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Biomedical subjects

G Adler

Publications and source records attributed to G Adler.

At least 127 records · Page 7Linked to original sources
PubMed2000

[Outcome quality of gerontopsychiatric day-clinic treatment: changes in life-satisfaction:].

OBJECTIVE: The variety of institutional treatments in psychiatry, as well as financial aspects make it necessary to evaluate these institutions for the quality of their medical care. At the Central Institute of Mental Health in Mannheim, the quality of treatment at the geronto-psychiatric day-clinic is assessed on the level of outcome quality. METHOD: The patients are examined at admission, at discharge, half a year and one year after discharge. Psychopathology, activities of daily living, social situation and quality of life are assessed by means of standardized instruments. RESULTS: Preliminary results show that at discharge, patients are less depressed, have achieved a higher level of social activities and contacts and that their quality of life improved in most domains. In some domains of quality of life improvement is highly correlated with the amelioration of depressive symptoms, in others not. CONCLUSION: Whether these effects of treatment will last, has to be studied in follow-up examinations.

Activities of Daily Living↗
PubMed1999

Infection with Helicobacter pylori is not a major independent risk factor for stable coronary heart disease: lack of a role of cytotoxin-associated protein A-positive strains and absence of a systemic inflammatory response.

BACKGROUND: There is controversy about the association between Helicobacter pylori infection and manifestations of coronary heart disease (CHD), the potential role of the more virulent H pylori strains, and whether or not a positive serostatus is related to increased levels of markers of systemic inflammation. METHODS AND RESULTS: We assessed the prevalence of an infection with H pylori and in particular the anti-cytotoxin-associated protein A (CagA) antibody response of the more virulent strains expressing CagA in 312 patients with stable CHD and in 479 control subjects. Serological prevalence of H pylori infection (IgG titer) was significantly higher in patients than in control subjects after adjustment for age and sex (44.2% versus 31.3%, P<0.001). After adjustment for various covariates in multiple logistic regression, the odds ratio (OR) for CHD was 1.3 (95% CI, 0.9 to 1.9) given a positive IgG serostatus. The prevalence of CagA-positive strains was 27.9% in patients and 21.7% in control subjects (P=0.076 adjusted for age and sex). The OR for CHD in the fully adjusted model was 1.1 (95% CI, 0.7 to 1.7). None of the inflammatory markers (C-reactive protein, fibrinogen, plasma viscosity, or leukocytes) was significantly different according to serostatus. CONCLUSIONS: In this large case-control study, the association of H pylori infection with stable CHD was strongly reduced and was no longer statistically significant after controlling for potential confounders. We also found no independent association between the more virulent strains and CHD. In addition, a positive serostatus was not associated with a systemic inflammatory response. Thus, these data do not support the hypothesis that infection with H pylori might be a major risk factor for stable CHD.

Aged↗
PubMed1999

Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells.

The FRAP-p70s6K signaling pathway was found to be constitutively phosphorylated/active in MiaPaCa-2 and Panc-1 human pancreatic cancer cells and a pancreatic cancer tissue sample as judged by the retarded electrophoretic mobility of the two major FRAP downstream targets, p70s6K and 4E-BP1. Treatment of cells with rapamycin, a selective FRAP Inhibitor, inhibited basal p70s6K kinase activity and induced dephosphorylation of p70s6K and 4E-BP1. Moreover, rapamycin inhibited DNA synthesis as well as anchorage-dependent and -independent proliferation in MiaPaCa-2 and Panc-1 cells. Finally, rapamycin strikingly inhibited cyclin D1 expression in pancreatic cancer cells. Thus, inhibitors of the constitutively active FRAP-p70s6K pathway may provide a novel therapeutic approach for pancreatic cancer.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1999

Strategies for the detection of disease genes in pancreatic cancer.

The present review summarizes our strategies aimed at identifying and characterizing genetic alterations occurring at the transcriptional and chromosomal level in pancreatic cancer. To study transcriptional alterations we have used a number of techniques including modified versions of differential hybridizations and cDNA RDA (representational difference analysis). These approaches have led to the identification of more than 500 genes with differential expression in pancreatic cancer. To study chromosomal aberrations occurring in pancreatic cancer tissues we used comparative genomic hybridization (CGH). This allowed the identification of a number of chromosomal regions containing putative tumor suppressor genes or oncogenes. Genes isolated in both approaches represent potential new disease genes for pancreatic cancer and are at present being characterized by individual or serial analysis.

