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Background The optimal timing of anticoagulation following acute ischaemic stroke or TIA in patients with atrial fibrillation (AF) is a frequent challenge. Early initiation of anticoagulation can reduce the risk for recurrent ischaemic events, but may lead to an increased risk for intracerebral haemorrhage. Aim The Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) study was initiated to investigate outcome events under antithrombotic therapy after ischaemic stroke or TIA in patients with AF. The main objective is to compare the three-month rates of major haemorrhagic events between early (≤ 7 days) versus late (> 7 days) administration of dabigatran or treatment with vitamin-K antagonists started at any time. Occurrences of ischaemic and major haemorrhagic events will be evaluated to determine the optimal time point for initiation or resumption of anticoagulation. Design and Methods PRODAST is a prospective, multicenter, observational, non-interventional post-authorization safety study. 10,000 patients with recent (≤ 1 week from index event) ischaemic stroke or TIA and non-valvular AF were recruited at 86 German sites starting in July 2015. The observational plan includes a baseline visit, documentation of data during hospitalization and a telephone-based, central follow-up at three months after the index event. The primary endpoint is the major bleeding rate within three months. Secondary endpoints include rates of recurrent ischaemic or haemorrhagic stroke, TIA, systemic embolism, myocardial infarction and death. Summary PRODAST will provide important real-world data on safety and efficacy of antithrombotic therapy after acute stroke and TIA in patients with AF.

Background Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth. Aims To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage. Methods Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used. Results One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in n = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0–3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay. Conclusion Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.

To safeguard key workers involved in development and production of medicines and ensure business continuity, we developed an occupational healthcare program, performed by our company’s occupational healthcare services, to assess the infection and immune status for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This pilot program, conducted at our company facilities, evaluated the suitability of diagnostic tools in our setting for program upscaling. We used different marketed in vitro diagnostics (including tests for antibodies against spike protein subunits S1 and S2 and nucleocapsid [N] protein) combined with medical history, symptoms and likelihood of infection. We evaluated the testing strategy over four visits in 141 employees (known positive COVID-19 history, n = 20; unknown status, n = 121) between April and June 2020 at four company locations in Germany. Digital self-monitoring over the pilot program duration was also included. No incident infections were detected. Based on immune status, medical history and likelihood of infection, 10 participants (8.3%) with previously unknown history of COVID-19 were identified to have been infected before entering the program. These participants, who recalled no or mild symptoms in the preceding months, were primarily identified using an assay that detected both S1 and S2 immunoglobulin (Ig) G. The frequency of positive lateral flow assay (LFA) results (IgM or IgG directed against the N-protein) in this cohort was lower compared with participants with a known history of COVID-19 (0‒10.8% vs. 33.8‒75.7%, respectively). Data from this pilot program suggest that LFA for antibodies may not always reliably detect current, recent or past infections; consequently, these have not been included in our upscaled occupational healthcare program. Regular testing strategies for viral RNA and antibodies directed against different SARS-CoV-2 proteins, combined with hygiene rules and a comprehensive baseline assessment, are recommended to ensure avoidance of infections at workplace as reliably as possible.

Recently we have shown that idarucizumab application in acute stroke patients treated with dabigatran improves clinical outcome parameters. In this retrospective series of 120 cases positive effects of dabigatran reversal could be documented regarding mortality and modified Rankin scale in patients with acute hemorrhagic stroke (ICH). At the same time, individuals with acute ischemic stroke (IS) regained eligibiliy for intravenous thrombolysis, thereby improving substantially in NIHSS. Here, we report results on medication and blood parameters from this case series. In acute ICH, 15 of 40 patients were on dabigatran 150mg bid, while 25 took 110mg bid. CrCl was above 50ml/min in all cases while TT upon admission was elevated substantially in almost all cases examined. aPTT was normal in 79.5%. In acute IS, 32 patients received 150 mg, 48 received 110 mg dabigatran bid. The vast majority of patients with ischemic stroke had a CrCl above 50 ml/min. TT was prolonged above 35 seconds in 91.4% of cases while aPTT values were normal in 48.1% of patients. These data underline the necessity to prescribe the appropriate dosage recommended in the prescription protocol to all patients since ICH and IS incidence seems to be dose-independent. Furthermore, global hemostasis parameters like aPTT again prove to be not useful for therapeutic decisions. Finally, inclusion of TT values into emergency laboratory examination in patients with acute stroke under dabigatran is helpful to identify patients with impaired hemostasis potentially benefitting from idarucizumab application.

