CIRCULATING AUTOANTIBODIES IN HUMAN TRAUMATIC SPINAL CORD INJURY SUBJECTS AND THEIR RELATIONSHIP TO THE DEVELOPMENT OF NEUROPATHIC PAIN

Background: Approximately 17,500 spinal cord injuries (SCI) occur yearly in the U.S. causing considerable morbidity and mortality. Neuropathic pain (NP) ensues in 40-70% of SCI. An autoimmune response resulting from disruption of the blood-spinal cord-barrier may be a contributor to NP. However, the relationship between autoantibodies and NP after SCI in humans has not been thoroughly characterized nor have autoantigens been identified. Glial fibrillary acidic protein (GFAP) and collapsin response mediator protein2 (CRMP2) were identified as candidate autoantigens. The hypothesis is that proteins from the injured spinal cord released by SCI trigger autoantibody production which can lead to the development of NP. Results: The presence of autoantibodies to GFAP (GFAPab) and CRMP2 (CRMP2ab) and their correlation to the development of NP was evaluated. GFAPab was present in 21 of 38 (55%) acute SCI, 34 of 80 (43%) chronic SCI. CRMP2ab was present in 8/35 (23%) acute SCI patient plasma samples. Complement C3 and C5 were elevated in acute SCI. Peak autoantibody levels were detected at 16±7 days post injury. The peak plasma GFAPab levels were higher in patients that subsequently developed NP versus those who did not (T=219, p=0.02). Receiver operator characteristic curve analysis shows that plasma GFAPab levels had an area under the curve of 0.71 (95% CI, 0.53-0.89 p=0.03) for the discrimination of patients that developed NP within 6 months after injury. Patients with GFAPab and/or CRMP2ab had a 9.5 times increased odds of developing NP. Discussion: Results show that SCI triggers an autoimmune response leading to production of autoantibodies. The 16±7 day level of GFAPab post-SCI is a predictor of the development of NP. The levels of GFAPab returned to levels found in healthy volunteers by 96±54 days post-injury. A panel of GFAPab and CRMP2ab showed 9.5 times increased odds of developing NP (95% CI, 2.08-43.50, p=0.006). Future studies will examine the possibility that other autoantibodies contribute to the development of NP. Measuring GFAPab and CRMP2ab post-SCI may help identify patients at risk for subsequently developing NP. A reduction of GFAPab and/or CRMP2ab in the acute stages of injury may decrease the likelihood for developing NP

Moment Matching and Modal Truncation for Linear Systems

While moment matching can effectively reduce the dimension of a linear, time-invariant system, it can simultaneously fail to improve the stable time-step for the forward Euler scheme. In the context of a semi-discrete heat equation with spatially smooth forcing, the high frequency modes are virtually insignificant. Eliminating such modes dramatically improves the stable time-step without sacrificing output accuracy. This is accomplished by modal filtration, whose computational cost is relatively palatable when applied following an initial reduction stage by moment matching. A bound on the norm of the difference between the transfer functions of the moment-matched system and its modally-filtered counterpart yields an intelligent choice for the mode of truncation. The dual-stage algorithm disappoints in the context of highly nonnormal semi-discrete convection-diffusion equations. There, moment matching can be ineffective in dimension reduction, precluding a cost-effective modal filtering step

Hypothermia for patients requiring evacuation of subdural hematoma: A multicenter randomized clinical trial

BACKGROUND: Hypothermia is neuroprotective in some ischemia-reperfusion injuries. Ischemia-reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia-reperfusion injury and improve global neurologic outcome. METHODS: This international, multicenter randomized controlled trial enrolled adult patients with SDH requiring evacuation of hematoma within 6 h of injury. The intervention was controlled temperature management of hypothermia to 35 °C prior to dura opening followed by 33 °C for 48 h compared with normothermia (37 °C). Investigators randomly assigned patients at a 1:1 ratio between hypothermia and normothermia. Blinded evaluators assessed outcome using a 6-month Glasgow Outcome Scale Extended score. Investigators measured circulating glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 levels. RESULTS: Independent statisticians performed an interim analysis of 31 patients to assess the predictive probability of success and the Data and Safety Monitoring Board recommended the early termination of the study because of futility. Thirty-two patients, 16 per arm, were analyzed. Favorable 6-month Glasgow Outcome Scale Extended outcomes were not statistically significantly different between hypothermia vs. normothermia groups (6 of 16, 38% vs. 4 of 16, 25%; odds ratio 1.8 [95% confidence interval 0.39 to ∞], p = .35). Plasma levels of glial fibrillary acidic protein (p = .036), but not ubiquitin C-terminal hydrolase L1 (p = .26), were lower in the patients with favorable outcome compared with those with unfavorable outcome, but differences were not identified by temperature group. Adverse events were similar between groups. CONCLUSIONS: This trial of hypothermia after acute SDH evacuation was terminated because of a low predictive probability of meeting the study objectives. There was no statistically significant difference in functional outcome identified between temperature groups

