Structure-specific binding of MeCP2 to four-way junction DNA through its methyl CpG-binding domain

MeCP2, whose methylated DNA-binding domain (MBD) binds preferentially to DNA containing 5Me-CpG relative to linear unmethylated DNA, also binds preferentially, and with similar affinity, to unmethylated four-way DNA junctions through the MBD. The Arg133Cys (R133C) mutation in the MBD, a Rett syndrome mutation that abolishes binding to methylated DNA, leads to only a slight reduction in the affinity of the MBD for four-way junctions, suggesting distinct but partially overlapping modes of binding to junction and methylated DNA. Binding to unmethylated DNA junctions is likely to involve a subset of the interactions that occur with methylated DNA. High-affinity, methylation-independent binding to four-way junctions is consistent with additional roles for MeCP2 in chromatin, beyond recognition of 5Me-CpG

Safety aspects of infliximab in inflammatory bowel disease patients - A retrospective cohort study in 100 patients of a German University Hospital

Background: Infliximab, a chimeric anti-tumour necrosis factor monoclonal antibody with potent anti-inflammatory effects, represents an effective treatment option in patients with severe inflammatory bowel disease (IBD). Serious side-effects of such an immunomodulating therapy are speculated and therefore we reviewed our clinical experience in a retrospective safety study looking upon a single cohort of 100 IBD patients from a large German University Hospital. Methods: 100 patients with severe Crohn's disease (n = 92), ulcerative colitis (n = 7) or indeterminate colitis (n = 1) treated with infliximab (5 mg/kg) from January 2000 to December 2003 were retrospectively analysed for acute and subacute adverse events by chart review. Results: Overall, infliximab therapy was generally well tolerated. No fatal complications, malignancies, autoimmune diseases, neurologic or cardiovascular complications were observed in the cohort during the study period. Overall, adverse events were observed in 10 patients: 2 patients showed an acute infusion reaction, 1 patient a serum sickness-like reaction, in 4 patients a bacterial or viral infection occurred, in 1 patient pancytopenia and 2 patients developed surgical complications. Only 6 patients with adverse events required admission to hospital. A case of tuberculosis after infliximab was not found. The lack of adverse side-effects was associated with young median age and infrequent comorbidities of the cohort. Conclusion: Regarding its strong immunomodulating capacity, infliximab appears to be an efficient and relatively safe therapeutic option for patients with severe IBD. However, the use of infliximab requires careful screening and close patient monitoring to identify patients at risk and the infrequent, but sometimes serious complications of infliximab. Copyright (C) 2004 S. Karger AG, Basel

Using Residential History and Groundwater Modeling to Examine Drinking Water Exposure and Breast Cancer

BACKGROUND. Spatial analyses of case-control data have suggested a possible link between breast cancer and groundwater plumes in upper Cape Cod, Massachusetts. OBJECTIVE. We integrated residential histories, public water distribution systems, and groundwater modeling within geographic information systems (GIS) to examine the association between exposure to drinking water that has been contaminated by wastewater effluent and breast cancer. METHODS. Exposure was assessed from 1947 to 1993 for 638 breast cancer cases who were diagnosed from 1983 to 1993 and 842 controls; we took into account residential mobility and drinking water source. To estimate the historical impact of effluent on drinking water wells, we modified a modular three-dimensional finite-difference groundwater model (MODFLOW) from the U.S. Geological Survey. The analyses included latency and exposure duration. RESULTS. Wastewater effluent impacted the drinking water wells of study participants as early as 1966. For > 0-5 years of exposure (versus no exposure), associations were generally null. Adjusted odds ratios (AORs) for > 10 years of exposure were slightly increased, assuming latency periods of 0 or 10 years [AOR = 1.3; 95% confidence interval (CI), 0.9-1.9 and AOR = 1.6; 95% CI, 0.8-3.2, respectively]. Statistically significant associations were estimated for ever-exposed versus never-exposed women when a 20-year latency period was assumed (AOR = 1.9; 95% CI, 1.0-3.4). A sensitivity analysis that classified exposures assuming lower well-pumping rates showed similar results. CONCLUSION. We investigated the hypothesis generated by earlier spatial analyses that exposure to drinking water contaminated by wastewater effluent may be associated with breast cancer. Using a detailed exposure assessment, we found an association with breast cancer that increased with longer latency and greater exposure duration.National Cancer Institute (5R03CA119703-02); National Institute of Environmental Health Sciences (5P42 ES007381

Effects of zinc and fluoride on the remineralisation of artificial carious lesions under simulated plaque fluid conditions.

