean and a thermodynamic sea ice model, two states, the Aquaplanet and the Cryoplanet, are found for high and low stellar irradiance, respectively. In addition, four stable states with seasonally and perennially open water are discovered if comprehensively exploring a parameter space of obliquity from 0° to 90° and stellar irradiance from 70% to 135% of the present-day solar constant. Within 11% of today’s solar irradiance, we find a rich structure of stable states that extends the area of habitability considerably. For the same set of parameters, different stable states result if simulations are initialized from an aquaplanet or a cryoplanet state. This demonstrates the possibility of multiple equilibria, hysteresis, and potentially rapid climate change in response to small changes in the orbital parameters. The dynamics of the atmosphere of an aquaplanet or a cryoplanet state is investigated for similar values of obliquity and stellar irradiance. The atmospheric circulation substantially differs in the two states owing to the relative strength of the primary drivers of the meridional transport of heat and momentum. At 90° obliquity and present-day solar constant, the atmospheric dynamics of an Aquaplanet state and one with an equatorial ice cover is analyzed.

In vitro Development of Chemotherapy and Targeted Therapy Drug-Resistant Cancer Cell Lines: A Practical Guide with Case Studies

PubMed Central

McDermott, Martina; Eustace, Alex J.; Busschots, Steven; Breen, Laura; Crown, John; Clynes, Martin; O’Donovan, Norma; Stordal, Britta

2014-01-01

The development of a drug-resistant cell line can take from 3 to 18 months. However, little is published on the methodology of this development process. This article will discuss key decisions to be made prior to starting resistant cell line development; the choice of parent cell line, dose of selecting agent, treatment interval, and optimizing the dose of drug for the parent cell line. Clinically relevant drug-resistant cell lines are developed by mimicking the conditions cancer patients experience during chemotherapy and cell lines display between two- and eight-fold resistance compared to their parental cell line. Doses of drug administered are low, and a pulsed treatment strategy is often used where the cells recover in drug-free media. High-level laboratory models are developed with the aim of understanding potential mechanisms of resistance to chemotherapy agents. Doses of drug are higher and escalated over time. It is common to have difficulty developing stable clinically relevant drug-resistant cell lines. A comparative selection strategy of multiple cell lines or multiple chemotherapeutic agents mitigates this risk and gives insight into which agents or type of cell line develops resistance easily. Successful selection strategies from our research are presented. Pulsed-selection produced platinum or taxane-resistant large cell lung cancer (H1299 and H460) and temozolomide-resistant melanoma (Malme-3M and HT144) cell lines. Continuous selection produced a lapatinib-resistant breast cancer cell line (HCC1954). Techniques for maintaining drug-resistant cell lines are outlined including; maintaining cells with chemotherapy, pulse treating with chemotherapy, or returning to master drug-resistant stocks. The heterogeneity of drug-resistant models produced from the same parent cell line with the same chemotherapy agent is explored with reference to P-glycoprotein. Heterogeneity in drug-resistant cell lines reflects the heterogeneity that can occur in clinical drug resistance. PMID:24639951

Natural history and prognostic factors in alcoholic cardiomyopathy.

PubMed

Guzzo-Merello, Gonzalo; Segovia, Javier; Dominguez, Fernando; Cobo-Marcos, Marta; Gomez-Bueno, Manuel; Avellana, Patricia; Millan, Isabel; Alonso-Pulpon, Luis; Garcia-Pavia, Pablo

2015-01-01

This study sought to determine the natural history of contemporary alcoholic cardiomyopathy (ACM), to compare it with that of idiopathic dilated cardiomyopathy (IDCM), and to identify risk factors for poor outcome. ACM is a common cause of dilated cardiomyopathy (DCM), but little is known about its natural history or the effect of reducing alcohol intake on disease progression. We studied the clinical characteristics and outcomes of 94 consecutive patients with ACM and 188 with IDCM, evaluated over the period between 1993 and 2011. After a median follow-up of 59 months (interquartile range: 25 to 107 months), 14 ACM patients (15%) had died from cardiovascular causes (6 from heart failure and 8 from sudden cardiac death), 14 (15%) underwent heart transplantation, 35 (37%) experienced recovery in left ventricular function, and 31 (33%) remained clinically stable without improvement in systolic function. Transplantation-free survival was higher in ACM patients than in IDCM patients (p = 0.002), and ACM was associated with a favorable outcome on multiple analysis of the entire cohort (odds ratio [OR]: 0.4; 95% confidence interval [CI]: 0.2 to 0.8; p = 0.01). Independent predictors of death or heart transplantation in ACM identified by multiple logistic regression analysis were atrial fibrillation (OR: 9.7; 95% CI: 2.56 to 36.79; p = 0.001); QRS duration >120 ms (OR: 7.2; 95% CI: 2.02 to 26; p = 0.002), and lack of beta-blocker therapy (OR: 4.4; 95% CI: 1.35 to 14.49; p = 0.014). ACM patients who reduced their alcohol intake to moderate levels exhibited similar survival (p = 0.22) and cardiac function recovery (p = 0.8) as abstainers. ACM has a better prognosis than IDCM. Atrial fibrillation, QRS width >120 ms, and the absence of beta-blocker therapy identify patients with a poor outcome. Alcohol abstainers and those who reduce intake to a moderate degree show similar clinical outcomes. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Local functional connectivity suggests functional immaturity in children with attention-deficit/hyperactivity disorder.

PubMed

Marcos-Vidal, Luis; Martínez-García, Magdalena; Pretus, Clara; Garcia-Garcia, David; Martínez, Kenia; Janssen, Joost; Vilarroya, Oscar; Castellanos, Francisco X; Desco, Manuel; Sepulcre, Jorge; Carmona, Susanna

2018-06-01

Previous studies have associated Attention-Deficit/Hyperactivity Disorder (ADHD) with a maturational lag of brain functional networks. Functional connectivity of the human brain changes from primarily local to more distant connectivity patterns during typical development. Under the maturational lag hypothesis, we expect children with ADHD to exhibit increased local connectivity and decreased distant connectivity compared with neurotypically developing (ND) children. We applied a graph-theory method to compute local and distant connectivity levels and cross-sectionally compared them in a sample of 120 children with ADHD and 120 age-matched ND children (age range = 7-17 years). In addition, we measured if potential group differences in local and distant connectivity were stable across the age range considered. Finally, we assessed the clinical relevance of observed group differences by correlating the connectivity levels and ADHD symptoms severity separately for each group. Children with ADHD exhibited more local connectivity than age-matched ND children in multiple brain regions, mainly overlapping with default mode, fronto-parietal and ventral attentional functional networks (p < .05- threshold free-cluster enhancement-family-wise error). We detected an atypical developmental pattern of local connectivity in somatomotor regions, that is, decreases with age in ND children, and increases with age in children with ADHD. Furthermore, local connectivity within somatomotor areas correlated positively with clinical severity of ADHD symptoms, both in ADHD and ND children. Results suggest an immature functional state of multiple brain networks in children with ADHD. Whereas the ADHD diagnosis is associated with the integrity of the system comprising the fronto-parietal, default mode and ventral attentional networks, the severity of clinical symptoms is related to atypical functional connectivity within somatomotor areas. Additionally, our findings are in line with the view of ADHD as a disorder of deviated maturational trajectories, mainly affecting somatomotor areas, rather than delays that normalize with age. © 2018 Wiley Periodicals, Inc.

Self-organization and progenitor targeting generate stable patterns in planarian regeneration.

PubMed

Atabay, Kutay Deniz; LoCascio, Samuel A; de Hoog, Thom; Reddien, Peter W

2018-04-27

During animal regeneration, cells must organize into discrete and functional systems. We show that self-organization, along with patterning cues, govern progenitor behavior in planarian regeneration. Surgical paradigms allowed the manipulation of planarian eye regeneration in predictable locations and numbers, generating alternative stable neuroanatomical states for wild-type animals with multiple functional ectopic eyes. We used animals with multiple ectopic eyes and eye transplantation to demonstrate that broad progenitor specification, combined with self-organization, allows anatomy maintenance during regeneration. We propose a model for regenerative progenitors involving (i) migratory targeting cues, (ii) self-organization into existing or regenerating eyes, and (iii) a broad zone, associated with coarse progenitor specification, in which eyes can be targeted by progenitors. These three properties help explain how tissues can be organized during regeneration. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Interaction of pulsating and spinning waves in nonadiabatic flame propagation

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

Booty, M.R.; Margolis, S.B.; Matkowsky, B.J.

1987-12-01

The authors consider nonadiabatic premixed flame propagation in a long cylindrical channel. A steadily propagating planar flame exists for heat losses below a critical value. It is stable provided that the Lewis number and the volumetric heat loss coefficient are sufficiently small. At critical values of these parameters, bifurcated states, corresponding to time-periodic pulsating cellular flames, emanate from the steadily propagating solution. The authors analyze the problem in a neighborhood of a multiple primary bifurcation point. By varying the radius of the channel, they split the multiple bifurcation point and show that various types of stable periodic and quasi-periodic pulsatingmore » flames can arise as secondary, tertiary, and quaternary bifurcations. Their analysis describes several types of spinning and pulsating flame propagation which have been experimentally observed in nonadiabatic flames, and also describes additional quasi-periodic modes of burning which have yet to be documented experimentally.« less

Multistability in Chua's circuit with two stable node-foci

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

Bao, B. C.; Wang, N.; Xu, Q.

2016-04-15

Only using one-stage op-amp based negative impedance converter realization, a simplified Chua's diode with positive outer segment slope is introduced, based on which an improved Chua's circuit realization with more simpler circuit structure is designed. The improved Chua's circuit has identical mathematical model but completely different nonlinearity to the classical Chua's circuit, from which multiple attractors including coexisting point attractors, limit cycle, double-scroll chaotic attractor, or coexisting chaotic spiral attractors are numerically simulated and experimentally captured. Furthermore, with dimensionless Chua's equations, the dynamical properties of the Chua's system are studied including equilibrium and stability, phase portrait, bifurcation diagram, Lyapunov exponentmore » spectrum, and attraction basin. The results indicate that the system has two symmetric stable nonzero node-foci in global adjusting parameter regions and exhibits the unusual and striking dynamical behavior of multiple attractors with multistability.« less

Trends in overall survival and costs of multiple myeloma, 2000-2014.

PubMed

Fonseca, R; Abouzaid, S; Bonafede, M; Cai, Q; Parikh, K; Cosler, L; Richardson, P

2017-09-01

Little real-world evidence is available to describe the recent trends in treatment costs and outcomes for patients with multiple myeloma (MM). Using the Truven Health MarketScan Research Databases linked with social security administration death records, this study found that the percentage of MM patients using novel therapy continuously increased from 8.7% in 2000 to 61.3% in 2014. Compared with MM patients diagnosed in earlier years, those diagnosed after 2010 had higher rates of novel therapy use and better survival outcomes; patients diagnosed in 2012 were 1.25 times more likely to survive 2 years than those diagnosed in 2006. MM patients showed improved survival over the study period, with the 2-year survival gap between MM patients and matched controls decreasing at a rate of 3% per year. Total costs among MM patients have increased in all healthcare services over the years; however, the relative contribution of drug costs has remained fairly stable since 2009 despite new novel therapies coming to market. Findings from this study corroborate clinical data, suggesting a paradigm shift in MM treatment over the past decade that is associated with substantial survival gains. Future studies should focus on the impact on specific novel agents on patients' outcomes.

High-precision measurement of variations in calcium isotope ratios in urine by multiple collector inductively coupled plasma mass spectrometry

USGS Publications Warehouse

Morgan, J.L.L.; Gordon, G.W.; Arrua, R.C.; Skulan, J.L.; Anbar, A.D.; Bullen, T.D.

2011-01-01

We describe a new chemical separation method to isolate Ca from other matrix elements in biological samples, developed with the long-term goal of making high-precision measurement of natural stable Ca isotope variations a clinically applicable tool to assess bone mineral balance. A new two-column procedure utilizing HBr achieves the purity required to accurately and precisely measure two Ca isotope ratios (44Ca/42Ca and 44Ca/43Ca) on a Neptune multiple collector inductively coupled plasma mass spectrometer (MC-ICPMS) in urine. Purification requirements for Sr, Ti, and K (Ca/Sr > 10000; Ca/Ti > 10000000; and Ca/K > 10) were determined by addition of these elements to Ca standards of known isotopic composition. Accuracy was determined by (1) comparing Ca isotope results for samples and standards to published data obtained using thermal ionization mass spectrometry (TIMS), (2) adding a Ca standard of known isotopic composition to a urine sample purified of Ca, and (3) analyzing mixtures of urine samples and standards in varying proportions. The accuracy and precision of δ44/42Ca measurements of purified samples containing 25 μg of Ca can be determined with typical errors less than ±0.2‰ (2σ).

Oligoclonal bands in multiple sclerosis reactive against two herpesviruses and association with magnetic resonance imaging findings

PubMed Central

Virtanen, JO; Wohler, J; Fenton, K; Reich, DS; Jacobson, S

2016-01-01

Background Two human herpesviruses, human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV), have been repeatedly linked to multiple sclerosis (MS). Objective The aim of this study was to investigate HHV-6 and EBV reactive oligoclonal bands (OCBs), and viral DNA in the intrathecal compartment in MS. Methods The reactivity of OCBs in cerebrospinal fluid (CSF) for EBV and HHV-6 antigens and stability of virus reactive OCBs over time were studied in a well-characterized MS patient cohort. Associations between virus reactive OCBs and viral DNA in CSF (and any clinical and/or radiological findings) were investigated. Results Of patients with MS, 38% had OCBs reactive to either one of the viruses studied, compared to none in the patients with other inflammatory neurological diseases (p=0.005). The banding pattern of virus reactive OCBs remained the same over time. Furthermore, MS patients with viral DNA in CSF had more contrast enhancing lesions (CELs). Conclusion The stable presence of herpesvirus reactive OCBs in CSF further strengthens the association of MS with these viruses. The finding that herpesviruses might be linked to the appearance of active lesions warrants investigation of new therapeutic strategies to treat these viruses in MS. PMID:23722324

[Dynamic mutations--a newly detected category of mutations which is the basis for certain neurologic diseases].

PubMed

Mardesić, D

1995-01-01

This review offers some basic information on the discovery of a new type of mutations being the cause of some significant neurologic diseases: myotonic dystrophy, Huntington's disease, spinocerebellar ataxia type 1, spinobulbar pallido-louysian muscular atrophy, fragile X syndrome and some other, up to a total of ten entities. The basis of the so-called dynamic mutations is an abnormal multiplication of a trinucleotide producing sequences of several hundreds or even thousands of identical copies in the respective gene. The result is designated as expanded or amplified trinucleotide (or triplet) repeat. These sequences are not stable, but increase (or exceptionally decrease) in length during cell multiplication in successive generations. They segregate within families with the affected members, demonstrating a significant correlation between the length of the repeat sequence, the severity of the pathologic phenotype and an inverse correlation with the age at the clinical manifestation of the disease. Thus, at least, a formal explanation for the anticipation phenomenon of the age at which the disease is manifested within a family is offered. The importance of the discovery of dynamic mutations lies in the possibility for more precise and reliable genetic counselling. The discovery has opened a lot of new questions giving a new impetus for intensive research.

The Nature of Stable Insomnia Phenotypes

PubMed Central

Pillai, Vivek; Roth, Thomas; Drake, Christopher L.

2015-01-01

Study Objectives: We examined the 1-y stability of four insomnia symptom profiles: sleep onset insomnia; sleep maintenance insomnia; combined onset and maintenance insomnia; and neither criterion (i.e., insomnia cases that do not meet quantitative thresholds for onset or maintenance problems). Insomnia cases that exhibited the same symptom profile over a 1-y period were considered to be phenotypes, and were compared in terms of clinical and demographic characteristics. Design: Longitudinal. Setting: Urban, community-based. Participants: Nine hundred fifty-four adults with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition based current insomnia (46.6 ± 12.6 y; 69.4% female). Interventions: None. Measurements and results: At baseline, participants were divided into four symptom profile groups based on quantitative criteria. Follow-up assessment 1 y later revealed that approximately 60% of participants retained the same symptom profile, and were hence judged to be phenotypes. Stability varied significantly by phenotype, such that sleep onset insomnia (SOI) was the least stable (42%), whereas combined insomnia (CI) was the most stable (69%). Baseline symptom groups (cross-sectionally defined) differed significantly across various clinical indices, including daytime impairment, depression, and anxiety. Importantly, however, a comparison of stable phenotypes (longitudinally defined) did not reveal any differences in impairment or comorbid psychopathology. Another interesting finding was that whereas all other insomnia phenotypes showed evidence of an elevated wake drive both at night and during the day, the “neither criterion” phenotype did not; this latter phenotype exhibited significantly higher daytime sleepiness despite subthreshold onset and maintenance difficulties. Conclusions: By adopting a stringent, stability-based definition, this study offers timely and important data on the longitudinal trajectory of specific insomnia phenotypes. With the exception of daytime sleepiness, few clinical differences are apparent across stable phenotypes. Citation: Pillai V, Roth T, Drake CL. The nature of stable insomnia phenotypes. SLEEP 2015;38(1):127–138. PMID:25325468

Viruses in bronchiectasis: a pilot study to explore the presence of community acquired respiratory viruses in stable patients and during acute exacerbations.

PubMed

Mitchell, Alicia B; Mourad, Bassel; Buddle, Lachlan; Peters, Matthew J; Oliver, Brian G G; Morgan, Lucy C

2018-05-22

Bronchiectasis is a chronic respiratory condition. Persistent bacterial colonisation in the stable state with increased and sometimes altered bacterial burden during exacerbations are accepted as key features in the pathophysiology. The extent to which respiratory viruses are present during stable periods and in exacerbations is less well understood. This study aimed to determine the incidence of respiratory viruses within a cohort of bronchiectasis patients with acute exacerbations at a teaching hospital and, separately, in a group of patients with stable bronchiectasis. In the group of stable patients, a panel of respiratory viruses were assayed for using real time quantitative PCR in respiratory secretions and exhaled breath. The Impact of virus detection on exacerbation rates and development of symptomatic infection was evaluated. Routine hospital-based viral PCR testing was only requested in 28% of admissions for an exacerbation. In our cohort of stable bronchiectasis patients, viruses were detected in 92% of patients during the winter season, and 33% of patients during the summer season. In the 2-month follow up period, 2 of 27 patients presented with an exacerbation. This pilot study demonstrated that respiratory viruses are commonly detected in patients with stable bronchiectasis. They are frequently detected during asymptomatic viral periods, and multiple viruses are often present concurrently.

Stochastic stability in three-player games.

PubMed

Kamiński, Dominik; Miekisz, Jacek; Zaborowski, Marcin

2005-11-01

Animal behavior and evolution can often be described by game-theoretic models. Although in many situations the number of players is very large, their strategic interactions are usually decomposed into a sum of two-player games. Only recently were evolutionarily stable strategies defined for multi-player games and their properties analyzed [Broom, M., Cannings, C., Vickers, G.T., 1997. Multi-player matrix games. Bull. Math. Biol. 59, 931-952]. Here we study the long-run behavior of stochastic dynamics of populations of randomly matched individuals playing symmetric three-player games. We analyze the stochastic stability of equilibria in games with multiple evolutionarily stable strategies. We also show that, in some games, a population may not evolve in the long run to an evolutionarily stable equilibrium.

A multiple-orbit time-of-flight mass spectrometer based on a low energy electrostatic storage ring

NASA Astrophysics Data System (ADS)

Sullivan, M. R.; Spanjers, T. L.; Thorn, P. A.; Reddish, T. J.; Hammond, P.

2012-11-01

The results are presented for an electrostatic storage ring, consisting of two hemispherical deflector analyzers (HDA) connected by two separate sets of cylindrical lenses, used as a time-of-flight mass spectrometer. Based on the results of charged particle simulations and formal matrix model, the Ion Storage Ring is capable of operating with multiple stable orbits, for both single and multiply charged ions simultaneously.

Rapid label-free profiling of oral cancer biomarker proteins using nano-UPLC-Q-TOF ion mobility mass spectrometry.

PubMed

Nassar, Ala F; Williams, Brad J; Yaworksy, Dustin C; Patel, Vyomesh; Rusling, James F

2016-03-01

It has become quite clear that single cancer biomarkers cannot in general provide high sensitivity and specificity for reliable clinical cancer diagnostics. This paper explores the feasibility of rapid detection of multiple biomarker proteins in model oral cancer samples using label-free protein relative quantitation. MS-based label-free quantitative proteomics offer a rapid alternative that bypasses the need for stable isotope containing compounds to chemically bind and label proteins. Total protein content in oral cancer cell culture conditioned media was precipitated, subjected to proteolytic digestion, and then analyzed using a nano-UPLC (where UPLC is ultra-performance liquid chromatography) coupled to a hybrid Q-Tof ion-mobility mass spectrometry (MS). Rapid, simultaneous identification and quantification of multiple possible cancer biomarker proteins was achieved. In a comparative study between cancer and noncancer samples, approximately 952 proteins were identified using a high-throughput 1D ion mobility assisted data independent acquisition (IM-DIA) approach. As we previously demonstrated that interleukin-8 (IL-8) and vascular endothelial growth factor A (VEGF-A) were readily detected in oral cancer cell conditioned media(1), we targeted these biomarker proteins to validate our approach. Target biomarker protein IL-8 was found between 3.5 and 8.8 fmol, while VEGF-A was found at 1.45 fmol in the cancer cell media. Overall, our data suggest that the nano-UPLC-IM-DIA bioassay is a feasible approach to identify and quantify proteins in complex samples without the need for stable isotope labeling. These results have significant implications for rapid tumor diagnostics and prognostics by monitoring proteins such as IL-8 and VEGF-A implicated in cancer development and progression. The analysis in tissue or plasma is not possible at this time, but the subsequent work would be needed for validation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Clinical presentation and management of stable coronary artery disease in Austria.

PubMed

Pichlhöfer, Otto; Maier, Manfred; Badr-Eslam, Roza; Ristl, Robin; Zebrowska, Magdalena; Lang, Irene M

2017-01-01

Cardiovascular disease is the main cause of death in Austria. However, no systematic information exists regarding characteristics and treatments of contemporary patients with stable coronary artery disease (CAD) in Austria. We assembled two retrospective physicians' databases to describe demographics, clinical profiles, and therapeutic strategies in patients with stable CAD. In addition, we compared patient profiles of secondary care internists and hospital-based cardiologists with those of general practitioners in a primary care setting outside of hospital. The study population was identified from retrospective chart review of 1020 patients from 106 primary care physicians in Austria (ProCor II registry), and was merged with a previous similar database of 1280 patients under secondary care (ProCor I registry) to yield a total patient number of 2300. Female patients with stable CAD were older, had more angina and/or heart failure symptoms, and more depression than males. Female gender, type 2 diabetes mellitus, higher CCS class and asthma/COPD were predictors of elevated heart rate, while previous coronary events/revascularization predicted a lower heart rate in multivariate analysis. There were no significant differences with regard to characteristics and management of patients of general practitioners in the primary care setting versus internists in secondary care. Characteristics and treatments of unselected patients with stable ischemic heart disease in Austria resemble the pattern of large international registries of stable ischemic heart disease, with the exception that diabetes and systemic hypertension were more prevalent.

Multiple current peaks in room-temperature atmospheric pressure homogenous dielectric barrier discharge plasma excited by high-voltage tunable nanosecond pulse in air

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

Yang, De-Zheng; Wang, Wen-Chun; Zhang, Shuai

2013-05-13

Room temperature homogenous dielectric barrier discharge plasma with high instantaneous energy efficiency is acquired by using nanosecond pulse voltage with 20-200 ns tunable pulse width. Increasing the voltage pulse width can lead to the generation of regular and stable multiple current peaks in each discharge sequence. When the voltage pulse width is 200 ns, more than 5 organized current peaks can be observed under 26 kV peak voltage. Investigation also shows that the organized multiple current peaks only appear in homogenous discharge mode. When the discharge is filament mode, organized multiple current peaks are replaced by chaotic filament current peaks.

Poisson-Nernst-Planck equations with steric effects - non-convexity and multiple stationary solutions

NASA Astrophysics Data System (ADS)

Gavish, Nir

2018-04-01

We study the existence and stability of stationary solutions of Poisson-Nernst-Planck equations with steric effects (PNP-steric equations) with two counter-charged species. We show that within a range of parameters, steric effects give rise to multiple solutions of the corresponding stationary equation that are smooth. The PNP-steric equation, however, is found to be ill-posed at the parameter regime where multiple solutions arise. Following these findings, we introduce a novel PNP-Cahn-Hilliard model, show that it is well-posed and that it admits multiple stationary solutions that are smooth and stable. The various branches of stationary solutions and their stability are mapped utilizing bifurcation analysis and numerical continuation methods.

The nature of stable insomnia phenotypes.

PubMed

Pillai, Vivek; Roth, Thomas; Drake, Christopher L

2015-01-01

We examined the 1-y stability of four insomnia symptom profiles: sleep onset insomnia; sleep maintenance insomnia; combined onset and maintenance insomnia; and neither criterion (i.e., insomnia cases that do not meet quantitative thresholds for onset or maintenance problems). Insomnia cases that exhibited the same symptom profile over a 1-y period were considered to be phenotypes, and were compared in terms of clinical and demographic characteristics. Longitudinal. Urban, community-based. Nine hundred fifty-four adults with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition based current insomnia (46.6 ± 12.6 y; 69.4% female). None. At baseline, participants were divided into four symptom profile groups based on quantitative criteria. Follow-up assessment 1 y later revealed that approximately 60% of participants retained the same symptom profile, and were hence judged to be phenotypes. Stability varied significantly by phenotype, such that sleep onset insomnia (SOI) was the least stable (42%), whereas combined insomnia (CI) was the most stable (69%). Baseline symptom groups (cross-sectionally defined) differed significantly across various clinical indices, including daytime impairment, depression, and anxiety. Importantly, however, a comparison of stable phenotypes (longitudinally defined) did not reveal any differences in impairment or comorbid psychopathology. Another interesting finding was that whereas all other insomnia phenotypes showed evidence of an elevated wake drive both at night and during the day, the 'neither criterion' phenotype did not; this latter phenotype exhibited significantly higher daytime sleepiness despite subthreshold onset and maintenance difficulties. By adopting a stringent, stability-based definition, this study offers timely and important data on the longitudinal trajectory of specific insomnia phenotypes. With the exception of daytime sleepiness, few clinical differences are apparent across stable phenotypes. © 2014 Associated Professional Sleep Societies, LLC.

[Magnetic Resonance Imaging Conversion Predictors of Clinically Isolated Syndrome to Multiple Sclerosis].

PubMed

Peixoto, Sara; Abreu, Pedro

2016-11-01

Clinically isolated syndrome may be the first manifestation of multiple sclerosis, a chronic demyelinating disease of the central nervous system, and it is defined by a single clinical episode suggestive of demyelination. However, patients with this syndrome, even with long term follow up, may not develop new symptoms or demyelinating lesions that fulfils multiple sclerosis diagnostic criteria. We reviewed, in clinically isolated syndrome, what are the best magnetic resonance imaging findings that may predict its conversion to multiple sclerosis. A search was made in the PubMed database for papers published between January 2010 and June 2015 using the following terms: 'clinically isolated syndrome', 'cis', 'multiple sclerosis', 'magnetic resonance imaging', 'magnetic resonance' and 'mri'. In this review, the following conventional magnetic resonance imaging abnormalities found in literature were included: lesion load, lesion location, Barkhof's criteria and brain atrophy related features. The non conventional magnetic resonance imaging techniques studied were double inversion recovery, magnetization transfer imaging, spectroscopy and diffusion tensor imaging. The number and location of demyelinating lesions have a clear role in predicting clinically isolated syndrome conversion to multiple sclerosis. On the other hand, more data are needed to confirm the ability to predict this disease development of non conventional techniques and remaining neuroimaging abnormalities. In forthcoming years, in addition to the established predictive value of the above mentioned neuroimaging abnormalities, different clinically isolated syndrome neuroradiological findings may be considered in multiple sclerosis diagnostic criteria and/or change its treatment recommendations.

HIV-related high-risk behaviors among Chinese migrant construction laborers in Nantong, Jiangsu.

