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Biomedical subjects

W Domschke

Publications and source records attributed to W Domschke.

At least 55 records · Page 3Linked to original sources
PubMed2002

Fluorescence endoscopy using a fluorescein-labeled monoclonal antibody against carcinoembryonic antigen in patients with colorectal carcinoma and adenoma.

BACKGROUND AND STUDY AIMS: Various methods of fluorescence excitation and detection have been developed in gastrointestinal endoscopy. This study reports an endoscopic technique using locally applied fluorescein-labeled antibodies for in-vivo detection of colorectal dysplasia and carcinoma. PATIENTS AND METHODS: Fluorescence endoscopy with a fluorescein-labeled monoclonal antibody against carcinoembryonic antigen (CEA) was carried out in 27 patients with colonic polypoid lesions. During conventional colonoscopy, the monoclonal antibody was applied directly onto the mucosal surface. After an incubation time of 10 min, specific fluorescence was visualized with a conventional endoscope whose optical range was increased via two narrow-band filters. RESULTS: Fluorescence in vivo was present in 19 out of 25 carcinomas and in three of eight adenomas. The technique failed in the presence of mucosal ulceration or bleeding. One fluorescence-positive villous adenoma showed high-grade dysplasia, and another fluorescence-positive polypoid lesion was diagnosed as carcinoma in adenoma. Normal-appearing mucosa was fluorescence-negative in all cases. Endoscopic fluorescence significantly correlated with the CEA expression of luminal epithelial cells as determined immunohistochemically (Wilcoxon-Mann-Whitney U-test, P < 0.01). In all cases without ulceration or bleeding, the specificity of fluorescence endoscopy was 100%, the sensitivity was 78.6%, and the accuracy was 89.3%. CONCLUSIONS: Fluorescence endoscopy using fluorescein-labeled monoclonal antibody against CEA was shown to be positive in most cancers and some adenomas. Further and larger studies will be needed to demonstrate the value of this technique for differential diagnosis.

Adenoma↗
PubMed2002

Silicone breast implants: correlation between implant ruptures, magnetic resonance spectroscopically estimated silicone presence in the liver, antibody status and clinical symptoms.

OBJECTIVE: To determine the impact of implant integrity on clinical symptoms and antibody status in women with silicone breast implants (SBIs). METHODS: Ninety consecutive women were examined by means of magnetic resonance imaging (MRI) to assess the integrity of their silicone breast implants. The presence of silicone in the liver was estimated by (1)H localized stimulated echo acquisition mode (STEAM) magnetic resonance spectroscopy (MRS). Results were correlated with patients' complaints, as evaluated by a standardized questionnaire, physical examination by a rheumatologist and antibody screening. RESULTS: Breast MRI revealed defects in 24 patients (26.6%); in 13 (54.2%) of these women, silicone was detected in the liver by MRS. Of the 66 patients with MRI-estimated intact implants, 15 (22.7%) had apparent silicone in their liver, arguing for gel bleeding. Clinically, two patients had had rheumatoid arthritis before SBIs, whereas the other patients revealed no typical symptoms of arthritis or connective tissue disease (CTD). The patients with MRS evidence of silicone in the liver had no statistically significant differences in their complaints with the exception of the most frequent symptom, tingling/numbness of the fingers (82.1 vs 51.6%, P=0.006). A positive pattern of antinuclear antibodies (ANA) was obtained in 13 of the 28 MRS-positive patients (46.4%) and in 15 of the 62 MRS-negative patients (24.2%, P=0.033). However, in only one of these 28 ANA-positive patients was a specific weak antibody titre against SS-A detected by ELISA. CONCLUSION: Implant integrity has no major impact on rheumatic symptoms of women with SBIs. This finding supports the standpoint that silicone does not cause either a specific CTD or any other distinct disease entity. However, the moderately increased incidences of ANA-positivity and neuropathy-associated symptoms require explanation.

Adult↗
PubMed2002

Endoscopic transpapillary biopsies and intraductal ultrasonography in the diagnostics of bile duct strictures: a prospective study.

