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G Adler

Publications and source records attributed to G Adler.

At least 145 records · Page 8Linked to original sources
PubMed1999

Transforming growth factor alpha activates Ha-Ras in human pancreatic cancer cells with Ki-ras mutations.

BACKGROUND & AIMS: The aim of this study was to identify signaling pathways that mediate cell proliferation in response to a Ras-activating growth factor, transforming growth factor (TGF)-alpha, in two pancreatic cancer cell lines with constitutively active Ki-Ras, MiaPaCa-2, and Panc-1. METHODS: ERK1/-2- and p90(rsk) activation were determined by immune complex kinase assays. AP-1 and E74 activation were assessed in transient transfections using luciferase reporter plasmids. Ha-Ras activation was determined using a glutathione S-transferase fusion protein comprising the Ras-binding domain of Raf and by immunocytochemistry, growth by DNA synthesis and colony formation in softagar. RESULTS: TGF-alpha stimulated activation of ERK1/-2, which was dependent on MEK-1, but independent of PKC activity. TGF-alpha-induced activation of an AP-1 reporter plasmid also required MEK-1 and Ras activity. Using an E74 reporter plasmid, we demonstrate that TGF-alpha indeed activates Ras in both cell lines. In particular, TGF-alpha induced membrane translocation and activation of the Ras isoform Ha-Ras. Finally, TGF-alpha-stimulated DNA synthesis and clonal growth in soft agar were prevented by treatment of cells with a MEK-1 inhibitor or a Ras farnesyl transferase inhibitor. CONCLUSIONS: The Ha-Ras-ERK cascade plays an important role in TGF-alpha-induced growth of pancreatic cancer cells with activating Ki-ras mutations. Inhibitors of this cascade could constitute novel anticancer agents for pancreatic tumors.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1999

Sympathetic modulation of lipolysis in subcutaneous adipose tissue: effects of gender and energy restriction.

To investigate the differences in the regulation of lipolysis between male and female obese subjects in vivo, we used an in situ microdialysis technique before and after 3 weeks of energy restriction. Using this method, we examined glycerol, glucose, and lactate responses after 5 minutes of epinephrine stimulation in the adipose tissues. Glycerol releases after the perfusion of phentolamine, orciprenaline, and propranolol were also studied. Sixteen subjects were studied (8 men, 8 women, 35 to 45 years of age, body mass index 38 to 50 kg/m2). In women, epinephrine provoked a greater glycerol release than in men in both abdominal and femoral regions (P < .05). In men and women there was a significant decrease in the concentration of glucose and a significant increase in lactate concentration after epinephrine stimulation (P < .001). After 3 weeks of energy restriction, glycerol release after epinephrine stimulation was greater in both sexes than that observed before energy restriction (P < .05). Both phentolamine and orciprenaline stimulated the release of glycerol (P < .01); phentolamine had a higher effect in women, while propranolol had no effect on glycerol release in both sexes. In summary, we have demonstrated that epinephrine provoked a greater lipolytic response in obese women in both abdominal and femoral adipose tissues. The lipolytic response was further enhanced after 3 weeks of energy restriction in each gender. The decrease in glucose concentration suggests that glucose may be reutilized for synthesis into new triacylglycerol. Knowledge about the sensitivity to lipolytic agents in subcutaneous adipose tissue may provide potential new approaches for modulating the lipolytic responses of subcutaneous adipose tissue differently in men and women.

Abdomen↗
PubMed1999

Expression of the highly conserved RNA binding protein KOC in embryogenesis.

The human KOC gene which is highly expressed in cancer shows typical structural features of an RNA binding protein. We analyzed the temporal and spatial expression pattern of KOC in mouse embryos at different gestational ages. The expression of KOC seems to be ubiquitous at early stages. During advanced gestation highest KOC expression occurs in the gut, pancreas, kidney, and in the developing brain. The expression pattern of KOC was compared to its Xenopus homologue Vg1-RBP during frog development. Similar expression was found in these organs suggesting an important functional role of the homologous proteins in embryonic development.