PubMed

Zhuang, Xun; Wu, Zunyou; Poundstone, Katharine; Yang, Changqing; Zhong, Yaqin; Jiang, Shengyang

2012-01-01

HIV transmission in rural areas of China is being fueled in part by migrant workers who acquire HIV outside of their hometowns. Recent surveillance statistics indicate that HIV prevalence among returning migrants has increased significantly. We conducted a community-based cross-sectional study to assess HIV-related knowledge, attitudes and behaviors among migrant returnees in Nantong, Jiangsu Province, one of the largest exporters of migrant laborers. A total of 1625 subjects were enrolled with a response rate of 89%. All participants were male and of the majority Han ethnicity. The mean age was 39.0 years (SD = 6.7; range: 18 to 63), and most had a stable partner (N = 1533, 94.3%). Most correctly identified the major modes of HIV transmission (68.9%-82.0%), but fewer were able to identify ways that HIV cannot be transmitted. Nearly one-third of participants held positive attitudes toward having multiple sex partners, and nearly half believed that sex work should be legalized. Multiple logistic regression analysis indicated that risky sexual behavior (defined as sex with a casual or commercial sex partner) was associated with no stable partner; working abroad; correct condom use; age <22 at first sex; higher coital frequency; and having a positive attitude towards multiple sex partners. We found high levels of reported sex with a casual or commercial sex partner and low levels of consistent condom use. HIV prevention interventions among migrant workers need to focus on younger migrants, migrants without stable partners, and migrants who travel abroad for work.

HIV-Related High-Risk Behaviors among Chinese Migrant Construction Laborers in Nantong, Jiangsu

PubMed Central

Zhuang, Xun; Wu, Zunyou; Poundstone, Katharine; Yang, Changqing; Zhong, Yaqin; Jiang, Shengyang

2012-01-01

Background HIV transmission in rural areas of China is being fueled in part by migrant workers who acquire HIV outside of their hometowns. Recent surveillance statistics indicate that HIV prevalence among returning migrants has increased significantly. Methods We conducted a community-based cross-sectional study to assess HIV-related knowledge, attitudes and behaviors among migrant returnees in Nantong, Jiangsu Province, one of the largest exporters of migrant laborers. Results A total of 1625 subjects were enrolled with a response rate of 89%. All participants were male and of the majority Han ethnicity. The mean age was 39.0 years (SD = 6.7; range: 18 to 63), and most had a stable partner (N = 1533, 94.3%). Most correctly identified the major modes of HIV transmission (68.9%–82.0%), but fewer were able to identify ways that HIV cannot be transmitted. Nearly one-third of participants held positive attitudes toward having multiple sex partners, and nearly half believed that sex work should be legalized. Multiple logistic regression analysis indicated that risky sexual behavior (defined as sex with a casual or commercial sex partner) was associated with no stable partner; working abroad; correct condom use; age <22 at first sex; higher coital frequency; and having a positive attitude towards multiple sex partners. Conclusions We found high levels of reported sex with a casual or commercial sex partner and low levels of consistent condom use. HIV prevention interventions among migrant workers need to focus on younger migrants, migrants without stable partners, and migrants who travel abroad for work. PMID:22479313

Objective Sepsis Surveillance Using Electronic Clinical Data

PubMed Central

Rhee, Chanu; Kadri, Sameer; Huang, Susan S.; Murphy, Michael V.; Li, Lingling; Platt, Richard; Klompas, Michael

2016-01-01

OBJECTIVE To compare the accuracy of surveillance of severe sepsis using electronic health record clinical data vs claims and to compare incidence and mortality trends using both methods. DESIGN We created an electronic health record–based surveillance definition for severe sepsis using clinical indicators of infection (blood culture and antibiotic orders) and concurrent organ dysfunction (vasopressors, mechanical ventilation, and/or abnormal laboratory values). We reviewed 1,000 randomly selected medical charts to characterize the definition’s accuracy and stability over time compared with a claims-based definition requiring infection and organ dysfunction codes. We compared incidence and mortality trends from 2003–2012 using both methods. SETTING Two US academic hospitals. PATIENTS Adult inpatients. RESULTS The electronic health record–based clinical surveillance definition had stable and high sensitivity over time (77% in 2003–2009 vs 80% in 2012, P=.58) whereas the sensitivity of claims increased (52% in 2003–2009 vs 67% in 2012, P=.02). Positive predictive values for claims and clinical surveillance definitions were comparable (55% vs 53%, P=.65) and stable over time. From 2003 to 2012, severe sepsis incidence imputed from claims rose by 72% (95% CI, 57%–88%) and absolute mortality declined by 5.4% (95% CI, 4.6%–6.7%). In contrast, incidence using the clinical surveillance definition increased by 7.7% (95% CI, −1.1% to 17%) and mortality declined by 1.7% (95% CI, 1.1%–2.3%). CONCLUSIONS Sepsis surveillance using clinical data is more sensitive and more stable over time compared with claims and can be done electronically. This may enable more reliable estimates of sepsis burden and trends. PMID:26526737

Trophodynamics of the Hanna Shoal Ecosystem (Chukchi Sea, Alaska): Connecting multiple end-members to a rich food web

NASA Astrophysics Data System (ADS)

McTigue, N. D.; Dunton, K. H.

2017-10-01

Predicting how alterations in sea ice-mediated primary production will impact Arctic food webs remains a challenge in forecasting ecological responses to climate change. One top-down approach to this challenge is to elucidate trophic roles of consumers as either specialists (i.e., consumers of predominantly one food resource) or generalists (i.e., consumers of multiple food resources) to categorize the dependence of consumers on each primary producer. At Hanna Shoal in the Chukchi Sea, Alaska, we used stable carbon and nitrogen isotope data to quantify trophic redundancy with standard ellipse areas at both the species and trophic guild levels. We also investigated species-level trophic plasticity by analyzing the varying extents that three end-members were assimilated by the food web using the mixing model simmr (Stable Isotope Mixing Model in R). Our results showed that ice algae, a combined phytoplankton and sediment organic matter composite (PSOM), and a hypothesized microphytobenthos (MPB) component were incorporated by consumers in the benthic food web, but their importance varied by species. Some primary consumers relied heavily on PSOM (e.g, the amphipods Ampelisca sp. and Byblis sp.; the copepod Calanus sp.), while others exhibited generalist feeding and obtained nutrition from multiple sources (e.g., the holothuroidean Ocnus glacialis, the gastropod Tachyrhynchus sp., the sipunculid Golfingia margaritacea, and the bivalves Ennucula tenuis, Nuculana pernula, Macoma sp., and Yoldia hyperborea). Most higher trophic level benthic predators, including the gastropods Buccinum sp., Cryptonatica affinis, and Neptunea sp, the seastar Leptasterias groenlandica, and the amphipod Anonyx sp. also exhibited trophic plasticity by coupling energy pathways from multiple primary producers including PSOM, ice algae, and MPB. Our stable isotope data indicate that consumers in the Hanna Shoal food web exhibit considerable trophic redundancy, while few species were specialists and assimilated only one end-member. Although most consumers were capable of obtaining nutrition from multiple food sources, the timing, quantity, and quality of ice-mediated primary production may still have pronounced effects on food web structure.

Identification of new biosignatures for clinical outcomes in stable coronary artery disease - The study protocol and initial observations of a prospective follow-up study in Taiwan.

PubMed

Leu, Hsin-Bang; Yin, Wei-Hsian; Tseng, Wei-Kung; Wu, Yen-Wen; Lin, Tsung-Hsien; Yeh, Hung-I; Chang, Kuan-Cheng; Wang, Ji-Hung; Wu, Chau-Chung; Chen, Jaw-Wen

2017-01-28

Either classic or novel biomarkers have not been well investigated for clinical outcomes of coronary artery disease (CAD) in Asian people especially ethnic Chinese. We reported here a prospective national-based follow-up study that aims to elucidate the clinical profiles and to identify the new biosignatures (especially the non-lipid profile and inflammatory biomakers) for future clinical outcomes in a sizable cohort of stable CAD patients in Taiwan. A total of 2500 CAD patients under stable condition after successful percutaneous coronary intervention will be enrolled for clinical data collection and blood/urine sampling in northern, southern, western, or eastern part of Taiwan between 2012 and 2017. They will be regularly followed up at least annually for 5 years to assess all cause deaths, hard clinical events (including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke), and total cardiovascular events (including hard events, unplanned revascularization procedures, unplanned hospitalization for refractory or unstable angina, and for other causes such as stroke, transient ischemic attack, heart failure, or peripheral arterial occlusive disease). The classic and newly defined biosignatures will be compared in patients with and without clinical events during follow-up. The novel biomarkers will be identified via metabolomics analyses. Additionally, psychological personality and lifestyle data will be incorporated to explore the new dimensional views of the complex mechanisms of the disease. Till December 2014, the initial 1663 patients have been successfully enrolled. Among them, 85.93% are male; 36.22% have type 2 diabetes; 64.82% have hypertension; 56.04% are smokers and 20.44% have a family history of CAD. Their lipid profiles are under contemporary medical control with a mean plasma total cholesterol level of 163.51 ± 36.99 mg/dL and a mean low-density lipoprotein cholesterol level of 95.21 ± 29.98 mg/dL. This nationwide study has successfully started to update the contemporary information and to investigate the potential predictors for clinical outcomes of stable CAD patients in Taiwan. The identification of new biomarkers, lifestyle and psychological personality may help to elucidate the complex mechanisms and provide the novel rational to the individual treatment strategies in Asian especially ethnic Chinese patients with CAD.

Stability of FeNO and airway hyperresponsiveness to mannitol in untreated asthmatics.

PubMed

Udesen, Pernille Bækgaard; Westergaard, Christian Grabow; Porsbjerg, Celeste; Backer, Vibeke

2017-06-01

Airway hyperresponsiveness and airway inflammation are important hallmarks of asthma and are useful in asthma diagnosing, monitoring and treatment. The aim of the study was to assess whether two commonly used clinical tests, the mannitol challenge and Fraction of exhaled NO (FeNO), were stable clinical indicators over time in stable untreated asthmatics. 54 non-smoking, asthma patients not treated with steroids were enrolled in the study and assessed at baseline and a median of 6 months later. At baseline and follow-up, FeNO and airway hyperesponsiveness to mannitol were measured, and asthma control was assessed with the Asthma Control Questionnaire (ACQ). A total of 41 subjects completed both visits. Mean (SD) FEV1% at baseline was 94.1% (17.7) and at re-examination 94.6% (19.7) (ns). The ACQ score was unchanged from baseline (Mean (SD): 0.90 (± 0.73)) to follow-up 0.90 (± 0.74) (ns), as was the FEV 1 % (94.1% (±17.1%) vs 94.6% (19.7%)(ns) indicating that patients were clinically stable during follow-up. The response to mannitol was unchanged at follow-up (Geometric mean (CI) of Response Dose Ratio (RDR) to mannitol: 0.026(0.013-0.046) vs 0.026(0.012-0.050) (ns). There was a slight decrease in FeNO at follow-up (25.5 ppb (19.7-32.9) to 21.9 ppb (17.1-28.2) (p < 0.001). In steroid-free non-smoking asthmatics with constant symptom scores and lung function, airway responsiveness to mannitol remained at the same level over a period of months, while a minor change in exhaled FeNO was reported. These results suggest that mannitol is a stable, reliable marker of clinical disease activity.

Incidence of mitral valve prolapse in one hundred clinically stable newborn baby girls: an echocardiographic study.

PubMed

Chandraratna, P A; Vlahovich, G; Kong, Y; Wilson, D

1979-09-01

Clinical and echocardiographic examinations were performed on 100 clinically stable, newborn baby girls. Mitral valve prolapse was noted on the echocardiograms of seven babies. Three subjects had systolic clicks, two of whom had systolic murmurs following the click. The four other babies who had echocardiographic evidence of mitral valve prolapse had no abnormal auscultatory signs. Of the 93 babies without evidence of mitral prolapse, 91 had normal echocardiograms and auscultatory features; one was noted to have a murmur consistent with a ventricular septal defect, and another had an eccentric aortic valve on the echocardiogram which was suggestive of a bicuspid aortic valve. Serial studies on our group of subjects will yield useful information regarding the natural history of mitral valve prolapse.

Comparison of everolimus- and paclitaxel-eluting stents in patients with acute and stable coronary syndromes: pooled results from the SPIRIT (A Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System) and COMPARE (A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice) Trials.

PubMed

Planer, David; Smits, Pieter C; Kereiakes, Dean J; Kedhi, Elvin; Fahy, Martin; Xu, Ke; Serruys, Patrick W; Stone, Gregg W

2011-10-01

This study sought to compare the clinical outcomes of everolimus-eluting stents (EES) versus paclitaxel-eluting stents (PES) in patients with acute coronary syndromes (ACS) and stable coronary artery disease (CAD). Although randomized trials have shown superiority of EES to PES, the safety and efficacy of EES in ACS is unknown. We performed a patient-level pooled analysis from the prospective, randomized SPIRIT (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System) II, III, IV, and COMPARE (A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice) trials in which 2,381 patients with ACS and 4,404 patients with stable CAD were randomized to EES or to PES. Kaplan-Meier estimates of death, myocardial infarction (MI), ischemia-driven target lesion revascularization, and stent thrombosis were assessed at 2 years and stratified by clinical presentation (ACS vs. stable CAD). At 2 years, patients with ACS compared with stable CAD had higher rates of death (3.2% vs. 2.4%, hazard ratio [HR]: 1.37 [95% confidence interval (CI): 1.02 to 1.85], p = 0.04) and MI (4.9% vs. 3.4%, HR: 1.45 [95% CI: 1.14 to 1.85], p = 0.02). In patients with ACS, EES versus PES reduced the rate of death or MI (6.6% vs. 9.3%, HR: 0.70 [95% CI: 0.52 to 0.94], p = 0.02), stent thrombosis (0.7% vs. 2.9%, HR: 0.25 [95% CI: 0.12 to 0.52], p = 0.0002), and ischemia-driven target lesion revascularization (4.7% vs. 6.2%, HR: 0.69 [95% CI: 0.48 to 0.99], p = 0.04). In patients with stable CAD, EES reduced the rate of death or MI (4.5% vs. 7.1%, HR: 0.62 [95% CI: 0.48 to 0.80], p = 0.0002), stent thrombosis (0.7% vs. 1.8%, HR: 0.34 [95% CI: 0.19 to 0.62], p = 0.0002), and ischemia-driven target lesion revascularization (3.9% vs. 6.9%, HR: 0.55 [95% CI: 0.42 to 0.73], p < 0.0001). Treatment with EES versus PES provides enhanced safety and efficacy regardless of the acuity of the clinical syndrome being treated and appears to mitigate the increased risk of stent thrombosis associated with ACS. (A Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients With de Novo Native Coronary Artery Lesions [SPIRIT II]; NCT00180310; SPIRIT III: A Clinical Evaluation of the Investigational Device XIENCE V Everolimus Eluting Coronary Stent System [EECSS] in the Treatment of Subjects With de Novo Native Coronary Artery Lesions [SPIRIT III]; NCT00180479; SPIRIT IV Clinical Trial: Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Subjects With de Novo Native Coronary Artery Lesions [SPIRIT IV]; NCT00307047; A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice: the COMPARE Trial [COMPARE]; NCT01016041). Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Quality improvement intervention to increase adherence to ART prescription policy at HIV treatment clinics in Lusaka, Zambia: A cluster randomized trial

PubMed Central

Subramaniam, Hamsa L.; Prust, Margaret L.; Prescott, Marta R.; Mpasela, Felton; Mwango, Albert; Namonje, Leah; Moyo, Crispin; Chibuye, Benjamin; van den Broek, Jan Willem; Hehman, Lindsey; Moberley, Sarah

2017-01-01

Introduction In urban areas, crowded HIV treatment facilities with long patient wait times can deter patients from attending their clinical appointments and picking up their medications, ultimately disrupting patient care and compromising patient retention and adherence. Methods Formative research at eight facilities in Lusaka revealed that only 46% of stable HIV treatment patients were receiving a three-month refill supply of antiretroviral drugs, despite it being national policy for stable adult patients. We designed a quality improvement intervention to improve the operationalization of this policy. We conducted a cluster-randomized controlled trial in sixteen facilities in Lusaka with the primary objective of examining the intervention’s impact on the proportion of stable patients receiving three-month refills. The secondary objective was examining whether the quality improvement intervention reduced facility congestion measured through two proxy indicators: daily volume of clinic visits and average clinic wait times for services. Results The mean change in the proportion of three-month refills among control facilities from baseline to endline was 10% (from 38% to 48%), compared to a 25% mean change (an increase from 44% to 69%) among intervention facilities. This represents a significant 15% mean difference (95% CI: 2%-29%; P = 0.03) in the change in proportion of patients receiving three-month refills. On average, control facilities had 15 more visits per day in the endline than in the baseline, while intervention facilities had 20 fewer visits per day in endline than in baseline, a mean difference of 35 fewer visits per day (P = 0.1). The change in the mean facility total wait time for intervention facilities dropped 19 minutes between baseline and endline when compared to control facilities (95% CI: -10.2–48.5; P = 0.2). Conclusion A more patient-centred service delivery schedule of three-month prescription refills for stable patients is viable. We encourage the expansion of this sustainable intervention in Zambia’s urban clinics. PMID:28419106

Quality improvement intervention to increase adherence to ART prescription policy at HIV treatment clinics in Lusaka, Zambia: A cluster randomized trial.

PubMed

McCarthy, Elizabeth A; Subramaniam, Hamsa L; Prust, Margaret L; Prescott, Marta R; Mpasela, Felton; Mwango, Albert; Namonje, Leah; Moyo, Crispin; Chibuye, Benjamin; van den Broek, Jan Willem; Hehman, Lindsey; Moberley, Sarah

2017-01-01

In urban areas, crowded HIV treatment facilities with long patient wait times can deter patients from attending their clinical appointments and picking up their medications, ultimately disrupting patient care and compromising patient retention and adherence. Formative research at eight facilities in Lusaka revealed that only 46% of stable HIV treatment patients were receiving a three-month refill supply of antiretroviral drugs, despite it being national policy for stable adult patients. We designed a quality improvement intervention to improve the operationalization of this policy. We conducted a cluster-randomized controlled trial in sixteen facilities in Lusaka with the primary objective of examining the intervention's impact on the proportion of stable patients receiving three-month refills. The secondary objective was examining whether the quality improvement intervention reduced facility congestion measured through two proxy indicators: daily volume of clinic visits and average clinic wait times for services. The mean change in the proportion of three-month refills among control facilities from baseline to endline was 10% (from 38% to 48%), compared to a 25% mean change (an increase from 44% to 69%) among intervention facilities. This represents a significant 15% mean difference (95% CI: 2%-29%; P = 0.03) in the change in proportion of patients receiving three-month refills. On average, control facilities had 15 more visits per day in the endline than in the baseline, while intervention facilities had 20 fewer visits per day in endline than in baseline, a mean difference of 35 fewer visits per day (P = 0.1). The change in the mean facility total wait time for intervention facilities dropped 19 minutes between baseline and endline when compared to control facilities (95% CI: -10.2-48.5; P = 0.2). A more patient-centred service delivery schedule of three-month prescription refills for stable patients is viable. We encourage the expansion of this sustainable intervention in Zambia's urban clinics.

Mitochondria DNA change and oxidative damage in clinically stable patients with major depressive disorder.

PubMed

Chang, Cheng-Chen; Jou, Shaw-Hwa; Lin, Ta-Tsung; Lai, Te-Jen; Liu, Chin-San

2015-01-01

To compare alterations of mitochondria DNA (mtDNA) copy number, single nucleotide polymorphisms (SNPs), and oxidative damage of mtDNA in clinically stable patients with major depressive disorder (MDD). Patients met DSM-IV diagnostic criteria for MDD were recruited from the psychiatric outpatient clinic at Changhua Christian Hospital, Taiwan. They were clinically stable and their medications had not changed for at least the preceding two months. Exclusion criteria were substance-induced psychotic disorder, eating disorder, anxiety disorder or illicit substance abuse. Comparison subjects did not have any major psychiatric disorder and they were medically healthy. Peripheral blood leukocytes were analyzed to compare copy number, SNPs and oxidative damage of mtDNA between the two groups. 40 MDD patients and 70 comparison subjects were collected. The median age of the subjects was 42 years and 38 years in MDD and comparison groups, respectively. Leukocyte mtDNA copy number of MDD patients was significantly lower than that of the comparison group (p = 0.037). MDD patients had significantly higher mitochondrial oxidative damage than the comparison group (6.44 vs. 3.90, p<0.001). After generalized linear model adjusted for age, sex, smoking, family history, and psychotropic use, mtDNA copy number was still significantly lower in the MDD group (p<0.001). MtDNA oxidative damage was positively correlated with age (p<0.001) and MDD (p<0.001). Antipsychotic use was negatively associated with mtDNA copy number (p = 0.036). The study is cross-sectional with no longitudinal follow up. The cohort is clinically stable and generalizability of our result to other cohort should be considered. Our study suggests that oxidative stress and mitochondria may play a role in the pathophysiology of MDD. More large-scale studies are warranted to assess the interplay between oxidative stress, mitochondria dysfunction and MDD.

Clinical, radiological, and morphological evaluations of posterior horn tears of the lateral meniscus left in situ during anterior cruciate ligament reconstruction.

PubMed

Lee, Dhong Won; Jang, Hyoung Won; Lee, Sung Rak; Park, Jung Ho; Ha, Jeong Ku; Kim, Jin Goo

2014-02-01

Recent studies have shown that lateral menisci have a higher healing potential and that they can be treated successfully without symptoms by being left in situ during anterior cruciate ligament (ACL) reconstruction. However, few studies have reported morphological results. Stable posterior horn tears of the lateral meniscus left in situ during ACL reconstruction could be healed spontaneously and would result in not only successful clinical outcomes but also morphological restoration. Cohort study; Level of evidence, 3. Among 367 patients who underwent primary ACL reconstruction between 2008 and 2010, 53 patients who had lateral meniscus tears that were left in situ were analyzed. These patients were evaluated subjectively and radiologically and compared with a matched control group that underwent ACL reconstruction without any other structural disorders. Of the 53 patients with stable posterior horn tears of the lateral meniscus left in situ, 28 patients were assessed by second-look arthroscopic surgery and magnetic resonance imaging (MRI). The mean follow-up of the study group and the control group was 36.47 and 37.26 months, respectively. There were no statistical differences in postoperative clinical outcomes between the 2 groups. Clinical results of both groups including the Lysholm score, Tegner activity score, and International Knee Documentation Committee (IKDC) score significantly improved. In the subgroup composed of 28 patients, follow-up MRI showed 25 (89%) and 24 (86%) healed menisci in sagittal and coronal views, respectively. Twenty-one (75%) were considered to be completely healed, and 5 (18%) were incompletely healed on second-look arthroscopic surgery. Stable posterior horn tears of the lateral meniscus left in situ at the time of ACL reconstruction revealed successful clinical outcomes compared with isolated ACL injuries and showed considerable healing and functional restoration of tears with repeat MRI and second-look arthroscopic surgery. Therefore, leaving stable posterior horn tears of the lateral meniscus in situ during ACL reconstruction should be considered.

Surgical management of brain-stem cavernous malformations: report of 137 cases.

PubMed

Wang, Chung-cheng; Liu, Ali; Zhang, Jun-ting; Sun, Bo; Zhao, Yuan-li

2003-06-01

With the improvement in neuroimaging and microsurgical techniques, brain stem cavernous malformations are no longer considered inoperable. Surgical indications for brainstem cavernoma are evolving, with better understanding of its natural history and decreasing surgical complications. During 1986 through 1998, a series of 137 patients (4 patients each with two brain stem lesions, total number of lesions, 141) with brain stem cavernous malformations were treated microsurgically at Beijing Neurosurgery Institute. The age distribution, lesion location, and clinical presentations were analyzed. The bleeding rate, surgical indications and microsurgical techniques were also discussed. In our series, 92 of 137 cases (67.2%) suffered more than one hemorrhage. Female patients had a higher risk of recurrent hemorrhage than that of male patients. Unlike cavernomas malformations from other locations, repeated hemorrhages from brain stem malformations are much more common and usually lead to new neurologic deficits. Among all 137 surgically treated patients, there was no operative mortality. Ninety-nine patients (72.3%) either improved or remained clinically stable postoperatively. The size of the cavernoma/hematoma does not necessarily correlate with the surgical result. While the acute hematoma can facilitate the surgical dissection, longer clinical history with multiple hemorrhages often makes total surgical resection difficult, partially because of the firmer capsule that may not shrink or collapse after hematoma is released. Pathologically those capsules were associated with more hyaline degeneration, fibrous proliferation and even calcifications. During the follow-up period between 0.5 to 11 years in 129 cases, 115 patients (89.2%) have been working, studying, or doing house work. Three patients (2.3%) suffered recurrent hemorrhages. Surgical indications of brain stem cavernoma include (1) progressive neurologic deficits; (2) overt acute or subacute hemorrhage on MRI either inside or outside cavernous malformations with mass effect; (3) cavernoma/hematoma reaching brainstem surface (<2 mm brain tissue between cavernoma /hematoma and pial surface). Grave clinical presentations like coma, respiratory, or cardiac instability are not surgical contraindications. Emergent surgical evacuation may lead to satisfactory outcome. Repeated hemorrhages will worsen the pre-existing neurologic deficits and possibly make the surgical dissections more difficult. Patients with minimum, stable neurologic deficits and lesion/hematoma that has not reached the brain stem surface should be followed conservatively.

One-step production of multiple emulsions: microfluidic, polymer-stabilized and particle-stabilized approaches.

PubMed

Clegg, Paul S; Tavacoli, Joe W; Wilde, Pete J

2016-01-28

Multiple emulsions have great potential for application in food science as a means to reduce fat content or for controlled encapsulation and release of actives. However, neither production nor stability is straightforward. Typically, multiple emulsions are prepared via two emulsification steps and a variety of approaches have been deployed to give long-term stability. It is well known that multiple emulsions can be prepared in a single step by harnessing emulsion inversion, although the resulting emulsions are usually short lived. Recently, several contrasting methods have been demonstrated which give rise to stable multiple emulsions via one-step production processes. Here we review the current state of microfluidic, polymer-stabilized and particle-stabilized approaches; these rely on phase separation, the role of electrolyte and the trapping of solvent with particles respectively.

Myocardial Injury Is Distinguished from Stable Angina by a Set of Candidate Plasma Biomarkers Identified Using iTRAQ/MRM-Based Approach.

PubMed

Cheow, Esther Sok Hwee; Cheng, Woo Chin; Yap, Terence; Dutta, Bamaprasad; Lee, Chuen Neng; Kleijn, Dominique P V de; Sorokin, Vitaly; Sze, Siu Kwan

2018-01-05

The lack of precise biomarkers that identify patients at risk for myocardial injury and stable angina delays administration of optimal therapy. Hence, the search for noninvasive biomarkers that could accurately stratify patients with impending heart attack, from patients with stable coronary artery disease (CAD), is urgently needed in the clinic. Herein, we performed comparative quantitative proteomics on whole plasma sampled from patients with stable angina (NMI), acute myocardial infarction (MI), and healthy control subjects (Ctrl). We detected a total of 371 proteins with high confidence (FDR < 1%, p < 0.05) including 53 preliminary biomarkers that displayed ≥2-fold modulated expression in patients with CAD (27 associated with atherosclerotic stable angina, 26 with myocardial injury). In the verification phase, we used label-free LC-MRM-MS-based targeted method to verify the preliminary biomarkers in pooled plasma, excluded peptides that were poorly distinguished from background, and performed further validation of the remaining candidates in 49 individual plasma samples. Using this approach, we identified a final panel of eight novel candidate biomarkers that were significantly modulated in CAD (p < 0.05) including proteins associated with atherosclerotic stable angina that were implicated in endothelial dysfunction (F10 and MST1), proteins associated with myocardial injury reportedly involved in plaque destabilization (SERPINA3, CPN2, LUM), and in tissue protection/repair mechanisms (ORM2, ACTG1, NAGLU). Taken together, our data showed that candidate biomarkers with potential diagnostic values can be successfully detected in nondepleted human plasma using an iTRAQ/MRM-based discovery-validation approach and demonstrated the plausible clinical utility of the proposed panel in discriminating atherosclerotic stable angina from myocardial injury in the studied cohort.

An Automated Statistical Technique for Counting Distinct Multiple Sclerosis Lesions.

