Medizin - Open Access LMU - Teil 14/22 Archiv

The IL23R gene has been identified as a susceptibility gene for inflammatory bowel disease (IBD) in the North American population. The aim of our study was to test this association in a large German IBD cohort and to elucidate potential interactions with other IBD genes as well as phenotypic consequences of IL23R variants. Genomic DNA from 2670 Caucasian individuals including 833 patients with Crohn's disease (CD), 456 patients with ulcerative colitis (UC), and 1381 healthy unrelated controls was analyzed for 10 IL23R SNPs. Genotyping included the NOD2 variants p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008 and polymorphisms in SLC22A4/OCTN1 (1672 C-->T) and SLC22A5/OCTN2 (-207 G-->C). All IL23R gene variants analyzed displayed highly significant associations with CD. The strongest association was found for the SNP rs1004819 [P = 1.92x10(-11); OR 1.56; 95 % CI (1.37-1.78)]. 93.2% of the rs1004819 TT homozygous carriers as compared to 78% of CC wildtype carriers had ileal involvement [P = 0.004; OR 4.24; CI (1.46-12.34)]. The coding SNP rs11209026 (p.Arg381Gln) was protective for CD [P = 8.04x10(-8); OR 0.43; CI (0.31-0.59)]. Similar, but weaker associations were found in UC. There was no evidence for epistasis between the IL23R gene and the CD susceptibility genes CARD15 and SLC22A4/5. IL23R is an IBD susceptibility gene, but has no epistatic interaction with CARD15 and SLC22A4/5. rs1004819 is the major IL23R variant associated with CD in the German population, while the p.Arg381Gln IL23R variant is a protective marker for CD and UC.

CD4+ T cell help is critical in maintaining antiviral immune responses and such help has been shown to be sustained in acute resolving hepatitis C. In contrast, in evolving chronic hepatitis C CD4+ T cell helper responses appear to be absent or short-lived, using functional assays. Here we used a novel HLA-DR1 tetramer containing a highly targeted CD4+ T cell epitope from the hepatitis C virus non-structural protein 4 to track number and phenotype of hepatitis C virus specific CD4+ T cells in a cohort of seven HLA-DR1 positive patients with acute hepatitis C in comparison to patients with chronic or resolved hepatitis C. We observed peptide-specific T cells in all seven patients with acute hepatitis C regardless of outcome at frequencies up to 0.65% of CD4+ T cells. Among patients who transiently controlled virus replication we observed loss of function, and/or physical deletion of tetramer+ CD4+ T cells before viral recrudescence. In some patients with chronic hepatitis C very low numbers of tetramer+ cells were detectable in peripheral blood, compared to robust responses detected in spontaneous resolvers. Importantly we did not observe escape mutations in this key CD4+ T cell epitope in patients with evolving chronic hepatitis C. During acute hepatitis C a CD4+ T cell response against this epitope is readily induced in most, if not all, HLA-DR1+ patients. This antiviral T cell population becomes functionally impaired or is deleted early in the course of disease in those where viremia persists.

Epstein-Barr virus (EBV) is associated with a number of human malignancies. EBV-positive post-transplant lymphoproliferative disease in solid organ and hematopoietic stem cell transplant recipients has been successfully treated by the adoptive transfer of polyclonal EBV-specific T cell lines containing CD4+ and CD8+ T cell components. Although patients receiving T cell preparations with a higher CD4+ T cell proportion show better clinical responses, the specificity of the infused CD4+ component has remained completely unknown. We generated LCL-stimulated T cell lines from 21 donors according to clinical protocols, and analyzed the antigen specificity of the CD4+ component in EBV-specific T cell preparations using a genetically engineered EBV mutant that is unable to enter the lytic cycle, and recombinantly expressed and purified EBV proteins. Surprisingly, CD4+ T cell lines from acutely and persistently EBV-infected donors consistently responded against EBV lytic cycle antigens and autoantigens, but barely against latent cycle antigens of EBV hitherto considered principal immunotherapeutic targets. Lytic cycle antigens were predominantly derived from structural proteins of the virus presented on MHC II via receptor-mediated uptake of released viral particles, but also included abundant infected cell proteins whose presentation involved intercellular protein transfer. Importantly, presentation of virion antigens was severely impaired by acyclovir treatment of stimulator cells, as currently performed in most clinical protocols. These results indicate that structural antigens of EBV are the immunodominant targets of CD4+ T cells in LCL-stimulated T cell preparations. These findings add to our understanding of the immune response against this human tumor-virus and have important implications for the improvement of immunotherapeutic strategies against EBV.

