Four-factor prothrombin complex concentrate versus andexanet alfa for the reversal of traumatic brain injuries.

BACKGROUND: Andexanet alfa was approved in 2018 for reversal of direct oral anticoagulants but due to issues of cost and access, four-factor prothrombin complex concentrate (4F-PCC) continues to be used for this indication. The objective of this study is to evaluate outcomes of reversal with these agents in patients with isolated traumatic brain injuries (TBI). METHODS: This is a retrospective review of 35 trauma centres from 2014 to 2021. Patients were included with an Abbreviated Injury Scale (AIS)>2 for head and having received andexanet alfa or 4F-PCC within 24 hours of admission. Patients were excluded if P2Y12 inhibitor use or AIS>2 outside of head. Primary outcome includes rate of mortality/hospice at hospital discharge. Secondary outcomes include a composite of serious hospital complications. A subgroup analysis of severe TBI patients (AIS head 4 or 5) was completed. Multivariable logistic regression was used to account for differences in comorbidities and TBI severity. RESULTS: 4F-PCC was given to 265 patients with another 59 receiving andexanet alfa. Patients in the andexanet alfa group were more likely to have an AIS head score of 5 (47.5% vs 26.1%; p<0.005). After adjusting for severity of TBI and comorbidities with regard to tomortality/hospice, there were 15 (25.4%) patients in the andexanet alfa group and 49 (18.5%) in the 4F-PCC group (OR 1.34; 95% CI 0.67 to 2.71). This remained consistent when looking at severe patients with TBI with 12 (28.6%) andexanet alfa patients and 37 (28.7%) 4F-PCC patients (OR 0.93 (95% CI 0.40 to 2.16)). Severe hospital complications were also similar between groups with 5 (8.5%) andexanet alfa patients as compared with 21 (7.9%) 4F-PCC patients (OR 1.01; 95% CI 0.36 to 2.88). CONCLUSION: There was no firm conclusion on the treatment effect in mortality/hospice or serious complications among isolated TBI patients reversed with 4F-PCC as compared with andexanet alfa.

Delayed Cranial Decompression Rates After Initiation of Unfractionated Heparin versus Low-Molecular-Weight Heparin in Traumatic Brain Injury.

BACKGROUND: Both unfractionated heparin (UH) and low-molecular-weight heparin (LMWH) are routinely used prophylactically after traumatic brain injury (TBI) to prevent deep vein thrombosis (DVT). Their comparative risk for development or worsening of intracranial hemorrhage necessitating cranial decompression is unclear. Furthermore, the absence of a specific antidote for LMWH may lead to UH being used more often for high-risk patients. This study aims to compare the incidence of delayed cranial decompression occurring after initiation of prophylactic UH versus LMWH using the National Trauma Data Bank. METHODS: Cranial decompression procedures included craniotomy and craniectomy. Multiple imputation was used for missing data. Propensity score matching was used to account for selection bias between UH and LMWH. The 1:1 matched groups were compared using logistic regression for the primary outcome of postprophylaxis cranial decompression. RESULTS: A total of 218,594 patients with TBI were included, with 61,998 (28.3%) receiving UH and 156,596 (71.7%) receiving LMWH as DVT prophylaxis. The UH group had higher patient age, body mass index, comorbidity rates, Injury Severity Score, and worse motor Glasgow Coma Scale score. After the UH and LMWH groups were matched for these factors, logistic regression showed lower rates of postprophylaxis cranial decompression for the LMWH group (odds ratio, 0.13; 95% confidence interval, 0.11-0.16; P < 0.001). CONCLUSIONS: Despite the absence of a specific antidote, LMWH was associated with lower rates of need for post-DVT-prophylaxis in craniotomy/craniectomy. This finding questions the notion of UH being safer for patients with TBI because it can be readily reversed. Randomized studies are needed to elucidate causality.

Early Vasopressor Utilization Strategies and Outcomes in Critically Ill Patients With Severe Traumatic Brain Injury.

