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Biomedical subjects

C Schindler

Publications and source records attributed to C Schindler.

At least 55 records · Page 3Linked to original sources
PubMed2000

Occupational exposure to inhalative irritants and methacholine responsiveness.

OBJECTIVES: Occupational exposures to inhalative irritants have been associated with an increased reporting of respiratory symptoms in previous studies. Methacholine responsiveness represents a continuous measure of airway responsiveness. As such, it may be less subject to recall bias and more sensitive to detecting effects of occupational exposure on airways. Such effects may be stronger among atopic persons. The objective of the study was to examine the relationship between self-reports of occupational exposure to dusts, gases, vapors, aerosols, and fumes and methacholine responsiveness. METHODS: A sample was studied of never smokers (N=3044) chosen randomly from 8 areas in Switzerland. Atopy was defined as any positive skin test to 8 inhalative allergens. Nonspecific bronchial reactivity was tested using methacholine chloride and quantified by calculating the slope of the dose-response. RESULTS: The methacholine slopes were 19% [95% confidence interval (95% CI) 6-32] higher for never smokers with exposure to dusts, fumes, vapors, gases, or aerosols than for the unexposed group. When only atopic never smokers were examined. the increase was larger (37%, 95% CI 7-75), and for persons with >2 positive skin prick tests the effect was still higher (42%, 95% CI -1.5-104). Exposure to vapors and aerosols was strongly associated with increased methacholine slopes among the atopic subjects. CONCLUSIONS: Occupational exposure, particularly to dusts and fumes, was associated with increased bronchial reactivity in never smokers in this study. The magnitude of the effect was larger among atopic subjects.

Adolescent↗
PubMed2000

Epigenetic regulation of gene expression in cervical cancer cells by the tumor microenvironment.

Evidence is accumulating that the adverse tumor microenvironment both modifies the malignant progression of tumor cells and contributes to chemotherapy and radiation resistance. We hypothesized that some of the effects on malignant progression are mediated through the transcriptional regulation of genes responsive to the stresses of the microenvironment, such as low oxygen or low glucose conditions. To determine epigenetic changes in gene expression that were consistent with that hypothesis, we used an in vitro subtractive hybridization method, representational difference analysis, to identify hypoxia-induced cDNAs from cultured human cervical epithelial cells. We identified 12 induced genes: two novel genes (HIG1 and HIG2), three genes known to be hypoxia-inducible (tissue factor, GAPDH, thioredoxin), and seven genes not previously identified as hypoxia-inducible [HNRNP(a1), ribosomal L7, annexin V, lipocortin 2, Ku(70), PRPP synthase, and acetoacetyl-CoA thiolase]. In cultured cells, HIG1 and HIG2 expression is induced by hypoxia and by glucose deprivation, but their expression is not induced by serum deprivation, UV, or ionizing radiation. The putative HIG1 and HIG2 open reading frames are expressed in cells, as confirmed by epitope tagging. In addition, tumor xenografts derived from human cervical cancer cells display increased expression of HIG1 and HIG2 when they are deprived of oxygen. Taken together, these data suggest a coordinated transcriptional response of eukaryotic cells to microenvironmental stresses found in the solid tumor.

Amino Acid Sequence↗
PubMed1999

Cytokines and JAK-STAT signaling.

Characterization of the ability of IFNs to induce immediate early genes led to the identification of the STAT (signal transducers and activators of transcription) signaling paradigm. STATs are activated at the receptor and then directly transduce signals to the nucleus. Subsequent studies have determined that all cytokines transduce critical signals through this pathway.

Cytokines↗
PubMed1999

Murine Stat2 is uncharacteristically divergent.

Characterization of the ability of human interferons (IFNs) to rapidly induce genes led to the identification of the first two members of the STAT (signal transducers and activators of transcription) family, Stat1 and Stat2. To study the unique role of this transcription factor in IFN signaling under more physiological conditions, murine Stat2 was isolated and found to be surprisingly divergent. This divergence was most striking in the C-terminal transcriptional activation domain. Studies on murine Stat2 indicate that it functions in IFN signaling. This includes IFN-alpha-dependent activation, nuclear translocation, DNA binding and activation of reporter genes. However, the profound divergence at the C-terminus suggests that murine Stat2 may have evolved to mediate some unique functions as well. To explore this possibility, proteins that interact with the C-termini of murine and human Stat2 were examined. These studies indicate that the murine and human C-termini interact with an overlapping, but distinct set of proteins.

