Lateral Fluid Percussion Injury Impairs Hippocampal Synaptic Soluble N-Ethylmaleimide Sensitive Factor Attachment Protein Receptor Complex Formation

Traumatic brain injury (TBI) and the activation of secondary injury mechanisms have been linked to impaired cognitive function, which, as observed in TBI patients and animal models, can persist for months and years following the initial injury. Impairments in neurotransmission have been well documented in experimental models of TBI, but the mechanisms underlying this dysfunction are poorly understood. Formation of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex facilitates vesicular docking and neurotransmitter release in the synaptic cleft. Published studies highlight a direct link between reduced SNARE complex formation and impairments in neurotransmitter release. While alterations in the SNARE complex have been described following severe focal TBI, it is not known if deficits in SNARE complex formation manifest in a model with reduced severity. We hypothesized that lateral fluid percussion injury (lFPI) reduces the abundance of SNARE proteins, impairs SNARE complex formation, and contributes to impaired neurobehavioral function. To this end, rats were subjected to lFPI or sham injury and tested for acute motor performance and cognitive function at 3 weeks post-injury. lFPI resulted in motor impairment between 1 and 5 days post-injury. Spatial acquisition and spatial memory, as assessed by the Morris water maze, were significantly impaired at 3 weeks after lFPI. To examine the effect of lFPI on synaptic SNARE complex formation in the injured hippocampus, a separate cohort of rats was generated and brains processed to evaluate hippocampal synaptosomal-enriched lysates at 1 week post-injury. lFPI resulted in a significant reduction in multiple monomeric SNARE proteins, including VAMP2, and α-synuclein, and SNARE complex abundance. The findings in this study are consistent with our previously published observations suggesting that impairments in hippocampal SNARE complex formation may contribute to neurobehavioral dysfunction associated with TBI

Field-based multiplex and quantitative assay platforms for diagnostics

The U.S. military has a continued interest in the development of handheld, field-usable sensors and test kits for a variety of diagnostic applications, such as traumatic brain injury (TBI) and infectious diseases. Field-use presents unique challenges for biosensor design, both for the readout unit and for the biological assay platform. We have developed robust biosensor devices that offer ultra-high sensitivity and also meet field-use needs. The systems under development include a multiplexed quantitative lateral flow test strip for TBI diagnostics, a field test kit for the diagnosis of pathogens endemic to the Middle East, and a microfluidic assay platform with a label-free reader for performing complex biological automated assays in the field

Erythropoietin Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy

Experimental studies targeting traumatic brain injury (TBI) have reported that erythropoietin (EPO) is an endogenous neuroprotectant in multiple models. In addition to its neuroprotective effects, it has also been shown to enhance reparative processes including angiogenesis and neurogenesis. Based on compelling pre-clinical data, EPO was tested by the Operation Brain Trauma Therapy (OBTT) consortium to evaluate therapeutic potential in multiple TBI models along with biomarker assessments. Based on the pre-clinical TBI literature, two doses of EPO (5000 and 10,000 IU/kg) were tested given at 15 min after moderate fluid percussion brain injury (FPI), controlled cortical impact (CCI), or penetrating ballistic-like brain injury (PBBI) with subsequent behavioral, histopathological, and biomarker outcome assessments. There was a significant benefit on beam walk with the 5000 IU dose in CCI, but no benefit on any other motor task across models in OBTT. Also, no benefit of EPO treatment across the three TBI models was noted using the Morris water maze to assess cognitive deficits. Lesion volume analysis showed no treatment effects after either FPI or CCI; however, with the 5000 IU/kg dose of EPO, a paradoxical increase in lesion volume and percent hemispheric tissue loss was seen after PBBI. Biomarker assessments included measurements of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) in blood at 4 or 24 h after injury. No treatment effects were seen on biomarker levels after FPI, whereas treatment at either dose exacerbated the increase in GFAP at 24 h in PBBI but attenuated 24-4 h delta UCH-L1 levels at high dose in CCI. Our data indicate a surprising lack of efficacy of EPO across three established TBI models in terms of behavioral, histopathological, and biomarker assessments. Although we cannot rule out the possibility that other doses or more prolonged treatment could show different effects, the lack of efficacy of EPO reduced enthusiasm for its further investigation in OBTT

