Minocycline and fulminant hepatic failure necessitating liver transplantation.
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Acne Vulgaris↗
Biomedical subjects
W Domschke
Publications and source records attributed to W Domschke.
Role of M cells in intestinal barrier function.
M cells are known as specialized epithelial cells of the follicle-associated epithelium of the gastrointestinal tract. As M cells have a high capacity for transcytosis of a wide range of microorganisms and macromolecules, they are believed to act as an antigen sampling system. The primary physiological role of M cells seems to be the rapid uptake and presentation of particular antigens and microorganisms to the immune cells of the lymphoid follicle to induce an effective immune response. In contrast to absorptive enterocytes, M cells do not exert direct defense mechanisms to antigens and pathogens in the gut lumen. Therefore, they provide functional openings of the epithelial barrier. Although M cells represent a weak point of the epithelial barrier, even under noninflamed conditions, there seems to be a balance between antigen uptake and immunological response. The low number of M cells in the gastrointestinal tract and the direct contact to immune cells in the lamina propria usually prevent the occurrence of mucosal inflammation. During chronic intestinal inflammation we observe an increase of M cell number and apoptosis selectively in M cells. M cell damage seems to be responsible for the increase of the uptake of microorganisms that is observed during intestinal inflammation. Under inflammatory conditions in the intestine, the maintenance of the epithelial barrier is broken and M cells seem to play a major role during this process.
Animals↗
Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis.
Autodigestion of the pancreas by its own prematurely activated digestive proteases is thought to be an important event in the onset of acute pancreatitis. The mechanism responsible for the intrapancreatic activation of digestive zymogens is unknown, but a recent hypothesis predicts that a redistribution of lysosomal cathepsin B (CTSB) into a zymogen-containing subcellular compartment triggers this event. To test this hypothesis, we used CTSB-deficient mice in which the ctsb gene had been deleted by targeted disruption. After induction of experimental secretagogue-induced pancreatitis, the trypsin activity in the pancreas of ctsb(-/-) animals was more than 80% lower than in ctsb(+/+) animals. Pancreatic damage as indicated by serum activities of amylase and lipase, or by the extent of acinar tissue necrosis, was 50% lower in ctsb(-/-) animals. These experiments provide the first conclusive evidence to our knowledge that cathepsin B plays a role in intrapancreatic trypsinogen activation and the onset of acute pancreatitis.
Acute Disease↗
Cerebral aspergillosis in systemic lupus erythematosus.
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Adult↗
Glucocorticoids induce apoptosis in human monocytes: potential role of IL-1 beta.
Glucocorticoids (GC) are potent anti-inflammatory and immunosuppressive agents that act on a variety of immune cells, including monocytes and macrophages. However, the exact cellular mechanisms underlying this anti-inflammatory capacity are still unknown. In our study, we determined the induction of apoptosis by GC in human monocytes. Peripheral blood monocytes were isolated by density centrifugation methods with a purity of >90% and were cultured in RPMI 1640 medium. Monocyte apoptosis was determined by four independent methods, including annexin-V staining, TUNEL, DNA-laddering, and typical morphology by means of transmission electron microscopy. TNF-alpha and IL-1beta were measured by ELISA. GC receptor was blocked with mifepristone. Caspase 3 was inhibited with caspase-3 inhibitor (DEVD-CHO). Stimulation with different GC at therapeutic concentrations resulted in monocyte apoptosis in a time- and dose-dependent manner. Necrosis was excluded by propidium iodide staining. Proinflammatory cytokines such as IL-1beta and TNF-alpha were down-regulated by GC treatment. Continuous treatment of monocytes with IL-1beta, but not with TNF-alpha, could almost completely prevent GC-induced cell death. The addition of mifepristone or caspase-3 inhibitor could partially abrogate GC-induced apoptosis as well as GC-induced inhibition of IL-1beta. This is the first study to demonstrate induction of apoptosis by GC in human monocytes. GC-induced monocyte apoptosis may be partially mediated through effects on IL-1beta production. It is conceivable that GC exert their anti-inflammatory capacity in various diseases, at least in part, by the induction of apoptosis in monocytes.
Apoptosis↗
Expression of constitutive nitric oxide synthase in rat and human gastrointestinal tract.
