Showing papers by "Ulrich Bogdahn published in 2012"

Amyloid-β Contributes to Blood–Brain Barrier Leakage in Transgenic Human Amyloid Precursor Protein Mice and in Humans With Cerebral Amyloid Angiopathy

Abstract: Background and Purpose—Cerebral amyloid angiopathy (CAA) is a degenerative disorder characterized by amyloid-β (Aβ) deposition in the blood–brain barrier (BBB). CAA contributes to injuries of the neurovasculature including lobar hemorrhages, cortical microbleeds, ischemia, and superficial hemosiderosis. We postulate that CAA pathology is partially due to Aβ compromising the BBB. Methods—We characterized 19 patients with acute stroke with “probable CAA” for neurovascular pathology based on MRI and clinical findings. Also, we studied the effect of Aβ on the expression of tight junction proteins and matrix metalloproteases (MMPs) in isolated rat brain microvessels. Results—Two of 19 patients with CAA had asymptomatic BBB leakage and posterior reversible encephalopathic syndrome indicating increased BBB permeability. In addition to white matter changes, diffusion abnormality suggesting lacunar ischemia was found in 4 of 19 patients with CAA; superficial hemosiderosis was observed in 7 of 9 patients. Aβ40 decr...

A Randomized, Double Blind, Placebo-Controlled Trial of Pioglitazone in Combination with Riluzole in Amyotrophic Lateral Sclerosis

Abstract: BACKGROUND: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). METHODS/PRINCIPAL FINDINGS: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. CONCLUSION/SIGNIFICANCE: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole. TRIAL REGISTRATION: Clinicaltrials.gov NCT00690118.

The Cancer Stem Cell Subtype Determines Immune Infiltration of Glioblastoma

Abstract: Immune cell infiltration varies widely between different glioblastomas (GBMs). The underlying mechanism, however, remains unknown. Here we show that TGF-beta regulates proliferation, migration, and tumorigenicity of mesenchymal GBM cancer stem cells (CSCs) in vivo and in vitro. In contrast, proneural GBM CSCs resisted TGF-beta due to TGFR2 deficiency. In vivo, a substantially increased infiltration of immune cells was observed in mesenchymal GBMs, while immune infiltrates were rare in proneural GBMs. On a functional level, proneural CSC lines caused a significantly stronger TGF-beta-dependent suppression of NKG2D expression on CD8+ T and NK cells in vitro providing a mechanistic explanation for the reduced immune infiltration of proneural GBMs. Thus, the molecular subtype of CSCs TGF-beta-dependently contributes to the degree of immune infiltration.

Transcranial Ultrasound from Diagnosis to Early Stroke Treatment - Part 2: Prehospital Neurosonography in Patients with Acute Stroke - The Regensburg Stroke Mobile Project

Abstract: Background and Purpose: The primary aim of this study was to investigate the diagnostic accuracy and time frames for neurological and transcranial color-coded sonography (TCCS) assessments in a prehospital ‘911’ emergency stroke situation by using portable duplex ultrasound devices to visualize the bilateral middle cerebral arteries (MCAs). Methods: This study was conducted between May 2010 and January 2011. Patients who had sustained strokes in the city of Regensburg and the surrounding area in Bavaria, Germany, were enrolled in the study. After a ‘911 stroke code’ call had been dispatched, stroke neurologists with expertise in ultrasonography rendezvoused with the paramedic team at the site of the emergency. After a brief neurological assessment had been completed, the patients underwent TCCS with optional administration of an ultrasound contrast agent in cases of insufficient temporal bone windows or if the agent had acute therapeutic relevance. The ultrasound studies were performed at the site of the emergency or in the ambulance during patient transport to the admitting hospital. Relevant timelines, such as the time from the stroke alarm to patient arrival at the hospital and the duration of the TCCS, were documented, and positive and negative predictive values for the diagnosis of major MCA occlusion were assessed. Results: A total of 113 patients were enrolled in the study. MCA occlusion was diagnosed in 10 patients. In 9 of these 10 patients, MCA occlusion could be visualized using contrast-enhanced or non-contrast-enhanced TCCS during patient transport and was later confirmed using computed tomography or magnetic resonance angiography. One MCA occlusion was missed by TCCS and 1 atypical hemorrhage was misdiagnosed. Overall, the sensitivity of a ‘field diagnosis’ of MCA occlusion was 90% [95% confidence interval (CI) 55.5–99.75%] and the specificity was 98% (95% CI 92.89–99.97%). The positive predictive value was 90% (95% CI 55.5–99.75%) and the negative predictive value was 98% (95% CI 92.89–99.97%). The mean time (standard deviation) from ambulance dispatch to arrival at the patient was 12.3 min (7.09); the mean time for the TCCS examination was 5.6 min (2.2); and the overall mean transport time to the hospital was 53 min (18). Conclusion: Prehospital diagnosis of MCA occlusion in stroke patients is feasible using portable duplex ultrasonography with or without administration of a microbubble contrast agent. Prehospital neurological as well as transcranial vascular assessments during patient transport can be performed by a trained neurologist with high sensitivity and specificity, perhaps opening an additional therapeutic window for sonothrombolysis or neuroprotective strategies.

The retrobulbar "spot sign" as a discriminator between vasculitic and thrombo-embolic affections of the retinal blood supply.