BACKGROUND: In bile duct strictures, examination of wall layers by intraductal ultrasonography (IDUS) performed during endoscopic retrograde cholangiopancreatography (ERCP) may be diagnostically useful. METHODS: In the present study 60 patients with bile duct strictures of unknown aetiology were examined preoperatively by ERCP, including transpapillary biopsies and IDUS. Histopathological correlation was available for all patients undergoing these procedures. RESULTS: Postoperative diagnosis revealed 30 pancreatic carcinomas, 17 bile duct cancers, three gall bladder cancers, and 10 benign bile duct strictures. Using endoscopic transpapillary forceps biopsies (ETP), a correct preoperative diagnosis was achieved in 36 of 60 patients (60% of cases). Among the 50 malignant tumours, preoperative diagnosis by ETP revealed a sensitivity of 52% and a specificity of 100%. ERCP supplemented by IDUS allowed for correct preoperative diagnosis in 83% of cases (50 of 60 patients), which was significantly higher than the accuracy of ETP (p=0.008). By combining ETP with IDUS, a correct preoperative diagnosis was made in 59 of 60 patients resulting in an accuracy rate of 98%. CONCLUSIONS: Because of its low accuracy, exclusive use of ETP is not a reliable diagnostic tool for a definitive preoperative diagnosis of bile duct strictures. By combining IDUS and ETP with ERCP however, preoperative diagnostic accuracy can be improved substantially.

Adolescent↗
PubMed2002

Gastric electrical stimulation in intractable symptomatic gastroparesis.

BACKGROUND: The treatment of gastroparesis remains unsatisfactory despite prokinetic and anti-emetic drugs. Gastric electrical stimulation has been proposed as a therapeutic option. We have assessed the effect of gastric electrical stimulation on symptoms, medical treatment, body weight and gastric emptying in patients with intractable symptomatic gastroparesis in a non-placebo-controlled study. METHODS: In this multicenter study, 38 highly symptomatic patients with drug-refractory gastroparesis were enrolled. Patients first received temporary electrical stimulation using percutaneous electrodes. The 33 responders to temporary stimulation then underwent surgical implantation of a permanent stimulator. Severity of vomiting and nausea was assessed before and after stimulation. Patients were reassessed 3, 6, and 12 months after permanent implantation. RESULTS: With stimulation, 35/38 patients (97%) experienced >80% reduction in vomiting and nausea. This effect persisted throughout the observation period (2.9-15.6 months, 341 patient-months). Gastric emptying did not initially change, but improved in most patients at 12 months. At 1 year, the average weight gain was 5.5% and 9/14 patients initially receiving enteral or parenteral nutrition were able to discontinue it. CONCLUSION: Electrical stimulation of the stomach has an immediate and potent anti-emetic effect. It offers a safe and effective alternative for patients with intractable symptomatic gastroparesis.

Adolescent↗
PubMed2001

alpha-Toxin is a mediator of Staphylococcus aureus-induced cell death and activates caspases via the intrinsic death pathway independently of death receptor signaling.

Infections with Staphylococcus aureus, a common inducer of septic and toxic shock, often result in tissue damage and death of various cell types. Although S. aureus was suggested to induce apoptosis, the underlying signal transduction pathways remained elusive. We show that caspase activation and DNA fragmentation were induced not only when Jurkat T cells were infected with intact bacteria, but also after treatment with supernatants of various S. aureus strains. We also demonstrate that S. aureus-induced cell death and caspase activation were mediated by alpha-toxin, a major cytotoxin of S. aureus, since both events were abrogated by two different anti-alpha-toxin antibodies and could not be induced with supernatants of an alpha-toxin-deficient S. aureus strain. Furthermore, alpha-toxin-induced caspase activation in CD95-resistant Jurkat sublines lacking CD95, Fas-activated death domain, or caspase-8 but not in cells stably expressing the antiapoptotic protein Bcl-2. Together with our finding that alpha-toxin induces cytochrome c release in intact cells and, interestingly, also from isolated mitochondria in a Bcl-2-controlled manner, our results demonstrate that S. aureus alpha-toxin triggers caspase activation via the intrinsic death pathway independently of death receptors. Hence, our findings clearly define a signaling pathway used in S. aureus-induced cytotoxicity and may provide a molecular rationale for future therapeutic interventions in bacterial infections.