Reports on neuroprotective effects of Insulin-like growth factor-1 (IGF-1) and Insulin-like growth factor binding protein-3 (IGFBP-3) in ischemic brain tissue are inconsistent. The aim of this study was to determine if plasma levels of IGF-1 and IGFBP-3 in acute stroke patients are indicative of 3 months functional outcome. Plasma levels were measured via chemiluminescence immunoassay in heparin blood samples of patients included in the EARLY trial (NCT00562588). Plasma samples were drawn on admission and 8 days post-stroke. Neurological deficits were assessed via modified Rankin Scale (mRS) 3 months post-stroke, resulting in favorable (mRS=0–2) or unfavorable (mRS=3–6) outcome. A multiple binary logistic regression including IGF-1 and IGFBP-3 levels and confounders was conducted. Out of 404 included patients, 89 patients had an unfavorable outcome. Mean mRS on admission as well as 3 months post-stroke was 2 (±1). Low IGF-1 levels (day 8) were independently associated with a decreased risk of an unfavorable outcome (OR 0.61; 95%CI 0.37–0.99; p=0.044). Low IGFBP-3 levels (day 8) were independently associated with an unfavorable outcome (OR 2.75; 95%CI 1.56–4.84; p Low IGFBP-3 levels and high IGF-1 levels in the subacute phase are predictive of unfavorable outcome 3 months after stroke.

Reversal of anticoagulation in patients treated with NOACs is a rare but sometimes urgently needed therapeutic demand. Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. It is approved for patients on dabigatran with life-threatening or uncontrolled bleeding and those requiring emergency intervention. Case reports and smaller case series suggest a benefit for dabigatran-treated patients suffering ischemic stroke to regain eligibility for rt-PA thrombolysis. To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of ischemic stroke or intracranial hemorrhage in clinical routine, we asked all German Departments of Neurology and Neurosurgery to contribute their retrospective data on the use of idarucizumab collected following product launch in January 2016 to June 2018. In 64 responding stroke centers 112 patients presenting with signs of stroke received idarucizumab. 74 patients treated with dabigatran presented with ischemic stroke. In patients receiving rt-PA thrombolysis following idarucizumab, 87% had a benefit from i.v. thrombolysis with a median NIHSS improvement of 6 points. No symptomatic bleeding complications were observed. Nine patients did not improve functionally. Of those, 4 patients deceased during hospital stay (5.4%). Bolus administration of idarucizumab did not delay thrombolysis indicating its value in this emergency situation. A total of 38 patients had intracranial bleeding (SAH n=1, SDH n=12, ICH n=25). Out of 25 patients presenting with intracerebral hemorrhage and treated with idarucizumab, hematoma growth with clinical worsening was documented in three. Outcome was favorable with a median NIHSS improvement of 4 points in 35 patients. Overall mortality was 13%. In conclusion, idarucizumab is a beneficial therapeutic option for patients under dabigatran treatment presenting with ischemic stroke or intracranial hemorrhage in daily German stroke center routine. A prospective registry with controls is ongoing in Germany.

