Arginase overexpression in neurons and its effect on traumatic brain injury.

Arginine is a semi-essential amino acid which serves as a substrate for nitric oxide (NO) production by nitric oxide synthase (NOS) and a precursor for various metabolites including ornithine, creatine, polyamines, and agmatine. Arginase competes with nitric oxide synthase for substrate arginine to produce orthinine and urea. There is contradictory evidence in the literature on the role of nitric oxide in the pathophysiology of traumatic brain injury (TBI). These contradictory perspectives are likely due to different NOS isoforms - endothelial (eNOS), inducible (iNOS) and neuronal (nNOS) which are expressed in the central nervous system. Of these, the role of nNOS in acute injury remains less clear. This study aimed to employ a genetic approach by overexpressing arginase isoforms specifically in neurons using a Thy-1 promoter to manipulate cell autonomous NO production in the context of TBI. The hypothesis was that increased arginase would divert arginine from pathological NO production. We generated 2 mouse lines that overexpress arginase I (a cytoplasmic enzyme) or arginase II (a mitochondrial enzyme) in neurons of FVB mice. We found that two-weeks after induction of controlled cortical injury, overexpressing arginase I but not arginase II in neurons significantly reduced contusion size and contusion index compared to wild-type (WT) mice. This study establishes enhanced neuronal arginase levels as a strategy to affect the course of TBI and provides support for the potential role of neuronal NO production in this condition.

Recent US Case of Variant Creutzfeldt-Jakob Disease-Global Implications.

Variant Creutzfeldt-Jakob disease (vCJD) is a rare, fatal prion disease resulting from transmission to humans of the infectious agent of bovine spongiform encephalopathy. We describe the clinical presentation of a recent case of vCJD in the United States and provide an update on diagnostic testing. The location of this patient's exposure is less clear than those in the 3 previously reported US cases, but strong evidence indicates that exposure to contaminated beef occurred outside the United States more than a decade before illness onset. This case exemplifies the persistent risk for vCJD acquired in unsuspected geographic locations and highlights the need for continued global surveillance and awareness to prevent further dissemination of vCJD.

Common data elements for traumatic brain injury: recommendations from the biospecimens and biomarkers working group.

Recent advances in genomics, proteomics, and biotechnology have provided unprecedented opportunities for translational research and personalized medicine. Human biospecimens and biofluids represent an important resource from which molecular data can be generated to detect and classify injury and to identify molecular mechanisms and therapeutic targets. To date, there has been considerable variability in biospecimen and biofluid collection, storage, and processing in traumatic brain injury (TBI) studies. To realize the full potential of this important resource, standardization and adoption of best practice guidelines are required to insure the quality and consistency of these specimens. The aim of the Biospecimens and Biomarkers Working Group was to provide recommendations for core data elements for TBI research and develop best practice guidelines to standardize the quality and accessibility of these specimens. Consensus recommendations were developed through interactions with focus groups and input from stakeholders participating in the interagency workshop on Standardization of Data Collection in TBI and Psychological Health held in Washington, DC, in March 2009. With the adoption of these standards and best practices, future investigators will be able to obtain data across multiple studies with reduced costs and effort and accelerate the progress of genomic, proteomic, and metabolomic research in TBI.

Neuroprotective effects of L-arginine administration after cortical impact injury in rats: dose response and time window.

Administration of L-arginine has been shown to increase cerebral blood flow and reduce neurological damage after experimental traumatic brain injury. The purpose of this study was to examine the optimal dose and time window for these neuroprotective effects. In a dose response experiment, doses of L-arginine ranging from 37.5 to 600 mg/kg were administered 5 min after a 5-m/s, 3-mm, controlled cortical impact in rats. The amount of brain injury found at 2 weeks after injury, both at the contusion site and in the ipsilateral hippocampus, were inversely related to the dose of L-arginine administered. Both 300- and 600-mg/kg doses of L-arginine significantly reduced contusion volume. The 300-mg/kg dose significantly increased the neuron density in the CA1 region of the hippocampus. Physiological effects of L-arginine were also dose-related. The greatest reduction in intracranial pressure occurred with the 300-mg/kg dose of L-arginine. Doses up to 300 mg/kg were well tolerated, but the 600-mg/kg dose resulted in transient hypotension. In another experiment, 300 mg/kg L-arginine was administered at times varying from 5 min to 48 h after injury. Contusion volume was significantly reduced when the L-arginine was given at 5 min and 1 h after injury. The protective effect was less when the same dose was given at the later times, but there was no evidence of an adverse effect even when the L-arginine was administered 48 h after injury.