Adaptor Proteins, Signal Transducing↗
PubMed2001

[Fulminant liver failure after administration of the herbal antidepressant Kava-Kava].

HISTORY AND CLINICAL FINDINGS: A 60 year-old woman was admitted to hospital because of jaundice, fatigue, weight loss over several months and icteric skin. Because of progressive liver failure, concomitant renal failure and progressive encephalopathy she was transferred to an intensive care unit. INVESTIGATIONS: Biochemical tests revealed acute liver failure with high levels of total and conjugated bilirubin (30 mg/dl) as well as aspartate aminotransferase (921 IU/l) and alanine aminotransferase (1350 IU/l) concentrations. Prothrombin time was less than 10 %. Serological tests could rule out viral hepatitis, metabolic or autoimmune causes of liver failure. On abdominal computed tomography and ultrasonography no pathological changes were detected. Above all portal vein thrombosis, ascites, focal lesions of the liver and extrahepatic cholestasis could be excluded. Liver histology showed extensive hepatocellular necrosis with intrahepatic cholestasis. TREATMENT AND CLINICAL COURSE: The patient's physical condition deteriorated. She had to be intubated because of respiratory insufficiency and encephalopathy stage IV. Because of progressive liver failure under conservative treatment the patient received an orthotopic liver transplant 11 days after admission. CONCLUSIONS: The exclusion of other causes and the histological diagnosis made Kava-Kava as the cause of acute liver failure most likely. This is the 18th case of Kava-Kava induced liver failure reported to the European regulatory authorities.

Alanine Transaminase↗
PubMed2001

Remodeling of extracellular matrix in gastric ulceration.

The quality of ulcer repair remains crucial for the stability of the injured tissue and for preventing recurrence. Therefore, we studied the temporo-spatial expression of the fibrillar and basement membrane collagens (types I, III, and IV), the collagenase MMP-2 as well as its inhibitor TIMP-1 before and after oral administration of basic fibroblast growth factor (b-FGF) over 30 days in acetic acid-induced rat gastric ulcers. The alterations and the exact location of the mRNA transcripts and their precipitated proteins were visualized by means of radioactive in situ hybridization and immunohistochemistry. Our data show that hybridization signals of procollagen I could first be identified 2 hours after ulcer induction. After 12 hours the ulcer was established and the mRNA was enhanced at the ulcer margin. After 24-48 hours the other procollagen transcripts were detected and all were further upregulated over the mesenchymal cells of all gastric layers up to 21 days, then declined at 30 days. In contrast, MMP-2 became prominent after 48 hours and up to 21 days. TIMP-1 was enhanced at 72 hours. After oral administration of b-FGF the transcriptional activity of the procollagens and MMP-2 was not significantly altered, while ulcer diameter was significantly reduced. We conclude that the early onset and long duration of collagens' expression points to their central structural and functional role in gastric ulcer healing. MMP-2 seems to be involved in both active ulceration and ECM remodeling. The timing of TIMP/MMP expression may be critical for proper restoration of gastric wall integrity.

Animals↗
PubMed2001

Effect of Helicobacter pylori eradication on cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) expression during gastric adaptation to aspirin (ASA) in humans.

Gastric adaptation to aspirin is impaired in Helicobacter pylori infection, but the mechanisms underlying this phenomenon are unclear. In this study, we compared gastric mucosal expression of iNOS and COX-2 during 14 days of aspirin ingestion in the same subjects before and 3 months after eradication of H. pylori. Compared to non-infected controls, mucosal expression of COX-2 and iNOS was enhanced before and 3 months after eradication of H. pylori. During aspirin ingestion, mucosal expression of COX-2 remained unchanged before eradication of H. pylori, but increased gradually after successful antimicrobial treatment. Independent of H. pylori status, expression of iNOS increased at the beginning of aspirin intake, but then returned to initial values. We conclude that COX-2 but not iNOS might be involved in gastric adaptation to aspirin in humans and that this mechanism appears to be impaired in H. pylori infection.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2001

Aspirin effects on gastric epithelial cell proliferation and cytokine expression.

