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Background: In contrast to osteoligamentous lumbar stenosis (LSS), outcome of surgical treatment for spinal epidural lipomatosis (SEL) is still not well defined. We present risk factors for SEL and clinical long-term outcome data after surgical treatment for patients with pure SEL and a mixed-type pathology with combined SEL and LSS (SEL+LSS) compared to patients with pure LSS., Methods: From our prospective institutional database, we identified all consecutive patients who were surgically treated for newly diagnosed SEL (n = 31) and SEL+LSS (n = 26) between 2018 and 2022. In addition, a matched control group of patients with pure LSS (n = 30) was compared. Microsurgical treatment aimed for posterior decompression of the spinal canal. Study endpoints were outcome data including clinical symptoms at presentation, MR-morphological analysis, evaluation of pain-free walking distance, pain perception by VAS-N/-R scales, and patient's satisfaction by determination of the Odom score., Results: Patients with osteoligamentous SEL were significantly more likely to suffer from obesity (body mass index (BMI) of 30.2 ± 5.5 kg/m 2 , p = 0.03), lumbar pain (p = 0.006), and to have received long-term steroid therapy (p = 0.01) compared to patients with SEL+LSS and LSS. In all three groups, posterior decompression of the spinal canal resulted in significant improvement of these symptoms. Patients with SEL had a significant increase in pain-free walking distance during the postoperative course, at discharge, and last follow-up (FU) (p < 0.0001), similar to patients with SEL+LSS and pure LSS. In addition, patients with pure SEL and SEL+LSS had a significant reduction in pain perception, represented by smaller values of VAS-N and -R postoperatively and at FU, similar to patients with pure LSS. In uni- and multivariate analysis, domination of lumbar pain and steroid long-term therapy were significant characteristic risk factors for SEL., Conclusions: Surgical treatment of pure SEL and SEL+LSS allows significant improvement in pain-free walking distance and pain perception immediately postoperatively and in long-term FU, similar to patients with pure LSS., (© 2023. The Author(s).)

Purpose: Surgical site infections (SSI) are a rare but dreaded cause for recurrent symptomatology requiring reoperation after degenerative spine surgery. We here aim to elucidate if routine microbiological smear testing during reoperation might be a useful tool for subsequent patient management., Methods: We investigated clinical, laboratory/imaging characteristics, and outcome of patients undergoing reoperation in the previously affected segment during follow-up after elective degenerative non-instrumented spine surgery. Microbiological cultures via multiple intraoperative smear tests of the superficial/deep wound layers were routinely performed and correlated with clinical/imaging/laboratory/surgical signs for SSI and outcome., Results: From altogether 2552 patients with degenerative spine surgery in 2014-2019, a total of 62 patients (m:f = 1.6:1, median 69 years) underwent same-level reoperation due to recurrent symptomatology (mean ∆-time:17 ± 36 months) with a predominance of the lumbar spine (90%). In 9 patients with imaging/laboratory suspicious for SSI, microbiological culturing of intraoperative smear testing revealed conclusive pathogen growth in 89% (100% with additional PCR analysis); the predominant pathogen was Staphylococcus aureus with detection mainly in the deep wound layers. In contrast, in 53 patients without clinical/imaging/laboratory/intraoperative signs for SSI microbiological culturing showed minor pathogen growth in 15% displaying bacterial colonization/contamination of the surgical site. The predominant pathogens in this cohort were Staphylococcus epidermidis and Cutibacterium acnes, and these patients had favorable outcomes when monitored with close surveillance without anti-infective treatment., Conclusion: Bacterial colonization/contamination occurs in 15% of patients without signs of infection undergoing same-level reoperation after degenerative spine surgery. These patients can be managed with close surveillance without antibiotic treatment., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Objective: Since the 1970s, the operating microscope (OM) has been a standard for visualization and illumination of the surgical field in spinal microsurgery. However, due to its limitations (e.g., size, costliness, and the limited movability of the binocular lenses, in addition to discomfort experienced by surgeons due to the posture required), there are efforts to replace the OM with exoscopic video telescopes. The authors evaluated the feasibility of a new 3D exoscope as an alternative to the OM in spine surgeries., Methods: Patients with degenerative pathologies scheduled for single-level lumbar or cervical spinal surgery with use of a high-definition 3D exoscope were enrolled in a prospective cohort study between January 2019 and September 2019. Age-, sex-, body mass index-, and procedure-matched patients surgically treated with the assistance of the OM served as the control group. Operative baseline and postoperative outcome parameters were assessed. Periprocedural handling, visualization, and illumination by the exoscope, as well as surgeons' comfort level in terms of posture, were scored using a questionnaire., Results: A 3D exoscope was used in 40 patients undergoing lumbar posterior decompression (LPD) and 20 patients undergoing anterior cervical discectomy and fusion (ACDF); an equal number of controls in whom an OM was used were studied. Compared with controls, there were no significant differences for mean operative time (ACDF: 132 vs 116 minutes; LPD: 112 vs 113 minutes) and blood loss (ACDF: 97 vs 93 ml; LPD: 109 vs 55 ml) as well as postoperative improvement of symptoms (ACDF/Neck Disability Index: p = 0.43; LPD/Oswestry Disability Index: p = 0.76). No intraoperative complications occurred in either group. According to the attending surgeon, the intraoperative handling of instruments was rated to be comparable to that of the OM, while the comfort level of the surgeon's posture intraoperatively (especially during "undercutting" procedures) was rated as superior. In cases of ACDF procedures and long approaches, depth perception, image quality, and illumination were rated as inferior when compared with the OM. By contrast, for operating room nursing staff participating in 3D exoscope procedures, the visualization of intraoperative process flow and surgical situs was rated to be superior to the OM, especially for ACDF procedures., Conclusions: A 3D exoscope seems to be a safe alternative for common spinal procedures with the unique advantage of excellent comfort for the surgical team, but the drawback is the still slightly inferior visualization/illumination quality compared with the OM.

