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Biomedical subjects

Martin Zeitz

Publications and source records attributed to Martin Zeitz.

At least 19 recordsLinked to original sources
PubMed2007

Psychological treatment may reduce the need for healthcare in patients with Crohn's disease.

BACKGROUND: Few published studies examine the influence of psychological treatment on health care utilization in Crohn's disease. METHODS: The present substudy of a prospective, randomized, multicenter trial conducted in 69 of 488 consecutive Crohn's disease (CD) patients was designed to investigate the way in which healthcare utilization is influenced by psychotherapy and relaxation in addition to standardized glucocorticoid therapy. Before and after a 1-year period of standardized somatic treatment the psychotherapy and control groups were compared with regard to hospital and sick-leave days. Predictors of healthcare utilization were analyzed. RESULTS: The comparison between groups before and after psychological treatment showed a significantly higher decrease of mean hospital days (P < 0.03) and sick-leave days in the treatment group compared with the controls. When a covariate analysis was applied to compare the data at randomization, the difference in hospital days remained statistically a trend (P < 0.1). Multivariate regression analysis detected a significant gender and depression effect for hospital days (cor r(2) = 0.114) and a significant gender and age effect for sick-leave days (cor r(2) = 0.112). CONCLUSION: A significant drop in healthcare utilization after psychological treatment demonstrates a clear benefit of this additional therapy. This is important, since the study failed to demonstrate significant changes in the psychosocial status or somatic course of study patients. Clinical and psychological factors influencing these outcomes are discussed.

Adolescent↗
PubMed2006

Proteasome-mediated degradation of IkappaBalpha and processing of p105 in Crohn disease and ulcerative colitis.

Enhanced NF-kappaB activity is involved in the pathology of both forms of inflammatory bowel disease (IBD), Crohn disease (CD) and ulcerative colitis (UC). Here we analyzed the mechanism of proteasome-mediated NF-kappaB activation in CD and UC. Our studies demonstrate that the subunit composition and the proteolytic function of proteasomes differ between UC and CD. High expression of the immunoproteasome subunits beta1i and beta2i is characteristic of the inflamed mucosa of CD. In line with this, we found enhanced processing of NF-kappaB precursor p105 and degradation of inhibitor of NF-kappaB, IkappaBalpha, by immunoproteasomes isolated from the mucosa of CD patients. In comparison with healthy controls and CD patients, UC patients exhibited an intermediate phenotype regarding the proteasome-mediated processing/degradation of NF-kappaB components. Finally, increased expression of the NF-kappaB family member c-Rel in the inflamed mucosa of CD patients suggests that p50/c-Rel is important for IFN-gamma-mediated induction of immunoproteasomes via IL-12-driven Th1 responses. These findings suggest that distinct proteasome subunits influence the intensity of NF-kappaB-mediated inflammation in IBD patients.

Animals↗
PubMed2006

Aggravation of intestinal inflammation by depletion/deficiency of gammadelta T cells in different types of IBD animal models.

The role of gammadelta T cells in inflammatory bowel disease (IBD) is still controversial. Although gammadelta T cells induce IBD in immunodeficient animals, others suggest a protective role of gammadelta T cells. Therefore, this study was conducted in order to elucidate the effect of gammadelta T cell depletion/deficiency on different IBD animal models. Mice depleted of or deficient in gammadelta T cells were exposed to dextran sodium sulfate (DSS) in order to induce colitis. In addition, gammadelta T cells were depleted in mice with terminal ileitis (TNFDeltaARE) or colitis due to interleukin 2 deficiency (IL-2 ko). Finally, DSS-induced colitis was studied in mice deficient in interferon gamma (IFN-gamma ko) upon gammadelta T cell depletion. Depletion of gammadelta T cells aggravated DSS-induced colitis and terminal ileitis of TNFDeltaARE mice. Exacerbated DSS-induced colitis was also found in gammadelta T cell-deficient mice. IL-2 ko mice showed increased mortality upon early (starting at 4 wk of age) but not late depletion (starting at 8 wk of age). Early gammadelta T cell depletion or deficiency resulted in increased IFN-gamma production by both lamina propria lymphocytes and splenocytes in every model investigated herein. In IFN-gamma ko mice, gammadelta T cell depletion did not affect the development and course of DSS-induced colitis. The protective effect of gammadelta T cells in IBD was confirmed in various IBD animal models. Particularly, during the early phase of intestinal inflammation, gammadelta T cells appear to be important. The mechanism seems to involve the control of IFN-gamma production and epithelial regeneration.