PubMed

Dworkin, J D; Linn, K A; Oguz, I; Fleishman, G M; Bakshi, R; Nair, G; Calabresi, P A; Henry, R G; Oh, J; Papinutto, N; Pelletier, D; Rooney, W; Stern, W; Sicotte, N L; Reich, D S; Shinohara, R T

2018-04-01

Lesion load is a common biomarker in multiple sclerosis, yet it has historically shown modest association with clinical outcome. Lesion count, which encapsulates the natural history of lesion formation and is thought to provide complementary information, is difficult to assess in patients with confluent (ie, spatially overlapping) lesions. We introduce a statistical technique for cross-sectionally counting pathologically distinct lesions. MR imaging was used to assess the probability of a lesion at each location. The texture of this map was quantified using a novel technique, and clusters resembling the center of a lesion were counted. Validity compared with a criterion standard count was demonstrated in 60 subjects observed longitudinally, and reliability was determined using 14 scans of a clinically stable subject acquired at 7 sites. The proposed count and the criterion standard count were highly correlated ( r = 0.97, P < .001) and not significantly different (t 59 = -.83, P = .41), and the variability of the proposed count across repeat scans was equivalent to that of lesion load. After accounting for lesion load and age, lesion count was negatively associated ( t 58 = -2.73, P < .01) with the Expanded Disability Status Scale. Average lesion size had a higher association with the Expanded Disability Status Scale ( r = 0.35, P < .01) than lesion load ( r = 0.10, P = .44) or lesion count ( r = -.12, P = .36) alone. This study introduces a novel technique for counting pathologically distinct lesions using cross-sectional data and demonstrates its ability to recover obscured longitudinal information. The proposed count allows more accurate estimation of lesion size, which correlated more closely with disability scores than either lesion load or lesion count alone. © 2018 by American Journal of Neuroradiology.

Difference in effect of single immunosuppressive agents (cyclophosphamide, CCNU, 5-FU) on peripheral blood immune cell parameters and central nervous system immunoglobulin synthesis rate in patients with multiple sclerosis.

PubMed Central

Shih, W W; Baumhefner, R W; Tourtellotte, W W; Haskell, C M; Korn, E L; Fahey, J L

1983-01-01

Cyclophosphamide (CY), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 5-fluorouracil (5-FU) were given in single course schedules to chronic progressive multiple sclerosis (MS) patients clinically stable for 6 months. The following peripheral immune cellular parameters were measured before, during and after each drug administration: white blood count (WBC), polymorphonuclear count (PMN), lymphocyte count, percentage of T cells, T cell response to phytohaemagglutinin (PHA), percentage of B cells, percentage of cells bearing receptors for the Fc portion of immunoglobulin (% FcR cells), killer (K) cell activity defined by antibody-dependent cellular cytotoxicity (ADCC), and natural killer (NK) cell activity. Central nervous system (CNS) immunoglobulin G (IgG) synthesis was also measured. The patients were followed carefully by both quantitative and qualitative methods for any change in their neurologic condition. Selective reduction in NK activity was observed with CY and 5-FU while no significant alteration was seen in %FcR cells and K activity. CY differed from 5-FU in reducing lymphocyte count and B cell percentage while 5-FU decreased the percentage of T cells. CCNU, but not the other drugs, reduced T cell proliferative response to PHA. In addition, CCNU, which is known to penetrate well into the nervous system, caused a modest reduction in CNS IgG synthesis, while 5-FU had an uncertain effect. Clinically the patients were unchanged or continued to progress in their disability. The results suggest an independence of the CNS immune from the systemic immune system in MS in response to many immunosuppressive drugs. PMID:6603303

Isolated cognitive relapses in multiple sclerosis.

PubMed

Pardini, Matteo; Uccelli, Antonio; Grafman, Jordan; Yaldizli, Özgür; Mancardi, Gianluigi; Roccatagliata, Luca

2014-09-01

While cognition can be affected during sensorimotor multiple sclerosis (MS) relapses, the relevance of isolated cognitive relapses (ICRs ie, those occurring in absence of new sensorimotor symptoms) remain poorly characterised. Here, we decided to explore the relationship between ICR, subjective evaluation of cognitive performance and long-term cognitive decline in a group of subjects with relapsing-remitting MS. We analysed the cognitive performance of 99 clinically stable relapsing-remitting MS for whom data from four consequent clinical and cognitive evaluations were available, that is, a baseline evaluation (t₀), followed in the subsequent 6 months by a second evaluation performed not later than 2 weeks after a routine brain scan positive for at least one area of gadolinium enhancement (t₁) and two gadolinium enhancement-negative follow-up evaluations after 6 months (t₂) and 1 year (t₃) from t₁. Based on published literature, we defined as a meaningful change in cognition a transient reduction of Symbol Digit Modalities Test score of at least four points at t₁ compared with t₀ and t₂. ICRs were found in 17 patients and were not associated with subjective cognitive deficits or depression. Subjects who presented with an ICR at t₁ presented with a significantly reduced cognitive performance at the follow-up evaluations compared with patients without ICR. We showed that ICRs were not associated with changes in mood, fatigue levels or cognitive performance self-evaluations. Our study introduces an operational definition of ICRs and suggests to their role as a factor for cognitive decline in MS. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Evaporation induced 18O and 13C enrichment in lake systems: A global perspective on hydrologic balance effects

NASA Astrophysics Data System (ADS)

Horton, Travis W.; Defliese, William F.; Tripati, Aradhna K.; Oze, Christopher

2016-01-01

Growing pressure on sustainable water resource allocation in the context of global development and rapid environmental change demands rigorous knowledge of how regional water cycles change through time. One of the most attractive and widely utilized approaches for gaining this knowledge is the analysis of lake carbonate stable isotopic compositions. However, endogenic carbonate archives are sensitive to a variety of natural processes and conditions leaving isotopic datasets largely underdetermined. As a consequence, isotopic researchers are often required to assume values for multiple parameters, including temperature of carbonate formation or lake water δ18O, in order to interpret changes in hydrologic conditions. Here, we review and analyze a global compilation of 57 lacustrine dual carbon and oxygen stable isotope records with a topical focus on the effects of shifting hydrologic balance on endogenic carbonate isotopic compositions. Through integration of multiple large datasets we show that lake carbonate δ18O values and the lake waters from which they are derived are often shifted by >+10‰ relative to source waters discharging into the lake. The global pattern of δ18O and δ13C covariation observed in >70% of the records studied and in several evaporation experiments demonstrates that isotopic fractionations associated with lake water evaporation cause the heavy carbon and oxygen isotope enrichments observed in most lakes and lake carbonate records. Modeled endogenic calcite compositions in isotopic equilibrium with lake source waters further demonstrate that evaporation effects can be extreme even in lake records where δ18O and δ13C covariation is absent. Aridisol pedogenic carbonates show similar isotopic responses to evaporation, and the relevance of evaporative modification to paleoclimatic and paleotopographic research using endogenic carbonate proxies are discussed. Recent advances in stable isotope research techniques present unprecedented opportunities to overcome the underdetermined nature of stable isotopic data through integration of multiple isotopic proxies, including dual element 13C-excess values and clumped isotope temperature estimates. We demonstrate the utility of applying these multi-proxy approaches to the interpretation of paleohydroclimatic conditions in ancient lake systems. Understanding past, present, and future hydroclimatic systems is a global imperative. Significant progress should be expected as these modern research techniques become more widely applied and integrated with traditional stable isotopic proxies.

Linear Combinations of Multiple Outcome Measures to Improve the Power of Efficacy Analysis ---Application to Clinical Trials on Early Stage Alzheimer Disease

PubMed Central

Xiong, Chengjie; Luo, Jingqin; Morris, John C; Bateman, Randall

2018-01-01

Modern clinical trials on Alzheimer disease (AD) focus on the early symptomatic stage or even the preclinical stage. Subtle disease progression at the early stages, however, poses a major challenge in designing such clinical trials. We propose a multivariate mixed model on repeated measures to model the disease progression over time on multiple efficacy outcomes, and derive the optimum weights to combine multiple outcome measures by minimizing the sample sizes to adequately power the clinical trials. A cross-validation simulation study is conducted to assess the accuracy for the estimated weights as well as the improvement in reducing the sample sizes for such trials. The proposed methodology is applied to the multiple cognitive tests from the ongoing observational study of the Dominantly Inherited Alzheimer Network (DIAN) to power future clinical trials in the DIAN with a cognitive endpoint. Our results show that the optimum weights to combine multiple outcome measures can be accurately estimated, and that compared to the individual outcomes, the combined efficacy outcome with these weights significantly reduces the sample size required to adequately power clinical trials. When applied to the clinical trial in the DIAN, the estimated linear combination of six cognitive tests can adequately power the clinical trial. PMID:29546251

Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study

PubMed Central

2012-01-01

Background Treatment options for patients suffering from progressive forms of multiple sclerosis (MS) remain inadequate. Mast cells actively participate in the pathogenesis of MS, in part because they release large amounts of various mediators that sustain the inflammatory network. Masitinib, a selective oral tyrosine kinase inhibitor, effectively inhibits the survival, migration and activity of mast cells. This exploratory study assessed the safety and clinical benefit of masitinib in the treatment of primary progressive MS (PPMS) or relapse-free secondary progressive MS (rfSPMS). Methods Multicenter, randomized, placebo-controlled, proof-of-concept trial. Masitinib was administered orally at 3 to 6 mg/kg/day for at least 12 months, with dose adjustment permitted in event of insufficient response with no toxicity. The primary response endpoint was the change relative to baseline in the multiple sclerosis functional composite score (MSFC). Clinical response was defined as an increase in MSFC score relative to baseline of > 100%. Results Thirty-five patients were randomized to receive masitinib (N = 27) or placebo (N = 8). Masitinib was relatively well tolerated with the most common adverse events being asthenia, rash, nausea, edema, and diarrhea. The overall frequency of adverse events was similar to the placebo group, however, a higher incidence of severe and serious events was associated with masitinib treatment. Masitinib appeared to have a positive effect on MS-related impairment for PPMS and rfSPMS patients, as evidenced by an improvement in MSFC scores relative to baseline, compared with a worsening MSFC score in patients receiving placebo; +103% ± 189 versus -60% ± 190 at month-12, respectively. This positive, albeit non-statistically significant response was observed as early as month-3 and sustained through to month-18, with similar trends seen in the PPMS and rfSPMS subpopulations. A total of 7/22 (32%) assessable masitinib patients reported clinical response following 12 months of treatment (according to the modified intent-to-treat population, observed cases) compared with none in the placebo group. The Expanded Disability Status Scale remained stable for both treatment groups. Conclusion These data suggest that masitinib is of therapeutic benefit to PPMS and rfSPMS patients and could therefore represent an innovative avenue of treatment for this disease. This exploratory trial provides evidence that may support a larger placebo-controlled investigation. PMID:22691628

Correlates of Suicidal Ideation and Attempt Among Female Sex Workers in China

PubMed Central

HONG, YAN; LI, XIAOMING; FANG, XIAOYI; ZHAO, RAN

2007-01-01

The purpose of this study was to explore the factors associated with suicidal ideation and attempt among female sex workers (FSWs) in China. A cross-sectional survey was administered among 454 FSWs in a rural county of Guangxi, China. About 14% of FSWs had thought of suicide and 8% had attempted suicide in the past 6 months. Multiple logistic regression analyses indicated that those FSWs who were dissatisfied with life, abused alcohol, were deceived or forced into commercial sex, and had stable sexual partners were more likely to report suicidal ideation. Female sex workers who had multiple stable partners, experienced sexual coercion, and worried about an inability to make enough money were more likely to report a suicide attempt. These FSWs who entered commercial sex because of financial needs or who were influenced by the peers were less likely to report a suicide attempt. Our data suggested that the rates of suicidal ideation and attempts were high among FSWs in China, and there were multiple factors associated with their suicidality. Future health education and promotion efforts among FSWs need to take into consideration substance abuse, interpartner conflict, and psychological stress. PMID:17469002

Residual Strength Prediction of Fuselage Structures with Multiple Site Damage

NASA Technical Reports Server (NTRS)

Chen, Chuin-Shan; Wawrzynek, Paul A.; Ingraffea, Anthony R.

1999-01-01

This paper summarizes recent results on simulating full-scale pressure tests of wide body, lap-jointed fuselage panels with multiple site damage (MSD). The crack tip opening angle (CTOA) fracture criterion and the FRANC3D/STAGS software program were used to analyze stable crack growth under conditions of general yielding. The link-up of multiple cracks and residual strength of damaged structures were predicted. Elastic-plastic finite element analysis based on the von Mises yield criterion and incremental flow theory with small strain assumption was used. A global-local modeling procedure was employed in the numerical analyses. Stress distributions from the numerical simulations are compared with strain gage measurements. Analysis results show that accurate representation of the load transfer through the rivets is crucial for the model to predict the stress distribution accurately. Predicted crack growth and residual strength are compared with test data. Observed and predicted results both indicate that the occurrence of small MSD cracks substantially reduces the residual strength. Modeling fatigue closure is essential to capture the fracture behavior during the early stable crack growth. Breakage of a tear strap can have a major influence on residual strength prediction.

Ergodicity-breaking bifurcations and tunneling in hyperbolic transport models

NASA Astrophysics Data System (ADS)

Giona, M.; Brasiello, A.; Crescitelli, S.

2015-11-01

One of the main differences between parabolic transport, associated with Langevin equations driven by Wiener processes, and hyperbolic models related to generalized Kac equations driven by Poisson processes, is the occurrence in the latter of multiple stable invariant densities (Frobenius multiplicity) in certain regions of the parameter space. This phenomenon is associated with the occurrence in linear hyperbolic balance equations of a typical bifurcation, referred to as the ergodicity-breaking bifurcation, the properties of which are thoroughly analyzed.

Applying a Multiple Group Causal Indicator Modeling Framework to the Reading Comprehension Skills of Third, Seventh, and Tenth Grade Students

PubMed Central

Tighe, Elizabeth L.; Wagner, Richard K.; Schatschneider, Christopher

2015-01-01

This study demonstrates the utility of applying a causal indicator modeling framework to investigate important predictors of reading comprehension in third, seventh, and tenth grade students. The results indicated that a 4-factor multiple indicator multiple indicator cause (MIMIC) model of reading comprehension provided adequate fit at each grade level. This model included latent predictor constructs of decoding, verbal reasoning, nonverbal reasoning, and working memory and accounted for a large portion of the reading comprehension variance (73% to 87%) across grade levels. Verbal reasoning contributed the most unique variance to reading comprehension at all grade levels. In addition, we fit a multiple group 4-factor MIMIC model to investigate the relative stability (or variability) of the predictor contributions to reading comprehension across development (i.e., grade levels). The results revealed that the contributions of verbal reasoning, nonverbal reasoning, and working memory to reading comprehension were stable across the three grade levels. Decoding was the only predictor that could not be constrained to be equal across grade levels. The contribution of decoding skills to reading comprehension was higher in third grade and then remained relatively stable between seventh and tenth grade. These findings illustrate the feasibility of using MIMIC models to explain individual differences in reading comprehension across the development of reading skills. PMID:25821346

Fingolimod hydrochloride for the treatment of relapsing remitting multiple sclerosis.

PubMed

Thomas, Katja; Proschmann, Undine; Ziemssen, Tjalf

2017-10-01

Fingolimod was the first oral and the first in class disease modifying treatment in multiple sclerosis that acts as sphingosine-1-phospathe receptor agonist. Since approval in 2010 there is a growing experience with fingolimod use in clinical practice, but also next-generation sphingosin-1-receptor agonists in ongoing clinical trials. Growing evidence demonstrates additional effects beyond impact on lymphocyte circulation, highlighting further promising targets in multiple sclerosis therapy. Areas covered: Here we present a systematic review using PubMed database searching and expert opinion on fingolimod use in clinical practice. Long-term data of initial clinical trials and post-marketing evaluations including long-term efficacy, safety, tolerability and management especially within growing disease modifying treatment options and pre-treatment constellation in multiple sclerosis patients are critically discussed. Furthermore novel findings in mechanism of actions and prospective on additional use in progressive forms in multiple sclerosis are presented. Expert opinion: There is an extensive long-term experience on fingolimod use in clinical practice demonstrating the favorable benefit-risk of this drug. Using a defined risk management approach experienced MS clinicians should apply fingolimod after critical choice of patients and review of clinical aspects. Further studies are essential to discuss additional benefit in progressive forms in multiple sclerosis.

Extended International Normalized Ratio testing intervals for warfarin-treated patients.

PubMed

Barnes, G D; Kong, X; Cole, D; Haymart, B; Kline-Rogers, E; Almany, S; Dahu, M; Ekola, M; Kaatz, S; Kozlowski, J; Froehlich, J B

2018-05-15

Essentials Warfarin typically requires International Normalized Ratio (INR) testing at least every 4 weeks. We implemented extended INR testing for stable warfarin patients in six anticoagulation clinics. Use of extended INR testing increased from 41.8% to 69.3% over the 3 year study. Use of extended INR testing appeared safe and effective. Background A previous single-center randomized trial suggested that patients with stable International Normalized Ratio (INR) values could safely receive INR testing as infrequently as every 12 weeks. Objective To test the success of implementation of an extended INR testing interval for stable warfarin patients in a practice-based, multicenter collaborative of anticoagulation clinics. Methods At six anticoagulation clinics, patients were identified as being eligible for extended INR testing on the basis of prior INR value stability and minimal warfarin dose changes between 2014 and 2016. We assessed the frequency with which anticoagulation clinic providers recommended an extended INR testing interval (> 5 weeks) to eligible patients. We also explored safety outcomes for eligible patients, including next INR values, bleeding events, and emergency department visits. Results At least one eligible period for extended INR testing was identified in 890 of 3362 (26.5%) warfarin-treated patients. Overall, the use of extended INR testing in eligible patients increased from 41.8% in the first quarter of 2014 to 69.3% in the fourth quarter of 2016. The number of subsequent out-of-range next INR values were similar between eligible patients who did and did not have an extended INR testing interval (27.3% versus 28.4%, respectively). The numbers of major bleeding events were not different between the two groups, but rates of clinically relevant non-major bleeding (0.02 per 100 patient-years versus 0.09 per 100 patient-years) and emergency department visits (0.07 per 100 patient-years versus 0.19 per 100 patient-years) were lower for eligible patients with extended INR testing intervals than for those with non-extended INR testing intervals. Conclusions Extended INR testing for stable warfarin patients can be successfully and safely implemented in diverse, practice-based anticoagulation clinic settings. © 2018 International Society on Thrombosis and Haemostasis.

Longitudinal Trajectories of Social Reticence with Unfamiliar Peers across Early Childhood

PubMed Central

Degnan, Kathryn A.; Almas, Alisa N.; Henderson, Heather A.; Hane, Amie Ashley; Walker, Olga L.; Fox, Nathan A.

2014-01-01

Behavioral inhibition is a temperament assessed in the toddler period via children’s responses to novel contexts, objects, and unfamiliar adults. Social reticence is observed as onlooking, unoccupied behavior in the presence of unfamiliar peers and is linked to earlier behavioral inhibition. In the current study, we assessed behavioral inhibition in a sample of 262 children at ages two and three, and then assessed social reticence in these same children as they interacted with an unfamiliar, same age, and same sex peer, at 2, 3, 4, and 5 years of age. As expected, early behavioral inhibition was related to social reticence at each age. However, multiple trajectories of social reticence were observed including High-Stable, High-Decreasing, and Low-Increasing, with the High-Stable and High-Decreasing trajectories associated with greater behavioral inhibition compared to the Low-Increasing trajectory. In addition, children in the High-Stable social reticence trajectory were rated higher than all others on 60-month Internalizing problems. Children in the Low-Increasing trajectory were rated higher on 60-month Externalizing problems than children in the High-Decreasing trajectory. These results illustrate the multiple developmental pathways for behaviorally inhibited toddlers and suggest patterns across early childhood associated with heightened risk for psychopathology. PMID:25181648

Insulin-loaded W/O/W multiple emulsions: comparison of the performances of systems prepared with medium-chain-triglycerides and fish oil.

PubMed

Cournarie, Fabienne; Savelli, Marie-Pierre; Rosilio, Véronique; Bretez, Françoise; Vauthier, Christine; Grossiord, Jean-Louis; Seiller, Monique

2004-11-01

Insulin-loaded W/O/W multiple emulsions (ME) composed of medium-chain triglycerides have been shown to decrease the blood glucose level after oral administration to diabetic rats. Fish oil (very long-chain triglycerides) could be an alternative to medium-chain triglycerides because its chronic consumption has beneficial therapeutic effects. The aim of this work was twofold: to obtain stable fish oil containing ME, based on a formulation optimized in a previous work with low medium-chain triglycerides content, and to compare their characteristics to those of ME composed of medium-chain triglycerides. Due to the higher viscosity and surface tension of fish oil compared to medium-chain triglycerides, preparation of ME appeared difficult to achieve. However, a stable unloaded-ME with low fish oil content was formed, by adapting the emulsification process. The characteristics of unloaded fish oil ME were almost similar to those of medium-chain triglycerides ME. In contrast to medium-chain triglycerides ME, the introduction of insulin did not improve the elasticity and consequently the characteristics and stability of fish oil ME. Nevertheless, the insulin-loaded fish oil containing ME was shown to be stable for 6 weeks at 4 degrees C.

Point defect induced segregation of alloying solutes in α-Fe

NASA Astrophysics Data System (ADS)

You, Yu-Wei; Zhang, Yange; Li, Xiangyan; Xu, Yichun; Liu, C. S.; Chen, J. L.; Luo, G.-N.

2016-10-01

Segregation of alloying solute toward clusters and precipitates can result in hardening and embrittlement of ferritic and ferritic/martensitic steels in aging nuclear power plants. Thus, it is essential to study the segregation of solute in α-Fe. In this study, the segregation of eight kinds of alloying solutes (Al, Si, P, S, Ga, Ge, As, Se) in defect-free system and at vacancy, divacancy, and self-interstitial atom in α-Fe has been systematically studied by first-principles calculations. We find that it is energetically favorable for multiple solute S or Se atoms to segregate in defect-free system to form solute clusters, whereas it is very difficult for the other solute atoms to form the similar clusters. With the presence of vacancy and divacancy, the segregation of all the solutes are significantly promoted to form vacancy-solute and divacancy-solute clusters. The divacancy-solute cluster is more stable than the vacancy-solute cluster. The most-stable self-interstitial atom 〈110〉 dumbbell is also found to tightly bind with multiple solute atoms. The 〈110〉-S is even more stable than divacancy-S cluster. Meanwhile, the law of mass action is employed to predict the concentration evolution of vacancy-Si, vacancy-P, and vacancy-S clusters versus temperature and vacancy concentration.

Stable long-term blood formation by stem cells in murine steady-state hematopoiesis.

PubMed

Zavidij, Oksana; Ball, Claudia R; Herbst, Friederike; Oppel, Felix; Fessler, Sylvia; Schmidt, Manfred; von Kalle, Christof; Glimm, Hanno

2012-09-01

Hematopoietic stem cells (HSCs) generate all mature blood cells during the whole lifespan of an individual. However, the clonal contribution of individual HSC and progenitor cells in steady-state hematopoiesis is poorly understood. To investigate the activity of HSCs under steady-state conditions, murine HSC and progenitor cells were genetically marked in vivo by integrating lentiviral vectors (LVs) encoding green fluorescent protein (GFP). Hematopoietic contribution of individual marked clones was monitored by determination of lentiviral integration sites using highly sensitive linear amplification-mediated-polymerase chain reaction. A remarkably stable small proportion of hematopoietic cells expressed GFP in LV-injected animals for up to 24 months, indicating stable marking of murine steady-state hematopoiesis. Analysis of the lentiviral integration sites revealed that multiple hematopoietic clones with both myeloid and lymphoid differentiation potential contributed to long-term hematopoiesis. In contrast to intrafemoral vector injection, intravenous administration of LV preferentially targeted short-lived progenitor cells. Myelosuppressive treatment of mice prior to LV-injection did not affect the marking efficiency. Our study represents the first continuous analysis of clonal behavior of genetically marked hematopoietic cells in an unmanipulated system, providing evidence that multiple clones are simultaneously active in murine steady-state hematopoiesis. Copyright © 2012 AlphaMed Press.

Ad hoc vs. Non-ad hoc Percutaneous Coronary Intervention Strategies in Patients With Stable Coronary Artery Disease.

PubMed

Toyota, Toshiaki; Morimoto, Takeshi; Shiomi, Hiroki; Ando, Kenji; Ono, Koh; Shizuta, Satoshi; Kato, Takao; Saito, Naritatsu; Furukawa, Yutaka; Nakagawa, Yoshihisa; Horie, Minoru; Kimura, Takeshi

2017-03-24

Few studies have evaluated the prevalence and clinical outcomes of ad hoc percutaneous coronary intervention (PCI), performing diagnostic coronary angiography and PCI in the same session, in stable coronary artery disease (CAD) patients.Methods and Results:From the CREDO-Kyoto PCI/CABG registry cohort-2, 6,943 patients were analyzed as having stable CAD and undergoing first PCI. Ad hoc PCI and non-ad hoc PCI were performed in 1,722 (24.8%) and 5,221 (75.1%) patients, respectively. The cumulative 5-year incidence and adjusted risk for all-cause death were not significantly different between the 2 groups (15% vs. 15%, P=0.53; hazard ratio: 1.15, 95% confidence interval: 0.98-1.35, P=0.08). Ad hoc PCI relative to non-ad hoc PCI was associated with neutral risk for myocardial infarction, any coronary revascularization, and bleeding, but was associated with a trend towards lower risk for stroke (hazard ratio: 0.78, 95% confidence interval: 0.60-1.02, P=0.06). Ad hoc PCI in stable CAD patients was associated with at least comparable 5-year clinical outcomes as with non-ad hoc PCI. Considering patients' preference and the cost-saving, the ad hoc PCI strategy might be a safe and attractive option for patients with stable CAD, although the prevalence of ad hoc PCI was low in the current study population.

Conditional probability of rainfall extremes across multiple durations

NASA Astrophysics Data System (ADS)

Le, Phuong Dong; Leonard, Michael; Westra, Seth

2017-04-01

The conditional probability that extreme rainfall will occur at one location given that it is occurring at another location is critical in engineering design and management circumstances including planning of evacuation routes and the sitting of emergency infrastructure. A challenge with this conditional simulation is that in many situations the interest is not so much the conditional distributions of rainfall of the same duration at two locations, but rather the conditional distribution of flooding in two neighbouring catchments, which may be influenced by rainfall of different critical durations. To deal with this challenge, a model that can consider both spatial and duration dependence of extremes is required. The aim of this research is to develop a model that can take account both spatial dependence and duration dependence into the dependence structure of extreme rainfalls. To achieve this aim, this study is a first attempt at combining extreme rainfall for multiple durations within a spatial extreme model framework based on max-stable process theory. Max-stable processes provide a general framework for modelling multivariate extremes with spatial dependence for just a single duration extreme rainfall. To achieve dependence across multiple timescales, this study proposes a new approach that includes addition elements representing duration dependence of extremes to the covariance matrix of max-stable model. To improve the efficiency of calculation, a re-parameterization proposed by Koutsoyiannis et al. (1998) is used to reduce the number of parameters necessary to be estimated. This re-parameterization enables the GEV parameters to be represented as a function of timescale. A stepwise framework has been adopted to achieve the overall aims of this research. Firstly, the re-parameterization is used to define a new set of common parameters for marginal distribution across multiple durations. Secondly, spatial interpolation of the new parameter set is used to estimate marginal parameters across the full spatial domain. Finally, spatial interpolation result is used as initial condition to estimate dependence parameters via a likelihood function of max-stable model for multiple durations. The Hawkesbury-Nepean catchment near Sydney in Australia was selected as case study for this research. This catchment has 25 sub-daily rain gauges with the minimum record length of 24 years over a region of 300 km × 300 km area. The re-parameterization was applied for each station for durations from 1 hour to 24 hours and then is evaluated by comparing with the at-site fitted GEV. The evaluation showed that the average R2 for all station is around 0.80 with the range from 0.26 to 1.0. The output of re-parameterization then was used to construct the spatial surface based on covariates including longitude, latitude, and elevation. The dependence model showed good agreements between empirical extremal coefficient and theoretical extremal coefficient for multiple durations. For the overall model, a leave-one-out cross-validation for all stations showed it works well for 20 out of 25 stations. The potential application of this model framework was illustrated through a conditional map of return period and return level across multiple durations, both of which are important for engineering design and management.