Background Intravenous thrombolysis with alteplase within a time window up to 4.5 h is the only approved pharmacological treatment for acute ischemic stroke. We studied whether acute ischemic stroke patients with penumbral tissue identified on magnetic resonance imaging 4.5–9 h after symptom onset benefit from intravenous thrombolysis compared to placebo. Methods Acute ischemic stroke patients with salvageable brain tissue identified on a magnetic resonance imaging were randomly assigned to receive standard dose alteplase or placebo. The primary end point was disability at 90 days assessed by the modified Rankin scale, which has a range of 0–6 (with 0 indicating no symptoms at all and 6 indicating death). Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events. Results The trial was stopped early for slow recruitment after the enrollment of 119 (61 alteplase, 58 placebo) of 264 patients planned. Median time to intravenous thrombolysis was 7 h 42 min. The primary endpoint showed no significant difference in the modified Rankin scale distribution at day 90 (odds ratio alteplase versus placebo, 1.20; 95% CI, 0.63–2.27, P = 0.58). One symptomatic intracranial hemorrhage occurred in the alteplase group. Mortality at 90 days did not differ significantly between the two groups (11.5 and 6.8%, respectively; P = 0.53). Conclusions Intravenous alteplase administered between 4.5 and 9 h after the onset of symptoms in patients with salvageable tissue did not result in a significant benefit over placebo. (Supported by Boehringer Ingelheim, Germany; ISRCTN 71616222).

Idarucizumab is an antibody fragment which is used to reverse the anticoagulant effects of dabigatran. We report on the first successful use of idarucizumab before performing an emergency lumbar puncture in a patient on effective anticoagulation with dabigatran thought to have infective cerebral disease (such as temporal encephalitis).

Background and Purpose— Therapeutic options for acute ischemic stroke patients presenting on effective anticoagulation are limited. Idarucizumab, a humanized, monoclonal antibody fragment for immediate reversal of dabigatran, may allow this subgroup of orally anticoagulated patients to regain eligibility for thrombolysis. Methods— We report the first successful acute antagonization of dabigatran by idarucizumab before intravenous thrombolysis with recombinant tissue-type plasminogen activator. Results— Idarucizumab was given to a 76-year-old male patient on dabigatran ≈3.5 hours after his last dose. Neurological status on admission was NIHSS (National Institutes of Health Stroke Scale) 11. Recombinant tissue-type plasminogen activator was initiated immediately after dabigatran reversal. The patient was discharged with a favorable outcome of NHISS 1 on day 7. No complications were observed. Conclusions— This case represents a new therapeutic paradigm. It is further supported by in vitro data showing no nonspecific interactions of idarucizumab with recombinant tissue-type plasminogen activator–induced thrombolysis. Thus, patients effectively anticoagulated with dabigatran who were previously contraindicated for thrombolytic therapy in this situation may now receive treatment because of the ability to rapidly reverse the anticoagulant activity of dabigatran with idarucizumab.

J-R. Liu, Y. Zhao, A. Patzer, N. Staak, R. Boehm, G. Deuschl, J. Culman, C. Bonny, T. Herdegen and C. Eschenfelder (2010) Neuropathology and Applied Neurobiology36, 211–224 The c-Jun N-terminal kinase (JNK) inhibitor XG-102 enhances the neuroprotection of hyperbaric oxygen after cerebral ischaemia in adult rats Aim: Both hyperbaric oxygenation (HBO) and inhibition of the c-Jun N-terminal kinases (JNKs) by the peptide inhibitor XG-102 (D-JNKI-1) are efficient protective strategies against ischaemia-induced neurodegeneration. The present study investigated whether the combination of HBO and JNK inhibitor, XG-102, provides additive neuroprotection against cerebral ischaemia. Methods: Rat middle cerebral artery was occluded (MCAO) for 90 min. XG-102 [2 mg/kg, intraperitoneally] or HBO (3 ATA, 60 min) was applied 3 h after the onset of MCAO. For the combination treatment, HBO was started 10 min after the injection of XG-102. Twenty-four hours after MCAO, the infarct area, the neurological score and the immunohistochemistry staining in brain slices for cleaved-PARP, transferase-mediated biotinylated UTP nick end labelling, c-Jun and phosphorylated (activated) c-Jun were observed. Results: XG-102 or HBO alone reduced the total infarct area by 43% and 63%, respectively. The combination diminished total infarct area by 78%, improved the neurological function and reduced brain oedema. Co-application of HBO and XG-102 also significantly reduced the cleavage of PARP, by 96% and 91% in cortical penumbra and ischaemic core, respectively. Moreover, cotreatment significantly attenuated the number of cells labelled with transferase-mediated biotinylated UTP nick end labelling and phosphorylated c-Jun. Conclusion: Our study demonstrates that HBO reinforces the efficiency of neuroprotective drugs such as XG-102 and vice versa. Both treatments, physical HBO and pharmacological XG-102, are already in phase I/II studies and promising strategies for clinical use.

