Markus Horn

Although use of oral anticoagulants (OACs) is increasing, there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage (ICH).To assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption.Retrospective cohort study at 19 German tertiary care centers (2006-2012) including 1176 individuals for analysis of long-term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption.Reversal of anticoagulation during acute phase, systolic BP at 4 hours, and reinitiation of OAC for long-term treatment.Frequency of hematoma enlargement in relation to international normalized ratio (INR) and BP. Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption. Factors associated with favorable (modified Rankin Scale score, 0-3) vs unfavorable functional outcome.Hemorrhage enlargement occurred in 307 of 853 patients (36.0%). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 [19.8%]) vs INR of ≥1.3 (264/636 [41.5%]; P < .001) and systolic BP <160 mm Hg at 4 hours (167/504 [33.1%]) vs ≥160 mm Hg (98/187 [52.4%]; P < .001). The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (35/193 [18.1%] vs 220/498 [44.2%] not achieving these values; OR, 0.28; 95% CI, 0.19-0.42; P < .001) and lower rates of in-hospital mortality (26/193 [13.5%] vs 103/498 [20.7%]; OR, 0.60; 95% CI, 0.37-0.95; P = .03). OAC was resumed in 172 of 719 survivors (23.9%). OAC resumption showed fewer ischemic complications (OAC: 9/172 [5.2%] vs no OAC: 82/547 [15.0%]; P < .001) and not significantly different hemorrhagic complications (OAC: 14/172 [8.1%] vs no OAC: 36/547 [6.6%]; P = .48). Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 (95% CI, 0.125-0.534; P < .001) for long-term mortality. Functional long-term outcome was unfavorable in 786 of 1083 patients (72.6%).Among patients with OAC-associated ICH, reversal of INR <1.3 within 4 hours and systolic BP <160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement, and resumption of OAC therapy was associated with lower risk of ischemic events. These findings require replication and assessment in prospective studies.clinicaltrials.gov Identifier: NCT01829581.

Background and Purpose— Adequate diagnosis of atrial fibrillation (AF), including paroxysmal AF, is an important part of stroke workup. Prolonged ECG monitoring may improve the detection of paroxysmal, previously undiagnosed AF (unknown AF). Therefore, we evaluated systematic 72-hour Holter ECG monitoring to detect unknown AF for the workup of patients with stroke. Methods— Unselected survivors of a stroke or transient ischemic attack (TIA) without known AF were enrolled in a prospective, multicenter cohort study of 72-hour Holter ECG monitoring in 9 German secondary and tertiary stroke centers between May 2010 and January 2011. In addition to standardized workup of stroke pathogenesis according to the German Stroke Unit protocol, all patients underwent 72-hour Holter ECG monitoring directly after admission. All ECGs were centrally analyzed by 2 independent observers. We determined the proportion of unknown AF and compared the detection rates of 72- and 24-hour monitoring. Results— A total of 1135 patients were enrolled (mean age, 67 years [SD, 13.1 years], 45% women, 29% TIA). Unknown AF was detected in 49 out of 1135 patients (4.3%, [95% confidence interval, 3.4–5.2%]) by 72-hour ECG monitoring. Unknown AF was diagnosed in 29 patients (2.6%) within the first 24 hours of ECG monitoring, and in 20 more patients only by 72 hours of ECG monitoring. The number needed to screen by 72-hour ECG was 55 patients (95% confidence interval [35–123]) for each additional AF diagnosis. Patients with unknown AF were significantly older and had more often a history of previous stroke. Patients with unknown AF were equally distributed within categories of pathogenesis according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Conclusions— In unselected survivors of stroke or TIA, 72-hour ECG monitoring is feasible and improves the detection rate of silent paroxysmal AF.

The glycosylphosphatidylinositol-anchored receptor CD14 plays a major role in the inflammatory response of monocytes to lipopolysaccharide. Here, we describe that ceramide, a constituent of atherogenic lipoproteins, binds to CD14 and induces clustering of CD14 to co-receptors in rafts. In resting cells, CD14 was associated with CD55, the Fcgamma-receptors CD32 and CD64 and the pentaspan CD47. Ceramide further recruited the complement receptor 3 (CD11b/CD18) and CD36 into proximity of CD14. Lipopolysaccharide, in addition, induced co-clustering with Toll-like receptor 4, Fcgamma-RIIIa (CD16a) and the tetraspanin CD81 while CD47 was dissociated. The different receptor complexes may be linked to ligand-specific cellular responses initiated by CD14.

Systemic thrombolysis represents the only proven therapy for acute ischemic stroke, but safe treatment is reported only in established stroke units. One major goal of the ongoing Telemedic Pilot Project for Integrative Stroke Care (TEMPiS) in Bavaria is to extend the use of tissue plasminogen activator (tPA) treatment in nonurban areas through telemedic support.The stroke centers in Munich-Harlaching and in Regensburg established a telestroke network to provide consultations for 12 local hospitals in eastern Bavaria. The telemedic system consists of a digital network that includes a 2-way video conference system and CT/MRI image transfer with a high-speed data transmission up to 2 Mb/s. Each network hospital established specialized stroke wards in which qualified teams treat acute stroke patients. Physicians in these hospitals are able to contact the stroke centers 24 hours per day.A total of 106 systemic thrombolyses were indicated via teleconsultations between February 1, 2003, and April 7, 2004. During the first 12 months, the rate of thrombolyses was 2.1% of all stroke patients. Mean age was 68 years, and median National Institutes of Health Stroke Scale score was 13. Mean delay between onset and hospital admission was 65 minutes, and door-to-needle time was on average 76 minutes, which included 15 minutes for the teleconsultation. Symptomatic hemorrhage occurred in 8.5% of patients, and in-hospital mortality was 10.4%.The present data suggest that systemic thrombolysis indicated via stroke experts in the setting of teleconsultation exhibits similar complication rates to those reported in the National Institute of Neurological Disorders and Stroke trial. Therefore, tPA treatment is also safe in this context and can be extended to nonurban areas.

<b>Background: </b> IV thrombolysis represents the most effective acute stroke therapy. However, it is almost exclusively performed in stroke centers and is not available in most community areas. The Telemedical Pilot Project for Integrative Stroke Care (TEMPiS) was started in February 2003. Twelve community hospitals with no or very limited stroke thrombolysis experience and two stroke centers were connected via a network providing online neurologic examination and transfer of neuroradiologic scans. Following recently published preliminary results on acute phase safety of telethrombolysis, the present study reports on its long-term functional outcome. <b>Methods: </b> Modified Rankin Scale (mRS), Barthel Index (BI), and mortality rate were prospectively collected 3 and 6 months after IV thrombolysis in patients of community network hospitals (telemedical group) and the stroke centers. Values of 95/100 for the BI and 0/1 for the mRS were defined as a favorable outcome. <b>Results: </b> Over the first 22 months, 170 patients were treated with tPA in the telemedical hospitals and 132 in the stroke center hospitals. Mortality rates were 11.2% vs 11.5% at 3 months (<i>p</i> = 0.55) and 14.2% vs 13% at 6 months (<i>p</i> = 0.45). A good functional outcome after 6 months was found in 39.5% of the telemedical hospitals vs 30.9% of the stroke centers (<i>p</i> = 0.10) for the mRS and 47.1% vs 44.8% (<i>p</i> = 0.44) regarding the BI. <b>Conclusions: </b> Mortality rates and functional outcomes for telemedicine-linked community hospitals and stroke centers were similar and comparable to the results from randomized trials.

