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Biomedical subjects

M V Singer

Publications and source records attributed to M V Singer.

At least 19 recordsLinked to original sources
PubMed2006

TGF-beta/Smad signaling in the injured liver.

TGF-beta, acting both directly and indirectly, represents a central mediator of fibrogenic remodeling processes in the liver. Besides hepatic stellate cells (HSCs), which are induced by TGF-beta to transdifferentiate to myofibroblasts and to produce extracellular matrix, hepatocytes are also strongly responsive for this cytokine, which induces apoptosis during fibrogenesis and provides growth control in regeneration processes. Based on this, TGF-beta-mediated hepatic responses to injury are the result of a complex interplay between the different liver cell types. In this review we summarize the knowledge about TGF-beta signal transduction in HSCs with special impact on Smad pathways. We further describe a molecular cross-talk between profibrogenic TGF-beta and antifibrogenic IFN-gamma signaling in liver cells. Finally, we introduce hepatocyte plasticity and epithelial-to-mesenchymal transition in the liver, which is well established in tumorigenesis, as a potential feature of fibrogenesis and highlight possible action points of TGF-beta in these contexts.

Animals↗
PubMed2005

[Conservative treatment of chronic pancreatitis].

Chronic pancreatitis represents an inflammatory disease of the pancreas with progressive fibrotic destruction of the gland. The disease is characterized by abdominal pain, exocrine and endocrine insufficiency. Morphological alterations of the pancreas and signs of exocrine and endocrine insufficiency are difficult to detect early in the course of the disease. The conservative treatment of chronic pancreatitis aims at (1) control of abdominal pain, (2) replacing lost exocrine function, (3) treatment of endocrine insufficiency, (4) prevention of weight loss or achievement of weight gain, (5) limiting progression and complications of the disease, and finally (6) psychiatric and social advice with special emphasis on the treatment of chronic alcohol abuse. The patient must be counselled about the importance of abstinence from alcohol. Abdominal pain is controlled with strict analgetic medication using a step-by-step approach in increasing the dosage. Exocrine insufficiency is treated with a diet of several small meals per day and supplementation of pancreatic enzymes. Endocrine insufficiency is treated with insulin.

Chronic Disease↗
PubMed2005

[Therapeutic options of chronic constipation].

Chronic constipation is a widespread disease affecting up to 25 percent of the population in western countries. The symptoms associated with constipation may lead to a heavy burden and a decrease in quality of life. The therapy of chronic constipation is based upon its type and severity. Patients with normal transit may benefit from lifestyle measures including dietetic advice. However, almost none of these measures has been validated in a controlled trial. Bulk forming laxatives such as psyllium seeds and probiotics have a moderate evidence (Grade B). In certain cases, the use of osmotic laxatives, e. g. polyethylene glycol solutions (Grade A), is necessary. Tegaserod, a selective agonist of the serotonine subtype 4 (5-HT(4)), has a good evidence to treat constipation (Grade A). Patients with slow-transit constipation (transit-time over 72 hours) are dependent on osmotic (polyethylene glycol solutions, Grade A) and stimulant laxatives (bisacodyl, Grade C). Patients who suffer from defecatory disorders (outlet constipation) should be treated with bulk forming laxatives (Grade B) together with suppositories (e. g. CO(2)-suppositories) and enemas.

Cathartics↗
PubMed2005

[Probiotics as therapeutic agents in irritable bowel syndrome].

Probiotics are defined as living micro-organisms which, when administered in large amounts, confer a health benefit on the host. The use of probiotics in the therapy of infectious bowel diseases as well as maintaining remission of ulcerative colitis and in pouchitis is evidence-based. Also, in several studies proof could be supplied that specific probiotics relieve the symptoms and the course of irritable bowel syndrome. Some trials showed a significant improvement of irritable bowel syndrome-related constipation via Lactobacillus casei Shirota and E. coli Nissle 1917. Lactobacillus plantarum has been proven effective in reducing pain and abdominal bloating. However, in most of the studies rather small numbers of patients were examined. Furthermore, these studies do not always closely follow scientific standards (randomised, double-blind, placebo-controlled). Therefore, confirmatory studies are necessary to examine the effect of probiotics in irritable bowel syndrome.

