[Chronically ill children become grown-up. What does the internist learn from the pediatrician?]. / Chronisch kranke Kinder werden erwachsen. Was lernt der Internist vom Pädiater?

Transition from the protective, child and family centered pediatric care to the adult health care system with the expectation of patient self care and self management, is challenging the adolescent as well as his adult specialist. The young patients often show a delayed somatic and psychosocial development and oppose not only against their parents but also against their medical team. Adult specialists feel not well trained and experienced in dealing with adolescents. They are worried about the difficulties in the guidance of the patients and the non adherence to therapeutic recommendations. Due to medical progress, many children with severe or/and fatal chronic disorders are now surviving into adulthood. Profound knowledge of diseases that were known until now almost exclusively in the pediatric population as well as an awareness of normal physical, mental and psychosocial development of childhood and adolescence is not training content of German internists. The intention of this article is to discuss some of the experiences of pediatricians that might be helpful to internists to take better care for these special young patients.

[Reflux disease and Barrett's oesophagus - are there gender-specific differences?]. / Refluxerkrankung und Barrett-Osophagus - Gibt es geschlechtsspezifische Unterschiede?

Studies of the prevalence of gastroesophageal reflux disease (GERD) have reported that male gender is an independent risk factor especially for erosive reflux disease (ERD). Non erosive GERD (NERD) is more common in females. The rate of prevalence and severity of reflux symptoms increase in females with age, while among men it peaked between 50 and 70 years and thereafter declined. The gender effect may be caused by differences in parietal cell mass between males and females. Barrett's esophagus is a major complication of gastroesophageal reflux disease and is associated with 30-125 times increased risk of developing carcinoma. Most studies have found gender differences with females significantly less likely to have Barrett's esophagus with a 20-yr age shift between the parallel age specific prevalence curves, for males between the ages of 20 and 59 yr and for females between the ages of 20 and 79 yr. Male predominance for ERD as a precursor to Barrett's esophagus may be partly explain the greater male/female sex ratio for Barrett's esophagus. Female sex hormones may play a protective role. Knowledge of gender-specific differences of reflux disease and Barrett's esophagus may be helpful to improve surveillance and screening strategies, although distinct recommendations are lacking so far .

Safety, tolerability and efficacy of peginterferon alpha-2a and ribavirin in chronic hepatitis C in clinical practice: The German Open Safety Trial.

The combination treatment of peginterferon alpha-2a (PEG-IFN alpha-2a; Pegasys) plus ribavirin (RBV) is recommended as a standard care for HCV infections. Side effects and aspects of efficacy and safety have to be balanced. This study evaluates clinical practice data on safety and efficacy of HCV treatment with PEG-IFN in combination with RBV over 24 and 48 weeks. This study was a phase III, multi-centre, open-label study with two treatment groups: PEG-IFN in combination with RBV for 24 or 48 weeks. The allocation to the treatment groups was at the discretion of the investigator; 309 patients entered active treatment: 90 patients received PEG-IFN plus RBV for 24 weeks and 219 patients PEG-IFN plus RBV for 48 weeks. A sustained virological response (SVR) was achieved in 48.9% of all patients. Genotype 1 patients with a 48-week combination treatment achieved an SVR of 39.9%. In the 48-week group a low baseline viral load was associated with a higher SVR rate (47.0% vs. 32.4%). For genotype 2 or 3 patients, the SVR was 67.9%. For these patients there was no relevant difference between patients with low and high viral loads; 97.7% of the patients experienced at least one adverse event. The incidence of serious adverse events was distinctly lower in the 24-week group (4.4% vs. 10.5%). This investigation confirms the well-known risk-benefit ratio found in controlled studies in a clinical practice setting. The safety profile is similar and shows the highest incidence of adverse events in the first 12 weeks of treatment.

Self-expanding Polyflex plastic stents in esophageal disease: various indications, complications, and outcomes.

