Biomedical subjects

C Schindler

Publications and source records attributed to C Schindler.

At least 73 records · Page 4Linked to original sources

PubMed1998

Protein-DNA interactions in interferon-gamma signaling.

The ability to rapidly activate new genes is essential for the biological effects mediated by IFN-gamma. Studies directed at understanding how these genes are induced by this ligand led to the identification of the STAT family of transcription factors. STATs are rapidly activated at the receptor, whereupon they translocate to the nucleus and bind to a unique enhancer found in the promoter of target genes. The ability to identify this IFN-gamma response element and the proteins that bind it was critical for the elucidation of this pathway. These techniques are the focus of this review.

Base Sequence↗

PubMed1998

Multidrug resistance in glioblastoma. Chemosensitivity testing and immunohistochemical demonstration of P-glycoprotein.

Chemosensitivity of previously untreated glioblastomas to mitoxantrone, methotrexate, ACNU and BCNU was tested on cultured tissue. Sixteen of 62 tumors were partially chemosensitive in vitro. The monoclonal antibody C 219 was used to demonstrate the presence of p-glycoprotein in the 16 sensitive and five highly resistant glioblastomas. All 21 tumors identically expressed p-glycoprotein. These results show that untreated glioblastomas primarily express p-glycoprotein even if they are at least partially chemosensitive in vitro. Therefore, immunohistochemical demonstration of p-glycoprotein with the monoclonal antibody C 219 can not provide reliable information on short term resistance of the individual tumors to antineoplastic drugs. P-glycoprotein expression could, however, help to explain the disappointing overall long-term efficacy of chemotherapy by showing the existence of cell populations with early drug resistance in these tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

STATs as activators of apoptosis.

STATs are a family of transcription factors that are activated in a ligand-dependent manner and promote the rapid induction of genes. They achieve this by directly transducing signals from the receptor into the nucleus. Consistent with their co-evolution with the cytokine family of ligands, studies have determined that STATs play a pivotal role in mediating the biological response for this family of ligands. However, STATs appear to have a dark side as well and contribute to programmed cell death. Intriguingly, a recent study suggests that this might occur in a manner that is distinct from the standard STAT signalling paradigm.

Animals↗

PubMed1998

Trace element supplementation modulates pulmonary infection rates after major burns: a double-blind, placebo-controlled trial.

Infections remain the leading cause of death after major burns. Trace elements are involved in immunity and burn patients suffer acute trace element depletion after injury. In a previous nonrandomized study, trace element supplementation was associated with increased leukocyte counts and shortened hospital stays. This randomized, placebo-controlled trial studied clinical and immune effects of trace element supplements. Twenty patients, aged 40 +/- 16 y (mean +/- SD), burned on 48 +/- 17% of their body surfaces, were studied for 30 d after injury. They consumed either standard trace element intakes plus supplements (40.4 micromol Cu, 2.9 micromol Se, and 406 micromol Zn; group TE) or standard trace element intakes plus placebo (20 micromol Cu, 0.4 micromol Se, and 100 micromol Zn; group C) for 8 d. Demographic data were similar for both groups. Mean plasma copper and zinc concentrations were below normal until days 20 and 15, respectively (NS). Plasma selenium remained normal for group TE but decreased for group C (P < 0.05 on days 1 and 5). Total leukocyte counts tended to be higher in group TE because of higher neutrophil counts. Proliferation to mitogens was depressed compared with healthy control subjects (NS). The number of infections per patient was significantly (P < 0.05) lower in group TE (1.9 +/- 0.9) than in group C (3.1 +/- 1.1) because of fewer pulmonary infections. Early trace element supplementation appears beneficial after major burns; it was associated with a significant decrease in the number of bronchopneumonia infections and with a shorter hospital stay when data were normalized for burn size.

Adult↗

PubMed1998

Current allergic asthma and rhinitis: diagnostic efficiency of three commonly used atopic markers (IgE, skin prick tests, and Phadiatop). Results from 8329 randomized adults from the SAPALDIA Study. Swiss Study on Air Pollution and Lung Diseases in Adults.