The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established.To determine the association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH.Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015).Surgical hematoma evacuation vs conservative treatment.The primary outcome was functional disability evaluated by the modified Rankin Scale ([mRS] score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH.Among 578 patients with cerebellar ICH, propensity score-matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm3 vs 18.8 cm3). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio [AOR], 0.94 [95% CI, 0.81 to 1.09], P = .43; adjusted risk difference [ARD], -3.7% [95% CI, -8.7% to 1.2%]) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 [95% CI, 1.07 to 1.45], P = .005; ARD, 18.5% [95% CI, 13.8% to 23.2%]) and at 12 months (71.7% vs 57.2%; AOR, 1.21 [95% CI, 1.03 to 1.42], P = .02; ARD, 17.0% [95% CI, 11.5% to 22.6%]). A volume range of 12 to 15 cm3 was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm3, 30.6% vs 62.3% [P = .003]; ARD, -34.7% [-38.8% to -30.6%]; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm3, 74.5% vs 45.1% [P < .001]; ARD, 28.2% [95% CI, 24.6% to 31.8%]; P value for interaction, .02).Among patients with cerebellar ICH, surgical hematoma evacuation, compared with conservative treatment, was not associated with improved functional outcome. Given the null primary outcome, investigation is necessary to establish whether there are differing associations based on hematoma volume.

Evidence is lacking regarding acute anticoagulation management in patients after intracerebral haemorrhage (ICH) with implanted mechanical heart valves (MHVs). Our objective was to investigate anticoagulation reversal and resumption strategies by evaluating incidences of haemorrhagic and thromboembolic complications, thereby defining an optimal time-window when to restart therapeutic anticoagulation (TA) in patients with MHV and ICH.We pooled individual patient-data (n = 2504) from a nationwide multicentre cohort-study (RETRACE, conducted at 22 German centres) and eventually identified MHV-patients (n = 137) with anticoagulation-associated ICH for outcome analyses. The primary outcome consisted of major haemorrhagic complications analysed during hospital stay according to treatment exposure (restarted TA vs. no-TA). Secondary outcomes comprised thromboembolic complications, the composite outcome (haemorrhagic and thromboembolic complications), timing of TA, and mortality. Adjusted analyses involved propensity-score matching and multivariable cox-regressions to identify optimal timing of TA. In 66/137 (48%) of patients TA was restarted, being associated with increased haemorrhagic (TA = 17/66 (26%) vs. no-TA = 4/71 (6%); P < 0.01) and a trend to decreased thromboembolic complications (TA = 1/66 (2%) vs. no-TA = 7/71 (10%); P = 0.06). Controlling treatment crossovers provided an incidence rate-ratio [hazard ratio (HR) 10.31, 95% confidence interval (CI) 3.67-35.70; P < 0.01] in disadvantage of TA for haemorrhagic complications. Analyses of TA-timing displayed significant harm until Day 13 after ICH (HR 7.06, 95% CI 2.33-21.37; P < 0.01). The hazard for the composite-balancing both complications, was increased for restarted TA until Day 6 (HR 2.51, 95% CI 1.10-5.70; P = 0.03).Restarting TA within less than 2 weeks after ICH in patients with MHV was associated with increased haemorrhagic complications. Optimal weighing-between least risks for thromboembolic and haemorrhagic complications-provided an earliest starting point of TA at Day 6, reserved only for patients at high thromboembolic risk.

Middle cerebral artery occlusion (MCAO) by an intraluminal filament is a widely accepted animal model of focal cerebral ischemia. In this procedure, cutting of the external carotid artery (ECA) is a prerequisite for thread insertion. However, the implications of ECA transsection have not yet been described.After 90 minutes of filament MCAO or sham surgery, rats were evaluated for up to 14 days in terms of body weight development, core temperature, and motor performance. Repeated in vivo MRI of the head and neck was performed for quantification of brain edema and infarct volume. The temporal muscles were histologically analyzed postmortem.In 47% of all rats, ischemic tissue damage to the ipsilateral ECA area, including temporal, lingual, and pharyngeal musculature, was detectable by MRI. Histology of temporal muscles confirmed acute ischemic myopathy. Animals with ECA territory ischemia (ECA-I) showed delayed body weight development and poorer recovery of motor function. There was no difference in the extent of brain edema or final cerebral lesion size between ECA-I-affected and unaffected rats.Filament MCAO was complicated by the consequences of ECA ischemia in approximately half of all rats. Impaired mastication and swallowing functions restricted ingestion and resulted in postsurgical body weight loss and worse motor performance. Impaired cerebral microperfusion resulting from dehydration and reduced spontaneous motor activity resulting from reduced food and water uptake might have contributed to poorer neurological recovery in ECA ischemic rats. Thus, adverse effects caused by extracerebral ischemia with potential impact on outcome have to be considered in this stroke model.

&lt;i&gt;Background:&lt;/i&gt; Providing stroke unit treatment for all stroke patients is a cross-national goal as stated in the WHO Helsingborg Declaration. In order to achieve specialized stroke care for a large area, two stroke centers and 12 community hospitals established an integrative stroke network. This evaluation was performed to analyze achieved advances in stroke management. &lt;i&gt;Methods:&lt;/i&gt; Core network elements are: (1) establishing stroke wards in all hospitals; (2) continuous training in stroke treatment; (3) telemedicine service staffed by a 24 h/day ‘strokologist’ with capability for high-speed videoconferencing and transfer of CT/MRI images. Data were prospectively documented in the databank of the telestroke service, in the Bavarian Stroke Registry and in the controlling departments. &lt;i&gt;Results:&lt;/i&gt; In 2003, 4,179 stroke patients were admitted to the regional network hospitals. Between February 2003 and January 2004 a total of 2,182 teleconsultations were conducted. 250 teleconsultations yielded a nonvascular diagnosis. Indicators for stroke management quality improved compared with other hospitals without stroke unit: the frequency of CT/MRI within 3 h was 59% compared to 46%, frequency of speech therapy 36% (21%), and of occupational therapy 38% (12%). Eighty-six (2.1%) of the patients received systemic thrombolysis compared to 10 patients in the preceding year. Mean length of in-hospital stay decreased from 12.4 in 2002 to 9.7 days in 2003. &lt;i&gt;Conclusions:&lt;/i&gt; This stroke network concept leads to a substantial improvement of stroke management. Telemedicine contributes to an early etiological assessment and fills the gap of specialized stroke expertise in neurologically underserved areas.