Animals↗
PubMed2006

Synthesis of collagen I in collagenous sprue.

BACKGROUND & AIMS: Collagenous sprue (CS) is a rare severe malabsorption syndrome of unknown etiology, characterized by villus atrophy and a broad subepithelial collagen band. We studied the expression patterns of genes involved in fibrogenesis and fibrolysis and analyzed the composition of the subepithelial collagen band in CS compared with untreated celiac diseases (CDs). METHODS: Duodenal biopsies from 2 patients with CS were hybridized with (35)S-labeled RNA probes for procollagen alpha1(I), matrix metalloproteinases (MMPs)-1 and -3, and tissue inhibitor of MMP-1 (TIMP-1). Numbers of positive subepithelial and lamina propria cells and grain density per cell were determined microscopically. Immunohistochemistry for collagens I, III, IV, XIV, and tenascin was performed by the immunoalkaline phosphatase method. Findings were compared with earlier data from patients with untreated CD. RESULTS: Numbers of cells expressing procollagen I, MMP-1, and MMP-3 mRNA were similar, but subepithelial procollagen I transcripts per cell were significantly increased (42 and 38 vs 18 [13-23]; P < .05) in CS compared with CD, whereas cellular transcript densities for MMP-1 and MMP-3 mRNA were similar. In addition, the number of TIMP-1 mRNA-positive cells was higher in CS compared with CD (32 and 25 vs 16.5 [4-25]; P < .05). The subepithelial collagenous bands stained for collagen I, collagen III, and tenascin. CONCLUSIONS: The prominent subepithelial matrix deposition in CS is due to increased expression of the main fibrogenic genes (procollagen I and TIMP-1) by myofibroblastic cells, whereas expression of fibrolytic MMPs remains unaltered.

Adult↗
PubMed2006

Effect of chronic Giardia lamblia infection on epithelial transport and barrier function in human duodenum.

BACKGROUND: Giardia lamblia causes infection of the small intestine, which leads to malabsorption and chronic diarrhoea. AIM: To characterise the inherent pathomechanisms of G lamblia infection. METHODS: Duodenal biopsy specimens from 13 patients with chronic giardiasis and from controls were obtained endoscopically. Short-circuit current (I(SC)) and mannitol fluxes were measured in miniaturised Ussing chambers. Epithelial and subepithelial resistances were determined by impedance spectroscopy. Mucosal morphometry was performed and tight junction proteins were characterised by immunoblotting. Apoptotic ratio was determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling staining. RESULTS: In giardiasis, mucosal surface area per unit serosa area was decreased to 75% (3%) of control, as a result of which epithelial resistance should increase. Instead, epithelial resistance of giardiasis biopsy specimens was decreased (19 (2) vs 25 (2) Omega cm(2); p<0.05) whereas mannitol flux was not significantly altered (140 (27) vs 105 (16) nmol/h/cm(2)). As structural correlate, reduced claudin 1 expression and increased epithelial apoptosis were detected. Furthermore, basal I(SC) increased from 191 (20) in control to 261 (12) microA/h/cm(2) in giardiasis. The bumetanide-sensitive portion of I(SC) in giardiasis was also increased (51 (5) vs 20 (9) microA/h/cm(2) in control; p<0.05). Finally, phlorizin-sensitive Na(+)-glucose symport was reduced in patients with giardiasis (121 (9) vs 83 (14) microA/h/cm(2)). CONCLUSIONS: G lamblia infection causes epithelial barrier dysfunction owing to down regulation of the tight junction protein claudin 1 and increased epithelial apoptoses. Na(+)-dependent d-glucose absorption is impaired and active electrogenic anion secretion is activated. Thus, the mechanisms of diarrhoea in human chronic giardiasis comprise leak flux, malabsorptive and secretory components.

