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Christian Schindler

Publications and source records attributed to Christian Schindler.

11 recordsLinked to original sources
PubMed2003

STATs dimerize in the absence of phosphorylation.

Upon activation by tyrosine kinases, members of the STAT family of transcription factors form stable dimers that are able to rapidly translocate to the nucleus and bind DNA. Although crystal structures of activated, near full-length, Stat1 and Stat3 illustrate how STATs bind to DNA, they provide little insight into the dynamic regulation of STAT activity. To explore the unique structural changes Stat1 and Stat3 undergo when they become activated, full-length inactive recombinant proteins were prepared. To our surprise, even though these proteins are unable to bind DNA, our studies demonstrate that they exist as stable homodimers. Similarly, the Stat1 and Stat3 found in the cytoplasm of unstimulated cells also exhibit a dimeric structure. These observations indicate that Stat1 and Stat3 exist as stable homodimers prior to activation.

3T3 Cells↗
PubMed2003

Cost-effectiveness of intracoronary ultrasound for percutaneous coronary interventions.

The Strategy for Intravascular Ultrasound (IVUS) guided PTCA and Stenting trial included a prospectively designed economic analysis to investigate whether routine IVUS guidance intervention is cost-effective. Consecutive patients (n = 269) with 356 lesions were randomly assigned to receive provisional stenting with angiographic guidance only (ANGIO) or with IVUS guidance. The 2-year major adverse cardiac event-free survival (effectiveness) was significantly higher in the IVUS-guided group (80% vs 69%, p <0.04). In-hospital costs for procedural personnel, capital equipment, and disposable equipment were higher in the IVUS group. This was offset by lower costs for inpatient care and urgent target vessel revascularization in the IVUS group. Therefore, the total in-hospital cost was only slightly higher with IVUS (5,245 +/- $2,256 [IVUS] vs 4,776 +/- $2,961 [ANGIO], $/patient, p = 0.15). During a 2-year follow-up, costs for cardiac hospitalizations were slightly lower in the IVUS group, whereas costs for medication and indirect costs were similar. This resulted in identical total costs over the 2-year period (15,947 +/- $8,545 [IVUS] vs 16,103 +/- $9,954 [ANGIO], $/patient, p = 0.89). The incremental cost-effectiveness ratio for IVUS guidance calculated to -$1,417/major adverse cardiac event-free survival gained. In 55.3% of bootstrapping replications, IVUS was less expensive and more effective. In conclusion, when used in a provisional stenting strategy, routine IVUS imaging is cost-saving half the time.

Angioplasty, Balloon, Coronary↗
PubMed2003

Single pollutant versus surrogate measure approaches: do single pollutant risk assessments underestimate the impact of air pollution on lung cancer risk?

Cancer risk as a result of air pollution may be quantified by different approaches. We compared the sum of unit risk based effects of single pollutants with an epidemiology-based method by using PM(10) as a surrogate of the total air pollution. The excess rate for lung cancer cases attributable to an increase of 10 microg/m3 in average PM(10) exposure was estimated from available cohort studies. Applying the epidemiology-based risk method to the air pollution situation in the Basel area (Switzerland) resulted in 13.3 (95% CI = 6.9-19.8) excess lung cancer cases per 100,000 person years. This estimate was considerably higher than the unit risk-based estimate yielding 1.1 (range, 0.45-2.8) cancer cases per 100,000 person years. We discuss these discrepancies in light of inherent differences between approaches in toxicology and epidemiology.

Air Pollutants↗
PubMed2003

Regulation of Stat3 nuclear export.

Stat3 is the most pleiotropic member of the signal transducer and activator of transcription (STAT) family of transcription factors and mediates pivotal responses for the cytokine family. In resting cells, STATs, including Stat3, reside largely in the cytoplasm. Upon cytokine stimulation, they rapidly translocate to the nucleus, where they promote the expression of target genes. During the subsequent period of signal decay they are re-exported back to the cytoplasm in preparation for the next round of signaling. This process of nuclear export can be blocked by the fungal toxin leptomycin B (LMB). In contrast to what appears to be the case for Stat1, LMB treatment not only blocks the poststimulation export of Stat3 from the nucleus back to the cytoplasm, but also promotes the nuclear accumulation of Stat3 in resting cells. Remarkably, the LMB-dependent nuclear accumulation of Stat3 in resting cells is independent of tyrosine phosphorylation, highlighting the existence of a "basal" signaling pathway. Subsequent studies identified three nuclear export signal (NES) elements. Two of these elements, Stat3(306-318) and Stat3(404-414), corresponded to those recently identified in Stat1, and a third, Stat3(524-535), is novel. Stat3(306-318) appears to be important in the rapid nuclear export seen after stimulation (poststimulation export), whereas the Stat3(404-414) and Stat3(524-535) play a more important role in regulating basal nuclear export. In summary, these studies indicate that the process of Stat3 nuclear export is dependent on multiple NES elements.

