Juvenile Traumatic Brain Injury Results in Cognitive Deficits Associated with Impaired Endoplasmic Reticulum Stress and Early Tauopathy.

The leading cause of death in the juvenile population is trauma, and in particular neurotrauma. The juvenile brain response to neurotrauma is not completely understood. Endoplasmic reticulum (ER) stress has been shown to contribute to injury expansion and behavioral deficits in adult rodents and furthermore has been seen in adult postmortem human brains diagnosed with chronic traumatic encephalopathy. Whether endoplasmic reticulum stress is increased in juveniles with traumatic brain injury (TBI) is poorly delineated. We investigated this important topic using a juvenile rat controlled cortical impact (CCI) model. We proposed that ER stress would be significantly increased in juvenile rats following TBI and that this would correlate with behavioral deficits using a juvenile rat model. A juvenile rat (postnatal day 28) CCI model was used. Binding immunoglobulin protein (BiP) and C/EBP homologous protein (CHOP) were measured at 4 h in the ipsilateral pericontusion cortex. Hypoxia-inducible factor (HIF)-1α was measured at 48 h and tau kinase measured at 1 week and 30 days. At 4 h following injury, BiP and CHOP (markers of ER stress) were significantly elevated in rats exposed to TBI. We also found that HIF-1α was significantly upregulated 48 h following TBI showing delayed hypoxia. The early ER stress activation was additionally asso-ciated with the activation of a known tau kinase, glycogen synthase kinase-3ß (GSK-3ß), by 1 week. Tau oligomers measured by R23 were significantly increased by 30 days following TBI. The biochemical changes following TBI were associated with increased impulsive-like or anti-anxiety behavior measured with the elevated plus maze, deficits in short-term memory measured with novel object recognition, and deficits in spatial memory measured with the Morris water maze in juvenile rats exposed to TBI. These results show that ER stress was increased early in juvenile rats exposed to TBI, that these rats developed tau oligomers over the course of 30 days, and that they had significant short-term and spatial memory deficits following injury.

Investigational chemotherapy and novel pharmacokinetic mechanisms for the treatment of breast cancer brain metastases.

In women, breast cancer is the most common cancer diagnosis and second most common cause of cancer death. More than half of breast cancer patients will develop metastases to the bone, liver, lung, or brain. Breast cancer brain metastases (BCBM) confers a poor prognosis, as current therapeutic options of surgery, radiation, and chemotherapy rarely significantly extend life and are considered palliative. Within the realm of chemotherapy, the last decade has seen an explosion of novel chemotherapeutics involving targeting agents and unique dosage forms. We provide a historical overview of BCBM chemotherapy, review the mechanisms of new agents such as poly-ADP ribose polymerase inhibitors, cyclin-dependent kinase 4/6 inhibitors, phosphatidyl inositol 3-kinaseinhibitors, estrogen pathway antagonists for hormone-receptor positive BCBM; tyrosine kinase inhibitors, antibodies, and conjugates for HER2+ BCBM; repurposed cytotoxic chemotherapy for triple negative BCBM; and the utilization of these new agents and formulations in ongoing clinical trials. The mechanisms of novel dosage formulations such as nanoparticles, liposomes, pegylation, the concepts of enhanced permeation and retention, and drugs utilizing these concepts involved in clinical trials are also discussed. These new treatments provide a promising outlook in the treatment of BCBM.

Supplements, nutrition, and alternative therapies for the treatment of traumatic brain injury.

Studies using traditional treatment strategies for mild traumatic brain injury (TBI) have produced limited clinical success. Interest in treatment for mild TBI is at an all time high due to its association with the development of chronic traumatic encephalopathy and other neurodegenerative diseases, yet therapeutic options remain limited. Traditional pharmaceutical interventions have failed to transition to the clinic for the treatment of mild TBI. As such, many pre-clinical studies are now implementing non-pharmaceutical therapies for TBI. These studies have demonstrated promise, particularly those that modulate secondary injury cascades activated after injury. Because no TBI therapy has been discovered for mild injury, researchers now look to pharmaceutical supplementation in an attempt to foster success in human clinical trials. Non-traditional therapies, such as acupuncture and even music therapy are being considered to combat the neuropsychiatric symptoms of TBI. In this review, we highlight alternative approaches that have been studied in clinical and pre-clinical studies of TBI, and other related forms of neural injury. The purpose of this review is to stimulate further investigation into novel and innovative approaches that can be used to treat the mechanisms and symptoms of mild TBI.