Brain edema formation contributes to secondary brain damage and unfavorable outcome after traumatic brain injury (TBI). Aquaporins (AQP), highly selective water channels, are involved in the formation of post-trauma brain edema; however, their regulation is largely unknown. Because vasopressin receptors are involved in AQP-mediated water transport in the kidney and inhibition of V 1a receptors reduces post-trauma brain edema formation, we hypothesize that cerebral AQPs may be regulated by V 1a receptors. Cerebral Aqp1 and Aqp4 messenger ribonucleic acid (mRNA) and AQP1 and AQP4 protein levels were quantified in wild-type and V 1a receptor knockout (V 1a -/- ) mice before and 15 min, 1, 3, 6, 12, or 24 h after experimental TBI by controlled cortical impact. In non-traumatized mice, we found AQP1 and AQP4 expression in cortical neurons and astrocytes, respectively. Experimental TBI had no effect on Aqp4 mRNA or AQP4 protein expression, but increased Aqp1 mRNA ( p  < 0.05) and AQP1 protein expression ( p  < 0.05) in both hemispheres. The Aqp1 mRNA and AQP1 protein regulation was blunted in V 1a receptor knockout mice. The V 1a receptors regulate cerebral AQP1 expression after experimental TBI, thereby unraveling the molecular mechanism by which these receptors may mediate brain edema formation after TBI.

Objective: Plasminogen activator inhibitor-1 (PAI-1) is the key endogenous inhibitor of fibrinolysis, and enhances clot formation after injury. In traumatic brain injury, dysregulation of fibrinolysis may lead to sustained microthrombosis and accelerated lesion expansion. In the present study, we hypothesized that PAI-1 mediates post-traumatic malfunction of coagulation, with inhibition or genetic depletion of PAI-1 attenuating clot formation and lesion expansion after brain trauma., Methods: We evaluated PAI-1 as a possible new target in a mouse controlled cortical impact (CCI) model of traumatic brain injury. We performed the pharmacological inhibition of PAI-1 with PAI-039 and stimulation by tranexamic acid, and we confirmed our results in PAI-1-deficient animals., Results: PAI-1 mRNA was time-dependently upregulated, with a 305-fold peak 12 hours after CCI, which effectively counteracted the 2- to 3-fold increase in cerebral tissue-type/urokinase plasminogen activator expression. PAI-039 reduced brain lesion volume by 26% at 24 hours and 43% at 5 days after insult. This treatment also attenuated neuronal apoptosis and improved neurofunctional outcome. Moreover, intravital microscopy demonstrated reduced post-traumatic thrombus formation in the pericontusional cortical microvasculature. In PAI-1-deficient mice, the therapeutic effect of PAI-039 was absent. These mice also displayed 13% reduced brain damage compared with wild type. In contrast, inhibition of fibrinolysis with tranexamic acid increased lesion volume by 25% compared with vehicle., Interpretation: This study identifies impaired fibrinolysis as a critical process in post-traumatic secondary brain damage and suggests that PAI-1 may be a central endogenous inhibitor of the fibrinolytic pathway, promoting a procoagulatory state and clot formation in the cerebral microvasculature. Ann Neurol 2019;85:667-680., (© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Arginine-vasopressin (AVP) V 1 receptors are known to mediate brain edema formation after traumatic brain injury (TBI). So far, however, AVP V 1 receptors were only inhibited by genetic deletion or prior to trauma. Therefore, the current study aimed to determine the therapeutic window of AVP V 1 receptor antagonization after TBI. Male C57BL/6 mice (n = 7 per group) were subjected to controlled cortical impact (CCI), and 500 ng of a selective peptide V 1 receptor antagonist (V1880) were applied by intracerebroventricular injection 5 min, and 1, 3, and 6 h thereafter. After 24 h, brain water content (BWC), intracranial pressure (ICP), and secondary contusion expansion volume were assessed. Neurological function was assessed daily for 7 days after trauma. Inhibition of AVP V 1 receptors within 1 h after TBI significantly reduced BWC from 81.6 ± 0.7 to 80.6 ± 0.7% (mean ± SD; p < 0.05). Reduction of brain edema resulted in a significant decrease in ICP from 25.9 ± 1.8 mm Hg to 21.0 ± 1.5 mm Hg (p < 0.05) and a reduction in contusion volume (26.1 ± 2.5 mm 3 vs. 30.1 ± 2.0 mm 3 in controls; p < 0.05). This reduction of brain injury resulted in a significantly improved neurological function 7 days after trauma. Treatments initiated 6 h after TBI had no effect. The results of the current study demonstrate that inhibition of AVP V 1 receptors improve outcome after experimental TBI when given within a clinically relevant time window. Therefore, AVP V 1 receptors may represent a therapeutic target with clinical potential.