Amino Acid Motifs↗
PubMed1999

Characterization of the Stat5 protease.

Immature myeloid cells have been shown to transduce signals through a carboxyl-terminally truncated isoform of Stat5. This functionally distinct signal transducer and activator of transcription isoform is generated through a unique protein-processing event. Evaluation of numerous cell lines has determined that there is a direct correlation between the expression of truncated Stat5 and protease activity. Moreover, protease activity is found only in the myeloid and not in lymphoid progenitors. To further characterize the protease small quantities have been purified to near homogeneity. Studies on this purified material indicate that the protease has an apparent molecular mass of approximately 25 kDa and is active over a wide range of pH values. The protease will also cleave both activated (i.e. tyrosine-phosphorylated) and inactivate Stat5. Although this activity is sensitive to phenylmethylsulfonyl fluoride, it is notably not sensitive to several other serine protease inhibitors. Additional studies have led to the identification of the unique site where the protease cleaves Stat5. Mutagenesis of this site renders Stat5 resistant to cleavage. Consistent with the model that Stat5 cleavage is important for early myeloid development, introduction of a "non-cleavable" isoform of Stat5 into FDC-P1 cells (a myeloid progenitor line) leads to significant phenotypic changes.

3T3 Cells↗
PubMed1999

Interferons as a paradigm for cytokine signal transduction.

Characterization of the ability of interferons to induce immediate early genes led to the identification of the signal transducer and activators of transcription (STAT) signaling paradigm, where a single protein transduces signals directly from the receptor to the nucleus. Subsequent studies have determined that all cytokines transduce pivotal signals through at least one of the seven members of this STAT family. Notably, cytokines can be placed in functional subgroups based on the STATs they activate.

Animals↗
PubMed1999

Role of current and childhood exposure to cat and atopic sensitization. European Community Respiratory Health Survey.

BACKGROUND: Clinical and population studies have shown that exposure and sensitization to allergens derived from furred pets, particularly cats, represent an important risk factor of allergic respiratory disease and also a significant risk factor for asthma. OBJECTIVE: In the framework of the multicenter European Community Respiratory Health Survey an analysis of the association of current and childhood exposure to cat with atopic sensitization to cat was conducted. METHODS: This study included cross-sectional data from 35 centers representing 16 countries. Altogether, 18,097 subjects were included, of whom 13,509 (75%) provided a blood sample for the measurement of specific IgE. Exposure data and data for potential confounders were extracted from an interviewer-led questionnaire. RESULTS: The prevalence of sensitization to cat (serum specific IgE >0.35 kU/L) was 9%. Among those who did not report allergic symptoms in the presence of pets or house dust, those who owned cats were significantly more likely to be sensitized to cats than were those who did not (odds ratio [95% confidence interval] 1.57 [1.20-2.06]. Childhood exposure to pets including cats was associated with lower sensitization to cats in adulthood, particularly among those with a positive family history of atopy (odds ratio [95% confidence interval] 0.68 [0.51-0.93]. Positive correlations were found between the community prevalence of cat and the prevalences of sensitization to cat, respiratory symptoms, physician-diagnosed asthma, and current asthma medication. CONCLUSIONS: Current cat ownership represents a significant risk for sensitization to cat if cats are allowed indoors. Our results support the hypothesis that childhood exposure to pets, including cats, might modulate immunologic mechanisms and reduce sensitization to cat in adulthood. The significant correlation found between the community prevalence of cat ownership and community prevalence of specific sensitization to cat represents the first documentation of such a relationship.

Adult↗
PubMed1999

Long-term ambient air pollution and respiratory symptoms in adults (SAPALDIA study). The SAPALDIA Team.