Crevicular fluid biomarkers and periodontal disease progression.

PubMed

Kinney, Janet S; Morelli, Thiago; Oh, Min; Braun, Thomas M; Ramseier, Christoph A; Sugai, Jim V; Giannobile, William V

2014-02-01

Assess the ability of a panel of gingival crevicular fluid (GCF) biomarkers as predictors of periodontal disease progression (PDP). In this study, 100 individuals participated in a 12-month longitudinal investigation and were categorized into four groups according to their periodontal status. GCF, clinical parameters and saliva were collected bi-monthly. Subgingival 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 to 12 months. GCF samples were analysed by ELISA for MMP-8, MMP-9, Osteoprotegerin, C-reactive Protein 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. 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). Signature of GCF fluid-derived biomarkers combined with pathogens and clinical measures provides a sensitive measure for discrimination of PDP (ClinicalTrials.gov NCT00277745). © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Stable mineral recrystallization in low temperature aqueous systems: A critical review

NASA Astrophysics Data System (ADS)

Gorski, Christopher A.; Fantle, Matthew S.

2017-02-01

Minerals may undergo recrystallization reactions in low temperature (<100 °C) aqueous systems, during which they exchange isotopes and trace elements with the dissolved reservoir without undergoing overt structural, bulk compositional, or morphological changes. These interfacial reactions, which are often referred to in the literature as "atom exchange" and herein as "stable mineral recrystallization", have important implications for the use of isotopic and elemental proxies to interpret past temperatures, oxidation states, and aqueous chemistries on Earth. The reactions are also significant for modern environments, including engineered systems, as they imply that mineral lattices may be substantially more open to exchanging toxic elements and radionuclides with coexisting solutions than previously thought. To date, observations of stable mineral recrystallization are distributed among several disciplines, and no work has attempted to review their findings comprehensively. Accordingly, this review article presents laboratory evidence for stable mineral recrystallization, describes data collection and interpretation strategies, summarizes similar recrystallization systematics observed in multiple studies, explores the potential occurrence of stable mineral recrystallization in natural systems, and discusses possible mechanisms by which stable mineral recrystallization occurs. The review focuses primarily on carbonates, sulfates, and iron oxides because these minerals have been studied most extensively to date. The review concludes by presenting key questions that should be addressed in this field to further understand and account for stable mineral recrystallization in natural and engineered aqueous systems at low temperatures.

Searching for neurodegeneration in multiple sclerosis at clinical onset: Diagnostic value of biomarkers.

PubMed

Novakova, Lenka; Axelsson, Markus; Malmeström, Clas; Imberg, Henrik; Elias, Olle; Zetterberg, Henrik; Nerman, Olle; Lycke, Jan

2018-01-01

Neurodegeneration occurs during the early stages of multiple sclerosis. It is an essential, devastating part of the pathophysiology. Tools for measuring the degree of neurodegeneration could improve diagnostics and patient characterization. This study aimed to determine the diagnostic value of biomarkers of degeneration in patients with recent clinical onset of suspected multiple sclerosis, and to evaluate these biomarkers for characterizing disease course. This cross-sectional study included 271 patients with clinical features of suspected multiple sclerosis onset and was the baseline of a prospective study. After diagnostic investigations, the patients were classified into the following disease groups: patients with clinically isolated syndrome (n = 4) or early relapsing remitting multiple sclerosis (early RRMS; n = 93); patients with relapsing remitting multiple sclerosis with disease durations ≥2 years (established RRMS; n = 39); patients without multiple sclerosis, but showing symptoms (symptomatic controls; n = 89); and patients diagnosed with other diseases (n = 46). In addition, we included healthy controls (n = 51) and patients with progressive multiple sclerosis (n = 23). We analyzed six biomarkers of neurodegeneration: cerebrospinal fluid neurofilament light chain levels; cerebral spinal fluid glial fibrillary acidic protein; cerebral spinal fluid tau; retinal nerve fiber layer thickness; macula volume; and the brain parenchymal fraction. Except for increased cerebral spinal fluid neurofilament light chain levels, median 670 ng/L (IQR 400-2110), we could not find signs of early degeneration in the early disease group with recent clinical onset. However, the intrathecal immunoglobin G production and cerebral spinal fluid neurofilament light chain levels showed diagnostic value. Moreover, elevated levels of cerebral spinal fluid glial fibrillary acidic protein, thin retinal nerve fiber layers, and low brain parenchymal fractions were associated with progressive disease, but not with the other phenotypes. Thin retinal nerve fiber layers and low brain parenchymal fractions, which indicated neurodegeneration, were associated with longer disease duration. In clinically suspected multiple sclerosis, intrathecal immunoglobin G production and neurofilament light chain levels had diagnostic value. Therefore, these biomarkers could be included in diagnostic work-ups for multiple sclerosis. We found that the thickness of the retinal nerve fiber layer and the brain parenchymal fraction were not different between individuals that were healthy, symptomatic, or newly diagnosed with multiple sclerosis. This finding suggested that neurodegeneration had not reached a significant magnitude in patients with a recent clinical onset of multiple sclerosis.

Evaluation of the fibromyalgia impact questionnaire at baseline as a predictor for time to pain improvement in two clinical trials of pregabalin.

PubMed

Bushmakin, A G; Cappelleri, J C; Chandran, A B; Zlateva, G

2013-01-01

The Fibromyalgia Impact Questionnaire (FIQ) is a patient-reported outcome that evaluates the impact of fibromyalgia (FM) on daily life. This study evaluated the relationships between the functional status of FM patients, measured with the FIQ at baseline, and median time to a clinically relevant pain reduction. Data were derived from two randomised, placebo-controlled trials that evaluated pregabalin 300, 450 and 600 mg/day for the treatment of FM. The Kaplan-Meier (nonparametric) method was applied to estimate median times to 'transient' and 'stable' events. The transient event was defined as a ≥ 27.9% improvement on an 11-point daily pain diary scale (0 = no pain, 10 = worst possible pain), and the stable event was defined as the mean of the daily improvements ≥ 27.9% relative to baseline over the subsequent study duration starting on the day of the transient event. A parametric model using time-to-event analysis was developed for evaluating the relationship between baseline FIQ score and the median time to these events. Median time was longer among patients treated with placebo relative to pregabalin for the transient events (11-12 days vs. 5-7 days) and stable events (86 days vs. 13-29 days). A significant association was observed between baseline FIQ scores and median time to transient and stable events (p < 0.001). Median times to events were similar between the studies. For transient pain reduction events, median times ranged from 3.0 to 4.5 days for baseline FIQ scores of 10, and 9.1-9.6 days for FIQ scores of 100; for stable pain reduction events, the median time ranged from 11.0 to 13.0 days and from 27.0 to 28.5 days for baseline FIQ scores of 10 and 100 respectively. Time to a clinically relevant reduction in pain was significantly associated with FM severity at baseline as measured by the FIQ. Such an analysis can inform patient and physician expectations in clinical practice. © 2012 Blackwell Publishing Ltd.

Functionalized poly(ethylene glycol) diacrylate microgels by microfluidics: In situ peptide encapsulation for in serum selective protein detection.

PubMed

Celetti, Giorgia; Natale, Concetta Di; Causa, Filippo; Battista, Edmondo; Netti, Paolo A

2016-09-01

Polymeric microparticles represent a robustly platform for the detection of clinically relevant analytes in biological samples; they can be functionalized encapsulating a multiple types of biologics entities, enhancing their applications as a new class of colloid materials. Microfluidic offers a versatile platform for the synthesis of monodisperse and engineered microparticles. In this work, we report microfluidic synthesis of novel polymeric microparticles endowed with specific peptide due to its superior specificity for target binding in complex media. A peptide sequence was efficiently encapsulated into the polymeric network and protein binding occurred with high affinity (KD 0.1-0.4μM). Fluidic dynamics simulation was performed to optimize the production conditions for monodisperse and stable functionalized microgels. The results demonstrate the easy and fast realization, in a single step, of functionalized monodisperse microgels using droplet-microfluidic technique, and how the inclusion of the peptide within polymeric network improve both the affinity and the specificity of protein capture. Copyright © 2016 Elsevier B.V. All rights reserved.

A repeatedly refuelable mediated biofuel cell based on a hierarchical porous carbon electrode

NASA Astrophysics Data System (ADS)

Fujita, Shuji; Yamanoi, Shun; Murata, Kenichi; Mita, Hiroki; Samukawa, Tsunetoshi; Nakagawa, Takaaki; Sakai, Hideki; Tokita, Yuichi

2014-05-01

Biofuel cells that generate electricity from renewable fuels, such as carbohydrates, must be reusable through repeated refuelling, should these devices be used in consumer electronics. We demonstrate the stable generation of electricity from a glucose-powered mediated biofuel cell through multiple refuelling cycles. This refuelability is achieved by immobilizing nicotinamide adenine dinucleotide (NAD), an electron-transfer mediator, and redox enzymes in high concentrations on porous carbon particles constituting an anode while maintaining their electrochemical and enzymatic activities after the immobilization. This bioanode can be refuelled continuously for more than 60 cycles at 1.5 mA cm-2 without significant potential drop. Cells assembled with these bioanodes and bilirubin-oxidase-based biocathodes can be repeatedly used to power a portable music player at 1 mW cm-3 through 10 refuelling cycles. This study suggests that the refuelability within consumer electronics should facilitate the development of long and repeated use of the mediated biofuel cells as well as of NAD-based biosensors, bioreactors, and clinical applications.

Human gingiva-derived mesenchymal stem cells are superior to bone marrow-derived mesenchymal stem cells for cell therapy in regenerative medicine

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

Tomar, Geetanjali B.; Srivastava, Rupesh K.; Gupta, Navita

2010-03-12

Mesenchymal stem cells (MSCs) are capable of self-renewal and differentiation into multiple cell lineages. Presently, bone marrow is considered as a prime source of MSCs; however, there are some drawbacks and limitations in use of these MSCs for cell therapy. In this study, we demonstrate that human gingival tissue-derived MSCs have several advantages over bone marrow-derived MSCs. Gingival MSCs are easy to isolate, homogenous and proliferate faster than bone marrow MSCs without any growth factor. Importantly, gingival MSCs display stable morphology and do not loose MSC characteristic at higher passages. In addition, gingival MSCs maintain normal karyotype and telomerase activitymore » in long-term cultures, and are not tumorigenic. Thus, we reveal that human gingiva is a better source of MSCs than bone marrow, and large number of functionally competent clinical grade MSCs can be generated in short duration for cell therapy in regenerative medicine and tissue engineering.« less

A repeatedly refuelable mediated biofuel cell based on a hierarchical porous carbon electrode.

PubMed

Fujita, Shuji; Yamanoi, Shun; Murata, Kenichi; Mita, Hiroki; Samukawa, Tsunetoshi; Nakagawa, Takaaki; Sakai, Hideki; Tokita, Yuichi

2014-05-13

Biofuel cells that generate electricity from renewable fuels, such as carbohydrates, must be reusable through repeated refuelling, should these devices be used in consumer electronics. We demonstrate the stable generation of electricity from a glucose-powered mediated biofuel cell through multiple refuelling cycles. This refuelability is achieved by immobilizing nicotinamide adenine dinucleotide (NAD), an electron-transfer mediator, and redox enzymes in high concentrations on porous carbon particles constituting an anode while maintaining their electrochemical and enzymatic activities after the immobilization. This bioanode can be refuelled continuously for more than 60 cycles at 1.5 mA cm(-2) without significant potential drop. Cells assembled with these bioanodes and bilirubin-oxidase-based biocathodes can be repeatedly used to power a portable music player at 1 mW cm(-3) through 10 refuelling cycles. This study suggests that the refuelability within consumer electronics should facilitate the development of long and repeated use of the mediated biofuel cells as well as of NAD-based biosensors, bioreactors, and clinical applications.

Structural and molecular interrogation of intact biological systems

PubMed Central

Chung, Kwanghun; Wallace, Jenelle; Kim, Sung-Yon; Kalyanasundaram, Sandhiya; Andalman, Aaron S.; Davidson, Thomas J.; Mirzabekov, Julie J.; Zalocusky, Kelly A.; Mattis, Joanna; Denisin, Aleksandra K.; Pak, Sally; Bernstein, Hannah; Ramakrishnan, Charu; Grosenick, Logan; Gradinaru, Viviana; Deisseroth, Karl

2014-01-01

Obtaining high-resolution information from a complex system, while maintaining the global perspective needed to understand system function, represents a key challenge in biology. Here we address this challenge with a method (termed CLARITY) for the transformation of intact tissue into a nanoporous hydrogel-hybridized form (crosslinked to a three-dimensional network of hydrophilic polymers) that is fully assembled but optically transparent and macromolecule-permeable. Using mouse brains, we show intact-tissue imaging of long-range projections, local circuit wiring, cellular relationships, subcellular structures, protein complexes, nucleic acids and neurotransmitters. CLARITY also enables intact-tissue in situ hybridization, immunohistochemistry with multiple rounds of staining and de-staining in non-sectioned tissue, and antibody labelling throughout the intact adult mouse brain. Finally, we show that CLARITY enables fine structural analysis of clinical samples, including non-sectioned human tissue from a neuropsychiatric-disease setting, establishing a path for the transmutation of human tissue into a stable, intact and accessible form suitable for probing structural and molecular underpinnings of physiological function and disease. PMID:23575631

Micro-CT image reconstruction based on alternating direction augmented Lagrangian method and total variation.

PubMed

Gopi, Varun P; Palanisamy, P; Wahid, Khan A; Babyn, Paul; Cooper, David

2013-01-01

Micro-computed tomography (micro-CT) plays an important role in pre-clinical imaging. The radiation from micro-CT can result in excess radiation exposure to the specimen under test, hence the reduction of radiation from micro-CT is essential. The proposed research focused on analyzing and testing an alternating direction augmented Lagrangian (ADAL) algorithm to recover images from random projections using total variation (TV) regularization. The use of TV regularization in compressed sensing problems makes the recovered image quality sharper by preserving the edges or boundaries more accurately. In this work TV regularization problem is addressed by ADAL which is a variant of the classic augmented Lagrangian method for structured optimization. The per-iteration computational complexity of the algorithm is two fast Fourier transforms, two matrix vector multiplications and a linear time shrinkage operation. Comparison of experimental results indicate that the proposed algorithm is stable, efficient and competitive with the existing algorithms for solving TV regularization problems. Copyright © 2013 Elsevier Ltd. All rights reserved.

Exchange of Computable Patient Data between the Department of Veterans Affairs (VA) and the Department of Defense (DoD): Terminology Mediation Strategy

PubMed Central

Bouhaddou, Omar; Warnekar, Pradnya; Parrish, Fola; Do, Nhan; Mandel, Jack; Kilbourne, John; Lincoln, Michael J.

2008-01-01

Complete patient health information that is available where and when it is needed is essential to providers and patients and improves healthcare quality and patient safety. VA and DoD have built on their previous experience in patient data exchange to establish data standards and terminology services to enable real-time bi-directional computable (i.e., encoded) data exchange and achieve semantic interoperability in compliance with recommended national standards and the eGov initiative. The project uses RxNorm, UMLS, and SNOMED CT terminology standards to mediate codified pharmacy and allergy data with greater than 92 and 60 percent success rates respectively. Implementation of the project has been well received by users and is being expanded to multiple joint care sites. Stable and mature standards, mediation strategies, and a close relationship between healthcare institutions and Standards Development Organizations are recommended to achieve and maintain semantic interoperability in a clinical setting. PMID:18096911

A repeatedly refuelable mediated biofuel cell based on a hierarchical porous carbon electrode

PubMed Central

Fujita, Shuji; Yamanoi, Shun; Murata, Kenichi; Mita, Hiroki; Samukawa, Tsunetoshi; Nakagawa, Takaaki; Sakai, Hideki; Tokita, Yuichi

2014-01-01

Biofuel cells that generate electricity from renewable fuels, such as carbohydrates, must be reusable through repeated refuelling, should these devices be used in consumer electronics. We demonstrate the stable generation of electricity from a glucose-powered mediated biofuel cell through multiple refuelling cycles. This refuelability is achieved by immobilizing nicotinamide adenine dinucleotide (NAD), an electron-transfer mediator, and redox enzymes in high concentrations on porous carbon particles constituting an anode while maintaining their electrochemical and enzymatic activities after the immobilization. This bioanode can be refuelled continuously for more than 60 cycles at 1.5 mA cm−2 without significant potential drop. Cells assembled with these bioanodes and bilirubin-oxidase-based biocathodes can be repeatedly used to power a portable music player at 1 mW cm−3 through 10 refuelling cycles. This study suggests that the refuelability within consumer electronics should facilitate the development of long and repeated use of the mediated biofuel cells as well as of NAD-based biosensors, bioreactors, and clinical applications. PMID:24820210

Early axonal damage and progressive myelin pathology define the kinetics of CNS histopathology in a mouse model of multiple sclerosis.

PubMed

Recks, Mascha S; Stormanns, Eva R; Bader, Jonas; Arnhold, Stefan; Addicks, Klaus; Kuerten, Stefanie

2013-10-01

Studies of MS histopathology are largely dependent on suitable animal models. While light microscopic analysis gives an overview of tissue pathology, it falls short in evaluating detailed changes in nerve fiber morphology. The ultrastructural data presented here and obtained from studies of myelin oligodendrocyte glycoprotein (MOG):35-55-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice delineate that axonal damage and myelin pathology follow different kinetics in the disease course. While myelin pathology accumulated with disease progression, axonal damage coincided with the initial clinical disease symptoms and remained stable over time. This pattern applied both to irreversible axolysis and early axonal pathology. Notably, these histopathological patterns were reflected by the normal-appearing white matter (NAWM), suggesting that the NAWM is also in an active neurodegenerative state. The data underline the need for neuroprotection in MS and suggest the MOG model as a highly valuable tool for the assessment of different therapeutic strategies. Copyright © 2013 Elsevier Inc. All rights reserved.

Game theory in the death galaxy: interaction of cancer and stromal cells in tumour microenvironment.

PubMed

Wu, Amy; Liao, David; Tlsty, Thea D; Sturm, James C; Austin, Robert H

2014-08-06

Preventing relapse is the major challenge to effective therapy in cancer. Within the tumour, stromal (ST) cells play an important role in cancer progression and the emergence of drug resistance. During cancer treatment, the fitness of cancer cells can be enhanced by ST cells because their molecular signalling interaction delays the drug-induced apoptosis of cancer cells. On the other hand, competition among cancer and ST cells for space or resources should not be ignored. We explore the population dynamics of multiple myeloma (MM) versus bone marrow ST cells by using an experimental microecology that we call the death galaxy, with a stable drug gradient and connected microhabitats. Evolutionary game theory is a quantitative way to capture the frequency-dependent nature of interactive populations. Therefore, we use evolutionary game theory to model the populations in the death galaxy with the gradients of pay-offs and successfully predict the future densities of MM and ST cells. We discuss the possible clinical use of such analysis for predicting cancer progression.

Influence of a multiple emulsion, liposomes and a microemulsion gel on sebum, skin hydration and TEWL.

PubMed

Mahrhauser, D; Nagelreiter, C; Baierl, A; Skipiol, J; Valenta, C

2015-04-01

In this study, the influence of three cosmetically relevant, priorly characterized vehicles on skin hydration, sebum content and transepidermal water loss was investigated. The chosen vehicles included a liposomal pre-formulation, a multiple W/O/W emulsion and a microemulsion gel. The in vivo effects of these vehicles were demonstrated and compared among them. The stability of the prepared vehicles was determined visually, microscopically, rheologically by pH measurements and particle size. Interactions with skin were assessed by non-invasive biophysical techniques using the Corneometer(®), Aqua Flux(®) and Sebumeter, measuring skin hydration, TEWL and skin sebum content, respectively. All vehicles remained stable over an observation period of 6 weeks. The multiple emulsion increased sebum content and skin hydration. In case of the liposomes, each monitored parameter remained almost constant. In contrast, the microemulsion gel lowered skin hydration and increased TEWL values, but even 1 week after termination of the treatment TEWL decreased almost close to control levels. All produced vehicles were proven to remain physically stable over the duration of this study. The used multiple emulsion showed very skin-friendly properties by increasing sebum and skin hydration. Likewise, the liposomal pre-formulation exhibited no negative effects. On the contrary, the investigated microemulsion gel seemed to have skin dehydrating and TEWL increasing features. However, the multiple emulsion as well as liposomes was identified to be well-tolerated vehicles for skin which might qualify them for the use in cosmetic formulations. © 2014 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Two-dimensional NMR spectroscopy reveals cation-triggered backbone degradation in polysulfone-based anion exchange membranes

PubMed Central

Arges, Christopher G.; Ramani, Vijay

2013-01-01

Anion exchange membranes (AEMs) find widespread applications as an electrolyte and/or electrode binder in fuel cells, electrodialysis stacks, flow and metal-air batteries, and electrolyzers. AEMs exhibit poor stability in alkaline media; their degradation is induced by the hydroxide ion, a potent nucleophile. We have used 2D NMR techniques to investigate polymer backbone stability (as opposed to cation stability) of the AEM in alkaline media. We report the mechanism behind a peculiar, often-observed phenomenon, wherein a demonstrably stable polysulfone backbone degrades rapidly in alkaline solutions upon derivatization with alkaline stable fixed cation groups. Using COSY and heteronuclear multiple quantum correlation spectroscopy (2D NMR), we unequivocally demonstrate that the added cation group triggers degradation of the polymer backbone in alkaline via quaternary carbon hydrolysis and ether hydrolysis, leading to rapid failure. This finding challenges the existing perception that having a stable cation moiety is sufficient to yield a stable AEM and emphasizes the importance of the often ignored issue of backbone stability. PMID:23335629

[Research progress on food sources and food web structure of wetlands based on stable isotopes].

PubMed

Chen, Zhan Yan; Wu, Hai Tao; Wang, Yun Biao; Lyu, Xian Guo

2017-07-18

The trophic dynamics of wetland organisms is the basis of assessing wetland structure and function. Stable isotopes of carbon and nitrogen have been widely applied to identify trophic relationships in food source, food composition and food web transport in wetland ecosystem studies. This paper provided an overall review about the current methodology of isotope mixing model and trophic level in wetland ecosystems, and discussed the standards of trophic fractionation and baseline. Moreover, we characterized the typical food sources and isotopic compositions of wetland ecosystems, summarized the food sources in different trophic levels of herbivores, omnivores and carnivores based on stable isotopic analyses. We also discussed the limitations of stable isotopes in tra-cing food sources and in constructing food webs. Based on the current results, development trends and upcoming requirements, future studies should focus on sample treatment, conservation and trophic enrichment measurement in the wetland food web, as well as on combing a variety of methodologies including traditional stomach stuffing, molecular markers, and multiple isotopes.

Use of echocardiography in outpatients with chest pain and normal resting electrocardiograms referred to Mayo Clinic Rochester.

PubMed

Gibbons, Raymond J; Carryer, Damita; Liu, Hongfang; Brady, Peter A; Askew, John Wells; Hodge, David; Ammash, Naser; Ebbert, Jon O; Roger, Veronique L

2018-02-01

To determine how often unnecessary resting echocardiograms that are "not recommended" by clinical practice guidelines are performed in patients with stable chest pain and normal resting electrocardiograms (ECGs). There are scant data to indicate how often Class III recommendations are ignored in clinical practice. We searched electronically all medical records of referral outpatients seen at Mayo Clinic Rochester from January 1, 2010, through December 31, 2013, to identify patients with stable chest pain and known or suspected coronary artery disease who underwent resting echocardiography and had normal resting ECGs and no other indication for echocardiography. Of the 15,529 referral outpatients who were evaluated at Mayo Clinic Rochester with chest pain, 3976 (25.6%) had resting echocardiograms. Eight hundred seventy of these 3976 patients (21.9%) had normal resting ECGs. Six hundred nineteen of these 870 patients (71.1%) had other indications for echocardiography. The remaining 251 patients (6.3% of all echocardiograms and 1.6% of all patients) had normal resting ECGs and no other indication for echocardiography. Two hundred thirty-nine of these 251 patients (95.2%) had normal echocardiograms. Of the 12 abnormal echocardiograms, only 4 led to any change in clinical management. Sixty-one of these 251 echocardiograms (24.3%) were "preordered" before the provider (physicians, nurses, physician assistants) visit. Echocardiograms were performed in 1 in 4 referral outpatients with chest pain seen at Mayo Clinic Rochester. However, only 1 in 16 of these echocardiograms was performed in violation of the class III recommendation in the American College of Cardiology Foundation/American Heart Association guidelines for the management of stable angina. These unnecessary echocardiograms were almost always normal, and had little impact on clinical management. The rate of unnecessary echocardiograms could be decreased by eliminating preordering. Copyright © 2017 Elsevier Inc. All rights reserved.

Volumetric modulated arc therapy with flattening filter free beams for isolated abdominal/pelvic lymph nodes: report of dosimetric and early clinical results in oligometastatic patients

PubMed Central

2012-01-01

Background SBRT is a safe and efficient strategy to locally control multiple metastatic sites. While research in the physics domain for Flattening Filter Free Beams (FFF) beams is increasing, there are few clinical data of FFF beams in clinical practice. Here we reported dosimentric and early clinical data of SBRT and FFF delivery in isolated lymph node oligometastatic patients. Methods Between October 2010 and March 2012, 34 patients were treated with SBRT for oligometastatic lymph node metastasis on a Varian TrueBeamTM treatment machine using Volumetric Modulated Arc Therapy (RapidArc). We retrospectively evaluated a total of 25 patients for isolated lymph node metastases in abdomen and/or pelvis treated with SBRT and FFF (28 treatments). Acute toxicity was recorded. Local control evaluation was scored by means of CT scan and/or PET scan. Results All dosimetric results are in line with what published for the same type of stereotactic abdominal lymph node metastases treatments and fractionation, using RapidArc. All 25 FFF SBRT patients completed the treatment. Acute gastrointestinal toxicity was minimal: one patient showed Grade 1 gastrointestinal toxicity. Three other patients presented Grade 2 toxicity. No Grade 3 or higher was recorded. All toxicities were recovered within one week. The preliminary clinical results at the median follow up of 195 days are: complete response in 12 cases, partial response in 11, stable disease in 5, with an overall response rate of 82%; no local progression was recorded. Conclusions Data of dosimetrical findings and acute toxicity are excellent for patients treated with SBRT with VMAT using FFF beams. Preliminary clinical results showed a high rate of local control in irradiated lesion. Further data and longer follow up are needed to assess late toxicity and definitive clinical outcomes. PMID:23216821

Signature program: a platform of basket trials.

PubMed

Slosberg, Eric D; Kang, Barinder P; Peguero, Julio; Taylor, Matthew; Bauer, Todd M; Berry, Donald A; Braiteh, Fadi; Spira, Alexander; Meric-Bernstam, Funda; Stein, Steven; Piha-Paul, Sarina A; Salvado, August

2018-04-20

Investigating targeted therapies can be challenging due to diverse tumor mutations and slow patient accrual for clinical studies. The Signature Program is a series of 8 phase 2, agent-specific basket protocols using a rapid study start-up approach involving no predetermined study sites. Each protocol evaluated 1 agent (buparlisib, dovitinib, binimetinib, encorafenib, sonidegib, BGJ398, ceritinib, or ribociclib) in patients with solid or hematologic malignancies and an actionable mutation. The primary endpoint of each study was the clinical benefit rate (ie, complete or partial response, or stable disease) at 16 weeks. A total of 192 individual sites were opened in the United States, with a median start-up time of 3.6 weeks. The most common tumor types among the 595 treated patients were colorectal (9.2%), non-small cell lung adenocarcinoma (9.1%), and ovarian (8.4%). Frequent genetic alterations were in PIK3CA , RAS , p16 , and PTEN . Overall, 30 partial or complete responses were observed with 6 compounds in 16 tumor types. The Signature Program presents a unique and successful approach for rapid signal finding across multiple tumors and allowed various agents to be evaluated in patients with rare alterations. Incorporating these program features in conventional studies could lead to improved trial efficiencies and patient outcomes.

