Basic and Clinical Studies of Pharmacologic Effects on Recovery from Brain Injury

Investigations in laboratory animals indicate that certain drugs that influence specific neurotransmitters can have profound effects on the recovery process. Even small doses of some drugs given after brain injury facilitate recovery while others are harmful. Preliminary clinical studies suggest that the same drugs that enhance recovery in laboratory animals (e.g., amphetamine) may have similar effects in humans after stroke. In addition, some of the drugs that impair recovery of function after focal brain injury in laboratory animals (e.g. haloperidol, benzodiazepines, clonidine, prazosin, phenytoin) are commonly given to stroke patients for coincident medical problems and may interfere with functional recovery in humans. Until the impact of pharmacologic agents on the recovering brain is better understood, the available data suggest that care should be exercised in the selection of drugs used in the treatment of the recovering stroke patient. Pharmacologic enhancement of recovery after focal brain injury may be possible in humans

Accuracy of ICD-9-CM Codes by Hospital Characteristics and Stroke Severity: Paul Coverdell National Acute Stroke Program

Background—Epidemiological and health services research often use International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM) codes to identify patients with clinical conditions in administrative databases. We determined whether there are systematic variations between stroke patient clinical diagnoses and ICD‐9‐CM codes, stratified by hospital characteristics and stroke severity. Methods and Results—We used the records of patients discharged from hospitals participating in the Paul Coverdell National Acute Stroke Program in 2013. Within this stroke‐enriched cohort, we compared agreement between the attending physician\u27s clinical diagnosis and principal ICD‐9‐CM code and determined whether disagreements varied by hospital characteristics (presence of a stroke unit, stroke team, number of hospital beds, and hospital location). For patients with a documented National Institutes of Health Stroke Scale score at admission, we assessed whether diagnostic agreement varied by stroke severity. Agreement was generally high (\u3e 89%); differences between the physician diagnosis and ICD‐9‐CM codes were primarily attributed to discordance between ischemic stroke and transient ischemic attack (TIA), and subarachnoid and intracerebral hemorrhage. Agreement was higher for patients in metropolitan hospitals with stroke units, stroke teams, and \u3e 200 beds (all P \u3c 0.001). Agreement was lowest (60.3%) for rural hospitals with ≤ 200 beds and without stroke units or teams. Agreement was also lower for milder (94.9%) versus more‐severe (96.4%) ischemic strokes (P \u3c 0.001). Conclusions—We identified disagreements in stroke/TIA coding by hospital characteristics and stroke severity, particularly for milder ischemic strokes. Such systematic variations in ICD‐9‐CM coding practices can affect stroke case identification in epidemiological studies and may have implications for hospital‐level quality metric

Influence of Dietary Salt Knowledge, Perceptions, and Beliefs on Consumption Choices After Stroke in Uganda

Background Previous research on Uganda\u27s poststroke population revealed that their level of dietary salt knowledge did not lead to healthier consumption choices. Purpose Identify barriers and motivators for healthy dietary behaviors and evaluate the understanding of widely accepted salt regulation mechanisms among poststroke patients in Uganda. Methods Convergent parallel mixed methods triangulation design comprised a cross-sectional survey (n = 81) and 8 focus group discussions with 7-10 poststroke participants in each group. We assessed participant characteristics and obtained insights into their salt consumption attitudes, perceptions, and knowledge. Qualitative responses were analyzed using an inductive approach with thematic analytic procedures. Relationships between healthy dietary salt compliance, dietary salt knowledge, and participant characteristics were assessed using logistic regression analyses. Results Healthy dietary salt consumption behaviors were associated with basic salt knowledge (P \u3c  .0001), but no association was found between compliance and salt disease-related knowledge (P = .314). Only 20% and 7% obtained health-related salt knowledge from their health facility and educational sources, respectively, whereas 44% obtained this information from media personalities; 92% of participants had no understanding of nutrition labels, and only 25% of the study population consumed potash—an inexpensive salt substitute that is both rich in potassium and low in sodium. Conclusion One barrier to healthy dietary consumption choices among Uganda\u27s stroke survivors is a lack of credible disease-related information. Improving health-care provider stroke-related dietary knowledge in Uganda and encouraging the use of potash as a salt substitute would help reduce hypertension and thereby lower the risk of stroke

