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• Nearly 10 % of patients with glioblastoma suffered from status epilepticus in this retrospective, single-centre analysis. • SE occurrence was linked to postoperative seizures and drug-resistant epilepsy. • Despite the dismal oncological prognosis of glioblastoma, SE was successfully treated in almost 80 % of the cases in our study. • Higher STESS and CCI scores were independently associated with adverse outcome. Epilepsy is a common comorbidity in patients with glioblastoma, however, clinical data on status epilepticus (SE) in these patients is sparse. We aimed to investigate the risk factors associated with the occurrence and adverse outcomes of SE in glioblastoma patients. We retrospectively analysed electronic medical records of patients with de-novo glioblastoma treated at our institution between 01/2006 and 01/2020 and collected data on patient, tumour, and SE characteristics. In the final cohort, 292/520 (56.2 %) patients developed seizures, with 48 (9.4 % of the entire cohort and 16.4 % of patients with epilepsy, PWE) experiencing SE at some point during the course of their disease. SE was the first symptom of the tumour in 6 cases (1.2 %) and the first manifestation of epilepsy in 18 PWE (6.2 %). Most SE episodes occurred postoperatively (n = 37, 77.1 %). SE occurrence in PWE was associated with postoperative seizures and drug-resistant epilepsy. Adverse outcome (in-house mortality or admission to palliative care, 10/48 patients, 20.8 %), was independently associated with higher status epilepticus severity score (STESS) and Charlson Comorbidity Index (CCI), but not tumour progression. 32/48 SE patients (66.7 %) were successfully treated with first- and second-line agents, while escalation to third-line agents was successful in 6 (12.5 %) cases. Our data suggests a link between the occurrence of SE, postoperative seizures, and drug-resistant epilepsy. Despite the dismal oncological prognosis, SE was successfully treated in 79.2 % of the cases. Higher STESS and CCI were associated with adverse SE outcomes. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate psychosocial long-term outcome in patients diagnosed with psychogenic nonepileptic seizures (PNES) and to predict outcome of PNES, economic status, and quality of life (QoL) at follow-up.Methods: Patients diagnosed with PNES in the video-EEG-monitoring unit at our Epilepsy center between 2002-2016 were contacted by phone 1-16 years after communicating the diagnosis. Patients underwent a structured interview asking for current PNES status, psychosocial situation (economic status, marital status, setting of living, driving), depression, and QoL.Results: Of 70 PNES patients without comorbid epilepsy (age: 41.1 ± 13.5 years; 74 % female, follow-up: 5.2 ± 4.2 years), 23 patients (33 %) reported to be free of PNES during the last 12 months. Patients with cessation of PNES were younger at PNES onset (p < .01) and diagnosis (p < .01) and had a higher education (p < .05). At follow-up, the proportion of economically active patients only increased in individuals with cessation of PNES (p < .001) while an increased number of patients with persisting PNES relied on governmental support (p < .001). Cessation of PNES was associated with better mood (p < .01) and QoL (p < .001). In multiple regression models, cessation of PNES was only predicted by younger age at onset, while good economic outcome was determined by younger age and good economic status at diagnosis and cessation of PNES at follow-up. Good QoL at follow-up was predicted by low depressive symptoms, freedom of PNES, and economic activity at follow-up.Conclusion: Long-term outcome in patients with PNES remains to be poor and the majority of patients continue to have PNES. Cessation of PNES was associated with good economic outcome, mood, and QoL. [ABSTRACT FROM AUTHOR]

Background and purpose Parkinson’s disease (PD) is characterised by neuropathological degenerative changes in the substantia nigra (SN). Our study aimed to evaluate whether high-resolution diffusion tensor-imaging (DTI) can detect anatomical biomarkers in early-stage PD, and has the potential to visualize asymmetry effects comparable to the 123I-FP-CIT SPECT (DaTSCAN). Methods Ten early-stage PD patients with mild disease severity and ten age- and gender-matched healthy controls were examined with a high-resolution DTI protocol at a 3 Tesla MRI scanner to assess fractional anisotropy (FA) values in the ventral, middle and dorsal region of SN. In addition, a subgroup of 5 PD patients underwent a DaTSCAN. Results PD subjects showed reduced FA values in all SN regions compared to controls, but post hoc analysis revealed a significant reduction (p = .032) in the dorsal region. There was no significant correlation between clinical data and FA values. Subgroup analysis of PD patients with asymmetric radioligand uptake in the DaTSCAN demonstrated also significant asymmetric FA values (p = .027) in the dorsal region of SN. Conclusions Our results provide preliminary evidence that high-resolution DTI can detect in early-stage PD patients with mild disease severity an anatomical biomarker in the dorsal region of SN, indicating microstructural disorganization. This biomarker, discriminating potentially in vivo between patients and healthy people, could be valuable for early PD diagnosis. If asymmetric radioligand uptake in the DaTSCAN was present, also asymmetry effects in the dorsal region of SN were obtained by DTI. These findings might contribute to improve effectiveness in diagnosing and monitoring PD. [ABSTRACT FROM AUTHOR]