BACKGROUND: Esophageal stenting has become an important technique in the treatment of different clinical problems such as malignant or benign stenosis, anastomotic leaks after surgery, or fistulas. In this study we present our experience with the self-expanding Polyflex plastic stent in various indications, arising complications, and patient's outcomes. METHODS: Over a three-year period, 35 patients underwent self-expanding Polyflex plastic stent placement for esophageal stenosis (n = 23) with 22 malignant, and for perforations, fistulas, or anastomotic leaks after surgery (n = 12). The short-term efficacy and long-term outcomes were analyzed. RESULTS: In patients with stenosis, implantation was performed without any complications in 91% (21/23). In one patient perforation occurred while passing the stenosis; in another patient the stent dislocated during the insertion procedure. Dysphagia score improved from 3.0 to 1.0 after stenting. In all patients with perforations, fistulas, or anastomotic leaks (n = 12), stents were placed successfully without any complication. Complete sealing of the mucosal defect was proven by radiography in 92% (n = 11) and healing was seen in 42% (n = 5). If indicated, stent removal was performed without any complications. Stent migration (n = 13; 37%) was the most common long-term complication. CONCLUSIONS: The placement of self-expanding Polyflex plastic stents is a highly sufficient and cost-effective treatment for malignant and benign esophageal disorders. Because the long-term results were highly favorable, self-expanding plastic stent placement could be used as the initial treatment for various conditions.

Hepatitis C - contamination of toothbrushes: myth or reality?

Chronic hepatitis C patients are advised not to share toothbrushes, razors, nail-scissors or other personal articles that potentially may have been in contact with blood, with others. This study examines the contamination of toothbrushes in patients with chronic hepatitis C as a model for a possible unconventional way of transmission. In 30 patients with chronic hepatitis C, 2 mL of saliva (before and after toothbrushing) and the toothbrush rinsing water after toothbrushing were tested for HCV-RNA. Saliva before and after toothbrushing was positive for HCV-RNA in nine (30%) and 11 patients (36.7%), respectively. Twelve of the toothbrush rinsing water specimens (40%) tested HCV-RNA-positive. In six of these 12 patients, the 'native' saliva had been negative for HCV-RNA. Patients with HCV-RNA-positive toothbrush rinsing water showed no significant differences from those with negative rinsing water with respect to certain clinical, biochemical and virological parameters. In conclusion, our study demonstrates a contamination with HCV-RNA of a considerable portion of toothbrushes used by hepatitis C patients, suggesting at least a theoretical risk of infection by sharing these objects and strengthening the recommendations to take care of a clear separation of these personal care objects between patients and their household members.

Lack of correlation between the vitamin D receptor Fokl start codon polymorphism and bone mineral density in patients with Crohn's disease.

INTRODUCTION: We have examined the association of bone mineral density of patients with inflammatory bowel disease with a polymorphism in the gene encoding the vitamin D receptor. The thymine/cytosine (T/C) polymorphism in the first of two start codons can be defined by a restriction fragment length polymorphism using the restriction endonuclease FokI. Vitamin D receptor alleles containing the polymorphism have been denoted by f and alleles lacking the site by F. METHODS: We report on an association analysis of a basic population of 244 caucasian patients with Crohn's disease. We have genotyped the FokI polymorphism of the VDR in these patients and associated the genotype with the bone mineral density of the lumbar spine and the femoral neck. RESULTS: In the cohort 42% of the patients were scored FF homozygous, 43.7% Ff heterozygous, and 14.3% ff homozygous. 14.4% of the FF patients, 18.8% of the Ff patients, and 9.7% of the ff patients had osteoporosis of the lumbar spine and 21.25% of the FF patients, 25.3% of the Ff patients, and 18.5% of the ff patients had osteoporosis of the femoral neck. In this cohort no association between the genotype and the bone mineral density in the group as a whole nor when separated according to sex or age was found. CONCLUSIONS: In summary in our cohort no association of the FokI polymorphism and the BMD of the lumbar spine and femoral neck in patients with inflammatory bowel disease was found.

Use of self-expandable plastic stents for the treatment of esophageal perforations and symptomatic anastomotic leaks.

