William P. Meehan

Blood pressure lowering by pioglitazone. Evidence for a direct vascular effect.

To examine potential mechanisms for the blood pressure-lowering action of the thiazolidinedione compound, pioglitazone (PIO), we studied the effects of the drug on blood pressure and insulin action in vivo and on vascular tissue in vitro. In vivo, PIO lowered blood pressure in fructose-fed and chow-fed rats to an extent that could not be explained by alterations in fasting plasma insulin or free magnesium concentrations or by alterations in whole-body insulin sensitivity. In vitro, PIO caused significant blunting of the contractile responses of aortic rings to NE, arginine vasopressin (AVP), and potassium chloride; the blunting of responses to NE was maintained after removal of the endothelium. To assess the potential importance of extracellular calcium to the vasodepressor effect of PIO, we measured contractile responses to NE in the absence of calcium, and then after acute restoration of calcium in the presence of NE. PIO had no effect on the contractile response in the absence of calcium. By contrast, PIO blunted by 42% the contractile response that occurred when the extracellular calcium supply was acutely restored in the presence of NE, suggesting that the blunting was mediated by blockade of calcium uptake by vascular smooth muscle. Such an effect was confirmed in cultured a7r5 vascular smooth muscle cells, which exhibited a brisk increase in intracellular calcium in response to AVP that was blocked by PIO in a dose-dependent fashion. Our data indicate that PIO has a direct vascular effect that appears to be mediated at least in part by inhibition of agonist-mediated calcium uptake by vascular smooth muscle. The direct vascular effect may contribute to the blood pressure-lowering actions of PIO in vivo, because that effect could not be explained by alterations in whole-body insulin sensitivity.

Consensus statement on concussion in sport-the 5th international conference on concussion in sport held in Berlin, October 2016

The 2017 Concussion in Sport Group (CISG) consensus statement is designed to build on the principles outlined in the previous statements1–4 and to develop further conceptual understanding of sport-related concussion (SRC) using an expert consensus-based approach. This document is developed for physicians and healthcare providers who are involved in athlete care, whether at a recreational, elite or professional level. While agreement exists on the principal messages conveyed by this document, the authors acknowledge that the science of SRC is evolving and therefore individual management and return-to-play decisions remain in the realm of clinical judgement. This consensus document reflects the current state of knowledge and will need to be modified as new knowledge develops. It provides an overview of issues that may be of importance to healthcare providers involved in the management of SRC. This paper should be read in conjunction with the systematic reviews and methodology paper that accompany it. First and foremost, this document is intended to guide clinical practice; however, the authors feel that it can also help form the agenda for future research relevant to SRC by identifying knowledge gaps. A series of specific clinical questions were developed as part of the consensus process for the Berlin 2016 meeting. Each consensus question was the subject of a specific formal systematic review, which is published concurrently with this summary statement. Readers are directed to these background papers in conjunction with this summary statement as they provide the context for the issues and include the scope of published research, search strategy and citations reviewed for each question. This 2017 consensus statement also summarises each topic and recommendations in the context of all five CISG meetings (that is, 2001, 2004, 2008, 2012 as well as 2016). Approximately 60 000 published articles were screened by the expert panels for the Berlin …

High School Concussions in the 2008-2009 Academic Year Mechanism, Symptoms, and Management

Background An estimated 136 000 concussions occur per academic year in high schools alone. The effects of repetitive concussions and the potential for catastrophic injury have made concussion an injury of significant concern for young athletes. Purpose The objective of this study was to describe the mechanism of injury, symptoms, and management of sport-related concussions using the High School Reporting Information Online (HS RIO) surveillance system. Study Design Descriptive epidemiology study. Methods All concussions recorded by HS RIO during the 2008-2009 academic year were included. Analyses were performed using SPSS software. Chi-square analysis was performed for all categorical variables. Statistical significance was considered for P < .05. Results A total of 544 concussions were recorded. The most common mechanism (76.2%) was contact with another player, usually a head-to-head collision (52.7%). Headache was experienced in 93.4%; 4.6% lost consciousness. Most (83.4%) had resolution of their symptoms within 1 week. Symptoms lasted longer than 1 month in 1.5%. Computerized neuropsychological testing was used in 25.7% of concussions. When neuropsychological testing was used, athletes were less likely to return to play within 1 week than those for whom it was not used (13.6% vs 32.9%; P < .01). Athletes who had neuropsychological testing appeared less likely to return to play on the same day (0.8% vs 4.2%; P = .056). A greater proportion of injured, nonfootball athletes had computerized neuropsychological testing than injured football players (23% vs 32%; P = .02) Conclusion When computerized neuropsychological testing is used, high school athletes are less likely to be returned to play within 1 week of their injury. Concussed football players are less likely to have computerized neuropsychological testing than those participating in other sports. Loss of consciousness is relatively uncommon among high school athletes who sustain a sport-related concussion. The most common mechanism is contact with another player. Some athletes (1.5%) report symptoms lasting longer than 1 month.