The Bar Examination

Transcript of Panel 3: The Bar Examination, from Assisting Law Students with Disabilities in the 21st Century: Brass Tacks, Washington, DC, March 28, 2007

Validity of self-reported smoking status: comparison of patients admitted to hospital with acute coronary syndrome and the general population

Many studies rely on self-reported smoking status. We hypothesized that patients with acute coronary syndrome (ACS), a smoking-related condition, would be more prone to misclassify themselves as ex-smokers, because of pressure to quit. We compared patients admitted with ACS with a general population survey conducted in the same country at a similar time. We determined whether ACS patients who classified themselves as ex-smokers (n = 635) were more likely to have cotinine levels suggestive of smoking deception than self-reported ex-smokers in the general population (n = 289). On univariate analysis, the percentage of smoking deceivers was similar among ACS patients and the general population (11% vs. 12%, p = .530). Following adjustment for age, sex and exposure to environmental tobacco smoke, ACS patients were significantly more likely to misclassify themselves (adjusted OR = 14.06, 95% CI 2.13-93.01, p = .006). There was an interaction with age whereby the probability of misclassification fell significantly with increasing age in the ACS group (adjusted OR = 0.95, 95% CI 0.93-0.97, p<.001), but not in the general population. Overall, smoking deception was more common among ACS patients than the general population. Studies comparing patients with cardiovascular disease and healthy individuals risk introducing bias if they rely solely on self-reported smoking status. Biochemical confirmation should be undertaken in such studies

Increasing physical activity and decreasing sedentary activity in adolescent girls – The Incorporating More Physical Activity and Calcium in Teens (IMPACT) study

<p>Abstract</p> <p>Background</p> <p>Lack of regular physical activity and consequent sub-optimal bone mass acquisition in youth has been implicated as a primary cause of adult-onset osteoporosis. IMPACT was a behavioral theory-based 1 1/2 year randomized controlled field study aimed at increasing bone accretion in middle school girls. The objective of this study was to determine the intervention effects of the IMPACT program upon key physical and sedentary activity endpoints among schools that participated in the IMPACT study. Endpoints examined included weight bearing physical activity (WBPA); moderate to vigorous physical activity (MVPA); vigorous physical activity (VPA); MET (metabolic equivalent) – weighted WBPA and MVPA; sedentary activity; before/after-school physical activity; and weekend physical activity.</p> <p>Methods</p> <p>Primary data analysis using a pretest-posttest control group design was conducted utilizing mixed model analysis of covariance. Data gathered from the IMPACT cohort from 2000–2002 were analyzed to determine baseline versus follow-up differences in activity endpoints. Confounders investigated included ethnicity, body mass index, menarcheal status, participation in 7^thgrade PE/athletics, friend/familial support and neighborhood safety.</p> <p>Results</p> <p>Follow-up means were higher for participating intervention schools relative to control schools for all physical activity variables but were statistically significant only for the following variables: daily minutes of vigorous physical activity (mean difference between Intervention (I) and Control (C) = 6.00↑ minutes, 95% CI = 5.82–6.18, p = 0.05), daily after school activity minutes (mean difference between I and C = 8.95↑ minutes, 95% CI = 8.69–9.21, p = 0.04), and daily weekend activity minutes (mean difference between I and C = 19.00↑ minutes, 95% CI = 18.40–19.60, p = 0.05). The intervention significantly reduced duration of student daily TV/Video watching (mean difference between I and C = 12.11↓ minutes, 95% CI = 11.74–12.48, p = 0.05) and total daily sedentary activity minutes (mean difference between I and C = 16.99↓ minutes, 95% CI = 16.49–17.50, p = 0.04).</p> <p>Conclusion</p> <p>A well designed and implemented school based health and physical activity intervention can result in a positive influence upon increasing physical activity levels and decreasing sedentary activity. Future interventions should consider a more structured intervention component to obtain significant changes in WBPA.</p