Chronic Systemic Immune Dysfunction in African-Americans with Small Vessel-Type Ischemic Stroke

The incidence of small vessel-type (lacunar) ischemic strokes is greater in African-Americans compared to whites. The chronic inflammatory changes that result from lacunar stroke are poorly understood. To elucidate these changes, we measured serum inflammatory and thrombotic biomarkers in African-Americans at least 6 weeks post-stroke compared to control individuals. Cases were African-Americans with lacunar stroke (n = 30), and controls were age-matched African-Americans with no history of stroke or other major neurologic disease (n = 37). Blood was obtained \u3e 6 weeks post-stroke and was analyzed for inflammatory biomarkers. Freshly isolated peripheral blood mononuclear cells were stimulated with lipopolysaccharide (LPS) to assess immune responsiveness in a subset of cases (n = 5) and controls (n = 4). After adjustment for covariates, the pro-inflammatory biomarkers, soluble vascular cadherin adhesion molecule-1 (sVCAM-1) and thrombin anti-thrombin (TAT), were independently associated with lacunar stroke. Immune responsiveness to LPS challenge was abnormal in cases compared to controls. African-Americans with lacunar stroke had elevated blood levels of VCAM-1 and TAT and an abnormal response to acute immune challenge \u3e 6 weeks post-stroke, suggesting a chronically compromised systemic inflammatory response

Analysis of cumulative strain in tendons and tendon sheaths

Twenty-five fresh frozen flexor digitorum profundus tendons stratified by sex were subjected to uniaxial step stress and cyclic loads in twelve intact human cadaver hands. By attaching specially designed clip strain gage transducers on tendons just proximal and distal to an undisrupted carpal tunnel, the interactions of the tendons, tendon sheath and retinacula were measured.The elastic and viscous response of the tendon composites to step stresses were found to fit fractional power functions of stress and time respectively. A significant and quantifiable decrease in strain from the proximal to the distal tendon segment was found to be a function of wrist deviation.The results indicate that an accumulation of strain does occur in tendinous tissues during physiologic loading.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26842/1/0000402.pd

Brain Microvascular Injury and White Matter Disease Provoked by Diabetes-Associated Hyperamylinemia

OBJECTIVE: The brain blood vessels of patients with type 2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone cosecreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by amylin transport in the brain via plasma apolipoproteins. METHODS: Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses of human brain tissues and studied the effects of the aggregated amylin on endothelial cells ex vivo. RESULTS: Amylin deposition in brain blood vessels is associated with vessel wall disruption and abnormal surrounding neuropil in patients with type 2 diabetes and dementia, in HIP rats, and in AKO rats infused with aggregated amylin. HIP rats have brain microhemorrhages, white matter injury, and neurologic deficits. Vascular amylin deposition provokes loss of endothelial cell coverage and tight junctions. Intravenous infusion in AKO rats of human amylin, or combined human amylin and apolipoprotein E4, showed that amylin binds to plasma apolipoproteins. The intravenous infusion of apolipoprotein E4 exacerbated the brain accumulation of aggregated amylin and vascular pathology in HIP rats. INTERPRETATION: These data identify vascular amylin deposition as a trigger of brain endothelial dysfunction that is modulated by plasma apolipoproteins and represents a potential therapeutic target in diabetes-associated dementia and stroke. Ann Neurol 2017;82:208-222

Hierarchical Clustering Analyses of Plasma Proteins in Subjects With Cardiovascular Risk Factors Identify Informative Subsets Based on Differential Levels of Angiogenic and Inflammatory Biomarkers