Aspirin is known to cause gastric injury and to delay ulcer healing. The effects of aspirin on gastric epithelial cell function are heterogeneous; in contrast to injuring the mucosa, aspirin may also act beneficially by inducing adaptation; a mechanism that is poorly understood. We aimed to document the effects of different doses of aspirin on gastric epithelial cell function defined as proliferation, and secretion as well as mRNA expression of cytokines. Furthermore, we studied the effects of aspirin pretreatment on cytokine secretion as a potential element of gastric adaptation. The proliferative activity of three different gastric epithelial cell lines (AGS, KATO III, RGM-1) was assessed by (3)H-thymidine incorporation; secretion of growth factors PDGF-AB and VEGF into culture supernatant was documented by ELISA. mRNA transcripts of both cytokines were quantified by real time RT-PCR. Low doses of aspirin did not alter the proliferative dynamics in two of the three studied cell lines; high doses abolished proliferation. Secretion of PDGF-AB and VEGF increased during the first days of low dose aspirin exposition; higher concentrations led to a depletion of cytokines after an initial liberation in the case of VEGF, mRNA of which was also dose-dependently increased by aspirin. Seven-day pretreatment with low amounts of aspirin did not alter the secretory response of the epithelia caused by higher doses of this drug. The secretion of cytokines and proliferation of gastric epithelial cells are adversely effected by aspirin in a similarly dose-dependent fashion as the intended effects of this drug on platelet function and pain relief.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Role of the CD95/CD95 ligand system in glucocorticoid-induced monocyte apoptosis.

Glucocorticoids (GC) act as potent anti-inflammatory and immunosuppressive agents on a variety of immune cells. However, the exact mechanisms of their action are still unknown. Recently, we demonstrated that GC induce apoptosis in human peripheral blood monocytes. In the present study, we examined the signaling pathway in GC-induced apoptosis. Monocyte apoptosis was demonstrated by annexin V staining, DNA laddering, and electron microscopy. Apoptosis required the activation of caspases, as different caspase inhibitors prevented GC-induced cell death. In addition, the proteolytic activation of caspase-8 and caspase-3 was observed. In additional experiments, we determined the role of the death receptor CD95 in GC-induced apoptosis. CD95 and CD95 ligand (CD95L) were up-regulated in a dose- and time-dependent manner on the cell membrane and also released after treatment with GC. Costimulation with the GC receptor antagonist mifepristone diminished monocyte apoptosis as well as CD95/CD95L expression and subsequent caspase-8 and caspase-3 activation. In contrast, the caspase inhibitor N:-acetyl-Asp-Glu-Val-Asp-aldehyde suppressed caspase-3 activation and apoptosis, but did not down-regulate caspase-8 activation and expression of CD95 and CD95L. Importantly, GC-induced monocyte apoptosis was strongly abolished by a neutralizing CD95L mAb. Therefore, our data suggest that GC-induced monocyte apoptosis is at least partially mediated by an autocrine or paracrine pathway involving the CD95/CD95L system.

Anti-Inflammatory Agents↗
PubMed2001

Intraductal ultrasound in the biliary tract.

Although endoscopic ultrasonography (EUS) represents a major advance in endoscopic imaging, endosonography using dedicated echoendoscopes has some serious drawbacks, including the diameter of the echoendoscope (12 to 13 mm), the lack of intraluminal examination of the pancreatobiliary duct system due to the size of the instrument, unsatisfactory image quality and resolution for small lesions, and the need for a second examination separate from the previous routine endoscopy. Recently developed ultrasonographic miniprobes (diameter, about 2 mm; frequency, 12 to 20 MHz) can be passed through the working channel of standard endoscopes to provide high-frequency ultrasound images. These miniprobes may overcome some of the noted drawbacks and add to the safety and convenience of patients. Moreover, in various diseases of the gastrointestinal tract and the pancreatobiliary ductal system, the diagnostic accuracy of miniprobe ultrasonography has been proven to be superior to that of EUS. Miniprobe ultrasonography is a promising tool that adds new capabilities to the armamentarium of gastroenterologic diagnostic assessment.