The neuroprotective effect of oxygen after acute stroke in rats has been shown previously. However, the question of optimal dosing still remains unanswered. Thus, we investigated the use of oxygen at different concentrations by either normobaric oxygenation (NBO) or hyperbaric oxygenation (HBO) at different pressures in a model of transient ischemia/reperfusion in rats. Animals underwent 90 min of middle cerebral artery occlusion (MCAO) followed by 90 min of reperfusion before oxygen treatment. Oxygen was applied either by NBO (100% O2; 1.0 absolute atmosphere, ATA) or HBO (100% O2; 1.5, 2.0, 2.5 or 3.0 ATA) for 1 h. Primary endpoints were infarct volume and clinical outcome measured 24 h and 7 days following the MCAO. A statistically significant and long-lasting reduction in infarct volume was seen in the HBO 2.5 ATA and 3.0 ATA groups over a period of 7 days. The reduced infarct volume was accompanied with a statistically significant improvement in clinical outcome in the high-dose oxygen-treated groups. The presented data indicate that oxygen is a highly neuroprotective molecule in transient focal cerebral ischemia in rats, when applied early and at high doses. The effect is dose dependent and shows a superiority of HBO over NBO, when the primary endpoints infarct volume reduction and clinical outcome are analyzed. These data are important for the development of new acute stroke treatment studies in humans.

Reversible posterior encephalopathy syndrome (RPES) is a clinical entity characterized with headache, nausea, vomiting, seizures, consciousness disturbance, and frequently visual disorders associated with neuroradiological findings, predominantly white matter abnormalities of the parieto-occipital lobes. The central nervous system manifestations of systemic lupus erythematosus (SLE) are highly diverse. However, SLE-associated RPES has been seldom reported. Here, we report a case with RPES in SLE and lupus nephritis with exclusive involvement of parietal and occipital cortices. A systematic review of the literature on the pathogenesis and treatment of SLE-associated RPES is included.

Background and Purpose— Fluorescent molecular peroxidation products (FMPPs) are considered potential markers of molecular oxidative damage and may provoke increased permeability and disruption of the blood–brain barrier. This study aimed to determine the value of FMPPs as a biomarker to predict neurological worsening related to early hemorrhagic transformation. Methods— Baseline FMPP levels were measured in 186 consecutive acute ischemic stroke patients before tissue plasminogen activator treatment was administered. A serial FMPP profile (baseline before tissue plasminogen activator treatment, and 1, 2, 12, and 24 hours from treatment) was determined in a subset of 100 patients. Computed tomographic scans were performed at admission and repeated at 24 to 48 hours or after neurological worsening occurred. Symptomatic intracranial hemorrhage was defined as blood at any site in the brain associated with neurological deterioration. Results— Patients who worsened had higher median FMPP levels compared with those who did not (59.68 [48.63–85.73] versus 44.87 [36.37–58.90] Uf/mL; P =0.035) at baseline. After logistic regression multivariate analysis, FMPP >48.2 Uf/mL together with age, hypertension, and systolic blood pressure remained baseline predictors of worsening at 48 hours. Moreover, baseline FMPP determination helped to distinguish between patients who worsened and those who did not (Integrated Discrimination Improvement index, 5.7%; P =0.0004). Finally, within patients who had worsened at 48 hours, those with symptomatic intracranial hemorrhage had higher FMPP levels ( P =0.038). Conclusions— FMPPs might be a valuable biomarker of poor early neurological outcome and be related to the appearance of symptomatic intracranial hemorrhage in tissue plasminogen activator–treated patients, one of the most feared neurological complications after thrombolytic treatment of acute ischemic stroke.