Objectives: Reported associations of self-employment with occupational injury and cerebrovascular disease suggest that worker safety and health precautions may vary by occupational status. The authors assessed the extent to which use of respiratory protection and ventilation equipment is associated with self-employed versus employee status among adults in an international study.Methods: The European Community Respiratory Health Survey II (ECRHS II) is a follow-up study conducted in a population-based random sample of adult ECRHS I participants. Men and women enrolled in the ECRHS II completed interviewer-administered questionnaires to provide information about their occupational status and job history during the 9-year ECRHS follow-up period. Respondents in selected occupational groups completed supplemental questionnaires about their jobs and use of respiratory protection and ventilation equipment on-the-job. The authors assessed self-reported use of respiratory and ventilation equipment among 72 self-employed and 371 employed adults in metalworking, soldering and welding occupations.Results: Local exhaust ventilation (fixed extraction: OR 0.37, 95% CI 0.17 to 0.80; mobile extraction: OR 0.23, 95% CI 0.09 to 0.60; on-tool extraction: OR 0.39, 95% CI 0.18 to 0.88) was reported less frequently among self-employed respondents than among employed respondents. The magnitude of the negative association between self-employment status and any of the three types of local exhaust ventilation was not attenuated by adjustment for duration of work per day or week or asthma and/or wheezing symptoms. Respiratory protection was not associated with employment status in these data.Conclusions: More limited use of local exhaust ventilation among self-employed workers compared to employees suggests the need to promote occupational safety among self-employed workers.

Objectives: To estimate long-term exposure to traffic-related air pollutants on an individual basis and to assess adverse health effects using a combination of air pollution measurement data, data from geographical information systems (GIS) and questionnaire data.Methods: 40 measurement sites in the city of Munich, Germany were selected at which to collect particulate matter with a 50% cut-off aerodynamic diameter of 2.5 µm (PM2.5) and to measure PM2.5 absorbance and nitrogen dioxide (NO2). A pool of GIS variables (information about street length, household and population density and land use) was collected for the Munich metropolitan area and was used in multiple linear regression models to predict traffic-related air pollutants. These models were also applied to the birth addresses of two birth cohorts (German Infant Nutritional Intervention Study (GINI) and Influence of Life-style factors on the development of the Immune System and Allergies in East and West Germany (LISA)) in the Munich metropolitan area. Associations between air pollution concentrations at birth address and 1-year and 2-year incidences of respiratory symptoms were analysed.Results: The following means for the estimated exposures to PM2.5, PM2.5 absorbance and NO2 were obtained: 12.8 \textgreekmg/m3, 1.7×10-5 m-1 and 35.3 \textgreekmg/m3, respectively. Adjusted odds ratios (ORs) for wheezing, cough without infection, dry cough at night, bronchial asthma, bronchitis and respiratory infections indicated positive associations with traffic-related air pollutants. After controlling for individual confounders, significant associations were found between the pollutant PM2.5 and sneezing, runny/stuffed nose during the first year of life (OR 1.16, 95% confidence interval 1.01 to 1.34) Similar effects were observed for the second year of life. These findings are similar to those from our previous analysis that were restricted to a subcohort in Munich city. The extended study also showed significant effects for sneezing, running/stuffed nose. Additionally, significant associations were found between NO2 and dry cough at night (or bronchitis) during the first year of life. The variable ``living close to major roads'' (

Objective: The authors examined the relations between self-reported work tasks, use of cleaning products and latex glove use with new-onset asthma among nurses and other healthcare workers in the European Community Respiratory Health Survey (ECRHS II).Methods: In a random population sample of adults from 22 European sites, 332 participants reported working in nursing and other related healthcare jobs during the nine-year ECRHS II follow-up period and responded to a supplemental questionnaire about their principal work settings, occupational tasks, products used at work and respiratory symptoms. Poisson regression models with robust error variances were used to compare the risk of new-onset asthma among healthcare workers with each exposure to that of respondents who reported professional or administrative occupations during the entire follow-up period (n = 2481).Results: Twenty (6%) healthcare workers and 131 (5%) members of the referent population reported new-onset asthma. Compared to the referent group, the authors observed increased risks among hospital technicians (RR 4.63; 95% CI 1.87 to 11.5) and among those using ammonia and/or bleach at work (RR 2.16; 95% CI 1.03 to 4.53).Conclusions: In the ECRHS II cohort, hospital technicians and other healthcare workers experience increased risks of new-onset current asthma, possibly due to specific products used at work.

Three dimensional eye rotations were measured using the magnetic search coil technique in a patient with a lesion of the right rostral interstitial nucleus of the medial longitudinal fasciculus (RIMLF) and in four control subjects. Up to 10° contralesional torsional deviations with each voluntary saccade were revealed, which also could be seen during bedside examination. There was no spontaneous nystagmus. Based on MRI criteria, the lesion involved the RIMLF but spared the interstitial nucleus of Cajal. To date, this deficit has not been described in patients. Our results support the hypothesis that the vertical--torsional saccade generator in humans is organised similarly as in monkeys: each RIMLF encodes torsional saccades in one direction, while both participate in vertical saccades.

Cryoglobulinaemia may cause cutaneous vasculitis and glomerulonephritis, potentially leading to end stage renal failure. An important proportion of cryoglobulinaemias are secondary to hepatitis C virus infection. Emerging antiviral treatment options offer a chance for causal therapy of these cases of cryoglobulinaemia. This review summarises the classification and clinical and therapeutic aspects of cryoglobulinaemic vasculitis and glomerulonephritis.