Background and Purpose The sensitivity and validity of serum neuron-specific enolase as a marker of brain injury were tested after global cerebral ischemia. Methods Sixty-nine Mongolian gerbils were perfusion fixed after variable reperfusion after 5-minute (group 1) or 15-minute (group 2) bilateral carotid occlusion. Neuron-specific enolase was analyzed by an enzyme immunoassay in serum of control, sham-operated, and ischemic animals before euthanasia and in nonischemic gerbil brains. Brains were processed for histology, immunohistochemistry, and morphometric evaluation of ischemic neuronal damage. Results After cerebral ischemia, loss of neuronal immunoreactivity was closely associated with increased neuron-specific enolase serum levels, which were significantly elevated by 24 hours (group 1) or by 4 hours (group 2) of reperfusion ( P &lt;.001). Response of serum levels depended on the duration of preceding ischemia, and maximum concentrations were approximately 3-fold (group 1) or 20-fold (group 2) those of nonischemic control. Morphological damage became apparent 48 hours (group 1) or 12 hours (group 2) after ischemia, as indicated by histological and morphometric data. Conclusions Significantly elevated neuron-specific enolase serum levels could be demonstrated as a consequence of ischemia-induced cytoplasmic loss of neuron-specific enolase in central nervous system neurons, corresponded quantitatively to the severity of cerebral ischemia, and were detectable before irreversible neuronal injury. Therefore, analysis of serum neuron-specific enolase is suggested to be both a valuable diagnostic tool in clinical management of the initial stages of global cerebral ischemia and a prognostic parameter during the postischemic course.

Contrast-enhanced MR angiography and extracranial color-coded duplex sonography are noninvasive, preoperative imaging modalities for evaluation of carotid artery stenosis. Innovative techniques and improvements in image quality require frequent reassessment of accuracy, reliability, and diagnostic value compared with those of digital subtraction angiography (DSA). We evaluated contrast-enhanced MR angiography and duplex sonography compared with DSA for detection of high-grade carotid artery stenoses.Four readers, blinded to clinical symptoms and the outcome of other studies, independently evaluated stenoses on contrast-enhanced MR angiograms in 71 vessels of 39 symptomatic patients. Duplex sonography was also performed in all vessels. The severity of stenosis was defined according to North American Symptomatic Carotid Endarterectomy Trial criteria (0-29%, 30-69%, 70-99%, 100%). Results of both modalities were compared with the corresponding DSA findings.Contrast-enhanced MR angiography had a sensitivity and specificity of 94.9% and 79.1%, respectively, for the identification of carotid artery stenoses of 70% or greater. Sensitivity and specificity of duplex sonography were 92.9% and 81.9%, respectively. Combining data from both tests revealed a sensitivity and specificity of 100% and 81.4%, respectively, for concordant results (80% of vessels).Concordant results of contrast-enhanced MR angiography and duplex sonography increase the diagnostic sensitivity to 100%. The reliability of MR angiography is comparable to that of DSA. The combination of contrast-enhanced MR angiography and duplex sonography might be preferable over DSA for preoperative evaluation in most patients, thus reducing the risk of perioperative morbidity and improving the overall outcome.

In vitro and in vivo data indicate that stem cells found in the bone marrow (BM) are capable of differentiating into neural cells. The aim of this study was to investigate whether potentially pluripotent hematopoietic stem and progenitor cells are recruited from the BM into the peripheral blood as a reaction to ischemic damage of neural tissues.The number of CD34+ cells, colony-forming cells (CFC) and long-term culture-initiating cells (LTC-IC) was measured within 24 h and on day 7 after stroke onset by flow cytometry, or in functional assays in the peripheral blood of 10 patients with acute middle cerebral artery infarct. The National Institute of Health stroke scale, Barthel index and modified Rankin scale were used to monitor the clinical outcome.In four patients receiving intravenous thrombolytic therapy (tissue plasminogen activator; TPA), no significant increase of CD34+ cells, CFC or LTC-IC was detected. In six patients without thrombolytic treatment, the mean number of CD34+ cells/mL increased significantly from 1181+/-248 at day 1 to 3001+/-881 at day 7. Accordingly, the numbers of CFC and LTC-IC increased 2.7- and 1.7-fold. Granulocyte colony-stimulating factor and neutrophil elastase were monitored by ELISA and remained unchanged during the study period.Our results showed a recruitment of hematopoietic progenitor cells from the BM into the peripheral blood after acute ischemic stroke when no thrombolytic treatment was given. Increased progenitor cell recruitment might be caused by so far unknown signaling stimuli of the ischemic penumbra for stem cell mobilization.

Background and Purpose- Given inconclusive studies, it is debated whether clinical and imaging characteristics, as well as functional outcome, differ among patients with intracerebral hemorrhage (ICH) related to vitamin K antagonists (VKA) versus non-vitamin K antagonist (NOAC)-related ICH. Notably, clinical characteristics according to different NOAC agents and dosages are not established. Methods- Multicenter observational cohort study integrating individual patient data of 1328 patients with oral anticoagulation-associated ICH, including 190 NOAC-related ICH patients, recruited from 2011 to 2015 at 19 tertiary centers across Germany. Imaging, clinical characteristics, and 3-months modified Rankin Scale (mRS) outcomes were compared in NOAC- versus VKA-related ICH patients. Propensity score matching was conducted to adjust for clinically relevant differences in baseline parameters. Subgroup analyses were performed regarding NOAC agent, dosing and present clinically relevant anticoagulatory activity (last intake <12h/24h or NOAC level >30 ng/mL). Results- Despite older age in NOAC patients, there were no relevant differences in clinical and hematoma characteristics between NOAC- and VKA-related ICH regarding baseline hematoma volume (median [interquartile range]: NOAC, 14.7 [5.1-42.3] mL versus VKA, 16.4 [5.8-40.6] mL; P=0.33), rate of hematoma expansion (NOAC, 49/146 [33.6%] versus VKA, 235/688 [34.2%]; P=0.89), and the proportion of patients with unfavorable outcome at 3 months (mRS, 4-6: NOAC 126/179 [70.4%] versus VKA 473/682 [69.4%]; P=0.79). Subgroup analyses revealed that NOAC patients with clinically relevant anticoagulatory effect had higher rates of intraventricular hemorrhage (n/N [%]: present 52/109 [47.7%] versus absent 9/35 [25.7%]; P=0.022) and hematoma expansion (present 35/90 [38.9%] versus absent 5/30 [16.7%]; P=0.040), whereas type of NOAC agent or different NOAC-dosing regimens did not result in relevant differences in imaging characteristics or outcome. Conclusions- If effectively anticoagulated, there are no differences in hematoma characteristics and functional outcome among patients with NOAC- or VKA-related ICH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT03093233.