OBJECTIVE The determination of gait improvement after lumbar puncture (LP) in idiopathic normal-pressure hydrocephalus (iNPH) is crucial, but the best time for such an assessment is unclear. The authors determined the time course of improvement in walking after LP for single-task and dual-task walking in iNPH. METHODS In patients with iNPH, sequential recordings of gait velocity were obtained prior to LP (time point [TP]0), 1-8 hours after LP (TP1), 24 hours after LP (TP2), 48 hours after LP (TP3), and 72 hours after LP (TP4). Gait analysis was performed using a pressure-sensitive carpet (GAITRite) under 4 conditions: walking at preferred velocity (STPS), walking at maximal velocity (STMS), walking while performing serial 7 subtractions (dual-task walking with serial 7 [DTS7]), and walking while performing verbal fluency tasks (dual-task walking with verbal fluency [DTVF]). RESULTS Twenty-four patients with a mean age of 76.1 ± 7.8 years were included in this study. Objective responder status moderately coincided with the self-estimation of the patients with subjective high false-positive results (83%). The extent of improvement was greater for single-task walking than for dual-task walking (p < 0.05). Significant increases in walking speed were found at TP2 for STPS (p = 0.042) and DTVF (p = 0.046) and at TP3 for STPS (p = 0.035), DTS7 (p = 0.042), and DTVF (p = 0.044). Enlargement of the ventricles (Evans Index) positively correlated with early improvement. Gait improvement at TP3 correlated with the shunt response in 18 patients. CONCLUSIONS Quantitative gait assessment in iNPH is important due to the poor self-evaluation of the patients. The maximal increase in gait velocity can be observed 24-48 hours after the LP. This time point is also best to predict the response to shunting. For dual-task paradigms, maximal improvement appears to occur later (48 to 72 hours). Assessment of gait should be performed at Day 2 or 3 after LP.

The attenuation of brain edema is a major therapeutic target after traumatic brain injury (TBI). Vasopressin (AVP) is well known to play a major role in the regulation of brain water content and vasoendothelial functions and to be involved in brain edema formation. Therefore, the aim of the current study was to analyze the antiedematous efficacy of a clinically relevant, nonpeptidic AVP V1a and V2 receptor antagonists. C57Bl6 mice were subjected to controlled cortical impact (CCI) and V1a or V2 receptors were inhibited by using the highly selective antagonists SR-49059 or SR-121463A either by systemic (intraperitoneal, IP) or intracerebroventricular (ICV) application. After 24 h, brain edema, intracranial pressure (ICP), and contusion volume were assessed. Systemically applied AVP receptor antagonists could not reduce secondary lesion growth. In contrast, ICV administration of AVP V1a receptor antagonist decreased brain edema formation by 68%, diminished post-traumatic increase of ICP by 46%, and reduced secondary contusion expansion by 43% 24 h after CCI. The ICV inhibition of V2 receptors resulted in significant reduction of post-traumatic brain edema by 41% 24 h after CCI, but failed to show further influence on ICP and lesion growth. Hence, centrally applied vasopressin V1a receptor antagonists may be used to reduce brain edema formation after TBI.