The aim of this study was to determine the expression of constitutive NO synthases (ecNOS and bNOS) at the protein level in rat and human gastrointestinal tract. We established a quantitative Western blotting method for detection and quantification of ecNOS and bNOS in both species. Human gastric fundus was further analyzed by immunohistochemistry. EcNOS expression at the protein level could be quantified in different organs of the rat gastrointestinal tract and in human gastric mucosal biopsies. Immunohistochemistry of gastric fundus revealed that immunoreactivity for ecNOS was localized mainly in the endothelium of small vessels. In rats, expression of bNOS at the protein level was highest in esophagus. By means of immunohistochemistry of human gastric fundus, immunoreactivity was detected mainly in the plexus of Auerbach. We conclude that isoforms of constitutive nitric oxide synthase can be identified and quantified at the protein level both in rat and human gastrointestinal tract. The presence of bNOS in nerve tissue supports previous observations that NO serves as a transmitter in non-adrenergic, non-cholinergic nerves in human esophagus and stomach. The observation that ecNOS has been found mainly in endothelial cells suggests the involvement of NO in the regulation of mucosal blood flow.
Aged↗
Protein tyrosine dephosphorylation and the maintenance of cell adhesions in the pancreas.
Cell-cell contacts are important regulatory elements in tissue development, organ morphogenesis and malignant tumor invasion. In recent in vivo studies we have identified the members of the cadherin/catenin family of cell adhesion proteins that are differentially expressed in the pancreas and have determined their cell biological dynamics during dissociation and repair of adherens junctions. To further characterize these events, epithelial cell culture systems were used and a number of type II protein tyrosine phosphatases (PTPs) were found to colocalize and interact with the cadherin/catenin complex. These observations suggest that tyrosine dephosphorylation in general and PTPs in particular are involved in cell contact formation. Our most recent experiments indicate 1) that inhibition of PTPs alone dissociates pancreatic adherens junctions, 2) that cytosolic and transmembrane PTPs are differentially expressed in acinar cells, and 3) that a subset of them can associate with proteins of the cadherin/catenin complex at pancreatic cell-cell adhesions.
Cell Adhesion↗
Maternal inheritance pattern of hereditary pancreatitis in patients with pancreatic carcinoma.
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Chronic Disease↗
Polypoid tumors of the major duodenal papilla: preoperative staging with intraductal US, EUS, and CT--a prospective, histopathologically controlled study.
BACKGROUND: An adenoma-carcinoma sequence also applies to adenomas of the major duodenal papilla. Therefore accurate preoperative diagnosis and tumor staging are essential to select the appropriate patients for adequate treatment. In a prospective, histopathologically controlled study of tumors of the main duodenal papilla, the preoperative diagnostic value of ultrasound (US) catheter probes applied during endoscopic retrograde cholangiopancreatography (ERCP) was investigated. METHODS: Intraductal US was compared with conventional endoscopic ultrasonography (EUS) and computed tomography (CT). In 27 consecutive patients with benign polypoid tumors of the major duodenal papilla (n = 12) and carcinomas of the papilla (n = 15), respectively, the value of these imaging procedures in determining tumor visualization, tumor diagnosis and tumor staging according to the TNM classification was assessed. Every patient underwent surgical resection; histopathologic evaluation of resected specimens served as the reference standard. RESULTS: Intraductal US was significantly superior to EUS and CT in terms of tumor visualization (100% vs 59.3% vs 29.6%, respectively). Sensitivity and specificity rates for intraductal US and EUS were 100% versus 62.5% and 75% versus 50%, respectively. Overall accuracy rate in tumor diagnosis for intraductal US (88.9%; 24 of 27) was significantly (p = 0.05) superior to EUS (56.3%; 9 of 16). The latter did not depict 4 adenomas and 7 carcinomas. Neither intraductal US nor EUS is suitable for detection of distant metastases. CONCLUSION: Intraductal US appears to be the most effective imaging method in visualizing, diagnosing and staging tumors of the major duodenal papilla. Combining ERCP with catheter probe sonography offers a new diagnostic modality that has some potential advantages for local staging of small tumors of the main duodenal papilla. Consequently, minimally invasive techniques for resection of seemingly benign tumors of the papilla or, even more so, of small carcinomas should preferably be based on intraductal US.