The association between long-term exposure to ambient air pollution and respiratory symptoms was investigated in a cross-sectional study in random population samples of adults (aged 18 to 60 yr, n = 9,651) at eight study sites in Switzerland. Information on respiratory symptoms was obtained with an extended version of the European Community Respiratory Health Survey questionnaire. The impact of annual mean concentrations of air pollutants was analyzed separately for never-, former, and current smokers. After controlling for age, body mass index, gender, parental asthma, parental atopy, low education, and foreign citizenship, we found positive associations between annual mean concentrations of NO2, total suspended particulates, and particulates of less than 10 micrometers in aerodynamic diameter (PM10) and reported prevalences of chronic phlegm production, chronic cough or phlegm production, breathlessness at rest during the day, breathlessness during the day or at night, and dyspnea on exertion. We found no associations with wheezing without cold, current asthma, chest tightness, or chronic cough. Among never-smokers, the odds ratio (95% confidence interval) for a 10 micrograms/ m3 increase in the annual mean concentration of PM10 was 1. 35 (1.11 to 1.65) for chronic phlegm production, 1.27 (1.08 to 1.50) for chronic cough or phlegm production, 1.48 (1.23 to 1.78) for breathlessness during the day, 1.33 (1.14 to 1.55) for breathlessness during the day or at night, and 1.32 (1.18 to 1.46) for dyspnea on exertion. No associations were found with annual mean concentrations of O3. Similar associations were also found for former and current smokers, except for chronic phlegm production. The observed associations remained stable when further control was applied for environmental tobacco smoke exposure, past and current occupational exposures, atopy, and early childhood respiratory infections when restricting the analysis to long-term residents and to non- alpine areas, and when excluding subjects with physician-diagnosed asthma. The high correlation between the pollutants makes it difficult to sort out the effect of one single pollutant. This study provides further evidence that long-term exposure to air pollution of rather low levels is associated with higher prevalences of respiratory symptoms in adults.

Adolescent↗
PubMed1999

Peak flow variability in the SAPALDIA study and its validity in screening for asthma-related conditions. The SPALDIA Team.

We used 3-wk peak expiratory flow (PEF) measurements (twice daily) made in the diary study of the population-based Swiss Study on Air Pollution and Lung Disease in Adults to describe PEF-variability (PEF(var)) (amplitude as a percent of the mean, PEF [i.e., difference between morning and evening values divided by the mean]) in the study population and in five subgroups (physician-diagnosed asthma; current asthma, or physician-diagnosed asthma plus asthma attacks and/or medication; history of wheezing without a cold; hyperreactive; and nonsymptomatic). We assessed the performance of PEF(var) as a potential tool with which to screen for asthma. Alternatively, subjects with a PEF(var) of >/= 20%, >/= 30%, and >/= 50% on at least 2 d were considered to have high variability. The analyses were conducted for subgroups with different pretest probabilities for asthma-related conditions. The median PEF(var) was 4.5%. Among asthmatic subjects, women had nonsignificantly higher PEF(var) values than did men. In all other groups, women had significantly lower PEF(var). Both in the entire population and in subgroups with a higher pretest probability for asthma-related conditions, screening performance of PEF was limited. A PEF(var) of >/= 20% on at least 2 d detected current asthma with a sensitivity of 36% (specificity = 90%; positive predictive value = 16.4%). Results were better among subjects with a history of wheezing without colds (sensitivity = 40.4%; specificity = 83.6%; positive predictive value = 45.2%). PEF(var), a useful measure both clinically and in epidemiology, is of limited value when unselected populations are screened for asthma-related conditions, since the overlap of PEF(var) distributions across subgroups is large.

Adolescent↗
PubMed1999

Activation of the transcription factor ISGF3 by interferon-gamma.

The interferon-stimulated gene factor 3 (ISGF3) transcription factor has been extensively studied in the context of the type I interferon (IFN-alpha/beta)-mediated antiviral response; it consists of the major DNA-binding component p48, and the signal transducers and activators of transcription (Stat)1 and Stat2. We show here that type II IFN (IFN-gamma) can also invoke the activation of ISGF3 in mouse primary embryonic fibroblasts. In fact, the two Stat proteins were tyrosine phosphorylated in IFN-gamma stimulated cells. Our present findings reveal an additional mechanism by which these two distinct types of cytokines, IFN-alpha/beta and -gamma, can commonly elicit antiviral activities.