Purpose: The incidence of epilepsy in older adults is growing, as does the incidence of comorbidities. Therefore, when it comes to epilepsy surgery in medically intractable epilepsy, age is often seen as a limiting factor. To investigate the outcome after epilepsy surgery in a population of older adults, we compared the benefit for patients aged 50-59 years with those aged 60 years and older in respect of efficacy and safety.Method: Patients aged ≥50 years with medically intractable epilepsy who underwent epilepsy surgery from 1990 to 2013 were selected from the database of a German epilepsy center. All of them received a standardised and detailed presurgical diagnostic evaluation. Follow-up included at least four scheduled visits with EEG, MRI and neuropsychological testing. Outcome was assessed using the Engel outcome scale.Results: 79 patients aged between 50 and 67 years were followed-up for a median of 4.7 years (2-16 years). 68% of patients were free of disabling seizures (Engel class I, ≥60 years: 75%) and 58% were seizure-free (Engel class IA, ≥60 years: 70%). 90% of our patients suffered from temporal lobe epilepsy (TLE), 9% from frontal lobe epilepsy (FLE) and one occipital lobe epilepsy (OLE). After surgery, 9% discontinued or tapered their medication. Permanent surgical complications occurred in 10% of cases and transient neurological deficits were seen in 11%. Older patients had a higher risk for postoperative hygroma (≥60 years 15%; <60 years 8%) and were more prone to postoperative memory deficits (≥60 years 45%), especially after resection of the dominant temporal lobe. Verbal and figural memory testing did not differ significantly between the groups.Conclusions: The results support the view that in selected older patients, epilepsy surgery shows equal or even higher success rates as compared to younger patients. However, patients of older age may be at greater risk for postoperative hygroma and memory deficits, especially after dominant temporal lobe resections. [ABSTRACT FROM AUTHOR]

Background: Direct oral anticoagulants (DOACs) are increasingly used for secondary prevention of cardioembolic stroke. While DOACs are associated with a long-term reduced risk of intracranial hemorrhage compared to vitamin K antagonists, pivotal trials avoided the very early period after stroke and few data exist on early initiation of DOAC therapy post stroke.Methods: We retrospectively analyzed data from our prospective database of all consecutive transient ischemic attack (TIA) or ischemic stroke patients with atrial fibrillation treated with DOACs during hospital stay. As per our institutional treatment algorithm for patients with cardioembolic ischemia DOACs are started immediately in TIA and minor stroke (group 1), within days 3-5 in patients with infarcts affecting one third or less of the middle cerebral artery, the anterior cerebral artery, or the posterior cerebral artery territories (group 2) as well as in infratentorial stroke (group 3) and after 1-2 weeks in patients with large infarcts (>⅓MCA territory, group 4). We investigated baseline characteristics, time to initiation of DOAC therapy after symptom onset, and hemorrhagic complications.Results: In 243 included patients, administration of DOAC was initiated 40.5 hours (interquartile range [IQR] 23.0-65.5) after stroke onset in group 1 (n = 41) and after 76.7 hours (IQR 48.0-134.0), 108.4 hours (IQR 67.3-176.4), and 161.8 hours (IQR 153.9-593.8) in groups 2-4 (n = 170, 28, and 4), respectively. Two cases of asymptomatic intracranial hemorrhage (.8%) and 1 case of symptomatic intracranial hemorrhage (.4%) were observed, both in group 2.Conclusions: No severe safety issues were observed in early initiation of DOACs for secondary prevention after acute stroke in our in-patient cohort. [ABSTRACT FROM AUTHOR]

Background: Oral anticoagulation with dabigatran was shown to be effective for stroke prevention in patients with nonvalvular atrial fibrillation without the need for laboratory monitoring. However, a recent publication based on data of the Randomized Evaluation of Long-Term Anticoagulation Therapy study reported that ischemic stroke and bleeding outcomes are correlated with dabigatran plasma concentration (DPC). DPC was determined at a prespecified time point and correlated with cardiovascular events at any time during follow-up. Because of the known variability of DPC, among others depending on renal function, this approach might compromise data evaluation. We report on dabigatran plasma levels in acute cerebrovascular events.Methods: Consecutive patients with acute ischemic stroke (AIS) or intracerebral hemorrhage (ICH) while taking dabigatran were retrospectively identified if admission DPC was available. DPC was determined using the diluted thrombin time (Hemoclot (HYPHEN BioMed, Neuville sur Oise, France)). Creatinine clearance (CrCl) was determined by measuring creatinine in plasma and 24-hour urine.Results: Fifteen AIS and 4 ICH patients were included. Median DPC on admission was significantly higher in ICH patients than in AIS patients (135 ng/mL [interquartile range {IQR} 79-218] and 69.1 ng/mL [IQR 20.6-85.0], respectively; P = .035). Increased CrCl (values above published normal range) was correlated with lower median DPC (60 ng/mL [IQR 10-69] versus 100 ng/mL [IQR 79-157] in patients with normal CrCl, P = .01).Conclusions: Higher DPC was found in ICH patients than in AIS patients in temporal proximity to the event. Both decreased and increased renal functions seem to have an important influence on DPC. [ABSTRACT FROM AUTHOR]

Background: Perfusion computed tomography (PCT) has emerged as alternative to magnetic resonance imaging (MRI) for assessment of patients clinically qualifying for off-label thrombolysis within 4.5 to 9 hours after onset of ischemic stroke. However, disadvantage of PCT is its often limited anatomic coverage with only 2 or 3 slices when using a 4- to 64-section scanner. Our purpose was therefore to evaluate the value of 2- and 3-slice perfusion compared to whole-brain perfusion.Methods: One hundred twenty-five patients undergoing MRI beyond 4.5 hours after symptom onset with supratentorial perfusion deficit were selected retrospectively. Accordingly to PCT slice positioning, 2 or 3 slices of the whole-brain perfusion weighted imaging data set were depicted. Volumes of infarct (using cerebral blood volume) and penumbra (using time-to-peak and cerebral blood volume) were calculated, and results were compared with 2- and 3-slice-derived volumes, respectively.Results: Whole-brain imaging revealed a mismatch of more than 20% in 68.8% of patients (defined as 100%). Two-slice imaging detected a perfusion deficit in 72% and a mismatch in 48.8% (sensitivity = 70.9%). Three-slice imaging detected a perfusion deficit in 76% and a mismatch in 50.4% (sensitivity = 73.3%). Although there was no significant difference between 2- and 3-slice imaging (P > .23), both techniques revealed significantly less patients with mismatch compared to whole-brain coverage (P < .01).Conclusions: Two- and 3-slice imaging like obtained with PCT on most installed CT systems to assess perfusion deficits with subsequent mismatch calculation in acute stroke outside the 4.5-hour time window is significantly inferior to whole-brain coverage and, hence, has to be considered as a less-than-ideal solution. [ABSTRACT FROM AUTHOR]