BACKGROUND: Early hypotension after severe traumatic brain injury (sTBI) is associated with increased mortality and poor long-term outcomes. Current guidelines suggest the use of intravenous vasopressors, commonly norepinephrine and phenylephrine, to support blood pressure after TBI. However, guidelines do not specify vasopressor type, resulting in variation in clinical practice. We describe early vasopressor utilization patterns in critically ill patients with TBI and examine the association between utilization of norepinephrine, compared to phenylephrine, with hospital mortality after sTBI. METHODS: We conducted a retrospective cohort study of US hospitals participating in the Premier Healthcare Database between 2009 and 2018. We examined adult patients (>17 years of age) with a primary diagnosis of sTBI who were treated in an intensive care unit (ICU) after injury. The primary exposure was vasopressor choice (phenylephrine versus norepinephrine) within the first 2 days of hospital admission. The primary outcome was in-hospital mortality. Secondary outcomes examined included hospital length of stay (LOS) and ICU LOS. We conducted a post hoc subgroup analysis in all patients with intracranial pressure (ICP) monitor placement. Regression analysis was used to assess differences in outcomes between patients exposed to phenylephrine versus norepinephrine, with propensity matching to address selection bias due to the nonrandom allocation of treatment groups. RESULTS: From 2009 to 2018, 24,718 (37.1%) of 66,610 sTBI patients received vasopressors within the first 2 days of hospitalization. Among these patients, 60.6% (n = 14,991) received only phenylephrine, 10.8% (n = 2668) received only norepinephrine, 3.5% (n = 877) received other vasopressors, and 25.0% (n = 6182) received multiple vasopressors. In that time period, the use of all vasopressors after sTBI increased. A moderate degree of variation in vasopressor choice was explained at the individual hospital level (23.1%). In propensity-matched analysis, the use of norepinephrine compared to phenylephrine was associated with an increased risk of in-hospital mortality (OR, 1.65; CI, 1.46-1.86; P < .0001). CONCLUSIONS: Early vasopressor utilization among critically ill patients with sTBI is common, increasing over the last decade, and varies across hospitals caring for TBI patients. Compared to phenylephrine, norepinephrine was associated with increased risk of in-hospital mortality in propensity-matched analysis. Given the wide variation in vasopressor utilization and possible differences in efficacy, our analysis suggests the need for randomized controlled trials to better inform vasopressor choice for patients with sTBI.

A perfect storm: The distribution of tissue damage depends on seizure duration, hemorrhage, and developmental stage in a gyrencephalic, multi-factorial, severe traumatic brain injury model.

The pathophysiology of extensive cortical tissue destruction observed in hemispheric hypodensity, a severe type of brain injury observed in young children, is unknown. Here, we utilize our unique, large animal model of hemispheric hypodensity with multifactorial injuries and insults to understand the pathophysiology of this severe type of traumatic brain injury, testing the effect of different stages of development. Piglets developmentally similar to human infants (1 week old, "infants") and toddlers (1 month old, "toddlers") underwent injuries and insults scaled to brain volume: cortical impact, creation of mass effect, placement of a subdural hematoma, seizure induction, apnea, and hypoventilation or a sham injury while anesthetized with a seizure-permissive regimen. Piglets receiving model injuries required overnight intensive care. Hemispheres were evaluated for damage via histopathology. The pattern of damage was related to seizure duration and hemorrhage pattern in "toddlers" resulting in a unilateral hemispheric pattern of damage ipsilateral to the injuries with sparing of the deep brain regions and the contralateral hemisphere. While "infants" had the equivalent duration of seizures as "toddlers", damage was less than "toddlers", not correlated to seizure duration, and was bilateral and patchy as is often observed in human infants. Subdural hemorrhagewas associate with adjacent focal subarachnoid hemorrhage. The percentage of the hemisphere covered with subarachnoid hemorrhage was positively correlated with damage in both developmental stages. In "infants", hemorrhage over the cortex was associated with damage to the cortex with sparing of the deep gray matter regions; without hemorrhage, damage was directed to the hippocampus and the cortex was spared. "Infants" had lower neurologic scores than "toddlers". This multifactorial model of severe brain injury caused unilateral, wide-spread destruction of the cortex in piglets developmentally similar to toddlers where both seizure duration and hemorrhage covering the brain were positively correlated to tissue destruction. Inherent developmental differences may affect how the brain responds to seizure, and thus, affects the extent and pattern of damage. Study into specifically how the "infant" brain is resistant to the effects of seizure is currently underway and may identify potential therapeutic targets that may reduce evolution of tissue damage after severe traumatic brain injury.

Risk of significant traumatic brain injury in adults with minor head injury taking direct oral anticoagulants: a cohort study and updated meta-analysis.