BACKGROUND AND STUDY AIMS: Extensive anastomotic leaks after esophageal resection and esophageal perforations are a therapeutic challenge. The aim of the present study was to assess the potential of the self-expandable Polyflex plastic stent for the treatment of these conditions. PATIENTS AND METHODS: Between January 2002 and March 2003, nine patients were treated with a self-expandable Polyflex plastic stent for sealing of thoracic esophagoenteric anastomotic leaks following surgical resection (n = 5) or esophageal perforation (n = 4). RESULTS: In all patients the stents were inserted successfully without technical problems. In all but two patients complete sealing of the leak was achieved as demonstrated by radiography with water-soluble contrast media. The stent migration rate was 30 % and repositioning of the migrated stents was possible in all cases. Complete mucosal healing of the esophageal leaks and stent extraction was achieved in six patients. The stents were in situ for an average period of 135 +/- 78 days. Two critically ill patients with anastomotic leaks died in spite of stent insertion due to sepsis and one patient with esophageal perforation died due to the underlying malignant disease. CONCLUSIONS: Our preliminary experience with the self-expanding and removable Polyflex plastic stent for the sealing of anastomotic leaks and esophageal perforations suggests that this stent is a feasible treatment option, in particular, for more extensive esophageal defects, patients with co-morbid conditions, and critically ill patients.

Inducible CD40 expression mediates NFkappaB activation and cytokine secretion in human colonic fibroblasts.

BACKGROUND: CD40 has been shown to be a functional activation antigen on a variety of cell types involved in immune responses. As intestinal fibroblasts and myofibroblasts may play a role during mucosal inflammation, we investigated the functional consequences of CD40 induction in primary cultures of human colonic fibroblasts. METHODS: Primary colonic lamina propria fibroblasts (PCLF) were isolated from endoscopic biopsies and surgical specimens. Cultures were used between passages 3 and 9. CD40 surface display was determined by FACS analysis and mRNA expression by reverse transcription-polymerase chain reaction. Secretion of cytokines was determined by ELISA. Nuclear factor kappaB (NFkappaB) activation was shown by electrophoretic mobility shift assay (EMSA). RESULTS: After priming with interferon gamma (IFN-gamma) (200 U/ml) for 72 hours, five of eight tested PCLF cultures showed induction of CD40 surface display (up to 10-fold). Induction of CD40 mRNA expression was demonstrated by semiquantitative polymerase chain reaction. In the responder-PCLF cultures, IFN-gamma alone caused a 1.5-5-fold increase in interleukin (IL)-8 secretion. Addition of 1 ng/ml CD40L was sufficient to achieve a further increase in IL-8, IL-6, or monocyte chemotactic protein 1 (MCP-1) secretion (2.5-18-fold of controls). Incubation with CD40L alone without priming with IFN-gamma had no effect. The proteasome inhibitor N-acetyl-leucinyl-leucinyl-norleucinal (ALLN 100 microM) reduced IFN-gamma/CD40L mediated cytokine induction, suggesting participation of NFkappaB, which was directly demonstrated by EMSA. CD4+ T cells induced MCP-1 secretion by PCLF, which was prevented by addition of an excess of CD40-IgG fusion protein. CD40 expression on PCLF could also be demonstrated in vivo by immunohistochemistry. CONCLUSION: The CD40-CD40L pathway augments mucosal inflammatory responses via mucosal PCLF. CD40-CD40L mediated T cell/PCLF interactions could play an important role during intestinal mucosal inflammation.

[Value of abdominal ultrasound screening in patients with benign diseases of the skin]. / Diagnostische Wertigkeit der Abdominalsonografie im Primärscreening benigner Hauterkrankungen.

OBJECTIVE: We investigated the value of abdominal ultrasound screening of abdominal foci in patients with benign diseases of the skin. PATIENTS AND METHODS: The data of 151 patients (age (mean) 56,6 years; male n = 79, female n = 72) from the department of dermatology were retrospectively analysed. The patients were sent for ultrasound evaluation of abdominal foci as cause of benign diseases of the skin. RESULTS: In these 151 patients 3 potential foci were found (2 yen suspicion of a liver tumor, 1 yen thickened bowel wall). The liver tumors could not be confirmed by computed tomography, in the patient with a thickened bowel wall, a Crohns disease was newly diagnosed. Abdominal ultrasound led to clinically relevant findings in fewer than 1 % of cases. We diagnosed 142 abnormal findings, mostly without clinical relevance. These abnormal findings caused follow-up examinations in 30 of the cases (19 computed tomographies; 2 magnetic resonance tomographies). CONCLUSION: Abdominal ultrasound does not seem useful in the primary screening of patients with benign diseases of the skin. Perhaps a more restrictive and selective use of ultrasound could be valuable.