Primary Endovascular Repair of Ilio-Caval Injury Encountered during Anterior Exposure Spine Surgery: Evolution of the Paradigm.

BACKGROUND: Rates of major venous injury are now being reported at between 1% and 15%. Risk factors for injury include the previous spine surgery, level of exposure, and number of retractors used. To review and describe the evolution of our use of stent grafts for repair of life-threatening ilio-caval injuries encountered during anterior exposure lumbosacral (L-S) spine surgery from rescue utilization after failed direct repair to preferred modality using occlusion balloons and covered stents akin to the modern management of the ruptured abdominal aortic aneurysm (AAA) with endovascular aneurysm repair. METHODS: Five-year retrospective review of all anterior and retroperitoneal spine procedures was performed at our institution. RESULTS: One hundred two procedures were done. Major ilio-caval injury occurred in 3/102 (2.9%) cases. Average blood loss per case decreased as our approach evolved from unsuccessful direct open repair with percutaneous endovascular rescue to primary percutaneous endovascular repair. All treated patients had patent venous repair in short-term follow-up with computed tomography angiography. CONCLUSIONS: Identification and rapid direct repair of major ilio-caval injuries during anterior approach spine surgery can be extremely challenging. When control of these potentially fatal injuries is required, our choice is primary endovascular repair using the modern techniques for endovascular management of ruptured AAA with endovascular aneurysm repair.

Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection.

Sigma-1 receptors are molecular chaperones that may act as pathological mediators and targets for novel therapeutic applications in neurodegenerative diseases. Accumulating evidence indicates that sigma-1 ligands can either directly or indirectly modulate multiple neurodegenerative processes, including excitotoxicity, calcium dysregulation, mitochondrial and endoplasmic reticulum dysfunction, inflammation, and astrogliosis. In addition, sigma-1 ligands may act as disease-modifying agents in the treatment for central nervous system (CNS) diseases by promoting the activity of neurotrophic factors and neural plasticity. Here, we summarize their neuroprotective and neurorestorative effects in different animal models of acute brain injury and chronic neurodegenerative diseases, and highlight their potential role in mitigating disease. Notably, current data suggest that sigma-1 receptor dysfunction worsens disease progression, whereas enhancement amplifies pre-existing functional mechanisms of neuroprotection and/or restoration to slow disease progression. Collectively, the data support a model of the sigma-1 receptor as an amplifier of intracellular signaling, and suggest future clinical applications of sigma-1 ligands as part of multi-therapy approaches to treat neurodegenerative diseases.

Elucidating the role of compression waves and impact duration for generating mild traumatic brain injury in rats.

BACKGROUND: In total, 3.8 million concussions occur each year in the US leading to acute functional deficits, but the underlying histopathologic changes that occur are relatively unknown. In order to improve understanding of acute injury mechanisms, appropriately designed pre-clinical models must be utilized. METHODS: The clinical relevance of compression wave injury models revolves around the ability to produce consistent histopathologic deficits. Mild traumatic brain injuries activate similar neuroinflammatory cascades, cell death markers and increases in amyloid precursor protein in both humans and rodents. Humans, however, infrequently succumb to mild traumatic brain injuries and, therefore, the intensity and magnitude of impacts must be inferred. Understanding compression wave properties and mechanical loading could help link the histopathologic deficits seen in rodents to what might be happening in human brains following concussions. RESULTS: While the concept of linking duration and intensity of impact to subsequent histopathologic deficits makes sense, numerical modelling of compression waves has not been performed in this context. In this interdisciplinary work, numerical simulations were performed to study the creation of compression waves in an experimental model. CONCLUSION: This work was conducted in conjunction with a repetitive compression wave injury paradigm in rats in order to better understand how the wave generation correlates with histopathologic deficits.