The aim was to study the effects of zinc (Zn) and fluoride (F) on remineralisation at plaque fluid concentrations. Artificial carious lesions were created in 2 acid-gel demineralising systems (initially infinitely undersaturated and partially saturated with respect to enamel) giving lesions with different mineral distribution characteristics (high and low R values, respectively) but similar integrated mineral loss values. Lesions of both types were assigned to 1 of 4 groups and remineralised for 5 days at 37°C. Zn and F were added, based on plaque fluid concentrations 1 h after application, to give 4 treatments: 231 μmol/l Zn, 10.5 μmol/l F, Zn/F combined and an unmodified control solution (non-F/non-Zn). Subsequently remineralisation was measured using microradiography. High-R lesions were analysed for calcium, phosphorus, F and Zn using electron probe micro-analysis. All lesions underwent statistically significant remineralisation. For low-R lesions, remineralisation was in the order F(a) < non-F/non-Zn(a) < Zn(a, b) < Zn/F(b), and for high-R lesions F(a) < non-F/non-Zn(b) < Zn(b) < Zn/F(c) (treatments with the same superscript letter not significantly different, at p < 0.05). Qualitatively, remineralisation occurred throughout non-F/non-Zn and Zn groups, predominantly at the surface zone (F) and within the lesion body (Zn/F). Electron probe micro-analysis revealed Zn in relatively large amounts in the outer regions (Zn, Zn/F). F was abundant not only at the surface (F), but also in the lesion body (Zn/F). Calcium:phosphate ratios were similar to hydroxyapatite (all). To conclude, under static remineralising conditions simulating plaque fluid, Zn/F treatment gave significantly greater remineralisation than did F treatment, possibly because Zn in the Zn/F group maintained greater surface zone porosity compared with F, facilitating greater lesion body remineralisation

High-resolution quantitative MRI of multiple sclerosis spinal cord lesions

Purpose: Validation of quantitative MR measuresfor myelin imaging in the postmortem multiple sclerosis spinal cord. Methods: Four fixed spinal cord samples were imaged first with a 3T clinical MR scannerto identify areas of interest forscanning, and then with a 7T small bore scanner using a multicomponent-driven equilibrium single-pulse observation of T1 and T2 protocol to produce apparent proton density, T1, T2, myelin water, intracellular water, and free-water fraction maps. After imaging, the cords were sectioned and stained with histological markers (hematoxylin and eosin, myelin basic protein, and neurofilament protein), which were quantitatively compared with the MR maps. Results: Excellent correspondence was found between high-resolution MR parameter maps and histology, particularly for apparent proton density MRI and myelin basic protein staining. Conclusion: High-resolution quantitative MRI of the spinal cord provides biologically meaningful measures, and could be beneficial to diagnose and track multiple sclerosis lesions in the spinal cord

High-resolution quantitative MRI of multiple sclerosis spinal cord lesions

PURPOSE: Validation of quantitative MR measures for myelin imaging in the postmortem multiple sclerosis spinal cord. METHODS: Four fixed spinal cord samples were imaged first with a 3T clinical MR scanner to identify areas of interest for scanning, and then with a 7T small bore scanner using a multicomponent‐driven equilibrium single‐pulse observation of T(1) and T(2) protocol to produce apparent proton density, T(1), T(2), myelin water, intracellular water, and free‐water fraction maps. After imaging, the cords were sectioned and stained with histological markers (hematoxylin and eosin, myelin basic protein, and neurofilament protein), which were quantitatively compared with the MR maps. RESULTS: Excellent correspondence was found between high‐resolution MR parameter maps and histology, particularly for apparent proton density MRI and myelin basic protein staining. CONCLUSION: High‐resolution quantitative MRI of the spinal cord provides biologically meaningful measures, and could be beneficial to diagnose and track multiple sclerosis lesions in the spinal cord