Background Growing evidence suggests that the heart rate (HR) at rest is an independent predictor of cardiovascular mortality. In ischemic stroke, continuous monitoring of HR is the standard of care, but systematic data on its dynamics and prognostic value during the acute phase are limited. Methods In this prospective observational study, HR was measured by continuous electrocardiographic monitoring on admission and during the first 72 hours of care among patients who were awake with ischemic stroke and survived until discharge. Functional outcome was assessed after 90 days. Results Data from 702 consecutive patients were analyzed (median age, 73 years, 54% men). The time course of HR was initially characterized by a rapid decline during the first 12 hours after admission. Among patients who survived until day 90, this was followed by a continuous downward trend in HR, whereas death after discharge was associated with a secondary increase and a reversal point 12 hours after admission. After adjustment for established risk factors, this secondary increase during the acute period was an independent predictor of death (hazard ratio, 3.73; 95% confidence interval, 1.47-9.43; P = .005). Conclusions A secondary rise of HR during care for acute ischemic stroke is an early sign of fatality and may represent a surrogate for an unfavorable sympathetic disinhibition. Further research is warranted to clarify the role of targeted HR reduction after ischemic stroke ( http://clinicaltrials.gov/ , unique identifier NCT01858779 ). [ABSTRACT FROM AUTHOR]

The term "neuroprotection" is often misused, overused, or misunderstood. A reasonable definition of neuroprotection refers to the preservation of "neuronal structure and/or function." Although our knowledge about the cellular and molecular mechanisms of neurodegeneration has expanded, experimental systems and animal models that mimic the process or allow translation into clinical success remain limited. This editorial discusses reasons for this gap and strategies to close it. Experimental models can only mirror certain aspects of disease mechanisms in humans. Therefore, findings in these models need to be linked with patient data to improve real-life relevance. Successful neuroprotection depends on finding the right "window of opportunity" which varies from very short (stroke) to very long (Alzheimer's disease), necessitating the need to focus on strategies for very early disease recognition. This need challenges the strategies to be chosen, trial approaches and methodologies, and the allocation of resources. Additionally, outcome measures are often not well suited to assess neuroprotection. To this end, surrogate measures, including biomarkers, are useful endpoints to demonstrate evidence of target directed therapeutic utility. Finally, studies have shown that neuroprotection is not likely to succeed when targeting only one pathway. These obstacles have reduced the level of enthusiasm for neuroprotection in certain disease areas (e.g., stroke). Academia, industry, regulatory authorities, funding agencies and patient organizations have to cooperate to a greater extent in order to overcome these impediments and to encourage nonclassical concepts. These concepts will be interdisciplinary in order to achieve meaningful disease modification. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with ischemic stroke caused by atrial fibrillation (AF) have a high risk of recurrence without adequate secondary prevention with oral anticoagulation (OAC). We investigated adherence to OAC in the first year after introduction of direct oral anticoagulants. METHODS: In 284 appropriate patients, the rate of anticoagulation (AC) at discharge, adherence at 90 days and 1 year, changes between substances, and predictors for adherence to AC were analyzed. Functional outcome was assessed using the modified Rankin Scale score. RESULTS: AC was initiated in 70.3% of survivors before discharge. In these patients, only 8.6% and 9.9% discontinued AC after 90 days and 1 year, respectively. In 22.1%, AC was recommended but not started before discharge. Only 53.2% of them received AC at 90 days, increasing to 67.5% at 1 year. A total of 7.6% of patients were deemed unsuitable for AC, none of them subsequently received AC. Overall, 85.4% of patients suitable for AC were treated at 1-year follow-up. No independent predictors for withholding AC were identified. Switching of medication occurred in only a minority of patients within the first year. CONCLUSIONS: AC is feasible in more than 90% patients with acute ischemic stroke and AF. When initiated during the acute hospital stay, AC is discontinued in only a minority of patients. However, if AC is recommended but not started during initial hospitalization the rate of AC treatment at 90 days and 1 year is much lower. Therefore, AC should be initiated within the acute hospital stay whenever possible. [ABSTRACT FROM AUTHOR]

Background: Stroke patients with atrial fibrillation (AF) are prone to have comorbidities such as impaired renal function. Because poly-pharmacotherapy is often required in those patients, renal function is important to consider in light of renally cleared medications such as direct oral anticoagulants. In this study, we analyzed frequency and predictors for impaired renal function and its impact on functional outcome in stroke patients with underlying AF. Methods: We analyzed 272 patients with acute ischemic stroke and AF of our prospective, observational stroke database. Estimated glomerular filtration rate (eGFR) was calculated on admission and during hospitalization from the equation of the Modification Diet for Renal Disease. Outcome measures included mortality and functional outcome at 90 days, assessed as modified Rankin Scale (mRS) score. Results: On admission, impaired renal function was found in 41.5% (n = 113) and was associated with worse 90-day outcome (mRS score ≤ 2: 26.5% versus 45.9%, P = .001) and a higher mortality rate (23.9% versus 14.5%, P = .043). Multivariate logistic regression identified older age and history of myocardial infarction as independent predictors of renal dysfunction on admission (P < .05). Normalization of eGFR during hospitalization was achieved in 55.8%. Conclusions: In patients with acute ischemic stroke and AF, impaired renal function on admission is frequent and associated with worse outcome. Normalization of eGFR can often be achieved during hospitalization, but in everyday life, fluctuations of renal function because of infection or dehydration have to be considered. Careful monitoring of renal status is indispensable and should influence drug treatment decisions. [Copyright &y& Elsevier]