Fluorescence endoscopy and photodynamic therapy.

Fluorescence endoscopy is a new technique which allows a better detection of non-visible malignant or premalignant lesions or, those which are difficult to detect. Exogenously applied sensitisers accumulate selectively in malignant lesions and induce fluorescence after illumination with light of adequate wavelength. However, also endogenous fluorophores, different located in malignant or benign lesions, induce a different autofluorescence in these lesions. Tissue fluorescence can be detected by optical sampling of the mucosa using fluorescence spectroscopy or by generating real time fluorescence images with specialised camera systems. Compared to point fluorescence spectroscopy the latter technique enables the screening of large surface areas of mucosa. Meanwhile, fluorescence endoscopy is a widely used technique in urology employing 5-aminolaevulinic acid sensitisation. In gastroenterology, this technique seems promising for the detection of early cancers or dysplasia in patients with Barrett's oesophagus or ulcerative colitis. Using different sensitisers, photodynamic therapy seems to be a promising option for patients with advanced oesophageal cancer and in the palliative treatment of non-resectable bile duct cancer, furthermore for patients with early gastric cancer and dysplasia in Barrett's oesophagus. Probably, by laser light fractionation or a combination of different sensitisers, an enhanced effect can be expected.

Regulation of migration of human colonic myofibroblasts.

BACKGROUND AND AIM: The migration of mesenchymal cells to areas of mucosal or submucosal tissue damage is an essential factor for wound healing in the intestine. Thus far, neither migration inducing factors nor signal transduction cascades involved in the migration of colonic myofibroblasts (CMF) have been studied in detail. METHODS: Primary CMF were isolated from the mucosa of surgical specimens or endoscopic biopsies. Migration assays of CMF were performed in the modified 48-well Boyden chamber. Secreted growth factors were quantified by ELISA. RESULTS: CMF secrete autocrine or paracrine migration stimulating factors. Culture supernatant of CMF collected after 24, 48, and 72 h ( = conditioned media) stimulated the migration of CMF (48.9+/-4.5; 60.3+/-5.3 and 67.8+/-6.4 cells/hpf, respectively). Heating of conditioned media to 95 degrees C or addition of cycloheximide during the conditioning period abolished migration. Addition of PDGF-AB (2.5-50 ng/ml) or IGF-I (10-300 ng/ml) to CMF conditioned media further increased the migration of CMF to a maximum of 177 and 160%, respectively, when compared to the migration induced by conditioned medium alone. Addition of EGF (2.5-50 ng/ml) or TGF-beta1 (1-50 microg/ml) caused an increased CMF migration up to 139 and 128%, respectively. MCP-1 (5-50 ng/ml) and bFGF (10-200 ng/ml) had no effect on CMF migration. CONCLUSION: The growth factors PDGF-AB, IGF-I, EGF and TGF-beta1 stimulate the migration of CMF. However, factors secreted by CMF are essential for their ability to migrate in response to these growth factors. The identification of physiologically relevant migration inducing factors may help to elucidate the network of interactions and the complex mechanisms involved in intestinal wound healing or fibrosis.

Association of HLA-DR genotypes and IL-1ra gene polymorphism with treatment failure of budesonide and disease patterns in Crohn's disease.

OBJECTIVE: Associations between HLA-DR genotypes and susceptibility to Crohn's disease (CD) have been reported. However, it is not known whether certain HLA-DR genotypes or IL-1ra gene polymorphism are associated with responsiveness to treatment or different clinical patterns of disease. DESIGN/SETTING: In a large, randomized, controlled multicentre trial, 318 patients with CD were treated with daily doses of 6, 9 or 18 mg budesonide. Patients were stratified into two groups: patients without steroid pretreatment and with active CD (CDAI > 150) and patients with conventional steroid pretreatment of < or= 30 mg prednisolone per day, which was replaced by oral budesonide within 3 weeks. MAIN OUTCOME MEASURES: The HLA-DRB1 genotypes 1-16 and the IL-1ra gene polymorphism were examined for an association with budesonide treatment failure. RESULTS: Only HLA-DR 8 was associated with treatment failure of budesonide. HLA-DR 8 is not very common. Only 17/243 patients who could be evaluated expressed this genotype, and 13 of these 17 patients did not respond to budesonide (P < 0.00067). Neither the other HLA-DR genotypes nor the IL-1ra gene polymorphism had an influence on treatment outcome of budesonide therapy. No significant association of fistulas, perianal disease, need for bowel resections, and disease localization with certain HLA-DRB1 genotypes or the IL-1ra gene polymorphism were found. CONCLUSIONS: This is the first description of an association of a certain HLA-DR genotype (HLA-DR 8) with treatment failure in inflammatory bowel disease (IBD).