Total serum IgE, Phadiatop, and the skin prick test (SPT) are commonly used to diagnose atopic diseases. However, no large study has ever been done to test their diagnostic efficiency. We studied the diagnostic value of these three atopic markers in 8329 well-randomized adults from the Swiss Population Registry. The prevalence of current allergic asthma (CAA) was 1.8% and of current allergic rhinitis (CAR) 16.3%. The prevalences of positive Phadiatop, positive SPT (at least, one out of eight SPT to common aeroallergens with a wheal of > or = 3 mm), and positive total IgE (IgE > or = 100 kU/l) were 29, 23, and 23%, respectively. To diagnose CAA and CAR, the sensitivity of Phadiatop was significantly higher than that of SPT (72.5% vs 65.4%, 77.1% vs 68.4% respectively; P < 0.01 and < 0.001) and IgE (72.5% vs 56.9%, 77.1% vs 43.9%, respectively; both P < 0.001). The sensitivity of SPT was significantly higher (68.4% vs 43.9% P < 0.001) than that of IgE to diagnose CAR. When CAA and CAR were excluded, the SPT specificity was significantly higher than that of Phadiatop (77.8% vs 71.9% and 85.9% vs 80.5%, respectively; both P < 0.001): when CAR was excluded, SPT was significantly higher than IgE (85.9 vs 81.4%; P < 0.001). SPT had significantly the best positive predictive value for CAA (5.2% for SPT vs 4.6% for both IgE and Phadiatop; both P < 0.001) and CAR (48.7% for SPT vs 43.5% for Phadiatop and 31.6% for IgE; both P < 0.001). The three markers of atopy had roughly the same negative predictive value (NPV) for CAA, but IgE had a significantly lower NPV for CAR than SPT and Phadiatop (88.1% vs 93.3% and 94.7%, respectively; both P < 0.001). The diagnostic efficiency of SPT was significantly higher than that of Phadiatop (83.1% vs 79.9% and 77.6 vs 71.9%, respectively; both P < 0.001) to diagnose CAR and CAA. IgE and SPT had equal efficiency (77.6%), which was significantly higher than that of Phadiatop, to diagnose CAA (71.9%; both P < 0.001). In conclusion, SPT have the best positive predictive value and the best efficiency to diagnose respiratory atopic diseases. Furthermore, SPT give information on sensitivity to individual allergens and should therefore be used primarily by clinicians to assess respiratory allergic diseases. Moreover, they are cheaper and provide immediate, educational information for both patient and physician.

Adolescent↗

PubMed1998

Associations between lung function and estimated average exposure to NO2 in eight areas of Switzerland. The SAPALDIA Team. Swiss Study of Air Pollution and Lung Diseases in Adults.

In this paper, we present results from the SAPALDIA study (Swiss Study on Air Pollution and Lung Diseases in Adults) regarding associations between lung function [forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1)], as assessed during the cross-sectional study in 1991, and average levels of NO2 exposure within the eight study communities. We distinguished average home outdoor exposure and average personal exposure to NO2 and obtained exposure estimates by computing regional averages of passive sampler measurements performed by a random subsample of SAPALDIA participants in 1993. Previous analyses had revealed associations between average lung function and average air pollution levels between communities. The present results show that such associations may also be seen within communities: a 10-micrograms per m3 increase in average home outdoor and personal exposure to NO2 between zones of residence of the same community was associated with a change in average FVC by -0.59% [95% confidence limits (CL) = 0.01, -1.19] and -0.74% (95% CL = -0.07, -1.41), respectively. These values, however, are smaller than the ones found for the corresponding associations between study communities: -1.67% (95% CL = -1.01, -2.33) and -2.93% (95% CL = -2.11, -3.75), respectively. The different magnitudes of these two types of associations might be explained by differences in spatial variation between various components of air pollution.

Adult↗

PubMed1997

Retinoic acid enhances the expression of interferon-induced proteins: evidence for multiple mechanisms of action.

Retinoic acid (RA) and interferons (IFNs) are negative regulators of cell proliferation. In vitro and in vivo, their combination leads to a more potent growth inhibition. However, the molecular mechanisms by which RA and IFNs potentiate each other are not fully understood. As some IFN-induced gene products regulate cell growth and/or antiviral activity, we analysed the effects of RA on their expressions. RA increases the level of 2'5'oligoadenylate synthetase, p68 kinase, the promyelocytic leukemia protein (PML) and Sp100 in both HL-60 and WISH cells. Moreover, RA and IFN act cooperatively to increase the expression of these proteins. RA also inhibits vesicular stomatitis virus replication and induces a higher antiviral state and growth inhibition when combined with IFN. RA stimulates the IFN regulatory factor 1 (IRF-1) gene expression directly through the GAS motif and causes the induction and secretion of IFNalpha. Additional mechanisms could be involved as RA increases the level of signal transducing activators of transcription (STAT) proteins, and enhances the IFN-induced STAT activation, suggesting that cooperative effects by RA and IFN are mediated through multiple pathways.