The Effect of Sporting Events on Medical Transport Time at a Level 1 Trauma Center: a Retrospective Cohort Study.

OBJECTIVE: We investigate how West Virginia University football games affect transport to Ruby Memorial Hospital, which shares a parking lot with Milan Puskar Football Stadium. METHODS: A retrospective chart review of a trauma registry from a level 1-trauma center was conducted from 2007 to 2011 for all home and away football games. Home games served as time period of interest and away games served as a control time period. Patient charts were collected for a 36-hour time window surrounding the game. 250 patient charts were complete for home games and 185 patient charts for away games. Data analyzed were time from scene to arrival at hospital, use of air transport, transport time in relation to kick-off, and comparison between demographic and emergency department disposition of patients arriving during home games vs. patients arriving during away games. RESULTS: No statistically significant differences were found for demographic data or emergency department disposition between groups. For ground transport directly from scene, the average time to arrival at the hospital was 44.9 minutes for home games and 45.1 minutes for away games. For air transport directly from the scene, the average time to arrival at the hospital was 44.9 minutes for home games and 44.0 minutes for away games. For ground transfer from another facility, the average time to arrival at the hospital was 76.4 minutes for home games and 52.9 minutes for away games. For air transport from another facility, the average time to arrival at the hospital was 37.4 minutes for home games and 24.0 minutes for away games. Air transportation utilization was increased in inter-facility transfers during home games (5/16, 31.3% vs. 4/20, 22.2%), and helicopters traveled a further distance (avg. 66.6 vs. 50.25 air miles). For patients coming from the scene during a home game, if the start of the game occurred after the trauma but before arrival to the trauma center, the average time of ground transport increased from 44.9 minutes to 120 minutes (p<0.0001). CONCLUSION: A mass gathering in close proximity to a rural trauma center does affect transport patterns and transport times for trauma patients. Further investigation is warranted in order to improve patient care during mass gathering events.

Osteopathia striata with cranial sclerosis (OSCS): review of the literature and case report demonstrating challenges of spinal fusion after trauma.

Osteopathia striata with cranial sclerosis (OSCS) is a rare but well-described pathology characterized by abnormalities in bone deposition in the axial and cranial skeleton as well as other abnormalities and associated deficits. These skeletal abnormalities can lead to significant intra-operative challenges for the surgeon and influence outcomes for the patient. In this report, we present a case of a patient with OSCS who was involved in a traumatic motor vehicle crash and underwent posterior cervico-thoracic fusion for a T4 chance fracture. Bony abnormalities in the cervico-thoracic spine presented a significant operative challenge due to alterations in bony anatomy and bone architecture. This case serves as an example of the challenges that the spine surgeon faces when dealing with OSCS, and highlights the differences between OSCS and commoner skeletal hyperplasias such as osteopetrosis.

Stereotactic radiosurgery planning based on time-resolved CTA for arteriovenous malformation: a case report and review of the literature.

Stereotactic radiosurgery has long been recognized as the optimal form of management for high-grade arteriovenous malformations not amenable to surgical resection. Radiosurgical plans have generally relied upon the integration of stereotactic magnetic resonance angiography (MRA), standard contrast-enhanced magnetic resonance imaging (MRI), or computed tomography angiography (CTA) with biplane digital subtraction angiography (DSA). Current options are disadvantageous in that catheter-based biplane DSA is an invasive test associated with a small risk of complications and perhaps more importantly, the two-dimensional nature of DSA is an inherent limitation in creating radiosurgical contours. The necessity of multiple scans to create DSA contours for radiosurgical planning puts patients at increased risk. Furthermore, the inability to import two-dimensional plans into some radiosurgery programs, such as Cyberknife TPS, limits treatment options for patients. Defining the nidus itself is sometimes difficult in any of the traditional modalities as all draining veins and feeding arteries are included in the images. This sometimes necessitates targeting a larger volume, than strictly necessary, with stereotactic radiosurgery for treatment of the AVM. In this case report, we show the ability to use a less-invasive and three-dimensional form of angiography based on time-lapsed CTA (4D-CTA) rather than traditional DSA for radiosurgical planning. 4D-CTA may allow generation of a series of images, which can show the flow of contrast through the AVM. A review of these series may allow the surgeon to pick and use a volume set that best outlines the nidus with least interference from feeding arteries or draining veins. In addition, 4D-CTA scans can be uploaded into radiosurgery programs and allow three-dimensional targeting. This is the first reported case demonstrating the use of a 4D CTA and an MRI to delineate the AVM nidus for Gamma Knife radiosurgery, with complete obliteration of the nidus over time and subsequent management of associated radiation necrosis with bevacizumab.