Sport-Related Concussion

Sport-related concussion is a common injury in children and adolescents. Athletes seldom report concussive symptoms, which makes the diagnosis a challenge. The management of sport-related concussion has changed significantly over the last several years. The previously used grading systems and return-to-play guidelines have been abandoned in favor of more individualized assessment and management. Neuropsychological testing is being used more frequently to assist in management. After recovery, it is recommended that an athletes return-to-play progress in a gradual, stepwise fashion while being monitored by a health care provider. Proper assessment and management of a sport-related concussion is crucial, because repeat concussions can result in decreased neurocognitive functioning, increased symptomatology, and, at times, catastrophic outcomes.

Time Interval Between Concussions and Symptom Duration

OBJECTIVE: To test the hypothesis that children with a previous history of concussion have a longer duration of symptoms after a repeat concussion than those without such a history. METHODS: Prospective cohort study of consecutive patients 11 to 22 years old presenting to the emergency department of a childrens hospital with an acute concussion. The main outcome measure was time to symptom resolution, assessed by the Rivermead Post-Concussion Symptoms Questionnaire (RPSQ). Patients and providers completed a questionnaire describing mechanism of injury, associated symptoms, past medical history, examination findings, diagnostic studies, and the RPSQ. Patients were then serially administered the RPSQ for 3 months after the concussion or until all symptoms resolved. RESULTS: A total of 280 patients were enrolled over 12 months. Patients with a history of previous concussion had a longer duration of symptoms than those without previous concussion (24 vs 12 days, P = .02). Median symptom duration was even longer for patients with multiple previous concussions (28 days, P = .03) and for those who had sustained a concussion within the previous year (35 days, P = .007) compared with patients without those risk factors. In a multivariate model, previous concussion, absence of loss of consciousness, age ≥13, and initial RPSQ score >18 were significant predictors of prolonged recovery. CONCLUSIONS: Children with a history of a previous concussion, particularly recent or multiple concussions, are at increased risk for prolonged symptoms after concussion. These findings have direct implications on the management of patients with concussion who are at high risk for repeat injuries.

Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy

Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer’s disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term ‘cistauosis’, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer’s disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy (CTE) and Alzheimers disease (AD), whose defining pathologic features include tauopathy made of phosphorylated tau (p-tau). However, tauopathy has not been detected in early stages after TBI and how TBI leads to tauopathy is unknown. Here we find robust cis p-tau pathology after sport- and military-related TBI in humans and mice. Acutely after TBI in mice and stress in vitro, neurons prominently produce cis p-tau, which disrupts axonal microtubule network and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, termed “cistauosis”, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis p-tau is a major early driver after TBI and leads to tauopathy in CTE and AD, and cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.

Effect of Cognitive Activity Level on Duration of Post-Concussion Symptoms

OBJECTIVE: To determine the effect of cognitive activity level on duration of post-concussion symptoms. METHODS: We conducted a prospective cohort study of patients who presented to a Sports Concussion Clinic within 3 weeks of injury between October 2009 and July 2011. At each visit, patients completed a scale that recorded their average level of cognitive activity since the previous visit. The product of cognitive activity level and days between visits (cognitive activity-days) was calculated and divided into quartiles. Kaplan-Meier Product Limit method was used to generate curves of symptom duration based on cognitive activity level. To adjust for other possible predictors of concussion recovery, we constructed a Cox proportional hazard model with cognitive activity-days as the main predictor. RESULTS: Of the 335 patients included in the study, 62% were male, 19% reported a loss of consciousness, and 37% reported experiencing amnesia at the time of injury. The mean age of participants was 15 years (range, 8–23) and the mean number of previous concussions was 0.76; 39% of athletes had sustained a previous concussion. The mean Post-Concussion Symptom Scale score at the initial visit was 30 (SD, 26). The overall mean duration of symptoms was 43 days (SD, 53). Of all variables assessed, only total symptom burden at initial visit and cognitive activity level were independently associated with duration of symptoms. CONCLUSIONS: Increased cognitive activity is associated with longer recovery from concussion. This study supports the use of cognitive rest and adds to the current consensus opinion.

