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Schrijvers E.M.C.,Erasmus Medical Center | Schrijvers E.M.C.,Netherlands Genomics Initiative sponsored Netherlands Consortium for Healthy Aging | Schurmann B.,University of Bonn | Koudstaal P.J.,Erasmus Medical Center | And 26 more authors.
Stroke | Year: 2012

Background and Purpose-: Most studies investigating the genetics of dementia have focused on Alzheimer disease, but little is known about the genetics of vascular dementia. The aim of our study was to identify new loci associated with vascular dementia. Methods-: We performed a genome-wide association study in the Rotterdam Study, a large prospective population-based cohort study in the Netherlands. We sought to replicate genome-wide significant loci in 2 independent replication samples. Results-: In the discovery analysis of 5700 dementia-free individuals, 67 patients developed incident vascular dementia over a mean follow-up time of 9.3±3.2 years. We showed genome-wide significance for rs12007229, which is located on the X chromosome near the androgen receptor gene (OR, 3.7; 95% CI, 2.3-5.8, per copy of the minor allele; P=1.3×10-8). This association was further confirmed in 2 independent populations (probability value of combined replication samples=0.024). Conclusions-: Our study shows a novel genetic locus for vascular dementia on the X chromosome. Further replication of this finding is required. © 2011 American Heart Association, Inc.


Salzwedel A.,Charite CBF | Salzwedel A.,Rehabilitation Center for Internal Medicine | Salzwedel A.,University of Potsdam | Wegscheider K.,University of Hamburg | And 7 more authors.
Aging Clinical and Experimental Research | Year: 2015

Methods: The impact of baseline characteristics on the success of CR, measured by MOC, was analysed using a mixed model for 1,220 older patients (70.9 ± 7.0 years, 78.3 % men) who enrolled in 12 CR clinics. A multitude of potentially influential baseline patient characteristics was considered including sociodemographic variables, comorbidity, duration of hospital stay, exercise capacity, cardiovascular risk factors, emotional status, and laboratory and echocardiographic data.Background: Cardiac rehabilitation (CR) seeks to simultaneously improve several outcome parameters related to patient risk factors, exercise capacity and subjective health. A single score, the multiple outcome criterion (MOC), comprised of alterations in 13 outcome variables was used to measure the overall success of CR in an older population. As this success depends on the older patient’s characteristics at the time of admission to CR, we attempted to determine the most important influences.Results: Overall, CR was successful, as indicated by the mean value of the MOC (0.6 ± 0.45; min −1.0, max 2.0; positive values denoting improvement, negative ones deterioration). Examples of association with negative MOC values included smoking (MOC −0.15, p < 0.001), female gender (MOC −0.07, p = 0.049), and a longer hospital stay (MOC −0.03, p = 0.03). An example of association with positive MOC value was depression score (MOC 0.06, p = 0.003). Further associations included maximal exercise capacity, blood pressure, heart rate and the rehabilitation centre attended.Conclusion: Our results emphasize the necessity to take into consideration baseline characteristics when evaluating the success of CR and setting treatment targets for older patients. © 2014, Springer International Publishing Switzerland.


Schuster R.,Charite Campus Benjamin Franklin | Bechrakis N.E.,Innsbruck Medical University | Stroux A.,Institute of Medical Informatics Biometry and Clinical Epidemiology | Busse A.,Charite Campus Benjamin Franklin | And 4 more authors.
Oncology | Year: 2011

Objective: Uveal melanoma primarily metastasizes hematogenously with metastases often confined to the liver. The aim of this study was to investigate the presence of circulating tumor cells (CTC) in patients with metastatic disease as a marker for systemic disease and to determine their prognostic relevance. Methods: Blood samples from 68 patients were collected at the time of initial treatment of metastases. mRNA expression of tyrosinase and MelanA/MART1 as a surrogate marker for the presence of CTC was analyzed by real-time RT-PCR and compared with patient characteristics. Results: CTC were detected in 63% of all patients and in 67% of the 48 patients with only liver metastases. Univariate and multivariate analyses revealed PCR results and serum lactate dehydrogenase as independent prognostic factors for progression-free (hazard ratios 2.2/3.5) and overall survival (hazard ratios 4.0/6.5). Combination of PCR and lactate dehydrogenase divided the patient cohort into 3 groups with distinct prognosis. Conclusion: CTC as evidence for systemic disease can be found in the majority of patients with metastatic uveal melanoma, including patients with visible disease confined to the liver. Detection of CTC-specific mRNA transcripts for tyrosinase and MelanA/MART1 by PCR is a poor prognostic factor for progression-free and overall survival. Characterization of CTC could improve the understanding of their biology. © 2011 S. Karger AG, Basel.