Adenocarcinoma↗
Intraductal ultrasonography (IDUS) of the pancreato-biliary duct system. Personal experience and review of literature.
Endoscopic ultrasonography (EUS) represents a major advance in endoscopic imaging. Usefulness and effectiveness of EUS have been established during the past few years. However, endosonography using dedicated echoendoscopes (7.5/12 MHz) has some serious drawbacks: (1) combining endoscopy and ultrasonography in one instrument increases the diameter of such echoendoscopes (13 mm); (2) as a result of the large diameter insertion into the pancreato-biliary duct system is not feasible at all; (3) image quality and resolution for small lesions is not always satisfactory; and (4) conventional endosonography needs a second examination separate from the previous routine endoscopy. Recently developed ultrasonographic miniprobes (diameters about 2 mm; frequencies 12-20 MHz) can be passed through the working channel of standard endoscopes to provide high-frequency ultrasound images. These miniprobes might overcome some of the above mentioned drawbacks and contribute to patients' security and convenience. Moreover, in various diseases of the pancreato-biliary duct system diagnostic accuracy of miniprobe ultrasonography has been shown to be superior to that of EUS. In summary, miniprobe ultrasonography appears to be a promising addition to the armamentarium of gastroenterologic diagnostics.
Ampulla of Vater↗
Tumors of the papilla of Vater--inadequate diagnostic impact of endoscopic forceps biopsies taken prior to and following sphincterotomy.
BACKGROUND: It has been proposed that adenomas of the papilla of Vater are precursors of adenocarcinomas. Duodenoscopy with ERCP and forceps biopsies have substantially improved the morphologic exploration of the major duodenal papilla. Yet there is little and contradictory information as to the diagnostic accuracy of endoscopic biopsies in tumors of the papilla. Moreover, after endoscopic sphincterotomy data on the diagnostic impact of endoscopic biopsies from the papilla are scarce and, in most cases, retrospectively obtained. Thus, the aim of the present prospective and histopathologically controlled study was to assess the diagnostic accuracy of endoscopic biopsies taken from tumors of the papilla before and after sphincterotomy. PATIENTS AND METHODS: Forty patients with tumors of the papilla of Vater were included in the study. In each case, a comparison was made between endoscopic forceps biopsy diagnoses prior to and following sphincterotomy and the definitive histological diagnosis after surgical tumor resection. RESULTS: Resected tumors were diagnosed histomorphologically as follows: 19 adenocarcinomas (47%), 6 tubular adenomas (15%), 7 villous adenomas (17%), 7 inflammatory non-neoplastic lesions (pseudotumors) (17%), and one adenomyoma (2%). Overall accuracy for preoperative histopathological diagnosis was 62% (25 of 40, 95% CI: 47%-76%) prior to sphincterotomy while it was 70% (28 of 40, 95% CI: 55%-81%) following the procedure. Regarding adenocarcinomas, sensitivity was found to be 21% (4 of 19, 95% CI: 8%-43%) prior to and 37% (7 of 19, 95% CI: 19%-58%) after sphincterotomy while specificity was 100% at both times. CONCLUSIONS: Endoscopic forceps biopsies do not allow for reliable preoperative diagnosis of tumors of the papilla of Vater.
Adenocarcinoma↗
Interleukin (IL)-13 and IL-4 are potent inhibitors of IL-8 secretion by human intestinal epithelial cells.
Intestinal epithelial cells are able to produce soluble mediators that initiate or amplify inflammatory events in the intestinal mucosa. Interleukin (IL) -8 is suggested to be a cytokine playing a major role during the acute and chronic processes in inflammatory bowel disease (IBD). TH-2 cytokines have been described as down-regulating the inflammatory response. We analyzed the effects of IL-10, IL-13, and IL-4 on IL-8 secretion in intestinal epithelial cells. The human colonic epithelial cell line Caco-2 and freshly isolated intestinal epithelial cells were used. Cells were stimulated with IL-1beta after treatment with TH-2 cytokines. Levels of IL-8 were determined by employing enzyme-linked immunosorbent assay (ELISA). Stimulation with IL-1beta results in a time-dependent IL-8 secretion. The addition of IL-4 and IL-13, but not IL-10, to activated epithelial cells resulted in a strong decrease in IL-8 secretion. Maximal inhibition required that TH-2 cytokines be added up to 60 min before or simultaneous with stimulatory agents. We present novel findings that IL-4 and IL-13 strongly down-regulate IL-8 secretion from intestinal epithelial cells. A microenvironment containing high concentrations of IL-4 and IL-13 may alter the recruitment of immune cells to enterocytes at least partly by inhibiting IL-8 production. This inhibition might diminish the severity of the intestinal inflammatory response and, thus reduce clinical disease activity.