Pediatric concussions in United States emergency departments in the years 2002 to 2006.

OBJECTIVES To estimate the incidence and demographics of concussions in children coming to emergency departments (EDs) in the United States and describe the rates of neuroimaging and follow-up instructions in these patients. STUDY DESIGN This is a cross-sectional study of children 0 to 19 years old diagnosed with concussion from the National Hospital Ambulatory Medical Care Survey. National Hospital Ambulatory Medical Care Survey collects data on approximately 25,000 visits annually to 600 randomly selected hospital emergency and outpatient departments. We examined visits to United States emergency departments between 2002 and 2006. Simple descriptive statistics were used. RESULTS Of the 50,835 pediatric visits in the 5-year sample, 230 observations, representing 144,000 visits annually, were for concussions. Sixty-nine percent of concussion visits were by males. Thirty percent were sports-related. Sixty-nine percent of patients diagnosed with a concussion had head imaging. Twenty-eight percent of patients were discharged without specific instructions to follow-up with an outpatient provider for further treatment. CONCLUSIONS Approximately 144,000 pediatric patients present to emergency departments each year with a concussion. Most of these patients undergo computed tomography of the head, and nearly one-third are discharged without specific instructions to follow-up with an outpatient provider for further treatment.

Symptom Severity Predicts Prolonged Recovery after Sport-Related Concussion, but Age and Amnesia Do Not

OBJECTIVE To identify predictors of prolonged symptoms in athletes who sustain concussions. STUDY DESIGN This was a multicenter prospective cohort study of patients in 2 sport concussion clinics. Possible predictors of prolonged symptoms from concussion were compared in 2 groups, those whose symptoms resolved within 28 days and those whose symptoms persisted beyond 28 days. Candidate predictor variables were entered into a logistic regression model that was used to generate aORs. RESULTS A total of 182 patients met the inclusion criteria during the study period. The mean patient age was 15.2 ± 3.04 years. More than one-third of the patients (n = 65) underwent computerized neurocognitive testing on their initial visit. On univariate analyses, Post-Concussion Symptom Scale (PCSS) score and all composite scores on computerized neurocognitive testing were apparently associated with prolonged symptom duration. Sex, age, loss of consciousness at time of injury, and amnesia at time of injury were not associated with prolonged symptom duration. After adjusting for potential confounding, only total PCSS score was associated with the odds of suffering prolonged symptoms. CONCLUSION Further efforts to develop clinical tools for predicting which athletes will suffer prolonged recoveries after concussion should focus on initial symptom score.

Duration and Course of Post-Concussive Symptoms

OBJECTIVES: To examine the incidence, duration, and clinical course of individual post-concussive symptoms in patients presenting to a pediatric emergency department (ED) with a concussion. METHODS: We conducted secondary analysis of a prospective cohort study of patients 11 to 22 years old presenting to the ED of a children’s hospital with an acute concussion. The main outcome measure was duration of symptoms, assessed by the Rivermead Post-Concussion Symptoms Questionnaire (RPSQ). Patients initially completed a questionnaire describing mechanism of injury, associated symptoms, past medical history, and the RPSQ, then were serially administered the RPSQ for 3 months after the concussion or until all symptoms resolved. RESULTS: Headache, fatigue, dizziness, and taking longer to think were the most common symptoms encountered at presentation, whereas sleep disturbance, frustration, forgetfulness, and fatigue were the symptoms most likely to develop during the follow-up period that had not initially been present. Median duration of symptoms was the longest for irritability (16 days), sleep disturbance (16 days), frustration (14 days), and poor concentration (14 days), whereas nausea, depression, dizziness, and double-vision abated most quickly. One month after injury, nearly a quarter of children still complained of headache, >20% suffered from fatigue, and nearly 20% reported taking longer to think. CONCLUSIONS: Among patients presenting to a pediatric ED after a concussion, physical symptoms such as headache predominate immediately after the injury, emotional symptoms tend to develop later in the recovery period, and cognitive symptoms may be present throughout.