Active Transport, Cell Nucleus↗
PubMed2003

Dysregulated Sonic hedgehog signaling and medulloblastoma consequent to IFN-alpha-stimulated STAT2-independent production of IFN-gamma in the brain.

The type I IFNs (IFN-alpha and IFN-beta), which are crucial in antiviral defense and immune regulation, signal via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway with activation of STAT1 and STAT2. Here, the function of STAT2 was studied in transgenic mice (termed GIFN/STAT2-/-) with CNS production of IFN-alpha. Surprisingly, GIFN/STAT2-/-, but not GIFN/STAT1-null, transgenic mice, with CNS production of IFN-alpha, died prematurely with medulloblastoma. An immune response also induced in the brain of the GIFN/STAT2-/- mice was associated with IFN-gamma gene expression by CD3+ T cells and the activation of the STAT1, STAT3, STAT4, and STAT5 molecules. Expression of the Sonic hedgehog (Shh) and the downstream transcriptional factor Gli-1 genes, implicated in the pathogenesis of medulloblastoma, was found to be significantly increased and cotranscribed in cerebellar granule neurons of the GIFN/STAT2-/- mice. IFN-gamma, but not IFN-alpha, induced STAT1-dependent expression of the Shh gene in cultured cerebellar granule neurons. Thus, there is an unexpected and extraordinarily adverse biological potency of IFN-alpha in the CNS when the primary signal transduction molecule STAT2 is absent. Moreover, a hitherto unknown role is indicated for the immune system in the pathogenesis of developmental disorders and tumorigenesis of the CNS via dysregulated Shh signaling mediated by IFN-gamma.

Animals↗
PubMed2002

N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials.

PURPOSE: Observational studies have shown an inconsistent association between n-3 polyunsaturated fatty acids and the risk of coronary heart disease. We investigated the effects of dietary and non-dietary (supplemental) intake of n-3 polyunsaturated fatty acids on coronary heart disease. SUBJECTS AND METHODS: We searched the literature to identify randomized controlled trials that compared dietary or non-dietary intake of n-3 polyunsaturated fatty acids with a control diet or placebo in patients with coronary heart disease. Studies had to have at least 6 months of follow-up data, and to have reported clinical endpoint data. We identified 11 trials, published between 1966 and 1999, which included 7951 patients in the intervention and 7855 patients in the control groups. RESULTS: The risk ratio of nonfatal myocardial infarction in patients who were on n-3 polyunsaturated fatty acid-enriched diets compared with control diets or placebo was 0.8 (95% confidence interval [CI]: 0.5 to 1.2, P = 0.16; Breslow-Day test for heterogeneity, P = 0.01), and the risk ratio of fatal myocardial infarction was 0.7 (95% CI: 0.6 to 0.8, P <0.001; heterogeneity P >0.20). In 5 trials, sudden death was associated with a risk ratio of 0.7 (95% CI: 0.6 to 0.9, P <0.01; heterogeneity P >0.20), whereas the risk ratio of overall mortality was 0.8 (95% CI: 0.7 to 0.9, P <0.001; heterogeneity P >0.20). There was no difference in summary estimates between dietary and non-dietary interventions of n-3 polyunsaturated fatty acids for all endpoints. CONCLUSION: This meta-analysis suggests that dietary and non-dietary intake of n-3 polyunsaturated fatty acids reduces overall mortality, mortality due to myocardial infarction, and sudden death in patients with coronary heart disease.

Aged↗
PubMed2002

Estimating phosphate removal in haemodialysis: an additional tool to quantify dialysis dose.