Caco-2 Cells↗
Expression of endothelial cell-derived nitric oxide synthase (eNOS) is increased during gastric adaptation to chronic aspirin intake in humans.
BACKGROUND: Gastric adaptation to aspirin is well-documented. However, the mechanisms underlying the reduction of aspirin-induced mucosal damage despite continued ingestion of the drug remain poorly understood. METHODS: Eight healthy volunteers who received aspirin 1 g b.d. for 14 days were compared with eight placebo-dosed controls. Gastroscopy with mucosal biopsy was performed, and gastric mucosal blood flow was measured before and following 3, 7 and 14 days of aspirin treatment. At the same time points, tissue concentration and the content of prostaglandin E2 in the gastric juice were determined and expression of endothelial cell-derived nitric oxide synthase (eNOS) in mucosal biopsies was measured using Western blot analysis. RESULTS: Aspirin-induced mucosal damage that reached a maximum on day 3, declining significantly by day 14. Concomitantly, mucosal blood flow significantly increased on day 3 and returned to initial values on day 14. Aspirin intake led to a significant decrease in prostaglandin E2 concentration in the gastric mucosa and in gastric juice during the whole period of aspirin consumption. eNOS expression started to increase on day 7 in oxyntic mucosa and on day 3 in antral mucosa, reaching its highest values at the end of the consumption of aspirin. CONCLUSIONS: The human gastric mucosa adapts to prolonged aspirin intake, and this is accompanied by an increase in mucosal blood flow and reduced prostaglandin synthesis. Increase of mucosal eNOS expression might compensate for reduced prostaglandin synthesis and be responsible for gastric adaptation to chronic aspirin intake in humans.
Adult↗
Endogenous nitric oxide in the regulation of gastric secretory and motor activity in humans.
BACKGROUND: Studies in animals have shown that nitric oxide (NO) affects gastric secretory and motor functions. However, little information is available about the involvement of this substance in the control of gastric secretory and motor activity in man. METHODS: This study, performed on 18 healthy, Helicobacter pylori-negative volunteers, was designed to evaluate the role of NO in the control of gastric acid secretion and of gastrin and somatostatin release in response to ordinary feeding (group A) and on gastric motor and electrical activity (group B). Gastric acid secretion was determined by means of intragastric pH-metry before and after feeding with a semi-liquid meal. Plasma levels of gastrin and somatostatin were measured using specific radioimmunoassays. Gastric emptying rate was measured using the 13C-acetate breath test, antral motor activity using a manometric catheter and myoelectric activity using cutaneous electrogastrography. Studies were repeated following pre-treatment with NG-monomethyl-L-Arginine (L-NMMA), L-Arginine (L-Arg) or their combination. RESULTS: L-NMMA delayed the recovery of intragastric pH to the pre-meal value, and suppressed postprandial gastrin release while increasing the plasma somatostatin level. L-Arg did not affect postprandial pH and plasma hormones, but reversed L-NMMA-induced alterations in intragastric pH and in plasma gastrin and somatostatin levels. Both postprandial antral motor activity (motility index) and gastric emptying significantly increased in tests with L-NMMA, but this was not observed when L-NMMA was given in combination with L-Arg or when L-Arg alone was used. The gastric electrical pattern, as measured by cutaneous electrogastrography, was not affected by L-NMMA, L-Arg or their combination. CONCLUSIONS: (1) Endogenous NO appears to be involved in the regulation of postprandial gastric acid secretion. This effect may be mediated by the changes in release of gastrin and somatostatin. (2) Endogenous NO delays gastric emptying and antral motor activity without affecting gastric myoelectrical activity.