To examine the long-term prognosis in patients with ‘malignant’ supratentorial ischemia of the right hemisphere treated with hemicraniectomy, especially in respect to depression, with a focus on age as a possible predictor of outcome. We performed a prospective, long-term, follow-up examination in 23 survivors of 32 patients (mortality 28.1%) treated with hemicraniectomy for malignant middle cerebral artery (MCA) infarction of the right hemisphere, who were identified in our data bank since 1993. Long-term was defined as at least 20 months after craniectomy. Outcome data consisted of the items functionality, depression and quality of life. Tests applied included the Barthel Index (BI), the modified Rankin Scale (mRS), Beck Depression Inventory (BDI) and stroke-specific quality of life (QoL) scale. Of the 23 patients 15 (65.2%) had a BI ≥ 60, 11 (47.8%) a mRS < 4 and 9 (39.1%) a SS-QOL ≥ 60%, each representing a favourable outcome. In retrospect, 14 (60.9%) patients approved the surgery. Depression, i.e. a BDI > 9, was diagnosed in 13 (56.5%) patients and 5 (38.5%) of them were treated with antidepressants. In a multiple linear regression analysis age at craniectomy was a predictor of a low BI (beta = −0.863; p = 0.031), but not of the other outcome parameters. Depression is a common and rarely treated long-term complication after ‘malignant’ right hemispheric ischemia. While high age is a strong predictor of poor functional outcome, it has no impact on depression and retrospective approval of craniectomy.

Objective To determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH. Methods Retrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC. Results IHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04–1.93) vs non-LDSH: 1.32 (0.33–3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38–4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4–6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume &lt;4.4 mL: 0.18 (0.04–0.78); p=0.022) and low National Institutes of Health Stroke Scale (NIHSS) score on admission (OR: NIHSS &lt;4: 0.29 (0.11–0.78); p=0.014) were significantly associated with fewer IHC. Conclusions Heparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention.

Middle cerebral artery occlusion (MCAO) in Fischer-344 rats results in a small variance of infarct size. However, complications are frequent especially in aged Fisher-344 rats undergoing endovascular suture occlusion of the middle cerebral artery. Analyzing our experiences with 165 Wistar, 13 Sprague-Dawley and 10 F-344 rats, we compared the incidence of impossible thread advancement and subarachnoid hemorrhage, respectively. Magnetic resonance angiography (MRA) was applied to study the course of the internal carotid artery (ICA) in Fischer and Wistar rats. Finally, we performed a structured review of the literature from 1991 to 2005 evaluating reports on Fischer rats subjected to intraluminal filament MCAO. Complications like fruitless filament advancement or subarachnoid hemorrhage were found to be significantly more frequent in Fischer rats than in other strains. MRA revealed significantly more pronounced kinking of the ICA in F-344 than in Wistar rats. In seven publications available on filament MCAO in F-344 rats, complication rates of 50-100% were reported, corroborating our data. Surgical difficulties accompanied by high complication rates due to their cerebrovascular anatomy make Fischer rats unsuitable for filament MCAO. If the use of Fischer rats for studies on focal cerebral ischemia is indicated, other ischemia models than intraluminal suture occlusion should be chosen.

Elevated concentrations of D-dimers (DDs) in patients with acute ischemic stroke may cause differential diagnostic problems with regard to pulmonary or deep venous thrombosis. The true relationship between plasma DDs and acute ischemic stroke remains uncertain. We studied acute stroke patients admitted to a single acute neurology department with a specialized stroke unit. As part of our clinical protocol, blood samples of each patient had been taken within the first 24 hours after the onset of stroke symptoms and before anticoagulant treatment had been started, to evaluate the coagulation profile. Each patient's medical record was reviewed, and demographic, clinical, laboratory and neuroimaging information was abstracted. Univariate and multivariate statistical analyses were performed. A total of 59 patients admitted to our stroke unit between October 2003 and March 2004 with different stroke subtypes according to the TOAST criteria were evaluated to characterize the impact of stroke category on DD concentration. Family members (n = 23) served as controls in this study. Multivariate regression analysis revealed that patients who sustained cardioembolic stroke had significantly higher DD concentrations than controls and patients who sustained transient ischemic attacks. We identified a correlation between plasma DD levels and different acute ischemic stroke subtypes before any stroke treatment was started. Thus DD concentrations may be considered a direct consequence of marked cerebral infarction and may be useful for physicians when making decisions on treatment for acute ischemic stroke.

In vivo imaging of rats represents an important tool for outcome evaluation in research on stroke, brain trauma, and other neurologic diseases. Since sedation of animals is necessary to avoid artifacts, a mixture of ketamine and xylazine is frequently used for anesthesia. We assessed the suitable dosage of narcotics and its correlation to severe respiratory adverse events in 269 cases of ketamine/xylazine anesthesia in male Wistar rats for performance of magnetic resonance imaging after middle cerebral artery occlusion (MCAO) or sham surgery. Anesthesia depth was not measured. Anesthesia was efficacious in avoiding movement artifacts during imaging. Necessary dosage was lower if rodents were subjected to MCAO instead of sham surgery, if body weight was below baseline, and if time since surgery was short. If anesthesia was induced during the first 2 days after surgery in animals with body weight loss, necessary dose rates were 27% below doses required for rats more than 10 days post-surgery with body weight above baseline (91.4/8.3 versus 125.1/11.3 mg of ketamine/xylazine/kg). A dose adaptation scale for the prediction of necessary dose rates was developed. Apnea developed in 3.3% of all animals. Use of ketamine/xylazine anesthesia for imaging procedures is feasible and safe, though it is associated with a small risk of respiratory arrest. In case of apnea, inspiration can be provoked by a puff of air into the rat's pelt. If unsuccessful, endotracheal intubation and mechanical ventilation are needed until spontaneous breathing is restored or xylazine effects are antagonized.

In the intraluminal suture model of middle cerebral artery occlusion (MCAO) in the rat, lesions of the masticator muscles associated with impaired functional outcome occur. We evaluated the role of external carotid artery (ECA) transection. We assessed whether isolated interruption of an arterial or a venous connection to the ECA territory was sufficient to induce masticatory hypoperfusion and lesions. We also evaluated a direct access to the common carotid artery (CCA) with subsequent vascular closure with regard to its feasibility, frequency of masticatory lesions, complications, and cerebral ischemia. Cerebral and masticatory lesions and perfusion deficits were assessed by in vivo magnetic resonance imaging (MRI). Vessel patency was evaluated using computerized tomography angiography and histology. An interruption of arterial blood flow led to masticatory hypoperfusion. Masticatory lesions occurred in 6% of the rats. Access to and closure of the CCA were feasible in all animals, leading to moderate or severe vessel stenosis in 20%, and intraarterial thrombosis in 25% of the rats. Reproducible cerebral infarctions were obtained in all animals. In 24% of the rats, hyperintense MRI signal changes were observed in the ipsilateral temporal muscle. Thus, the induction of masticatory hypoperfusion and lesions by arterial transection supports the role of the ECA in this context. Direct access to the CCA with subsequent vessel closure led to stenosis in most animals. Preservation of ECA continuity was not suitable to fully prevent masticatory lesions.

We describe a preterm infant of 32 weeks' gestation with hydrops fetalis due to intrauterine supraventricular tachycardia. On the second day of life, cranial ultrasound showed a mainly right-sided periventricular leukomalacia already with porencephalic cysts. These findings were confirmed by autopsy. An association of intrauterine tachycardia with periventricular leukomalacia must be assumed.