Agglomerative hierarchical clustering analysis (HCA) is a commonly used unsupervised machine learning approach for identifying informative natural clusters of observations. HCA is performed by calculating a pairwise dissimilarity matrix and then clustering similar observations until all observations are grouped within a cluster. Verifying the empirical clusters produced by HCA is complex and not well studied in biomedical applications. Here, we demonstrate the comparability of a novel HCA technique with one that was used in previous biomedical applications while applying both techniques to plasma angiogenic (FGF, FLT, PIGF, Tie-2, VEGF, VEGF-D) and inflammatory (MMP1, MMP3, MMP9, IL8, TNFα) protein data to identify informative subsets of individuals. Study subjects were diagnosed with mild cognitive impairment due to cerebrovascular disease (MCI-CVD). Through comparison of the two HCA techniques, we were able to identify subsets of individuals, based on differences in VEGF (p \u3c 0.001), MMP1 (p \u3c 0.001), and IL8 (p \u3c 0.001) levels. These profiles provide novel insights into angiogenic and inflammatory pathologies that may contribute to VCID

Observational constraints on the global atmospheric budget of ethanol

Energy security and climate change concerns have led to the promotion of biomass-derived ethanol, an oxygenated volatile organic compound (OVOC), as a substitute for fossil fuels. Although ethanol is ubiquitous in the troposphere, our knowledge of its current atmospheric budget and distribution is limited. Here, for the first time we use a global chemical transport model in conjunction with atmospheric observations to place constraints on the ethanol budget, noting that additional measurements of ethanol (and its precursors) are still needed to enhance confidence in our estimated budget. Global sources of ethanol in the model include 5.0 Tg yr−1 from industrial sources and biofuels, 9.2 Tg yr−1 from terrestrial plants, ~0.5 Tg yr−1 from biomass burning, and 0.05 Tg yr−1 from atmospheric reactions of the ethyl peroxy radical (C2H5O2) with itself and with the methyl peroxy radical (CH3O2). The resulting atmospheric lifetime of ethanol in the model is 2.8 days. Gas-phase oxidation by the hydroxyl radical (OH) is the primary global sink of ethanol in the model (65%), followed by dry deposition (25%), and wet deposition (10%). Over continental areas, ethanol concentrations predominantly reflect direct anthropogenic and biogenic emission sources. Uncertainty in the biogenic ethanol emissions, estimated at a factor of three, may contribute to the 50% model underestimate of observations in the North American boundary layer. Current levels of ethanol measured in remote regions are an order of magnitude larger than those in the model, suggesting a major gap in understanding. Stronger constraints on the budget and distribution of ethanol and OVOCs are a critical step towards assessing the impacts of increasing the use of ethanol as a fuel

White Matter Hyperintensity Regression: Comparison of Brain Atrophy and Cognitive Profiles with Progression and Stable Groups

Subcortical white matter hyperintensities (WMHs) in the aging population frequently represent vascular injury that may lead to cognitive impairment. WMH progression is well described, but the factors underlying WMH regression remain poorly understood. A sample of 351 participants from the Alzheimer’s Disease Neuroimaging Initiative 2 (ADNI2) was explored who had WMH volumetric quantification, structural brain measures, and cognitive measures (memory and executive function) at baseline and after approximately 2 years. Selected participants were categorized into three groups based on WMH change over time, including those that demonstrated regression (n = 96; 25.5%), stability (n = 72; 19.1%), and progression (n = 209; 55.4%). There were no significant differences in age, education, sex, or cognitive status between groups. Analysis of variance demonstrated significant differences in atrophy between the progression and both regression (p = 0.004) and stable groups (p = 0.012). Memory assessments improved over time in the regression and stable groups but declined in the progression group (p = 0.003; p = 0.018). WMH regression is associated with decreased brain atrophy and improvement in memory performance over two years compared to those with WMH progression, in whom memory and brain atrophy worsened. These data suggest that WMHs are dynamic and associated with changes in atrophy and cognition