Alzheimer's disease-like alterations in peripheral cells from presenilin-1 transgenic mice

Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS1) gene. Expression of PS1 mutations in cell culture systems and in primary neurons from transgenic mice increases their vulnerability to cell death. Interestingly, enhanced vulnerability to cell death has also been demonstrated for peripheral lymphocytes from AD patients. We now report that lymphocytes from PS1 mutant transgenic mice show a similar hypersensitivity to cell death as do peripheral cells from AD patients and several cell culture systems expressing PS1 mutations. The cell death-enhancing action of mutant PS1 was associated with increased production of reactive oxygen species and altered calcium regulation, but not with changes of mitochondrial cytochrome c. Our study further emphasizes the pathogenic role of mutant PS1 and may provide the fundamental basis for new efforts to close the gap between studies using neuronal cell lines transfected with mutant PS1, neurons from transgenic animals, and peripheral cells from AD patients. Copyright 2001 Academic Press

Reduced antioxidant enzyme activity in brains of mice transgenic for human presenilin-1 with single or multiple mutations

Alzheimer's disease-related mutations in the presenilin-1 gene (PS1) are leading to an elevated production of neurotoxic beta-amyloid 1-42 and may additionally enhance oxidative stress. Here, we provide in vivo evidence indicating that brains of transgenic mice expressing different human Alzheimer-linked PS1 mutations exhibit a reduced activity of two antioxidant enzymes. For this purpose, mice transgenic for human PS1 and for single and multiple PS1 mutations were generated. Mice with multiple PS1 mutations showed a significantly decreased activity of the antioxidant enzymes Cu/Zn superoxide dismutase and glutathione reductase already at an age of 3-4 months. As expected, this effect was less pronounced for the mice with a single PS1 mutation. By contrast, animals bearing normal human PS1 showed significantly elevated enzyme activities relative to non-transgenic littermate controls

Sustained Splits of Attention within versus across Visual Hemifields Produce Distinct Spatial Gain Profiles

Visual attention can be focused concurrently on two stimuli at noncontiguous locations while intermediate stimuli remain ignored. Nevertheless, behavioral performance in multifocal attention tasks falters when attended stimuli fall within one visual hemifield as opposed to when they are distributed across left and right hemifields. This “different-hemifield advantage” has been ascribed to largely independent processing capacities of each cerebral hemisphere in early visual cortices. Here, we investigated how this advantage influences the sustained division of spatial attention. We presented six isoeccentric light-emitting diodes (LEDs) in the lower visual field, each flickering at a different frequency. Participants attended to two LEDs that were spatially separated by an intermediate LED and responded to synchronous events at to-be-attended LEDs. Task-relevant pairs of LEDs were either located in the same hemifield (“within-hemifield” conditions) or separated by the vertical meridian (“across-hemifield” conditions). Flicker-driven brain oscillations, steady-state visual evoked potentials (SSVEPs), indexed the allocation of attention to individual LEDs. Both behavioral performance and SSVEPs indicated enhanced processing of attended LED pairs during “across-hemifield” relative to “within-hemifield” conditions. Moreover, SSVEPs demonstrated effective filtering of intermediate stimuli in “across-hemifield” condition only. Thus, despite identical physical distances between LEDs of attended pairs, the spatial profiles of gain effects differed profoundly between “across-hemifield” and “within-hemifield” conditions. These findings corroborate that early cortical visual processing stages rely on hemisphere-specific processing capacities and highlight their limiting role in the concurrent allocation of visual attention to multiple locations

Outcome of radioiodine therapy without, on or 3days off carbimazole: a prospective interventional three-group comparison

Purpose: Carbimazole ameliorates hyperthyroidism but reduces radioiodine uptake and adversely affects the outcome of simultaneous radioiodine therapy. We explored whether withdrawal of carbimazole for 3 days can restore the outcome of radioiodine treatment without concurrent exacerbation of hyperthyroidism. By generating three groups with comparable radioiodine uptake, we also investigated whether the effect of carbimazole depends on the radioiodine uptake. Methods: Stratified by a radioiodine uptake >30%, 227 consecutive adult patients were prospectively assigned to radioiodine therapy (target dose 200Gy) without, on or 3days off carbimazole. Patients were clinically (Crooks-Wayne score) and biochemically (T3, fT4, TSH) followed up after 3, 6 and 12months. Primary endpoint was outcome 12months after radioiodine therapy. Results: A total of 207 patients completed follow-up (toxic nodular goitre, n=117; Graves' disease, n=90). The overall success rate was 71.5%. Patients without and 3days off carbimazole had similar biochemical (81.4% and 83.3%, respectively; p=0.82) and clinical outcomes [median (range) Crooks-Wayne score 0 (0-16) and 1 (0-10), respectively; p=0.73], which were both higher than in patients on carbimazole [42.6%, p<0.001; Crooks-Wayne score 3 (0-30), p<0.03]. Time to achieve cure was delayed on carbimazole. No changes in thyroid hormone levels occurred after 3days' discontinuation of carbimazole. Logistic regression revealed that all observed cure rates were independent of entity, sex, age, thyroid volume, radioiodine uptake, radioiodine half-life, fT4, T3 and TSH. Conclusion: Patients under carbimazole treatment can be referred for radioiodine therapy after withdrawal of carbimazole for only 3days. Three days of carbimazole withdrawal is long enough to restore the success of radioiodine therapy and short enough to avoid the risk of exacerbation of hyperthyroidis

The value of [18F]FDG-PET in the diagnosis of large-vessel vasculitis and the assessment of activity and extent of disease

