Andreas Gleiss

Association of an ABCB1 gene haplotype with pharmacoresistance in temporal lobe epilepsy

The multidrug transporter P-glycoprotein is suspected of contributing to pharmacoresistance in temporal lobe epilepsy (TLE). To assess the role of functional variations in its coding gene (ABCB1) the authors genotyped 210 patients with TLE who were stratified according to their degree of drug resistance. They identified a common haplotype that when present in the homozygous state significantly increased the risk for pharmacoresistance.

Peroxisomal alterations in Alzheimer’s disease

In Alzheimer’s disease (AD), lipid alterations are present early during disease progression. As some of these alterations point towards a peroxisomal dysfunction, we investigated peroxisomes in human postmortem brains obtained from the cohort-based, longitudinal Vienna-Transdanube Aging (VITA) study. Based on the neuropathological Braak staging for AD on one hemisphere, the patients were grouped into three cohorts of increasing severity (stages I–II, III–IV, and V–VI, respectively). Lipid analyses of cortical regions from the other hemisphere revealed accumulation of C22:0 and very long-chain fatty acids (VLCFA, C24:0 and C26:0), all substrates for peroxisomal β-oxidation, in cases with stages V–VI pathology compared with those modestly affected (stages I–II). Conversely, the level of plasmalogens, which need intact peroxisomes for their biosynthesis, was decreased in severely affected tissues, in agreement with a peroxisomal dysfunction. In addition, the peroxisomal volume density was increased in the soma of neurons in gyrus frontalis at advanced AD stages. Confocal laser microscopy demonstrated a loss of peroxisomes in neuronal processes with abnormally phosphorylated tau protein, implicating impaired trafficking as the cause of altered peroxisomal distribution. Besides the original Braak staging, the study design allowed a direct correlation between the biochemical findings and the amount of neurofibrillary tangles (NFT) and neuritic plaques, quantified in adjacent tissue sections. Interestingly, the decrease in plasmalogens and the increase in VLCFA and peroxisomal volume density in neuronal somata all showed a stronger association with NFT than with neuritic plaques. These results indicate substantial peroxisome-related alterations in AD, which may contribute to the progression of AD pathology.

Five Genes from Chromosomal Band 8p22 Are Significantly Down-Regulated in Ovarian Carcinoma N33 and EFA6R Have a Potential Impact on Overall Survival

Loss of heterozygosity on chromosomal band 8p22 is a common event in several epithelial tumors including ovarian carcinoma. So far, no clear evidence for a tumor suppressor gene (TSG) in this region has been found.

Comparison of Midregional Pro-Atrial and B-Type Natriuretic Peptides in Chronic Heart Failure Influencing Factors, Detection of Left Ventricular Systolic Dysfunction, and Prediction of Death

OBJECTIVES Midregional pro-atrial natriuretic peptide (MR-proANP) was assessed for the importance of influencing factors, the ability to detect left ventricular systolic dysfunction, and the prognostic power compared with B-type natriuretic peptide (BNP) and amino-terminal pro-B-type natriuretic peptide (NT-proBNP) in chronic heart failure (HF). BACKGROUND MR-proANP is a biologically stable natriuretic peptide measured by a recently developed assay, with potential advantages over conventional natriuretic peptides such as BNP and NT-proBNP. METHODS We measured MR-proANP, BNP, and NT-proBNP in 797 patients with chronic HF. RESULTS All 3 natriuretic peptides were independently influenced by left ventricular ejection fraction (LVEF), glomerular filtration rate (GFR), and the presence of ankle edema. Area under receiver-operator characteristic curves for detection of an LVEF <40% were similar between MR-proANP (0.799 [95% confidence interval (CI): 0.753 to 0.844]), BNP (0.803 [95% CI: 0.757 to 0.849]), and NT-proBNP (0.730 [95% CI: 0.681 to 0.778]). During a median observation time of 68 months, 492 (62%) patients died. In multiple Cox regression analysis each natriuretic peptide was the strongest prognostic parameter among various clinical variables. Proportion of explained variation showed that NT-proANP (4.36%) was a significantly stronger predictor of death than both NT-proBNP (2.47%, p < 0.0001) and BNP (2.42%, p < 0.0001). CONCLUSIONS Despite similarities in influencing factors and detection of reduced LVEF, MR-proANP outperformed BNP and NT-proBNP in the prediction of death. A new assay technology and the high biological stability of MR-proANP are potential explanations for these findings.

