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Biomedical subjects

W Domschke

Publications and source records attributed to W Domschke.

At least 19 recordsLinked to original sources
PubMed2006

Clinical and immunological characteristics of patients with Sjögren's syndrome in relation to alpha-fodrin antibodies.

OBJECTIVES: To analyse the prevalence of alpha-fodrin antibodies in patients with primary (pSS) and secondary Sjögren's syndrome (sSS) and the relation to clinical, serological and immunological features. METHODS: Serum IgA and IgG antibodies to the 120 kDa alpha-fodrin were determined by ELISA technique in 62 pSS patients and 28 sSS patients. Results were correlated with clinical symptoms and laboratory findings as well as with the HLA-DR genotype. Additionally, antibody concentrations were correlated with the numbers of peripheral blood mononuclear cells (PBMCs) secreting interleukin (IL)-6, IL-10, interferon-gamma (INF)-gamma, and tumour necrosis factor-alpha determined by ELISPOT analysis. Lymphocytes and monocytes were examined flow-cytometrically for the expression of activation markers. Healthy age- and sex-matched volunteers served as controls. RESULTS: The sensitivity of IgA and IgG alpha-fodrin antibodies was 35 and 31%, respectively, in pSS patients. In sSS patients, the sensitivity was 29 and 21%, respectively. In pSS patients with IgG antibodies, recurrent parotid swelling was significantly more prevalent. Also the number of INF-gamma secreting PBMCs and the percentage of CD4/CD71+ lymphocytes as well as CD14/HLA-DR+ monocytes were significantly increased in this group compared with alpha-fodrin-negative patients or with controls. Interestingly, these patients also had a shorter disease duration. No association of alpha-fodrin antibodies with the HLA-DR genotype was found. CONCLUSION: Due to the low prevalence, serum antibodies to alpha-fodrin turned out to be of limited diagnostic value in our study. However, our data suggest that IgG antibodies to alpha-fodrin are indicative of clinical and immunological activity in pSS especially in patients with shorter disease duration and may thus serve as a marker of disease activity.

Adult↗
PubMed2006

Role of receptor tyrosine kinases in gastric cancer: new targets for a selective therapy.

Receptor tyrosine kinases (RTKs) such as the epidermal growth factor receptor family participate in several steps of tumor formation including proliferation and metastatic spread. Several known RTKs are upregulated in gastric cancer being prime targets of a tailored therapy. Only preliminary data exist, however, on the use of the currently clinically available drugs such as trastuzumab, cetuximab, bevacizumab, gefitinib, erlotinib, and imatinib in the setting of gastric cancer. Preclinical data suggest a potential benefit of their use, especially in combination with "conventional" cytostatic therapy. This review summarizes the current knowledge about their use in cancer therapy as well as new approaches and drugs to optimize treatment success.

Adenocarcinoma↗
PubMed2006

Crucial role of the melanocortin receptor MC1R in experimental colitis.

BACKGROUND AND AIMS: alpha-Melanocyte stimulating hormone (alpha MSH) is known to exert anti-inflammatory effects, for example in murine DSS (dextran sodium sulphate induced) colitis. The anti-inflammatory functions of alpha MSH are mediated by the melanocortin1-receptor (MC1R) in an autoregulatory loop. The aim of this study was therefore to determine whether a breakdown of the alpha MSH-MC1R pathway leads to worsening of disease. METHODS: Experimental colitis was induced in mice with a frameshift mutation in the MC1R gene (MC1Re/e), C57BL/6 wild type mice, and MC1Re/e-C57BL/6 bone marrow chimeras. The course of inflammation was monitored by weight loss, histological changes in the colon, and myeloperoxidase activity. In addition, MC1R expression was analysed in intestinal epithelial cells. RESULTS: While the colon of untreated MC1Re/e appeared normal, the course of DSS-colitis in MC1Re/e mice was dramatically aggravated, with a significantly higher weight loss and marked histological changes compared to C57BL/6WT. The inflammation eventually led to death in all MC1Re/e, while all C57BL/6WT survived. Similar observations were detected in a transmissible murine colitis model induced by Citrobacter rodentium. Infected MC1Re/e showed delayed clearance of infection. To determine whether missing haematopoietic cell expressed MC1R was responsible, DSS colitis was induced in MC1Re/e-C57BL/6 bone marrow chimeras. MC1Re/e mice receiving MC1R+ bone marrow showed a similar course of inflammation to non-transplanted MC1Re/e. Likewise, transplantation of MC1R bone marrow into C57BL/6WT mice did not lead to any worsening of disease. CONCLUSIONS: This is the first study to show a functional role of MC1R in intestinal inflammation. The data suggest a pivotal role of non-haematopoietic cell expressed MC1R in the host's response to pathogenic stimuli.