Background: In gliomas molecular biomarkers are increasingly gaining diagnostic, prognostic and predictive significance. Determination of biomarker status after biopsy is important as not all patients are eligible for open tumor resection. We developed and validated prospectively (6/10-12/11) a protocol allowing for both reliable determination of multiple biomarkers and representative histological diagnoses from small-sized biopsies., Methods: All molecular stereotactic biopsies were performed according to a detailed workflow. The selection of specimens best suited for molecular analyses was intra-operatively guided by the attending neuropathologist. Postoperative screening was done by methylation specific PCR using two distinct cryopreserved specimens to test for reproducibility of the findings and to rule out contamination. The DNA of a single best-suited specimen (1 mm(3)) was subjected to detailed molecular analysis (MGMT promoter methylation, IDH1/2 mutational status, LOH 1p and/or 19q)., Results: 159 consecutively enrolled untreated gliomas were analyzed (94 glioblastomas, 2 gliosarcomas, 24 anaplastic astrocytomas, 10 oligo-tumors grade II/III, 20 grade II astrocytomas and 9 pilocytic astrocytomas). Transient morbidity was 2 %. Overall, the drop-out rate due to tissue contamination was 0.4 %. Median time from biopsy to histological and molecular genetic analyses was 3 and 5 days, respectively. Distributions of the respective biomarker status for tumor subgroups were consistent with the literature. The final histological diagnosis was changed/modified in 5/159 patients according to molecular findings. Treatment after molecular biopsy was highly personalized., Conclusions: Molecular stereotactic biopsy is feasible and safe, can be implemented in daily clinical practice, improves diagnostic precision and enables personalized treatment.

The formation of brain edema and subsequent intracranial hypertension are major predictors of unfavorable outcome following traumatic brain injury (TBI). Previously, we reported that arginine vasopressin (AVP) receptor antagonists reduce post-traumatic and post-ischemic brain edema in mice. The aim of the current study was to investigate further the contribution of arginine vasopressin V1a receptors to TBI-induced secondary brain damage in V1a receptor knock-out mice. V1a receptor knock-out (V1a -/-) and wild-type mice were subjected to controlled cortical impact (CCI), and edema (brain water content measured before and 24 h after CCI), primary and secondary contusion volume (15 min and 24 h after CCI), neurological function (one day before and seven days after CCI), body weight (before and seven days after CCI) and mortality were measured. Twenty-four h after CCI, V1a receptor knock-out mice had significantly less brain water content than wild-type mice (mean±standard error of the mean: 79.8%±0.3 vs. 80.6%±0.2, respectively), and secondary contusion volume was significantly smaller (38.2±1.7 mm(3) vs. 45.1±1.5 mm(3) in wild-type mice). Furthermore, the V1a receptor knock-out mice had less neurological dysfunction (3.2±0.8 vs. 7.0±1.4 in wild-type mice) and weight loss (1.0±1.0% vs. 4.9±1.8% in wild-type mice) seven days after CCI. Our data show that mice lacking V1a receptors have less secondary brain damage following experimental traumatic brain injury. We therefore conclude that V1a receptors may represent a novel drug target for preventing post-traumatic brain edema.

Background: Leukocytes are believed to be involved in delayed cell death following traumatic brain injury (TBI). However, data demonstrating that blood-borne inflammatory cells are present in the injured brain prior to the onset of secondary brain damage have been inconclusive. We therefore investigated both the interaction between leukocytes and the cerebrovascular endothelium using in vivo imaging and the accumulation of leukocytes in the penumbra following experimentally induced TBI., Methods: Experimental TBI was induced in C57/Bl6 mice (n = 42) using the controlled cortical impact (CCI) injury model, and leukocyte-endothelium interactions (LEI) were quantified using both intravital fluorescence microscopy (IVM) of superficial vessels and 2-photon microscopy of cortical vessels for up to 14 h post-CCI. In a separate experimental group, leukocyte accumulation and secondary lesion expansion were analyzed in mice that were sacrificed 15 min, 2, 6, 12, 24, or 48 h after CCI (n = 48). Finally, leukocyte adhesion was blocked with anti-CD18 antibodies, and the effects on LEI and secondary lesion expansion were determined 16 (n = 12) and 24 h (n = 21), respectively, following TBI., Results: One hour after TBI leukocytes and leukocyte-platelet aggregates started to roll on the endothelium of pial venules, whereas no significant LEI were observed in pial arterioles or in sham-operated mice. With a delay of >4 h, leukocytes and aggregates did also firmly adhere to the venular endothelium. In deep cortical vessels (250 μm) LEIs were much less pronounced. Transmigration of leukocytes into the brain parenchyma only became significant after the tissue became necrotic. Treatment with anti-CD18 antibodies reduced adhesion by 65%; however, this treatment had no effect on secondary lesion expansion., Conclusions: LEI occurred primarily in pial venules, whereas little or no LEI occurred in arterioles or deep cortical vessels. Inhibiting LEI did not affect secondary lesion expansion. Importantly, the majority of migrating leukocytes entered the injured brain parenchyma only after the tissue became necrotic. Our results therefore suggest that neither intravascular leukocyte adhesion nor the migration of leukocytes into cerebral tissue play a significant role in the development of secondary lesion expansion following TBI.