Background: Hyperbaric oxygen can cause central nervous system (CNS) toxicity with seizures. We tested the hypothesis that CNS toxicity could be predictable by cerebral blood flow velocity (CBFV) monitoring. Method: We monitored 369 mandatory oxygen tolerance tests (30 min, 280 kPa O2) by video-documentation and since May 2005 by additional CBFV registration (n = 61). Results: The onset of early manifestations of CNS toxicity was documented in 11 of 369 tests within 22 ± 3 min. These included twitches and/or agitation, 6 of 11 and tonic–clonic seizures in 5 of 11 cases. In both cases with CBFV monitoring, an increase in CBFV preceded symptom onset, once followed by seizure, once without seizure after timely oxygen reduction. Conclusions: During exposure to 280 kPa oxygen at rest a constant delay of approximately 20 min precedes the onset of central nervous oxygen toxicity. An increase in CBFV may indicate the impending seizure.

Background There are two widely used transient middle cerebral artery occlusion (MCAO) methods, which differ in the use of unilateral or bilateral carotid artery reperfusion (UNICAR and BICAR). Of the two methods, UNICAR is easier to perform. This study was designed to comprehensively compare the two reperfusion methods to determine if there are any differences in outcomes. Results The UNICAR and BICAR groups each included 9 rats. At baseline, the average pO2 was 20.54 ± 9.35 and 26.43 ± 7.39, for the UNICAR and BICAR groups, respectively (P = 0.519). Changes in pO2, as well as other physiological parameters measured within the ischemic lesion, were similar between the UNICAR and BICAR groups during 90 min of MCAO and the first 30 min of reperfusion (all P > 0.05). Furthermore, both the Bederson score and Garcia score, which are used for neurological assessment, were also similar (both P > 0.05). There were also no significant differences in T2WI lesion volume, DWI lesion volume, PWI lesion volume, or TTC staining infarct volume between the two groups (all P > 0.05). Conclusion UNICAR and BICAR have similar capability for inducing acute brain ischemic injury and can be considered interchangeable up to 24 hours after reperfusion.

The possible involvement of substance P released from primary afferents in rat skin was investigated in cutaneous inflammation following ultraviolet (UV) irradiation. Recordings from c-fibres innervating the UV-exposed hindpaw skin showed long-lasting low-frequency (0.8-1.25 Hz) spontaneous activity. Spontaneously active c-fibres increased to constitute 35.3% of the total population 72 h after UV exposure. Immunohistochemical analysis of substance P-containing nerve fibres in hindpaw skin revealed a significant increase in substance P immunoreactivity 24 h after UV irradiation. Average length of substance P-immunolabelled nerve fibres was about two times higher in UV-exposed compared to control skin. UV-induced oedema was investigated in rat ears using an ear-swelling test. Intradermal injection of either peptide (Spantide) or nonpeptide (CP-96,345) substance P antagonists and epicutaneous application of CP-96,345 reduced UV-induced oedema significantly in the late phase of sunburn (> 12 h after UV exposure). The UV-induced increase in skin blood flow was investigated in hindpaw skin up to 72 h by the laser Doppler technique. Epicutaneous application of CP-96,345 reduced erythema significantly between 12 and 72 h after UV exposure. Thus, our findings suggest the involvement of neurogenic substance P as a proinflammatory mediator in the late phase of UV-induced cutaneous inflammation in rats.