Animals↗
PubMed2006

[Medicinal prevention of gastrointestinal tumors: aspirin, Helicobacter and more?].

Despite the huge number of drugs on the market and recent advances in pharmacotherapy, only a few substances are available for the prevention of gastrointestinal tumors--most of which are not approved for this indication or not validated in appropriately designed randomized trials. General recommendations include lifestyle modifications such as avoidance of smoking, only moderate consumption of alcohol, regular physical exercise and a nutrition rich in fresh fruits and vegetables with limited meat. A global eradication therapy for Helicobacter pylori would be desirable to prevent gastric carcinoma, but this does not seem feasible from the socio-economic point of view. Therefore, at least patients at high risk should be screened and this pathogen eradicated, preferentially in their youth. Hepatitis B vaccination of newborns to prevent the development of hepatocellular carcinoma has already been established in Germany; a specific antiviral therapy should be offered to all patients with hepatitis B or C infections, taking into consideration the risks associated with this treatment. The use of non-steroidal anti-inflammatory drugs (NSAIDs) to prevent gastrointestinal malignancies cannot generally be recommended and should be restricted to patients at high risk and to clinical studies. However, the appropriate substance, dose and duration of NSAID therapy are still being debated.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

[Joint involvement in chronic inflammatory bowel disease--current diagnostics and treatment options].

Joint involvement is the most frequent extra-intestinal manifestation of chronic inflammatory bowel disease (IBD). Arthralgias are common and spondylarthropathy may affect peripheral joints, the spine as well as tendons. Clinical assessment has the greatest impact on diagnostics and therapy. In particular, a history of "inflammatory back pain" should lead to further investigations. HLA-B27 may be indicative of ankylosing spondylitis in IBD. Ultrasound and magnetic resonance imaging are preferred diagnostic modalities for the assessment of inflammation. Arthralgia often improves during treatment of IBD. In contrast, polyarticular arthritis, sacroiliitis, ankylosing spondylitis and enthesitis often require additional continuous therapy. Baseline therapy includes analgesics, intra-articular corticosteroid administration, and physiotherapy. Disease-modifying antirheumatic drugs such as sulfasalazine and methotrexate are used in polyarticular arthritis. Sulfasalazine may be effective in patients with early axial disease as well. Tumor necrosis factor (TNF) blocking agents may be employed in patients with active disease not responding to conventional treatment. For patients who fail to respond to TNF blockade, the emergence of other targets of the inflammatory cascade may provide more treatment choices in the future.

Anti-Inflammatory Agents↗
PubMed2006

Recurrent obscure gastrointestinal bleeding caused by aorto-enteric fistula.

Aorto-enteric fistulas are rare but serious clinical conditions that may arise as a complication following abdominal aortic surgery. Clinical symptoms in affected patients range from obscure recurrent gastrointestinal bleeding and intermittent unexplained fever attacks to fulminant hematochezia and rapid exsanguination. A high degree of clinical alertness and suspicion is critical for both accurate diagnosis and timely surgical therapy in these patients. This case report describes a patient who was referred to our department six months after abdominal aortic surgery. The patient presented with septic illness and episodes of obscure gastrointestinal bleeding. Diagnostic work-up revealed a retroperitoneal infection of the aortic graft. A false aneurysm led to recurrent duodenal bleeding, which was accompanied by perforation of the obliterated aortic graft into the cecum. After immediate surgical repair, the patient recovered and continues to do well. We present a brief review of the current literature on this entity, outlining different surgical strategies and their outcomes.

Arterio-Arterial Fistula↗
PubMed2006

Acetylsalicylic acid enhances antiproliferative effects of the EGFR inhibitor gefitinib in the absence of activating mutations in gastric cancer.