Cortical spreading depolarization (CSD) promotes the progression of neuronal injury after cerebral ischemia. However, the mechanisms of propagation of postischemic CSD events are still unclear. In this study we characterized the role of the main neuronal gap junction protein connexin 36 (Cx36) in generating postischemic CSDs. In Cx36-deficient mice and controls we occluded the distal middle cerebral artery. To detect CSD events we recorded the direct current and laser Doppler flow. In addition, locomotor function and the infarct size were determined. Cx36-deficient mice had significantly fewer and shorter CSD events than wild-type controls. Additionally, Cx36 deletion is neuroprotective, leading to a better functional outcome and decreased infarct size after ischemia. These results suggest a detrimental role for Cx36 after ischemia, possibly by promoting CSD., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Anesthesia is indispensable for in vivo research but has the intrinsic potential to alter study results. The aim of the current study was to investigate the impact of three common anesthesia protocols on physiological parameters and outcome following the most common experimental model for subarachnoid hemorrhage (SAH), endovascular perforation., Methods: Sprague-Dawley rats (n = 38) were randomly assigned to (1) chloral hydrate, (2) isoflurane or (3) midazolam/medetomidine/fentanyl (MMF) anesthesia. Arterial blood gases, intracranial pressure (ICP), mean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), and regional cerebral blood flow (rCBF) were monitored before and for 3 hours after SAH. Brain water content, mortality and rate of secondary bleeding were also evaluated., Results: Under baseline conditions isoflurane anesthesia resulted in deterioration of respiratory parameters (arterial pCO2 and pO2) and increased brain water content. After SAH, isoflurane and chloral hydrate were associated with reduced MAP, incomplete recovery of post-hemorrhagic rCBF (23 ± 13% and 87 ± 18% of baseline, respectively) and a high anesthesia-related mortality (17 and 50%, respectively). Anesthesia with MMF provided stable hemodynamics (MAP between 100-110 mmHg), high post-hemorrhagic rCBF values, and a high rate of re-bleedings (> 50%), a phenomenon often observed after SAH in humans., Conclusion: Based on these findings we recommend anesthesia with MMF for the endovascular perforation model of SAH.

Inflammatory mechanisms are known to contribute to the pathophysiology of traumatic brain injury (TBI). Since bradykinin is one of the first mediators activated during inflammation, we investigated the role of bradykinin and its receptors in posttraumatic secondary brain damage. We subjected wild-type (WT), B(1)-, and B(2)-receptor-knockout mice to controlled cortical impact (CCI) and analyzed tissue bradykinin as well as kinin receptor mRNA and protein expression up to 48 h thereafter. Brain edema, contusion volume, and functional outcome were assessed 24 h and 7 days after CCI. Tissue bradykinin was maximally increased 2 h after trauma (P<0.01 versus sham). Kinin B(1) receptor mRNA was upregulated up to four-fold 24 h after CCI. Immunohistochemistry showed that B(1) and B(2) receptors were expressed in the brain and were significantly upregulated in the traumatic penumbra 1 to 24 h after CCI. B(2)R(-/-) mice had significantly less brain edema (-51% versus WT, 24 h; P<0.001), smaller contusion volumes ( approximately 50% versus WT 24 h and 7 d after CCI; P<0.05), and better functional outcome 7 days after TBI as compared with WT mice (P<0.05). The present results show that bradykinin and its B(2) receptors play a causal role for brain edema formation and cell death after TBI.

Traumatic brain injury (TBI) is associated with an almost immediate reduction in cerebral blood flow (CBF). Because cerebral perfusion pressure is often normal under these circumstances it was hypothesized that the reduction of post-traumatic CBF has to occur at the level of the microcirculation. The aim of the current study was to investigate whether cerebral microvessels are involved in the development of blood flow disturbances following experimental TBI. C57/BL6 mice (n = 12) were intubated and ventilated under control of end-tidal Pco(2) ((ET)P(CO2)). After preparation of a cranial window and baseline recordings, the animals were subjected to experimental TBI by controlled cortical impact (CCI; 6 m/sec, 0.5 mm). Vessel lumina and intravascular cells were visualized by in vivo fluorescence microscopy (IVM) using the fluorescent dyes FITC-dextran and rhodamine 6G, respectively. Vessel diameter, cell-endothelial interactions, and thrombus formation were quantified within the traumatic penumbra by IVM up to 2 h after CCI. Arteriolar diameters increased after CCI by 26.2 +/- 2.5% (mean +/- SEM, p < 0.01 versus baseline), and remained at this level until the end of the observation period. Rolling of leukocytes on the cerebrovascular endothelium was observed both in arterioles and venules, while leukocyte-platelet aggregates were found only in venules. Microthrombi occluded up to 70% of venules and 33% of arterioles. The current data suggest that the immediate post-traumatic decrease in peri-contusional blood flow is not caused by arteriolar vasoconstriction, but by platelet activation and the subsequent formation of thrombi in the cerebral microcirculation.