Occlusion of a brain vessel leads to a critical reduction in cerebral perfusion and, within minutes, to ischemic infarction with a central infarct core of irreversibly damaged brain tissue and a more or less large area of hypoperfused but still vital brain tissue (the ischemic penumbra), which can be salvaged by rapid restoration of blood flow. Therefore, the underlying rationale for the introduction and application of thrombolytic agents is the lysis of an obliterating thrombus and thus reestablishment of cerebral blood flow by cerebrovascular recanalization with subsequent reperfusion. After introduction of thrombolytic therapy for the treatment of acute myocardial infarction in the early 1990s, major trials for the evaluation of this new therapeutic approach to ischemic stroke were initiated. There are in general two strategies in thrombolytic therapy, a local (intraarterial) approach and a systemic (intravenous) application of the thrombolytic agent. Only the latter has been proven to be effective in larger randomized trials and is a Class 1/Level A recommendation in national or international guidelines. This review summarizes the evidence for thrombolytic therapy of acute ischemic stroke with emphasis on progress regarding the approved intravenous treatment. Finally intraarterial approaches as well as combined systemic and interventional therapies are discussed. [ABSTRACT FROM AUTHOR]

Summary: Space-occupying, malignant middle cerebral artery (MCA) infarctions are still one of the most devastating forms of ischaemic stroke, with a mortality of up to 80% in untreated patients. An early diagnosis is essential and depends on CT and MRI to aid the prediction of a malignant course. Several pharmacological strategies have been proposed but the efficacy of these approaches has not been supported by adequate evidence from clinical trials and, until recently, treatment of malignant MCA infarctions has been a major unmet need. Over the past 3 years, results from randomised controlled trials and their pooled analyses have provided evidence that an early hemicraniectomy leads to a substantial decrease in mortality at 6 and 12 months and is likely to improve functional outcome. Hemicraniectomy is now in routine use for the clinical management of malignant MCA infarction in patients younger than 60 years of age. However, there are still important questions about the individual indication for decompressive surgery, particularly with regard to the ideal timing of hemicraniectomy, a potential cut-off age for the procedure, the hemisphere affected, and ethical considerations about functional outcome in surviving patients. [Copyright &y& Elsevier]

Abstract: Acetylsalicylic acid (ASA; Aspirin) has a neuroprotective potential by its anti-excitotoxic and anti-inflammatory effects. A temporary middle cerebral artery occlusion (tMCAO) model was used in 80 Wistar rats to evaluate whether a high dose of Aspirin (40 mg/kg) applied with different initiation time points after stroke onset (30 min, 3 h, 6 h, 12 h, 20 rats for each time group) and followed by repeated administration (1, 2 and 3 days) is neuroprotective. Neurological score and brain infarct volume were analyzed and indicated that postischemic therapy initiation at 30 min and as late as 6 h led to better neurological recovery (6 h, p =0.0046) and significant smaller infarct size (6 h, 57±9 mm3, n =10, p =0.0043) compared to the saline control group (110±13 mm3, n =10). Thus, there may be a relatively wide time window for acute stroke therapy with high dose Aspirin. [Copyright &y& Elsevier]

Copper based fungicides are plant protection products prevalently used in organic agriculture to control several plant diseases. Since copper can have various negative effects on the environment, the amount used should be reduced to the minimum necessary. However, this reduction should not lead to a loss of efficacy, as otherwise the quality and quantity of the yield would be at risk. During this study, a copper sulfate/copper hydroxide mixture was combined with an agent for better adhesion to grapevines. This was achieved by microencapsulation of the active agents into a fat matrix which resulted in the so called CuCaps. Laboratory analysis of dispersibility and particle size proved that CuCaps form an applicable powder, suitable for use in commercial crop protection sprayers. Field experiments demonstrated that CuCaps have an equivalent effect compared to a commercially available copper-based fungicide (CCF). Both, CuCaps and CCF were able to significantly (p < 0.05) reduce disease severity (DS) on leaves and bunches in three independent years compared to an untreated control (UTC). This was even true if the applied amount of CuCaps was reduced by one third to 2 kg copper per year and hectare. Additionally, in the particularly severe P. viticola epidemic of 2016, CuCaps showed a remarkably better effect on flower clusters and bunches compared to the CCF. However, this effect was not statistically significant due to strong variation within the repetitions. Taken together, this study shows that copper minimization by microencapsulation is possible. Considering the restricted use of copper-based fungicides, CuCaps can be a valuable option for organic farmers, especially in difficult years. • Copper was microencapsulated in a fatty matrix resulting in the so called CuCaps. • CuCaps are suitable for use in standard crop protection sprayers. • CuCaps are equally efficient against P. viticola than approved copper fungicides. • Reduction of applied copper amounts is possible without loss of efficiency. • CuCaps seem to improve the effect of copper used for P. viticola control on bunches. [ABSTRACT FROM AUTHOR]

Introduction: The number of patients with left ventricular assist devices (LVAD) is rapidly growing in industrialized countries. While cerebrovascular events comprise a significant complication, data on stroke etiology, clinical management and functional outcome are scarce.Methods: Consecutive LVAD patients with ischemic or hemorrhagic stroke receiving treatment at an university stroke center between 2010 and 2018 were included into an institutional registry. Clinical characteristics, causes, management and functional outcome of stroke occurring within this cohort are reported. Acceptable functional outcome was defined as mRS 0-3.Results: N = 30 acute strokes occurred in 20 patients (77% ischemic, 23% hemorrhagic, mean age 57 ± 13 years, 10% female, 8 patients (40%) had more than one event). 87% of all events happened with non-pulsatile devices, on average 9 (IQR 3-22) months after the implantation. All patients used oral anticoagulation with a Vitamin-K antagonist in combination with anti-platelets. The international normalized ratio (INR)-values were outside the therapeutic range in 39% of ischemic strokes and in 57% of hemorrhagic strokes. Ischemic strokes were predominantly of cardioembolic origin (92%) and of mild to moderate clinical severity (median NIHSS 6 (IQR 4-10). None qualified to receive intravenous thrombolysis or intra-arterial endovascular therapy. 61% of IS-patients showed an acceptable functional outcome after three months. 4/7 patients with hemorrhagic stroke received immediate reversal of anticoagulation without any thrombotic complications.Conclusion: The majority of LVAD patients with ischemic stroke had an acceptable functional outcome after three months. Future clinical research is warranted to improve therapeutic strategies for acute care and stroke prevention. [ABSTRACT FROM AUTHOR]