Adult↗
PubMed2006

Reduced peripheral and mucosal Tropheryma whipplei-specific Th1 response in patients with Whipple's disease.

Whipple's disease is a rare infectious disorder caused by Tropheryma whipplei. Major symptoms are arthropathy, weight loss, and diarrhea, but the CNS and other organs may be affected, too. The incidence of Whipple's disease is very low despite the ubiquitous presence of T. whipplei in the environment. Therefore, it has been suggested that host factors indicated by immune deficiencies are responsible for the development of Whipple's disease. However, T. whipplei-specific T cell responses could not be studied until now, because cultivation of the bacteria was established only recently. Thus, the availability of T. whipplei Twist-Marseille(T) has enabled the first analysis of T. whipplei-specific reactivity of CD4(+) T cells. A robust T. whipplei-specific CD4(+) Th1 reactivity and activation (expression of CD154) was detected in peripheral and duodenal lymphocytes of all healthy (16 young, 27 age-matched, 11 triathletes) and disease controls (17 patients with tuberculosis) tested. However, 32 Whipple's disease patients showed reduced or absent T. whipplei-specific Th1 responses, whereas their capacity to react to other common Ags like tetanus toxoid, tuberculin, actinomycetes, Giardia lamblia, or CMV was not reduced compared with controls. Hence, we conclude that an insufficient T. whipplei-specific Th1 response may be responsible for an impaired immunological clearance of T. whipplei in Whipple's disease patients and may contribute to the fatal natural course of the disease.

Actinomycetales↗
PubMed2006

Prevention of colitis-associated carcinogenesis in a mouse model by diet supplementation with ursodeoxycholic acid.

Bile acids in the intestinal lumen contribute to the homeostatic regulation of proliferation and death of the colonic epithelial cells: Deoxycholic acid (DCA) appears to enhance and ursodeoxycholic acid (UDCA) to attenuate the process of chemically induced carcinogenesis. We studied the effects of UDCA on colitis-related colorectal carcinogenesis. Three groups of 25 mice were given 0.7% dextran sulphate in drinking water for 7 days and pure water for 10 days and were fed a standard diet containing double iron concentration. In 2 groups, the diet was supplemented with 0.2% cholic acid (CA), the precursor of DCA, or with 0.4% UDCA. After 15 cycles, the histology, the expression of MUC2, beta-catenin, p27 and p16 and the fecal water concentration of DCA and UDCA were investigated. All animals showed colitis with similar severity and histologic as well as immunophenotypic alterations, resembling those of human colitis. Among the animals fed the nonsupplemented diet, 46% developed colorectal adenocarcinomas and 54% anal-rectal squamous cell carcinomas. The prevalence of dysplasia and carcinomas did not change significantly in the animals given CA. Among the mice fed with UDCA, none developed adenocarcinomas and 20% squamous carcinomas. Dysplastic lesions were found in 88%, 67% and 40% of each group, respectively. The prevalence of dysplasia as well as of carcinoma showed an inverse relationship to the UDCA concentration in the fecal water. These data indicate that UDCA suppresses colitis-associated carcinogenesis. This model is suitable for investigation of the mechanism of the anticarcinogenic effect of UDCA in vivo.

Administration, Oral↗
PubMed2006

Mucosal but not peripheral FOXP3+ regulatory T cells are highly increased in untreated HIV infection and normalize after suppressive HAART.