Amino Acid Sequence↗
PubMed1999

Acinar-ductal-carcinoma sequence in transforming growth factor-alpha transgenic mice.

Transgenic mice overexpressing transforming growth factor-alpha (TGF-alpha) display an expansion of intrapancreatic fibroblasts and a progressive accumulation of extracellular matrix. This massive fibrosis is associated with an increase in pancreatic size and weight. In parallel, tubular complexes appear that are composed of acinar cells with a decreased height. These acinar cell lose zymogen granules and become transitional cells, which subsequently gain duct cell features. In animals older than one year dysplastic lesions develop, which originate from tubular complexes. Occasionally these dysplastic foci transform to papillary and cystic pancreatic carcinoma. These tumors are positive for the duct-specific antigen Duct-1 and carbonic anhydrase activity indicative of ductal differentiation. Tumors overexpress the epidermal growth factor (EGF)-receptor and p53, but lack K-ras mutations. These data suggest an acinar-ductal-carcinoma sequence in TGF-alpha transgenic mice.

3T3 Cells↗
PubMed1999

[Prospective Epidemiologic Study of Epigastric Discomfort (PRESTO). Ground work and preliminary results].

BACKGROUND AND OBJECTIVE: Symptoms of dyspepsia (indigestion; upper abdominal discomfort) are one of the most frequent reasons for consulting a general practitioner or internist. Yet there are no up-to-date national data on the epidemiology and course of this symptom complex. PATIENTS AND METHODS: In an open, prospective, multicentre, epidemiological study (PRESTO) 3016 patients with the suspected diagnosis of "functional dyspepsia" (1228 males, 1788 females, mean age 50 +/- 15 years) were followed for 2 years by 983 physicians in private practice (general practitioners or specialists in internal medicine). Patients with proven gastro-oesophageal reflux or peptic ulcer were excluded. Treatment was at the discretion of the physician. Patients were seen after one month (if under treatment) and then at 6, 12, 18 and 24 months. In addition to personal data, (1) symptoms, diagnosis and treatment of the dyspepsia, (2) socioeconomic aspects and (3) any limitations and the quality of life of each patient were recorded in a standard manner. RESULTS: At the first interim analysis more than half the patients judged there situation to be one of "chronic stress" or having to cope with a stressful event; nearly 50% thought this to be the cause of the symptoms. Concomitant illnesses were present in 63% of patients. Oesophagogastroduodenoscopy with subsequent medication was performed in 20.6%, a trial of medication (usually drugs stimulating gastric motility) in 65%. No medication was initially given to 14.4% of patients. The most common symptoms were feeling of fullness (92.9%, epigastric pressure sensation (91.5%) and flatulence (87.4%). CONCLUSION: These preliminary results indicate that a large epidemiological study can be performed by general practitioners and has advantages over the more usual method of enquiry by telephone. Dyspepsia exerts an unusually high degree of stress and results in considerable demands on medical facilities.

Adolescent↗
PubMed1999

Inverse graded relation between alcohol consumption and active infection with Helicobacter pylori.

Alcoholic beverages are known to have strong antibacterial activity. It is unclear, however, to what degree their consumption affects colonization of the human stomach with the bacterium Helicobacter pylori, a risk factor of various chronic diseases. The authors assessed the relation between alcohol consumption and active infection with H. pylori in a cross-sectional study among employees of a health insurance company and their household members (n = 425) in southern Germany. Quantitative information on alcohol consumption by beverage type and other factors that were known or suspected to be related to infection status was collected by a standardized questionnaire, and active infection was measured by the 13C-urea breath test. After control for confounding factors, there was a monotonic inverse graded relation between alcohol consumption and H. pylori infection (p for trend = 0.017). The odds ratio of infection among subjects who consumed more than 75 g of alcohol per week compared with subjects who did not drink alcohol was 0.31 (95 percent confidence interval 0.12-0.81). The inverse relation with H. pylori infection was stronger for alcohol consumed in the form of wine than for alcohol from beer. Notwithstanding its cross-sectional design, this study seems to support the hypothesis that alcohol consumption, particularly wine consumption, may reduce the odds of active infection with H. pylori.