BACKGROUND: Patients taking direct oral anticoagulants (DOACs) commonly undergo CT head imaging after minor head injury, regardless of symptoms or signs. However, the risk of intracranial haemorrhage (ICH) in such patients is unclear, and further research has been recommended by the UK National Institute for Health and Care Excellence head injury guideline group. METHODS: An observational cohort study was performed in the UK South Yorkshire major trauma centre between 26 June and 3 September 2018. Adult patients taking DOACs with minor head injury were prospectively identified, with case ascertainment supplemented by screening of radiology and ED information technology systems. Clinical and outcome data were subsequently collated from patient records. The primary endpoint was adverse outcome within 30 days, comprising: neurosurgery, ICH or death due to head injury. A previously published meta-analysis was updated with the current results and the findings of other recent studies. RESULTS: 148 patients with minor head injury were included (GCS 15, n=107, 72%; GCS 14, n=41, 28%). Patients were elderly (median 82 years) and most frequently injured from ground level falls (n=142, 96%). Overall risk of adverse outcome was 3.4% (5/148, 95% CI 1.4% to 8.0%). Five patients had ICH, of whom one died within 30 days. One patient was treated with prothrombin complex concentrate but no patient received critical care management or underwent neurosurgical intervention. Updated random effects meta-analysis, including the current results and two further recent studies, showed a weighted overall risk of adverse outcome of 3.2% (n=29/787, 95% CI 2.0% to 4.4%). CONCLUSIONS: The risk of adverse outcome following mild head injury in patients taking DOACs appears low. These findings would support shared patient-clinician decision making, rather than routine imaging, following minor head injury while taking DOACs.

Oxidative stress contributes to cerebral metabolomic profile changes in animal model of blast-induced traumatic brain injury.

INTRODUCTION: Blast-induced neurotrauma (BINT) has been recognized as the common mode of traumatic brain injury amongst military and civilian personnel due to an increased insurgent activity domestically and abroad. Previous studies from this laboratory have identified three major pathological events following BINT which include blood brain barrier disruption the earliest event, followed by oxidative stress and neuroinflammation as secondary events occurring a few hours following blast. OBJECTIVES: Our recent studies have also identified an increase in oxidative stress mediated by the activation of superoxide producing enzyme NADPH oxidase (NOX) in different brain regions at varying levels with neurons displaying higher oxidative stress (NOX activation) compared to any other neural cell. Since neurons have higher energy demands in brain and are more prone to oxidative damage, this study evaluated the effect of oxidative stress on blast-blast induced changes in metabolomics profiles in different brain regions. METHODS: Animals were exposed to mild/moderate blast injury (180 kPa) and examined the metabolites of energy metabolism, amino acid metabolism as well as the profiles of plasma membrane metabolites in different brain regions at different time points (24 h, 3 day and 7 day) after blast using 1H NMR spectroscopy. Effect of apocynin, an inhibitor of superoxide producing enzyme NADPH oxidase on cerebral metabalomics profiles was also examined. RESULTS: Several metabolomic profile changes were observed in frontal cortex and hippocampus with concomitant decrease in energy metabolism. In addition, glutamate/glutamine and other amino acid metabolism as well as metabolites involved in plasma membrane integrity were also altered. Hippocampus appears metabolically more vulnerable than the frontal cortex. A post-treatment of animals with apocynin, an inhibitor of NOX activation significantly prevented the changes in metabolite profiles. CONCLUSION: Together these studies indicate that blast injury reduces both cerebral energy and neurotransmitter amino acid metabolism and that oxidative stress contributes to these processes. Thus, strategies aimed at reducing oxidative stress can have a therapeutic benefit in mitigating metabolic changes following BINT.

Additive Effect of Resveratrol on Astrocyte Swelling Post-exposure to Ammonia, Ischemia and Trauma In Vitro.