Animals↗
PubMed1998

Amino-terminal signal transducer and activator of transcription (STAT) domains regulate nuclear translocation and STAT deactivation.

The first approximately 100 amino acids of the STAT (signal transducer and activator of transcription) family of transcription factors share a high degree of sequence similarity. To determine whether they encode a functionally conserved domain, amino-terminal chimeric STATs were created. These chimeric STATs share a number of properties with wild-type Stat1, including a predominately cytoplasmic pattern of expression in unstimulated cells. Upon stimulation with ligand, the chimeric STATs rapidly become tyrosine-phosphorylated, dimerize, and are able to bind DNA. They are also able to heterodimerize with coexpressed wild-type Stat1. Yet in contrast to wild-type Stat1, the chimeric STATs exhibit a marked defect in deactivation. Moreover, the persistence of active chimeras correlates directly with an inability to translocate to the nucleus. The defects both in nuclear translocation and in deactivation are rescued by heterodimerization with coexpressed wild-type Stat1. This study indicates that STAT amino termini provide a signal that is important for nuclear translocation and, subsequently, deactivation. It also suggests that deactivation may depend on a prior nuclear localization event.

Amino Acid Sequence↗
PubMed1998

Use of transition probabilities to estimate the effect of smoking on the duration of episodes of respiratory symptoms in diary data: the Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA).

Incompletely documented symptom episodes pose methodological problems in the analysis of diary data. The aim of this study was to develop a method of estimating the average durations of symptomatic and nonsymptomatic episodes, respectively, coping with the problem of bias due to undocumented days and censored episodes that is found in most diary studies. The authors derived their outcome variables from a Markov model using transition probabilities. To evaluate this method, the authors assessed the impact of active smoking on the duration of episodes of bronchitis symptoms and the corresponding nonsymptomatic periods, respectively, using diary data (1992-1993) obtained from 801 participants in the Swiss Study on Air Pollution and Lung Diseases in Adults. Covariate-adjusted distribution curves for the mean durations of individual episodes were estimated by Cox regression. Median values for light smokers (<10 cigarettes/day) were 60.0 symptom-free days (95% confidence interval (CI) 42.0-78.5) and 4.0 symptomatic days (95% CI 3.0-6.0), respectively, compared with medians of only 21.0 days (95% CI 16.2-29.8) for periods without bronchitis symptoms and 6.0 days (95% CI 4.9-9.0) for episodes of bronchitis symptoms in heavy smokers (> or =30 cigarettes/day). The authors suggest that the Markov method is a feasible approach to the assessment of long term effects of smoking and environmental risk factors on the average duration of symptomatic and nonsymptomatic respiratory episodes.

Adult↗
PubMed1998

Personal exposure to nitrogen dioxide in Switzerland. SAPALDIA team. Swiss Study on Air Pollution and Lung Diseases in Adults.

Home indoor and outdoor levels, and personal exposures to NO2 were determined for more than 500 subjects in a subpopulation of SAPALDIA by using passive samplers. The overall personal NO2 average was found to be 27 micrograms m-3, the overall indoor average 21 micrograms m-3 and the overall outdoor average 31 micrograms m-3. Personal NO2 levels ranged between the outdoor and indoor levels, with the exception of study areas with low NO2 concentrations. In the winter, the indoor/outdoor ratios were lower than in the summer. Outdoor NO2 levels were higher in winter. In some study areas, indoor NO2 levels were lower in the winter than in the summer due to reduced ventilation but this was not consistent. Personal NO2 concentrations were very similar during all seasons. Gas-cooking and smoking were important factors for elevated indoor and personal NO2 levels (contribution: 5 micrograms m-3, 2 micrograms m-3, respectively). Personal exposure to NO2 correlated best with the indoor NO2 concentrations.

Adult↗
PubMed1998

A PCR fingerprinting technique to distinguish isolates of Lactococcus lactis.