We report the first case of acute subdural hematoma (SDH) developing after tightening the halo of an osteoporotic 61-year-old woman on warfarin therapy for bilateral traumatic vertebral artery dissection. We discuss literature relevant to this case with an emphasis on identifying warning signs, including recurrent pin loosening, especially in patients with compromised bone structure and high risk of bleeding. Our 61-year-old patient presented to neurosurgery clinic for a 2-month follow-up of a type-III odontoid fracture sustained in a motor vehicle accident. The patient had repeatedly loosened halo pins, and shortly after the pins were tightened, the patient had a syncopal event and struck her head. An emergent computed tomography scan revealed acute SDH requiring emergent craniotomy and evacuation. SDH following pin penetration in a patient with bilateral vertebral artery dissection, osteoporosis, and anticoagulation has not been reported as a complication of the use of the halo vest for stabilization of the cervical spine. The risk of this serious complication can be minimized by giving special consideration to patients with comorbidities and by repositioning problematic pins. This case demonstrates the importance of special attention to bone strength, bleeding risk, and recurrent minor complaints with use of the halo vest. Nous rapportons le cas d’un hématome sous-dural aigu survenu après le resserrage d’un halo chez une patiente ostéoporotique de 61 ans, recevant de la warfarine pour une dissection bilatérale de l’artère vertébrale. Nous discutons la littérature en rapport avec ce cas en soulignant l’importance d’identifier les signes d’alarme, en particulier le lâchage itératif des pointes, surtout chez les patients ayant une altération de la structure osseuse et un haut risque hémorragique. Cette patiente de 61 ans s’est présentée en neurochirurgie pour le suivi à deux mois d’une fracture type III de l’odontoïde, consécutive à un accident de la route. La patiente a, de façon répétitive, perdu ses pointes et, peu de temps après que les pointes aient été resserrées, la patiente a fait une syncope suivie d’un traumatisme crânien. Le scanner effectué en urgence a montré un hématome sous-dural aigu, imposant une craniotomie immédiate pour son évacuation. L’hématome sous-dural aigu consécutif à la pénétration d’une pointe chez une patiente ayant une dissection bilatérale de l’artère vertébrale, une ostéoporose et un traitement anti-coagulation, n’a encore jamais été rapporté en tant que complication du halo vest pour stabilisation du rachis cervical. Le risque de complication grave peut être diminué en prenant en compte les comorbidités des patients et en repositionnant les pointes à problèmes.

Fibrin sealants are used in a variety of surgical procedures, mainly for purposes of hemostasis and assisted wound healing. The combined use of fibrin sealant and autologous muscle pads for hemostasis was not reported previously. Arterial incisions in the common carotid artery in rats were closed by the combined application of fibrin sealant and an autologous muscle pad. Postsurgical vessel patency and degree of stenosis were evaluated by color duplex sonography, computed tomography angiography, and postmortem histology. The combined application of muscle pad and fibrin sealant and achievement of hemostasis was feasible in all animals. Seventy-eight percent of animals showed no or only slight postsurgical vessel stenosis. Our method is simple and quick to perform, showing a high potential for hemostasis in microvascular lesions. Therefore, it might be used in future experimental studies for conservation of vessel patency after arterial catheterization and in experimental or clinical vascular surgery. © 2005 Wiley-Liss, Inc. Microsurgery 25:570–574, 2005.