Busse A.,Charite CBF | Letsch A.,Charite CBF | Scheibenbogen C.,Institute of Medical Immunology | Nonnenmacher A.,Charite CBF | And 3 more authors.
Journal of Translational Medicine | Year: 2010

Background: Efficacy of cancer vaccines may be limited due to immune escape mechanisms like loss or mutation of target antigens. Here, we analyzed 10 HLA-A2 positive patients with acute myeloid leukemia (AML) for loss or mutations of the WT1 epitope or epitope flanking sequences that may abolish proper T cell recognition or epitope presentation.Methods: All patients had been enrolled in a WT1 peptide phase II vaccination trial (NCT00153582) and ultimately progressed despite induction of a WT1 specific T cell response. Blood and bone marrow samples prior to vaccination and during progression were analyzed for mRNA expression level of WT1. Base exchanges within the epitope sequence or flanking regions (10 amino acids N- and C-terminal of the epitope) were assessed with melting point analysis and sequencing. HLA class I expression and WT1 protein expression was analyzed by flow cytometry.Results: Only in one patient, downregulation of WT1 mRNA by 1 log and loss of WT1 detection on protein level at time of disease progression was observed. No mutation leading to a base exchange within the epitope sequence or epitope flanking sequences could be detected in any patient. Further, no loss of HLA class I expression on leukemic blasts was observed.Conclusion: Defects in antigen presentation caused by loss or mutation of WT1 or downregulation of HLA molecules are not the major basis for escape from the immune response induced by WT1 peptide vaccination. © 2010 Busse et al; licensee BioMed Central Ltd.


Busse A.,Charite CBF | Rapion J.,European Organisation for Research | Fusi A.,Charite CBF | Suciu S.,European Organisation for Research | And 10 more authors.
Cancer Immunology, Immunotherapy | Year: 2013

We analysed mRNA levels of interferon response genes (ISG15, STAT1, CXCL10) of inhibitors of the JAK/STAT pathway (STAT3, SOCS1, SOCS3) and of cytokines (TNFα, IL10, TGFß1) in peripheral blood of 91 stage III melanoma patients enrolled in EORTC 18991 trial to find biomarkers indicative for disease stage and predictive for efficacy of pegylated interferon alpha-2b (PEG-IFNα-2b) therapy. mRNA levels were analysed at baseline and after 6 months. Univariate and multivariate analyses were performed to estimate the prognostic and predictive role of mRNA levels for distant metastasis-free survival (DMFS) and relapse-free survival (RFS). Compared to healthy controls, melanoma patients showed significantly higher TGFβ1 mRNA levels. In a multivariate model, increasing SOCS1 and SOCS3 mRNA levels were associated with worse RFS (P = 0.02 and P = 0.04, respectively) and DMFS (P = 0.05 and P = 0.05, respectively) due to negative correlation between, respectively, SOCS1/SOCS3 mRNA levels and ulceration or Breslow thickness. No impact of PEG-IFNα-2b on mRNA levels was observed except for ISG15 mRNA levels, which decreased in the treatment arm (P = 0.001). It seems that patients with a decrease >60 % of ISG15 mRNA levels during 6 months PEG-IFNα-2b had inferior outcome. © 2013 Springer-Verlag Berlin Heidelberg.


Haibel H.,Charite CBF | Sieper J.,Charite CBF
Clinical and Experimental Rheumatology | Year: 2010

The disease modifying antirheumatic drug (DMARD) methotrexate (MTX) is widely used and well accepted for the treatment of patients with rheumatoid arthritis (RA). In ankylosing spondylitis (AS), the use of MTX is not recommended for the axial manifestations and may have some efficacy in the peripheral involvement. For this disease there is a lack of clinical trials, and most of the trials did not show efficacy on the axial symptoms of the disease. Furthermore, there is no evidence that MTX increases the effects or prevents the side effects of TNF-blockers if given in combination. In this paper the available data of MTX in AS will be discussed. © Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2010.