Delivering an In-Home Exercise Program via Telerehabilitation: A Pilot Study of Lung Transplant Go (LTGO)

We evaluated the feasibility, safety, system usability, and intervention acceptability of Lung Transplant Go (LTGO), an 8-week in-home exercise intervention for lung transplant recipients using a telerehabilitation platform, and described changes in physical function and physical activity from baseline to post-intervention. The intervention was delivered to lung transplant recipients in their home via the Versatile and Integrated System for TeleRehabilitation (VISYTER). The intervention focused on aerobic and strengthening exercises tailored to baseline physical function. Participants improved walk distance (6-minute walk distance), balance (Berg Balance Scale), lower body strength (30-second chair stand test) and steps walked (SenseWear Armband®). No adverse events were reported. Participants rated the program highly positively in regard to the technology and intervention. The telerehabilitation exercise program was feasible, safe, and acceptable. Our findings provide preliminary support for the LTGO intervention to improve physical function and promote physical activity in lung transplant recipients.

Energy Expenditure and Enjoyment of Active Television Viewing

International Journal of Exercise Science 9(1): 64-76, 2016. This study examined energy expenditure and enjoyment during sedentary television viewing (SED-TV), stepping in place during television commercials (COMM-TV), and physical activity prompted by common character phrases/mannerisms within a television program (PA-TV). Adults (N=38, age: 27.0±8.0 years, BMI: 25.4±4.2 kg/m2) completed three 30-minute sessions in random order: SED-TV, COMM-TV, and PA-TV. Energy expenditure and heart rate were assessed during each session. Enjoyment was assessed after the initial experimental session and at completion of the study. Energy expenditure was greater in the active versus sedentary sessions (COMM-TV vs SED-TV: difference = 32.7±1.9 kcal, p3.0 METS was lower in SED-TV (median = 0 minutes) compared to COMM-TV [median = 4.0 minutes (Inter-Quartile Range: 0.8, 7.3)] (p50% of age-predicted maximal heart rate. Both COMM-TV and PA-TV were reported to be significantly more enjoyable than SED-TV. COMM-TV and PA-TV resulted in higher energy expenditure, more minutes of moderate intensity physical activity, and higher reported enjoyment compared to SED-TV. These findings have implications for reducing sedentary time during television viewing, which may impact health-related outcomes. Intervention trials are warranted to determine the effectiveness of these strategies

THSD1 (Thrombospondin Type 1 Domain Containing Protein 1) Mutation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage

Background and Purpose A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage (SAH). This study seeks to define a specific gene whose mutation leads to disease. Methods More than 500 IA probands and 100 affected families were enrolled and clinically characterized. Whole exome sequencing was performed on a large family, revealing a segregating THSD1 mutation. THSD1 was sequenced in other probands and controls. Thsd1 loss-of-function studies in zebrafish and mice were used for in vivo analyses, and functional studies performed using an in vitro endothelial cell model. Results A nonsense mutation in THSD1 (thrombospondin type-1 domain-containing protein 1) was identified that segregated with the 9 affected (3 suffered SAH; 6 had unruptured IA) and 13 unaffected family members (LOD score 4.69). Targeted THSD1 sequencing identified mutations in 8 of 507 unrelated IA probands, including 3 who had suffered SAH (1.6% [95% CI, 0.8%–3.1%]). These THSD1 mutations/rare variants were highly enriched in our IA patient cohort relative to 89,040 chromosomes in ExAC database (p\u3c0.0001). In zebrafish and mice, Thsd1 loss-of-function caused cerebral bleeding (which localized to the subarachnoid space in mice) and increased mortality. Mechanistically, THSD1 loss impaired endothelial cell focal adhesion to the basement membrane. These adhesion defects could be rescued by expression of wild-type THSD1 but not THSD1 mutants identified in IA patients. Conclusions This report identifies THSD1 mutations in familial and sporadic IA patients, and shows that THSD1 loss results in cerebral bleeding in two animal models. This finding provides new insight into IA and SAH pathogenesis and provides new understanding of THSD1 function, which includes endothelial cell to extracellular matrix adhesion