Background: Whether time of hospital admission-during or outside regular working hours-affects functional outcome in intracerebral hemorrhage (ICH) is unestablished as previous analyses have focused on mortality only. We here investigate whether on- versus off-hour hospital admission in ICH is associated with levels of invasiveness and clinical outcomes.Methods: Based on the UKER registry (NCT03183167) we grouped ICH-patients according to on- versus off-hour hospital admission. Primary outcome measures was functional outcome after 3 months using the modified Rankin scale (mRS) dichotomized into favorable (mRS = 0-3) and unfavorable (mRS = 4-6). Multivariate regression analyses were used to adjust for baseline imbalances, and subgroup analyses were performed to explore associations of on- versus off-hour admission with invasiveness of therapeutic interventions.Results: A total of 438/1269 (34.5%) of ICH-patients were admitted during regular working hours. Mortality rates were not significantly different among patients with on- versus off-hour admission. On-hour patients showed a significantly larger proportion of patients with favorable outcome (on-hour: mRS = 0-3 after 3 months: 176/416 (42.3%) versus off-hour: 265/784 (33.8%); P = .004). Analysis of invasive therapeutic interventions revealed that likelihood of favorable outcome was significantly increased among on-hour admitted patients who did not require neurosurgical interventions (no external ventricular drain n = 349, OR: 1.67[1.13-2.48], P < .05; no hematoma evacuation surgery n = 423, OR: 1.51[1.07-2.14], P < .05).Conclusion: This study verified an "off-hour effect" in ICH that relates to functional outcome, rather than mortality, and which may be linked to different levels of invasive therapeutic interventions in patients admitted during off-hour. [ABSTRACT FROM AUTHOR]

Abstract: Since pravastatin, a HMG-CoA reductase inhibitor, has recently been shown to reduce infarct volumes and glutamate release in a rat model of ischemic stroke, the aim of the present study was to investigate whether this neuroprotective effect may be due to a modulation of excitatory and inhibitory neurotransmitter receptors. Therefore, Wistar rats were treated six times in 4 days with pravastatin or saline and allowed to survive for 6 hours or 5 days (n =10 per time point and group), respectively. Using quantitative receptor autoradiography, ligand binding densities of [3H]MK-801, [3H]AMPA, and [3H]muscimol for labeling of NMDA, AMPA, and GABAA receptors were analyzed in sensorimotor cortices Par1 and Par2, the striatum, and the hippocampus. Statin therapy induced complex alterations of ligand binding densities in different brain regions. Labeling of NMDA receptors was significantly increased in Par2, both after 6 hours and 5 days, respectively. Within the striatum, AMPA as well as GABAA receptor binding values were significantly increased on day 5. Furthermore, a marked and significant increase of [3H]muscimol ligand binding to GABAA receptors throughout all hippocampal subfields was seen after 6 hours. This complexity could easily be unraveled when focusing on the balance between excitatory glutamate and inhibitory GABAA receptors, in which case only the increase of hippocampal [3H]muscimol ligand binding 6 hours after the first application of pravastatin was accompanied by a net shift towards inhibition. Consequently, our data suggest an additional regulatory pathway induced by statins, namely modification of the abundance of excitatory and inhibitory neurotransmitter receptors. [Copyright &y& Elsevier]

We have previously shown that exogenous application of brain-derived neurotrophic factor (BDNF) reduces infarct volume in the cortical ischemic penumbra after experimental focal ischemia [Stroke 31 (2000) 2212–2217]. Since BDNF is known to modulate the expression and function of various neurotransmitter receptors, we addressed the question whether BDNF may act via modification of postischemic ligand binding to excitatory NMDA and AMPA and/or inhibitory GABAA receptors, respectively. Transient focal cerebral ischemia was induced in male Wistar rats for 2 h using the suture occlusion technique. A period of 30 min after occlusion of the middle cerebral artery, BDNF (300 μg/kg per hour in vehicle; n=5) or vehicle alone (n=5) was continuously infused intravenously for 3 h. Using quantitative receptor autoradiography, postischemic ligand binding of [3H]MK-801, [3H]AMPA and [3H]muscimol was analyzed in the ischemic core, the ischemic cortical penumbra and corresponding regions of the contralateral hemisphere. Transient focal ischemia caused a significant reduction of [3H]muscimol binding to GABAA receptors within the ischemic cortical penumbra of placebo-treated rats. This was largely prevented by exogenous application of BDNF. [3H]MK-801 and [3H]AMPA binding values were also reduced in the cortical penumbra and the corresponding area of the contralateral hemisphere. Our data suggest that the neuroprotective effect of BDNF against ischemic damage in the cortical penumbra may be mediated in part by maintained activity of the inhibitory GABAergic system which likely counteracts glutamate induced excitotoxicity. [Copyright &y& Elsevier]