2',5'-Oligoadenylate Synthetase↗

PubMed1997

IFN-gamma potentiates atherosclerosis in ApoE knock-out mice.

The early colocalization of T cells and the potent immunostimulatory cytokine IFN-gamma to atherosclerotic lesions suggest that the immune system contributes to atherogenesis. Since mice with a targeted disruption of the apoE gene (apoE 0 mice) develop profound atherosclerosis, we examined the role of IFN-gamma in this process. First, the presence of CD4(+) and CD8(+) cells, which secrete lesional IFN-gamma, was documented in apoE 0 atheromata. Then, the apoE 0 mice were crossed with IFN-gamma receptor (IFNgammaR) 0 mice to generate apoE 0/IFNgammaR 0 mice. Compared to the apoE 0 mice, the compound knock-out mice exhibited a substantial reduction in atherosclerotic lesion size, a 60% reduction in lesion lipid accumulation, a decrease in lesion cellularity, but a marked increase in lesion collagen content. Evaluation of the plasma lipoproteins showed that the compound knockout mice had a marked increase in potentially atheroprotective phospholipid/apoA-IV rich particles as well. This correlated with an induction of hepatic apoA-IV transcripts. These observations suggest that IFN-gamma promotes and modifies atherosclerosis through both local effects in the arterial wall as well as a systemic effect on plasma lipoproteins. Therefore, therapeutic inhibition of IFN-gamma signaling may lead to the formation of more lipid-poor and stable atheromata.

Animals↗

PubMed1997

Plastic neuronal remodeling is impaired in patients with Alzheimer's disease carrying apolipoprotein epsilon 4 allele.

A relationship between the apolipoprotein E (apoE) genotype and the risk to develop Alzheimer's disease has been established recently. Apolipoprotein synthesis is implicated in developmental processes and in neuronal repair of the adult nervous system. In the present study, we investigated the influence of the apolipoprotein polymorphism on the severity of neuronal degeneration and the extent of plastic dendritic remodeling in Alzheimer's disease. Changes in length and arborization of dendrites of Golgi-impregnated neurons in the basal nucleus of Meynert, locus coeruleus, raphe magnus nucleus, medial amygdaloid nucleus, pedunculopontine tegmental nucleus, and substantia nigra were analyzed after three-dimensional reconstruction. Patients with either one or two apoE epsilon 4 alleles not only showed a more severe degeneration in all areas investigated than in patients lacking the apoE 4 allele but also revealed significantly less plastic dendritic changes. ApoE epsilon 4 allele copy number, furthermore, had a significant effect on the pattern of dendritic arborization. Moreover, the relationship between the intensity of dendritic growth and both the extent of neuronal degeneration and the stage of the disease seen in patients lacking the apoE epsilon 4 allele was very weak in the presence of one epsilon 4 allele and completely lost in patients homozygous for the epsilon 4 allele. The results provide direct evidence that neuronal reorganization is affected severely in patients with Alzheimer's disease carrying the apoE epsilon 4 allele. This impairment of neuronal repair might lead to a more rapid functional decompensation, thereby contributing to an earlier onset and more rapid progression of the disease.

Aged↗

PubMed1997

SAPALDIA: methods and participation in the cross-sectional part of the Swiss Study on Air Pollution and Lung Diseases in Adults.

SAPALDIA--the Swiss Study on Air Pollution and Lung Diseases in Adults--focuses on the long term health effects of low to moderate levels of air pollutants as typically seen in different parts of Switzerland. The aim of the SAPALDIA cross-sectional study carried out in 1991 was to determine the prevalence of bronchial asthma, chronic bronchitis and allergic conditions in the adult population of Switzerland and to identify and to determine the respective importance of potentially influencing factors. These could be both personal (smoking habits, allergy status, family history, occupation) and environmental (outdoor and indoor pollution, aeroallergens, climate). A further aim of the cross-sectional study consisted in the identification of individuals susceptible to present symptoms during a two year observation period and to be included in the SAPALDIA follow-up study. This technical report represents the methodological documentation for the cross-sectional study of SAPALDIA. The instruments and the methods of standardisation are presented and discussed. The medical examination consisted of a computerised interview using a standardised questionnaire, the taking of a blood sample for serological tests, allergy skin testing, the measurement of end expiratory CO and body height, and pulmonary function testing followed by methacholine challenge testing or bronchodilatation testing. The pattern of participation and the 9651 participants of the study, representing 59.3% of the sample, are described. Based on information on non-participants gained by telephone interviews and mailed short questionnaires, possible selection biases are quantified and discussed.

Adult↗

PubMed1997

[Juxta-facet cysts. Pathogenesis, clinical symptoms and therapy].