Differential activation of cytokine secretion in primary human colonic fibroblast/myofibroblast cultures.

BACKGROUND: Fibroblasts and myofibroblasts are known to secrete a wide spectrum of cytokines, but the individual spectrum is tissue-specific. We investigated the effect of cell activation on cytokine secretion of isolated human colonic fibroblasts/myofibroblasts from control patients and patients with mucosal inflammation. METHODS: Primary cultures of human colonic submucosal fibroblasts/myofibroblasts were incubated with IL-1alpha (100 U/ml), IL-Ibeta (10 ng/ml), IL-10 (10 ng/ml), TNF (10 ng/ml), PMA (10 ng/ml), LPS (50 ng/ml), IL-4 (10 ng/ml), or a combination of IL-1 and TNF. Secreted cytokines were determined by ELISA. NF-kappaB activation was demonstrated by electrophoretic mobility-shift assays (EMSA). RESULTS: Incubation of colonic fibroblasts/myofibroblasts with IL-1, LPS, TNF and PMA induced secretion of IL-6, IL-8, M-CSF and GM-CSF. IL-8 and IL-6 secretion could be stimulated by IL-1alpha, IL-1beta, TNF, PMA and LPS within 6 h of incubation. IL-6 secretion was stimulated from 0.5 +/- 0.01 pg/h x microg fibroblast protein to 18.5 +/- 2.6 pg/h x microg fibroblast protein with IL-1beta (P < 0.01). IL-8 secretion was stimulated from 1.0 +/- 0.1 pg/h x microg fibroblast protein to 41.1 +/- 3.6 pg/h x microg (P < 0.005). IL-4 and IL-10 did not change cytokine secretion significantly. No significant differences between cultures from normal and inflamed mucosa were observed. TNF and IL-1 induced NF-kappaB activation. ALLN, a proteasome and NF-kappaB activation inhibitor, reduced TNF-mediated IL-8, GM-CSF and M-CSF induction significantly, whereas induction of IL-6 secretion remained unchanged. CONCLUSION: Human colonic myofibroblasts can secrete large amounts of IL-6, IL-8, M-CSF and GM-CSF upon stimulation. The induction of IL-8, M-CSF and GM-CSF, but not of IL-6 secretion, is mediated mainly by NF-kappaB activation. The cytokine profile and the total amounts of cytokines released suggest that colonic myofibroblasts can play a role in leukocyte recruitment and during mucosal inflammation. They therefore have to be regarded as an important part of the mucosal immune system.

Prediction of treatment refractoriness in ulcerative colitis and Crohn's disease--do we have reliable markers?

Treatment refractoriness is a severe problem in the management of patients with ulcerative colitis and Crohn's disease. Despite some promising new therapeutic approaches, corticosteroids are still the preferential primary treatment for moderate to severe Crohn's disease and of severe ulcerative colitis. However, clinical response to corticosteroids varies, and many patients are resistant to such treatment. Since corticosteroids have frequent and even severe side effects, and toxicity increases with chronic steroid intake, factors predictive of response to such treatment would be very helpful for decisions on further management of these patients. At least in severe attacks of ulcerative colitis, the consensus seems to be that a high frequency of bowel movements as well as a high C-reactive protein and low serum albumin recorded after a few days of intensive medical treatment are important signs for early prediction of treatment failure in the majority of the patients. In Crohn's disease thus far, data on predictive factors are conflicting. No reliable marker with sufficient predictive value for treatment refractoriness could be identified. This might be due to the tremendous heterogeneity of Crohn's disease with many clinical phenotypes, which requires subgroup analysis with sufficient numbers of patients. Corticosteroids as well as other immunomodulating and immunosuppressive medications interfere with the immune system, which plays a central role in the mediation of intestinal inflammation. Treatment refractoriness might have its origin in specific immunological peculiarities eventually reflected in abnormal immunological, biochemical, and clinical parameters. Further exploration of those parameters to predict treatment refractoriness in patients with ulcerative colitis or Crohn's disease is of great clinical importance for safe and efficient management of patients.