Polynitroxylated Pegylated Hemoglobin: A Novel Neuroprotective Hemoglobin for Acute Volume-Limited Fluid Resuscitation After Combined Traumatic Brain Injury and Hemorrhagic Hypotension in Mice

Objective: Resuscitation of hemorrhagic hypotension after traumatic brain injury is challenging. A hemoglobin-based oxygen carrier may offer advantages. The novel therapeutic hemoglobin-based oxygen carrier, polynitroxylated pegylated hemoglobin (PNPH), may represent a neuroprotective hemoglobin-based oxygen carrier for traumatic brain injury resuscitation.Hypotheses: 1) PNPH is a unique non-neurotoxic hemoglobin-based oxygen carrier in neuronal culture and is neuroprotective in in vitro neuronal injury models. 2) Resuscitation with PNPH would require less volume to restore mean arterial blood pressure than lactated Ringer\u27s or Hextend and confer neuroprotection in a mouse model of traumatic brain injury plus hemorrhagic hypotension.Design: Prospective randomized, controlled experimental study.Setting: University center.Measurements and Main Results: In rat primary cortical neuron cultures, control bovine hemoglobin was neurotoxic (lactate dehydrogenase release; 3-[4,5-dimethylthiazol-2-yl-]-2,5-diphenyltetrazolium bromide assay) at concentrations from 12.5 to 0.625 [mu]M, whereas polyethylene glycol-conjugated hemoglobin showed intermediate toxicity. PNPH was not neurotoxic (p \u3c .05 vs. bovine hemoglobin and polyethylene glycol hemoglobin; all concentrations). PNPH conferred neuroprotection in in vitro neuronal injury (glutamate/glycine exposure and neuronal stretch), as assessed via lactate dehydrogenase and 3-[4,5-dimethylthiazol-2-yl-]-2,5-diphenyltetrazolium bromide (all p \u3c .05 vs. control). C57BL6 mice received controlled cortical impact followed by hemorrhagic hypotension (2 mL/100 g, mean arterial blood pressure ~35-40 mm Hg) for 90 min. Mice were resuscitated (mean arterial blood pressure \u3e50 mm Hg for 30 min) with lactated Ringer\u27s, Hextend, or PNPH, and then shed blood was reinfused. Mean arterial blood pressures, resuscitation volumes, blood gasses, glucose, and lactate were recorded. Brain sections at 7 days were examined via hematoxylin and eosin and Fluoro-Jade C (identifying dying neurons) staining in CA1 and CA3 hippocampus. Resuscitation with PNPH or Hextend required less volume than lactated Ringer\u27s (both p \u3c .05). PNPH but not Hextend improved mean arterial blood pressure vs. lactated Ringer\u27s (p \u3c .05). Mice resuscitated with PNPH had fewer Fluoro-Jade C positive neurons in CA1 vs. Hextend and lactated Ringer\u27s, and CA3 vs. Hextend (p \u3c .05).Conclusions: PNPH is a novel neuroprotective hemoglobin-based oxygen carrier in vitro and in vivo that may offer unique advantages for traumatic brain injury resuscitation

Neuroplasticity and functional recovery: Training models and compensatory strategies in music therapy