The epidermal growth factor receptor (EGFR) is highly expressed in gastric cancer indicating its suitability as a target for receptor tyrosine kinase (RTK) inhibitors. In the current study we explored the role of EGFR and its potential use as a therapeutic target in gastric cancer. First we analyzed 66 gastric cancer samples of Asian and Caucasian patients for the presence of EGFR mutations. No activating EGFR mutations were found and gefitinib alone was only weakly effective in gastric cancer cell lines. However, acetylsalicylic acid (ASA) significantly enhanced the inhibitory effects of gefitinib indicating synergistic action. Whole genome expression profiling indicated significant regulation of 120 genes in the case of co-administration of gefitinib and ASA (32 induced, 88 repressed) in gastric adenocarcinoma cells. Further analyses indicated that several important signalling pathways were effectively inhibited by simultaneous exposure to gefitinib and ASA. Our findings indicate that although gastric cancer does not seem to harbour mutations which render the cancer cells constitutively susceptible to gefitinib, the co-administration of ASA can strengthen RTK inhibitor activity in adenocarcinoma cells by EGFR activation. This is the first report of effective modulation of EGFR-inhibition activity in cancer.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Protein tyrosine phosphatase kappa and SHP-1 are involved in the regulation of cell-cell contacts at adherens junctions in the exocrine pancreas.

BACKGROUND: We have previously shown that cell contacts between pancreatic acinar cells dissociate early in pancreatitis and that this is a prerequisite for the development of pancreatic oedema. Here we studied the underlying mechanism. METHODS: Employing experimental caerulein induced pancreatitis in vivo and isolated pancreatic acini ex vivo, in conjunction with protein chemistry, morphology, and electron microscopy, we determined whether cell contact regulation in the pancreas requires or involves: (1) changes in cadherin-catenin protein expression, (2) tyrosine phosphorylation of adhesion proteins, or (3) alterations in the actin cytoskeleton. RESULTS: During initial cell-cell contact dissociation at adherens junctions, expression of adhesion proteins remained stable. At time points of dissociated adherens junctions, the cadherin-catenin complex was found to be tyrosine phosphorylated and internalised. The receptor type protein tyrosine phosphatase (PTP)kappa was constitutively associated with the cadherin-catenin complex at intact cell contacts whereas following the dissociation of adherens junctions, the internalised components of the cadherin-catenin complex were tyrosine phosphorylated and associated with the cytosolic PTP SHP-1. In isolated acini, inhibition of endogenous protein tyrosine phosphatases alone was sufficient to induce dissociation of adherens junctions analogous to that found with supramaximal caerulein stimulation. Dissociation of actin microfilaments had no effect on adherens junction integrity. CONCLUSIONS: These data identify tyrosine phosphorylation as the key regulator for cell contacts at adherens junctions and suggest a definitive role for the protein tyrosine phosphatases PTPkappa and SHP-1 in the regulation, maintenance, and restitution of cell adhesions in a complex epithelial organ such as the pancreas.

Actins↗
PubMed2005

[Cardiovascular monitoring of patients with systemic lupus erythematosus].

Accelerated atherosclerotic cardiovascular disease is increasingly recognized as a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Cardiac manifestations of SLE are frequent and can involve almost all components of the heart. Pulmonary hypertension often develops during the course of SLE. The high incidence of cardiovascular complications may justify a screening of SLE patients in order to ensure early diagnosis and therapy. Results of diagnostic procedures that detect coronary insufficiency, surrogates of atherosclerotic burden and echocardiographic findings are often abnormal in SLE. However, evidence to support a routine screening for cardiovascular disease is currently not available. Therefore, based on the recommendations that have been proposed for other conditions associated with cardiovascular disease, we suggest assessment of risk factors and the performance of echocardiography at least annually in asymptomatic SLE patients. If two or more risk factors are present, an exercise ECG is recommended. The benefit, however, of screening SLE patients for cardiovascular disease has to be confirmed in prospective studies.

Cardiovascular Diseases↗
PubMed2005

[Four-year observation of etanercept therapy for rheumatoid arthritis in a single German center].