Brettschneider F.,Charite CBF | Jankowski V.,Charite CBF | Gunthner T.,Charite CBF | Salem S.,Charite CBF | And 4 more authors.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2010

Acetonitrile, which is a by-product of acrylonitrile synthesis, is the commonly used solvent in ion-pair reversed phase chromatography. In consequence of the decreasing demand for acrylonitrile due to the financial crisis, a worldwide shortage of acetonitrile is observed. Therefore, the aim of this study was to establish ion-pair reversed phase chromatographic assays using alternative eluents for acetonitrile and to decrease costs incurred hereby. We compared the performance of ion-pair reversed phase chromatography using acetonitrile with the alternative eluents methanol, ethanol and n-propanol, using monolithic reversed phase C5 as well as C18 chromatography columns. We used triethylammonium acetate (TEAA) and tetrabutylammonium sulfate (TBA) as representative cationic ion-pair reagents and trifluoroacetic acid (TFA) as representative anionic ion-pair reagent. For covering a large field of applications, we fractionated representative low, middle and high-molecular weight biomolecules, in particular dinucleoside polyphosphates, peptides, proteins and tryptic digested human serum albumin. Whereas the chromatographic characteristics of both methanol and n-propanol were partly insufficient, ethanol was characterised equally or partly even better in the matter of elution strength and separation quality compared to the eluent water-acetonitrile. In conclusion, ethanol is an appropriate alternative for acetonitrile in ion-pair reversed phase chromatography of biomolecules. © 2010.


PubMed | Charite CBF
Type: Journal Article | Journal: Clinical and experimental rheumatology | Year: 2010

The disease modifying antirheumatic drug (DMARD) methotrexate (MTX) is widely used and well accepted for the treatment of patients with rheumatoid arthritis (RA). In ankylosing spondylitis (AS), the use of MTX is not recommended for the axial manifestations and may have some efficacy in the peripheral involvement. For this disease there is a lack of clinical trials, and most of the trials did not show efficacy on the axial symptoms of the disease. Furthermore, there is no evidence that MTX increases the effects or prevents the side effects of TNF-blockers if given in combination. In this paper the available data of MTX in AS will be discussed.


PubMed | Charite CBF
Type: Journal Article | Journal: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences | Year: 2010

Acetonitrile, which is a by-product of acrylonitrile synthesis, is the commonly used solvent in ion-pair reversed phase chromatography. In consequence of the decreasing demand for acrylonitrile due to the financial crisis, a worldwide shortage of acetonitrile is observed. Therefore, the aim of this study was to establish ion-pair reversed phase chromatographic assays using alternative eluents for acetonitrile and to decrease costs incurred hereby. We compared the performance of ion-pair reversed phase chromatography using acetonitrile with the alternative eluents methanol, ethanol and n-propanol, using monolithic reversed phase C5 as well as C18 chromatography columns. We used triethylammonium acetate (TEAA) and tetrabutylammonium sulfate (TBA) as representative cationic ion-pair reagents and trifluoroacetic acid (TFA) as representative anionic ion-pair reagent. For covering a large field of applications, we fractionated representative low, middle and high-molecular weight biomolecules, in particular dinucleoside polyphosphates, peptides, proteins and tryptic digested human serum albumin. Whereas the chromatographic characteristics of both methanol and n-propanol were partly insufficient, ethanol was characterised equally or partly even better in the matter of elution strength and separation quality compared to the eluent water-acetonitrile. In conclusion, ethanol is an appropriate alternative for acetonitrile in ion-pair reversed phase chromatography of biomolecules.


PubMed | Charite CBF
Type: Journal Article | Journal: Aging clinical and experimental research | Year: 2015

Cardiac rehabilitation (CR) seeks to simultaneously improve several outcome parameters related to patient risk factors, exercise capacity and subjective health. A single score, the multiple outcome criterion (MOC), comprised of alterations in 13 outcome variables was used to measure the overall success of CR in an older population. As this success depends on the older patients characteristics at the time of admission to CR, we attempted to determine the most important influences.The impact of baseline characteristics on the success of CR, measured by MOC, was analysed using a mixed model for 1,220 older patients (70.9 7.0 years, 78.3 % men) who enrolled in 12 CR clinics. A multitude of potentially influential baseline patient characteristics was considered including sociodemographic variables, comorbidity, duration of hospital stay, exercise capacity, cardiovascular risk factors, emotional status, and laboratory and echocardiographic data.Overall, CR was successful, as indicated by the mean value of the MOC (0.6 0.45; min -1.0, max 2.0; positive values denoting improvement, negative ones deterioration). Examples of association with negative MOC values included smoking (MOC -0.15, p < 0.001), female gender (MOC -0.07, p = 0.049), and a longer hospital stay (MOC -0.03, p = 0.03). An example of association with positive MOC value was depression score (MOC 0.06, p = 0.003). Further associations included maximal exercise capacity, blood pressure, heart rate and the rehabilitation centre attended.Our results emphasize the necessity to take into consideration baseline characteristics when evaluating the success of CR and setting treatment targets for older patients.

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