Alzheimer's disease and chronic traumatic encephalopathy: Distinct but possibly overlapping disease entities.

BACKGROUND: Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE) have long been recognized as sharing some similar neuropathological features, mainly the presence of neurofibrilary tangles and hyperphosphorylated tau, but have generally been described as distinct entities. Evidence indicates that neurotrauma increases the risk of developing dementia and accelerates the progression of disease. Findings are emerging that CTE and AD may be present in the same patients. CLINICAL PRESENTATION: This study presents a series of previously unpublished cases, with one case demonstrating possible neurotrauma-related AD, one pure CTE, and an example of a case exhibiting features of both AD and CTE. The future significance of this work lies not only in the confirmation of AD-CTE co-existence, but, more importantly, ways of generating a hypothesis about the possibility that CTE may accelerate AD development. Understanding the relationship between neurotrauma and neurodegenerative disease will help elucidate how distinct disease entities can co-exist in the same patient. It will ultimately require the use of pre-clinical animal models and repeat injury paradigms to investigate clinically relevant injury mechanisms. These models should produce a CTE-like phenotype that must be both neuropathologically and behaviourally similar to human disease. CONCLUSION: This case series and review of the literature presents a discussion of AD and CTE in the context of neurotrauma. It highlights recent work from repetitive neurotrauma models with an emphasis on those exhibiting a CTE-like phenotype. Potential mechanisms of interest shared amongst AD and CTE are briefly addressed and future experiments are advocated for to enhance understanding of CTE pathophysiology and the relationship between CTE and AD.

Aneurysmal Subarachnoid Hemorrhage and Neuroinflammation: A Comprehensive Review.

Aneurysmal subarachnoid hemorrhage (SAH) can lead to devastating outcomes including vasospasm, cognitive decline, and even death. Currently, treatment options are limited for this potentially life threatening injury. Recent evidence suggests that neuroinflammation plays a critical role in injury expansion and brain damage. Red blood cell breakdown products can lead to the release of inflammatory cytokines that trigger vasospasm and tissue injury. Preclinical models have been used successfully to improve understanding about neuroinflammation following aneurysmal rupture. The focus of this review is to provide an overview of how neuroinflammation relates to secondary outcomes such as vasospasm after aneurysmal rupture and to critically discuss pharmaceutical agents that warrant further investigation for the treatment of subarachnoid hemorrhage. We provide a concise overview of the neuroinflammatory pathways that are upregulated following aneurysmal rupture and how these pathways correlate to long-term outcomes. Treatment of aneurysm rupture is limited and few pharmaceutical drugs are available. Through improved understanding of biochemical mechanisms of injury, novel treatment solutions are being developed that target neuroinflammation. In the final sections of this review, we highlight a few of these novel treatment approaches and emphasize why targeting neuroinflammation following aneurysmal subarachnoid hemorrhage may improve patient care. We encourage ongoing research into the pathophysiology of aneurysmal subarachnoid hemorrhage, especially in regards to neuroinflammatory cascades and the translation to randomized clinical trials.

Role of sigma-1 receptors in neurodegenerative diseases.

Neurodegenerative diseases with distinct genetic etiologies and pathological phenotypes appear to share common mechanisms of neuronal cellular dysfunction, including excitotoxicity, calcium dysregulation, oxidative damage, ER stress and mitochondrial dysfunction. Glial cells, including microglia and astrocytes, play an increasingly recognized role in both the promotion and prevention of neurodegeneration. Sigma receptors, particularly the sigma-1 receptor subtype, which are expressed in both neurons and glia of multiple regions within the central nervous system, are a unique class of intracellular proteins that can modulate many biological mechanisms associated with neurodegeneration. These receptors therefore represent compelling putative targets for pharmacologically treating neurodegenerative disorders. In this review, we provide an overview of the biological mechanisms frequently associated with neurodegeneration, and discuss how sigma-1 receptors may alter these mechanisms to preserve or restore neuronal function. In addition, we speculate on their therapeutic potential in the treatment of various neurodegenerative disorders.