Progressive multifocal leukoencephalopathy (PML) is a rare, opportunistic and often fatal disease of the CNS which may occur under immunosuppression in transplant patients. Brain stem PML is associated with a particularly bad prognosis. Here, we present a case of a renal transplant patient treated with mycophenolate mofetil (MMF) and tacrolimus who developed brain stem PML with limb ataxia, dysarthria and dysphagia. Diagnosis was established by typical MRI features and detection of JCV-DNA in the CSF. Immune reconstitution after stopping MMF and tacrolimus led to a complete and sustained remission of symptoms with improvement of the brain stem lesion over a follow-up over 20 months. In summary, early detection of PML and consequent treatment may improve neurological outcomes even in brain stem disease with a notorious bad prognosis. [ABSTRACT FROM AUTHOR]

Objective: Contradictory results were reported for the outcome after endovascular recanalization (ERT) in acute anterior circulation ischemic stroke. We assessed whether a clinical/perfusion CT cerebral blood volume (CBV) mismatch concept (CPM) can identify patients who will benefit from reperfusion therapy. Methods: Imaging and clinical data of 58 consecutive ERT cases with acute anterior circulation stroke (ICA, M1, proximal M2) undergoing intraarterial thrombectomy within 4.5 h after symptom onset were analyzed retrospectively. CPM was defined as NIHSS ≥ 8 and PCT CBV ASPECTS ≥ 7. Minor CBV lesion was defined as PCT CBV ASPECTS ≥ 7. Results: All baseline characteristics other than blood glucose did not differ between the paired groups. Revascularization was achieved in 87.9% of all patients without significant difference between the paired groups. Favorable clinical outcome after 3 months (mRS ≤ 2) resulted in 29.3% of all patients, in contrast to 47.4% of the CPM positive and 52.2% of the minor CBV lesion groups. Conclusion: CPM can identify patients who will benefit from reperfusion therapy in acute anterior circulation ischemic stroke. [ABSTRACT FROM AUTHOR]

Abstract: The endocannabinoids anandamide (AEA) and palmitoylethanolamide (PEA) act as endogenous protective factors of the brain, using different pathways of neuroprotection against neuronal damage. Although several in vivo and in vitro studies confirmed the neuroprotective efficacy of endocannabinoids, no experimental settings compare and explore the neuroprotective potential of AEA and PEA in an acute stroke model. In this study, we investigated the neuroprotective potential by infarct measurement after high (30 mg/kg body weight) and low dosage administration (10 mg/kg body weight) of the endocannabinoid PEA in 49 male Wistar rats. In additions we studied infarct volumes of 22 male Wistar rats receiving the endocannabinoid AEA with a dosage of 10 mg/kg body weight or placebo. The neurological outcome was assessed 24 h after ischemia. Endocannabinoids were given intraperitoneally 30 min after initiation of transient middle cerebral artery occlusion (tMCAO). Infarct volume was calculated on the basis of 2.3.5-triphenyltetrazolium chloride staining. In the PEA high-dose group a significant total infarct reduction of 35% compared to the control group could be observed. AEA-treated rats presented a total infarct reducing effect of 26% compared to controls. Neurological scores, evaluated 24 h after tMCAO and physiological parameters, obtained 45 and 90 min after onset of ischemia showed no significant differences among the groups. As shown here, the endocannabinoids AEA and PEA achieved a significant neuroprotective effect by reducing size of infarcted tissue after tMCAO. Both endocannabinoids may have the potential to treat acute stroke and exert neuroprotection through a variety of mechanisms. [Copyright &y& Elsevier]

The genus Bacillus has been isolated from a wide range of environments and comprises species with biotechnological applications, such as bioinseticides, biofungicides, and biofertilizers. This study investigated the endophytic occurrence and diversity of Bacilli in the apoplastic fluid of sugarcane cultivated in Brazil. Their biocontrol activity against fungi and their plant growth promotion (PGP) potential in sugarcane mini-set plants were also evaluated. Forty-two Bacillus colonies were isolated from the apoplastic fluid of one-year-old commercial sugarcane varieties and analyzed by sequencing the 16S rRNA gene. The ability to produce indols and siderophores and to solubilize phosphate and zinc were evaluated in vitro , along with their cellulose and protease activity and, antagonistic activity against sugarcane phytopatogenic fungi. The PGP potential was determined using strains which were inoculated in sugarcane mini-set plants grown in sterile substrate and later in unsterilized soil pots. The 16S rRNA analyses demonstrated high bacterial diversity with the majority closely related to B. megaterium followed by B. aryabhattai and B. cereus. B. pumilus , B. velezensis , B. safensis , B. flexus and Paenibacillus taichungensis species were also identified. Most strains were able to produce indol, solubilize zinc oxide and presented cellulase activity, while phosphate solubilization and siderophore production was observed in only few strains. The strains LMC21, LMC44 and LMC48 presented high biocontrol activity against the sugarcane fungi Colletotrichum falcatum. The spore formation was observed for strains grown for 8 days in the HCT medium but not in presence of sugarcane juice. Some strains also accumulated higher biomass in sugarcane (sterile conditions) and a mixture of three Bacillus strains performed better in the soil-pot inoculation experiment. These findings show for the first time that many Bacillus species are present in the apoplastic fluid of sugarcane grown in Brazil and indicate that some strains have PGP and biocontrol potential for application as biofertilizer in sugarcane plants. • Apoplast fluid of sugarcane plants as ecological niche for Bacillus species. • Bacillus species presented high biological activity against sugarcane fungi Colletotrichum falcatum. • A Bacillu s inoculant consortium stimulates growth of sugarcane plants. [ABSTRACT FROM AUTHOR]