Summary Background Little is known about the best antiplatelet treatment immediately after ischaemic stroke or transient ischaemic attack (TIA). The EARLY trial aimed to compare outcome in patients given aspirin plus extended-release dipyridamole twice daily either within 24 h of stroke or TIA or after 7 days of aspirin monotherapy. Methods In 46 stroke units in Germany, patients aged 18 years or more who presented with symptoms of an acute ischaemic stroke that caused a measurable neurological deficit (National Institutes of Health stroke scale score ≤20) were randomly assigned to receive 25 mg aspirin plus 200 mg extended-release dipyridamole open-label twice daily or 100 mg aspirin monotherapy open-label once daily for 7 days. Patients were randomised by use of a pseudorandom number generator. All patients were then given open-label aspirin plus extended-release dipyridamole for up to 90 days. The primary endpoint was modified Rankin scale score as recorded by centralised, blinded assessment by telephone (tele-mRS) at 90 days. Vascular adverse events (non-fatal stroke, TIA, non-fatal myocardial infarction, and major bleeding complications) and mortality were assessed in a composite safety and efficacy endpoint. Patients were analysed as treated. This trial is registered, number NCT00562588. Findings Between July, 2007, and February, 2009, 543 patients were treated: 283 received early aspirin plus extended-release dipyridamole and 260 received aspirin plus extended-release dipyridamole after 7 days on aspirin. At day 90, 154 (56%) patients in the aspirin plus early extended-release dipyridamole group and 133 (52%) in the aspirin plus later extended-release dipyridamole group had no or mild disability (tele-mRS 0 or 1; difference 4·1%, 95% CI −4·5 to 12·6, p=0·45). 28 patients in the early initiation group and 38 in the late initiation group reached the composite endpoint (hazard ratio 0·73, 95% CI 0·44–1·19 p=0·20). Interpretation Early initiation of aspirin plus extended-release dipyridamole within 24 h of stroke onset is likely to be as safe and effective in preventing disability as is later initiation after 7 days. Funding Boehringer Ingelheim.

Introduction qT2′-maps are calculated by subtracting T2- from T2*-relaxation rates. They are oxygen-sensitive and depict oxygen extraction. In several studies they have been used to describe the penumbra in patients with acute ischemic stroke. No correlation between rCBF and qT2′ has been performed to date. In this study a correlation between rCBF and qT2′ was performed in a temporary middle cerebral occlusion–reperfusion model of the rat. Materials and methods Temporary middle cerebral artery occlusion was performed on seven Sprague–Dawley rats. After 60 min of occlusion and 90 min of reperfusion MRI was performed including DWI, dynamic susceptibility contrast-weighted MR imaging (DSC-MRI) and qT2′. ROIs were placed inside the DWI lesion and transferred to rCBF- and qT2′-maps. rCBF and qT2′ were compared to corresponding tissue in the contralateral hemisphere. Results qT2′ was lower in the infarcted areas when compared to the contralateral hemisphere. Correlation between rCBF and qT2′ was r = 0.41, p = 0.14 (Pearson's correlation coefficient), when corrected for outliers it was r = 0.58, p = 0.04. Conclusion Our results show that there is a moderate correlation between rCBF and qT2′. qT2′-maps could be used to explore cerebral perfusion without the application of contrast agent or radiation.

In the present study, we investigated whether activation of mitochondrial ATP-sensitive potassium channel is involved in the neuroprotective effect offered by early hyperbaric oxygenation after cerebral ischemia. The selective mitochondrial ATP-sensitive potassium channel antagonist 5-hydroxydecanoate was infused intracerebroventricularly before hyperbaric oxygenation treatment initiated 3 h after middle cerebral artery occlusion for 90 min. Neurological status was evaluated and brains were removed for the measurement of infarct size and immunohistochemical evaluation of apoptosis 24 h after middle cerebral artery occlusion. Early hyperbaric oxygenation treatment improved neurologic deficits and reduced infarct volume, while these effects were reversed by the administration of 5-hydroxydecanoate. Furthermore, early hyperbaric oxygenation significantly decreased the number of apoptotic cells in the peri-infarct cortex 24 h after ischemic insult and this effect was also blocked by 5-hydroxydecanoate. The present findings suggest that early hyperbaric oxygenation therapy prevents apoptosis and promotes neurologic functional recovery after focal cerebral ischemia, and the opening of mitochondrial ATP-sensitive potassium channel plays a role in this antiapoptotic effect of early hyperbaric oxygenation.