Abstract: Purpose: Sudden retinal blindness is a common complication of temporal arteritis (TA). Another common cause is embolic occlusion of the central retinal artery (CRA). The aim of this prospective study was to examine the diagnostic value of hyperechoic material in the CRA for the exclusion of vasculitis as a cause. The authors used orbital color-coded sonography (OCCS) for the detection of hyperechoic material. Materials and Methods: 24 patients with sudden vision loss were included in the study after the exclusion of other causes (e. g. vitreous bleeding, retinal detachment). Parallel to routine diagnostic workup, OCCS was performed in all patients. Results: 7 patients with a diagnosis of TA presented with different degrees of hypoperfusion in the CRA without hyperechoic material (referred to as “spot sign”) detected by OCCS. Diagnostic workup in the remaining 17 patients revealed other causes of sudden vision loss, such as central retinal artery occlusion (CRAO) (12), anterior ischemic optic neuropathy (AION) (2), upstream vascular stenosis or occlusion (2) and delayed reperfusion of the CRA (1). The hyperechoic “spot sign” was visible in 10 of 12 patients (83 %) with embolic CRAO. The detection of embolic CRAO using the “spot sign” had a sensitivity of 83 % and a specificity of 100 %. The missing “spot sign” in patients with TA was a highly specific finding (p-value 0.01). Conclusion: The detection of the “spot sign” specifically minimizes the probability of TA as a reason for sudden blindness.

ATP-binding cassette transporters in immortalised human brain microvascular endothelial cells in normal and hypoxic conditions

Abstract: Background Rapid reperfusion following ischemia is the most effective therapy in stroke therapy. However, the success may be compromised by ischemia & reperfusion (I/R) injury and at the human blood–brain barrier (BBB), therefore the effects on transendothelial transport are of special interest. Current studies suggest the ATP-binding cassette (ABC) transporters to be regulated upon ischemic stroke in a way that impedes the effects of drug therapy. The immortalised human brain microvascular endothelial cell line hCMEC/D3 provides most of the unique properties of the BBB with respect to transport and might be a reliable in vitro model to study transendothelial transport after I/R.

Indikationen und Outcome beatmeter Patienten einer neurologischen Intensivstation

Abstract: In dieser Studie charakterisierten wir die beatmeten Patienten einer neurologischen Intensivstation (NITS) im Zeitraum 2006 bis 2008 in einer rein neurologischen Klink in einer sog. „Stand-alone-Situation. Zudem untersuchten wir die Langzeitprognose und Lebensqualitat der Uberlebenden. Diese retrospektive Studie umfasst alle beatmeten Patienten von 10/2006 bis 12/2008 einer neurologischen Intensivstation, analysiert mit prospektiv definierten Kriterien anhand der Aktenlage den Intensivaufenthalt und erfasst die aktuelle Lebensqualitat. Wir ermittelten unter anderem die endgultigen Diagnosen, Dauer der Intensivpflichtigkeit und Beatmungsdauer sowie den jeweils hochsten SAPS-II-Score und die Komplikationen wahrend des Aufenthaltes. Anhand der Diagnosen wurden die Patienten in Gruppen eingeteilt: vaskular, entzundlich, neurodegenerativ, hereditar, epileptisch und sonstige. Zusatzlich wurden die Patienten kontaktiert und per Fragebogen der Barthel-Index (BI) sowie die Werte auf der modifizierten Rankin-Skala (mRS) ermittelt. Insgesamt wurden im beobachteten Zeitraum 201 von 512 Patienten auf der NITS beatmet. Vaskulare Erkrankungen waren fuhrende Ursache fur die Therapie auf der Intensivstation (47,8%), gefolgt von entzundlichen Erkrankungen (22,8%) und Epilepsien (13%). Die Dauer der Beatmung betrug median 9 Tage bei einer mittleren Behandlungsdauer von 16 Tagen (Range 1–57). Bereits wahrend des Aufenthaltes verstarben 31 Patienten (entsprechen15,4% aller Behandelten). Weitere 32 der 170 uberlebenden Patienten (entsprechen 18,8% der entlassenen Patienten) verstarben im Median von 2 Monaten nach Entlassung. Outcomedaten konnten anhand von 67 von 170 versandten Fragebogen und 86 Rehabilitationsabschlussberichten erhoben werden, sodass letztendlich Nachuntersuchungsdaten von insgesamt 121 Patienten der 170 uberlebenden beatmeten Intensivpatienten vorlagen. Davon gaben 42,2% keine bzw. leichte Beeintrachtigungen/Pflegebedurftigkeit im Alltag, allerdings auch 38,0% schwere Beeintrachtigungen/dauerhafte Pflegebedurftigkeit laut BI an. Die Auswertung der mRS ergab, dass immerhin noch 49,6% der 170 nachuntersuchten Patienten subjektiv eine schwere Restsymptomatik aufweisen. Das impliziert, dass vorhandene Residuale nicht zwangslaufig zu einer entsprechenden Pflegebedurftigkeit fuhren. Mehr als ein Drittel der Patienten der hier analysierten NITS wurden beatmungspflichtig, wobei der Schwerpunkt bei den vaskularen Erkrankungen liegt und somit die Uberschneidung zwischen Stroke-Unit und Intensivstation verdeutlicht. Trotz langer Beatmungs- und Intensivdauer zeigt mehr als ein Drittel der uberlebenden Patienten nur leichte oder gar keine Beeintrachtigungen bei Aktivitaten des taglichen Lebens, wobei doch scheinbar ein Teil der Patienten trotzdem subjektiv unter einer nicht unerheblichen Restsymptomatik leidet. Ein weiteres Drittel uberlebte mit schweren Einschrankungen bis hin zur kompletten Pflegebedurftigkeit. Die Daten unterscheiden sich bez. den wenigen Publikationen uber NITS trotz der besonderen Stand-alone-Situation kaum. Der Case-Mix-Index betrug im Mittel 0,3/Tag und zeigt die wirtschaftliche Bedeutung im Vergleich zu anderen neurologischen Behandlungsformen an.