Signature program: a platform of basket trials

PubMed Central

Peguero, Julio; Taylor, Matthew; Bauer, Todd M.; Berry, Donald A.; Braiteh, Fadi; Spira, Alexander; Meric-Bernstam, Funda; Stein, Steven; Piha-Paul, Sarina A.; Salvado, August

2018-01-01

Investigating targeted therapies can be challenging due to diverse tumor mutations and slow patient accrual for clinical studies. The Signature Program is a series of 8 phase 2, agent-specific basket protocols using a rapid study start-up approach involving no predetermined study sites. Each protocol evaluated 1 agent (buparlisib, dovitinib, binimetinib, encorafenib, sonidegib, BGJ398, ceritinib, or ribociclib) in patients with solid or hematologic malignancies and an actionable mutation. The primary endpoint of each study was the clinical benefit rate (ie, complete or partial response, or stable disease) at 16 weeks. A total of 192 individual sites were opened in the United States, with a median start-up time of 3.6 weeks. The most common tumor types among the 595 treated patients were colorectal (9.2%), non-small cell lung adenocarcinoma (9.1%), and ovarian (8.4%). Frequent genetic alterations were in PIK3CA, RAS, p16, and PTEN. Overall, 30 partial or complete responses were observed with 6 compounds in 16 tumor types. The Signature Program presents a unique and successful approach for rapid signal finding across multiple tumors and allowed various agents to be evaluated in patients with rare alterations. Incorporating these program features in conventional studies could lead to improved trial efficiencies and patient outcomes. PMID:29765547

A Robust Protocol for Using Multiplexed Droplet Digital PCR to Quantify Somatic Copy Number Alterations in Clinical Tissue Specimens.

PubMed

Hughesman, Curtis B; Lu, X J David; Liu, Kelly Y P; Zhu, Yuqi; Poh, Catherine F; Haynes, Charles

2016-01-01

The ability of droplet digital PCR (ddPCR) to accurately determine the concentrations of amplifiable targets makes it a promising platform for measuring copy number alterations (CNAs) in genomic biomarkers. However, its application to clinical samples, particularly formalin-fixed paraffin-embedded specimens, will require strategies to reliably determine CNAs in DNA of limited quantity and quality. When applied to cancerous tissue, those methods must also account for global genetic instability and the associated probability that the abundance(s) of one or more chosen reference loci do not represent the average ploidy of cells comprising the specimen. Here we present an experimental design strategy and associated data analysis tool that enables accurate determination of CNAs in a panel of biomarkers using multiplexed ddPCR. The method includes strategies to optimize primer and probes design to cleanly segregate droplets in the data output from reaction wells amplifying multiple independent templates, and to correct for bias from artifacts such as DNA fragmentation. We demonstrate how a panel of reference loci can be used to determine a stable CNA-neutral benchmark. These innovations, when taken together, provide a comprehensive strategy that can be used to reliably detect biomarker CNAs in DNA extracted from either frozen or FFPE tissue biopsies.

A Guide to Approaching Regulatory Considerations for Lentiviral-Mediated Gene Therapies.

PubMed

White, Michael; Whittaker, Roger; Gándara, Carolina; Stoll, Elizabeth A

2017-08-01

Lentiviral vectors are increasingly the gene transfer tool of choice for gene or cell therapies, with multiple clinical investigations showing promise for this viral vector in terms of both safety and efficacy. The third-generation vector system is well characterized, effectively delivers genetic material and maintains long-term stable expression in target cells, delivers larger amounts of genetic material than other methods, is nonpathogenic, and does not cause an inflammatory response in the recipient. This report aims to help academic scientists and regulatory managers negotiate the governance framework to achieve successful translation of a lentiviral vector-based gene therapy. The focus is on European regulations and how they are administered in the United Kingdom, although many of the principles will be similar for other regions, including the United States. The report justifies the rationale for using third-generation lentiviral vectors to achieve gene delivery for in vivo and ex vivo applications; briefly summarizes the extant regulatory guidance for gene therapies, categorized as advanced therapeutic medicinal products (ATMPs); provides guidance on specific regulatory issues regarding gene therapies; presents an overview of the key stakeholders to be approached when pursuing clinical trials authorization for an ATMP; and includes a brief catalogue of the documentation required to submit an application for regulatory approval of a new gene therapy.

A Newly Defined and Xeno-Free Culture Medium Supports Every-Other-Day Medium Replacement in the Generation and Long-Term Cultivation of Human Pluripotent Stem Cells.

PubMed

Ahmadian Baghbaderani, Behnam; Tian, Xinghui; Scotty Cadet, Jean; Shah, Kevan; Walde, Amy; Tran, Huan; Kovarcik, Don Paul; Clarke, Diana; Fellner, Thomas

2016-01-01

Human pluripotent stem cells (hPSCs) present an unprecedented opportunity to advance human health by offering an alternative and renewable cell resource for cellular therapeutics and regenerative medicine. The present demand for high quality hPSCs for use in both research and clinical studies underscores the need to develop technologies that will simplify the cultivation process and control variability. Here we describe the development of a robust, defined and xeno-free hPSC medium that supports reliable propagation of hPSCs and generation of human induced pluripotent stem cells (hiPSCs) from multiple somatic cell types; long-term serial subculturing of hPSCs with every-other-day (EOD) medium replacement; and banking fully characterized hPSCs. The hPSCs cultured in this medium for over 40 passages are genetically stable, retain high expression levels of the pluripotency markers TRA-1-60, TRA-1-81, Oct-3/4 and SSEA-4, and readily differentiate into ectoderm, mesoderm and endoderm. Importantly, the medium plays an integral role in establishing a cGMP-compliant process for the manufacturing of hiPSCs that can be used for generation of clinically relevant cell types for cell replacement therapy applications.

Sexual behaviour and sexually transmitted infections in sexually transmitted infection clinic attendees in the Netherlands, 2007-2011.

PubMed

de Coul, E L M Op; Warning, T D; Koedijk, F D H

2014-01-01

High annual figures of sexually transmitted infections (STIs) are diagnosed in the Netherlands despite significant efforts to control them. Herein, we analyse trends and determinants of STI diagnoses, co-infections, and sexual risks among visitors of 26 STI clinics between 2007 and 2011. We recorded increased positivity rates of STIs (chlamydia, syphilis, gonorrhoea, and/or HIV) in women and heterosexual men up to 12.6% and 13.4%, respectively, in 2011, while rates in men having sex with men (MSM) were stable but high (18.8%) through the documented years. Younger age, origin from Surinam/Antilles, history of previous STI, multiple partners, or a previous notification are the identified risk factors for an STI in this population. Known HIV-infected men (MSM and heterosexuals) were at highest risk for co-infections (relative rate heterosexual men: 15.6; MSM: 11.6). STI positivity rates remained high (MSM) or increased over time (women and heterosexual men), a fact that highlights the importance of continuing STI prevention. Most importantly, the very high STI co-infection rates among HIV-positive men requires intensified STI reduction strategies to put an end to the vicious circle of re-infection and spread of HIV and other STIs.

Development and validation of an HPLC–MS/MS method to determine clopidogrel in human plasma

PubMed Central

Liu, Gangyi; Dong, Chunxia; Shen, Weiwei; Lu, Xiaopei; Zhang, Mengqi; Gui, Yuzhou; Zhou, Qinyi; Yu, Chen

2015-01-01

A quantitative method for clopidogrel using online-SPE tandem LC–MS/MS was developed and fully validated according to the well-established FDA guidelines. The method achieves adequate sensitivity for pharmacokinetic studies, with lower limit of quantifications (LLOQs) as low as 10 pg/mL. Chromatographic separations were performed on reversed phase columns Kromasil Eternity-2.5-C18-UHPLC for both methods. Positive electrospray ionization in multiple reaction monitoring (MRM) mode was employed for signal detection and a deuterated analogue (clopidogrel-d4) was used as internal standard (IS). Adjustments in sample preparation, including introduction of an online-SPE system proved to be the most effective method to solve the analyte back-conversion in clinical samples. Pooled clinical samples (two levels) were prepared and successfully used as real-sample quality control (QC) in the validation of back-conversion testing under different conditions. The result showed that the real samples were stable in room temperature for 24 h. Linearity, precision, extraction recovery, matrix effect on spiked QC samples and stability tests on both spiked QCs and real sample QCs stored in different conditions met the acceptance criteria. This online-SPE method was successfully applied to a bioequivalence study of 75 mg single dose clopidogrel tablets in 48 healthy male subjects. PMID:26904399

A Guide to Approaching Regulatory Considerations for Lentiviral-Mediated Gene Therapies

PubMed Central

White, Michael; Whittaker, Roger; Gándara, Carolina; Stoll, Elizabeth A.

2017-01-01

Lentiviral vectors are increasingly the gene transfer tool of choice for gene or cell therapies, with multiple clinical investigations showing promise for this viral vector in terms of both safety and efficacy. The third-generation vector system is well characterized, effectively delivers genetic material and maintains long-term stable expression in target cells, delivers larger amounts of genetic material than other methods, is nonpathogenic, and does not cause an inflammatory response in the recipient. This report aims to help academic scientists and regulatory managers negotiate the governance framework to achieve successful translation of a lentiviral vector-based gene therapy. The focus is on European regulations and how they are administered in the United Kingdom, although many of the principles will be similar for other regions, including the United States. The report justifies the rationale for using third-generation lentiviral vectors to achieve gene delivery for in vivo and ex vivo applications; briefly summarizes the extant regulatory guidance for gene therapies, categorized as advanced therapeutic medicinal products (ATMPs); provides guidance on specific regulatory issues regarding gene therapies; presents an overview of the key stakeholders to be approached when pursuing clinical trials authorization for an ATMP; and includes a brief catalogue of the documentation required to submit an application for regulatory approval of a new gene therapy. PMID:28817344

Modal control of an oblique wing aircraft

NASA Technical Reports Server (NTRS)

Phillips, James D.

1989-01-01

A linear modal control algorithm is applied to the NASA Oblique Wing Research Aircraft (OWRA). The control law is evaluated using a detailed nonlinear flight simulation. It is shown that the modal control law attenuates the coupling and nonlinear aerodynamics of the oblique wing and remains stable during control saturation caused by large command inputs or large external disturbances. The technique controls each natural mode independently allowing single-input/single-output techniques to be applied to multiple-input/multiple-output systems.

The Effects of Towfish Motion on Sidescan Sonar Images: Extension to a Multiple-Beam Device

DTIC Science & Technology

1994-02-01

simulation, the raw simulated sidescan image is formed from pixels G , which are the sum of energies E,", assigned to the nearest range- bin k as noted in...for stable motion at constant velocity V0, are applied to (divided into) the G ,, and the simulated sidescan image is ready to display. Maximal energy...limitation is likely to apply to all multiple-beam sonais of similar construction. The yaw correction was incorporated in the MBEAM model by an

Designing Biomedical Informatics Infrastructure for Clinical and Translational Science

ERIC Educational Resources Information Center

La Paz Lillo, Ariel Isaac

2009-01-01

Clinical and Translational Science (CTS) rests largely on information flowing smoothly at multiple levels, in multiple directions, across multiple locations. Biomedical Informatics (BI) is seen as a backbone that helps to manage information flows for the translation of knowledge generated and stored in silos of basic science into bedside…

Multiplexed Quantitation of Endogenous Proteins in Dried Blood Spots by Multiple Reaction Monitoring - Mass Spectrometry

PubMed Central

Chambers, Andrew G.; Percy, Andrew J.; Yang, Juncong; Camenzind, Alexander G.; Borchers, Christoph H.

2013-01-01

Dried blood spot (DBS) sampling, coupled with multiple reaction monitoring mass spectrometry (MRM-MS), is a well-established approach for quantifying a wide range of small molecule biomarkers and drugs. This sampling procedure is simpler and less-invasive than those required for traditional plasma or serum samples enabling collection by minimally trained personnel. Many analytes are stable in the DBS format without refrigeration, which reduces the cost and logistical challenges of sample collection in remote locations. These advantages make DBS sample collection desirable for advancing personalized medicine through population-wide biomarker screening. Here we expand this technology by demonstrating the first multiplexed method for the quantitation of endogenous proteins in DBS samples. A panel of 60 abundant proteins in human blood was targeted by monitoring proteotypic tryptic peptides and their stable isotope-labeled analogs by MRM. Linear calibration curves were obtained for 40 of the 65 peptide targets demonstrating multiple proteins can be quantitatively extracted from DBS collection cards. The method was also highly reproducible with a coefficient of variation of <15% for all 40 peptides. Overall, this assay quantified 37 proteins spanning a range of more than four orders of magnitude in concentration within a single 25 min LC/MRM-MS analysis. The protein abundances of the 33 proteins quantified in matching DBS and whole blood samples showed an excellent correlation, with a slope of 0.96 and an R2 value of 0.97. Furthermore, the measured concentrations for 80% of the proteins were stable for at least 10 days when stored at −20 °C, 4 °C and 37 °C. This work represents an important first step in evaluating the integration of DBS sampling with highly-multiplexed MRM for quantitation of endogenous proteins. PMID:23221968

ERP correlates of word production predictors in picture naming: a trial by trial multiple regression analysis from stimulus onset to response.

PubMed

Valente, Andrea; Bürki, Audrey; Laganaro, Marina

2014-01-01

A major effort in cognitive neuroscience of language is to define the temporal and spatial characteristics of the core cognitive processes involved in word production. One approach consists in studying the effects of linguistic and pre-linguistic variables in picture naming tasks. So far, studies have analyzed event-related potentials (ERPs) during word production by examining one or two variables with factorial designs. Here we extended this approach by investigating simultaneously the effects of multiple theoretical relevant predictors in a picture naming task. High density EEG was recorded on 31 participants during overt naming of 100 pictures. ERPs were extracted on a trial by trial basis from picture onset to 100 ms before the onset of articulation. Mixed-effects regression models were conducted to examine which variables affected production latencies and the duration of periods of stable electrophysiological patterns (topographic maps). Results revealed an effect of a pre-linguistic variable, visual complexity, on an early period of stable electric field at scalp, from 140 to 180 ms after picture presentation, a result consistent with the proposal that this time period is associated with visual object recognition processes. Three other variables, word Age of Acquisition, Name Agreement, and Image Agreement influenced response latencies and modulated ERPs from ~380 ms to the end of the analyzed period. These results demonstrate that a topographic analysis fitted into the single trial ERPs and covering the entire processing period allows one to associate the cost generated by psycholinguistic variables to the duration of specific stable electrophysiological processes and to pinpoint the precise time-course of multiple word production predictors at once.

Determining the optimal number of independent components for reproducible transcriptomic data analysis.

PubMed

Kairov, Ulykbek; Cantini, Laura; Greco, Alessandro; Molkenov, Askhat; Czerwinska, Urszula; Barillot, Emmanuel; Zinovyev, Andrei

2017-09-11

Independent Component Analysis (ICA) is a method that models gene expression data as an action of a set of statistically independent hidden factors. The output of ICA depends on a fundamental parameter: the number of components (factors) to compute. The optimal choice of this parameter, related to determining the effective data dimension, remains an open question in the application of blind source separation techniques to transcriptomic data. Here we address the question of optimizing the number of statistically independent components in the analysis of transcriptomic data for reproducibility of the components in multiple runs of ICA (within the same or within varying effective dimensions) and in multiple independent datasets. To this end, we introduce ranking of independent components based on their stability in multiple ICA computation runs and define a distinguished number of components (Most Stable Transcriptome Dimension, MSTD) corresponding to the point of the qualitative change of the stability profile. Based on a large body of data, we demonstrate that a sufficient number of dimensions is required for biological interpretability of the ICA decomposition and that the most stable components with ranks below MSTD have more chances to be reproduced in independent studies compared to the less stable ones. At the same time, we show that a transcriptomics dataset can be reduced to a relatively high number of dimensions without losing the interpretability of ICA, even though higher dimensions give rise to components driven by small gene sets. We suggest a protocol of ICA application to transcriptomics data with a possibility of prioritizing components with respect to their reproducibility that strengthens the biological interpretation. Computing too few components (much less than MSTD) is not optimal for interpretability of the results. The components ranked within MSTD range have more chances to be reproduced in independent studies.

Chronic neural probe for simultaneous recording of single-unit, multi-unit, and local field potential activity from multiple brain sites

NASA Astrophysics Data System (ADS)

Pothof, F.; Bonini, L.; Lanzilotto, M.; Livi, A.; Fogassi, L.; Orban, G. A.; Paul, O.; Ruther, P.

2016-08-01

Objective. Drug resistant focal epilepsy can be treated by resecting the epileptic focus requiring a precise focus localisation using stereoelectroencephalography (SEEG) probes. As commercial SEEG probes offer only a limited spatial resolution, probes of higher channel count and design freedom enabling the incorporation of macro and microelectrodes would help increasing spatial resolution and thus open new perspectives for investigating mechanisms underlying focal epilepsy and its treatment. This work describes a new fabrication process for SEEG probes with materials and dimensions similar to clinical probes enabling recording single neuron activity at high spatial resolution. Approach. Polyimide is used as a biocompatible flexible substrate into which platinum electrodes and leads are integrated with a minimal feature size of 5 μm. The polyimide foils are rolled into the cylindrical probe shape at a diameter of 0.8 mm. The resulting probe features match those of clinically approved devices. Tests in saline solution confirmed the probe stability and functionality. Probes were implanted into the brain of one monkey (Macaca mulatta), trained to perform different motor tasks. Suitable configurations including up to 128 electrode sites allow the recording of task-related neuronal signals. Main results. Probes with 32 and 64 electrode sites were implanted in the posterior parietal cortex. Local field potentials and multi-unit activity were recorded as early as one hour after implantation. Stable single-unit activity was achieved for up to 26 days after implantation of a 64-channel probe. All recorded signals showed modulation during task execution. Significance. With the novel probes it is possible to record stable biologically relevant data over a time span exceeding the usual time needed for epileptic focus localisation in human patients. This is the first time that single units are recorded along cylindrical polyimide probes chronically implanted 22 mm deep into the brain of a monkey, which suggests the potential usefulness of this probe for human applications.

Language growth in children with heterogeneous language disorders: a population study.

PubMed

Norbury, Courtenay Frazier; Vamvakas, George; Gooch, Debbie; Baird, Gillian; Charman, Tony; Simonoff, Emily; Pickles, Andrew

2017-10-01

Language development has been characterised by significant individual stability from school entry. However, the extent to which trajectories of language growth vary in children with language disorder as a function of co-occurring developmental challenges is a question of theoretical import, with implications for service provision. SCALES employed a population-based survey design with sample weighting procedures to estimate growth in core language skills over the first three years of school. A stratified sample (n = 529) received comprehensive assessment of language, nonverbal IQ, and social, emotional and behavioural difficulties at 5-6 years of age and 95% of the sample (n = 499) were assessed again at ages 7-8. Language growth was measured using both raw and standard scores in children with typical development, children with language disorder of unknown origin, and children with language disorders associated with a known clinical condition and/or intellectual disability. Overall, language was stable at the individual level (estimated ICC = 0.95) over the first three years of school. Linear mixed effects models highlighted steady growth in language raw scores across all three groups, including those with multiple developmental challenges. There was little evidence, however, that children with language disorders were narrowing the gap with peers (z-scores). Adjusted models indicated that while nonverbal ability, socioeconomic status and social, emotional and behavioural deficits predicted initial language score (intercept), none predicted language growth (slope). These findings corroborate previous studies suggesting stable language trajectories after ages 5-6 years, but add considerably to previous work by demonstrating similar developmental patterns in children with additional nonverbal cognitive deficits, social, emotional, and behavioural challenges, social disadvantage or clinical diagnoses. © 2017 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.

Determination of suvorexant in human plasma using 96-well liquid-liquid extraction and HPLC with tandem mass spectrometric detection.

PubMed

Breidinger, S A; Simpson, R C; Mangin, E; Woolf, E J

2015-10-01

A method, using liquid chromatography with tandem mass spectrometric detection (LC-MS/MS), was developed for the determination of suvorexant (MK-4305, Belsomra(®)), a selective dual orexin receptor antagonist for the treatment insomnia, in human plasma over the concentration range of 1-1000ng/mL. Stable isotope labeled (13)C(2)H3-suvorexant was used as an internal standard. The sample preparation procedure utilized liquid-liquid extraction, in the 96-well format, of a 100μL plasma sample with methyl t-butyl ether. The compounds were chromatographed under isocratic conditions on a Waters dC18 (50×2.1mm, 3μm) column with a mobile phase consisting of 30/70 (v/v %) 10mM ammonium formate, pH3/acetonitrile at a flow rate of 0.3mL/min. Multiple reaction monitoring of the precursor-to-product ion pairs for suvorexant (m/z 451→186) and (13)C(2)H3-suvorexant (m/z 455→190) on an Applied Biosystems API 4000 tandem mass spectrometer was used for quantitation. Intraday assay precision, assessed in six different lots of control plasma, was within 10% CV at all concentrations, while assay accuracy ranged from 95.6 to 105.0% of nominal. Quality control (QC) samples in plasma were stored at -20°C. Initial within day analysis of QCs after one freeze-thaw cycle showed accuracy within 9.5% of nominal with precision (CV) of 6.7% or less. The plasma QC samples were demonstrated to be stable for up to 25 months at -20°C. The method described has been used to support clinical studies during Phase I through III of clinical development. Copyright © 2015 Elsevier B.V. All rights reserved.

"Long-term stability of stimulating spiral nerve cuff electrodes on human peripheral nerves".

PubMed

Christie, Breanne P; Freeberg, Max; Memberg, William D; Pinault, Gilles J C; Hoyen, Harry A; Tyler, Dustin J; Triolo, Ronald J

2017-07-11

Electrical stimulation of the peripheral nerves has been shown to be effective in restoring sensory and motor functions in the lower and upper extremities. This neural stimulation can be applied via non-penetrating spiral nerve cuff electrodes, though minimal information has been published regarding their long-term performance for multiple years after implantation. Since 2005, 14 human volunteers with cervical or thoracic spinal cord injuries, or upper limb amputation, were chronically implanted with a total of 50 spiral nerve cuff electrodes on 10 different nerves (mean time post-implant 6.7 ± 3.1 years). The primary outcome measures utilized in this study were muscle recruitment curves, charge thresholds, and percent overlap of recruited motor unit populations. In the eight recipients still actively involved in research studies, 44/45 of the spiral contacts were still functional. In four participants regularly studied over the course of 1 month to 10.4 years, the charge thresholds of the majority of individual contacts remained stable over time. The four participants with spiral cuffs on their femoral nerves were all able to generate sufficient moment to keep the knees locked during standing after 2-4.5 years. The dorsiflexion moment produced by all four fibular nerve cuffs in the active participants exceeded the value required to prevent foot drop, but no tibial nerve cuffs were able to meet the plantarflexion moment that occurs during push-off at a normal walking speed. The selectivity of two multi-contact spiral cuffs was examined and both were still highly selective for different motor unit populations for up to 6.3 years after implantation. The spiral nerve cuffs examined remain functional in motor and sensory neuroprostheses for 2-11 years after implantation. They exhibit stable charge thresholds, clinically relevant recruitment properties, and functional muscle selectivity. Non-penetrating spiral nerve cuff electrodes appear to be a suitable option for long-term clinical use on human peripheral nerves in implanted neuroprostheses.

Chronic neural probe for simultaneous recording of single-unit, multi-unit, and local field potential activity from multiple brain sites.

PubMed

Pothof, F; Bonini, L; Lanzilotto, M; Livi, A; Fogassi, L; Orban, G A; Paul, O; Ruther, P

2016-08-01

Drug resistant focal epilepsy can be treated by resecting the epileptic focus requiring a precise focus localisation using stereoelectroencephalography (SEEG) probes. As commercial SEEG probes offer only a limited spatial resolution, probes of higher channel count and design freedom enabling the incorporation of macro and microelectrodes would help increasing spatial resolution and thus open new perspectives for investigating mechanisms underlying focal epilepsy and its treatment. This work describes a new fabrication process for SEEG probes with materials and dimensions similar to clinical probes enabling recording single neuron activity at high spatial resolution. Polyimide is used as a biocompatible flexible substrate into which platinum electrodes and leads are integrated with a minimal feature size of 5 μm. The polyimide foils are rolled into the cylindrical probe shape at a diameter of 0.8 mm. The resulting probe features match those of clinically approved devices. Tests in saline solution confirmed the probe stability and functionality. Probes were implanted into the brain of one monkey (Macaca mulatta), trained to perform different motor tasks. Suitable configurations including up to 128 electrode sites allow the recording of task-related neuronal signals. Probes with 32 and 64 electrode sites were implanted in the posterior parietal cortex. Local field potentials and multi-unit activity were recorded as early as one hour after implantation. Stable single-unit activity was achieved for up to 26 days after implantation of a 64-channel probe. All recorded signals showed modulation during task execution. With the novel probes it is possible to record stable biologically relevant data over a time span exceeding the usual time needed for epileptic focus localisation in human patients. This is the first time that single units are recorded along cylindrical polyimide probes chronically implanted 22 mm deep into the brain of a monkey, which suggests the potential usefulness of this probe for human applications.

Cognitive processes during acute psychosis: the role of heightened responsibility and catastrophic misinterpretations.

PubMed

Luzón, Olga; Harrop, Chris; Nolan, Fiona

2009-07-01

This study investigated the role of cognitive mechanisms underlying obsessive compulsive and panic disorders in psychosis, and in particular, their possible contributions to acute psychosis. A total of 90 participants were recruited comprising three equal-size groups, including two clinical groups (acute and stable) and one non-clinical matched control group. Symptom severity and distress was assessed using the PSYRATS, and questionnaire measures of anxiety and obsessive beliefs were administered to all participants. Individuals with a diagnosis of psychosis reported significantly higher levels of obsessional beliefs and anxiety sensitivity than the non-clinical group. Furthermore, acutely psychotic patients reported a significantly higher sense of responsibility and catastrophic misinterpretation than the stable psychiatric controls, and than samples of OCD and GAD patients. Results suggest that these anxiety processes are particularly important during acute psychotic episodes, beyond the reported comorbidity. The theoretical and clinical implications of these findings, the limitations of the methodology employed, and suggestions for future research are discussed.

Clinic flow for STI, HIV, and TB patients in an urban infectious disease clinic offering point-of-care testing services in Durban, South Africa.

PubMed

Stime, Katrina J; Garrett, Nigel; Sookrajh, Yukteshwar; Dorward, Jienchi; Dlamini, Ntuthu; Olowolagba, Ayo; Sharma, Monisha; Barnabas, Ruanne V; Drain, Paul K

2018-05-11

Many clinics in Southern Africa have long waiting times. The implementation of point-of-care (POC) tests to accelerate diagnosis and improve clinical management in resource-limited settings may improve or worsen clinic flow and waiting times. The objective of this study was to describe clinic flow with special emphasis on the impact of POC testing at a large urban public healthcare clinic in Durban, South Africa. We used time and motion methods to directly observe patients and practitioners. We created patient flow maps and recorded individual patient waiting and consultation times for patients seeking STI, TB, or HIV care. We conducted semi-structured interviews with 20 clinic staff to ascertain staff opinions on clinic flow and POC test implementation. Among 121 observed patients, the total number of queues ranged from 4 to 7 and total visit times ranged from 0:14 (hours:minutes) to 7:38. Patients waited a mean of 2:05 for standard-of-care STI management, and approximately 4:56 for STI POC diagnostic testing. Stable HIV patients who collected antiretroviral therapy refills waited a mean of 2:42 in the standard queue and 2:26 in the fast-track queue. A rapid TB test on a small sample of patients with the Xpert MTB/RIF assay and treatment initiation took a mean of 6:56, and 40% of patients presenting with TB-related symptoms were asked to return for an additional clinic visit to obtain test results. For all groups, the mean clinical assessment time with a nurse or physician was 7 to 9 min, which accounted for 2 to 6% of total visit time. Staff identified poor clinic flow and personnel shortages as areas of concern that may pose challenges to expanding POC tests in the current clinic environment. This busy urban clinic had multiple patient queues, long clinical visits, and short clinical encounters. Although POC testing ensured patients received a diagnosis sooner, it more than doubled the time STI patients spent at the clinic and did not result in same-day diagnosis for all patients screened for TB. Further research on implementing POC testing efficiently into care pathways is required to make these promising assays a success.

Landscape of Microsatellite Instability Across 39 Cancer Types.