Follow-Up Studies↗
PubMed2005

[Effects of alcohol on the upper gastrointestinal tract and the pancreas--an up-to-date overview].

The oesophagus, stomach and pancreas are primary target organs for ethanol-related diseases. In the oesophagus and stomach, ethanol induces motility disorders and mucosal lesions that are dose-dependent and reversible under acute conditions. Chronic consumption of alcohol causes a significant increase in the risk for squamous carcinoma of the oesophagus. All of these effects are mainly caused by direct contact of alcohol or its metabolite acetaldehyde with the mucosa. Non-alcoholic components are responsible for many effects of alcoholic beverages, including the powerful stimulation of gastric acid secretion by beverages that are produced by fermentation. In the exocrine pancreas, alcohol induces secretory alterations that are mainly affected by the manner and duration of alcohol exposure, the additional administration of food, the type of beverage or the basal secretory state of the gland. Because the pancreas is not topically exposed to ethanol, these ethanol effects on pancreatic secretion are primarily caused by systemic cholinergic mechanisms of the vagus nerve. Chronic alcohol abuse may cause chronic alcoholic pancreatitis after recurrent subclinical inflammatory episodes. Genetic predispositions are believed to play an additional role in the pathomechanism of the disease. In contrast to the cardiovascular system, moderate consumption of alcoholic beverages does not have any beneficial health effects on the oesophagus, stomach or pancreas. Future research needs to define the exact molecular mechanisms and the role of different genetic predispositions for alcohol-induced diseases as well as the effects of the non-alcoholic components of alcoholic beverages.

Acute Disease↗
PubMed2004

Effect of ethanol and some alcoholic beverages on gastric emptying in humans.

BACKGROUND: There is a paucity of detailed and controlled studies on the action of ethanol and alcoholic beverages on gastric emptying in humans. This study was designed to compare the effect of beer, red wine, whisky and their comparable pure ethanol solutions on gastric emptying in a controlled and randomized investigation. METHODS: On separate days, 10 healthy, fasted subjects received the following solutions, in random order, through a gastric tube: 500 mL beer, red wine, comparable pure ethanol solutions (4% and 10% v/v), glucose (5.5% and 11.4% w/v) and water, 125 mL whisky and 40% (v/v) ethanol (both followed by 125 mL water) and 250 mL water. Gastric emptying of the test solutions was assessed using ultrasonography of the antrum. RESULTS: As measured by ultrasonography of the antrum, half emptying times of the ethanol solutions (4%, 10% and 40% v/v) were significantly (P < 0.05) longer (22.6 +/- 4.8, 22.7 +/- 4.3 and 27.8 +/- 3.3 min, respectively, n=10) than those of water (14.6 +/- 1.9 min (500 mL) and 13.2 +/- 1.7 min (250 mL), respectively). The half emptying times of beer (39.3 +/- 4.3 min) and red wine (72.6 +/- 7.6 min) were significantly longer than those of the corresponding ethanol concentrations, whereas whisky was emptied at nearly the same rate (26.4 +/- 5.9 min) as 40% (v/v) ethanol. Emptying of glucose 5.5% and 11.4% (w/v) was significantly and dose dependently slower (29.7 +/- 4.5 and 64.8 +/- 8.9 min) than water. CONCLUSIONS: 1) Pure ethanol in concentrations of 4%, 10% and 40% (v/v) inhibits gastric emptying. 2) The inhibitory effect of beer and red wine, but not of whisky, is stronger than that of their comparable ethanol concentrations. 3) Caloric content and non-alcoholic ingredients in alcoholic beverages produced by fermentation (beer and wine), but not in those produced by distillation (whisky), are most likely responsible for this effect.

Adult↗
PubMed2004

Reliability of the [13C]-acetate breath test in the measurement of gastric emptying of ethanol solutions: a methodological study.