The term "juxta facet cyst" was coined in 1974 by Kao et al. and combines synovial cysts arising from the synovial outpouchings through areas of weakened or destroyed capsular tissue and ganglion cysts developing from mucinous degeneration of periarticular connective tissue. We have operated on 16 patients with juxta facet cysts during the last 3 years. One cyst was located in the thoracic spine, causing a transverse syndrome; 15 cysts were located in the lumbar spine, causing nerve root compression. Diagnosis was established preoperatively by MR in 10 and CT in 3 cases, respectively. The definite classification of the cystic processes was made by histopathologic examination. Surgical treatment consisted of resection of the cyst. Postoperatively, all but 2 patients were free of complaints and no recurrence was observed in the mean follow-up period of 15.5 months. Juxta facet cysts are an uncommon finding, but must be considered in the differential diagnosis of epidural compressive syndromes of the spine.

Aged↗

PubMed1997

Functionally distinct isoforms of STAT5 are generated by protein processing.

The interleukin-3 family of cytokines, which play an important role in the development of myeloid lineages, transduce signals through the JAK-STAT pathway. Previous studies demonstrate that this process entails the activation of four distinct isoforms of STAT5, where two shorter isoforms are activated in a distinct population of cells. We now demonstrate that the shorter isoforms represent carboxy-terminal truncations. Moreover, these truncations are not generated by RNA processing, but by a specific proteolytic activity. Consistent with the notion that truncated STAT5 isoforms transduce distinct signals, they fail to promote the activation of several known interleukin-3 target genes. These studies suggest that the activity of a specific protease may play a critical role in defining the biological responses transduced by STAT5.

Cells, Cultured↗

PubMed1997

Lung function and long term exposure to air pollutants in Switzerland. Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) Team.

The effect of long-term exposure to air pollutants was studied in a cross-sectional population-based sample of adults (aged 18 to 60 yr; n = 9,651) residing in eight different areas in Switzerland. Standardized medical examination included questionnaire data, lung function tests, skin-prick testing, and end-expiratory CO concentration. The impact of annual means of air pollutants on FVC and FEV1 was tested (controlling for age and age squared, sex, height, weight, educational level, nationality, and workplace exposure). Analyses were done separately for healthy never-smokers, ex-smokers (controlling for pack-yr), for current smokers (controlling for cigarettes per day and pack-yr smoked), and for the whole population. Significant and consistent effects on FVC and FEV1 were found for NO2, SO2, and particulate matter < 10 microm (PM10) in all subgroups and in the total population, with PM10 showing the most consistent effect of a 3.4% change in FVC per 10 microg/m3. Results for ozone were less consistent. Atopy did not influence this relationship. The limited number of study areas and high intercorrelation between the pollutants make it difficult to assess the effect of one single pollutant. Our conclusion is that air pollution from fossil fuel combustion, which is the main source of air pollution with SO2, NO2, and PM10 in Switzerland, is associated with decrements in lung function parameters in this study.

Adolescent↗

PubMed1997

Respiratory health and long-term exposure to air pollutants in Swiss schoolchildren. SCARPOL Team. Swiss Study on Childhood Allergy and Respiratory Symptoms with Respect to Air Pollution, Climate and Pollen.

The impact of long-term exposure to air pollution on respiratory and allergic symptoms and illnesses was assessed in a cross-sectional study of schoolchildren (ages 6 to 15 yr, n = 4,470) living in 10 different communities in Switzerland. Air pollution measurements (particulate matter less than 10 microns in diameter [PM10], nitrogen dioxide [NO2], sulfur dioxide [SO2], and ozone) and meteorologic data were collected in each community. Reported symptom rates of chronic cough, nocturnal dry cough, and bronchitis, adjusted for individual risk factors, were positively associated with PM10, NO2, and SO2. The strongest relationship was observed for PM10 (adjusted odds ratios for chronic cough, nocturnal dry cough, and bronchitis between the most and the least polluted community for PM10 were 3.07 [95% CI: 1.62 to 5.81], 2.88 [95% CI: 1.69 to 4.89], and 2.17 [95% CI: 1.21 to 4.89], respectively). The high correlation between the average concentrations of the pollutants makes the assessment of the relative importance of each pollutant difficult. No association between long-term exposure to air pollution and classic asthmatic and allergic symptoms and illnesses was found. There was some indication that frequency of fog is a risk factor of chronic cough and bronchitis, independent of air pollution. In conclusion, this study provides further evidence that rates of respiratory illnesses and symptoms among children augment with increasing levels of air pollution even in countries like Switzerland with moderate average air pollution concentrations.