Brain edema formation, resulting in increased intracranial pressure (ICP), is one of the most deleterious consequences of traumatic brain injury (TBI). Nitric oxide (NO) has previously been shown to be involved in the damage of the blood-brain barrier (BBB) and, thus, in the formation of post-traumatic brain edema; however, this knowledge never resulted in a clinically relevant therapeutic option because available NO synthase inhibitors have serious side effects in man. The aim of the current study was to investigate the therapeutic efficacy of VAS203, a novel tetrahydrobiopterine (BH3)-based NOS inhibitor, in experimental TBI. When added to isolated vessels rings obtained from rat basilar and middle cerebral arteries (n = 32-35) VAS203 showed the same vasoconstrictive effect as the classical NO synthase inhibitor L-(G)-nitro-arginine-methylester (L-NAME). VAS203 passed the BBB both in healthy and traumatized mouse brain (C57/BL6, n = 5 per group) and did not show any systemic side effects at therapeutic concentrations. When administered 30 min after experimental TBI (controlled cortical impact, 2.2 mg/kg/min i.v., n = 7 per group), VAS203 prevented any further increase in ICP or deterioration of cerebral blood flow. This effect was dose-dependent and long-lasting (i.e., 24 h after trauma, brain edema formation was still significantly reduced [-40%, p < 0.008; n = 7 per group] and functional improvements were present up to 7 days after TBI [p < 0.02 on post-trauma day 6; n = 8 per group]). Therefore, VAS203 may represent a promising candidate for the treatment of acute intracranial hypertension following TBI.

Objective: After a subarachnoid hemorrhage (SAH), the primary cause of mortality is secondary brain injury occurring within the first 48 hours after the initial bleeding. Because of the unknown pathophysiology of these early events, therapeutic approaches are scarce. Because mild hypothermia (33 degrees C) is among the strongest neuroprotectants known so far, the aim of this study was to investigate acute and delayed effects of hypothermia if applied after SAH., Methods: Male Sprague-Dawley rats were subjected to SAH and randomly assigned to the following groups: 1) SAH under normothermia, 2) SAH followed by 2 hours of hypothermia starting 1 hour after the bleeding, and 3) SAH followed by 2 hours of hypothermia starting 3 hours after the bleeding. Cerebral blood flow and intracranial pressure were continuously measured up to 6 hours after SAH. Mortality, neurological deficits, and body weight were assessed from postoperative day 1 to day 7. Brain water content and morphological brain damage were quantified 24 hours and 7 days after SAH, respectively., Results: Mild hypothermia reduced intracranial pressure (P < 0.001) and posthemorrhagic neurological deficits (P < 0.05) and improved postoperative weight gain significantly (P < 0.05). Mortality, cerebral blood flow, and the formation of cerebral edema were not significantly influenced by mild hypothermia., Conclusion: The current results show that mild hypothermia (33 degrees C) exhibits sustained neuroprotection if applied up to 3 hours after SAH. Overall, mild hypothermia seems to be an effective neuroprotective strategy after SAH and should therefore be evaluated as a treatment option for SAH in patients.

Brain edema is still one of the most deleterious sequels of traumatic brain injury (TBI), and its pathophysiology is not sufficiently understood. The goal of the current study was to investigate the role of arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), an important regulator of tissue water homeostasis, for the formation of post-traumatic brain edema, intracranial pressure (ICP), brain damage, and functional deficits following brain trauma. C57/B16 mice (n=112) were subjected to controlled cortical impact (CCI; 8m/s, 1 mm). At 3 min after trauma, animals received 500 ng of the AVP V(1a)-receptor antogonist (deamino-Pen(1), O-Me-Tyr(2), Arg(8)]-Vasopressin) or 500 ng of the AVP V2-receptor antagonist (adamantaneacetyl(1), O-Et-D-Tyr(2),Val(4), Abu(6),Arg(8,9)]-Vasopressin) by intracerebroventricular injection. After trauma, cerebral water content (24 h), ICP (24 h), contusion volume (24 h and 7 days), and functional outcome (1-7 days) were assessed (n=8 per experimental group). Post-traumatic inhibition of AVP V(1A) receptors reduced ICP by 29% (p < 0.05), brain water content by 45% (p < 0.05), and secondary contusion expansion by 37% (p < 0.05), and it significantly improved motor function 6 and 7 days after trauma (p < 0.05). Inhibition of AVP V2 receptors had no significant effect. The current results demonstrate that vasopressin V(1A) receptors are involved in the pathogenesis of brain edema formation and the subsequent development of secondary brain damage after traumatic brain injury. Accordingly, our study suggests that vasopressin V(1A) receptors may represent a novel therapeutic target for the treatment of post-traumatic brain edema and secondary brain damage.