New research developments in the recovery of function following neurological trauma as well as basic and applied research relevant to music perception and production, seem to point to the suggestion that specific music therapy interventions that irectly address the restoration of function as opposed to developing compensatory mechanisms, in certain circumstances, may now be a more appropriate treatment approach. We will address the issue of appropriate timing for the introduction of each strategy and discuss potential outcomes of each approach. As one might imagine, much of this research is published in the neurological journals, which music herapists may not regularly consult. It seems challenging enough just to keep abreast of new music therapy literature. Further, there is so much neurological research that the music therapy clinician often finds it difficult to know where to begin. This text provides an overview of a growing concept related to recovery known as neuroplasticity, and how specific training models in music therapy utilize this relatively recently identified phenomenon. Also, a framework will be provided to help guide the practicing clinician when attempting to build a lineage of systematic thought relevant to the use of music in neurorehabilitation, as well as discuss the frequently employed concept of behavioural compensation. Some music therapy literature that relates to these different concepts is outlined. Discussions surrounding the decision to use either of these two approaches are presented in relation to stages of recovery and the clinical presentation of the client

Elephant (Loxodonta africana) Home Ranges in Sabi Sand Reserve and Kruger National Park: A Five-Year Satellite Tracking Study

During a five-year GPS satellite tracking study in Sabi Sand Reserve (SSR) and Kruger National Park (KNP) we monitored the daily movements of an elephant cow (Loxodonta africana) from September 2003 to August 2008. The study animal was confirmed to be part of a group of seven elephants therefore her position is representative of the matriarchal group. We found that the study animal did not use habitat randomly and confirmed strong seasonal fidelity to its summer and winter five-year home ranges. The cow's summer home range was in KNP in an area more than four times that of her SSR winter home range. She exhibited clear park habitation with up to three visits per year travelling via a well-defined northern or southern corridor. There was a positive correlation between the daily distance the elephant walked and minimum daily temperature and the elephant was significantly closer to rivers and artificial waterholes than would be expected if it were moving randomly in KNP and SSR. Transect lines established through the home ranges were surveyed to further understand the fine scale of the landscape and vegetation representative of the home ranges

Acute kidney disease and renal recovery : consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of > 90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD

Working in the Public Interest Law Conference

Entirely student organized, WIPI seeks to bring together eminent practitioners in their respective fields, students, and faculty to discuss practical approaches to lawyering which can best serve the poor. Practical methods of challenging poverty are often not covered in traditional law school courses. This conference seeks to remedy that and provide dynamic, creative ways to combat poverty through the vehicle of the law

The influence of contextual factors on healthcare quality improvement initiatives:a realist review

Background Recognising the influence of context and the context-sensitive nature of quality improvement (QI) interventions is crucial to implementing effective improvements and successfully replicating them in new settings, yet context is still poorly understood. To address this challenge, it is necessary to capture generalisable knowledge, first to understand which aspects of context are most important to QI and why, and secondly, to explore how these factors can be managed to support healthcare improvement, in terms of implementing successful improvement initiatives, achieving sustainability and scaling interventions. The research question was how and why does context influence quality improvement initiatives in healthcare? Methods A realist review explored the contextual conditions that influence healthcare improvement. Realist methodology integrates theoretical understanding and stakeholder input with empirical research findings. The review aimed to identify and understand the role of context during the improvement cycle, i.e. planning, implementation, sustainability and transferability; and distil new knowledge to inform the design and development of context-sensitive QI initiatives. We developed a preliminary theory of the influence of context to arrive at a conceptual and theoretical framework. Results Thirty-five studies were included in the review, demonstrating the interaction of key contextual factors across healthcare system levels during the improvement cycle. An evidence-based explanatory theoretical model is proposed to illustrate the interaction between contextual factors, system levels (macro, meso, micro) and the stages of the improvement journey. Findings indicate that the consideration of these contextual factors would enhance the design and delivery of improvement initiatives, across a range of improvement settings. Conclusions This is the first realist review of context in QI and contributes to a deeper understanding of how context influences quality improvement initiatives. The distillation of key contextual factors offers the potential to inform the design and development of context-sensitive interventions to enhance improvement initiatives and address the challenge of spread and sustainability. Future research should explore the application of our conceptual model to enhance improvement-planning processes