The tumor necrosis factor blocking agent etanercept is effective in the treatment of chronic inflammatory diseases. Previously published studies provided no evidence for an elevated frequency of severe adverse events under therapy. The present work documents efficacy and safety of long-term treatment with etanercept up to four years in 29 patients with rheumatoid arthritis in single German study center. Follow-up examinations were conducted at monthly intervals. The response was assessed in an intention-to-treat analysis (last observation carried forward) according to the ACR and EULAR criteria. The evaluation is based on 95 patient years, the median observation period was 50 (4-52) months. After four years, 21 patients were still in the study. Reasons for study dropouts were inefficacy (n=3), severe adverse events (n=1), long distance to study center (n=2), scheduled surgery (n=1), and desire for pregnancy (n=1). Morning stiffness, the number of painful and swollen joints, C-reactive protein, erythrocyte sedimentation rate, and DAS28 significantly decreased within 6 months. At their most recent visit, 26 patients (90%) had achieved the ACR20, 17 patients (59%) the ACR50, and 6 patients (21%) the ACR70 criteria. Subject to the EULAR criteria, 14 patients (48%) responded well and another 12 patients (41%) moderately well. Severe adverse events occurred in the form of a sigma perforation with subsequent sepsis (week 17), suture insufficiency (twice) following rupture of an Achilles tendon (weeks 3 and 9), pneumonia (week 121), and breast cancer (week 197). In our patients, long-term treatment with etanercept continued to be effective and safe up to four years. Severe adverse events were rare and not more frequent than expected. For the detection of uncommon or late occurring severe adverse events under the treatment with biologic agents, documentation in central registers should be encouraged.

Adult↗
PubMed2005

Gastric electrical stimulation results in improved metabolic control in diabetic patients suffering from gastroparesis.

AIMS/HYPOTHESIS: Symptoms of gastroparesis possess a heavy impact on the quality of life; delayed gastric emptying may result in poor metabolic control in diabetics. Gastric electrical stimulation (GES) has recently been introduced as a treatment option in patients with drug refractory gastroparesis to increase the quality of life by alleviating nausea and vomiting frequencies. However, the effect of GES on metabolic control has not been assessed yet. METHODS: We performed a prospective single center study on the long-term effect (12 months) of continuous high-frequency/low-energy GES on symptoms, gastric emptying (measured scintigraphically), and metabolic control (HbA1c) in insulin-dependent diabetic subjects suffering from drug-refractory gastroparesis for more than one year. RESULTS: Seventeen (12 female, 5 male) patients entered the study; all were available for analysis at all time points. No therapy-associated adverse events occurred. Weekly vomiting and nausea frequencies decreased significantly at 6 and 12 months. Gastric retention rates improved significantly from 83 % (2 h) and 38 % (4 h) to 35 % (2 h)/14 % (4 h) and 25 % (2 h)/17 % (4 h) at 6 and 12 months, respectively. HbA1c values were lowered in all 17 subjects; initially, all HbA1c values were above 7.5 %; at 6 and 12 months, mean values had significantly decreased from 8.6 % to 6.2 % and 6.5 %, respectively. CONCLUSIONS/INTERPRETATION: Gastric electrical stimulation offers symptom control in diabetics with drug-refractory gastroparesis and decreases gastric retention. This study, for the first time, documents a positive effect of this therapy on metabolic control as indicated by HbA1c, a surrogate marker of the risk of diabetic complications.

Adult↗
PubMed2005

Amelanotic malignant melanoma of the esophagus: case report.

We present the case of a primary malignant esophageal melanoma arising in a 75-year-old male, initially diagnosed as anaplastic squamous cell carcinoma. After resection of the tumor, histological work-up was indicative of a marked morphological heterogeneity, resembling a focally amelanotic primary malignant melanoma. Primary malignant melanomas of the esophagus are exceptionally rare. An exact preoperative diagnosis is critical with respect to the appropriate therapeutic strategy. Clinicopathological features of this entity with a brief review of the literature are presented.

Carcinoma, Squamous Cell↗
PubMed2005

Gastric duplication cyst: a rare endosonographic finding in an adult.

Cystic lesions located in the gastric wall are a rare finding in endosonography of the gastrointestinal tract. Compared to all forms of benign and malignant tumours of the stomach, gastric duplication cysts are an uncommon anomaly--especially in adults. We report on a 59-year-old woman suffering from intermittent abdominal pain, weight loss and nausea. A gastric duplication cyst was identified by endoscopic ultrasound (EUS), but malignancy was excluded by EUS and fine-needle aspiration histology. Because of continuously increasing abdominal complaints, surgery was performed with partial resection of the gastric corpus and splenectomy. Gross anatomy and histology showed a gastric cyst measuring 150 mm in maximum diameter with no evidence of malignancy or inflammation. Following surgery, the patient's condition recovered fully.