Amino Acid Sequence↗
PubMed1999

Active infection with Helicobacter pylori in healthy couples.

The mode of spread of Helicobacter pylori infection is subject to ongoing debate. Recent studies among patients with gastrointestinal disorders suggest a potential role of conjugal transmission. In this study, the clustering of H. pylori infection was assessed among 110 employees of a health insurance company and their partners. Active infection with H. pylori was measured by the 13C-urea breath test. Information on potential confounders was collected by a standardized questionnaire. Overall, 16 employees (14.5%) and 24 partners (21.8%) were infected. While only 7% (6/86) of employees with an uninfected partner were infected, this applied to 42% (10/24) of employees with an infected partner. A very strong relation between partners' infection status persisted after control for age and other potential confounders (adjusted odds ratio, 7.0; 95% confidence interval, 1.8-26.7). Furthermore, the risk of infection increased with the number of years lived with an infected partner. These results support the hypothesis of a major role of spouse-to-spouse transmission of H. pylori infection.

Adult↗
PubMed1999

Helicobacter pylori in dental plaque: a comparison of different PCR primer sets.

This study was designed to compare different primer sets for PCR analysis of H. pylori in the same series of 40 dental plaque samples. Three pairs of primers, HPU1/HPU2, HP1/HP2, and EHC-U/EHC-L, directed to the urease A gene, 16S rRNA gene, or 860-bp DNA of H. pylori, respectively, were used. Our results demonstrate that EHC-L/EHC-U were more specific and sensitive for H. pylori added to saliva or dental plaque than HPU1/HPU2 and HP1/HP2. The detection rates for H. pylori DNA in dental plaque samples from randomly selected adult patients from the Dental Clinic of the University of Ulm were 26.5% (9/34) for HPU1/HPU2, 78.9% (30/38) for HP1/HP2, and 100% (40/40) for EHC-U/EHC-L (P < 0.001). Nested PCR using primers directed to the 860-bp DNA of H. pylori further confirmed the presence of H. pylori DNA (40/40) in all these samples. Our results indicate that primers EHC-U/EHC-L are to be recommended for PCR detection of H. pylori in the oral cavity.

Adult↗
PubMed1999

Inhibition of nuclear factor kappa B and induction of apoptosis in T-lymphocytes by sulfasalazine.

1. Chronic inflammatory diseases have been shown to be associated with NF-kappaB activation and impaired apoptosis of immune cells. The aim of the present study was to investigate if sulfasalazine and its colonic metabolites 5-aminosalicylic acid (5ASA) and sulfapyridine affect NF-kappaB/Rel activation and viability of T-lymphocytes. 2. Sulfasalazine inhibits NF-kappaB/Rel activation in the murine T-lymphocyte cell line RBL5 using electrophoretic mobility shift assays. In transfection assays sulfasalazine treatment for 4 h inhibits kappaB-dependent transcription with an IC50 value of approximately 0.625 mM. 3. Higher doses or prolonged treatment result in cell death of T-lymphocytes in a dose- and time-dependent manner. Cell death is caused by apoptosis as judged by DNA fragmentation, annexin V and Apo 2.7 staining. Induction of apoptosis is a fast event with 50% apoptotic cells after a 4 h incubation with 2.5 mM sulfasalazine. The ED50 value for apoptosis induction after 24 h treatment was approximately 0.625 mM. 4. In contrast, 5ASA and sulfapyridine neither inhibit NF-kappaB/Rel activation nor induce apoptosis in T-lymphocytes at doses up to 5.0 mM. 5. These results demonstrate that sulfasalazine, but not 5ASA or sulfapyridine, strongly inhibits NF-kappaB activation and potently induces apoptosis in T-lymphocytes. Inhibition of NF-kappaB/Rel activation and subsequent clearance of activated T-lymphocytes by apoptosis might thus explain the beneficial effects of sulfasalazine in the treatment of chronic inflammatory disorders.

Animals↗
PubMed1999

Metformin inhibits catecholamine-stimulated lipolysis in obese, hyperinsulinemic, hypertensive subjects in subcutaneous adipose tissue: an in situ microdialysis study.