HomeStrokeVol. 35, No. 7Cerebral Ischemia, Matrix Metalloproteinases, and TNF-α: MMP Inhibitors May Act Not Exclusively by Reducing MMP Activity Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBCerebral Ischemia, Matrix Metalloproteinases, and TNF-α: MMP Inhibitors May Act Not Exclusively by Reducing MMP Activity Michael Dittmar, MD Georgios Kiourkenidis, PhD and Markus Horn, MD Susanne Bollwein and Günther Bernhardt, PhD Michael DittmarMichael Dittmar Department of Anesthesiology, University of Regensburg, Regensburg, Germany Search for more papers by this author Georgios KiourkenidisGeorgios Kiourkenidis Department of Neurology, University of Regensburg, Regensburg, Germany Search for more papers by this author and Markus HornMarkus Horn Department of Neurology, University of Regensburg, Regensburg, Germany Search for more papers by this author Susanne BollweinSusanne Bollwein Institute of Pharmacy, University of Regensburg, Regensburg, Germany Search for more papers by this author and Günther BernhardtGünther Bernhardt Institute of Pharmacy, University of Regensburg, Regensburg, Germany Search for more papers by this author Originally published10 Jun 2004https://doi.org/10.1161/01.STR.0000135294.08862.5dStroke. 2004;35:e338–e340Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 10, 2004: Previous Version 1 To the Editor:We thank Drs Pfefferkorn and Rosenberg for their enlightening paper1 on matrix metalloproteinases (MMPs) after ischemic stroke.MMPs are attributed an important role in the pathophysiology of cerebral ischemia. The gelatinases MMP-2 and MMP-9 are of particular interest in this respect. In numerous experimental settings, the reduction of gelatinase activity has been demonstrated to be associated with improved outcome. Beside natural MMP inhibitors (tissue inhibitors of MMPs),2 monoclonal antibodies,3 and genetic approaches,4 the broad-spectrum MMP inhibitors BB-94, BB-1101, and KB-R7785 have proven to reduce ischemic damage.1,4–8In addition to their inhibitory effects on MMPs, broad-spectrum inhibitors impede the activity of other metalloendopeptidases such as tumor necrosis factor α (TNF-α) converting enzyme (TACE), which cleaves membrane-bound pro–TNF-α to active soluble TNF-α.9,10 TACE is inhibited by BB-94,11,12,13 BB-1101,14,15 and KB-R7785.16 TNF-α has been proven to display negative effects after cerebral ischemia,17 and its neutralization ameliorates ischemic lesions.17,18,19,20 TNF-α contributes to the opening of the blood–brain barrier (BBB) by a mechanism involving soluble guanylyl cyclase and protein tyrosine kinase.21 Therefore, broad-spectrum MMP inhibitors could have contributed to BBB protection via reducing TNF-α activity and not exclusively via inhibition of MMPs. Unfortunately, the literature on the impact of MMP inhibitors after stroke does not provide any insight into the possible involvement of TNF-α in this context.We investigated the specific MMP-2/MMP-9 inhibitor I, N-([1,1′-biphenyl]-4-ylsulfonyl)-d-phenylalanine (Calbiochem),22 in focal cerebral ischemia. Experimental procedures were carried out in accordance with guidelines of the German law governing animal care and the European Communities Council Directive (86/609/EEC). Protocols were approved by the Ethics Committee for Animal Research of the Bavarian government.Wistar rats (250 to 300 g; Charles River, Sulzfeld, Germany) were subjected to 90 minutes middle cerebral artery occlusion (n=38) or sham surgery (n=6) as described by Longa et al,23 with modifications previously described in detail.24 After reperfusion, the MMP-2/MMP-9 inhibitor I was locally infused into the internal carotid artery over 30 minutes. Nine animals received a dose of 1 mg/kg body weight or vehicle, respectively. A second consecutive group received 10 mg/kg or solvent (n=8 each). Four additional animals were used for quantification of plasma levels. They received a dose of 1 or 5 mg/kg (n=2, respectively). Blood specimens were collected before, immediately after, 30 minutes, 90 minutes, and 12 (n=1 per dosage) or 24 hours (n=1 per dosage) after infusion. Plasma levels were determined by isocratic (54% CH3CN/46% TFA (0.1%), 1 mL/min) high-performance liquid chromatography on a 5 μm LiChrospher 100 RP-18 column (250×4 mm) by uv detection (254 nm) using α-[([1,1′-biphenyl]-4-ylsulfonyl)amino]-N-hydroxy-(αR)-benzenepropanamide (MMP-2/MMP-9 inhibitor II; Calbiochem) as internal standard. Deproteinisation was carried out by addition of 2 aliquots of ice-cold CH3CN to the plasma samples.Rats were weighed, neurologically examined according to,25 and underwent in vivo magnet resonance imaging 24 hours, 2 days, and 8 days after surgery. Measurements were performed on a 1.5T MR scanner (Magnetom Symphony, Siemens). A T2-weighted turbo spin-echo sequence and a heavily T1-weighted inversion recovery sequence were applied in the axial and coronal orientations. Lesion volumes were determined from printed MR images. Midline shift was expressed as ratios of ischemic and nonischemic hemisphere diameters at the bottom of the 3rd ventricle.Results revealed no differences in physiological parameters. Plasma concentrations of MMP-2/MMP-9 inhibitor I are displayed in the Table. There were no significant differences in lesion volumes, midline shift, body weight, and neurological examination between inhibitor-treated animals and controls. Mean Plasma Concentrations of MMP-2/MMP-9 Inhibitor I [μmol] Over TimeDoseImmediately After Infusion+30 min+90 min+12 h+24 hIC50: MMP-2=0.31, MMP-9=0.24 μmol/L (22).ULD indicates under the limit of detection.1 mg/kg39.126.923.1ULDULD5 mg/kg303.5229.9134.411.25.1In conclusion, broad-spectrum MMP inhibitors have been repeatedly reported to have beneficial effects after cerebral ischemia. In our study, an MMP-2/MMP-9 inhibitor failed to influence the effects of transient focal cerebral ischemia. Neither a pharmacodynamic nor a pharmacokinetic malfunction of this inhibitor can be ruled out. Nevertheless, these data, together with the present literature, suggest that therapeutic success due to synthetic MMP inhibitors may possibly not be attributed exclusively to its effects on MMP-2 and MMP-9. This hypothesis concurs with the finding of Pfefferkorn and Rosenberg that BB-94 reduced BBB opening without influencing zymographically determined MMP-2 and MMP-9 levels.1 Since broad-spectrum MMP inhibitors affect other enzymes like TACE as well, the effects on TNF-α activity should not be underestimated in the discussion of these drugs.1 Pfefferkorn T, Rosenberg GA. Closure of the blood-brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion. Stroke. 2003; 34: 2025–2030.LinkGoogle Scholar2 Rosenberg GA, Kornfeld M, Estrada E, Kelley RO, Liotta LA, Stetler-Stevenson WG. TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase. Brain Res. 1992; 576: 203–207.CrossrefMedlineGoogle Scholar3 Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC. Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke. 1998; 29: 1020–1030.CrossrefMedlineGoogle Scholar4 Asahi M, Asahi K, Jung J-C, del Zoppo GJ, Fini ME, Lo EH. Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab. 2000; 20: 1681–1689.CrossrefMedlineGoogle Scholar5 Sumii T, Lo EH. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke. 2002; 33: 831–836.CrossrefMedlineGoogle Scholar6 Lee S-R, Tsuji K, Lee S-R, Lo EH. Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia. J Neurosci. 2004; 24: 671–678.CrossrefMedlineGoogle Scholar7 Rosenberg GA, Estrada EY, Dencoff JE. Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke. 1998; 29: 2189–2195.CrossrefMedlineGoogle Scholar8 Jiang X-F, Namura S, Nagata I. Matrix metalloproteinase inhibitor KB-R7785 attenuates brain damage resulting from permanent focal cerebral ischemia in mice. Neurosci Lett. 2001; 305: 41–44.CrossrefMedlineGoogle Scholar9 Gearing AJ, Beckett P, Christodoulou M, Churchill M, Clements J, Davidson AH, Drummond AH, Galloway WA, Gilbert R, Gordon JL, Leber TM, Mangan M, Miller K, Nayee P, Owen K, Patel S, Thomas W, Wells G, Wood LM, Woolley K. Processing of tumor necrosis factor-alpha precursor by metalloproteinases. Nature. 