PubMed

Bonneville, Russell; Krook, Melanie A; Kautto, Esko A; Miya, Jharna; Wing, Michele R; Chen, Hui-Zi; Reeser, Julie W; Yu, Lianbo; Roychowdhury, Sameek

2017-01-01

Microsatellite instability (MSI) is a pattern of hypermutation that occurs at genomic microsatellites and is caused by defects in the mismatch repair system. Mismatch repair deficiency that leads to MSI has been well described in several types of human cancer, most frequently in colorectal, endometrial, and gastric adenocarcinomas. MSI is known to be both predictive and prognostic, especially in colorectal cancer; however, current clinical guidelines only recommend MSI testing for colorectal and endometrial cancers. Therefore, less is known about the prevalence and extent of MSI among other types of cancer. Using our recently published MSI-calling software, MANTIS, we analyzed whole-exome data from 11,139 tumor-normal pairs from The Cancer Genome Atlas and Therapeutically Applicable Research to Generate Effective Treatments projects and external data sources across 39 cancer types. Within a subset of these cancer types, we assessed mutation burden, mutational signatures, and somatic variants associated with MSI. We identified MSI in 3.8% of all cancers assessed-present in 27 of tumor types-most notably adrenocortical carcinoma (ACC), cervical cancer (CESC), and mesothelioma, in which MSI has not yet been well described. In addition, MSI-high ACC and CESC tumors were observed to have a higher average mutational burden than microsatellite-stable ACC and CESC tumors. We provide evidence of as-yet-unappreciated MSI in several types of cancer. These findings support an expanded role for clinical MSI testing across multiple cancer types as patients with MSI-positive tumors are predicted to benefit from novel immunotherapies in clinical trials.

Quantification of cytokine mRNA in peripheral blood mononuclear cells using branched DNA (bDNA) technology.

PubMed

Shen, L P; Sheridan, P; Cao, W W; Dailey, P J; Salazar-Gonzalez, J F; Breen, E C; Fahey, J L; Urdea, M S; Kolberg, J A

1998-06-01

Changes in the patterns of cytokine expression are thought to be of central importance in human infectious and inflammatory diseases. As such, there is a need for precise, reproducible assays for quantification of cytokine mRNA that are amenable to routine use in a clinical setting. In this report, we describe the design and performance of a branched DNA (bDNA) assay for the direct quantification of multiple cytokine mRNA levels in peripheral blood mononuclear cells (PBMCs). Oligonucleotide target probe sets were designed for several human cytokines, including TNFalpha, IL-2, IL-4, IL-6, IL-10, and IFNgamma. The bDNA assay yielded highly reproducible quantification of cytokine mRNAs, exhibited a broad linear dynamic range of over 3-log10, and showed a sensitivity sufficient to measure at least 3000 molecules. The potential clinical utility of the bDNA assay was explored by measuring cytokine mRNA levels in PBMCs from healthy and immunocompromised individuals. Cytokine expression levels in PBMCs from healthy blood donors were found to remain relatively stable over a one-month period of time. Elevated levels of IFNgamma mRNA were detected in PBMCs from HIV-1 seropositive individuals, but no differences in mean levels of TNFalpha or IL-6 mRNA were detected between seropositive and seronegative individuals. By providing a reproducible method for quantification of low abundance transcripts in clinical specimens, the bDNA assay may be useful for studies addressing the role of cytokine expression in disease.

Distribution, function and physiological role of melatonin in the lower gut

PubMed Central

Chen, Chun-Qiu; Fichna, Jakub; Bashashati, Mohammad; Li, Yong-Yu; Storr, Martin

2011-01-01

Melatonin is a hormone with endocrine, paracrine and autocrine actions. It is involved in the regulation of multiple functions, including the control of the gastrointestinal (GI) system under physiological and pathophysiological conditions. Since the gut contains at least 400 times more melatonin than the pineal gland, a review of the functional importance of melatonin in the gut seems useful, especially in the context of recent clinical trials. Melatonin exerts its physiological effects through specific membrane receptors, named melatonin-1 receptor (MT1), MT2 and MT3. These receptors can be found in the gut and their involvement in the regulation of GI motility, inflammation and pain has been reported in numerous basic and clinical studies. Stable levels of melatonin in the lower gut that are unchanged following a pinealectomy suggest local synthesis and, furthermore, implicate physiological importance of endogenous melatonin in the GI tract. Presently, only a small number of human studies report possible beneficial and also possible harmful effects of melatonin in case reports and clinical trials. These human studies include patients with lower GI diseases, especially patients with irritable bowel syndrome, inflammatory bowel disease and colorectal cancer. In this review, we summarize the presently available information on melatonin effects in the lower gut and discuss available in vitro and in vivo data. We furthermore aim to evaluate whether melatonin may be useful in future treatment of symptoms or diseases involving the lower gut. PMID:22025877

Cevipabulin (TTI-237): preclinical and clinical results for a novel antimicrotubule agent.

PubMed

Ayral-Kaloustian, S; Zhang, N; Beyer, C

2009-09-01

Antimitotic agents are among the most effective drugs for the treatment of solid tumors and metastatic cancer. These drugs promote cell death by interfering with the crucial structural and regulatory function of microtubules in cells. Most of the agents of clinical relevance are natural products or semisynthetic derivatives thereof, and they fall into two major classes: microtubule stabilizers such as the taxanes, which enhance tubulin polymerization, and microtubule destabilizers such as the Vinca alkaloids, which lead to the depolymerization of existing microtubules. While these drugs are effective in inhibiting the progression of certain types of tumors, their utility is limited in part by incomplete tumor responses and/or significant side effects. In addition, inherent resistance is encountered in many tumor types, or acquired resistance may occur as a result of multiple cycles of therapy. Cevipabulin (TTI-237) is a novel, small synthetic molecule with an unusual biological mode of action. It appears to bind at the vinca site, but exhibits some properties similar to those of taxane-site ligands, such as enhancing tubulin polymerization. The compound works against a variety of tumors, including those resistant to paclitaxel and vincristine. Furthermore, cevipabulin is stable and water-soluble, and can be administered i.v. or p.o. in saline. It can be synthesized in bulk quantities efficiently. Based on these properties, cevipabulin was selected for clinical development. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

A Theoretical Model of Resource-Oriented Music Therapy with Informal Hospice Caregivers during Pre-Bereavement.

PubMed

Potvin, Noah; Bradt, Joke; Ghetti, Claire

2018-03-09

Over the past decade, caregiver pre-bereavement has received increased scholarly and clinical attention across multiple healthcare fields. Pre-bereavement represents a nascent area for music therapy to develop best practices in and an opportunity to establish clinical relevancy in the interdisciplinary team. This study was an exploratory inquiry into the role of music therapy with pre-bereaved informal hospice caregivers. This study intended to articulate (a) what pre-bereavement needs are present for informal hospice caregivers, (b) which of those needs were addressed in music, and (c) the process by which music therapy addressed those needs. A constructivist grounded theory methodology using situational analysis was used. We interviewed 14 currently bereaved informal hospice caregivers who had participated in music therapy with the care recipient. Analysis resulted in a theoretical model of resource-oriented music therapy promoting caregiver resilience. The resource, caregivers' stable caring relationships with care recipients through their pre-illness identities (i.e., spouse, parent, or child), is amplified through music therapy. Engagement with this resource mediates the risk of increased care burden and results in resilience fostering purposefulness and value in caregiving. Resource-oriented music therapy provides a unique clinical avenue for supporting caregivers through pre-bereavement, and was acknowledged by caregivers as a unique and integral hospice service. Within this model, caregivers are better positioned to develop meaning from the experience of providing care through the death of a loved one.

In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: Evidence from clinical, cellular and molecular parameters.

PubMed

Luque, Raul M; Sampedro-Nuñez, Miguel; Gahete, Manuel D; Ramos-Levi, Ana; Ibáñez-Costa, Alejandro; Rivero-Cortés, Esther; Serrano-Somavilla, Ana; Adrados, Magdalena; Culler, Michael D; Castaño, Justo P; Marazuela, Mónica

2015-08-14

Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1-ghrelin and truncated-GHSR1b splicing variants can promote development/progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value.

In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: Evidence from clinical, cellular and molecular parameters

PubMed Central

Gahete, Manuel D.; Ramos-Levi, Ana; Ibáñez-Costa, Alejandro; Rivero-Cortés, Esther; Serrano-Somavilla, Ana; Adrados, Magdalena; Culler, Michael D.; Castaño, Justo P.; Marazuela, Mónica

2015-01-01

Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1-ghrelin and truncated-GHSR1b splicing variants can promote development/progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value. PMID:26124083

Short, multiple-stranded β-hairpin peptides have antimicrobial potency with high selectivity and salt resistance.

PubMed

Chou, Shuli; Shao, Changxuan; Wang, Jiajun; Shan, Anshan; Xu, Lin; Dong, Na; Li, Zhongyu

2016-01-01

The β-hairpin structure has been proposed to exhibit potent antimicrobial properties with low cytotoxicity, thus, multiple β-hairpin structures have been proved to be highly stable in structures containing tightly packed hydrophobic cores. The aim of this study was to develop peptide-based synthetic strategies for generating short, but effective AMPs as inexpensive antimicrobial agents. Multiple-stranded β-hairpin peptides with the same β-hairpin unit, (WRXxRW)n where n=1, 2, 3, or 4 and Xx represent the turn sequence, were synthesized, and their potential as antimicrobial agents was evaluated. Owning to the tightly packed hydrophobic core and paired Trp of this multiple-stranded β-hairpin structure, all the 12-residues peptides exhibited high cell selectivity towards bacterial cells over human red blood cells (hRBCs), and the peptide W2 exhibited stronger antimicrobial activities with the MIC values of 2-8μM against various tested bacteria. Not only that, but W2 also showed obvious synergy with streptomycin and chloramphenicol against Escherichia coli, and displayed synergy with ciprofloxacin against Staphylococcus aureus with the FICI values ⩽0.5. Fluorescence spectroscopy and electron microscopy analyses indicated that W2 kills microbial cells by permeabilizing the cell membrane and damaging membrane integrity. Collectively, based on the multiple β-hairpin peptides, the ability to develop libraries of short and effective peptides will be a powerful approach to the discovery of novel antimicrobial agents. We successfully screened a peptide W2 ((WRPGRW)2) from a series of multiple-stranded β-hairpin antimicrobial peptides based on the "S-shaped" motif that induced the formation of a globular structure, and Trp zipper was used to replace the disulfide bonds to reduce the cost of production. This novel structure applied to AMPs improved cell selectivity and salt stability. The findings of this study will promote the development of peptide-based antimicrobial biomaterials. Further exploration of these AMPs will allow for diverse biotechnological and clinical applications such as biomedical coating, food storaging, and animal feeding. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

A Study on Lebesgue Decomposition of Measures Induced by Stable Processes.

DTIC Science & Technology

1987-11-01

multiple Wiener integrals. Dec. 86. 171. J. Nolan, Local properties of index- O stable fields. Dec. 86. Ann. Probability. to appear. 172. R . Menich and... R ). Ac ? RER\\A;A( A)= o - Thus a SaS process will have admissible translates if it is a mixture of Gaussian processes whose RKHS’s have a common part...trarslates of X, namely -€, V"" ",-". -% LA ? ’,& t,-Jr. , -I. P U n RKHS( R ) c. .I AC3? RER\\AA(^)= o Conversely, if s is a singular translate of a.e

Fat embolism syndrome after nailing an isolated open tibial fracture in a stable patient: a case report.

PubMed

Aparicio, Gustavo; Soler, Isabel; López-Durán, Luis

2014-04-14

Fat embolism syndrome is a potentially fatal complication of long bone fractures. It is usually seen in the context of polytrauma or a femoral fracture. There are few reports of fat embolism syndrome occurring after isolated long bone fractures other than those of the femur. We describe a case of fat embolism syndrome in a 33-year-old Caucasian man. He was being seen for an isolated Gustilo's grade II open tibial fracture. He was deemed clinically stable, so we proceeded to treat the fracture with intramedullary reamed nailing. He developed fat embolism syndrome intraoperatively and was treated successfully. This case caused us to question the use of injury severity scoring for isolated long bone fractures. It suggests that parameters that have been described in the literature other than that the patient is apparently clinically stable should be used to establish the best time for nailing a long bone fracture, thereby improving patient safety.

Fat embolism syndrome after nailing an isolated open tibial fracture in a stable patient: a case report

PubMed Central

2014-01-01

Background Fat embolism syndrome is a potentially fatal complication of long bone fractures. It is usually seen in the context of polytrauma or a femoral fracture. There are few reports of fat embolism syndrome occurring after isolated long bone fractures other than those of the femur. Case presentation We describe a case of fat embolism syndrome in a 33-year-old Caucasian man. He was being seen for an isolated Gustilo’s grade II open tibial fracture. He was deemed clinically stable, so we proceeded to treat the fracture with intramedullary reamed nailing. He developed fat embolism syndrome intraoperatively and was treated successfully. Conclusion This case caused us to question the use of injury severity scoring for isolated long bone fractures. It suggests that parameters that have been described in the literature other than that the patient is apparently clinically stable should be used to establish the best time for nailing a long bone fracture, thereby improving patient safety. PMID:24731759

An Indirect System Identification Technique for Stable Estimation of Continuous-Time Parameters of the Vestibulo-Ocular Reflex (VOR)

NASA Technical Reports Server (NTRS)

Kukreja, Sunil L.; Wallin, Ragnar; Boyle, Richard D.

2013-01-01

The vestibulo-ocular reflex (VOR) is a well-known dual mode bifurcating system that consists of slow and fast modes associated with nystagmus and saccade, respectively. Estimation of continuous-time parameters of nystagmus and saccade models are known to be sensitive to estimation methodology, noise and sampling rate. The stable and accurate estimation of these parameters are critical for accurate disease modelling, clinical diagnosis, robotic control strategies, mission planning for space exploration and pilot safety, etc. This paper presents a novel indirect system identification method for the estimation of continuous-time parameters of VOR employing standardised least-squares with dual sampling rates in a sparse structure. This approach permits the stable and simultaneous estimation of both nystagmus and saccade data. The efficacy of this approach is demonstrated via simulation of a continuous-time model of VOR with typical parameters found in clinical studies and in the presence of output additive noise.

Overwintering Habitats of Migratory Juvenile American Shad in Chesapeake Bay

EPA Science Inventory

We describe overwintering habitats of age-0 American shad in the lower Chesapeake Bay estuary through analyses of multiple, complementary data sets, including bottom-trawls of the Virginia portion of Chesapeake Bay and its tributaries, stable isotope analysis of American shad a...

A study of natural circulation in the evaporator of a horizontal-tube heat recovery steam generator

NASA Astrophysics Data System (ADS)

Roslyakov, P. V.; Pleshanov, K. A.; Sterkhov, K. V.

2014-07-01

Results obtained from investigations of stable natural circulation in an intricate circulation circuit with a horizontal layout of the tubes of evaporating surface having a negative useful head are presented. The possibility of making a shift from using multiple forced circulation organized by means of a circulation pump to natural circulation in vertical heat recovery steam generator is estimated. Criteria for characterizing the performance reliability and efficiency of a horizontal evaporator with negative useful head are proposed. The influence of various design solutions on circulation robustness is considered. With due regard of the optimal parameters, the most efficient and least costly methods are proposed for achieving more stable circulation in a vertical heat recovery steam generator when a shift is made from multiple forced to natural circulation. A procedure for calculating the circulation parameters and an algorithm for checking evaporator performance reliability are developed, and recommendations for the design of heat recovery steam generator, nonheated parts of natural circulation circuit, and evaporating surface are suggested.

Correlating Polymer Crystals via Self-Induced Nucleation

NASA Astrophysics Data System (ADS)

Reiter, Günter

Crystallizable polymers often form multiple stacks of uniquely oriented lamellae, which have good registry despite being separated by amorphous fold surfaces. These correlations require multiple synchronized, yet unidentified, nucleation events. Here, we demonstrate that in thin films of isotactic polystyrene, the probability of generating correlated lamellae is controlled by the branched morphology of a single primary lamella. The nucleation density ns of secondary lamellae is found to be dependent on the width of the branches of the primary lamella. This relation is independent of molecular weight, crystallization temperature, and film thickness. We propose a nucleation mechanism based on the insertion of polymers into a branched primary lamellar crystal. Even in single crystals, characterized by faceted structures with a well-defined envelope reflecting the underlying crystal unit cell, polymers are folded and thus in a meta-stable state. Annealing such meta-stable single crystals allowed to unveil the initial morphological framework of a dendritic single crystal, i.e. the initial stages of growth.

Reliability of psychophysiological responses across multiple motion sickness stimulation tests

NASA Technical Reports Server (NTRS)

Stout, C. S.; Toscano, W. B.; Cowings, P. S.

1995-01-01

Although there is general agreement that a high degree of variability exists between subjects in their autonomic nervous system responses to motion sickness stimulation, very little evidence exists that examines the reproducibility of autonomic responses within subjects during motion sickness stimulation. Our objectives were to examine the reliability of autonomic responses and symptom levels across five testing occasions using the (1) final minute of testing, (2) change in autonomic response and the change in symptom level, and (3) strength of the relationship between the change in symptom level and the change in autonomic responses across the entire motion sickness test. The results indicate that, based on the final minute of testing, the autonomic responses of heart rate, blood volume pulse, and respiration rate are moderately stable across multiple tests. Changes in heart rate, blood volume pulse, respiration rate, and symptoms throughout the test duration are less stable across the tests. Finally, autonomic responses and symptom levels are significantly related across the entire motion sickness test.

Germline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas

PubMed Central

Palles, Claire; Cazier, Jean-Baptiste; Howarth, Kimberley M; Domingo, Enric; Jones, Angela M.; Broderick, Peter; Kemp, Zoe; Spain, Sarah L; Almeida, Estrella Guarino; Salguero, Israel; Sherborne, Amy; Chubb, Daniel; Carvajal-Carmona, Luis G; Ma, Yusanne; Kaur, Kulvinder; Dobbins, Sara; Barclay, Ella; Gorman, Maggie; Martin, Lynn; Kovac, Michal B; Humphray, Sean; Lucassen, Anneke; Holmes, Christopher; Bentley, David; Donnelly, Peter; Taylor, Jenny; Petridis, Christos; Roylance, Rebecca; Sawyer, Elinor J; Kerr, David J.; Clark, Susan; Grimes, Jonathan; Kearsey, Stephen E; Thomas, Huw JW; McVean, Gilean; Houlston, Richard S; Tomlinson, Ian

2013-01-01

Many individuals with multiple or large colorectal adenomas, or early-onset colorectal cancer (CRC), have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple adenoma and/or CRC cases, but in no controls. The susceptibility variants appear to have high penetrance. POLD1 is also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proof-reading (exonuclease) domain of DNA polymerases ε and δ, and are predicted to impair correction of mispaired bases inserted during DNA replication. In agreement with this prediction, mutation carriers’ tumours were microsatellite-stable, but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently-described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE exonuclease domain mutations. PMID:23263490

A field-shaping multi-well avalanche detector for direct conversion amorphous selenium

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

Goldan, A. H.; Zhao, W.

2013-01-15

Purpose: A practical detector structure is proposed to achieve stable avalanche multiplication gain in direct-conversion amorphous selenium radiation detectors. Methods: The detector structure is referred to as a field-shaping multi-well avalanche detector. Stable avalanche multiplication gain is achieved by eliminating field hot spots using high-density avalanche wells with insulated walls and field-shaping inside each well. Results: The authors demonstrate the impact of high-density insulated wells and field-shaping to eliminate the formation of both field hot spots in the avalanche region and high fields at the metal-semiconductor interface. Results show a semi-Gaussian field distribution inside each well using the field-shaping electrodes,more » and the electric field at the metal-semiconductor interface can be one order-of-magnitude lower than the peak value where avalanche occurs. Conclusions: This is the first attempt to design a practical direct-conversion amorphous selenium detector with avalanche gain.« less

Burden of a multiple sclerosis relapse: the patient's perspective.

PubMed

Oleen-Burkey, Merrikay; Castelli-Haley, Jane; Lage, Maureen J; Johnson, Kenneth P

2012-01-01

Relapses are a common feature of relapsing-remitting multiple sclerosis (RRMS) and increasing severity has been shown to be associated with higher healthcare costs, and to result in transient increases in disability. Increasing disability likely impacts work and leisure productivity, and lowers quality of life. The objective of this study was to characterize from the patient's perspective the impact of a multiple sclerosis (MS) relapse in terms of the economic cost, work and leisure productivity, functional ability, and health-related quality of life (HR-QOL), for a sample of patients with RRMS in the US treated with immunomodulatory agents. A cross-sectional, web-based, self-report survey was conducted among members of MSWatch.com, a patient support website now known as Copaxone.com. Qualified respondents in the US had been diagnosed with RRMS and were using an immunomodulatory agent. The survey captured costs of RRMS with questions about healthcare resource utilization, use of community services, and purchased alterations and assistive items related to MS. The Work and Leisure Impairment instrument and the EQ-5D were used to measure productivity losses and HR-QOL (health utility), respectively. The Goodin MS neurological impairment questionnaire was used to measure functional disability; questions were added about relapses in the past year. Of 711 qualified respondents, 67% reported having at least one relapse during the last year, with a mean of 2.2 ± 2.3 relapses/year. Respondents who experienced at least one relapse had significantly higher mean annual direct and indirect costs compared with those who did not experience a relapse ($US38 458 vs $US28 669; p = 0.0004) [year 2009 values]. Direct health-related costs accounted for the majority of the increased cost ($US5201; 53%) and were mainly due to increases in hospitalizations, medications, and ambulatory care. Indirect costs, including informal care and productivity loss, accounted for the additional 47% of increased cost ($US4588). Accounting for the mean number of relapses associated with these increased costs, the total economic cost of one relapse episode could be estimated at about $US4449, exclusive of intangible costs. The mean self-reported Expanded Disability Status Scale (EDSS) score, derived from the Goodin MS questionnaire, was significantly higher with relapse than with a clinically stable state (EDSS 4.3 vs 3.7; p < 0.0001), while the mean health utility score was significantly lower with relapse compared with a clinically stable state (0.66 vs 0.75; p = 0.0001). The value of these intangible costs of relapse can be estimated at $US5400. The overall burden (direct, indirect, and intangible costs) of one relapse in patients treated with immunomodulatory agents is therefore estimated conservatively at $US9849. This study shows that from a patient's perspective an MS relapse is associated with a significant increase in the economic costs as well as a decline in HR-QOL and functional ability.

Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research

PubMed Central

Waldman, Amy; Ghezzi, Angelo; Bar-Or, Amit; Mikaeloff, Yann; Tardieu, Marc; Banwell, Brenda

2015-01-01

The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood—and adolescent—onset multiple sclerosis have been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis. The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume. Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis. Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed. PMID:25142460

Principles for computational design of binding antibodies

PubMed Central

Pszolla, M. Gabriele; Lapidoth, Gideon D.; Norn, Christoffer; Dym, Orly; Unger, Tamar; Albeck, Shira; Tyka, Michael D.; Fleishman, Sarel J.

2017-01-01

Natural proteins must both fold into a stable conformation and exert their molecular function. To date, computational design has successfully produced stable and atomically accurate proteins by using so-called “ideal” folds rich in regular secondary structures and almost devoid of loops and destabilizing elements, such as cavities. Molecular function, such as binding and catalysis, however, often demands nonideal features, including large and irregular loops and buried polar interaction networks, which have remained challenging for fold design. Through five design/experiment cycles, we learned principles for designing stable and functional antibody variable fragments (Fvs). Specifically, we (i) used sequence-design constraints derived from antibody multiple-sequence alignments, and (ii) during backbone design, maintained stabilizing interactions observed in natural antibodies between the framework and loops of complementarity-determining regions (CDRs) 1 and 2. Designed Fvs bound their ligands with midnanomolar affinities and were as stable as natural antibodies, despite having >30 mutations from mammalian antibody germlines. Furthermore, crystallographic analysis demonstrated atomic accuracy throughout the framework and in four of six CDRs in one design and atomic accuracy in the entire Fv in another. The principles we learned are general, and can be implemented to design other nonideal folds, generating stable, specific, and precise antibodies and enzymes. PMID:28973872

Gender- and age-related differences in clinical presentation and management of outpatients with stable coronary artery disease.

PubMed

Ferrari, Roberto; Abergel, Hélène; Ford, Ian; Fox, Kim M; Greenlaw, Nicola; Steg, Ph Gabriel; Hu, Dayi; Tendera, Michal; Tardif, Jean-Claude

2013-09-10

Contemporary generalizable data on the demographics and management of outpatients with stable coronary artery disease (CAD) in routine clinical practice are sparse. Using the data from the CLARIFY registry we describe gender- and age-related differences in baseline characteristics and management of these patients across broad geographic regions. This international, prospective, observational, longitudinal registry enrolled stable CAD outpatients from 45 countries in Africa, Asia, Australia, Europe, the Middle East, and North, Central, and South America. Baseline data were available for 33280 patients. Mean (SD) age was 64 (10.5) years and 22.5% of patients were female. The prevalence of CAD risk factors was generally higher in women than in men. Women were older (66.6 vs 63.4 years), more frequently diagnosed with diabetes (33% vs 28%), hypertension (79% vs 69%), and higher resting heart rate (69 vs 67 bpm), and were less physically active. Smoking and a history of myocardial infarction were more common in men. Women were more likely to have angina (28% vs 20%), but less likely to have undergone revascularization procedures. CAD was more likely to be asymptomatic in older patients perhaps because of reduced levels of physical activity. Prescription of evidence-based medication for secondary prevention varied with age, with patients ≥ 75 years treated less often with beta blockers, aspirin and angiotensin-converting enzyme inhibitors than patients <65 years. Important gender-related differences in clinical characteristics and management continue to exist in all age groups of outpatients with stable CAD. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Stable isotope-resolved metabolomics and applications for drug development

PubMed Central

Fan, Teresa W-M.; Lorkiewicz, Pawel; Sellers, Katherine; Moseley, Hunter N.B.; Higashi, Richard M.; Lane, Andrew N.

2012-01-01

Advances in analytical methodologies, principally nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS), during the last decade have made large-scale analysis of the human metabolome a reality. This is leading to the reawakening of the importance of metabolism in human diseases, particularly cancer. The metabolome is the functional readout of the genome, functional genome, and proteome; it is also an integral partner in molecular regulations for homeostasis. The interrogation of the metabolome, or metabolomics, is now being applied to numerous diseases, largely by metabolite profiling for biomarker discovery, but also in pharmacology and therapeutics. Recent advances in stable isotope tracer-based metabolomic approaches enable unambiguous tracking of individual atoms through compartmentalized metabolic networks directly in human subjects, which promises to decipher the complexity of the human metabolome at an unprecedented pace. This knowledge will revolutionize our understanding of complex human diseases, clinical diagnostics, as well as individualized therapeutics and drug response. In this review, we focus on the use of stable isotope tracers with metabolomics technologies for understanding metabolic network dynamics in both model systems and in clinical applications. Atom-resolved isotope tracing via the two major analytical platforms, NMR and MS, has the power to determine novel metabolic reprogramming in diseases, discover new drug targets, and facilitates ADME studies. We also illustrate new metabolic tracer-based imaging technologies, which enable direct visualization of metabolic processes in vivo. We further outline current practices and future requirements for biochemoinformatics development, which is an integral part of translating stable isotope-resolved metabolomics into clinical reality. PMID:22212615

Fixed points, stable manifolds, weather regimes, and their predictability

DOE PAGES

Deremble, Bruno; D'Andrea, Fabio; Ghil, Michael

2009-10-27

In a simple, one-layer atmospheric model, we study the links between low-frequency variability and the model’s fixed points in phase space. The model dynamics is characterized by the coexistence of multiple ''weather regimes.'' To investigate the transitions from one regime to another, we focus on the identification of stable manifolds associated with fixed points. We show that these manifolds act as separatrices between regimes. We track each manifold by making use of two local predictability measures arising from the meteorological applications of nonlinear dynamics, namely, ''bred vectors'' and singular vectors. These results are then verified in the framework of ensemblemore » forecasts issued from clouds (ensembles) of initial states. The divergence of the trajectories allows us to establish the connections between zones of low predictability, the geometry of the stable manifolds, and transitions between regimes.« less

Chip Scale Ultra-Stable Clocks: Miniaturized Phonon Trap Timing Units for PNT of CubeSats

NASA Technical Reports Server (NTRS)

Rais-Zadeh, Mina; Altunc, Serhat; Hunter, Roger C.; Petro, Andrew

2016-01-01

The Chip Scale Ultra-Stable Clocks (CSUSC) project aims to provide a superior alternative to current solutions for low size, weight, and power timing devices. Currently available quartz-based clocks have problems adjusting to the high temperature and extreme acceleration found in space applications, especially when scaled down to match small spacecraft size, weight, and power requirements. The CSUSC project aims to utilize dual-mode resonators on an ovenized platform to achieve the exceptional temperature stability required for these systems. The dual-mode architecture utilizes a temperature sensitive and temperature stable mode simultaneously driven on the same device volume to eliminate ovenization error while maintaining extremely high performance. Using this technology it is possible to achieve parts-per-billion (ppb) levels of temperature stability with multiple orders of magnitude smaller size, weight, and power.