A fingerprinting technique similar to repetitive extragenic palindromic PCR was developed to identify strains of Lactococcus lactis. The method distinguishes closely related strains and discriminates among some with identical ldh sequences. The fingerprinting primer LL-Rep1 complements a moderately repeated sequence found in low G + C Gram-positive bacteria and may therefore prove useful for discriminating among strains of other low G + C Gram-positive species.

Base Composition↗
PubMed1998

[Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA)].

Long-term health effects of moderate ambient air pollution are rarely investigated. In Switzerland, no large-scale study has addressed this issue so far. Important results of the Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA) are presented. During the period 1991-1993, SAPALDIA investigated a random population sample (18-60 years) in eight Swiss areas with different environmental characteristics (Aarau, Basel, Davos, Geneva, Lugano, Montana, Payerne, Wald). In total, 9651 adults (60%) participated in the cross-sectional investigation (part 1, 1991), consisting of the following standardized procedures: questionnaire (interview), forced expiratory lung function test, bronchial challenge with methacholine, atopy assessment (Phadiatop, unspecific total IgE), allergy skin tests, and endexpiratory CO-measurements. Subjects with a history of respiratory symptoms, increased bronchial reactivity, reduced lung function (FEV1/FVC < 80% predicted) and 150 healthy never-smokers were included in the subsequent diary study (part 2; n = 3281, 1992/93). Peak flow (morning and evening), symptoms, medication, personal activity and visits to the doctor were monitored. Across regions, annual mean values ranged from 9 to 52 mg/m3 (NO2) and 10 to 33 mg/m3 (PM10) respectively. Air pollution had effects on prevalence of dyspnea (+41% per 10 mg/m3 increment of the annual mean PM10, 95% CI 20-65%), on symptoms of chronic bronchitis (+31%, 10-55%), on FVC (-3.1%; -3.7 to -2.6%), and FEV1 (-1.1%; -1.7% to -0.5%), on the incidence of respiratory symptoms and the length of symptomfree intervals (11% change per 10 mg/m3 PM10), but not on the prevalence of asthma. Environmental tobacco smoke (ETS) showed impact on wheezing (OR 1.94; 1.39-2.70), asthma (1.39; 1.04-1.86), bronchitis (1.60; 1.24-2.08) and chronic bronchitis (1.50; 1.11-2.02). Health effects of moderate air pollution were confirmed in Switzerland. Although for the individual the relative risks are small, the public health impact may be considerable. An ongoing follow-up will investigate the mortality profile of the SAPALDIA cohort.

Adolescent↗
PubMed1998

Portosystemic hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with cirrhosis: clinical, laboratory, psychometric, and electroencephalographic investigations.

A prospective study of hepatic encephalopathy (HE) including neuropsychiatric and psychometric evaluation, electroencephalography, and determination of arterial ammonia levels was performed in 55 cirrhotic patients treated consecutively by transjugular intrahepatic portosystemic shunt (TIPS). The cumulative HE rate increased from 23.6% within the 3-month interval before TIPS to 50. 9% within the first 3-month interval post-TIPS (P = .003). Significant and independent predictors of HE post-TIPS were the presence of HE pre-TIPS and reduced liver function. The cumulative HE rate declined in the second 3-month interval post-TIPS and reached the pre-TIPS level. Chronic forms of HE exceeding grade I were not observed. In a subgroup of 22 nonencephalopathic TIPS patients, the prevalence of subclinical HE did not change after TIPS. Among individual psychometric tests, the block design test gave the highest proportion of pathological results (about 50%), whereas selective reminding gave the lowest (10%-25%). Electroencephalography (EEG) showed a temporary increase of pathological results at 1 month after TIPS, when patients with overt HE (grade I) were included (proportion of 21.1% before vs. 57.1%, P = .005). Arterial ammonia concentration increased from a mean of 94 +/- 26 microgram/dL to 140 +/- 28 microgram/dL at 3 months after TIPS (P < .001). Elevated ammonia levels persisted. TIPS led to a temporary increase of HE incidence within 3 months. The decline of the HE rate beyond 3 months despite a sustained increase of arterial ammonia levels could not entirely be explained by reduction of shunt flow, nor by alteration of liver function. Instead, cerebral adaptation to gut-derived neurotoxins might be anticipated.

Adolescent↗