AIMS: Metformin has been reported to decrease the plasma concentrations of non-esterified fatty acids in Type 2 diabetic subjects. This study investigated the effects of metformin on basal and catecholamine-stimulated lipolysis in abdominal subcutaneous adipose tissue of obese, hyperinsulinaemic, hypertensive subjects. METHODS: Fourteen subjects with severe obesity (12 female, twomale, age 35.4 +/- 4 years, body mass index 48.2 +/- 2 kg/m2, body fat mass 63.3 +/- 5 kg) were recruited. Glycerol and lactate concentrations were determined in the presence of metformin and after administration of catecholamines using microdialysis. Simultaneously, blood flow was assessed with the ethanol escape method. RESULTS: Glycerol release was lowered by metformin during the 3-h experiment (P<0.01). The lipolytic activity of catecholamines was suppressed when adipose tissue was pre-treated with metformin (P<0.001). Lactate concentration increased after application of metformin (P<0.01) and catecholamines (P<0.001). Blood flow was decreased in the presence of adrenaline (P < 0.01), but this effect was abolished by metformin. CONCLUSIONS: The present data demonstrate the effects of metformin on lipolysis in subcutaneous adipose tissue in vivo. In the large body fat mass of obese subjects, a reduction of lipolysis in adipose tissue may contribute to a decrease of VLDL synthesis in the liver resulting in a lowered plasma triglyceride concentration.

Adipose Tissue↗
PubMed1999

Prospective evaluation of brush cytology of biliary strictures during endoscopic retrograde cholangiopancreatography.

BACKGROUND AND STUDY AIMS: Cytological methods may be used to differentiate benign from malignant biliary strictures. We evaluated the diagnostic accuracy of an endobiliary cytotechnique which can easily be performed during endoscopic retrograde cholangiopancreatography. PATIENTS AND METHODS: Cytological samples were obtained by brushing biliary strictures via a guide wire in 86 patients with strictures of unknown status. Samples were classified by an expert cytologist as normal (including reactive cells), severely dysplastic (atypical cells suspicious of malignancy) and clearly malignant. A final diagnosis was achieved in 78 patients based on intraoperative findings and histological investigation, autopsy or prolonged follow-up. Strictures were malignant in 57 cases (31 pancreatic carcinoma, 20 cholangiocarcinoma, 6 others) and benign in 21 cases (11 chronic pancreatitis, 5 chronic nonspecific inflammation, 5 others). RESULTS: The overall results for brush cytological investigation were sensitivity 56.1%, specificity 90.5%, positive predictive value 94.1%, negative predictive value 43.2 %, and accuracy 65.4 %. Sensitivity was significantly higher (P<0.005) in cholangiocarcinoma (80%) compared with pancreatic carcinoma (35.5%). The overall specificity of less than 100 % resulted from dysplasia in two patients with chronic pancreatitis and inflammatory mass. No procedure-related complications occurred. CONCLUSIONS: Brush cytology is helpful for differentiating between benign and malignant biliary strictures, especially in suspected cholangiocarcinoma. Dysplastic cells may occur in the absence of malignancy and their presence should therefore be interpreted cautiously.

Adult↗
PubMed1999

Prevalence of resistance to clarithromycin and its clinical impact on the efficacy of Helicobacter pylori eradication.