Acetates↗
Effect of basic fibroblast growth factor on gastric ulcer healing and its own mRNA expression.
BACKGROUND: The application of an acid-stable mutein of basic fibroblast growth factor (bFGF) called CS23 results in acceleration of ulcer healing. The modes by which this cytokine exerts these effects are not yet completely understood. AIM: To describe the pattern of bFGF-mRNA expression during ulcer healing and to examine the effects of exogenously applied CS23 on gastric ulcer healing in an animal model. METHODS: The speed of healing of gastric ulcers, expression of extracellular matrix gene mRNAs such as pro alpha(I) collagen (by non-radioactive in situ hybridization), cellular proliferation evidenced by the display of PCNA (by immunohistochemistry), angiogenesis, and the feedback of this growth factor on its own mRNA expression pattern were used to evaluate the effects of CS23 on rat gastric ulcer healing in an animal model. RESULTS: CS23 accelerates gastric ulcer healing at 7, 14 and 21 days after ulcer induction. We found an increase in connective tissue beneath the ulcer bed in treated animals in comparison to controls. The expression of PCNA as well as pro alpha(I) collagen mRNA was markedly increased in ulcers, yet there was no distinct difference between treatment arms. In contrast, the density of microvessels was significantly increased in the submucosa of ulcers by CS23 application. bFGF-mRNA expression is up-regulated in the submucosa during early ulcer healing; this increase diminishes within days but can be restituted by the exogenous application of CS23. CONCLUSIONS: CS23 speeds gastric ulcer healing and significantly increases the density of microvessels in the ulcerated tissue without affecting the numbers of proliferating cells or the transcription of collagen mRNA. In addition, it augments the expression of bFGF-mRNA during the later stages of healing, suggesting a positive feedback loop.
Animals↗
Interleukin-15 strongly inhibits interleukin-8 and monocyte chemoattractant protein-1 production in human colonic epithelial cells.
Interleukin-15 (IL-15) is a novel cytokine with actions similar to IL-2 because of common receptor components. Although IL-15 is expressed in colonic epithelial cells and may regulate epithelial cell function, its effects on these cells are not fully defined. We explored the regulatory effects of IL-15 on IL-8 and monocyte-chemoattractant protein-1 (MCP-1) production in the colonic epithelial cell line Caco-2 as well as in freshly isolated human colonic epithelial cells. IL-15 was added to intestinal epithelial cells under various culture conditions. Levels of chemokines were determined by enzyme-linked immunosorbent assay. To determine the elements of the IL-2/IL-15R complex involved we used neutralizing antibodies specific for individual receptor chains. IL-15 down-regulates IL-8 and MCP-1 production in Caco-2 cells as well as in freshly isolated human colonic epithelial cells in a dose-dependent manner. Intestinal epithelial cells became more responsive to IL-15-induced suppression when activated with greater IL-1 doses. Strong chemokine suppression was seen when IL-15 was given prior to, simultaneous with, or after stimulatory agent. Anti-IL-2Rgamma antibodies efficiently blocked (82% inhibition) the suppression induced by IL-15, while anti-IL-2Rbeta antibodies were less effective. The involvement of beta-chain was further suggested by the finding that a mixture of both monoclonal antibodies (mAb) at a suboptimal concentration (1 microgram/ml of each mAb) produced a synergistic inhibitory effect on down-regulation of epithelial chemokine production. These results show that IL-15 can suppress IL-8 and MCP-1 secretion by intestinal epithelial cells. A microenvironment containing high concentrations of IL-15 may alter the recruitment of neutrophils to enterocytes at least partly by inhibiting IL-8 and MCP-1 production.
Antibodies, Monoclonal↗
CRH test prior to discontinuation of long-term low-dose glucocorticoid therapy.