Local Tumor Control, Visual Acuity, and Survival After Hypofractionated Stereotactic Photon Radiotherapy of Choroidal Melanoma in 212 Patients Treated Between 1997 and 2007

PURPOSE To evaluate long-term local tumor control, visual acuity, and survival after hypofractionated linear accelerator-based stereotactic photon radiotherapy in patients with choroidal melanoma. METHODS AND MATERIALS Between 1997 and 2007, 212 patients with choroidal melanoma unsuitable for ruthenium-106 brachytherapy or local resection were treated stereotactically at a linear accelerator with 6-MV photon beams at the Medical University of Vienna in five fractions over 7 days. Twenty-four patients received a total dose of 70 Gy (five fractions of 14 Gy), 158 a total dose of 60 Gy (five fractions of 12 Gy) and 30 patients a total dose of 50 Gy (five fractions of 10 Gy) applied on the 80% isodose. Ophthalmologic examinations were performed at baseline and every 3 months in the first 2 years, every 6 months until 5 years, and once a year thereafter until 10 years after radiotherapy. Assessment of visual acuity, routine ophthalmologic examinations, and measurement of tumor base dimension and height using standardized A-scan and B-scan echography were done at each visit. Funduscopy and fluorescein angiography were done when necessary to document tumor response. RESULTS Median tumor height and volume decreased from 4.8 mm and 270.7 mm3 at baseline to 2.6 mm and 86.6 mm3 at the last individual follow-up, respectively (p<0.001, p<0.001). Median visual acuity decreased from 0.55 at baseline to hand motion at the last individual follow-up (p<0.001). Local tumor control was 95.9% after 5 years and 92.6% after 10 years. Thirty-two patients developed metastatic disease, and 22 of these patients died during the follow-up period. CONCLUSION Hypofractionated stereotactic photon radiotherapy with 70 to 50 Gy delivered in five fractions in 7 days is sufficient to achieve excellent local tumor control in patients with malignant melanoma of the choroid. Disease outcome and vision are comparable to those achieved with proton beam radiotherapy. Decreasing the total dose below 60 Gy seems to be possible.

Methylation Status of TUSC3 Is a Prognostic Factor in Ovarian Cancer

Current prognostic information in ovarian cancer is based on tumor stage, tumor grade, and postoperative tumor size. Reliable molecular prognostic markers are scarce. In this article, the authors describe epigenetic events in a frequently deleted region on chromosome 8p22 that influence the expression of tumor suppressor candidate 3 (TUSC3), a putative tumor suppressor gene in ovarian cancer.