Abstract: Pleiotropic mechanisms beyond their cholesterol lowering effect of 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins such as pravastatin are known. We used a temporary middle cerebral artery occlusion (tMCAO) model in 114 Wistar rats to assess i) whether repeated injections of various doses of pravastatin (0.1, 0.5, 1 and 2 mg/kg) at 30 min, 6 h, 1, 2, 3, and 4 days after stroke onset are neuroprotective, ii) whether attenuation of striatal glutamate and interleukin-6 (IL-6) release is part of the neuroprotective mechanism, and iii) how local cerebral blood flow (CBF) is influenced by pravastatin both in the acute and late stage of ischemia. Animals were sacrificed 5 days after MCAO, infarct size was analyzed with 2,3,5-triphenyltetrazolium chloride (TTC) staining. As compared to saline (139±14 mm3, n =11), higher doses of pravastatin beyond 0.1 mg/kg significantly reduced infarct size with the greatest effect obtained with 1 mg/kg (60±14 mm3, n =11, P =0.0004). Using cerebral microdialyis in this dose group, we demonstrated that striatal glutamate increase in the ischemic hemisphere was attenuated by pravastatin compared to placebo. Likewise, IL-6 release was diminished at 2 h, but not at 6 h after tMCAO. Improvement of local CBF by pravastatin was observed at day 5, but not at 5 h after tMCAO, thus representing a more long term effect of pravastatin. In conclusion, a relatively high dose of pravastatin administered repetitively after stroke onset improved neurological outcome through various cholesterol-independent mechanisms. [Copyright &y& Elsevier]

Abstract: Background: This study investigated whether brief exposure to nitrous oxide (N2O) exacerbates levodopa-induced hyperhomocysteinemia, and if co-treatment with folate or entacapone could reduce total plasma homocysteine (tHcy) levels. Methods: Male Wistar rats ( per group) were randomly treated with vehicle/N2O (group 1), levodopa/nitrogen (group 2), levodopa/N2O (group 3), levodopa/N2O+folate (group 4), or levodopa/N2O+entacapone (group 5). tHcy was measured at 12min, 4, 8, and 12h after anesthesia. Results and conclusion: The combination of N2O-exposure and levodopa treatment significantly increased tHcy in rats. This hyperhomocysteinemia could be prevented by entacapone but not folate co-administration. [Copyright &y& Elsevier]

Summary: Background: Malignant infarction of the middle cerebral artery (MCA) is associated with an 80% mortality rate. Non-randomised studies have suggested that decompressive surgery reduces this mortality without increasing the number of severely disabled survivors. To obtain sufficient data as soon as possible to reliably estimate the effects of decompressive surgery, results from three European randomised controlled trials (DECIMAL, DESTINY, HAMLET) were pooled. The trials were ongoing when the pooled analysis was planned. Methods: Individual data for patients aged between 18 years and 60 years, with space-occupying MCA infarction, included in one of the three trials, and treated within 48 h after stroke onset were pooled for analysis. The protocol was designed prospectively when the trials were still recruiting patients and outcomes were defined without knowledge of the results of the individual trials. The primary outcome measure was the score on the modified Rankin scale (mRS) at 1 year dichotomised between favourable (0–4) and unfavourable (5 and death) outcome. Secondary outcome measures included case fatality rate at 1 year and a dichotomisation of the mRS between 0–3 and 4 to death. Data analysis was done by an independent data monitoring committee. Findings: 93 patients were included in the pooled analysis. More patients in the decompressive-surgery group than in the control group had an mRS≤4 (75%vs 24%; pooled absolute risk reduction 51% [95% CI 34–69]), an mRS≤3 (43%vs 21%; 23% [5–41]), and survived (78%vs 29%; 50% [33–67]), indicating numbers needed to treat of two for survival with mRS≤4, four for survival with mRS≤3, and two for survival irrespective of functional outcome. The effect of surgery was highly consistent across the three trials. Interpretation: In patients with malignant MCA infarction, decompressive surgery undertaken within 48 h of stroke onset reduces mortality and increases the number of patients with a favourable functional outcome. The decision to perform decompressive surgery should, however, be made on an individual basis in every patient. [Copyright &y& Elsevier]

Abstract: The prognosis of vertebrobasilar occlusion is grave and therapeutic options are limited. The aim of the present study was to develop a new model of embolic hindbrain ischemia in the rat that closely resembles the clinical situation and that can be used to study pathophysiology and treatment options. After thoracotomy in 20 male Wistar rats, 15 animals received an injection of in vitro prepared autologous blood clots into the left vertebral artery. Five animals without clot injection served as controls. Neurological deficits were assessed in all animals 2h after embolism. After 2h, five animals were sacrificed to measure cerebral blood flow (CBF) by iodo-antipyridine autoradiography, and to calculate early cerebellar swelling by comparison of both hemispheres in brain slices. In these animals, autoradiography revealed ipsilesional brain swelling and significantly reduced blood flow values relative to the contralateral (unaffected) structures. Immunohistology showed the typical pattern of focal cerebral ischemia in the brain stem and/or cerebellum in 7 of 10 animals allowed to recover to 24h. Hence, successful thromboembolism was achieved in 12 of 15 animals (80%). With this novel model, the pathophysiology and potential treatments of posterior circulation stroke can be investigated. [Copyright &y& Elsevier]

Abstract: Background and purpose: The timing and mechanisms of protection by hyperbaric oxygen (HBO) in cerebral ischemia have only been partially elucidated. We monitored the early in vivo effects of HBO after 2 h transient focal ischemia using repetitive MRI. Methods: Wistar rats underwent filament occlusion of the middle cerebral artery (MCAO). 40 min after MCAO, rats were placed in a HBO chamber and breathed either 100% O2 at 3.0 atmospheres absolute (ata; n = 24) or at 1.0 ata (control; n = 24) for 1 h. Diffusion, perfusion and T2-weighted MR-images were obtained after 15 min and 3, 6 and 24 h of reperfusion. In 6 axial MR slices, volume of abnormal diffusion and T2w signals were measured in the ischemic hemisphere. Furthermore, hemispheric mean apparent diffusion coefficient- (ADC) and T2 values were calculated for statistical analysis. Results: HBO significantly reduced volume of abnormal DWI signal beginning immediately after reperfusion (control: 92 ± 28 mm3; HBO: 64 ± 17) and lesion size on T2w (control: 375 ± 91 mm3; HBO: 225 ± 39) after 24 h. Correspondingly, mean ADC levels were lower and T2 values higher in the ischemic hemisphere in the control group. HBO reduced histological infarct size at 24 h. Conclusion: High-dose intraischemic HBO therapy has an immediate protective on the brain which is superior to normobaric oxygen. [Copyright &y& Elsevier]