Objective—Acute coronary syndromes and ischemic cerebral stroke share similarities regarding elevated platelet activation. In coronary syndromes, the importance of inflammation with platelet-leukocyte interaction has been demonstrated. Recent infection is an established risk factor for ischemic stroke; the role of platelet-leukocyte interaction in these patients had not been investigated.Methods and Results—Using a flow cytometric assay we investigated 58 stroke patients, 21 with and 37 without infection 1 week before acute cerebral ischemia, and compared them to 58 controls with regard to platelet-leukocyte aggregation and platelet activation on admission and on day 7. Patients with previous infection were significantly up-regulated with regard to platelet activation and platelet-leukocyte aggregation compared with patients without infection. On day 7, these increases in the postinfective group had drawn level with the lower values of the other patients. As reported previously, recent infection was associated with a more severe postischemic deficit.Conclusions—These results suggest an important role of intercellular platelet-leukocyte interaction in the pathophysiology of acute cerebral ischemia which may also contribute to the increased incidence and clinical severity of ischemic stroke following infection. This may lead to therapeutic considerations of blocking intercellular adhesion molecules like P-selectin or the P-selectin glycoprotein ligand.

Background and Purpose— Hyperbaric oxygenation (HBO) is an attractive procedure that has been used frequently in cerebral ischemia. However, depending on the model of cerebral ischemia and HBO protocol, different and conflicting results were obtained in the past. This study was undertaken to reevaluate the effects of single administration of HBO in 2 models of acute cerebral ischemia: transient or permanent focal ischemia in rats. A comparison of the 2 ischemia models was undertaken to search for a putative therapeutic window. Methods— The intraluminal middle cerebral artery occlusion model (MCAO) was used. The effect of single HBO therapy (3 atm absolute, 60 minutes) on transient or permanent focal ischemia, when applied at different times (3, 6, or 12 hours) after MCAO, was investigated; infarct volume and neurological deficits were assessed at 24 hours and up to 7 days. Results— HBO had neuroprotective effects on transient MCAO when HBO was initiated within the first 6 hours, while it aggravated the ischemic injury histologically and clinically when initiated 12 hours after MCAO. In permanent MCAO, HBO did not reduce tissue damage regardless of the timing of therapy. Conclusions— HBO is highly efficient in reducing infarct volume and improving neurobehavioral outcome in transient MCAO within the first 6 hours. HBO at later time points (≥12 hours) is harmful by increasing infarct volume. In permanent MCAO, HBO failed to improve infarct volume and clinical outcome.

Objectives: Sacral neuromodulation represents chronic stimulation of the sacral (S3) nerve. So far, the mode of action and neuro-anatomical basis is unclear. Sacral reflex mechanisms as well as pontine or cortical centers of modulation have been postulated. Our aim was to evaluate possible alterations in electroencephalogram (EEG) activity as an indicator of a supraspinally mediated mechanism of sacral neuromodulation. Materials and Methods: We analyzed serial EEGs (apparatus: Kolner Vitaport System) using electrodes placed at Fz, Cz, Cz′ and Pz in 10 patients. Subsequently, the sacral (S3) nerve was stimulated by means of an impulse generator (Medtronic, Interstim 3023) using an on-off paradigm with a 1.5 s “on” interval followed by a 10 s stimulation break. Raw data were analyzed using both Matlab 4.0 software and a specially developed averaging routine. Results: All patients demonstrated a cortical potential complex following sacral root stimulation with an early electronegative component at 50 ms with a mean amplitude of 23 μV followed by a late potential component with a mean latency of 253 ms and a mean amplitude of 5 μV, both with a maximum at Cz, corresponding to the post-central gyrus. This finding occurred irrespective of patient’s reports of actually feeling the neuromodulator being switched on and off. Conclusion: In neuromodulation responders, both short and long latency cortical potentials can be reproduced with a maximum at the sensory cortical area. Although these potentials are similar to cognitively mediated “event-related potentials”, they are clearly distinct from any subjective sensory or even painful response since several patients of this series have not been able to feel any neuromodulator action. Therefore, this pilot study indicates a supraspinally mediated site of modulation, most probably in sensory cortex areas.