Traumatic brain injury (TBI) consists of two phases: an immediate phase in which damage is caused as a direct result of the mechanical impact; and a late phase of altered biochemical events that results in delayed tissue damage and is therefore amenable to therapeutic treatment. Because the molecular mechanisms of delayed post-traumatic neuronal cell death are still poorly understood, we investigated whether apoptosis-inducing factor (AIF), a pro-apoptotic mitochondrial molecule and the key factor in the caspase-independent, cell death signaling pathway, plays a causal role in neuronal death following TBI. Using an in vitro model of neuronal stretch injury, we demonstrated that AIF translocated from mitochondria to the nucleus of neurons displaying axonal disruption, chromatin condensation, and nuclear pyknosis in a caspase-independent manner, whereas astrocytes remained unaffected. Similar findings were observed following experimental TBI in mice, where AIF translocation to the nucleus coincided with delayed neuronal cell death in both cortical and hippocampal neurons. Down-regulation of AIF in vitro by siRNA significantly reduced stretch-induced neuronal cell death by 67%, a finding corroborated in vivo using AIF-deficient harlequin mutant mice, where secondary contusion expansion was significantly reduced by 44%. Hence, our current findings demonstrate that caspase-independent, AIF-mediated signaling pathways significantly contribute to post-traumatic neuronal cell death and may therefore represent novel therapeutic targets for the treatment of TBI.

In recent years, several studies have unequivocally shown the occurrence of cortical spreading depressions (CSDs) after stroke and traumatic brain injury (TBI) in humans. The fundamental question, however, is whether CSDs cause or result from secondary brain damage. The aim of the current study was, therefore, to investigate the role of CSDs for secondary brain damage in an experimental model of TBI. C57/BL6 mice were traumatized by controlled cortical impact. Immediately after trauma, each animal showed one heterogeneous direct current (DC) potential shift accompanied by a profound depression of electroencephalogram (EEG) amplitude, and a temporary decrease of ipsi- and contralateral regional cerebral blood flow (rCBF) suggesting bilateral CSDs. Within the next 3 h after TBI, CSDs occurred at a low frequency (0.38 CSD/h per animal, n=7) and were accompanied by rCBF changes confined to the ipsilateral hemisphere. No significant relationship between the number of SDs and lesion size or intracranial pressure (ICP) could be detected. Even increasing the number of posttraumatic CSDs by application of KCl by more than six times did not increase ICP or contusion volume. We therefore conclude that CSDs may not contribute to posttraumatic secondary brain damage in the normally perfused and oxygenated brain.

Although changes of cerebral blood flow (CBF) in and around traumatic contusions are well documented, the role of CBF for the delayed death of neuronal cells in the traumatic penumbra ultimately resulting in secondary contusion expansion remains unclear. The aim of the current study was therefore to investigate the relationship between changes of CBF and progressive peri-contusional cell death following traumatic brain injury (TBI). CBF and contusion size were measured in C57Bl6 mice under continuous on-line monitoring of (ETp)CO2 before, and at 15 min and 24 h following controlled cortical impact by 14C-iodoantipyrine autoradiography (IAP-AR; n = 5-6 per group) and by Nissl staining, respectively. Contused and ischemic (CBF < 10%) tissue volumes were calculated and compared over time. Cortical CBF in not injured mice varied between 69 and 93 mL/100mg/min depending on the anatomical location. Fifteen minutes after trauma, CBF decreased in the whole brain by approximately 50% (39 +/- 18 mL/100mg/min; p < 0.05), except in contused tissue where it fell by more than 90% (3 +/- 2 mL/100mg/min; p < 0.001). Within 24 h after TBI, CBF recovered to normal values in all brain areas except the contusion where it remained reduced by more than 90% (p < 0.001). Contusion volume expanded from 24.9 to 35.5 mm3 (p < 0.01) from 15 min to 24 h after trauma (+43%), whereas the area of severe ischemia (CBF < 10%) showed only a minimal (+13%) and not significant increase (22.3 to 25.1 mm3). The current data therefore suggest that the delayed secondary expansion of a cortical contusion following traumatic brain injury may not be caused by a reduction of CBF alone.