1994; 370: 555–557.CrossrefMedlineGoogle Scholar10 Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature. 1997; 385: 729–733.CrossrefMedlineGoogle Scholar11 Parvathy S, Karran EH, Turner AJ, Hooper NM. The secretases that cleave angiotensin converting enzyme and the amyloid precursor protein are distinct from tumour necrosis factor-K convertase. FEBS Letters. 1998; 431: 63–65.CrossrefMedlineGoogle Scholar12 Corbel M, Lanchou J, Germain N, Malledant Y, Boichot E, Lagente V. Modulation of airway remodeling-associated mediators by the antifibrotic compound, pirfenidone, and the matrix metalloproteinase inhibitor, batimastat, during acute lung injury in mice. Eur J Pharmacol. 2001; 426: 113–121.CrossrefMedlineGoogle Scholar13 Hernandez-Pando R, Orozoco H, Arriaga K, Pavön L, Rook G. Treatment with BB-94, a broad spectrum inhibitor of zinc-dependent metalloproteinases, causes deviation of the cytokine profile towards type-2 in experimental pulmonary tuberculosis in Balb/c mice. Int J Exp Path. 2000; 81: 199–209.MedlineGoogle Scholar14 Clements JM, Cossins JA, Wells GM, Corkill DJ, Helfrich K, Wood LM, Pigott R, Stabler G, Ward GA, Gearing AJ, Miller KM. Matrix metalloproteinase expression during experimental autoimmune encephalomyelitis and effects of a combined matrix metalloproteinase and tumor necrosis factor-alpha inhibitor. J Neuroimmunol. 1997; 74: 85–94.CrossrefMedlineGoogle Scholar15 Barlaam B, Bird TG, Lambert-van der Brempt C, Campbell D, Foster SJ, Maciewicz R. New alpha-substituted succinate-based hydroxamic acids as TNFalpha convertase inhibitors. J Med Chem. 1999; 42: 4890–4908.CrossrefMedlineGoogle Scholar16 Morimoto Y, Nishikawa K, Ohashi M. KB-R7785, a novel matrix metalloproteinase inhibitor, exerts its antidiabetic effect by inhibiting tumor necrosis factor-alpha production. Life Sci. 1997; 61: 795–803.CrossrefMedlineGoogle Scholar17 Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, Lysko PG, Feuerstein GZ. Tumor necrosis factor-alpha: a mediator of focal ischemic brain injury. Stroke. 1997; 28: 1233–1244.CrossrefMedlineGoogle Scholar18 Nawashiro H, Martin D, Hallenbeck JM. Inhibition of tumor necrosis factor and amelioration of brain infarction in mice. J Cereb Blood Flow Metab. 1997; 17: 229–232.CrossrefMedlineGoogle Scholar19 Yang GY, Gong C, Qin Z, Ye W, Mao Y, Bertz AL. Inhibition of TNFalpha attenuates infarct volume and ICAM-1 expression in ischemic mouse brain. Neuroreport. 1998; 9: 2131–2134.CrossrefMedlineGoogle Scholar20 Martin-Villalba A, Hahne M, Kleber S, Vogel J, Falk W, Schenkel J, Krammer PH. Therapeutic neutralization of CD95-ligand and TNF attenuates brain damage in stroke. Cell Death Differ. 2001; 8: 679–686.CrossrefMedlineGoogle Scholar21 Mayhan WG. Cellular mechanisms by which tumor necrosis factor-alpha produces disruption of the blood-brain barrier. Brain Res. 2002; 927: 144–152.CrossrefMedlineGoogle Scholar22 Tamura Y, Watanabe F, Nakatani T, Yasui K, Fuji M, Komurasaki T, Tsuzuki H, Maekawa R, Yoshioka T, Kawada K, Sugita K, Ohtani M. Highly selective and orally active inhibitors of type IV collagenase (MMP-9 and MMP-2): N-sulfonylamino acid derivates. J Med Chem. 1998; 41: 640–649.CrossrefMedlineGoogle Scholar23 Longa EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989; 20: 84–91.CrossrefMedlineGoogle Scholar24 Dittmar M, Spruss T, Schuierer G, Horn M. External carotid artery territory ischemia impairs outcome in the endovascular filament model of middle cerebral artery occlusion in rats. Stroke. 2003; 34: 2252–2257.LinkGoogle Scholar25 Menzies SA, Hoff JT, Betz AL. Middle cerebral artery occlusion in rats: a neurological and pathological evaluation of a reproducible model. Neurosurgery. 1992; 31: 100–107.MedlineGoogle ScholarstrokeahaStrokeStrokeStroke0039-24991524-4628Lippincott Williams & WilkinsResponse:Rosenberg Gary A., , MD and Pfefferkorn Thomas, , MD01072004We appreciate the comments of Dr Dittmar and colleagues on the role of selective MMP-2/MMP-9 inhibitors in cerebral ischemia. Most of the inhibitors used in the neurological studies have been broad-spectrum agents such as the one that we used.1 The finding that an MMP-2/MMP-9 inhibitor failed to affect the endpoints they tested suggests that other MMPs or possibly tumor necrosis factor-α converting enzyme (TACE) are also involved. The emphasis of the earlier studies on MMP-2 and MMP-9 (gelatinase A and B, respectively) was based on the availability of gelatin zymography, a highly sensitive quantitative method to detect gelatinases.2 It is not surprising to find that selective blockade of MMP-2 and MMP-9 is not sufficient to block ischemic damage since over 20 MMPs have been discovered.3 Other MMPs implicated in stroke include MMP-3 (stromelysin-1) and MMP-14 (membrane-bound MMP).4,5The current MMP inhibitors, including the one tested by Dittmar and colleagues, are poorly soluble.6 Little is known about the penetration of these agents into the brain. Because they are poorly soluble, a diluent such as DSMO, which may be neuroprotective by itself, is used. The authors do not specify the diluent used. Another potential drawback of this study is that the selected endpoints did not address the effect on the blood-brain barrier (BBB), which is the major site of action of the MMP inhibitors. It would be interesting to know whether the MMP-2/MMP-9 inhibitor had any effect on the BBB, which may be separate from its effect on lesion size.Computer-aided drug design has increased the number of selective MMP inhibitors.7 The challenge will be to compare the ones with promising drug profiles against the broad-spectrum inhibitors and other classes of agents that interfere with the expression or action of the MMPs, such as the tetracycline derivatives doxycycline and minocycline.8 Studies such as that described by Dittmar and colleagues will aid greatly in the selection of optimal agents to control the neuroinflammation associated with MMP expression in stroke. Previous Back to top Next FiguresReferencesRelatedDetailsCited By Bi J and Yi L (2014) Effects of integrins and integrin αvβ3 inhibitor on angiogenesis in cerebral ischemic stroke, Journal of Huazhong University of Science and Technology [Medical Sciences], 10.1007/s11596-014-1274-4, 34:3, (299-305), Online publication date: 1-Jun-2014. Mehta V, Russin J, Spirtos A, He S, Adamczyk P, Amar A and Mack W (2013) Matrix Metalloproteinases in Cerebral Vasospasm following Aneurysmal Subarachnoid Hemorrhage, Neurology Research International, 10.1155/2013/943761, 2013, (1-4), . Park C, Shin T, Lee H, Kim S and Lee W (2011) Matrix Metalloproteinase Inhibitors Attenuate Neuroinflammation Following Focal Cerebral Ischemia in Mice, The Korean Journal of Physiology and Pharmacology, 10.4196/kjpp.2011.15.2.115, 15:2, (115), . Gibson L, Brazzelli M, Thomas B and Sandercock P (2010) A systematic review of clinical trials of pharmacological interventions for acute ischaemic stroke (1955-2008) that were completed, but not published in full, Trials, 10.1186/1745-6215-11-43, 11:1, Online publication date: 1-Dec-2010. Diener H, Schneider D, Lampl Y, Bornstein N, Kozak A and Rosenberg G (2008) DP-b99, a Membrane-Activated Metal Ion Chelator, as Neuroprotective Therapy in Ischemic Stroke, Stroke, 39:6, (1774-1778), Online publication date: 1-Jun-2008. Lapchak P and Araujo D (2007) Advances in hemorrhagic stroke therapy: conventional and novel approaches, Expert Opinion on Emerging Drugs, 10.1517/14728214.12.3.389, 12:3, (389-406), Online publication date: 1-Sep-2007. Lapchak P (2007) Tumor necrosis factor-α is involved in thrombolytic-induced hemorrhage following embolic strokes in rabbits, Brain Research, 10.1016/j.brainres.2007.06.072, 1167, (123-128), Online publication date: 1-Sep-2007. July 2004Vol 35, Issue 7 Advertisement Article InformationMetrics https://doi.org/10.1161/01.STR.0000135294.08862.5dPMID: 15192238 Originally publishedJune 10, 2004 PDF download Advertisement