Adolescent↗

PubMed1997

Congenital microvillous atrophy: report of two cases.

2 infants with chronic severe diarrhoea from birth and with lethal outcome have been studied. Small intestinal biopsies were examined by light and electron microscopy. Severe villous atrophy, complete loss of microvilli or rudimentary forms, intracytoplasmic vesicles, and microvillous inclusions are the characteristic features of the disease. The etiology is unknown. A disturbance in the transport of brush-border proteins to the cell surface is assumed to be the reason for congenital microvillous atrophy.

Atrophy↗

PubMed1996

Home versus hospital deliveries: follow up study of matched pairs for procedures and outcome. Zurich Study Team.

OBJECTIVE: To assess procedures and outcomes in deliveries planned at home versus those planned in hospital among women choosing the place of delivery. DESIGN: Follow up study of matched pairs. SETTING: Antenatal clinics and reference hospitals in Zurich between 1989 and 1992. SUBJECTS: 489 women opting for home delivery and 385 opting for hospital delivery; the women comprised all those attending members of the study team for antenatal care and those attending the reference hospital for antenatal care who could be matched with the women planning home confinement. MAIN OUTCOME MEASURES: Need for medication and incidence of interventions during delivery (caesarean section, forceps, vacuum extraction, episiotomy), duration of labour, occurrence of severe perineal lesions, maternal blood loss, and perinatal morbidity and death. RESULTS: All women were followed up from their first antenatal visit till three months after delivery. Referrals during pregnancy (n = 37) and labour (70), changes of mind (15 home to hospital, eight hospital to home), and 17 miscarriages resulted in 369 births occurring at home and 486 in hospital. During delivery the home birth group needed significantly less medication and fewer interventions whereas no differences were found in durations of labour, occurrence of severe perineal lesions, and maternal blood loss. Perinatal death was recorded in one planned hospital delivery and one planned home delivery (overall perinatal mortality 2.3/1000). There was no difference between home and hospital delivered babies in birth weight, gestational age, or clinical condition. Apgar scores were slightly higher and umbilical cord pH lower in home births, but these differences may have been due to differences in clamping and the time of transportation. CONCLUSION: Healthy low risk women who wish to deliver at home have no increased risk either to themselves or to their babies.

Abortion, Spontaneous↗

PubMed1996

The SH2 domains of Stat1 and Stat2 mediate multiple interactions in the transduction of IFN-alpha signals.

Analysis of the ability of IFN-alpha to rapidly stimulate genes has led to the identification of a new family of signal transducing factors (STFs). The STF activated by IFN-alpha consists of two members of the STAT (Signal Transducers and Activators of Transcription) family of signaling proteins, Stat1 and Stat2. Sequence comparison of these STATs has determined that they share several conserved domains, the most notable of which is an SH2 domain. Recently, studies have determined that these SH2 domains can mediate a specific association between a STAT and the cytoplasmic domain of the appropriate receptor. Once associated with the receptor, the STATs become activated by an associated tyrosine kinase, whereupon they dissociate from the receptor and dimerize to form active STFs. The SH2 domain has also been implicated in the formation of STAT dimers found in STFs, suggesting it may play multiple roles in signaling. We have carried out a detailed analysis on the role of the Stat1 and Stat2 SH2 domains in the mediation of IFN-alpha stimulated signals. These studies, which have determined that the SH2 domain of Stat1 and Stat2 can mediate homo- as well as heterodimerization, suggest that a single SH2 domain-phosphotyrosyl interaction is sufficient for dimerization. Moreover, they provide the first direct evidence that the target of the SH2 domain is the STAT tyrosine activation site. In addition, these studies implicate the SH2 domain in another step in the signaling cascade, namely mediation of the interaction between STATs and their activating kinases (i.e. the JAKs).

Animals↗

PubMed1996

[Early manifestation of polycystic kidney changes in tuberous sclerosis].

Tuberous sclerosis (McKusick number: 19110) is well documented as an inheritable autosomal dominant disorder. On the occasion of results of an autopsy of a male fetus (1950 g, 29th gestational week) we report on the very early onset of a giant cell astrocytoma (microcalzified focally) and a cystic kidney disorder which in association with this phacomatosis is described first for this age. Thus, based on sonography there is a new differential diagnosis for the weighty prenatal diagnosis of a "Potter syndrome" or of "cystic kidneys". Moreover, on a chromosomal level we discuss possible connections between tuberous sclerosis and distinct forms of autosomal dominant polycystic kidney disease, ADPKD.

Adult↗