Adolescent↗
PubMed1999

Transforming growth factor-beta-induced upregulation of transforming growth factor-beta receptor expression in pancreatic regeneration.

The transforming growth factor-beta (TGFbeta) signaling pathway is one important player in the regulation of extracellular matrix turnover and cell proliferation in epithelial regeneration. We used cerulein-induced pancreatitis in rats as a model to investigate the regulation of TGFbeta receptor type I and type II expression on protein and messenger RNA level during regeneration. In the regenerating pancreas, mRNA levels of TGFbeta receptor I and II were significantly increased with a maximum after 2 days. On protein level, expression of TGFbeta receptor II was significantly increased after three to 3-5 days. This elevated expression could be inhibited by neutralizing the endogenous biological activity of TGFbeta1 with a specific antibody. In cultured pancreatic epithelial cells, TGFbeta1 reduced cell proliferation as measured by [3H]thymidine incorporation. Furthermore the transcript levels of TGFbeta1 as well as mRNA and protein concentrations of type I and type II receptor increased during TGFbeta stimulation in vitro. These results indicate that epithelial pancreatic cells contribute to the enhanced TGFbeta1 synthesis during pancreatic regeneration by an autocrine mechanism. TGFbeta1, furthermore, upregulates the expression of its own receptors during the regenerative process, thereby contributing to the increase of the TGFbeta-induced cellular responses.

Animals↗
PubMed1999

Integrin alpha6beta1 role in metastatic behavior of human pancreatic carcinoma cells.

The factors that determine the metastatic behavior of pancreatic tumor cells are incompletely understood. In this study, we first demonstrate differences in adhesion properties, integrin expression and in vivo integrin function in the metastatic tumor cell line PaTu 8988s compared with the non-metastatic cell line PaTu 8988t. Both cell lines were derived from the same original tumor and exhibit identical genetic fingerprints. Using in vitro adhesion assays performed on purified extracellular matrix components, adhesion of PaTu 8988s cells was significantly increased on the basal membrane component laminin and decreased on the interstitial matrix protein fibronectin compared to PaTu 8988t cells. By immunocytochemistry and flow cytometry, and in correspondence with their adhesive properties, the metastatic PaTu 8988s cells did express a distinct pattern of integrin subunits. Laminin-binding integrins alpha6 and beta4 were overexpressed in PaTu 8988s cells. Fibronectin-binding alpha5 integrins were present at higher levels in the non-metastatic PaTu 8988t cells, whereas the beta1 subunit expression did not differ. Adhesion to laminin or fibronectin was specific and was mediated via integrins alpha6beta1 and alpha5beta1, respectively. In addition, metastasis formation in vivo after injection of cells into the tail vein of nude mice was inhibited by preincubation of PaTu 8988s cells with antibodies directed against the integrin alpha6 or beta1. We conclude that alpha6beta1 integrins are overexpressed and functionally active in metastatic human pancreatic carcinoma cells, and participate in metastasis formation probably through binding to the basal membrane component laminin.

Animals↗
PubMed1999

Expression and differential regulation of connective tissue growth factor in pancreatic cancer cells.

CTGF is an immediate early growth responsive gene that has been shown to be a downstream mediator of TGFbeta actions in fibroblasts and vascular endothelial cells. In the present study hCTGF was isolated as immediate early target gene of EGF/TGFalpha in human pancreatic cancer cells by suppression hybridization. CTGF transcripts were found in 13/15 pancreatic cancer cell lines incubated with 10% serum. In 3/7 pancreatic cancer cell lines EGF/TGFalpha induced a significant rise of CTGF transcript levels peaking 1-2 h after the start of treatment. TGFbeta increased CTGF transcript levels in 2/7 pancreatic cancer cell lines after 4 h of treatment and this elevation was sustained after 24 h. Only treatment with TGFbeta was accompanied by a parallel induction of collagen type I transcription. 15/19 human pancreatic cancer tissues were shown to overexpress high levels of CTGF transcripts. CTGF transcript levels in pancreatic cancer tissues and nude mouse xenograft tumors showed a good correlation to the degree of fibrosis. In situ hybridization and the nude mouse experiments revealed that in pancreatic cancer tissues, fibroblasts are the predominant site of CTGF transcription, whereas the tumor cells appear to contribute to a lesser extent. We conclude that CTGF may be of paramount importance for the development of the characteristic desmoplastic reaction in pancreatic cancer tissues.