BACKGROUND: The [13C]-acetate breath test is a clinically well-established test for measuring gastric emptying of liquids and correlates significantly with scintigraphy. However, no studies have been undertaken to examine the relationship between gastric emptying measured by the [13C]-acetate breath test and ultrasonography. Furthermore, it is not known how ethanol may affect gastric emptying as measured by the [13C]-acetate breath test. This is particularly important because of the additional steps of absorption, metabolism and exhalation of the tracer involved in the [13C]-acetate breath test compared to the simple measurement of gastric emptying by ultrasonography. The aim of the present study was to examine the relationship between the gastric half emptying times measured by the [13C]-acetate breath test and by ultrasonography and to determine the effect of ethanol on the comparability between both methods. METHODS: On separate days, 10 healthy, fasted randomly selected subjects received the following solutions by gastric tube: 500 mL water, 4% and 10% (v/v) ethanol, 5.5% and 11.4 % (w/v) glucose. Gastric half emptying times of the test solutions were simultaneously determined using the [13C]-acetate breath test and ultrasonography of the fundus and the antrum. RESULTS: The gastric emptying rates determined by ultrasonography of the fundus correlated significantly with the results obtained using the [13C]-acetate breath test for all test solutions (r = 0.64-0.92, P < 0.05 for all), whereas ultrasonography of the antrum correlated significantly with the breath test only when water (r = 0.94, P = 0.001) was used. The difference between the mean half-emptying times obtained using the [13C]-acetate breath test and ultrasonography of the fundus was 55 +/- 1.8 min. This difference was significantly longer when 4% and 10% (v/v) ethanol solutions were given (61.2 +/- 3.3 and 71.2 +/- 2.9 min) compared to water (P < 0.05). CONCLUSIONS: A good correlation was found between gastric emptying as measured by the [13C]-acetate breath test and ultrasonography of the fundus. Measurements that were obtained using the [13C]-acetate breath test demonstrate a longer gastric half emptying time compared with those obtained using ultrasonography. This difference is even more marked when ethanol solutions are used. Presumably, this is because ethanol affects the absorption and/or the hepatic metabolism of the tracer. The [13C]-acetate breath test is therefore not a reliable gastric emptying test for comparison of different solutions, especially when ethanol-containing liquids are used.

Acetates↗
PubMed2003

Butyrate modulates intestinal epithelial cell-mediated neutrophil migration.

Butyrate, a short-chain fatty acid released by colonic bacteria and administered therapeutically in inflammatory bowel diseases, exerts immunomodulatory properties. The aim of the study was to determine the functional consequences of butyrate exposure on the proinflammatory responsiveness of human intestinal epithelial cells (IEC). IL-8 promoter activity in IEC pretreated with butyrate then exposed to proinflammatory stimuli was assayed by transfection of luciferase constructs. IL-8 secretion was determined by ELISA and neutrophil migration by flow cytometry. Receptor mRNA was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). Butyrate modulated proinflammatory IL-8 secretion differentially in Caco-2 and HT-29 cells on the transcriptional level. Pointing to the potentially underlying mechanism of increased IL-1 beta-stimulated IL-8 secretion in HT-29 cells, butyrate up-regulated IL-1RI mRNA but not IL-1RII. Butyrate pretreatment of IEC lines stimulated by IL-1 beta modulated neutrophil migration significantly: reduction towards Caco-2 and enhancement towards HT-29/p cells. Pharmacological inhibition of protein tyrosine phosphatases or treatment with mesalamine or sulphasalazine diminished IL-1 beta-stimulated IL-8 secretion by butyrate-exposed HT-29 cells substantially. Immunomodulatory effects of butyrate on IEC are functionally relevant for neutrophil migration. Pharmacological inhibition of enhanced IL-1 beta-mediated IL-8 secretion in a subpopulation of IEC may improve the clinical efficacy of butyrate.

Adjuvants, Immunologic↗
PubMed2003

Reducing psychological distress in patients with inflammatory bowel disease by cognitive-behavioural treatment: exploratory study of effectiveness.