Effects of cutaneous ultraviolet (UV) irradiation on superficial nerve fibres are controversial. In the present study we demonstrate by electron microscopy that single high-dose UV exposure of rat skin results in membrane damage in peripheral nerves. Furthermore, a UV-induced accumulation of nerve growth factor (NGF) within the irradiated epidermis and a delayed increase in nuclear Jun immunoreactivity in dorsal root ganglion neurones were detected by immunohistochemistry. Our results suggest that UV-mediated alterations of axonal membranes leads to an activation of Jun transcription factor within affected neurones despite an increase in neurotrophic NGF within their innervation area.

Evidence from our previous work suggests that neurogenic mediators contribute to the inflammation following ultraviolet (UV) irradiation of the skin. We have investigated whether calcitonin gene-related peptide (CGRP), substance P and nitric oxide (NO) participate in the cutaneous inflammatory reaction of the rat hind paw and ear to UV irradiation. Skin blood flow was measured by laser Doppler technique. Oedema was quantified using a spring loaded micrometer to measure ear thickness. UV irradiation of the rat skin lead to a long lasting increase in skin blood flow. This increase was dose dependently attenuated by the CGRP receptor antagonist CGRP-(8-37) (0.15 nmol in 25 microliters to 6.0 nmol in 25 microliters, s.c.) up to 51% with a maximum of effectiveness at 24 h post irradiation. The inhibitor of NO synthase NG-nitro-L-arginine methyl ester hydrochloride (L-NAME, 25 nmol in 25 microliters, s.c.) attenuated skin blood flow by 38%. Concurrent injections s.c. of CGRP-(8-37) (1.5 nmol in 12.5 microliters) and L-NAME (25 nmol in 12.5 microliters) demonstrated an augmentive effect in attenuating skin blood flow. The tachykinin NK1 receptor antagonist CP-96,345 (6.0 nmol in 25 microliters, s.c.) attenuated skin blood flow by 27%. NG-Nitro-D-arginine methyl ester hydrochloride (D-NAME) and CP-96.344 showed no effects on skin blood flow after UV irradiation. CGRP-(8-37) (0.6 nmol in 10 microliters) i.d. and L-NAME (10 nmol in 10 microliters) i.d. had no effect of oedema formation after UV irradiation. Furthermore, post UV irradiation enhanced CGRP- and NO synthase-immunoreactivity in nerve fibres in the exposed skin area were visible. Taken these findings together we suggest the involvement of the neuropeptides CGRP and substance P and of neuronal NO on the vasodilatory component of the UV-induced inflammatory reaction of the rat skin. CGRP contributing to UV-induced vasodilation acts in an endothelial NO-independent manner.

Background and Purpose —Shifts of the balance between coagulation and fibrinolysis play a crucial role in pathogenesis and treatment of cerebral ischemia. In this study, we characterized the kinetics of hemostatic abnormalities induced by acute ischemic stroke and its thrombolytic (recombinant tissue plasminogen activator [rtPA]) or anticoagulant (heparin) treatment. Methods —Systemic generation of molecular markers of hemostasis (fibrin monomer, d -dimer, thrombin-antithrombin complex, and fibrinopeptide 1.2) was monitored in acute ischemic stroke, and the effects of thrombolytic and anticoagulant treatments were analyzed. Results —Thrombolysis with rtPA induced a massive response of markers of coagulation activation and fibrin formation that peaked after 1 to 3 hours and persisted for up to 72 hours. In contrast, only minor hemostatic changes were induced by acute ischemic stroke itself. Administration of heparin did not significantly affect these hemostatic abnormalities. Conclusions —This first characterization of the coagulation activation induced by rtPA treatment for acute ischemic stroke and the failure to abolish such hemostatic abnormalities by heparin may be of value for further refinement of the currently discussed thrombolytic therapy and the controversial adjunctive anticoagulant prophylaxis in stroke patients.