Often long-term low-dosage glucocorticoid therapy cannot be terminated. This is due to the fact that even low doses which are within the physiological replacement range can cause a detectable, though clinically insignificant suppression of the adrenal gland function, resulting in "corticosteroid withdrawal syndrome". Another reason is the fact that it is necessary to be able to suppress undesirable inflammatory reactions caused by the underlying disease. ACTH testing of the adrenal capacity is widespread, but repeated testing may lead to undesirable side effects, such as allergic reactions. This study investigates the usefulness of testing the function of the pituitary-adrenal axis in predicting withdrawal problems. In 21 patients with chronic inflammatory disease who were treated with glucocorticoid doses of 5 to 10 mg prednisolone equivalent daily for a period of 2 to 131 months, stimulation with 100 microg hCRH (human corticotrophin-releasing hormone) was performed prior to the gradual withdrawal of medication. Blood samples were taken at baseline and after 45 minutes to measure ACTH and cortisol levels. Four weeks after steroid withdrawal the patients were reevaluated for signs of a relapse of the underlying disease in order to establish the necessity of reintroducing steroid therapy. This reevalution comprised clinical criteria, laboratory tests and the patients' own assessment of his/her well-being. In sixteen patients who later successfully withdrew from glucocorticoid therapy, a significant increase in cortisal levels was noticed after stimulation with CRH (p < 0.05). In five patients, with whom steroid withdrawal was not successful, baseline levels of cortisol were significantly lower than in the others (p < 0.05) and no sufficient increase was achieved after stimulation with CRH. These results show that successful withdrawal of a long-term low-dosage glucocorticoid therapy depends on the integrity of the pituitary-adrenal axis. Therefore CRH testing for evaluation of the pituitary-adrenal axis can be helpful in identifying patients in whom glucocorticoid withdrawal would be troublesome.
Adolescent↗
Preoperative staging of esophageal carcinoma: miniprobe sonography versus conventional endoscopic ultrasound in a prospective histopathologically verified study.
BACKGROUND AND STUDY AIMS: Endosonographic staging of esophageal carcinoma may be limited by non-traversable tumor stenoses. Dilation of malignant esophageal strictures carries a significant risk of esophageal perforation. We therefore evaluated the use of ultrasonic miniprobes in the staging of stenotic esophageal carcinoma compared with conventional endoscopic ultrasound. PATIENTS AND METHODS: In a blinded, prospective study, which included histopathological evaluation, 53 consecutive patients (43 male, 10 female, mean age 61 years) with stenosing esophageal carcinomas were examined preoperatively. Endosonography was done using the optical GF-UM3 echo endoscope. If tumor strictures were not traversable with this instrument, a blind esophagoprobe, the MH-908 was used for endosonography. Miniprobe sonography (MPS) was done during esophagoscopy in all patients. The various imaging modalities were assessed in terms of complete tumor traversability and correct tumor staging. Every patient underwent surgical tumor resection. RESULTS: MPS of the esophagus and proximal parts of the stomach was possible in all 53 patients without prior dilation of tumor stenoses. Endosonography with the GF-UM3 instrument was precluded in 23 patients (43.4%) while in 20 of the latter patients the MH 908 esophagoprobe could be passed through tumor stenoses. The overall accuracy rates for depth of tumor infiltration (T) staging were: 62% (31/50) for endosonography (GF-UM3 plus esophagoprobe) and 86.8% (46/53) for MPS. The accuracy rates for T staging in tumors traversable both with the GF-UM3 echo endoscope and with miniprobes were 56.7% (17/30) for GF-UM3 and 80% (24/30) for MPS. The accuracy rates for T staging in tumors traversable only with the MH-908 esophagoprobe and with miniprobes were 70% (14/20) for the MH-908 and 95% (19/20) for MPS. With regard to the presence or absence of peri-esophageal metastatic lymph nodes (N staging), the accuracy rates were 83% (25/30) for MPS and 70% (21/30) for the GF-UM3, and 80% (16/20) for MPS and 70% (14/20) for the MH-908. CONCLUSION: Compared with conventional endosonography using 7.5-MHz large diameter instruments, MPS enables: a) safe passage through high-grade malignant esophageal strictures, achieving b) higher accuracy rates for T staging, and c) similar rates for N staging. The use of MPS can also represent an improvement in the comfort and safety of patients. Moreover, miniprobe sonography is highly cost-effective compared with conventional endosonography. Thus, MPS appears to be a valuable addition to the armamentarium for staging esophageal carcinoma.
Adult↗