BACKGROUND: This prospective study aimed to determine whether cognitive-behavioural group treatment accompanying medical standard care is effective in reducing psychological distress in patients with inflammatory bowel disease. METHODS: Twenty-eight outpatients with Crohn disease or ulcerative colitis completed the treatment programme. Psychological treatment consisting of 12 weekly sessions was conducted in a group setting. Medical and psychometric assessments were taken at the beginning of the 3-month pretreatment waiting period, at pretreatment, at post-treatment and at the 3, 6 and 9-month follow-ups. RESULTS: During baseline, no change was observed in psychological distress. Disease-related worries and concerns decreased significantly from pretreatment to the follow-ups. The disease groups differed in the decline of concerns between pre- and post-treatment, with a significant reduction of concerns in patients with ulcerative colitis but not Crohn disease. This difference did not occur at the follow-ups, indicating long-term improvement for both disease groups. Depressive coping decreased significantly in women and remained stable at the follow-ups, whereas depressive coping did not change in men. The same gender difference was found for depressive symptoms. CONCLUSIONS: The exploratory findings suggest that psychological group treatment for outpatients is a feasible and effective approach for the short- and long-term reduction of psychological distress for patients with inflammatory bowel disease. However, the revealed gender differences on coping and depression might indicate the necessity to consider gender-specific aspects of inflammatory bowel disease when designing and evaluating psychological interventions.

Adaptation, Psychological↗
PubMed2003

Role of the brain-gut axis in alcohol-related gastrointestinal diseases--what can we learn from new animal models?

Ethanol exerts multiple actions on nearly all organs of the body, especially on the central nervous system and the gastrointestinal tract. However, little is known about the effects ethanol has on the brain-gut axis, the linkage between the central neural system and the autonomous innervation of the gastrointestinal tract. It is indisputable that ethanol consumption does affect e.g. exocrine pancreatic secretion or intestinal motility, but it is poorly understood, how alcohol consumption may disturb the brain-gut axis and how this may cause damage to gastrointestinal organs. Due to difficulties in directly assessing ethanol effects on the brain-gut axis in humans, animal models represent a versatile tool to study this topic. However, conventional animal models widely utilized in alcohol research, e.g. the Tsukamoto-French model or the Lieber-DeCarli model, do not mimic the human conditions of ethanol consumption and are therefore not suitable for studies of the brain-gut axis. Established models from other alcohol research disciplines, e.g. addiction research, are by far more applicable. Due to this reason, we have established an animal model of alcohol-dependent rats for the use in gastrointestinal alcohol research. In this model, rats are given free access to different of alcohol solutions (5% and 20% v/v) and tap water. Over time, the rats develop signs of alcohol dependence as seen in humans (e.g. deprivation effect). Organs isolated from rats exposed to this model are currently investigated in our laboratory for alcohol-related gene-regulation compared to non-alcoholic littermates. In addition, non-alcoholic components of alcoholic beverages might affect the brain-gut axis or possibly potentiate the toxicity of ethanol. In our model, commonly ingested alcoholic beverages such as beer, wine, cognac, vodka, and whisky and their non-alcoholic constituents will be tested in future animal studies.

Alcohol Drinking↗
PubMed2002

[Differential diagnosis and therapy of acute pancreatitis].

Acute pancreatitis is classified in an interstitial edematous pancreatitis and a hemorrhagic necrotizing pancreatitis comprising 80% and 20% respectively of all cases. 80% of acute pancreatitis are attributed to biliary and alcoholic origin whereas in more than 10% no etiology can be established comprising the idiopathic forms of acute pancreatitis. Clinical symptoms are rather unspecific resulting in a large number of abdominal and extraabdominal diseases that have to be considered regarding the differential diagnosis. Diagnosis is based on clinical examination, laboratory findings and ultrasound. However it has to be taken into account that a lack of abdominal symptoms and unaltered amylase and lipase levels may be present in spite of overt pancreatitis. As severe pancreatitis is associated with a steep increase in mortality the early identification of severe pancreatitis is crucial. Several prognostic scores like the Ranson-, Glasgow- and APACHE-II score were developed to achieve a higher sensitivity detecting transition to severe pancreatitis. In addition new prognostic serum parameters are applicable. A prophylactic antibiotic therapy is recommended in patients with sterile necrosis whereas an infected necrosis requires organ preserving necrosectomy and retroperitoneal lavage which can be done surgically or referring to new concepts endoscopically. Apart from renal and respiratory failure, necrosis, pseudocysts and pancreatic abscess are the main complications. In the presence of detected stones in the common bile tract ERCP in combination with stone extraction and papillotomy reduces morbidity and mortality in patients with biliary pancreatitis. Laparoscopic cholecystectomy should be performed as soon as the patient has recovered and preferably during the same hospital admission.