Fixed points, stable manifolds, weather regimes, and their predictability.

PubMed

Deremble, Bruno; D'Andrea, Fabio; Ghil, Michael

2009-12-01

In a simple, one-layer atmospheric model, we study the links between low-frequency variability and the model's fixed points in phase space. The model dynamics is characterized by the coexistence of multiple "weather regimes." To investigate the transitions from one regime to another, we focus on the identification of stable manifolds associated with fixed points. We show that these manifolds act as separatrices between regimes. We track each manifold by making use of two local predictability measures arising from the meteorological applications of nonlinear dynamics, namely, "bred vectors" and singular vectors. These results are then verified in the framework of ensemble forecasts issued from "clouds" (ensembles) of initial states. The divergence of the trajectories allows us to establish the connections between zones of low predictability, the geometry of the stable manifolds, and transitions between regimes.

Seshat: A Web service for accurate annotation, validation, and analysis of TP53 variants generated by conventional and next-generation sequencing.

PubMed

Tikkanen, Tuomas; Leroy, Bernard; Fournier, Jean Louis; Risques, Rosa Ana; Malcikova, Jitka; Soussi, Thierry

2018-07-01

Accurate annotation of genomic variants in human diseases is essential to allow personalized medicine. Assessment of somatic and germline TP53 alterations has now reached the clinic and is required in several circumstances such as the identification of the most effective cancer therapy for patients with chronic lymphocytic leukemia (CLL). Here, we present Seshat, a Web service for annotating TP53 information derived from sequencing data. A flexible framework allows the use of standard file formats such as Mutation Annotation Format (MAF) or Variant Call Format (VCF), as well as common TXT files. Seshat performs accurate variant annotations using the Human Genome Variation Society (HGVS) nomenclature and the stable TP53 genomic reference provided by the Locus Reference Genomic (LRG). In addition, using the 2017 release of the UMD_TP53 database, Seshat provides multiple statistical information for each TP53 variant including database frequency, functional activity, or pathogenicity. The information is delivered in standardized output tables that minimize errors and facilitate comparison of mutational data across studies. Seshat is a beneficial tool to interpret the ever-growing TP53 sequencing data generated by multiple sequencing platforms and it is freely available via the TP53 Website, http://p53.fr or directly at http://vps338341.ovh.net/. © 2018 Wiley Periodicals, Inc.

A Multidimensional Computerized Adaptive Short-Form Quality of Life Questionnaire Developed and Validated for Multiple Sclerosis: The MusiQoL-MCAT.

PubMed

Michel, Pierre; Baumstarck, Karine; Ghattas, Badih; Pelletier, Jean; Loundou, Anderson; Boucekine, Mohamed; Auquier, Pascal; Boyer, Laurent

2016-04-01

The aim was to develop a multidimensional computerized adaptive short-form questionnaire, the MusiQoL-MCAT, from a fixed-length QoL questionnaire for multiple sclerosis.A total of 1992 patients were enrolled in this international cross-sectional study. The development of the MusiQoL-MCAT was based on the assessment of between-items MIRT model fit followed by real-data simulations. The MCAT algorithm was based on Bayesian maximum a posteriori estimation of latent traits and Kullback-Leibler information item selection. We examined several simulations based on a fixed number of items. Accuracy was assessed using correlations (r) between initial IRT scores and MCAT scores. Precision was assessed using the standard error measurement (SEM) and the root mean square error (RMSE).The multidimensional graded response model was used to estimate item parameters and IRT scores. Among the MCAT simulations, the 16-item version of the MusiQoL-MCAT was selected because the accuracy and precision became stable with 16 items with satisfactory levels (r ≥ 0.9, SEM ≤ 0.55, and RMSE ≤ 0.3). External validity of the MusiQoL-MCAT was satisfactory.The MusiQoL-MCAT presents satisfactory properties and can individually tailor QoL assessment to each patient, making it less burdensome to patients and better adapted for use in clinical practice.

A Multidimensional Computerized Adaptive Short-Form Quality of Life Questionnaire Developed and Validated for Multiple Sclerosis

PubMed Central

Michel, Pierre; Baumstarck, Karine; Ghattas, Badih; Pelletier, Jean; Loundou, Anderson; Boucekine, Mohamed; Auquier, Pascal; Boyer, Laurent

2016-01-01

Abstract The aim was to develop a multidimensional computerized adaptive short-form questionnaire, the MusiQoL-MCAT, from a fixed-length QoL questionnaire for multiple sclerosis. A total of 1992 patients were enrolled in this international cross-sectional study. The development of the MusiQoL-MCAT was based on the assessment of between-items MIRT model fit followed by real-data simulations. The MCAT algorithm was based on Bayesian maximum a posteriori estimation of latent traits and Kullback–Leibler information item selection. We examined several simulations based on a fixed number of items. Accuracy was assessed using correlations (r) between initial IRT scores and MCAT scores. Precision was assessed using the standard error measurement (SEM) and the root mean square error (RMSE). The multidimensional graded response model was used to estimate item parameters and IRT scores. Among the MCAT simulations, the 16-item version of the MusiQoL-MCAT was selected because the accuracy and precision became stable with 16 items with satisfactory levels (r ≥ 0.9, SEM ≤ 0.55, and RMSE ≤ 0.3). External validity of the MusiQoL-MCAT was satisfactory. The MusiQoL-MCAT presents satisfactory properties and can individually tailor QoL assessment to each patient, making it less burdensome to patients and better adapted for use in clinical practice. PMID:27057832

Use of hyperbaric oxygen therapy and PEGylated carboxyhemoglobin bovine in a Jehovah's Witness with life-threatening anemia following postpartum hemorrhage.

PubMed

Thenuwara, K; Thomas, J; Ibsen, M; Ituk, U; Choi, K; Nickel, E; Goodheart, M J

2017-02-01

We present a case of a Jehovah's Witness patient who refused blood products, with the exception of albumin and clotting factors, and underwent cesarean section under spinal anesthesia complicated by postpartum hemorrhage. She was fluid resuscitated and treated with multiple uterotonics and internal iliac artery embolization. Because of agitation she required emergency tracheal intubation. Her hemoglobin concentration dropped from a preoperative value of 12mg/dL to 3mg/dL on postoperative day one. She was acidotic, requiring vasopressors for hemodynamic stability and remained ventilated and sedated. She was treated with daily erythropoietin, iron therapy and cyanocobalamin. Because of ongoing hemorrhage, continued acidemia and vasopressor requirements she was co-treated with PEGylated carboxyhemoglobin bovine and hyperbaric oxygen therapy to reverse her oxygen debt. On postoperative day eight her hemoglobin concentration was 7mg/dL, she was hemodynamically stable and vasopressors were discontinued. She was extubated and discharged from the intensive care unit on postoperative day eight. This report highlights the multiple modalities used in treating a severely anemic patient who refused blood, the use of an investigational new drug, the process of obtaining this drug via the United States Food and Drug Administration emergency expanded access regulation for single patient clinical treatment, and ethical dilemmas faced during treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

The impact of stabilizing forces on postsurgical recovery in ostomy patients.

PubMed

Nichols, Thom R; Riemer, Michael

2008-01-01

Patient recovery from life-altering surgery is a complex event requiring interactions among multiple factors that influence recovery. Two such factors are occupational stability and spouse/partner relationship stability. We surveyed persons who have undergone ostomy surgery. Subjects were recruited from the general population, without regard to geographic region or clinical setting. Participation in the study was voluntary; subjects had given prior permission to be contacted about survey-based research. Additional subjects were recruited from Web-based ostomy sites and local ostomy support group meetings. The survey instrument contains 113 items designed to investigate pre- and postsurgery aspects of the lives of those who have undergone ostomy surgery. Ostomates experiencing a postsurgery change in both occupation and work habits were significantly more likely to report a nonpositive life satisfaction score than those experiencing no postoperative change in occupation or work habit. Additionally, a stable spouse/life partner relationship emerged as predictive of positive life satisfaction scores. For those that were married prior to surgery and remained married after surgery, and in which there was no change in occupation or work habit, 95.7% reported a positive life satisfaction score. Multiple stabilizing forces exist that influence the recovery of a patient following life-altering surgery such as creation of a stoma. Stability in occupation and spouse/partner relationship positively influenced life satisfaction scores following ostomy surgery.

Long-term natalizumab treatment is associated with sustained improvements in quality of life in patients with multiple sclerosis.

PubMed

Foley, John F; Nair, Kavita V; Vollmer, Timothy; Stephenson, Judith J; Niecko, Timothy; Agarwal, Sonalee S; Watson, Crystal

2017-01-01

Multiple sclerosis (MS) patients experience lower health-related quality of life (HRQoL) than the general population. In clinical trials, natalizumab significantly improved HRQoL and reduced relapse rates and disability progression in patients with relapsing MS. In a 1-year analysis of patients included in the current study, HRQoL improvement occurred within 3 months of natalizumab initiation and continued for 1 year thereafter. However, natalizumab's long-term efficacy in improving HRQoL has not been studied. In this longitudinal, observational, single-arm US study, HRQoL and treatment satisfaction were evaluated in MS patients receiving intravenous natalizumab 300 mg every 4 weeks in clinical settings. Patients completed surveys at baseline and every 6 months for 3 years and reported the following measures: Short Form-12 Version 2 (SF-12v2), Multiple Sclerosis Impact Scale (MSIS-29), and Treatment Satisfaction Questionnaire for Medication. In this study, 120 patients completed ≥3 years of natalizumab treatment. Significant HRQoL improvements were evident from baseline to year 3 by increases in SF-12v2 Physical Component Summary (PCS) and Mental Component Summary scores ( P <0.01) and decreases in MSIS-29 physical and psychological scores ( P <0.0001). Patients with less physical disability (baseline Disease Steps [DS] 0-2) had significant improvement from baseline to year 3 in SF-12v2 PCS ( P <0.05) and MSIS-29 physical scores ( P <0.05). Physical HRQoL outcomes in patients with baseline DS 3-6 remained stable over 3 years. Treatment satisfaction increased significantly from baseline to year 1 ( P <0.0001) and was maintained in the following 2 years. Patients reported physical and psychological HRQoL improvements over 3 years of natalizumab treatment, supporting the long-term efficacy of natalizumab in real-world settings. Lower baseline disease activity and earlier treatment were related to better outcomes, indicating the importance of starting natalizumab early in the disease course. Treatment satisfaction increased after natalizumab initiation and remained high over 3 years of treatment.

Fractional flow reserve-guided management in stable coronary disease and acute myocardial infarction: recent developments

PubMed Central

Berry, Colin; Corcoran, David; Hennigan, Barry; Watkins, Stuart; Layland, Jamie; Oldroyd, Keith G.

2015-01-01

Coronary artery disease (CAD) is a leading global cause of morbidity and mortality, and improvements in the diagnosis and treatment of CAD can reduce the health and economic burden of this condition. Fractional flow reserve (FFR) is an evidence-based diagnostic test of the physiological significance of a coronary artery stenosis. Fractional flow reserve is a pressure-derived index of the maximal achievable myocardial blood flow in the presence of an epicardial coronary stenosis as a ratio to maximum achievable flow if that artery were normal. When compared with standard angiography-guided management, FFR disclosure is impactful on the decision for revascularization and clinical outcomes. In this article, we review recent developments with FFR in patients with stable CAD and recent myocardial infarction. Specifically, we review novel developments in our understanding of CAD pathophysiology, diagnostic applications, prognostic studies, clinical trials, and clinical guidelines. PMID:26038588

Chronic Kidney Disease and Risk of Presenting with Acute Myocardial Infarction versus Stable Exertional Angina in Adults with Coronary Heart Disease

PubMed Central

Go, Alan S.; Bansal, Nisha; Chandra, Malini; Lathon, Phenius V.; Fortmann, Stephen P.; Iribarren, Carlos; Hsu, Chi-yuan; Hlatky, Mark A.

2011-01-01

Objective To examine whether kidney dysfunction is associated with the type of clinical presentation of coronary heart disease (CHD). Background Reduced kidney function increases risk of developing CHD, but it is not known whether it also influences the acuity of clinical presentation, which has important prognostic implications. Methods We conducted a case-control study of subjects whose first clinical presentation of CHD was either acute myocardial infarction or stable exertional angina between October 2001-December 2003. Glomerular filtration rate (eGFR) before the incident event was estimated using calibrated serum creatinine and the abbreviated MDRD equation. Patient characteristics and use of medications were ascertained from self-report and health plan databases. We used multivariable logistic regression to examine the association of reduced eGFR and CHD presentation. Results We studied 803 adults with incident acute myocardial infarction and 419 adults with incident stable exertional angina who had a baseline eGFR ≤130 ml/min/1.73 m2. Mean eGFR was lower among subjects with acute myocardial infarction compared with stable angina. Compared with eGFR 90–130 ml/min/1.73 m2, we found a strong, graded independent association between reduced eGFR and presenting with acute myocardial infarction: adjusted odds ratio (OR) 1.36 (95% CI: 0.99 to 1.86) for eGFR 60–89 ml/min/1.73 m2, OR 1.55 (0.92 to 2.62) for eGFR 45–59 ml/min/1.73 m2 and OR 3.82 (1.55 to 9.46) for eGFR <45 ml/min/1.73 m2 (P<0.001 for trend). Conclusion eGFR less than 45 ml/min/1.73 m2 is a strong, independent predictor of presenting with acute myocardial infarction versus stable angina as the initial manifestation of CHD. PMID:21958887

The Challenges of Measuring Glycemic Variability

PubMed Central

Rodbard, David

2012-01-01

This commentary reviews several of the challenges encountered when attempting to quantify glycemic variability and correlate it with risk of diabetes complications. These challenges include (1) immaturity of the field, including problems of data accuracy, precision, reliability, cost, and availability; (2) larger relative error in the estimates of glycemic variability than in the estimates of the mean glucose; (3) high correlation between glycemic variability and mean glucose level; (4) multiplicity of measures; (5) correlation of the multiple measures; (6) duplication or reinvention of methods; (7) confusion of measures of glycemic variability with measures of quality of glycemic control; (8) the problem of multiple comparisons when assessing relationships among multiple measures of variability and multiple clinical end points; and (9) differing needs for routine clinical practice and clinical research applications. PMID:22768904

The role of systemic steroids and phototherapy in the treatment of stable vitiligo: a randomized controlled trial.

PubMed

El Mofty, Medhat; Essmat, Samia; Youssef, Randa; Sobeih, Sherine; Mahgoub, Doaa; Ossama, Sherine; Saad, Akmal; El Tawdy, Amira; Mashaly, Heba M; Saney, Iman; Helal, Rana; Shaker, Olfat

2016-11-01

Pathogenesis of vitiligo is believed to be multifactorial disease with a wide variety of therapeutic modalities. The aim of this work is to assess the efficacy of oral mini-pulse steroids (OMP) plus Nb-U.V.B in comparison to OMP alone and Nb-U.V.B alone in treating stable vitiligo. A prospective randomized controlled study including 45 patients categorized into three groups receiving therapy for 3 months; Group A received Nb-U.V.B plus OMP, Group B received OMP alone while Group C received Nb-U.V.B alone. Clinical assessment and PCR evaluation of bFGF, ICAM1, and ELISA for AMA were done. Patients receiving Nb-U.V.B plus OMP and using Nb-U.V.B alone gave statistically significant clinical response than those treated with OMP alone. Statistically significant rise of BFGF was noticed after treatment with Nb-U.V.B plus OMP and with Nb-U.V.B alone. Patients treated with OMP alone and with Nb-U.V.B alone showed statistically significant drop of ICAM-1 after therapy. NB-U.V.B plus OMP and Nb-U.V.B alone were found to be clinically superior over OMP alone in treating stable vitiligo patients, hence suggesting that adding OMP to Nb-U.V.B can maintain clinical and laboratory success for a longer period of time and with less relapse. © 2016 Wiley Periodicals, Inc.

Angular stable plates in proximal meta-epiphyseal tibial fractures: study of joint restoration and clinical and functional evaluation.

PubMed

Giannotti, S; Giovannelli, D; Dell'Osso, G; Bottai, V; Bugelli, G; Celli, F; Citarelli, C; Guido, G

2016-04-01

The tibial plateau fractures involve one of the main weight bearing joints of the human body. The goals of surgical treatment are anatomical reduction, articular surface reconstruction and high primary stability. The aim of this study was to evaluate the clinical and functional outcomes after internal plate fixation of this kind of fractures. From January 2009 to December 2012, we treated 75 cases of tibial plateau fracture with angular stable plates. We used Rasmussen Score and the Knee Society Score for the clinical and functional evaluation. Twenty-five cases that underwent hardware removal had arthroscopic and CT evaluation of the joint. No complications occurred. The clinical and functional evaluation, performed by the KSS and Rasmussen Score, highlighted the high percentage of good-to-excellent results (over 90 %). In every case, the range of motion was good with flexion >90°. Arthroscopy showed the presence of chondral damage in 100 % of patients. In all the cases, we found that X-ray images seem better than the CT images. Angular stable plates allow to obtain a good primary stability, permitting an early joint recovery with an excellent range of motion. Avoiding to perform a knee arthrotomy at the time of fracture reduction could prove to be an advantage in terms of functional recovery. The meniscus on the injured bone should be preserved in order to maintain good function of the joint. X-ray images remain the gold standard in checking the progression of post-traumatic osteoarthritis.

Determining the elastic properties of aptamer-ricin single molecule multiple pathways

USDA-ARS?s Scientific Manuscript database

Ricin and an anti-ricin aptamer showed three stable binding conformations with their special chemomechanical properties. The elastic properties of the ricin-aptamer single-molecule interactions were investigated by the dynamic force spectroscopy (DFS). The worm-like-chain model and Hook’s law were ...

Enzyme linked immunoassay with stabilized polymer saccharide enzyme conjugates

DOEpatents

Callstrom, Matthew R.; Bednarski, Mark D.; Gruber, Patrick R.

1997-01-01

An improvement in enzyme linked immunoassays is disclosed wherein the enzyme is in the form of a water soluble polymer saccharide conjugate which is stable in hostile environments. The conjugate comprises the enzyme which is linked to the polymer at multiple points through saccharide linker groups.

Prenatal Drug Exposure: Meeting the Challenge.

ERIC Educational Resources Information Center

Sluder, Linda C.; And Others

1997-01-01

Stresses need for early childhood educators to be prepared for prenatal drug exposed children, who may exhibit multiple disabilities in many areas. Suggests that cognitive and behavioral extremes preclude a list of best practices with this population. Recommends small, stable learning environments. Discusses need for educators and care providers…

A STATISTICAL MODELING METHODOLOGY FOR THE DETECTION, QUANTIFICATION, AND PREDICTION OF ECOLOGICAL THRESHOLDS

EPA Science Inventory

This study will provide a general methodology for integrating threshold information from multiple species ecological metrics, allow for prediction of changes of alternative stable states, and provide a risk assessment tool that can be applied to adaptive management. The integr...

Developing Scenarios: Linking Environmental Scanning and Strategic Planning.

ERIC Educational Resources Information Center

Whiteley, Meredith A.; And Others

1990-01-01

The multiple scenario analysis technique for organizational planning used by multinational corporations is adaptable for colleges and universities. Arizona State University launched a futures-based planning project using the Delphi technique and cross-impact analysis to produce three alternative scenarios (stable, turbulent, and chaotic) to expand…

Multiple Epistemological Coherences in an Eighth-Grade Discussion of the Rock Cycle

ERIC Educational Resources Information Center

Rosenberg, Seth; Hammer, David; Phelan, Jessica

2006-01-01

Research on personal epistemologies (Hofer & Pintrich, 2002) has mostly conceptualized them as stable beliefs or stages of development. On these views, researchers characterize individual students' epistemologies with single, coherent descriptions. Evidence of variability in student epistemologies, however, suggests the need for more complex…

Ridge: a computer program for calculating ridge regression estimates

Treesearch

Donald E. Hilt; Donald W. Seegrist

1977-01-01

Least-squares coefficients for multiple-regression models may be unstable when the independent variables are highly correlated. Ridge regression is a biased estimation procedure that produces stable estimates of the coefficients. Ridge regression is discussed, and a computer program for calculating the ridge coefficients is presented.

Stable Isotopes in Evaluation of Greenhouse Gas Emissions

USDA-ARS?s Scientific Manuscript database

Isotopes offer a unique way to have natural tracers present in the ecosystem to track produced greenhouse gases (GHG) through multiple scales. Isotopes are simply atoms of the same element (same number of protons) with differing number of neutrons. This differing number of neutrons leads to differen...

Identification and Quantification of Preterm Birth Biomarkers in Human Cervicovaginal Fluid by Liquid Chromatography/Tandem Mass Spectrometry

PubMed Central

Shah, Sumit J.; Yu, Kenneth H.; Sangar, Vineet; Parry, Samuel I.; Blair, Ian A.

2009-01-01

Spontaneous preterm birth (PTB) before 37 completed weeks of gestation resulting from preterm labor (PTL) is a leading contributor of perinatal morbidity and mortality. Early identification of at-risk women by reliable screening tests could alleviate this health issue; however, conventional methods such as obstetric history and clinical risk factors, uterine activity monitoring, biochemical markers, and cervical sonography for screening women at risk for PTB have proven unsuccessful in lowering the rate of PTB. Cervicovaginal fluid (CVF) might prove to be a useful, readily available biological fluid for identifying diagnostic PTB biomarkers. Human columnar epithelial endocervical-1 (End1) and vaginal (Vk2) cell secretomes were employed to generate a stable isotope labeled proteome (SILAP) standard to facilitate characterization and relative quantification of proteins present in CVF. The SILAP standard was prepared using stable isotope labeling by amino acids in cell culture (SILAC) of End1 and Vk2 through seven passages. The labeled secreted proteins from both cell lines were combined and characterized by liquid-chromatography-tandem mass spectrometry (LC-MS/MS). 1211 proteins were identified in the End1-Vk2 SILAP standard, with 236 proteins being consistently identified in each of the replicates analyzed. Individual proteins were found to contain < 0.5 % of the endogenous unlabeled forms. Identified proteins were screened to provide a set of fifteen candidates that have either previously been identified as potential PTB biomarkers or could be linked mechanistically to PTB. Stable isotope dilution LC-multiple reaction monitoring (MRM/MS) assays were then developed for conducting relative quantification of the fifteen candidate biomarkers in human CVF samples from term and PTB cases. Three proteins were significantly elevated in PTB cases (desmoplakin isoform 1, stratifin, and thrombospondin 1 precursor), providing a foundation for further validation in larger patient cohorts. PMID:19271751

Identification and quantification of preterm birth biomarkers in human cervicovaginal fluid by liquid chromatography/tandem mass spectrometry.

PubMed

Shah, Sumit J; Yu, Kenneth H; Sangar, Vineet; Parry, Samuel I; Blair, Ian A

2009-05-01

Spontaneous preterm birth (PTB) before 37 completed weeks of gestation resulting from preterm labor (PTL) is a leading contributor of perinatal morbidity and mortality. Early identification of at-risk women by reliable screening tests could alleviate this health issue; however, conventional methods such as obstetric history and clinical risk factors, uterine activity monitoring, biochemical markers, and cervical sonography for screening women at risk for PTB have proven unsuccessful in lowering the rate of PTB. Cervicovaginal fluid (CVF) might prove to be a useful, readily available biological fluid for identifying diagnostic PTB biomarkers. Human columnar epithelial endocervical-1 (End1) and vaginal (Vk2) cell secretomes were employed to generate a stable isotope labeled proteome (SILAP) standard to facilitate characterization and relative quantification of proteins present in CVF. The SILAP standard was prepared using stable isotope labeling by amino acids in cell culture (SILAC) of End1 and Vk2 through seven passages. The labeled secreted proteins from both cell lines were combined and characterized by liquid-chromatography-tandem mass spectrometry (LC-MS/MS). In total, 1211 proteins were identified in the End1-Vk2 SILAP standard, with 236 proteins being consistently identified in each of the replicates analyzed. Individual proteins were found to contain <0.5% of the endogenous unlabeled forms. Identified proteins were screened to provide a set of 15 candidates that have either previously been identified as potential PTB biomarkers or could be linked mechanistically to PTB. Stable isotope dilution LC-multiple reaction monitoring (MRM/MS) assays were then developed for conducting relative quantification of the 15 candidate biomarkers in human CVF samples from term and PTB cases. Three proteins were significantly elevated in PTB cases (desmoplakin isoform 1, stratifin, and thrombospondin 1 precursor), providing a foundation for further validation in larger patient cohorts.

The effects of surface condition on abdominal muscle activity during single-legged hold exercise.

PubMed

Ha, Sung-min; Oh, Jae-seop; Jeon, In-cheol; Kwon, Oh-yun

2015-02-01

To treat low-back pain, various spinal stability exercises are commonly used to improve trunk muscle function and strength. Because human movement for normal daily activity occurs in multi-dimensions, the importance of exercise in multi-dimensions or on unstable surfaces has been emphasized. Recently, a motorized rotating platform (MRP) for facilitating multi-dimensions dynamic movement was introduced for clinical use. However, the abdominal muscle activity with this device has not been reported. The purpose of this study was to compare the abdominal muscle activity (rectus abdominis, external and internal oblique muscles) during an active single-leg-hold (SLH) exercise on a floor (stable surface), foam roll, and motorized rotating platform (MRP). Thirteen healthy male subjects participated in this study. Using electromyography, the abdominal muscle activity was measured while the subjects performed SLH exercises on floor (stable surface), foam roll, and MRP. There were significant differences in the abdominal muscle activities among conditions (P<.05), except for left EO (P>.05) (Fig. 2). After the Bonferroni correction, however, no significant differences among conditions remained, except for differences in both side IO muscle activity between the floor and foam roll conditions (padj<0.017). The findings suggest that performing the SLH exercises on a foam roll and MRP is more effective increased activities of both side of RA and IO, and Rt. EO compared to floor condition. However, there were no significant differences in abdominal muscles activity in the multiple comparison between conditions (mean difference were smaller than the standard deviation in the abdominal muscle activities) (padj>0.017), except for differences in both side IO muscle activity between the floor (stable surface) and foam roll (padj<0.017) (effect size: 0.79/0.62 (non-supporting/supporting leg) for foam-roll versus floor). Copyright © 2014 Elsevier Ltd. All rights reserved.

Host-guest chemistry of dendrimer-drug complexes: 7. Formation of stable inclusions between acetylated dendrimers and drugs bearing multiple charges.