[Liver histology in hepatitis C: correlation with different biochemical and virological parameters]. / Leberhistologie bei Hepatitis C: Korrelation mit verschiedenen biochemischen und virologischen Parametern.

BACKGROUND AND AIM: According to the German consensus statement, the indication for treatment of HCV-RNA-positive chronic hepatitis C is not derived from histopathology but from elevated aminotransferases. The indication for liver biopsy has been discussed controversely. This study aimed at investigating the correlation between different biochemical and virological parameters and histological scores of inflammation and fibrosis in chronic hepatitis C. PATIENTS AND METHODS: In a retrospective study, data of 126 patients with chronic hepatitis C who had undergone liver biopsy between January 1994 and March 1998 were analyzed. Histology was interpreted according to a defined numerical score of inflammation and fibrosis by a single pathologist. Scores of fibrosis and inflammation were correlated with biochemical and virological parameters. RESULTS: Inflammatory grading showed a moderate but significant correlation with ALT (r = 0.33, p < 0.001), whereas staging of fibrosis did not correlate with ALT (r = 0.15). There was no association between grading or staging and HCV genotype (n = 110) or serum viral load (n = 57). Grading and staging showed a significant association with each other (p < 0.0001). CONCLUSION: Aminotransferases as "surrogate markers" reflect more or less the histological inflammatory activity but do not allow any estimation of the extent of fibrosis. Some patients may have a high inflammatory activity with low aminotransferases or high aminotransferases with low inflammatory activity. Virological parameters such as HCV genotype or viral load do not allow an estimation of histological findings. If prior to treatment of chronic hepatitis C liver biopsy is omitted and the decision for treatment depends solely on the measurement of surrogate markers, considerable misjudgement of the actual status of liver inflammation or fibrosis may result.

Strictures in Crohn's disease are characterised by an accumulation of mast cells colocalised with laminin but not with fibronectin or vitronectin.

BACKGROUND/AIMS: Intestinal fibrosis and stricture formation is an unresolved problem in Crohn's disease. The aim of this study was to investigate whether mast cells accumulate in these tissues and whether their localisation is associated with extracellular matrix components. METHODS: Mast cells were visualised by immunohistochemical staining of the mast cell specific proteases chymase and tryptase. Their localisation in relation to extracellular matrix components was shown by immunohistochemical double labelling. RESULTS: In strictures in Crohn's disease, a striking accumulation of mast cells was seen particularly in the hypertrophied and fibrotic muscularis propria, with a mean (SEM) mast cell number of 81.3 (14.9) v 1.5 (0.9)/mm(2) in normal bowel (p<0.0005). All mast cells in the muscularis propria were colocalised with patches of laminin. In contrast, in the submucosa, laminin was exclusively found in the basal lamina of blood vessels where many adherent mast cells were seen. No colocalisation of mast cells was found with fibronectin or vitronectin. CONCLUSIONS: The large accumulation of mast cells in the muscle layer of strictured bowel suggests a functional role for these cells in the hypertrophic and fibrotic response of the smooth muscle cells. The colocalisation with laminin indicates a mechanism of interaction between smooth muscle cells and mast cells that may be important in the role of mast cells in the process of fibrosis.

Spontaneous rupture of liver in a patient with Ehlers Danlos disease type IV.

Ehlers-Danlos syndrome (EDS) type IV is an autosomal dominant connective tissue disease caused by mutations in the type III collagen gene resulting in extreme tissue fragility. Affected individuals are at risk of dramatic and often fatal complications, mostly spontaneous arterial, uterine, or colonic ruptures. Phenotypic expression of EDS type IV is variable and clinical signs are generally quite subtle, thus making a prompt diagnosis difficult. The case of a 33-year-old woman is described who presented with a wide range of clinical features and sequelae that eventually led to the diagnosis of EDS type IV. She presented with spontaneous liver rupture, renal infarction, and pneumothorax, all representing rare complications of EDS type IV. Prior history revealed a uterine rupture in advanced pregnancy associated with ischemic necrosis of the descending and sigmoid colon. EDS type IV should be suspected in young individuals who present with such unusual complications. Early diagnosis is essential if severe or even lethal complications are to be avoided in the diagnostic and therapeutic management of such patients.