Biliary Tract↗
PubMed2001

Diagnostic value of DNA image cytometry in ulcerative colitis.

The increased risk of colorectal cancer in patients with extensive, long-standing ulcerative colitis is well established. The interpretation of dysplasia as the common precursor lesion of colorectal cancer in ulcerative colitis is, however, subject to inter- and intraobserver variation. The histologic diagnosis is particularly difficult in the presence of acute inflammation. Therefore, the analysis of ploidy patterns might be a more objective diagnostic tool. In the present study, the correlation of ploidy and dysplasia of the colonic mucosa was evaluated in the absence and presence of inflammation. Image cytometry was performed on 561 fixed, paraffin-embedded tissue specimens from 67 patients with ulcerative colitis. Twenty patients had long-standing and extensive disease, including eight patients in whom the colitis was associated with colorectal cancer. Dysplasia was only found in patients with long-standing colitis or with colorectal cancer and was significantly more often diagnosed in the case of concomitant inflammation. On the other hand, aneuploid patterns were shown to occur independent of inflammatory activity. Aneuploidy was present in all colorectal carcinomas associated with ulcerative colitis and in 46.2% of specimens with dysplasia. Moreover, aneuploidy was detectable in four of 12 samples with low-grade dysplasia as well as in one case devoid of any dysplastic alteration. Ulcerative colitis patients with low-grade dysplasia plus aneuploidy probably represent a subgroup that might be at higher risk of developing colorectal cancer than patients with low-grade dysplasia alone. All in all, image cytometry analysis might be instrumental in identifying neoplastic lesions even in cases of increased inflammatory activity or regenerative change.

Adolescent↗
PubMed2001

Role of reactive oxygen metabolites in aspirin-induced gastric damage in humans: gastroprotection by vitamin C.

BACKGROUND: The roles of active oxygen metabolites and anti-oxidative defenses in aspirin (ASA)-induced gastric damage have been little studied. AIM: We determined the effects of aspirin (400 mg b.d.) with or without vitamin C (480 mg b.d.) for 3 days on gastric mucosa in human volunteers. METHODS: Gastric injury was assessed endoscopically; gastric blood flow, reactive oxygen release (quantified by chemiluminescence), lipid peroxidation, myeloperoxidase, superoxide dismutase and glutathione peroxidase activity and intragastric vitamin C content were measured. Expression of superoxide dismutase and glutathione peroxidase mRNAs was assayed semi-quantitatively. RESULTS: ASA produced erosions, a marked increase in chemiluminescence, lipid peroxidation, and myeloperoxidase activity. It also resulted in a suppression of gastric blood flow, intragastric vitamin C levels, superoxide dismutase and glutathione peroxidase activities. The addition of vitamin C significantly attenuated gastric damage and reversed the effects of ASA on these parameters. Superoxide dismutase and glutathione peroxidase mRNAs were decreased in ASA-treated subjects; the addition of vitamin C restored their regular levels. CONCLUSIONS: (i) free radical-induced lipid peroxidation and suppression of antioxidizing enzymes play an important role in gastric damage induced by aspirin; (ii) increased myeloperoxidase activity suggests activated neutrophils to be the major source of these radicals; (iii) vitamin C protects against ASA-induced damage due to its anti-oxidizing activity.

Administration, Oral↗
PubMed2001

Patients with inflammatory bowel disease (IBD) reveal increased induction capacity of intracellular interferon-gamma (IFN-gamma) in peripheral CD8+ lymphocytes co-cultured with intestinal epithelial cells.