Recent evidence indicates that regulatory T cells (T(regs)) play an important role in HIV infection. However, although the gastrointestinal mucosa is a key compartment in HIV disease, no data on mucosal T(regs) in HIV infection are available. In this study, we compared the frequency of T(regs) in duodenal mucosa and peripheral blood (PB) of 13 treatment-naive and 13 suppressively treated HIV-infected patients with that of 6 patients with norovirus infection and 12 healthy controls. T(regs) were quantified by immunohistochemistry (CD3/FOXP3) and further characterized (CD25, CTLA-4, GITR) by immunohistochemistry, immunofluorescence, and fluorescence-activated cell sorting (FACS). Both the frequency and the absolute count of mucosal T(regs) were highly increased in untreated HIV patients but were normal in treated HIV patients. In contrast, in peripheral blood of HIV patients, the absolute number of T(regs) was not increased, and their frequency was only slightly elevated. In norovirus infection, frequency of mucosal T(regs) in the CD4+ T-cell subset was not elevated. The high increase in count and frequency of mucosal T(regs) seems to be a characteristic feature of untreated HIV infection, suggesting a significant contribution of T(regs) to the pathogenesis of HIV disease. Their role may be 2-edged: attenuating HIV-induced immune hyperactivation while suppressing the immune response to HIV and mucosal pathogens.

Adult↗
PubMed2006

Restoration of ENaC expression by glucocorticoid receptor transfection in human HT-29/B6 colon cells.

The epithelial sodium channel (ENaC) controls colonic sodium absorption. So far, investigation of ENaC was limited by an unexplained lack of steroid-dependent ENaC expression in cultured intestinal cells, which we aimed to resolve. HT-29/B6 cells constitutively expressed the alpha-ENaC subunit, while beta- and gamma-ENaC subunits could not be detected due to deficient basal as well as corticosteroid-induced transcription. This was due to a lack of expression of both activating and inhibiting isoforms of glucocorticoid receptor (GR-alpha, -beta) and mineralocorticoid receptor. Stable transfection of GR-alpha restored intestine-specific glucocorticoid upregulation of beta- and gamma-ENaC in HT-29/B6 cells, which was followed by intact targeting of ENaC channels to the apical cell membrane and dose-dependent induction of electrogenic sodium absorption. In conclusion, ENaC deficiency is due to a lack of steroid receptors and not the consequence of a crypt-like phenotype of cultured intestinal cells. By stable GR transfection we obtained a model, in which ENaC regulation can be studied.

Colon↗
PubMed2006

Histone hyperacetylation is associated with amelioration of experimental colitis in mice.

Inhibitors of histone deacetylases (HDAC) are being studied for their antiproliferative effects in preclinical cancer trials. Recent studies suggest an anti-inflammatory role for this class of compounds. Because inflammatory bowel disease is associated with an increased risk of malignancies, agents with antiproliferative and anti-inflammatory properties would be of therapeutic interest. HDAC inhibitors from various classes were selected and evaluated for their in vitro capacity to suppress cytokine production and to induce apoptosis and histone acetylation. Valproic acid (VPA) and suberyolanilide hydroxamic acid (SAHA) were chosen for further studies in dextran sulfate sodium- and trinitrobenzene sulfonic acid-induced colitis in mice. In vitro, inhibition of HDAC resulted in a dose-dependent suppression of cytokine synthesis and apoptosis induction requiring higher concentrations of HDAC inhibitors for apoptosis induction compared with cytokine inhibition. Oral administration of either VPA or SAHA reduced disease severity in dextran sulfate sodium-induced colitis. The macroscopic and histologic reduction of disease severity was associated with a marked suppression of colonic proinflammatory cytokines. In parallel to the beneficial effect observed, a dose-dependent increase in histone 3 acetylation at the site of inflammation was shown under VPA treatment. Furthermore, SAHA as well as VPA treatment resulted in amelioration of trinitrobenzene sulfonic acid-induced colitis, which was associated with an increase of apoptosis of lamina propria lymphocytes. Inhibitors of HDAC reveal strong protective effects in different models of experimental colitis by inducing apoptosis and suppressing proinflammatory cytokines, thereby representing a promising class of compounds for clinical studies in human inflammatory bowel disease.

Acetylation↗
PubMed2006

Therapy with budesonide in patients with refractory sprue.