The present study reports a new method for the densitometric measurement of the intensity of immunohistochemical reactions. This method is based on a programm for the Kontron VIDAS image analysis system and has been designed for the measurement of small differences in the relative intensity of immunohistochemical reactions. Immunohistochemistry was performed with the avidin-biotin-peroxidase complex and diaminobenzidine-HCl and H2O2 for enzyme visualization. Several methods for shade correction and image processing were elaborated. The study was carried out on gerbil Purkinje cells using monoclonal antibodies raised against calbindin D28k. Prerequesites of correct measurement were standardized preparation, Le., identical thickness of the paraffin sections, identical performance of immunohistochemistry, and avoidance of any counterstaining. The evaluation of small intensity differences of immunohistochemical reactions was found to be feasible either by substractive shade correction and standardized normalization or by shade correction by division by a reference image and standardized thresholding. Small differences in antigen concentration were not detectable without additional image processing.

ABSTRACT Background and Purpose. Noninvasive small animal imaging allows for reduction of the required numbers of animals in research by providing the possibility of long‐term follow‐up at various time points. Additionally, correlation to the investigated respective human disease is possible as equivalent equipment is employed. The authors therefore evaluate feasibility and potential of color duplex sonography, computed tomography angiography (CTA), and magnetic resonance angiography (MRA) by the use of clinical scanners for carotid artery imaging in rats. Methods . Male Wistar rats (n = 17) were subjected to color duplex sonography, CTA, and MRA of the common carotid artery (CCA) and the carotid bifurcation. Clinical scanners were used for the experiments and optimal parameter settings evaluated accounting for the different size of the animals. The applied imaging methods were analyzed in regard to image quality and practicability in laboratory settings. Results . The CCA could be clearly displayed by all imaging modalities in all rats. Duplex sonography provided distinct images and reproducible basic functional information. CTA and MRA provided distinct images of the CCA and the carotid bifurcation in both axial and reconstructed 3‐dimensional images. The authors further describe different indications for these imaging methods regarding spatial resolution, acquisition times, possible scanning range, and application of contrast agent. Conclusions . Color duplex sonography, CTA, and MRAare all feasible methods for imaging of the carotid arteries in rats. Images of sufficient clarity and resolution could be obtained by the use of clinical scanners, yielding information about vessel size, direction of blood flow, and adjacent structures. Further studies need to be performed that Address investigations of pathological conditions such as flow disturbances or vessel stenosis.

Fragestellung: Das intraluminale Fadenmodell der Arteria-cerebri-media-Okklusion (MCA-O) an der Ratte ist ein oft verwendetes und weithin akzeptiertes Modell der fokalen zerebralen Ischämie, allerdings existieren wenig vergleichende Daten über die Anwendbarkeit dieses Modells in verschiedenen Rattenstämmen. Wir untersuchten daher vergleichend die praktische Durchführbarkeit und Komplikationsraten der intraluminalen MCA-O in drei Rattenstämmen.

Annals of the New York Academy of SciencesVolume 723, Issue 1 p. 480-483 Bidirectional, Transmembranal Protein Shifts in Hippocampal Neurons during Early Postischemic Reperfusion of the Gerbil Brain M. HORN, M. HORN Institute of Neurology (Edinger-Institute) University of Frankfurt/Main Deutschordenstraβe 46 60528 Frankfurt am Main 71Search for more papers by this authorW. HIRSCHBERGER, W. HIRSCHBERGER Institute of Neurology (Edinger-Institute) University of Frankfurt/Main Deutschordenstraβe 46 60528 Frankfurt am Main 71Search for more papers by this authorA. SIEBERT, A. SIEBERT Max Planck-Institute for Brain Research Frankfurt/Main, GermanySearch for more papers by this authorW. HOFER, W. HOFER Max Planck-Institute for Brain Research Frankfurt/Main, GermanySearch for more papers by this authorW. SCHLOTE, W. SCHLOTE Institute of Neurology (Edinger-Institute) University of Frankfurt/Main Deutschordenstraβe 46 60528 Frankfurt am Main 71Search for more papers by this author M. HORN, M. HORN Institute of Neurology (Edinger-Institute) University of Frankfurt/Main Deutschordenstraβe 46 60528 Frankfurt am Main 71Search for more papers by this authorW. HIRSCHBERGER, W. HIRSCHBERGER Institute of Neurology (Edinger-Institute) University of Frankfurt/Main Deutschordenstraβe 46 60528 Frankfurt am Main 71Search for more papers by this authorA. SIEBERT, A. SIEBERT Max Planck-Institute for Brain Research Frankfurt/Main, GermanySearch for more papers by this authorW. HOFER, W. HOFER Max Planck-Institute for Brain Research Frankfurt/Main, GermanySearch for more papers by this authorW. SCHLOTE, W. SCHLOTE Institute of Neurology (Edinger-Institute) University of Frankfurt/Main Deutschordenstraβe 46 60528 Frankfurt am Main 71Search for more papers by this author First published: June 1994 https://doi.org/10.1111/j.1749-6632.1994.tb36783.xCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume723, Issue1Cellular, Biochemical, and Molecular Aspects of Reperfusion InjuryJune 1994Pages 480-483 RelatedInformation

The authors describe their own modification of closure of an atrial septal defect (ASD) from right anterolateral minothoracotomy. This minimally invasive approach was selected in girls and women. Right anterolateral thoracotomy was used in 1987 to 1994 in twelve female patients. With regard to the general trend towards aesthetic surgery the authors use at present minimal anterolateral right-sided thoracotomy which with regard to its close relationship with the right atrium makes a safe surgical access to the atrial septum possible. Extracorporeal circulation is implemented by cannulation of the iliac artery in the groin, venous return is ensured by cannulas inserted into the venae cavae in the surgical field (by the auricle of the right atrium into the vena cava superior and the right atrial wall into the vena cava inferior). The operation itself is performed with electric fibrillation of the heart and tightening of the venous tourniquets. Between January 1995 till March 1996 the authors made by the thus modified approach a closure of the ASD type secundum in four female patients age 17, 29, 35 and 40 years. ASD was located always in the fossa ovalis and was repaired by direct suture. The duration of the extracorporeal circulation was on average 30 minutes. The length of the skin incision was 8-10 cm. The operation was free from complications. The cosmetic result is excellent and is consistent with principles of aesthetic surgery. If an arterial cannula is inserted into the groin minithoracotomy can be recommended for closure of ASD with extracorporeal circulation as a safe method.

Neuron-specific enolase (NSE) represents the y,y isoenzyme of the dimeric protein enolase which is a soluble enzyme of the glycolytical pathway. Physiologically, NSE is specifically present in neuronal cytoplasm and dendrites, and in cells of the amine precursor uptake and decarboxylation (APUD) cell system [5]. Since patients suffering from APUDomas, neuroblastomas, or small cell carcinoma of the lung show elevated NSE titers in serum, NSE has been clinically established as a diagnostic and prognostic marker in such neoplasms [1, 5, 8]. However, recently obtained immunohistochemical findings of a decrease in neuronal NSE immunoreactivity in experimental animals and humans following transient cerebral ischemia suggested cytoplasmic NSE loss due to ischemia [3, 6]. Previous studies have shown intracellular compounds, especially NSE, to accumulate in the extracellular fluid and cerebrospinal fluid (CSF) after ischemia [7]. The present study was performed in order to clarify if neuronal NSE release in ischemic brain damage is accompanied by an increase of NSE levels in serum. Therefore, serum NSE was measured at various times after experimental transient forebrain ischemia followed by histological evaluation of ischemic neuronal damage.