Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue.

Spinal muscular atrophy type 1 (SMA1) is a debilitating neurodegenerative disease resulting from survival motor neuron 1 gene (SMN1) deletion/mutation. Onasemnogene abeparvovec (formerly AVXS-101) is a gene therapy that restores SMN production via one-time systemic administration. The present study demonstrates widespread biodistribution of vector genomes and transgenes throughout the central nervous system (CNS) and peripheral organs, after intravenous administration of an AAV9-mediated gene therapy.

Poor Corticospinal Motor Neuron Health Is Associated with Increased Symptom Severity in the Acute Phase Following Repetitive Mild TBI and Predicts Early ALS Onset in Genetically Predisposed Rodents.

Traumatic brain injury (TBI) is a well-established risk factor for several neurodegenerative disorders including Alzheimer's disease and Parkinson's disease, however, a link between TBI and amyotrophic lateral sclerosis (ALS) has not been clearly elucidated. Using the SOD1 rat model known to recapitulate the human ALS condition, we found that exposure to mild, repetitive TBI lead ALS rats to experience earlier disease onset and shortened survival relative to their sham counterparts. Importantly, increased severity of early injury symptoms prior to the onset of ALS disease symptoms was linked to poor health of corticospinal motor neurons and predicted worsened outcome later in life.

Extended neuromuscular blockade in acute respiratory distress syndrome does not increase mortality.

Background: Neuromuscular blockade (NMB) is often utilized in the treatment of acute respiratory distress syndrome (ARDS). Its use for a period of 48 h has been shown to improve mortality in randomized control trials. We aimed to characterize outcomes associated with a prolonged NMB.

Transplantation of Neural Progenitor Cells Expressing Glial Cell Line-Derived Neurotrophic Factor into the Motor Cortex as a Strategy to Treat Amyotrophic Lateral Sclerosis.

Early dysfunction of cortical motor neurons may underlie the initiation of amyotrophic lateral sclerosis (ALS). As such, the cortex represents a critical area of ALS research and a promising therapeutic target. In the current study, human cortical-derived neural progenitor cells engineered to secrete glial cell line-derived neurotrophic factor (GDNF) were transplanted into the SOD1 ALS rat cortex, where they migrated, matured into astrocytes, and released GDNF.

Impact of early positive cultures in the elderly with traumatic brain injury.

Background: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in the United States, especially in the elderly, who have the highest rates of TBI-related hospitalizations and deaths among all age groups. Sepsis is one of many risk factors that is associated with higher mortality and longer length of hospital stay in this population partially due to the immunosuppressive effects of TBI. The significance of early indicators of infection, such as a positive blood, sputum, or urine culture, is not well described.

Nonoperative Management of Blunt Splenic Trauma in Patients with Traumatic Brain Injury: Feasibility and Outcomes.

Introduction: Preventing secondary insult to the brain is imperative following traumatic brain injury (TBI). Although TBI does not preclude nonoperative management (NOM) of splenic injuries, development of hypotension in this setting may be detrimental and could therefore lead trauma surgeons to a lower threshold for operative intervention and a potentially higher risk of failure of NOM (FNOM). We hypothesized that the presence of a TBI in patients with blunt splenic injury would lead to a higher risk of FNOM.

Patterns of vasopressor utilization during the resuscitation of massively transfused trauma patients.

Background: The use of vasopressors (VP) in the resuscitation of massively transfused trauma patients might be considered a marker of inadequate resuscitation. We sought to characterize the utilization of VP in patients receiving massive transfusion and examine the association of their use with mortality.

Methods: Trauma patients admitted from January 2011 to October 2016 receiving massive transfusion, defined as 3 units of pRBC within the first hour from admission, were selected for analysis.

Dopamine neuron dependent behaviors mediated by glutamate cotransmission.

Dopamine neurons in the ventral tegmental area use glutamate as a cotransmitter. To elucidate the behavioral role of the cotransmission, we targeted the glutamate-recycling enzyme glutaminase (gene ). In mice with a dopamine transporter ()-driven conditional heterozygous (cHET) reduction of in their dopamine neurons, dopamine neuron survival and transmission were unaffected, while glutamate cotransmission at phasic firing frequencies was reduced, enabling a selective focus on the cotransmission.

Clinical correlates to assist with chronic traumatic encephalopathy diagnosis: Insights from a novel rodent repeat concussion model.