INTRODUCTION: Refractory sprue (RS) is a rare malabsorption syndrome, which often requires long-term corticosteroid treatment. Locally acting budesonide could replace systemic corticosteroid therapy and reduce toxicity in patients with RS. AIMS: To evaluate the efficacy and toxicity of budesonide in patients with RS. PATIENTS AND METHODS: Clinical and histological data from patients with RS who received budesonide were analyzed. RS was defined as villous atrophy and malabsorption in spite of a strict gluten-free diet persisting for >6 months or requiring earlier therapeutic intervention. RESULTS: We identified 9 patients (1 with autoimmune enteropathy, 4 with RS type I without and 3 with RS type II with signs of early T cell lymphoma and 1 with CD4-positive sprue-like intestinal T cell lymphoma), who received 9 mg/day of budesonide (range 6-12) for 24 months (1-60), and 7 of whom had an initial treatment with 40 mg/day of prednisolone (30-60) for 4 months (1-144). The initial body mass index was 18 (13.1-22.8) and increased similarly under prednisolone [21.5 (14.9-26.7), p < 0.05] and budesonide therapy [21 (18-27.2), p < 0.05]. The stool frequency per day also decreased similarly from 6 (2-8) to 2 (1-3) and 2 (1-5), each p < 0.05, under prednisolone and budesonide therapy, respectively. Two patients with RS type II did not respond and 7, including all 4 with RS type I, were clinically stable with budesonide therapy. Skin fragility in 1 patient was the only adverse effect of budesonide therapy. CONCLUSIONS: Budesonide may be an effective treatment option in patients with RS type I, which can stabilize the clinical condition similar to prednisolone.

Adolescent↗
PubMed2006

An unusual case of deep candidosis presenting as an infiltrating tumour of the chest wall.

A 45-year-old man presented with an unclear rapidly growing, infiltrating tumour of the anterior chest wall. Biopsies were non-specific, serologies remained unremarkable. Shortly after admission the patient developed blurred vision. Ophthalmoscopical findings were typical of candida endophthalmitis. Meanwhile, the tumour continued to grow. When it was resected, hyphae of Candida albicans were yielded from the tissue revealing it as a manifestation of deep candidosis. The infection had probably been acquired endogenously during abdominal surgery for early stage rectal carcinoma which the patient had undergone several weeks ago and which was followed by an unexplained fever. Interestingly, deep candidosis presenting as an infiltrating tumour of the anterior chest wall often combined with candidal endophthalmitis has been described almost exclusively in intravenous drug users after the injection of contaminated heroin [Collignon PJ, Sorrell TC. Disseminated candidiasis: evidence of a distinctive syndrome in heroin abusers. Br Med J (Clin Res Ed) 1983;287(6396):861-2; Dupont B, Drouhet E. Cutaneous, ocular, and osteoarticular candidiasis in heroin addicts: new clinical and therapeutic aspects in 38 patients. J Infect Dis 1985;152(3):577-91; Bisbe J, Miro JM, Latorre X, Moreno A, Mallolas J, Gatell JM, et al. Disseminated candidiasis in addicts who use brown heroin: report of 83 cases and review. Clin Infect Dis 1992;15(6):910-23.]. Why the tumours only develop on the anterior thoracic wall is unknown. To our knowledge this is the first case described in literature in which endogenously acquired deep candidosis manifested as an infiltrating tumour in a patient who was neither immunosuppressed nor had a history of intravenous drug use.

Antifungal Agents↗
PubMed2006

[The German competence network inflammatory bowel disease (KNCED) -- network research leads to the identification of the cause of disease and to the improvement in patient care].

The competence network chronic inflammatory bowel disease (KN-CED) is one of 17 networks of competence initiated by the German Federal Ministry of Education and Research (BMBF). These networks are concerned with disease patterns which are characterized by their high frequency, high mortality rate or which present a large expense factor. The project-executing organization is the German Center for Air and Space Travel (DLR e. V.). The central structure of organization is the Telematic Platform for medical Networks (TMF e. V.). Aim of the KN-CED is to investigate, in their complexity, the incurable chronic diseases ulcerative colitis and Crohn's disease, particularly with regard to the causes of disease, the establishment of new therapy standards as well as patient care. To achieve this goal, the competence network is integrated into both national and international research associations and is also backed by the national self-help group DCCV and the pharmaceutical industry. Principal items of the competence network are the core facilities and their main focus on molecular genetics, animal and cell models and serum markers. Having stored the data of more than 4,000 patients so far, the central database of the competence network is one of the largest databases worldwide with regard to inflammatory bowel disease (IBD). The successful cooperation within the network is reflected in numerous publications. Thus, two of the three known genes of Crohn's disease were identified. Also with the participation of the competence network national guidelines for the diagnosis and therapy of IBD were generated.Furthermore, the competence network operates study centers where significant therapeutic developments in the field of biotechnological drugs are taking place. The analysis of existing structures of care as well as the development of standards of organization for patients with IBD top the research within the competence network and emphasize the claim to find comprehensive answers to the questions connected with IBD.