Swelling of astrocytes represents a major component of the brain edema associated with many neurological conditions, including acute hepatic encephalopathy (AHE), traumatic brain injury (TBI) and ischemia. It has previously been reported that exposure of cultured astrocytes to ammonia (a factor strongly implicated in the pathogenesis of AHE), oxygen/glucose deprivation, or to direct mechanical trauma results in an increase in cell swelling. Since dietary polyphenols have been shown to exert a protective effect against cell injury, we examined whether resveratrol (RSV, 3,5,4'-trihydroxy-trans-stilbene, a stilbenoid phenol), has a protective effect on astrocyte swelling following its exposure to ammonia, oxygen-glucose deprivation (OGD), or trauma in vitro. Ammonia increased astrocyte swelling, and pre- or post-treatment of astrocytes with 10 and 25 µM RSV displayed an additive effect, while 5 µM did not prevent the effect of ammonia. However, pre-treatment of astrocytes with 25 µM RSV slightly, but significantly, reduced the trauma-induced astrocyte swelling at earlier time points (3 h), while post-treatment had no significant effect on the trauma-induced cell swelling at the 3 h time point. Instead, pre- or post-treatment of astrocytes with 25 µM RSV had an additive effect on trauma-induced astrocyte swelling. Further, pre- or post-treatment of astrocytes with 5 or 10 µM RSV had no significant effect on trauma-induced astrocyte swelling. When 5 or 10 µM RSV were added prior to, or during the process of OGD, as well as post-OGD, it caused a slight, but not statistically significant decline in cell swelling. However, when 25 µM RSV was added during the process of OGD, as well as after the cells were returned to normal condition (90 min period), such treatment showed an additive effect on the OGD-induced astrocyte swelling. Noteworthy, a higher concentration of RSV (25 µM) exhibited an additive effect on levels of phosphorylated forms of ERK1/2, and p38MAPK, as well as an increased activity of the Na+-K+-Cl- co-transporter-1 (NKCC1), factors known to induce astrocytes swelling, when the cells were treated with ammonia or after trauma or ischemia. Further, inhibition of ERK1/2, and p38MAPK diminished the RSV-induced exacerbation of cell swelling post-ammonia, trauma and OGD treatment. These findings strongly suggest that treatment of cultured astrocytes with RSV enhanced the ammonia, ischemia and trauma-induced cell swelling, likely through the exacerbation of intercellular signaling kinases and ion transporters. Accordingly, caution should be exercised when using RSV for the treatment of these neurological conditions, especially when brain edema is also suspected.

Administration of a 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor Improves Outcome in a Rat Model of Pediatric Traumatic Brain Injury.

The arachidonic acid pathway metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to ischemia/reperfusion brain injury. Inhibition of 20-HETE formation can protect the developing brain from global ischemia. Here, we examined whether treatment with the 20-HETE synthesis inhibitor N-hydroxy-N-4-butyl-2-methylphenylformamidine (HET0016) can protect the immature brain from traumatic brain injury (TBI). Male rats at postnatal day 9-10 underwent controlled cortical impact followed by intraperitoneal injection with vehicle or HET0016 (1 mg/kg, 5 min and 3 h post-injury). HET0016 decreased the lesion volume by over 50% at 3 days of recovery, and this effect persisted at 30 days as the brain matured. HET0016 decreased peri-lesion gene expression of proinflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1ß [IL-1ß]) at 1 day and increased reparative cytokine (IL-4, IL-10) expression at 3 days. It also partially preserved microglial ramified processes, consistent with less activation. HET0016 decreased contralateral hindlimb foot faults and improved outcome on the novel object recognition memory task 30 days after TBI. In cultured BV2 microglia, HET0016 attenuated the lipopolysaccharide-evoked increase in release of TNF-α. Our data show that HET0016 improves acute and long-term histologic and functional outcomes, in association with an attenuated neuroinflammatory response after contusion of an immature rat brain.

Neurotoxicity Associated with Traumatic Brain Injury, Blast, Chemical, Heavy Metal and Quinoline Drug Exposure.

Chronic, excessive exposure, and accumulation of neurotoxic agents such as heavy metals (lead, mercury, cadmium), mefloquine (Lariam), and food additives such as monosodium glutamate and aspartame cause neurotoxicity and brain damage. This chemical-induced brain damage closely resembles the pathophysiology of classical traumatic brain injury with decreased cognitive function, neurodegeneration, and increased psychiatric manifestations (depression, anxiety, sleep disturbances, and irritability). Current evidence supports a strong causal relationship between military-related exposure to specific neurotoxins, and the development of serious medical conditions and higher rates of suicide among service members. To address this current deficit in military health care, it is recommended that efficacious, nontoxic, neuroprotective, and neuroregenerative agents such as highly bioavailable magnesium, nutritional lithium, zinc, selenium, boron, ascorbate, tocopherols, heavy metal chelators, and glutathione precursors such as N-acetyl-cysteine be immediately used as a "protective shield" and to support critical healing processes in the brain and nervous system.

Risk of Deterioration of Geriatric Traumatic Brain Injury in Patients Treated with Antithrombotic Drugs.