Interventional Treatment of Symptomatic Vasospasm in the Setting of Traumatic Brain Injury: A Systematic Review of Reported Cases.

Traumatic subarachnoid hemorrhage (tSAH) is frequently comorbid with traumatic brain injury (TBI) and may induce secondary injury through vascular changes such as vasospasm and subsequent delayed cerebral ischemia (DCI). While aneurysmal SAH is well studied regarding vasospasm and DCI, less is known regarding tSAH and the prevalence of vasospasm and DCI, the consequences of vasospasm in this setting, when treatment is indicated, and which management strategies should be implemented. In this article, a systematic review of the literature that was conducted for cases of symptomatic vasospasm in patients with TBI is reported, association with tSAH is reported, risk factors for vasospasm and DCI are summarized, and commonalities in diagnosis and management are discussed. Clinical characteristics and treatment outcomes of 38 cases across 20 studies were identified in which patients with TBI with vasospasm underwent medical or endovascular management. Of the patients with data available for each category, the average age was 48.7 ± 20.3 years (n = 31), the Glasgow Coma Scale score at presentation was 10.6 ± 4.5 (n = 35), and 100% had tSAH (n = 29). Symptomatic vasospasm indicative of DCI was diagnosed on average at postinjury day 8.4 ± 3.0 days (n = 30). Of the patients, 56.6% (n = 30) had a new ischemic change associated with vasospasm confirming DCI. Treatment strategies are discussed, with 11 of 12 endovascularly treated and 19 of 26 medically treated patients surviving to discharge. tSAH is associated with vasospasm and DCI in moderate and severe TBI, and patients with clinical and radiographic evidence of symptomatic vasospasm and subsequent DCI may benefit from endovascular or medical management strategies.

Age and the metabolic syndrome as risk factors for ischemic stroke: improving preclinical models of ischemic stroke.

Ischemic stroke represents a leading cause of morbidity and mortality in the developed world. This disabling and sometimes fatal event puts an ever increasing burden on the family members and medical professionals who care for stroke victims. Preclinical ischemic stroke research has predominantly utilized young adult, healthy animals, a clear discrepancy when considering the clinical population affected by stroke. A broad spectrum of risk factors such as age, obesity, diabetes, and hypertension has been associated with an increased stroke risk. The effect of these comorbidities on both stroke pathophysiology and outcome has not been emphasized and has been recognized as a shortcoming of preclinical studies. By addressing these conditions in experimental models of ischemic stroke, it may be possible to more accurately represent the clinical scenario and improve therapeutic translation from bench-to-bedside. In this work, we review many of the risk factors associated with increased stroke risk, particularly as each risk factor relates to inflammation. Additionally, we explore potential animal models that could be utilized in identifying the contribution of these risk factors to stroke outcome. By investigating the risk factors for stroke and how these may alter stroke pathophysiology, the present discrepancies between preclinical studies and the clinical reality can be reconciled in an effort to improve therapeutic development and translation from bench-to-bedside.

Acupuncture and Spinal Stenosis: Considerations for Treatment.

Acupuncture has been a staple of Eastern medicine for thousands of years. Recent evidence has shown that benefits for spinal stenosis are strong. In this comprehensive review, we overview the history and available literature. We discuss how the techniques have evolved and the clinical utility. The process and progression of spinal stenosis is addressed. We discuss mechanism of action for acupuncture as well as relevant treatment implications. This is important in alleviating pain and providing strong quality of life. We highlight both the findings in the pre-operative, peri-operative, and post-operative periods. Finally, the pre-clinical data provides compelling evidence in terms of novel pathways being targeted. This resource will serve as a user-friendly guide for the clinician and scientist regarding this important topic. It will be the catalyst of ongoing investigation from both the clinical and pre-clinical side.