Acute Disease↗
PubMed2001

Expression and localization of IL-1beta mRNA is interrelated with cytoskeletal rearrangement in monocytes stimulated by adherence: a light microscopy in situ hybridization study.

Differences in IL-1beta mRNA expression, stability and translation between non-adherent monocytes and those stimulated by adherence suggest that cytokine regulation is coupled to the function and assembly of cytoskeletal structures. In situ hybridization studies were performed to visualize expression and positioning of IL-1beta mRNA in adherently cultivated monocytes. IL-1beta mRNA expression was heterogeneous with high transcript levels found in spread or polarized cells. Transcripts were compartmentalized to the perinuclear region in spread cells, and partially redistributed with polarization. In contrast to mRNA distribution in other motile cell populations, IL-1beta mRNA did not localize to the distal or proximal actin cytoskeleton. Perinuclear confinement of transcripts required intact actin microfilaments. Treatment with cytoskeleton disruption and detergent extraction suggested that most non-translated IL-1beta mRNA was associated with intermediate filaments. In monocytes stimulated by LPS, IL-1beta, but not IL-1Ra transcripts were redistributed and partially associated, yet not bound to actin microfilaments. The present study demonstrates that IL-1beta mRNA expression and localization in adherent monocytes is interrelated with the cytoskeletal rearrangement upon adherence, spreading and polarization.

Actins↗
PubMed2001

4-day triple therapy with rabeprazole, amoxicillin and clarithromycin in the eradication of Helicobacter pylori in patients with peptic ulcer disease--A pilot study.

BACKGROUND: It is well established that a 7-day triple therapy achieves eradication rates of Helicobacter pylori between 90% and 95%. Due to a lack of highly effective short-term eradication studies the aim of the present pilot study was to investigate the effect of a 4-day triple therapy with the new proton pump inhibitor rabeprazole (20 mg b. i. d.) in combination with clarithromycin (500 mg b. i. d.) and amoxicillin (1 g b. i. d.) without acid-suppressive pre-treatment in patients with H. pylori-related peptic ulcer disease. METHODS: 20 patients (11 men, 9 women) with endoscopically diagnosed peptic ulcers (gastric ulcer: n = 5; duodenal ulcer: n = 9; combined gastric and duodenal ulcer: n = 2, gastric or duodenal ulcer scars: n = 4) and H. pylori infection were consecutively recruited. The Helicobacter pylori status was assessed by means of histology, CLO (urea-) test and C13-urea breath test (C13-UBT) at entry. Treatment success was determined by C13-UBT 35-42 days after end of treatment. RESULTS: In 18 out of the 20 patients (90%) [77-100%, 95%-CI] a negative test result was found in C13-UBT 35-42 days after treatment. The 2 patients who remained H. pylori-positive had a duodenal ulcer. CONCLUSION: A 4-day triple therapy of rabeprazole in combination with clarithromycin and amoxicillin seems to be highly effective in eradicating H. pylori and well tolerated in patients with gastric and duodenal ulcer disease. The achieved eradication rate of 90% is comparable with the established 7-day triple therapy regimens. On the basis of these results and considering costs, side effects and compliance a large number of patients should be enrolled in a confirmatory 4-day eradication trial.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2001

Fecal elastase-1 determination: 'gold standard' of indirect pancreatic function tests?