Purpose: This study was performed to investigate the value of 18F-fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) in the diagnosis of large-vessel vasculitis and the assessment of activity and extent of disease. Methods: Twenty-six consecutive patients (21 females, 5 males; median age -years, range 17-86years) with giant cell arteritis or Takayasu's arteritis were examined with [18F]FDG-PET. Follow-up scans were performed in four patients. Twenty-six age- and gender-matched controls (21 females, 5 males; median age 71years, range 17-86years) were included. The severity of large-vessel [18F]FDG uptake was visually graded using a four-point scale. C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) were measured and correlated with [18F]FDG-PET results by logistic regression. Results: [18F]FDG-PET revealed pathological findings in 18 of 26 patients. Three scans were categorised as grade I, 12 as grade II and 3 as grade III arteritis. Visual grade was significantly correlated with both CRP and ESR levels (p=0.002 and 0.007 respectively; grade I: CRP 4.0mg/l, ESR 6mm/h; grade II: CRP 37mg/l, ESR 46mm/h; grade III: CRP 172mg/l, ESR 90mm/h). Overall sensitivity was 60% (95% CI 40.6-77.3%), specificity 99.8% (95% CI 89.1-100%), positive predictive value 99.7% (95% CI 77-100%), negative predictive value 67.9% (95% CI 49.8-80.9%) and accuracy 78.6% (95% CI 65.6-88.4%). In patients presenting with a CRP <12mg/l or an ESR <12mm/h, logistic regression revealed a sensitivity of less than 50%. In patients with high CRP/ESR levels, sensitivity was 95.5%/80.7%. Conclusion: [18F]FDG-PET is highly effective in assessing the activity and the extent of large-vessel vasculitis. Visual grading was validated as representing the severity of inflammation. Its use is simple and provides high specificity, while high sensitivity is achieved by scanning in the state of active inflammatio

Impact of aging : sporadic, and genetic risk factors on vulnerability to apoptosis in Alzheimer's disease

The identification of specific genetic (presenilin-1 [PS1] and amyloid precursor protein [APP] mutations) and environmental factors responsible for Alzheimer's disease (AD) has revealed evidence for a shared pathway of neuronal death. Moreover, AD-specific cell defects may be observed in many other nonneuronal cells (e.g., lymphocytes). Thus, lymphocytes may serve as a cellular system in which to study risk factors of sporadic, as well as genetic AD in vivo. The aim of our present study was to clarify whether lymphocytes bearing genetic or sporadic risk factors of AD share an increased susceptibility to cell death. Additionally we examined whether a cell typespecific vulnerability pattern was present and how normal aging, the main risk factor of sporadic AD, contributes to changes in susceptibility to cell death. Here, we report that lymphocytes affected by sporadic or genetic APP and PS1 AD risk factors share an increased vulnerability to cell death and exhibit a similar cell type-specific pattern, given that enhanced vulnerability was most strongly developed in the CD4+ T-cell subtype. In this paradigm, sporadic risk factors revealed the highest impact on cell type-specific sensitivity of CD4+ T cells to apoptosis. In contrast, normal aging results in an increased susceptibility to apoptosis of both, CD4+ and CD8+ T cells

Projekte praxisbezogener Lehre und Forschung am Department of Community Health Bochum

Als Reaktion auf eine sich diversifizierende Gesellschaft in Deutschland widmet sich Community Health gesundheitsrelevanten Bedarfen von gesellschaftlichen Gruppen, um Teilhabe und Chancengleichheit zu fördern und die Versorgung zu verbessern. So nimmt die Lehre am Department of Community Health der HS Gesundheit in Bochum individuelle Bedarfe und Lebensrealitäten von Communities in den Blick. Drei Angebote einer praxisbezogenen, partizipativen und transdisziplinären Lehr-Forschungsstruktur werden vorgestellt und deren Zusammenwirken beschrieben. Abschließend werden die Erfahrungen partizipativer und transdisziplinärer Ansätze im Sinne von Campus-Community-Partnerships diskutiert

Neutrophil gelatinase-associated lipocalin (NGAL) predicts response to neoadjuvant chemotherapy and clinical outcome in primary human breast cancer

In our previous work we showed that NGAL, a protein involved in the regulation of proliferation and differentiation, is overexpressed in human breast cancer (BC) and predicts poor prognosis. In neoadjuvant chemotherapy (NACT) pathological complete response (pCR) is a predictor for outcome. The aim of this study was to evaluate NGAL as a predictor of response to NACT and to validate NGAL as a prognostic factor for clinical outcome in patients with primary BC. Immunohistochemistry was performed on tissue microarrays from 652 core biopsies from BC patients, who underwent NACT in the GeparTrio trial. NGAL expression and intensity was evaluated separately. NGAL was detected in 42.2% of the breast carcinomas in the cytoplasm. NGAL expression correlated with negative hormone receptor (HR) status, but not with other baseline parameters. NGAL expression did not correlate with pCR in the full population, however, NGAL expression and staining intensity were significantly associated with higher pCR rates in patients with positive HR status. In addition, strong NGAL expression correlated with higher pCR rates in node negative patients, patients with histological grade 1 or 2 tumors and a tumor size <40 mm. In univariate survival analysis, positive NGAL expression and strong staining intensity correlated with decreased disease-free survival (DFS) in the entire cohort and different subgroups, including HR positive patients. Similar correlations were found for intense staining and decreased overall survival (OS). In multivariate analysis, NGAL expression remained an independent prognostic factor for DFS. The results show that in low-risk subgroups, NGAL was found to be a predictive marker for pCR after NACT. Furthermore, NGAL could be validated as an independent prognostic factor for decreased DFS in primary human BC