Pediatric Traumatic Brain Injury: An Update on Preclinical Models, Clinical Biomarkers, and the Implications of Cerebrovascular Dysfunction.

Traumatic brain injury (TBI) is a leading cause of pediatric morbidity and mortality. Recent studies suggest that children and adolescents have worse post-TBI outcomes and take longer to recover than adults. However, the pathophysiology and progression of TBI in the pediatric population are studied to a far lesser extent compared to the adult population. Common causes of TBI in children are falls, sports/recreation-related injuries, non-accidental trauma, and motor vehicle-related injuries. A fundamental understanding of TBI pathophysiology is crucial in preventing long-term brain injury sequelae. Animal models of TBI have played an essential role in addressing the knowledge gaps relating to pTBI pathophysiology. Moreover, a better understanding of clinical biomarkers is crucial to diagnose pTBI and accurately predict long-term outcomes. This review examines the current preclinical models of pTBI, the implications of pTBI on the brain's vasculature, and clinical pTBI biomarkers. Finally, we conclude the review by speculating on the emerging role of the gut-brain axis in pTBI pathophysiology.

Low-intensity Blast Wave Model for Preclinical Assessment of Closed-head Mild Traumatic Brain Injury in Rodents.

Traumatic brain injury (TBI) is a large-scale public health problem. Mild TBI is the most prevalent form of neurotrauma and accounts for a large number of medical visits in the United States. There are currently no FDA-approved treatments available for TBI. The increased incidence of military-related, blast-induced TBI further accentuates the urgent need for effective TBI treatments. Therefore, new preclinical TBI animal models that recapitulate aspects of human blast-related TBI will greatly advance the research efforts into the neurobiological and pathophysiological processes underlying mild to moderate TBI as well as the development of novel therapeutic strategies for TBI. Here we present a reliable, reproducible model for the investigation of the molecular, cellular, and behavioral effects of mild to moderate blast-induced TBI. We describe a step-by-step protocol for closed-head, blast-induced mild TBI in rodents using a bench-top setup consisting of a gas-driven shock tube equipped with piezoelectric pressure sensors to ensure consistent test conditions. The benefits of the setup that we have established are its relative low-cost, ease of installation, ease of use and high-throughput capacity. Further advantages of this non-invasive TBI model include the scalability of the blast peak overpressure and the generation of controlled reproducible outcomes. The reproducibility and relevance of this TBI model has been evaluated in a number of downstream applications, including neurobiological, neuropathological, neurophysiological and behavioral analyses, supporting the use of this model for the characterization of processes underlying the etiology of mild to moderate TBI.

Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment.

Sepsis is a systemic inflammatory disease resulting from an infection. This disorder affects 750 000 people annually in the United States and has a 62% rehospitalization rate. Septic symptoms range from typical flu-like symptoms (eg, headache, fever) to a multifactorial syndrome known as sepsis-associated encephalopathy (SAE). Patients with SAE exhibit an acute altered mental status and often have higher mortality and morbidity. In addition, many sepsis survivors are also burdened with long-term cognitive impairment. The mechanisms through which sepsis initiates SAE and promotes long-term cognitive impairment in septic survivors are poorly understood. Due to its unique role as an interface between the brain and the periphery, numerous studies support a regulatory role for the blood-brain barrier (BBB) in the progression of acute and chronic brain dysfunction. In this review, we discuss the current body of literature which supports the BBB as a nexus which integrates signals from the brain and the periphery in sepsis. We highlight key insights on the mechanisms that contribute to the BBB's role in sepsis which include neuroinflammation, increased barrier permeability, immune cell infiltration, mitochondrial dysfunction, and a potential barrier role for tissue non-specific alkaline phosphatase (TNAP). Finally, we address current drug treatments (eg, antimicrobials and intravenous immunoglobulins) for sepsis and their potential outcomes on brain function. A comprehensive understanding of these mechanisms may enable clinicians to target specific aspects of BBB function as a therapeutic tool to limit long-term cognitive impairment in sepsis survivors.