Early craniectomy has shown to reduce infarction size in experimental large MCA infarction probably due to improved leptomeningeal perfusion. Based on the hypothesis that craniectomy may also be beneficial in smaller MCA infarction we evaluated the effects of craniectomy on infarction size in small thromboembolic cerebral infarction in rats.Therefore, thromboembolic cerebral ischemia was induced in 40 rats by endovascular injection of autologous, fibrin-rich emboli. Twenty-one animals with a diffusion-weighted MR imaging (DWI)-derived infarction size of 50–100mm3 (involving one- to two-third of the MCA territory) at 1h after injection were randomly assigned to two groups. Eleven animals of group 1 immediately underwent craniectomy, ten animals of group 2 (controls) were not treated. Serial DWI was performed at 4 and 24h. Infarction size was assessed by TTC-staining at 48h after emboli injection.As result, prior to treatment, at 1h after emboli injection, infarction size in groups 1 and 2 was 65.9 ± 16.0mm3 and 67.9 ± 17.8mm3, respectively. At 4 and 24h, infarction size in group 1 was 73.5 ± 22.1mm3 and 85.2 ± 24.7mm3, and 76.3 ± 21.0mm3 and 83.4 ± 22.9mm3 in group 2, respectively. TTC-derived infarction size was 84.0 ± 23.3mm3 and 82.7 ± 21.5mm3, respectively. There was no significant difference between the two groups (P > 0.79).In conclusion, our results demonstrate that for small thromboembolic MCA infarction early craniectomy is not beneficial. [Copyright &y& Elsevier]

Acetylsalicylic acid (ASA) is neuroprotective through various pharmacological action sites. We used a temporary middle cerebral artery occlusion (tMCAO) model in 56 Wistar rats to assess whether repeated ASA injections at 30 min, 6 h, 1, 2, 3, and 4 days after stroke onset are neuroprotective. Animals were sacrificed 5 days after MCAO; infarct size was analyzed with 2,3,5-triphenyltetrazolium chloride staining. As compared to saline (164±13 mm3, n=14), only repeated injections of 40 mg/kg ASA (79±18 mm3, n=14, P=0.0029), but not of 20 mg/kg ASA (129±19 mm3, n=15), reduced infarct volume significantly. No significant change was noted with 40 mg/kg ASA injected only once at 30 min after MCAO (117±16 mm3, n=13). [Copyright &y& Elsevier]

To test the hypothesis that presence of metalloproteases (MMPs), their inhibitors (TIMPs) and their substrate laminin-5 differs between the ischemic core and the surrounding tissue, we examined the impact of middle cerebral artery occlusion/reperfusion (MCA:O/R) on these molecules in different regions of the infarct. We also investigated the influence of hypothermia on the progression of the ischemic lesion and MMP activity. Brain sections from 64 Wistar rats subjected to MCA:O/R were examined by means of cytohistochemistry and zymography. The artery was occluded for 2 h followed by 3, 5, 8 and 12 h of reperfusion. Well characterized antibodies against laminin-5, MMPs and TIMP-2 were used. A total of 32 rats were treated with hypothermia. The presence of each antigen was related to the following regions of interest: ischemic core with BBB breakdown (Ic), surrounding ischemic tissue without BBB breakdown (Ir), and the contralateral non-ischemic region (N). Regions of interest were defined by MRI. The Ic increased over time at the cost of the Ir. BBB breakdown occurred early in the ischemic core and increased over time. Hypothermia reduced the BBB breakdown at all time points. A graded decreased presence of laminin-5 was observed with 16.5±3.7(N)>10±2.8(Ir)>4±1.4(Ic) immunopositive microvessels/mm2 at 3 h of reperfusion. MMP-9 showed a reverse pattern with 0 (N)<4±0.8(Ir)<10±1.5(Ic) immunopositive microvessels/mm2. Hypothermia decreased the MMP activity measured by zymography. Laminin-5 and MMP presence relate directly to the degree of postischemic injury. Hypothermia reduces the conversion from the Ir to ischemic core and the degree of BBB as well as MMP abundance. [Copyright &y& Elsevier]

• G. diazotrophicus mCherry -tagged colonizing elephant grass. • The strain LP343 quickly attached itself to the roots. • The xylem vessels of PCEA were colonized by the strain LP343. Gluconacetobacter diazotrophicus is a species of great agronomic potential due to its growth-promotion traits. Its colonization process in different plants has been reported. However, there have been no studies regarding its structural colonization in elephant grass. This is a fast-growing C4- Poaceae plant, and its application in Brazil is mainly aimed at feeding dairy cattle, due to its high nutritional value. Also, in the last decade, this grass has been applied in the production of biofuels. The present study aimed to monitor the colonization process of strain LP343 of G. diazotrophicus inoculated in elephant grass seedlings of PCEA genotype, by using a mCherry- tagged bacterium. Samples of roots and shoots collected at different periods were visualized by confocal laser-scanning microscopy. The colony-counting assay was used to compare the number of cells recovered in different niches and a qPCR was performed for the quantification of endophytic cells in root and shoot tissues. Results suggested that the strain LP343 quickly recognized the PCEA roots as host, attached to the elephant grass roots at 6 h, and 7 days after inoculation were able to colonize the xylem vessels of roots and shoots of elephant grass. This study advances our knowledge about the colonization process of G. diazotrophicus species in elephant grass, contributing to future studies involving the plant-bacteria interaction cultivated under gnotobiotic conditions. [ABSTRACT FROM AUTHOR]