Animals↗
PubMed1999

Cholecystokinin-induced redistribution of paxillin in rat pancreatic acinar cells.

Cholecystokinin (CCK) dose-dependently stimulates enzyme secretion or loss of cell integrity in the exocrine pancreas. Signaling mechanims include tyrosine phosphorylation of p125(FAK) and paxillin. Here, we examine their potential function. Maximum phosphorylation of both proteins was observed after stimulation of freshly isolated rat pancreatic acini with 10 nM CCK, a concentration known to initiate breakdown of the terminal actin web and cell damage. Under these conditions, CCK initiated transient redistribution of paxillin from the apical cytosol to the apical and lateral plasma membrane within 2 min, where it colocalized with the terminal actin web. Relocation of paxillin was confirmed in subcellular fractions by western blotting and coincided with maximum phosphorylation of membrane-bound p125(FAK) and paxillin. Subsequently, paxillin was redistributed to the basolateral cytosol and was degraded. p125(FAK) remained membrane-bound. We conclude that phosphorylation and redistribution of paxillin and phosphorylation of p125(FAK) may participate in the CCK-induced disassembly of acinar cell actin.

Animals↗
PubMed1999

Use of representational difference analysis to study the effect of TGFB on the expression profile of a pancreatic cancer cell line.

It has been shown that TGFBs, their receptors, or downstream targets show genetic alterations in pancreatic cancer. This study was designed to identify transcriptional alterations induced by prolonged treatment of pancreatic cancer cell lines with TGFB. The TGFB-responsive PANC-1 cell line was treated with 10-ng/ml TGFB1 for 24 hr. cDNA representational difference analysis was used to generate subtracted hybridization probes enriched for TGFB regulated genes. These probes were hybridized on gridded arrays of cDNA clones containing genes differentially expressed in pancreatic cancer. Twenty-seven distinct cDNA clones were shown to be TGFB target genes. Eleven genes were upregulated by TGFB and were associated with extracellular matrix composition and formation, including genes usually transcribed by cells of mesenchymal origin only. Transcript levels of 16 genes were downregulated by TGFB and could mainly be classified into markers of epithelial differentiation and genes involved in the transcriptional and translational machinery. In conclusion, a 24-hr treatment of PANC-1 cells with TGFB induced a loss of epithelial and a gain of mesenchymal markers. As in other tumors, this epithelial-mesenchymal transdifferentiation may be of general importance during pancreatic carcinogenesis, and may participate, e.g., in the development of the desmoplastic reaction or the acquisition of an invasive phenotype of pancreatic tumor cells. This study demonstrates the usefulness of cDNA RDA and gridded clone libraries to study the effect of signaling cascades on the expression profile of tumor cells. Similar approaches may be helpful in the context of the genome project for the characterization of novel genes. Genes Chromosomes Cancer 26:70-79, 1999.

Cell Division↗
PubMed1999

Genomic organization and chromosomal mapping of mouse nuclear factor kappa B 2 (NFKB2).