OBJECTIVE: Developed countries have rapidly aging populations and the use of antithrombotic drugs is increasing. We investigated the effects of antithrombotic drugs and reversal of these drugs in patients with geriatric traumatic brain injury (TBI). METHODS: Age, sex, mechanism of injury, Glasgow Coma Scale on admission, head computed tomography findings, antithrombotic therapy, acute exacerbation, and outcomes at discharge were examined in 711 patients with geriatric TBI, complicated with traumatic intracranial hemorrhage using data from the Japan Neurotrauma Data Bank Project 2015 (JNTDB P2015). These items were compared between patients who did and did not receive antithrombotic therapy. We also conducted a questionnaire survey of reversal of antithrombotic therapy at hospitals participating in the JNTDB P2015. Acute exacerbation was compared in hospitals that did and did not regularly use reversal of this therapy. RESULTS: The major cause of injury was a fall. In head computed tomography, acute subdural hematoma was found in 65.7% of the subjects. Antithrombotic therapy was performed in 30.4% of subjects, and these subjects were significantly older than those who did not receive this therapy; many had a fall as the mechanism of injury, and the level of consciousness was significantly exacerbated with this therapy. In hospitals that performed regular reversal, late exacerbation of the level of consciousness was suppressed. CONCLUSIONS: Patients with geriatric TBI who are given antithrombotic drugs have a risk for late exacerbation, even if initially diagnosed with mild TBI. Therefore, there is a possibility that reversal of antithrombotic drugs is important to suppress the risk of deterioration of patients with TBI.

Neutral Sphingomyelinase Inhibition Alleviates LPS-Induced Microglia Activation and Neuroinflammation after Experimental Traumatic Brain Injury.

Neuroinflammation is one of the key secondary injury mechanisms triggered by traumatic brain injury (TBI). Microglial activation, a hallmark of brain neuroinflammation, plays a critical role in regulating immune responses after TBI and contributes to progressive neurodegeneration and neurologic deficits following brain trauma. Here we evaluated the role of neutral sphingomyelinase (nSMase) in microglial activation by examining the effects of the nSMase inhibitors altenusin and GW4869 in vitro (using BV2 microglia cells and primary microglia), as well as in a controlled cortical injury (CCI) model in adult male C57BL/6 mice. Pretreatment of altenusin or GW4869 prior to lipopolysaccharide (LPS) stimulation for 4 or 24 hours, significantly downregulated gene expression of the pro-inflammatory mediators TNF-α, IL-1ß, IL-6, iNOS, and CCL2 in microglia and reduced the release of nitric oxide and TNF-α These nSMase inhibitors also attenuated the release of microparticles and phosphorylation of p38 MAPK and ERK1/2. In addition, altenusin pretreatment also reduced the gene expression of multiple inflammatory markers associated with microglial activation after experimental TBI, including TNF-α, IL-1ß, IL-6, iNOS, CCL2, CD68, NOX2, and p22phox Overall, our data demonstrate that nSMase inhibitors attenuate multiple inflammatory pathways associated with microglial activation in vitro and after experimental TBI. Thus, nSMase inhibitors may represent promising therapeutics agents targeting neuroinflammation.

Mitochondrial uncoupling prodrug improves tissue sparing, cognitive outcome, and mitochondrial bioenergetics after traumatic brain injury in male mice.

Traumatic brain injury (TBI) results in cognitive impairment, which can be long-lasting after moderate to severe TBI. Currently, there are no FDA-approved therapeutics to treat the devastating consequences of TBI and improve recovery. This study utilizes a prodrug of 2,4-dinitrophenol, MP201, a mitochondrial uncoupler with extended elimination time, that was administered after TBI to target mitochondrial dysfunction, a hallmark of TBI. Using a model of cortical impact in male C57/BL6 mice, MP201 (80 mg/kg) was provided via oral gavage 2-hr post-injury and daily afterwards. At 25-hr post-injury, mice were euthanized and the acute rescue of mitochondrial bioenergetics was assessed demonstrating a significant improvement in both the ipsilateral cortex and ipsilateral hippocampus after treatment with MP201. Additionally, oxidative markers, 4-hydroxyneneal and protein carbonyls, were reduced compared to vehicle animals after MP201 administration. At 2-weeks post-injury, mice treated with MP201 post-injury (80 mg/kg; q.d.) displayed significantly increased cortical sparing (p = .0059; 38% lesion spared) and improved cognitive outcome (p = .0133) compared to vehicle-treated mice. Additionally, vehicle-treated mice had significantly lower (p = .0019) CA3 neuron count compared to sham while MP201-treated mice were not significantly different from sham levels. These results suggest that acute mitochondrial dysfunction can be targeted to impart neuroprotection from reactive oxygen species, but chronic administration may have an added benefit in recovery. This study highlights the potential for safe, effective therapy by MP201 to alleviate negative outcomes of TBI.