BACKGROUND: Tubeless pancreatic function tests measuring the content of elastase-1 and the activity of chymotrypsin in stool are used with different cut-off levels and with varying success in diagnosing functional impairment of the pancreas. The aim of our study was to re-evaluate the sensitivity and specificity of elastase-1 and chymotrypsin in stool in the assessment of exocrine pancreatic insufficiency. METHODS: In 127 patients displaying clinical signs of malassimilation, the secretin-caerulein test ('gold standard'), fecal fat analysis, fecal chymotrypsin activity and fecal elastase-1 concentration were performed. Exocrine pancreatic insufficiency was graded, according to the results of the secretin-caerulein test, into mild, moderate and severe. Chymotrypsin and elastase-1 in stool were estimated using two commercially available test kits. Fecal elastase-1 concentration of 200 and 100 microg/g stool and chymotrypsin activity of 6 and 3 U/g stool were used separately as cut-off levels for calculation. RESULTS: 1) In 65 patients, a normal pancreatic function was found using the secretin-caerulein test. In 62 patients, an exocrine pancreatic insufficiency was found and classified into severe (n = 25), moderate (n = 14) and mild (n = 23). 2) The correlation between fecal elastase-1 and chymotrypsin with duodenal enzyme outputs of amylase, lipase, trypsin, chymotrypsin and elastase-1 ranged between 33% and 55% and 25% and 38%, respectively. 3) Using a cut-off of 200 microg elastase-1/g, stool sensitivities of fecal elastase-1 and fecal chymotrypsin (cut-off: 6 U/g) were 100% and 76%, respectively (P < 0.0001 and P < 0.001 respectively) in severe exocrine pancreatic insufficiency, 89% and 47% respectively (P < 0.001; P = 0.34, respectively) in moderate and 65% for both in mild pancreatic insufficiency. Specificities of elastase-1 and chymotrypsin in stool were 55% and 47%, respectively. 4) Elastase-1 based diagnostic provided a positive predictive value of 50% using a cut-off' 200 microg/g stool in a representative group of consecutively recruited patients with gastroenterological disorders. CONCLUSION: Determination of fecal elastase-1 is highly sensitive in the diagnosis of severe and moderate exocrine pancreatic insufficiency and is of significantly higher sensitivity than fecal chymotrypsin estimation. Specificity for both stool tests is low. Correlation between elastase-1 and chymotrypsin in stool and duodenal enzyme outputs is moderate. Neither test is suitable for screening, as they provide a pathologic result in roughly half of 'non-pancreas' patients.

Biomarkers↗
PubMed2001

Gene expression of interleukin 18 in unstimulated peripheral blood mononuclear cells of patients with alcoholic cirrhosis.

BACKGROUND: Most patients with alcohol induced cirrhosis (AC) and chronic endotoxinaemia are not suffering from clinically evident systemic inflammatory reactions. This may be due to altered gene expression of cytokines, possibly related to endotoxin (for example, tolerance and sensitisation). Interleukin 18 (IL-18; interleukin gamma inducing factor) modulates local cytokine production in response to endotoxin (lipopolysaccharide (LPS)). AIM: To investigate the systemic immune response of patients with AC and to see if unstimulated peripheral blood mononuclear cells (PBMC) from patients with AC are activated and contribute to gene expression of IL-18. METHODS: Plasma levels of endotoxin (LPS) and serum levels of IL-18 were measured by enzyme linked immunoassay and the amoebocyte lysate test in 74 abstinent patients with different stages of AC (Child-Pugh stage A, n=18; B, n=22; C, n=34) and compared with healthy controls (n=43). Gene expression of IL-18 was assessed by semiquantitative reverse transcription-polymerase chain reaction in freshly isolated unstimulated PBMC of a subgroup of 14 patients with AC compared with five healthy controls. RESULTS: Gene expression of IL-18 specific mRNA in unstimulated PBMC was significantly enhanced in patients with advanced AC (Child-Pugh stage C) and correlated with plasma LPS and serum CD14 levels (Spearman rank correlation factors r=0.76 and r=0.72). Serum concentrations of IL-18 were also elevated compared with healthy controls (p<0.001) but correlation with serum levels of CD14 and plasma levels of LPS was much weaker compared with mRNA data (Spearman rank correlation factors r=0.47 and r=0.26). CONCLUSIONS: Our in vivo data suggest a presensitisation of "unstimulated" PBMC in the circulation of patients with AC by endotoxin. The term "unstimulated" may be inadequate in patients with AC. Further investigations are needed to define the exact mechanisms and localisation of sensitisation of PBMC in vivo.

Case-Control Studies↗