PubMed

Fang, Min; Zhang, Jiahai; Wu, Qinglin; Xu, Tongwen; Cheng, Yiyun

2012-03-15

Drug molecules bearing multiple charges usually form precipitates with cationic dendrimers, which presents a challenge during the preparation of dendrimer inclusions for these drugs. In the present study, fully acetylated polyamidoamine (PAMAM) dendrimers were proposed as stable vehicles for drug molecules bearing two negative charges such as Congo red and indocyanine green. NMR techniques including (1)H NMR and (1)H-(1)H NOESY were used to characterize the host-guest chemistry of acetylated dendrimer and these guest molecules. The cationic PAMAM dendrimer was found to form a precipitate with Congo red and indocyanine green, but the acetylated one avoided the formation of cross-linking structures in aqueous solutions. NOESY studies revealed the encapsulation of Congo red and indocyanine green within the interior cavities of PAMAM dendrimers at mild acidic conditions and acetylated dendrimers show much stronger ability to encapsulate the guest molecules than cationic ones. Also, UV-vis-NIR studies suggest that acetylated dendrimers significantly improve the photostability of indocyanine green and prevent the formation of indocyanine green J-aggregates in aqueous solutions. The present study provides a new insight into dendrimer-based host-guest systems, especially for those guest molecules bearing multiple charges. © 2012 American Chemical Society

Modeling Spatial Dependence of Rainfall Extremes Across Multiple Durations

NASA Astrophysics Data System (ADS)

Le, Phuong Dong; Leonard, Michael; Westra, Seth

2018-03-01

Determining the probability of a flood event in a catchment given that another flood has occurred in a nearby catchment is useful in the design of infrastructure such as road networks that have multiple river crossings. These conditional flood probabilities can be estimated by calculating conditional probabilities of extreme rainfall and then transforming rainfall to runoff through a hydrologic model. Each catchment's hydrological response times are unlikely to be the same, so in order to estimate these conditional probabilities one must consider the dependence of extreme rainfall both across space and across critical storm durations. To represent these types of dependence, this study proposes a new approach for combining extreme rainfall across different durations within a spatial extreme value model using max-stable process theory. This is achieved in a stepwise manner. The first step defines a set of common parameters for the marginal distributions across multiple durations. The parameters are then spatially interpolated to develop a spatial field. Storm-level dependence is represented through the max-stable process for rainfall extremes across different durations. The dependence model shows a reasonable fit between the observed pairwise extremal coefficients and the theoretical pairwise extremal coefficient function across all durations. The study demonstrates how the approach can be applied to develop conditional maps of the return period and return level across different durations.

Two pathways through adversity: Predicting well-being and housing outcomes among homeless service users.

PubMed

Walter, Zoe C; Jetten, Jolanda; Dingle, Genevieve A; Parsell, Cameron; Johnstone, Melissa

2016-06-01

People who experience homelessness face many challenges and disadvantages that negatively impact health and well-being and form barriers to achieving stable housing. Further, people who are homeless often have limited social connections and support. Building on previous research that has shown the beneficial effect of group identification on health and well-being, the current study explores the relationship between two social identity processes - multiple group memberships and service identification - and well-being and positive housing outcomes. Measures were collected from 76 participants while they were residing in a homeless accommodation service (T1) and again 2-4 weeks after leaving the service (or 3 months after T1 if participants had not left the service). Mediation analyses revealed that multiple group memberships and service identification at T1 independently predicted well-being at T2 indirectly, via social support. Further, both social identity processes also indirectly predicted housing outcomes via social support. The implications of these findings are twofold. First, while belonging to multiple social groups may provide a pathway to gaining social support and well-being, group belonging may not necessarily be beneficial to achieve stable housing. Second, fostering identification with homeless services may be particularly important as a source of support that contributes to well-being. © 2015 The British Psychological Society.

Multiple response optimization of processing and formulation parameters of Eudragit RL/RS-based matrix tablets for sustained delivery of diclofenac.

PubMed

Elzayat, Ehab M; Abdel-Rahman, Ali A; Ahmed, Sayed M; Alanazi, Fars K; Habib, Walid A; Sakr, Adel

2017-11-01

Multiple response optimization is an efficient technique to develop sustained release formulation while decreasing the number of experiments based on trial and error approach. Diclofenac matrix tablets were optimized to achieve a release profile conforming to USP monograph, matching Voltaren ® SR and withstand formulation variables. The percent of drug released at predetermined multiple time points were the response variables in the design. Statistical models were obtained with relative contour diagrams being overlaid to predict process and formulation parameters expected to produce the target release profile. Tablets were prepared by wet granulation using mixture of equivalent quantities of Eudragit RL/RS at overall polymer concentration of 10-30%w/w and compressed at 5-15KN. Drug release from the optimized formulation E4 (15%w/w, 15KN) was similar to Voltaren, conformed to USP monograph and found to be stable. Substituting lactose with mannitol, reversing the ratio between lactose and microcrystalline cellulose or increasing drug load showed no significant difference in drug release. Using dextromethorphan hydrobromide as a model soluble drug showed burst release due to higher solubility and formation of micro cavities. A numerical optimization technique was employed to develop a stable consistent promising formulation for sustained delivery of diclofenac.

Multiple large solar lentigos on the upper back as clinical markers of past severe sunburn: a case-control study.

PubMed

Derancourt, C; Bourdon-Lanoy, E; Grob, J-J; Guillaume, J-C; Bernard, P; Bastuji-Garin, S

2007-01-01

Multiple solar lentigos commonly seen on the upper back and shoulders of adults are classically considered as a sign of photodamage, although epidemiological studies are scarce. To assess whether these lesions are clinical markers of past severe sunburn. A case-control study in two outpatient dermatology clinics in French university hospitals. Past episodes of moderate and severe sunburn were compared between 145 adult patients with multiple solar lentigos on the upper back and 145 matched controls. In multivariate analysis adjusted for potential confounders, recalled episodes of sunburn during childhood, adolescence and adulthood were independently associated with the presence of multiple solar lentigos (adjusted odds ratios, 95% confidence intervals: 2.3 (1.1-5.2) and 28.1 (10.4-75.6) for moderate and severe sunburn, respectively). Multiple solar lentigos on the upper back and shoulders of adults are potential clinical markers of past severe sunburn which may thus be used to identify a population at higher risk of developing cutaneous malignant melanoma.

Neurofilament light chain and oligoclonal bands are prognostic biomarkers in radiologically isolated syndrome.

PubMed

Matute-Blanch, Clara; Villar, Luisa M; Álvarez-Cermeño, José C; Rejdak, Konrad; Evdoshenko, Evgeniy; Makshakov, Gleb; Nazarov, Vladimir; Lapin, Sergey; Midaglia, Luciana; Vidal-Jordana, Angela; Drulovic, Jelena; García-Merino, Antonio; Sánchez-López, Antonio J; Havrdova, Eva; Saiz, Albert; Llufriu, Sara; Alvarez-Lafuente, Roberto; Schroeder, Ina; Zettl, Uwe K; Galimberti, Daniela; Ramió-Torrentà, Lluís; Robles, René; Quintana, Ester; Hegen, Harald; Deisenhammer, Florian; Río, Jordi; Tintoré, Mar; Sánchez, Alex; Montalban, Xavier; Comabella, Manuel

2018-04-01

The prognostic role of cerebrospinal fluid molecular biomarkers determined in early pathogenic stages of multiple sclerosis has yet to be defined. In the present study, we aimed to investigate the prognostic value of chitinase 3 like 1 (CHI3L1), neurofilament light chain, and oligoclonal bands for conversion to clinically isolated syndrome and to multiple sclerosis in 75 patients with radiologically isolated syndrome. Cerebrospinal fluid levels of CHI3L1 and neurofilament light chain were measured by enzyme-linked immunosorbent assay. Uni- and multivariable Cox regression models including as covariates age at diagnosis of radiologically isolated syndrome, number of brain lesions, sex and treatment were used to investigate associations between cerebrospinal fluid CHI3L1 and neurofilament light chain levels and time to conversion to clinically isolated syndrome and multiple sclerosis. Neurofilament light chain levels and oligoclonal bands were independent risk factors for the development of clinically isolated syndrome (hazard ratio = 1.02, P = 0.019, and hazard ratio = 14.7, P = 0.012, respectively) and multiple sclerosis (hazard ratio = 1.03, P = 0.003, and hazard ratio = 8.9, P = 0.046, respectively). The best cut-off to classify cerebrospinal fluid neurofilament light chain levels into high and low was 619 ng/l, and high neurofilament light chain levels were associated with a trend to shorter time to clinically isolated syndrome (P = 0.079) and significant shorter time to multiple sclerosis (P = 0.017). Similarly, patients with radiologically isolated syndrome presenting positive oligoclonal bands converted faster to clinically isolated syndrome and multiple sclerosis (P = 0.005 and P = 0.008, respectively). The effects of high neurofilament light chain levels shortening time to clinically isolated syndrome and multiple sclerosis were more pronounced in radiologically isolated syndrome patients with ≥37 years compared to younger patients. Cerebrospinal fluid CHI3L1 levels did not influence conversion to clinically isolated syndrome and multiple sclerosis in radiologically isolated syndrome patients. Overall, these findings suggest that cerebrospinal neurofilament light chain levels and oligoclonal bands are independent predictors of clinical conversion in patients with radiologically isolated syndrome. The association with a faster development of multiple sclerosis reinforces the importance of cerebrospinal fluid analysis in patients with radiologically isolated syndrome.

ACUTE RETINAL ARTERIAL OCCLUSIVE DISORDERS

PubMed Central

Hayreh, Sohan Singh

2011-01-01

The initial section deals with basic sciences; among the various topics briefly discussed are the anatomical features of ophthalmic, central retinal and cilioretinal arteries which may play a role in acute retinal arterial ischemic disorders. Crucial information required in the management of central retinal artery occlusion (CRAO) is the length of time the retina can survive following that. An experimental study shows that CRAO for 97 minutes produces no detectable permanent retinal damage but there is a progressive ischemic damage thereafter, and by 4 hours the retina has suffered irreversible damage. In the clinical section, I discuss at length various controversies on acute retinal arterial ischemic disorders. Classification of acute retinal arterial ischemic disorders These are of 4 types: CRAO, branch retinal artery occlusion (BRAO), cotton wools spots and amaurosis fugax. Both CRAO and BRAO further comprise multiple clinical entities. Contrary to the universal belief, pathogenetically, clinically and for management, CRAO is not one clinical entity but 4 distinct clinical entities – non-arteritic CRAO, non-arteritic CRAO with cilioretinal artery sparing, arteritic CRAO associated with giant cell arteritis (GCA) and transient non-arteritic CRAO. Similarly, BRAO comprises permanent BRAO, transient BRAO and cilioretinal artery occlusion (CLRAO), and the latter further consists of 3 distinct clinical entities - non-arteritic CLRAO alone, non-arteritic CLRAO associated with central retinal vein occlusion and arteritic CLRAO associated with GCA. Understanding these classifications is essential to comprehend fully various aspects of these disorders. Central retinal artery occlusion The pathogeneses, clinical features and management of the various types of CRAO are discussed in detail. Contrary to the prevalent belief, spontaneous improvement in both visual acuity and visual fields does occur, mainly during the first 7 days. The incidence of spontaneous visual acuity improvement during the first 7 days differs significantly (p<0.001) among the 4 types of CRAO; among them, in eyes with initial visual acuity of counting finger or worse, visual acuity improved, remained stable or deteriorated in nonarteritic CRAO in 22%, 66% and 12% respectively; in nonarteritic CRAO with cilioretinal artery sparing in 67%, 33% and none respectively; and in transient nonarteritic CRAO in 82%, 18% and none respectively. Arteritic CRAO shows no change. Recent studies have shown that administration of local intra-arterial thrombolytic agent not only has no beneficial effect but also can be harmful. Prevalent multiple misconceptions on CRAO are discussed. Branch retinal artery occlusion Pathogeneses, clinical features and management of various types of BRAO are discussed at length. The natural history of visual acuity outcome shows a final visual acuity of 20/40 or better in 89% of permanent BRAO cases, 100% of transient BRAO and 100% of nonarteritic CLRAO alone. Cotton wools spots These are common, non-specific acute focal retinal ischemic lesions, seen in many retinopathies. Their pathogenesis and clinical features are discussed in detail. Amaurosis fugax Its pathogenesis, clinical features and management are described. PMID:21620994

Stable isotope labeling by essential nutrients in cell culture for preparation of labeled coenzyme A and its thioesters.

PubMed

Basu, Sankha S; Mesaros, Clementina; Gelhaus, Stacy L; Blair, Ian A

2011-02-15

Stable isotope dilution mass spectrometry (MS) represents the gold standard for quantification of endogenously formed cellular metabolites. Although coenzyme A (CoA) and acyl-CoA thioester derivatives are central players in numerous metabolic pathways, the lack of a commercially available isotopically labeled CoA limits the development of rigorous MS-based methods. In this study, we adapted stable isotope labeling by amino acids in cell culture (SILAC) methodology to biosynthetically generate stable isotope labeled CoA and thioester analogues for use as internal standards in liquid chromatography/multiple reaction monitoring mass spectrometry (LC/MRM-MS) assays. This was accomplished by incubating murine hepatocytes (Hepa 1c1c7) in media in which pantothenate (a precursor of CoA) was replaced with [(13)C(3)(15)N(1)]-pantothenate. Efficient incorporation into various CoA species was optimized to >99% [(13)C(3)(15)N(1)]-pantothenate after three passages of the murine cells in culture. Charcoal-dextran-stripped fetal bovine serum (FBS) was found to be more efficient for serum supplementation than dialyzed or undialyzed FBS, due to lower contaminating unlabeled pantothenate content. Stable isotope labeled CoA species were extracted and utilized as internal standards for CoA thioester analysis in cell culture models. This methodology of stable isotope labeling by essential nutrients in cell culture (SILEC) can serve as a paradigm for using vitamins and other essential nutrients to generate stable isotope standards that cannot be readily synthesized.

The contemporary management of penetrating splenic injury.

PubMed

Berg, Regan J; Inaba, Kenji; Okoye, Obi; Pasley, Jason; Teixeira, Pedro G; Esparza, Michael; Demetriades, Demetrios

2014-09-01

Selective non-operative management (NOM) is standard of care for clinically stable patients with blunt splenic trauma and expectant management approaches are increasingly utilised in penetrating abdominal trauma, including in the setting of solid organ injury. Despite this evolution of clinical practice, little is known about the safety and efficacy of NOM in penetrating splenic injury. Trauma registry and medical record review identified all consecutive patients presenting to LAC+USC Medical Center with penetrating splenic injury between January 2001 and December 2011. Associated injuries, incidence and nature of operative intervention, local and systemic complications and mortality were determined. During the study period, 225 patients experienced penetrating splenic trauma. The majority (187/225, 83%) underwent emergent laparotomy. Thirty-eight clinically stable patients underwent a deliberate trial of NOM and 24/38 (63%) were ultimately managed without laparotomy. Amongst patients failing NOM, 3/14 (21%) underwent splenectomy while an additional 6/14 (42%) had splenorrhaphy. Hollow viscus injury (HVI) occurred in 21% of all patients failing NOM. Forty percent of all NOM patients had diaphragmatic injury (DI). All patients undergoing delayed laparotomy for HVI or a splenic procedure presented symptomatically within 24h of the initial injury. No deaths occurred in patients undergoing NOM. Although the vast majority of penetrating splenic trauma requires urgent operative management, a group of patients does present without haemodynamic instability, peritonitis or radiologic evidence of hollow viscus injury. Management of these patients is complicated as over half may remain clinically stable and can avoid laparotomy, making them potential candidates for a trial of NOM. HVI is responsible for NOM failure in up to a fifth of these cases and typically presents within 24h of injury. Delayed laparotomy, within this limited time period, did not appear to increase mortality nor preclude successful splenic salvage. In clinically stable patients, diagnostic laparoscopy remains essential to evaluate and repair occult DI. As NOM for penetrating abdominal trauma becomes more common, multi-centre data is needed to more accurately define the principles of patient selection and the limitations and consequences of this approach in the setting of splenic injury. Copyright © 2014 Elsevier Ltd. All rights reserved.

Assessing compartmentalized flux in lipid metabolism with isotopes

DOE PAGES

Allen, Doug K.

2016-03-18

Metabolism in plants takes place across multiple cell types and within distinct organelles. The distributions equate to spatial heterogeneity; though the limited means to experimentally assess metabolism frequently involve homogenizing tissues and mixing metabolites from different locations.Most current isotope investigations of metabolism therefore lack the ability to resolve spatially distinct events. Recognition of this limitation has resulted in inspired efforts to advance metabolic flux analysis and isotopic labeling techniques. Though a number of these efforts have been applied to studies in central metabolism; recent advances in instrumentation and techniques present an untapped opportunity to make similar progress in lipid metabolismmore » where the use of stable isotopes has been more limited. These efforts will benefit from sophisticated radiolabeling reports that continue to enrich our knowledge on lipid biosynthetic pathways and provide some direction for stable isotope experimental design and extension of MFA. Evidence for this assertion is presented through the review of several elegant stable isotope studies and by taking stock of what has been learned from radioisotope investigations when spatial aspects of metabolism were considered. The studies emphasize that glycerolipid production occurs across several locations with assembly of lipids in the ER or plastid, fatty acid biosynthesis occurring in the plastid, and the generation of acetyl-CoA and glycerol-3-phosphate taking place at multiple sites. Considering metabolism in this context underscores the cellular and subcellular organization that is important to enhanced production of glycerolipids in plants. An attempt is made to unify salient features from a number of reports into a diagrammatic model of lipid metabolism and propose where stable isotope labeling experiments and further flux analysis may help address questions in the field.« less

Self-organized criticality: An interplay between stable and turbulent regimes of multiple anodic double layers in glow discharge plasma

NASA Astrophysics Data System (ADS)

Alex, Prince; Carreras, Benjamin Andres; Arumugam, Saravanan; Sinha, Suraj Kumar

2018-05-01

The role of self-organized criticality (SOC) in the transformation of multiple anodic double layers (MADLs) from the stable to turbulent regime has been investigated experimentally as the system approaches towards critical behavior. The experiment was performed in a modified glow discharge plasma setup, and the initial stable state of MADL comprising three concentric perceptible layers was produced when the drift velocity of electrons towards the anode exceeds the electron thermal velocity (νd ≥ 1.3νte). The macroscopic arrangement of both positive and negative charges in opposite layers of MADL is attributed to the self-organization scenario. Beyond νd ≥ 3νte, MADL begins to collapse and approaches critical and supercritical states through layer reduction which continue till the last remaining layer of the double layer is transformed into a highly unstable radiant anode glow. The avalanche resulting from the collapse of MADL leads to the rise of turbulence in the system. Long-range correlations, a key signature of SOC, have been explored in the turbulent floating potential fluctuations using the rescaled-range analysis technique. The result shows that the existence of the self-similarity regime with self-similarity parameter H varies between 0.55 and 0.91 for time lags longer than the decorrelation time. The power law tail in the rank function, slowly decaying tail of the autocorrelation function, and 1/f behavior of the power spectra of the fluctuations are consistent with the fact that SOC plays a conclusive role in the transformation of MADL from the stable to turbulent regime. Since the existence of SOC gives a measure of complexity in the system, the result provides the condition under which complexity arises in cold plasma.

Assessing compartmentalized flux in lipid metabolism with isotopes

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

Allen, Doug K.

Metabolism in plants takes place across multiple cell types and within distinct organelles. The distributions equate to spatial heterogeneity; though the limited means to experimentally assess metabolism frequently involve homogenizing tissues and mixing metabolites from different locations.Most current isotope investigations of metabolism therefore lack the ability to resolve spatially distinct events. Recognition of this limitation has resulted in inspired efforts to advance metabolic flux analysis and isotopic labeling techniques. Though a number of these efforts have been applied to studies in central metabolism; recent advances in instrumentation and techniques present an untapped opportunity to make similar progress in lipid metabolismmore » where the use of stable isotopes has been more limited. These efforts will benefit from sophisticated radiolabeling reports that continue to enrich our knowledge on lipid biosynthetic pathways and provide some direction for stable isotope experimental design and extension of MFA. Evidence for this assertion is presented through the review of several elegant stable isotope studies and by taking stock of what has been learned from radioisotope investigations when spatial aspects of metabolism were considered. The studies emphasize that glycerolipid production occurs across several locations with assembly of lipids in the ER or plastid, fatty acid biosynthesis occurring in the plastid, and the generation of acetyl-CoA and glycerol-3-phosphate taking place at multiple sites. Considering metabolism in this context underscores the cellular and subcellular organization that is important to enhanced production of glycerolipids in plants. An attempt is made to unify salient features from a number of reports into a diagrammatic model of lipid metabolism and propose where stable isotope labeling experiments and further flux analysis may help address questions in the field.« less

Efficacy, safety, and cost of pomalidomide in relapsed and refractory multiple myeloma.

PubMed

Gueneau, Pauline; Chretien, Marie-Lorraine; Cransac-Miet, Amelie; Aho, Ludwig Serge; Lafon, Ingrid; Favennec, Camille; Guy, Julien; Caillot, Denis; Boulin, Mathieu

2018-05-01

To investigate the efficacy, safety, and cost of a pomalidomide-dexamethasone regimen in patients with relapsed and refractory multiple myeloma (RRMM). All patients (n = 63) treated with pomalidomide-dexamethasone for RRMM in our university hospital between August 2013 and October 2015 were included. Pomalidomide was discontinued early due to progression (before the 4th cycle) in 17 (27%) patients. No case was discontinued for intolerance. The only independent factor that predicted early pomalidomide discontinuation was time from diagnosis to pomalidomide initiation <3 years. Overall response rate was 51% including complete response in 8%, very good partial response in 25%, and partial response in 19% patients. Thirteen (33%) patients showed stable disease. Median overall survival was 6.4 months in the 17 patients who discontinued pomalidomide early vs 26.8 months in the 14 patients with stable disease vs not achieved in the 32 responders (log-rank; P < 10 -3 ). The most common grade ≥3 adverse events were neutropenia (14%) and infections (25%). The incremental cost-effectiveness ratio of pomalidomide-dexamethasone compared with dexamethasone alone was estimated at €39 911 per life-year gained. The study demonstrated that pomalidomide-dexamethasone regimen has a long-term favorable safety-efficacy profile in RRMM patients. The survival benefit is substantial even in patients with stable disease. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Stable antigen-specific T-cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients.

PubMed

Raϊch-Regué, Dàlia; Grau-López, Laia; Naranjo-Gómez, Mar; Ramo-Tello, Cristina; Pujol-Borrell, Ricardo; Martínez-Cáceres, Eva; Borràs, Francesc E

2012-03-01

Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease of the central nervous system. Current therapies decrease the frequency of relapses and limit, to some extent, but do not prevent disease progression. Hence, new therapeutic approaches that modify the natural course of MSneed to be identified. Tolerance induction to self-antigens using monocyte-derived dendritic cells (MDDCs) is a promising therapeutic strategy in autoimmunity. In this work, we sought to generate and characterize tolerogenic MDDCs (tolDCs) from relapsing-remitting (RR) MSpatients, loaded with myelin peptides as specific antigen, with the aim of developing immunotherapeutics for MS. MDDCs were generated from both healthy-blood donors and RR-MSpatients, and MDDCmaturation was induced with a proinflammatory cytokine cocktail in the absence or presence of 1α,25-dihydroxyvitamin-D(3) , a tolerogenicity-inducing agent. tolDCs were generated from monocytes of RR-MSpatients as efficiently as from monocytes of healthy subjects. The RR-MStolDCs expressed a stable semimature phenotype and an antiinflammatory profile as compared with untreated MDDCs. Importantly, myelin peptide-loaded tolDCs induced stable antigen-specific hyporesponsiveness in myelin-reactive T cells from RR-MS patients. These results suggest that myelin peptide-loaded tolDCs may be a powerful tool for inducing myelin-specific tolerance in RR-MS patients. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Reliability and Clinical Significance of Mobility and Balance Assessments in Multiple Sclerosis

ERIC Educational Resources Information Center

Learmonth, Yvonne C.; Paul, Lorna; McFadyen, Angus K.; Mattison, Paul; Miller, Linda

2012-01-01

The aim of the study was to establish the test-retest reliability, clinical significance and precision of four mobility and balance measures--the Timed 25-Foot Walk, Six-minute Walk, Timed Up and Go and the Berg Balance Scale--in individuals moderately affected by multiple sclerosis. Twenty four participants with multiple sclerosis (Extended…

Increased calcium absorption from synthetic stable amorphous calcium carbonate: double-blind randomized crossover clinical trial in postmenopausal women.

PubMed

Vaisman, Nachum; Shaltiel, Galit; Daniely, Michal; Meiron, Oren E; Shechter, Assaf; Abrams, Steven A; Niv, Eva; Shapira, Yami; Sagi, Amir

2014-10-01

Calcium supplementation is a widely recognized strategy for achieving adequate calcium intake. We designed this blinded, randomized, crossover interventional trial to compare the bioavailability of a new stable synthetic amorphous calcium carbonate (ACC) with that of crystalline calcium carbonate (CCC) using the dual stable isotope technique. The study was conducted in the Unit of Clinical Nutrition, Tel Aviv Sourasky Medical Center, Israel. The study population included 15 early postmenopausal women aged 54.9 ± 2.8 (mean ± SD) years with no history of major medical illness or metabolic bone disorder, excess calcium intake, or vitamin D deficiency. Standardized breakfast was followed by randomly provided CCC or ACC capsules containing 192 mg elemental calcium labeled with 44Ca at intervals of at least 3 weeks. After swallowing the capsules, intravenous CaCl2 labeled with 42Ca on was administered on each occasion. Fractional calcium absorption (FCA) of ACC and CCC was calculated from the 24-hour urine collection following calcium administration. The results indicated that FCA of ACC was doubled (± 0.96 SD) on average compared to that of CCC (p < 0.02). The higher absorption of the synthetic stable ACC may serve as a more efficacious way of calcium supplementation. © 2014 American Society for Bone and Mineral Research.

An Update on the Global Initiative for Chronic Obstructive Lung Disease 2017 Guidelines With a Focus on Classification and Management of Stable COPD.

PubMed

Burkes, Robert M; Donohue, James F

2018-06-01

The 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines offer important changes to the assessment and management of stable COPD of importance to practitioners, respiratory therapists, pharmacists, and nurses who care for patients with COPD. Therapies are now chosen based on the burden of symptoms and the history of COPD exacerbations, and inhaler regimens are modifiable based on continual clinical reassessment. Although identifying the degree of airway obstruction remains important for informing the clinical status of the patient with COPD, FEV 1 is no longer used to direct the therapeutic approach. Therapies and modes of inhaled medication delivery for each GOLD grouping have been modified and reflect the need for reevaluation of patient symptoms and COPD exacerbation history as an indicator to add or withdraw therapies. As the knowledge of this important disease continues to expand, exacerbation and symptom prevention in patients with stable COPD will remain as an important target of COPD therapies and research. Novel drug combinations and delivery devices are sure to positively affect the practitioner's approach to patients with stable COPD. The new 2017 GOLD guidelines represent a step toward personalized care of the patient with COPD. Copyright © 2018 by Daedalus Enterprises.

Relationship between cavitation and loss of echogenicity from ultrasound contrast agents

NASA Astrophysics Data System (ADS)

Radhakrishnan, Kirthi; Bader, Kenneth B.; Haworth, Kevin J.; Kopechek, Jonathan A.; Raymond, Jason L.; Huang, Shao-Ling; McPherson, David D.; Holland, Christy K.

2013-09-01

Ultrasound contrast agents (UCAs) have the potential to nucleate cavitation and promote both beneficial and deleterious bioeffects in vivo. Previous studies have elucidated the pulse-duration-dependent pressure amplitude threshold for rapid loss of echogenicity due to UCA fragmentation. Previous studies have demonstrated that UCA fragmentation was concomitant with inertial cavitation. The purpose of this study was to evaluate the relationship between stable and inertial cavitation thresholds and loss of echogenicity of UCAs as a function of pulse duration. Determining the relationship between cavitation thresholds and loss of echogenicity of UCAs would enable monitoring of cavitation based upon the onscreen echogenicity in clinical applications. Two lipid-shelled UCAs, echogenic liposomes (ELIP) and Definity®, were insonified by a clinical ultrasound scanner in duplex spectral Doppler mode at four pulse durations (‘sample volumes’) in both a static system and a flow system. Cavitation emissions from the UCAs insonified by Doppler pulses were recorded using a passive cavitation detection system and stable and inertial cavitation thresholds ascertained. Loss of echogenicity from ELIP and Definity® was assessed within regions of interest on B-mode images. A numerical model based on UCA rupture predicted the functional form of the loss of echogenicity from ELIP and Definity®. Stable and inertial cavitation thresholds were found to have a weak dependence on pulse duration. Stable cavitation thresholds were lower than inertial cavitation thresholds. The power of cavitation emissions was an exponential function of the loss of echogenicity over the investigated range of acoustic pressures. Both ELIP and Definity® lost more than 80% echogenicity before the onset of stable or inertial cavitation. Once this level of echogenicity loss occurred, both stable and inertial cavitation were detected in the physiologic flow phantom. These results imply that stable and inertial cavitation are necessary in order to trigger complete loss of echogenicity acoustically from UCAs and this finding can be used when planning diagnostic and therapeutic applications.