NFKB2 is a member of the NFKB/Rel gene family, which is known to be a pivotal regulator of the acute phase and immune responses. NF-kappaB2 is initially synthesized as a approximately 100 000 Mr protein which needs to be processed in order to bind DNA, either as homodimer or as heterodimer with other members of the NF-kappaB/Rel family. The unprocessed form of NF-kappaB2 acts as an IkappaB-like protein. Therefore, NF-kappaB2 has a dual function. In this report we describe the genomic structure, expression pattern, and chromosomal localization of mouse NFKB2. Genomic clones were isolated, which span the entire gene of approximately 8.5 kilobases (kb) including 1.5 kb of the promoter region. Comparison to its human and avian homologues revealed a strong evolutionary conservation of the gene structure including the exon/intron borders, sequence, and position of the nuclear localization signal, the glycine-hinge region, and the ankyrin repeats. By fluorescence in situ hybridization, mouse NFKB2 was mapped to Chromosome (Chr) MMU 19C3-D2, which is homologous to human Chr 10q24, at which position the human NFKB2 was previously located. NFKB2 is ubiquitously expressed, highest in lymph nodes and thymus, underlining its role in the immune function.

Animals↗
PubMed1999

Lipopolysaccharide-activated macrophages stimulate the synthesis of collagen type I and C-fibronectin in cultured pancreatic stellate cells.

We have recently identified and characterized pancreatic stellate cells (PSC) in rats and humans (Gastroenterology 1998, 15:421-435). PSC are suggested to represent the main cellular source of extracellular matrix in chronic pancreatitis. Now we describe a paracrine stimulatory loop between human macrophages and PSC (rat and human) that results in an increased extracellular matrix synthesis. Native and transiently acidified supernatants of cultured macrophages were added to cultured PSC in the presence of 0.1% fetal calf serum. Native supernatants of lipopolysaccharide-activated macrophages stimulated the synthesis of collagen type I 1.38 +/- 0.09-fold of control and c-fibronectin 1.89 +/- 0.18-fold of control. Transiently acidified supernatants stimulated collagen type I and c-fibronectin 2.10 +/- 0.2-fold and 2.80 +/- 0.05-fold of control, respectively. Northern blot demonstrated an increased expression of the collagen-I-(alpha-1)-mRNA and fibronectin-mRNA in PSC 10 hours after addition of the acidified macrophage supernatants. Cell proliferation measured by bromodeoxyuridine incorporation was not influenced by the macrophage supernatants. Unstimulated macrophages released 1.97 pg TGFbeta1/microgram of DNA over 24 hours and lipopolysaccharide-activated macrophages released 6.61pg TGFbeta1/microgram of DNA over 24 hours. These data together with the results that, in particular, transiently acidified macrophage supernatants increased matrix synthesis, identify TGFbeta as the responsible mediator. In conclusion, our data demonstrate a paracrine stimulation of matrix synthesis of pancreatic stellate cells via TGFbeta1 released by activated macrophages. We suggest that macrophages might play a pivotal role in the development of pancreas fibrosis.

Animals↗
PubMed1999

NF-kappaB/Rel activation in cerulein pancreatitis.

BACKGROUND & AIMS: Recent evidence suggests that a number of rapid signaling cascades are initiated during secretagogue-induced pancreatitis. However, little is known about the nuclear events. The aim of this study was to explore activation of the transcription factor NF-kappaB/Rel after supramaximal stimulation with the cholecystokinin analogue cerulein in the pancreas. METHODS & RESULTS: Nuclear appearance of NF-kappaB/Rel-binding activity was detectable 15 minutes after cerulein injection. The DNA-binding activity consisted of NF-kappaB1 p50, NF-kappaB2 p52, and RelA p65 as judged by supershift assays and Western blot analysis. The onset and termination of NF-kappaB/Rel activation correlated with the degradation and reappearance of IkappaBalpha. Cerulein in supramaximal but not in physiological doses activated NF-kappaB/Rel in vitro. After blocking of NF-kappaB/Rel activation with pyrrolidine dithiocarbamate, the degree of morphological alterations was more pronounced than in controls, serum amylase and lactate dehydrogenase levels were significantly increased, and messenger RNA levels of pancreatitis-associated protein were more strongly induced, reflecting a more severe degree of pancreatitis. Similar results were obtained when N-acetyl-L-cysteine was used as an inhibitor of NF-kappaB activation. CONCLUSIONS: These data show that NF-kappaB/Rel is rapidly activated during cerulein pancreatitis. This activation may induce a self-defending genetic program before the onset of cellular injury, which might prevent higher degrees of damage of pancreatic acinar cells after secretagogue hyperstimulation.

Acetylcysteine↗