Cysts↗
PubMed2005

Endosonographic and histopathological staging of extrahepatic bile duct cancer: time to leave the present TNM-classification?

OBJECTIVES: The discrepancy between high rates of sensitivity, specificity, and accuracy for intraductal ultrasonography (IDUS) in extrahepatic bile duct carcinoma and the failure to depict different wall layers as defined by the TNM classification have not yet been elucidated sufficiently. METHODS: In a prospective study, endosonographic images were correlated with histomorphology including immunohistochemistry. Using IDUS, we examined fresh resection specimens of patients who had undergone pancreato-duodenectomy. For histological analysis, the formalin-fixed and paraffin-embedded specimens were stained by hematoxylin-eosin, elastica-van-Gieson, and immunohistochemically by smooth muscle-actin. To confirm our hypothesis, further cases from the archives were analyzed histopathologically and immunohistochemically. RESULTS: The various wall layers of the extrahepatic bile duct as described by the International Union Against Cancer are neither histomorphologically nor immunohistochemically consistently demonstrable. Especially, a clear differentiation between tumor invasion beyond the wall of the bile duct (T2) and invasion of the pancreas (T3) by histopathological means is often not possible. Endosonographic images using high-resolution miniprobes similarly confirm the difficulty in imaging various layers in the bile duct wall. CONCLUSIONS: Most adaptations made by the sixth edition of the TNM classification accommodate to the endosonographic and most of the histopathological findings as demonstrated in our study. In contrast to the new edition, however, our findings suggest to combine T2- and T3-staged tumors into one single class leading to clarification, and improved reproducibility of histopathological staging.

Aged↗
PubMed2005

Stable remission after administration of rituximab in a patient with primary hepatic marginal zone B-cell lymphoma.

We describe a case of primary hepatic marginal zone B-cell lymphoma in a 36-year-old Caucasian male with a history of chronic hepatitis B infection. Immunohistochemically, extensive infiltration by a CD20-positive, CD5- negative and CD10-negative lymphoid cell population displaying a follicular arrangement was detected. Molecular analysis of immunoglobulin heavy chain gene rearrangements confirmed the clonal expansion of lymphoma cells. Fourteen months after surgical treatment, the tumour recurred in close proximity to the liver hilus, hampering further surgery. Therefore, we implemented a therapy using the monoclonal anti-CD20-antibody rituximab in a dose of 375 mg/m(2), administered four times once a week. Six, 10, 18, and 26 months later the recurrent lymphoma could no longer be detected as shown by abdominal ultrasonography and CT. This case report demonstrates the difficulties of treating this extremely rare liver disease and shows its response to rituximab therapy.

Adult↗
PubMed2004

Interleukin 10 promoter microsatellite polymorphisms are associated with response to long term treatment with etanercept in patients with rheumatoid arthritis.

OBJECTIVES: To analyse the association of interleukin 10 (IL10) promoter polymorphisms, which have been shown to be related to IL10 secretion capacity, with the response to long term treatment with etanercept in patients with rheumatoid arthritis (RA). METHODS: Fifty patients with active RA were treated for up to 4 years (median 39 months, range 3-52) with stable doses of etanercept as monotherapy. Treatment response was assessed as defined by the EULAR criteria in an intention to treat analysis, with the last observation carried forward. IL10 promoter microsatellite polymorphisms IL10.R and IL10.G were genotyped by fragment length analysis in patients and 189 healthy controls matched for ethnicity, age, and sex. Haplotypes were reconstructed using a method based on bayesian, coalescent theory with the PHASE software. RESULTS: IL10 microsatellite polymorphisms were not associated with susceptibility to RA. When patients with good treatment response (n = 25) were compared with patients with moderate (n = 17) or no response (n = 8), a significantly different distribution of the prevailing alleles R2, R3 and G9, G13, respectively, became evident. Good treatment response was associated with carriage of the R3 allele or R3-G9 haplotype, whereas the allele G13 and the haplotype R2-G13 predominated in patients with moderate or no response. CONCLUSION: Genotyping of the IL10 promoter microsatellites may be useful in predicting the clinical response to etanercept in patients with RA. The high prevalence of the presumptive IL10 low producer allele R3 in patients with a favourable response suggests that IL10 promotes disease activity in RA under the specific condition of tumour necrosis factor antagonism.

Adult↗