Vasogenic brain edema is one of the major determinants for mortality following subarachnoid hemorrhage (SAH). Although the formation of vasogenic brain edema occurs on the microvascular level by opening of endothelial tight junctions and disruption of the basal lamina, microvascular changes following experimental SAH are poorly characterized. The aim of the present study was therefore to investigate the time course of blood-brain barrier (BBB) dysfunction and basal lamina damage following SAH as a basis for the better understanding of the pathophysiology of SAH. SAH was induced in Sprague-Dawley rats by an endovascular filament. Animals were sacrificed 6, 24, 48, and 72 h thereafter (n=9 per group). Microvascular basal lamina damage was quantified by collagen type IV immunostaining. Western blotting was used to quantify collagen IV protein content and bovine serum albumin (BSA) extravasation as a measure for basal lamina damage and blood-brain barrier disruption, respectively. BSA Western blot revealed significant (p<0.05) BBB opening in the cerebral cortex ipsilateral to the hemorrhage beginning 6 h and peaking 48 h after SAH. Significant (p<0.05) basal lamina damage occurred with gradual increase from 24 to 72 h. Basal lamina damage correlated significantly with BBB dysfunction (r=-0.63; p=0.0001). Microvascular damage as documented by collagen IV degradation and albumin extravasation is a long lasting and ongoing process following SAH. Due to its delayed manner microvascular damage may be prone for therapeutic interventions. However, further investigations are needed to determine the molecular mechanisms responsible for basal lamina degradation and hence damage of the microvasculature following SAH.

Vancomycin-resistant Enterococcus faecium strains are a significant cause of nosocomial infections in predisposed patients. Multiple-locus variable-number tandem repeat analysis (MLVA) has been validated recently by use of a global strain collection. In this report, we applied MLVA together with multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) to type 14 isolates from three clusters of patients colonized or infected with vancomycin-resistant Enterococcus faecium and another 10 epidemiologically unrelated isolates from the same hospital. The clusters could be distinguished by all three typing methods, which proved to be concordant. PFGE patterns provided the highest resolution. We observed seven sequence types (ST), six MLVA types (MT), and nine distinct ST/MT combinations. The combination of MLST and MLVA may be an alternative to PFGE in hospital epidemiology, providing the benefits of high accuracy, reproducibility, and portability.

Perifocal depolarizations (PFD) have been observed after traumatic brain injury, are known to disturb cerebrovascular reactivity and thus may contribute to the morphological consequences of brain injury. In this investigation, the role of PFD was studied in focal brain lesions with/without induction of delayed hypotension. Cerebral freeze lesions were induced in anesthetized normotensive rats that underwent perfusion fixation of brains 5 min, 4 h or 24 h after lesioning, respectively, to obtain quantitative histopathology. In additional groups, a 45-min period of moderate hypobaric hypotension was applied 15 min post-trauma and brains were perfusion fixed after 4 h or 24 h. In a second series, the direct current (DC) potential and cortical laser-Doppler flow (LDF) were measured adjacent to lesions under normotensive or hypotensive conditions. Sham procedures were carried out in rats that underwent hypotension alone. Lesioning resulted in a significant LDF decrease to 50% of baseline, further decreased during hypotension to less than 40% of control (P < 0.05). Sham animals had LDF values between 60 and 70% of control when subjected to hypotension. Focal brain injury always induced a negative DC shift shortly after lesioning. In 6 of 8 rats that underwent cold lesion plus hypotension, a second PFD was observed approximately 2.5 min after onset of hypotension accompanied by a relative LDF increase by 25 +/- 12%. Lesion expansion was significantly worsened by hypotension (8.19 +/- 0.56 mm(3) at 24 h) compared with normotensive rats (7.01 +/- 0.3 mm(3) at 24 h, P < 0.01). We conclude that hypotension triggers depolarizations by an ischemic mechanism that contributes to final tissue damage.

We evaluated the ability of the new VITEK 2 version 4.01 software to identify and detect glycopeptide-resistant enterococci compared to that of the reference broth microdilution method and to classify them into the vanA, vanB, vanC1, and vanC2 genotypes. Moreover, the accuracy of antimicrobial susceptibility testing with agents with improved potencies against glycopeptide-resistant enterococci was determined. A total of 121 enterococci were investigated. The new VITEK 2 software was able to identify 114 (94.2%) enterococcal strains correctly to the species level and to classify 119 (98.3%) enterococci correctly to the glycopeptide resistance genotype level. One Enterococcus casseliflavus strain and six Enterococcus faecium vanA strains with low-level resistance to vancomycin were identified with low discrimination, requiring additional tests. One of the vanA strains was misclassified as the vanB type, and one glycopeptide-susceptible E. facium wild type was misclassified as the vanA type. The overall essential agreements for antimicrobial susceptibility testing results were 94.2% for vancomycin, 95.9% for teicoplanin, 100% for quinupristin-dalfopristin and moxifloxacin, and 97.5% for linezolid. The rates of minor errors were 9% for teicoplanin and 5% for the other antibiotic agents. The identification and susceptibility data were produced within 4 h to 6 h 30 min and 8 h 15 min to 12 h 15 min. In conclusion, use of VITEK 2 version 4.01 software appears to be a reliable method for the identification and detection of glycopeptide-resistant enterococci as well as an improvement over the use of the former VITEK 2 database. However, a significant reduction in the detection time would be desirable.