Clinical Trials as Topic↗
PubMed2006

DNA damage-induced expression of p53 suppresses mitotic checkpoint kinase hMps1: the lack of this suppression in p53MUT cells contributes to apoptosis.

DNA damage induced by the topoisomerase I inhibitor irinotecan (CPT-11) triggers in p53(WT) colorectal carcinoma cells a long term cell cycle arrest and in p53MUT cells a transient arrest followed by apoptosis (Magrini, R., Bhonde, M. R., Hanski, M. L., Notter, M., Scherübl, H., Boland, C. R., Zeitz, M., and Hanski, C. (2002) Int. J. Cancer 101, 23-31; Bhonde, M. R., Hanski, M. L., Notter, M., Gillissen, B. F., Daniel, P. T., Zeitz, M., and Hanski, C. (2006) Oncogene 25, 165-175). The mechanism of the p53-independent apoptosis still remains largely unclear. Here we used five p53WT and five p53MUT established colon carcinoma cell lines to identify gene expression alterations associated with apoptosis in p53MUT cells after treatment with SN-38, the irinotecan metabolite. After treatment, 16 mitosis-related genes were found to be expressed at least 2-fold stronger in the apoptosis-executing p53MUT cells than in the cell cycle-arrested p53WT cells by oligonucleotide microarray analysis. One of the genes whose strong post-treatment expression was associated with apoptosis was the mitotic checkpoint kinase hMps1 (human ortholog of the yeast monopolar spindle 1 kinase). hMps1 mRNA and protein expression were suppressed by the treatment-induced and by the exogenous adenovirus-coded p53 protein. The direct suppression of hMps1 on RNA level or inhibition of its activity by a dominant-negative hMps1 partly suppressed apoptosis. Together, these data indicate that the high expression of mitotic genes in p53MUT cells after SN-38 treatment contributes to DNA damage-induced apoptosis, whereas their suppression in p53WT cells acts as a safeguard mechanism preventing mitosis initiation and the subsequent apoptosis. hMps1 kinase is one of the mitotic checkpoint proteins whose expression after DNA damage in p53MUT cells activates the checkpoint and contributes to apoptosis.

Antineoplastic Agents, Phytogenic↗
PubMed2005

Cost-benefit analysis of screening colonoscopy in 40- to 50-year-old first-degree relatives of patients with colorectal cancer.

BACKGROUND AND AIMS: As shown previously, 40- to 50-year-old first-degree relatives of patients with colorectal cancer (CRC) have significantly more colorectal adenomas than controls of the same age. Screening colonoscopy of these persons at risk between 40 and 50 years might be cost beneficial. METHODS: We prepared a detailed cost-benefit analysis of screening colonoscopy and possible repeat endoscopies according to current expenditures for endoscopic procedures in Germany. Since screening colonoscopy is generally offered and reimbursed from 55 years on in Germany, we analysed the period between 45 and 55 years, taking an annual interest rate of 5% into account. Costs were analysed based on the results of a former study [11] depending on various participation rates in a general screening programme. FINDINGS: Based on the available 1994 figure of about 20,000 euros for diagnosis and treatment of one cancer case, screening colonoscopy is cost beneficial when participation is high. Under a more realistic assumption of currently about 40,000 euros per cancer case, screening colonoscopy is cost beneficial in any case. INTERPRETATION: Our data support that systematic screening colonoscopy in first-degree relatives of patients with CRC by the age of 45 years most likely demonstrates an economic benefit.

Adult↗