Anesthetics Influence Mortality in a Drosophila Model of Blunt Trauma With Traumatic Brain Injury.

BACKGROUND: Exposure to anesthetics is common in the majority of early survivors of life-threatening injuries. Whether and to what degree general anesthetics influence outcomes from major trauma is unknown. Potential confounding effects of general anesthetics on outcome measures are usually disregarded. We hypothesized that exposure to isoflurane or sevoflurane modulates the outcome from blunt trauma with traumatic brain injury (bTBI). METHODS: We tested the hypothesis in a novel model of bTBI implemented in Drosophila melanogaster. Fruit flies of the standard laboratory strain w were cultured under standard conditions. We titrated the severity of bTBI to a mortality index at 24 hours (MI24) of approximately 20% under control conditions. We administered standard doses of isoflurane and sevoflurane before, before and during, or after bTBI and measured the resulting MI24. We report the MI24 as mean ± standard deviation. RESULTS: Isoflurane or sevoflurane administered for 2 hours before bTBI reduced the MI24 from 22.3 ± 2.6 to 10.4 ± 1.8 (P < 10, n = 12) and from 19.3 ± 0.9 to 8.9 ± 1.1 (P < .0001, n = 8), respectively. In contrast, administration of isoflurane after bTBI increased the MI24 from 18.5% ± 4.3% to 25.3% ± 9.1% (P = .0026, n = 22), while sevoflurane had no effect (22.4 ± 7.1 and 21.5 ± 5.8, n = 22). CONCLUSIONS: In a whole animal model of bTBI, general anesthetics were not indifferent with respect to early mortality. Therefore, collateral effects of general anesthetics should be considered in the interpretation of results obtained in vertebrate trauma models. Invertebrate model organisms can serve as a productive platform to interrogate anesthetic targets that mediate collateral effects and to inform trauma research in higher organisms about the potential impact of anesthetics on outcomes.

Neuroprotective effect of acute ethanol intoxication in TBI is associated to the hierarchical modulation of early transcriptional responses.

Ethanol intoxication is a risk factor for traumatic brain injury (TBI) but clinical evidence suggests that it may actually improve the prognosis of intoxicated TBI patients. We have employed a closed, weight-drop TBI model of different severity (2cm or 3cm falling height), preceded (-30min) or followed (+20min) by ethanol administration (5g/Kg). This protocol allows us to study the interaction of binge ethanol intoxication in TBI, monitoring behavioral changes, histological responses and the transcriptional regulation of a series of activity-regulated genes (immediate early genes, IEGs). We demonstrate that ethanol pretreatment before moderate TBI (2cm) significantly reduces neurological impairment and accelerates recovery. In addition, better preservation of neuronal numbers and cFos+cells was observed 7days after TBI. At transcriptional level, ethanol reduced the upregulation of a subset of IEGs encoding for transcription factors such as Atf3, c-Fos, FosB, Egr1, Egr3 and Npas4 but did not affect the upregulation of others (e.g. Gadd45b and Gadd45c). While a subset of IEGs encoding for effector proteins (such as Bdnf, InhbA and Dusp5) were downregulated by ethanol, others (such as Il-6) were unaffected. Notably, the majority of genes were sensitive to ethanol only when administered before TBI and not afterwards (the exceptions being c-Fos, Egr1 and Dusp5). Furthermore, while severe TBI (3cm) induced a qualitatively similar (but quantitatively larger) transcriptional response to moderate TBI, it was no longer sensitive to ethanol pretreatment. Thus, we have shown that a subset of the TBI-induced transcriptional responses were sensitive to ethanol intoxication at the instance of trauma (ultimately resulting in beneficial outcomes) and that the effect of ethanol was restricted to a certain time window (pre TBI treatment) and to TBI severity (moderate). This information could be critical for the translational value of ethanol in TBI and for the design of clinical studies aimed at disentangling the role of ethanol intoxication in TBI.