ODOR IDENTIFICATION AND SELF-REPORTED OLFACTORY FUNCTIONING IN PATIENTS WITH SUBTYPES OF MILD COGNITIVE IMPAIRMENT

Olfactory dysfunction is a very early symptom of Alzheimers disease (AD), and olfactory dysfunction has also been found in mild cognitive impairment (MCI). The goal of the present study was to compare odor identification ability and self-reported olfactory functioning in patients with different types of MCI. We included 104 elderly participants classified into two groups: patients with mild cognitive impairment (MCI) and elderly controls (EC). Based on their performance in neuropsychological testing the study population was divided into four groups of participants based on cognitive features: amnestic MCI single domain (11), amnestic MCI multiple domain (19), non-amnestic MCI single domain (21) and non-amnestic MCI multiple domain (13), respectively. The MCI patients were compared to 40 elderly controls (EC) controls with no cognitive deficit. Comparison for odor identification revealed a significant difference between amnestic MCI multiple domain patients and the EC group. No other group comparison was significant. Statistical analyses for self-reported olfactory functioning revealed no significant group differences between any subgroup of MCI patients and the control group. Correlational analyses indicated that odor identification ability was related to cognition whereas no relationship was found for self-reported olfactory functioning. The present study showed that amnestic MCI patients with additional deficits in other cognitive domains have a specific odor identification impairment. Together with cognitive testing, olfactory testing may more accurately help predict whether or not a patient with MCI will convert to AD in the near future.

Influence of adjunctive classical homeopathy on global health status and subjective wellbeing in cancer patients — A pragmatic randomized controlled trial

OBJECTIVES The use of complementary and alternative medicine has increased over the past decade. The aim of this study was to evaluate whether homeopathy influenced global health status and subjective wellbeing when used as an adjunct to conventional cancer therapy. DESIGN In this pragmatic randomized controlled trial, 410 patients, who were treated by standard anti-neoplastic therapy, were randomized to receive or not receive classical homeopathic adjunctive therapy in addition to standard therapy. The study took place at the Medical University Vienna, Department of Medicine I, Clinical Division of Oncology. MAIN OUTCOME MEASURES The main outcome measures were global health status and subjective wellbeing as assessed by the patients. At each of three visits (one baseline, two follow-up visits), patients filled in two different questionnaires. RESULTS 373 patients yielded at least one of three measurements. The improvement of global health status between visits 1 and 3 was significantly stronger in the homeopathy group by 7.7 (95% CI 2.3-13.0, p=0.005) when compared with the control group. A significant group difference was also observed with respect to subjective wellbeing by 14.7 (95% CI 8.5-21.0, p<0.001) in favor of the homeopathic as compared with the control group. Control patients showed a significant improvement only in subjective wellbeing between their first and third visits. CONCLUSION Results suggest that the global health status and subjective wellbeing of cancer patients improve significantly when adjunct classical homeopathic treatment is administered in addition to conventional therapy.

Nucleic acid-stimulated antigen-presenting cells trigger T cells to induce disease in a rat transfer model of inflammatory arthritis

Autoimmune responses to heterogeneous nuclear ribonucleproteins (hnRNP) occur in many systemic autoimmune diseases, particularly in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus. In RA, humoral and/or cellular autoimmunity to hnRNP-A2/B1 is the most prominent anti-nuclear reactivity, being detectable in more than 50% of patients. However, its pathogenic role has not been fully elucidated yet. Here, we report that splenocytes from rats with pristane-induced arthritis transfer disease after in vitro restimulation with hnRNP-A/B antigens. Remarkably, disease transfer can be blocked by nuclease treatment of hnRNPs and is also achieved with splenocytes stimulated with hnRNP-A/B associated DNA or RNA oligonucleotides (ON) alone. Induction of proinflammatory cytokines in splenocytes stimulated with hnRNP-A/Bs or ONs involves Toll-like receptors (TLR) 7 and 9 but not TLR3. Furthermore, although T cells are the main mediators of disease transfer they require restimulation with TLR-activated antigen-presenting cells such as macrophages in order to become arthritogenic. Thus, the autoantigenic properties of hnRNPs appear to be mediated by their associated nucleic acids binding to TLR7 and 9. Our data explain the specific selection of hnRNP-A2/B1 as autoantigen in RA and reveal the requirement of interaction between innate and adaptive immunity to initiate and drive inflammation in autoimmune arthritis.

Analysis of four prevalent filaggrin mutations (R501X, 2282del4, R2447X and S3247X) in Austrian and German patients with atopic dermatitis.

Background  Recently, mutations in the filaggrin gene (FLG) have been shown to be a major predisposing factor for atopic dermatitis (AD).