Intestinal epithelial cells seem to play a key role during IBD. The network of cellular interactions between epithelial cells and lamina propria mononuclear cells is still incompletely understood. In the following co-culture model we investigated the influence of intestinal epithelial cells on cytokine expression of T cytotoxic and T helper cells from patients with IBD and healthy controls. Peripheral blood mononuclear cells (PBMC) were purified by a Ficoll-Hypaque gradient followed by co-incubation with epithelial cells in multiwell cell culture insert plates in direct contact as well as separated by transwell filters. We used Caco-2 cells as well as freshly isolated colonic epithelia obtained from surgical specimens. Three-colour immunofluorescence flow cytometry was performed after collection, stimulation and staining of PBMC with anti-CD4, anti-CD8, anti-IFN-gamma and anti-IL-4. Patients with IBD (Crohn's disease (CD), n = 12; ulcerative colitis (UC), n = 16) and healthy controls (n = 10) were included in the study. After 24 h of co-incubation with Caco-2 cells we found a significant increase of IFN-gamma-producing CD8+ lymphocytes in patients with IBD. In contrast, healthy controls did not respond to the epithelial stimulus. No significant differences could be found between CD and UC or active and inactive disease. A significant increase of IFN-gamma+/CD8+ lymphocytes in patients with UC was also seen after direct co-incubation with primary cultures of colonic crypt cells. The observed epithelial-lymphocyte interaction seems to be MHC I-restricted. No significant epithelial cell-mediated effects on cytokine expression were detected in the PBMC CD4+ subsets. Patients with IBD-even in an inactive state of disease-exert an increased capacity for IFN-gamma induction in CD8+ lymphocytes mediated by intestinal epithelial cells. This mechanism may be important during chronic intestinal inflammation, as in the case of altered mucosal barrier function epithelial cells may become targets for IFN-gamma-producing CD8+ lymphocytes.

Antibodies, Blocking↗
PubMed2001

Colonic epithelial cells induce endothelial cell expression of ICAM-1 and VCAM-1 by a NF-kappaB-dependent mechanism.

Epithelial cells are positioned in close proximity to endothelial cells. A non-contact coculture system was used to investigate whether colonic epithelial cells activated with various cytokines are able to provide signals that can modulate ICAM-1 and VCAM-1 expression on endothelial cells. Coculture of human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (HMEC-1) with TNF-alpha/IFN-gamma-stimulated human colon epithelial cell lines led to a significant up-regulation of endothelial ICAM-1 and VCAM-1 expression. Increased ICAM-1 and VCAM-1 expression by endothelial cells was accompanied by an increase in endothelial cell NF-kappaB p65 and NF-kappaB-DNA-binding activity. Inhibition of endothelial NF-kappaB activation using the proteosome inhibitors MG-132 and BAY 11-7082 resulted in a significant decrease of ICAM-1 expression, indicating an important role for NF-kappaB in this response. This cross-talk may represent a biological mechanism for the gut epithelium to control the colonic inflammatory response and the subsequent immune cell recruitment during inflammation.

Caco-2 Cells↗
PubMed2001

IFN-gamma synergizes with TNF-alpha but not with viable H. pylori in up-regulating CXC chemokine secretion in gastric epithelial cells.

Helicobacter pylori colonizes the gastric epithelial surface and induces epithelial cells to increase production of the neutrophil attractant IL-8. Little is known about the role of the gastric epithelium in regulating mucosal T cell trafficking. We therefore characterized constitutive and regulated epithelial expression of the CXC chemokines IP-10, I-TAC and Mig, which specifically attract CXCR3 expressing CD4(+) T cells. Human gastric epithelial cell lines (AGS, Kato III, NCI) were used to characterize the constitutive and regulated expression of three CXC chemokines in response to IFN-gamma, TNF-alpha and different H. pylori preparations. Chemokine mRNA and protein production were measured by RT-PCR and ELISA. Gastric epithelial cells constitutively expressed mRNA for IP-10, Mig and I-TAC. IFN-gamma in combination with TNF-alpha strongly induced secretion of those chemokines. Soluble or membranous fractions of H. pylori significantly inhibited IFN-gamma/TNF-alpha induced epithelial cell IP-10 and Mig production. Gastric epithelial cells may contribute to mucosal T cell trafficking. The capacity of H. pylori products to inhibit IP-10 and Mig secretion may explain, at least in part, the failure to induce protective immunity against this bacterium and the ability of H. pylori to affect the presentation of the local inflammation.

Cell Line↗