Nonessential Role for the NLRP1 Inflammasome Complex in a Murine Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) elicits the immediate production of proinflammatory cytokines which participate in regulating the immune response. While the mechanisms of adaptive immunity in secondary injury are well characterized, the role of the innate response is unclear. Recently, the NLR inflammasome has been shown to become activated following TBI, causing processing and release of interleukin-1ß (IL-1ß). The inflammasome is a multiprotein complex consisting of nucleotide-binding domain and leucine-rich repeat containing proteins (NLR), caspase-1, and apoptosis-associated speck-like protein (ASC). ASC is upregulated after TBI and is critical in coupling the proteins during complex formation resulting in IL-1ß cleavage. To directly test whether inflammasome activation contributes to acute TBI-induced damage, we assessed IL-1ß, IL-18, and IL-6 expression, contusion volume, hippocampal cell death, and motor behavior recovery in Nlrp1(-/-), Asc(-/-), and wild type mice after moderate controlled cortical impact (CCI) injury. Although IL-1ß expression is significantly attenuated in the cortex of Nlrp1(-/-) and Asc(-/-) mice following CCI injury, no difference in motor recovery, cell death, or contusion volume is observed compared to wild type. These findings indicate that inflammasome activation does not significantly contribute to acute neural injury in the murine model of moderate CCI injury.

Physical training decreases susceptibility to pilocarpine-induced seizures in the injured rat brain.

There is growing evidence that physical activity ameliorates the course of epilepsy in animal models as well as in clinical conditions. Since traumatic brain injury is one of the strongest determinants of epileptogenesis, the present study focuses on the question whether a moderate long-term physical training can decrease susceptibility to seizures evoked following brain damage. Wistar rats received a mechanical brain injury and were subjected to daily running sessions on a treadmill for 21 days. Thereafter, seizures were induced by pilocarpine injections in trained and non-trained, control groups. During the acute period of status epilepticus, the intensity of seizures was assessed within the six-hour observation period. The trained rats showed considerable amelioration of pilocarpine-induced motor symptoms when compared with their non-trained counterparts. Histological investigations of effects of the brain injury and of physical training detected significant quantitative changes in parvalbumin-, calretinin- and NPY-immunopositive neuronal populations. Some of the injury-induced changes, especially those shoved by parvalbumin-immunopositive neurons, were abolished by the subsequent physical training procedure and could, therefore, be considered as neuronal correlates of the observed functional amelioration of the injured brain.

Tuberculosis pulmonar y cerebral en un paciente inmunocompetente / No disponible

La infección por Mycobacterium tuberculosis tiene una alta prevalencia y está en íntima relación con la migración. Afecta fundamentalmente al pulmón, pero también a otros órganos, como el sistema nervioso central, conllevando una alta morbilidad y mortalidad. Se considera a los tuberculomas una forma de presentación a nivel cerebral, diagnosticándose mediante punción-aspiración o biopsia quirúrgica cuando es accesible o a través de técnicas de imagen. En caso de afectación meníngea, es obligado el estudio del líquido cefalorraquídeo. En función de la clínica, el tratamiento de los tuberculomas será quirúrgico o predominantemente farmacológico con cuatro antituberculostáticos y corticoides. Para la prevención de complicaciones, especialmente en inmunocomprometidos, es fundamental el diagnóstico precoz así como el tratamiento inmediato ante la mínima sospecha clínica. Presentamos el caso de un paciente varón de 41 años inmunocompetente que, tras estudio radiológico y microbiológico, se diagnosticó de tuberculosis pulmonar y cerebral y que mejoró satisfactoriamente

Infection with Mycobacterium tuberculosis is highly prevalent and is closely related to migration. It mainly affects lungs, but can also involve other organs such as the central nervous system. This neurologic complication is accompanied by a high morbidity and mortality. Tuberculomas are considered one form of presentation in the brain, and could be diagnosed by needle aspiration or surgical biopsy when they are accessible, or through imaging techniques. In the case of meningeal involvement, study of the cerebrospinal fluid is required for the diagnosis. Anti-tuberculosis drugs and corticosteroids are mainly used for the treatment of tuberculomas, but depending on the clinical situation, surgical procedures could also be performed. To prevent complications, especially in immunocompromised patients, early suspect and diagnosis is important to start immediately the administration of anti-tuberculosis drugs. We report the case of a 41-year-old-man immunocompetent who was diagnosed of pulmonary and cerebral tuberculosis and who was effectively treated