BACKGROUND: Triple therapy with a proton-pump inhibitor (PPI) in combination with metronidazole and clarithromycin is the method of choice for eradication of Helicobacter pylori. Failures have been primarily blamed on the development of resistance to clarithromycin. The present study investigated the prevalence and clinical significance of resistance to clarithromycin and metronidazole in determining therapeutic success of both triple therapy as a primary eradication method and high-dose dual therapy in non-responders. METHODS: On the basis of prior therapy, H. pylori-positive patients were assigned to one of two groups in the present prospective study. Group A (n = 93) included patients who had not undergone any prior eradication treatment, whereas group B (n = 15) consisted of patients who had received clarithromycin but in whom eradication had been unsuccessful. All patients underwent endoscopy with biopsy for bacterial culture and resistance studies. Patients in group A were treated with a 7-day regimen of pantoprazole (40 mg twice daily), metronidazole (500 mg twice daily), and clarithromycin (250 mg twice daily), whereas those in group B received omeprazole (40 mg three times a day) and amoxycillin (1000 mg three times a day ) for 14 days. Success of the eradication treatment was ascertained by means of the 13C urea breath test. RESULTS: In group A resistance to clarithromycin and metronidazole was identified in 3 patients (4.9%) and in 14 patients (22.9%), respectively. Eradication proved successful in 78 of 84 patients (92.6%) followed up. Two of the 3 patients with primary clarithromycin resistance and 1 of the 14 patients with metronidazole resistance did not respond to treatment. In group B isolated or combined resistance to clarithromycin was found in seven patients, whereas another four showed isolated resistance to metronidazole. Eradication proved successful in 10 of 13 controlled patients (76.9%) followed up, and only 2 patients reported severe side effects. CONCLUSION: Determination of antibiotic resistance before initiating therapy is not necessary, since primary resistance to clarithromycin is rare. The Italian triple therapy remains a highly effective primary therapeutic method. Further, routine determination of resistance in non-responders also seems to be superfluous because high-dose dual therapy is an effective and well-tolerated second-line therapy regardless of the patients' resistance status.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1999

Comparison between the oral and intravenous L-[1-13C]phenylalanine breath test for the assessment of liver function.

To simplify the L-[1-13C]phenylalanine breath test which is used to assess liver function the tracer is usually given orally, and CO2 production rate is estimated. In 12 healthy volunteers and 10 liver cirrhotics we compared the oral approach with i.v. tracer administration combined with measurement of individual CO2 production rate. The 13CO2/12CO2 enrichment was assessed by isotope-ratio mass spectrometry. After i.v. [1-13C]phenylalanine application exhaled 13C recovery per minute peaked within 10 minutes (controls: 0.17 +/- 0.06%; cirrhotics: 0.05 +/- 0.02%, p < 0.01). The oral approach yielded comparable separation between 30-60 minutes, with average peak values being 0.18 +/- 0.03% and 0.06 +/- 0.03% (p < 0.01), respectively. Variable gastrointestinal resorption kinetics after oral application probably causes this difference.

Administration, Oral↗
PubMed1999

Helicobacter pylori among preschool children and their parents: evidence of parent-child transmission.

This study assessed the role of parental infection status in the transmission of Helicobacter pylori infection in a large population-based sample of preschool-aged children. The subjects, who lived in Ulm, Germany, and in two nearby communities, were screened for school fitness between January and July 1997. Their H. pylori infection status was determined by 13C-urea breath test. Of 1522 eligible children, 1221 (80.2%) participated in the study. Crude prevalence of H. pylori infection in children was 11.3% (95% confidence interval [CI], 9.5-13.3) and 36.4% in their parents (95% CI, 33.5-39.4). The crude odds ratio (OR) for H. pylori infection of children whose mothers were infected was 16.5 (95% CI, 8.9-30.8) and 7.9 after adjustment for potential confounders (95% CI, 4.0-15.7). The crude OR if the child's father was infected was 7.8 (95% CI, 2. 5-24.2) and 3.8 after adjustment for potential confounders (except maternal infection) (95% CI, 0.8-19.1). The results suggest that infected parents, especially infected mothers, may have a key role in transmission of H. pylori within families.

Adult↗
PubMed1999

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Journal Article↗
PubMed1999

Metabolic and weight-loss effects of a long-term dietary intervention in obese patients.