Introduction: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repetitive head injuries. Chronic traumatic encephalopathy symptoms include changes in mood, behavior, cognition, and motor function; however, CTE is currently diagnosed only postmortem. Using a rat model of recurrent traumatic brain injury (TBI), we demonstrate rodent deficits that predict the severity of CTE-like brain pathology.

10-Year trend in crystalloid resuscitation: Reduced volume and lower mortality.

Background: Liberal emergency department (ED) resuscitation after trauma may lead to uncontrolled hemorrhage, reduced organ perfusion, and compartment syndrome. Recent guidelines reduced the standard starting point for crystalloid resuscitation from 2 L to 1 L and emphasized "balanced" resuscitation. The purpose of this study was to characterize how an urban, Level 1 trauma center has responded to changes in crystalloid resuscitation practices over time and to describe associated patient outcomes.

A model of recurrent concussion that leads to long-term motor deficits, CTE-like tauopathy and exacerbation of an ALS phenotype.

Background: Concussion injury is the most common form of traumatic brain injury (TBI). How recurrent concussions alter long-term outcomes is poorly understood, especially as related to the development of neurodegenerative disease. We evaluated the functional and pathological consequences of repeated TBI over time in wild type (WT) rats as well as rats harboring the human SOD1 mutation ("SOD1"), a model of familial amyotrophic lateral sclerosis (ALS).

Heart rate in pediatric trauma: rethink your strategy.

Background: The optimal heart rate (HR) for children after trauma is based on values derived at rest for a given age. As the stages of shock are based in part on HR, a better understanding of how HR varies after trauma is necessary. Admission HRs of pediatric trauma patients were analyzed to determine which ranges were associated with lowest mortality.

Early propranolol after traumatic brain injury is associated with lower mortality.

Background: β-Adrenergic receptor blockers (BBs) administered after trauma blunt the cascade of immune and inflammatory changes associated with injury. BBs are associated with improved outcomes after traumatic brain injury (TBI). Propranolol may be an ideal BB because of its nonselective inhibition and ability to cross the blood-brain barrier.

Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice.

Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge.

Thromboelastography After Murine TBI and Implications of Beta-Adrenergic Receptor Knockout.

Background: The source of coagulopathy in traumatic brain injury (TBI) is multifactorial and may include adrenergic stimulation. The aim of this study was to assess coagulopathy after TBI using thromboelastography (TEG), and to investigate the implications of β-adrenergic receptor knockout.

Methods: Adult male wild type c57/bl6 (WT) and β1/β2-adrenergic receptor knockout (BKO) mice were assigned to either TBI (WT-TBI, BKO-TBI) or sham injury (WT-sham, BKO-sham).

Acute Traumatic Brain Injury Does Not Exacerbate Amyotrophic Lateral Sclerosis in the SOD1 (G93A) Rat Model.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease in which upper and lower motor neurons degenerate, leading to muscle atrophy, paralysis, and death within 3 to 5 years of onset. While a small percentage of ALS cases are genetically linked, the majority are sporadic with unknown origin. Currently, etiological links are associated with disease onset without mechanistic understanding.

Delayed disease onset and extended survival in the SOD1G93A rat model of amyotrophic lateral sclerosis after suppression of mutant SOD1 in the motor cortex.

Sporadic amyotrophic lateral sclerosis (ALS) is a fatal disease with unknown etiology, characterized by a progressive loss of motor neurons leading to paralysis and death typically within 3-5 years of onset. Recently, there has been remarkable progress in understanding inherited forms of ALS in which well defined mutations are known to cause the disease. Rodent models in which the superoxide dismutase-1 (SOD1) mutation is overexpressed recapitulate hallmark signs of ALS in patients.

Traumatic brain injury reveals novel cell lineage relationships within the subventricular zone.

The acute response of the rodent subventricular zone (SVZ) to traumatic brain injury (TBI) involves a physical expansion through increased cell proliferation. However, the cellular underpinnings of these changes are not well understood. Our analyses have revealed that there are two distinct transit-amplifying cell populations that respond in opposite ways to injury.

The past, present and future of stem cell clinical trials for ALS.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that is characterized by progressive degeneration of motor neurons in the cortex, brainstem and spinal cord. This leads to paralysis, respiratory insufficiency and death within an average of 3 to 5 years from disease onset. While the genetics of ALS are becoming more understood in familial cases, the mechanisms underlying disease pathology remain unclear and there are no effective treatment options.