Epidermal growth factor inhibits Ca(2+)-dependent Cl- transport in T84 human colonic epithelial cells.

This study examined whether epidermal growth factor (EGF) inhibits Ca(2+)-dependent Cl- secretion by T84 cells. Basolateral EGF inhibited Cl- secretion induced by carbachol or thapsigargin, without blocking the rise in intracellular Ca2+. Studies have shown that carbachol renders T84 cells refractory to subsequent stimulation by thapsigargin, an effect ascribed to D-myo-inositol 3,4,5,6-tetrakisphosphate [D-Ins(3,4,5,6)P4]. EGF also increased DL-Ins(3,4,5,6)P4 to a maximum of 170% above control. However, despite the fact that EGF inhibited Cl- secretion at 1 min, DL-Ins(3,4,5,6)P4 was not elevated at this time point. EGF plus carbachol had a greater inhibitory effect on Cl- secretion than either alone, indicating the likely involvement of an additional inhibitory pathway activated by EGF. Staurosporine did not alter the ability of EGF to inhibit Cl- secretion or increase DL-Ins(3,4,5,6)P4. In contrast, genistein inhibited the rise in DL-Ins(3,4,5,6)P4 and partially reversed EGF's inhibitory effect on Cl- secretion. In conclusion, EGF and carbachol can both inhibit Cl- secretion via D-Ins(3,4,5,6)P4, whereas EGF also generates an additional inhibitory signal.

Role of histamine in a rat model of colitis.

We examined the possible involvement of mast cells in a rat model of colitis, by monitoring levels of histamine at various times after inducing inflammation with intrarectal trinitrobenzene sulfonic acid in 50% ethanol. The ability of a histamine H1 antagonist, diphenhydramine, to modify colitis was also assessed. As expected, trinitrobenzene sulfonic acid in 50% ethanol induced a sustained colitis. Myeloperoxidase levels in macroscopically damaged tissue peaked at one week, and declined thereafter. In contrast, tissue histamine levels were normal at one week, then increased in damaged tissue to approximately four times normal levels at four weeks. Indices of inflammation were markedly suppressed at one week by diphenhydramine, while tissue histamine levels were unaffected. Chronic colitis in rats is thus apparently accompanied by a local mast cell hyperplasia or influx. Moreover, antagonism of a major mast cell mediator, histamine, significantly reduces the severity of inflammation in this model.

Mast cells and histamine contribute to bile acid-stimulated secretion in the mouse colon.

Certain dihydroxy bile acids cause secretory diarrhea when present in the colonic lumen at inappropriately high concentrations. However, the mechanism underlying the secretagogue activity has not been fully elucidated. Experiments were performed to test whether mast cells and one of their major mediators, histamine, might contribute to the secretory effect. Chenodeoxycholic acid, a secretory bile acid, and ursodeoxycholic acid, a nonsecretory, hydrophilic bile acid, were compared for their ability to induce chloride secretion across segments of mouse colon mounted in Ussing chambers. Chenodeoxycholic acid, but not ursodeoxycholic acid, induced dose-dependent, biphasic chloride secretion that was greater after serosal than mucosal addition and was greater in distal versus proximal colonic segments. The secretory effect of chenodeoxycholic acid was inhibited by H1 histamine receptor antagonists and modified by the cyclooxygenase inhibitor indomethacin. However, it was unaffected by an H2 histamine receptor antagonist or by atropine. Secretory effects of chenodeoxycholic acid were diminished in magnitude and delayed in colonic tissues from mice with a genetic deficiency of tissue mast cells. Concentrations of chenodeoxycholic acid inducing secretion also released histamine from tissue segments. These data indicate that mast cells and histamine-mediated processes contribute significantly to the secretory effects of dihydroxy bile acids in the murine colon.