BACKGROUND: Obesity is a chronic disease that has become one of the most serious health problems in Western society. OBJECTIVE: We assessed the long-term effects of an energy-restricted diet combined with 1 or 2 daily meal replacements on body weight and biomarkers of disease risk in 100 obese patients. DESIGN: Phase 1 consisted of a 3-mo, prospective, randomized, parallel intervention study of 2 dietary interventions to reduce weight. The energy-restricted diet (5.2-6.3 MJ/d) consisted of conventional foods (group A) or an isoenergetic diet with 2 meals and 2 snacks replaced daily by energy-controlled, vitamin-and-mineral-supplemented prepared foods (group B). Phase 2 consisted of a 24-mo, case-control, weight-maintenance study with an energy-restricted diet and 1 meal and 1 snack replaced daily for all patients. RESULTS: Total weight loss (as a percentage of initial body weight) was 5.9+/-5.0% in group A and 11.3+/-6.8% in group B (P < 0.0001). During phase 1, mean weight loss in group B (n = 50) was 7.1+/-3.5 kg, with significant reductions in plasma triacylglycerol, glucose, and insulin concentrations (P < 0.0001). Group A patients (n = 50) lost an average of 1.3+/-2.2 kg with no significant improvements in these biomarkers. During phase 2, both groups lost on average an additional 0.07% of their initial body weight every month (P < 0.01). During the 27-mo study, both groups experienced significant reductions in systolic blood pressure and plasma concentrations of triacylglycerol, glucose, and insulin (P < 0.01). CONCLUSION: These findings support the hypothesis that defined meal replacements can be used for successful, long-term weight control and improvements in certain biomarkers of disease risk.

Adult↗
PubMed1999

Hepatocyte growth factor and fibroblast growth factor 2 are overexpressed after cerulein-induced acute pancreatitis.

The regenerative process after acute inflammation of the pancreas is characterized by cell proliferation as well as synthesis and transient deposition of extracellular matrix. Although the regulation of these processes is still unknown, there is growing evidence that the coordinated activity of various growth factors plays an important role in regeneration. Cerulein-induced pancreatitis in the rat was used to analyze whether growth factors and their receptor concentrations are changed in the acute pancreatitis. Messenger RNA hybridization revealed an individual expression pattern for each analyzed growth factor. The mRNA levels of platelet-derived growth factor B (PDGF B), epidermal growth factor (EGF), and insulin-like growth factor 2 (IGF-2) were not altered, whereas fibroblast growth factor-1 (FGF-1) and 2, IGF-1, transforming growth factor-alpha (TGFalpha), and hepatocyte growth factor (HGF) showed markedly increased concentrations with different expression maxima and duration compared with mRNA levels in healthy pancreata. The FGF-2 and IGF-1 expressions were increased between 1 and 3 days after induction of pancreatitis with maxima at day 2. HGF and FGF-1 mRNAs were upregulated between days 3 and 5. In contrast, TGFalpha exhibited the most prolonged overexpression. In the corresponding receptors, only c-met, the HGF-binding protein, showed higher mRNA and protein levels, whereas the expression of the other receptors did not change. Furthermore, in cultured pancreatic epithelial cells, HGF stimulated the expression of its own receptor in an autocrine manner. These results point out that the highly coordinated process of regeneration after pancreatitis may be influenced by a sequential induction and expression of peptide growth factors and their receptors.

Acute Disease↗
PubMed1999

Induction of TFF1 gene expression in pancreas overexpressing transforming growth factor alpha.