BACKGROUND: Half of the dialysis population suffers from hyperphosphataemia, which is now recognized as a major factor of haemodialysis (HD) morbidity and mortality. Current control is focussed on reducing dietary phosphate intake and diminishing absorption using phosphate binders, whereas control and quantification of phosphate removal by HD is undervalued. The aim of this prospective study was to develop a simple, bedside formula to estimate dialytic phosphate removal in stable HD patients. METHODS: This was a prospective, randomized trial. Phosphate and urea elimination were assessed in a representative group of patients at two dialysis centres using randomly different dialysers (1.3-2.4 m(2)). Quantification was performed by partial dialysate collection, concentration measurements in blood and effluent dialysate spot samples, and Kt/V(urea) during standard high-flux HD. Multiple linear regression analyses were used in 77% of all data sets to generate an equation to predict phosphate removal. The formula was validated in the remaining 23% of data sets, in the same group of patients using a large capillary filter, and in diabetic patients treated with a small dialyser at different blood flows (200, 250, and 300 ml/min). RESULTS: A formula allowing quantification of phosphate removal within one HD session was developed in 18 of 74 patients during 41 treatments (137 out of 177 data sets) and was determined as: M(PO4pred)=0.1t -17+50c(ds60)+11c(b60), where t is treatment time in min, c(ds60) and c(b60) are phosphate concentrations in dialysate and plasma measured 60 min into HD in mmol/l, and M(PO4pred) is estimated phosphate removed in mmol. The precision was remarkable (r(2)=0.92-0.94). The comparison of phosphate and Kt/V(urea) showed a significant association (r(2)=0.28), albeit with remarkable scatter. CONCLUSIONS: We present the first approach to quantify phosphate removal during high-flux HD by a bedside formula. Only 28% of the variation in phosphate removal was explained by Kt/V(urea). It appears that other factors not adequately accounted for by Kt/V(urea) affect phosphate removal. Therefore, we propose an individual control and quantification of phosphate removal in HD.

Aged↗
PubMed2002

Predictors of methacholine responsiveness in a general population.

OBJECTIVE: Methacholine responsiveness is an end point widely used in epidemiologic studies of asthma. This study aims to quantify the relative importance of different predictors of responsiveness such as age, sex, airway caliber, smoking and atopic status, and potential interactions deserving further investigation. METHODS: Methacholine challenge was performed in 7,126 participants (aged 18 to 60 years) of the Swiss Study on Air Pollution and Lung Diseases in Adults according to the European Respiratory Health Survey protocol. Responsiveness was quantified by the slope between percentage decrements in FEV(1) and cumulative methacholine dose. Variation of slopes according to sex, smoking, and atopy was then examined separately by multivariate regression models that controlled for baseline FEV(1). RESULTS: We found a nonlinear relationship between methacholine slope and baseline FEV(1) for both sexes, which could be well described by a quadratic function. The corresponding curves were almost identical in the region of overlap for male and female neversmokers. Methacholine responsiveness declined with age. The slope of this decline was less steep among nonatopic persons and nonsmokers compared with atopic neversmokers. Methacholine responsiveness increased with the number of cigarettes smoked per day and with the number of positive skin-prick test results (except among heavy smokers). CONCLUSIONS: Our multiple regression results show that bronchial responsiveness (BR) varies with age, FEV(1), and smoking and atopic status. They suggest that there is a physiologic basis for the univariate sex difference in BR. Secondly, they show that while smaller airways are more responsive than larger ones, the reduction of responsiveness diminishes with each increase of lung size. The quantification of the relative influence of the different factors examined should help in the interpretation of BR.

Adolescent↗
PubMedDate not supplied

Effect of amoxicillin-clavulanate in clinically diagnosed acute rhinosinusitis: a placebo-controlled, double-blind, randomized trial in general practice.

BACKGROUND: Acute rhinosinusitis is one of the most common reasons for prescribing antibiotics in primary care. However, it is not clear whether antibiotics improve the outcome for patients with clinically diagnosed acute rhinosinusitis. We evaluated the effect of a combination product of amoxicillin-potassium clavulanate on adults with acute rhinosinusitis that was clinically diagnosed in a general practice setting. METHODS: We conducted a randomized, placebo-controlled, double-blind trial with 252 adults recruited at 24 general practices and 2 outpatient clinics. Each patient had a history of purulent nasal discharge and maxillary or frontal pain for at least 48 hours. Patients were given amoxicillin, 875 mg, and clavulanic acid, 125 mg, or placebo twice daily for 6 days. Main outcome measures were time to cure (primary outcome), number of days during which rhinosinusitis restricted activities at home or work, and frequency of adverse effects (secondary outcomes). RESULTS: The adjusted hazard ratio for the effect of amoxicillin-clavulanate was 0.99 (95% confidence interval [CI], 0.68-1.45) on time to cure and 1.28 (95% CI, 0.80-2.05) in the prespecified subgroup of patients with a positive rhinoscopy result. At 7 days the mean difference between amoxicillin-clavulanate and placebo was -0.29 (95% CI, -0.93 to 0.34) in the number of days with restrictions due to rhinosinusitis and -0.60 (95% CI, -1.41 to 0.21) in patients with a positive rhinoscopy result. At 7 days patients who took amoxicillin-clavulanate were more likely to have diarrhea (odds ratio, 3.89; 95% CI, 2.09-7.25). CONCLUSIONS: Adult patients in general practice with clinically diagnosed acute rhinosinusitis experience no advantage with antibiotic treatment with amoxicillin-clavulanate and are more likely to experience adverse effects.

Acute Disease↗