BACKGROUND/AIMS: Chronic pancreatitis is an inflammatory disease of the exocrine pancreas associated with extensive fibrosis, enlarged pancreatic ducts, acinar cell degeneration, and the formation of tubular complexes. The molecular and biochemical alterations associated with these histological changes are not kown. Generally, the new family of TFF peptides (formerly known as P-domain peptides or trefoil factors) is aberrantly expressed during chronic inflammatory diseases of the gastrointestinal tract. METHODS: Using human pancreatic tissues obtained from patients with chronic pancreatitis and murine pancreatic tissues obtained from transgenic mice overexpressing transforming growth factor alpha (TGF-alpha), the expression and cellular distribution of TFF1 was analysed using northern blot analysis, polymerase chain reaction (PCR), and immunohistochemistry. RESULTS: In the normal human pancreas, TFF1 was scarce, with only a few ducts exhibiting cytoplasmic TFF1 immunoreactivity. In contrast, human chronic pancreatitis tissue specimens exhibited strong TFF1 immunoreactivity in ductal cells, areas of ductal hyperplasia, and tubular complexes. Semiquantitative PCR analysis of TFF1 mRNA levels showed enhanced expression of TFF1 in the pancreas of patients with chronic pancreatitis. Furthermore, TFF1 mRNA levels were detectable in the pancreas in four of five transgenic mice overexpressing TGF-alpha. In contrast, four of five wild type mice did not exhibit a TFF1 mRNA transcript. In addition, while no specific TFF1 immunoreactivity was present in the pancreas of the wild type mice, ductal epithelial cells and duct-like tubular complexes in the pancreas of the transgenic mice overexpressing TGF-alpha exhibited pronounced TFF1 immunoreactivity. CONCLUSIONS: Ductal cells and tubular complexes in pancreatic fibrosis express TFF1. As the 5'-flanking region of TFF1 contains an epidermal growth factor responsive enhancer region and the expression of epidermal growth factor and TGF-alpha is enhanced in pancreatic fibrosis, the enhanced expression of TFF1 in pancreatic fibrosis may be mediated by TGF-alpha.

Adolescent↗
PubMed1999

A randomised, double blind, multicentre trial of octreotide in moderate to severe acute pancreatitis.

BACKGROUND: The pharmacological inhibition of exocrine pancreatic secretion with the somatostatin analogue octreotide has been advocated as a specific treatment of acute pancreatitis. AIM: To investigate the efficacy of octreotide in acute pancreatitis in a randomised, placebo controlled trial. METHODS: 302 patients from 32 hospitals, fulfilling the criteria for moderate to severe acute pancreatitis within 96 hours of the onset of symptoms, were randomly assigned to one of three treatment groups: group P (n=103) received placebo, while groups O1 (n=98) and O2 (n=101) received 100 and 200 microg of octreotide, respectively, by subcutaneous injection three times daily for seven days. The primary outcome variable was a score composed of mortality and 15 typical complications of acute pancreatitis. RESULTS: The three groups were well matched with respect to pretreatment characteristics. An intent to treat analysis of all 302 patients revealed no significant differences among treatment groups with respect to mortality (P: 16%; O1: 15%; O2: 12%), the rate of newly developed complications, the duration of pain, surgical interventions, or the length of the hospital stay. A valid for efficacy analysis (251 patients) also revealed no significant differences. CONCLUSIONS: This trial shows no benefit of octreotide in the treatment of acute pancreatitis.

Acute Disease↗
PubMed1999

Fibroblasts stimulate acinar cell proliferation through IGF-I during regeneration from acute pancreatitis.

Pancreatic regeneration after caerulein-induced pancreatitis is characterized by transient fibroblast proliferation followed by replication of acinar cells. The mechanisms that coordinate regeneration are incompletely understood. In this study, we examine the role of insulin-like growth factor I (IGF-I). Acute edematous pancreatitis was induced in rats by 12 h caerulein infusion. Pancreatic IGF-I mRNA levels increased over 50-fold during regeneration, reaching a maximum at day 2. Immunohistochemically, IGF-I was localized to fibroblasts within the areas of interstitial tissue. IGF-I mRNA was demonstrated in primary cultures of pancreatic fibroblasts but not in cultured pancreatic acinar cells. However, with the use of Western blotting acinar cells did express IGF-I receptors. IGF-I stimulated 5-bromo-2'-deoxyuridine uptake and increased numbers of acinar cells in a dose-dependent manner. Stimulation was half maximal at 1.1 nM and completely inhibited by an IGF-I antagonist and by IGF binding protein-3 (IGFBP-3). Possible paracrine regulation was confirmed by stimulation of acinar cell proliferation with fibroblast-conditioned medium, which was partially inhibited by IGF-I antagonist or by IGFBP-3. We conclude that acinar cell proliferation during late regeneration from pancreatitis is mediated at least in part by paracrine release of IGF-I from fibroblasts.

Acute Disease↗