Background/aim: Interleukin 31 (IL31), primarily expressed in activated lymphocytes, signals through a heterodimeric receptor complex consisting of the IL31 receptor alpha (IL31R\textgreeka) and the oncostatin M receptor (OSMR). The aim of this study was to analyse IL31 receptor expression, signal transduction, and specific biological functions of this cytokine system in intestinal inflammation.Methods: Expression studies were performed by RT-PCR, quantitative PCR, western blotting, and immunohistochemistry. Signal transduction was analysed by western blotting. Cell proliferation was measured by MTS assays, cell migration by restitution assays.Results: Colorectal cancer derived intestinal epithelial cell (IEC) lines express both IL31 receptor subunits, while their expression in unstimulated primary murine IEC was low. LPS and the proinflammatory cytokines TNF-\textgreeka, IL1\textgreekb, IFN-\textgreekg, and sodium butyrate stimulation increased IL31, IL31R\textgreeka, and OSMR mRNA expression, while IL31 itself enhanced IL8 expression in IEC. IL31 mediates ERK-1/2, Akt, STAT1, and STAT3 activation in IEC resulting in enhanced IEC migration. However, at low cell density, IL31 had significant antiproliferative capacities (p

Objective: To evaluate the staining characteristics of bromphenol blue used during vitreoretinal surgery in humans.Patients and methods: 13 patients with epiretinal membranes were included. Before and after surgery a complete clinical examination including best corrected visual acuity, funduscopy, fluorescein angiography, OCT (Stratus), Goldmann perimetry and multifocal ERG as well as photography of the macular area was performed. Bromphenol blue was used in concentrations of 0.2% in most patients. Removed epiretinal tissue was evaluated using electron microscopy.Results: Using dye concentrations of 0.2% a good demarcation of epiretinal membranes was seen in 11/13 patients. Staining of vitreous remnants at the vitreous base was seen in all patients. No dye-related adverse events were seen during follow-up in the functional tests (VA, ERG, perimetry) performed. Histological evaluation of epiretinal membranes showed unremarkable aspects of epiretinal cellular layers and unremarkable retinal surface of the internal limiting membrane (ILM).Conclusion: Bromphenol blue appears to be a very helpful and safe tool in posterior segment surgery. The staining characteristics need to be further evaluated in prospective study settings and larger numbers of patients.

Background: In the present study we evaluated the functional success after macular hole surgery in correlation to visual quality of life and looked for predictive factors determining surgical success.Methods: Fifty-nine patients that underwent pars plana vitrectomy for idiopathic macular hole were included. Follow-up visits were performed in regular intervals after surgery and included a clinical examination, optical coherence tomography (OCT) and measurement of visual acuity. To assess the visual quality of life patients filled out the National Eye Institute 25-item Visual Function Questionnaire (VFQ-25) before and three months and one year after surgery.Results: Macular hole closure was achieved in 57 of 59 patients (97%). Mean visual acuity increased from 20/100 preoperatively to 20/34 one year after surgery (p = 0.02). Despite good visual acuity (20/27) in the fellow eye, visual quality of life (VFQ composite score) rose from 75.9 ± 14.4 (SD) to 81.5 ± 14.2 one year after surgery (p

Background/aims: Contaminated ophthalmic solutions represent a potential cause of avoidable ocular infection. This study aimed to determine the magnitude and pattern of microbial contamination of multi-dose ocular solutions at the Department of Ophthalmology, University of Nairobi, at the Kenyatta National Hospital, Kenya.Methods: 101 vials were obtained for microbial examination after an average use of 2 weeks. The dropper tip and the residual eye drop were examined for contamination. The specimens were cultured, the number of colonies counted, the organisms identified and susceptibility testing to selected antimicrobial agents was done.Results: Six (6%) of the 101 analysed vials were contaminated: 4/77 vials (5%) from a multi-user setting and 2/24 vials (8%) from a single user setting. Three contaminations (3/38, 8%) occurred in vials from the eye ward, another three (3/59, 5%) in vials from the outpatient clinic. Most bacteria identified belonged to the normal commensal flora of the eye. Isolated contaminants were micrococci (n = 2), Staphylococcus epidermidis, Haemophilus sp, Bacillus sp and a Gram negative rod. The dropper tip was more often contaminated (n = 6) than the residual solution (n = 1), and only one vial showed a contamination of both the drop and the tip.Conclusion: Our data show a contamination rate of 6%, which is in the lower range of data published on the contamination of eye drops elsewhere (0.07% to 35.8%).

Superficial haemosiderosis results from chronic subarachnoid haemorrhage during which haemosiderin is deposited in the leptomeninges around the brain, spinal cord and cranial nerves. We describe an exceptional case of superficial haemosiderosis characterised by two special aspects. (1) The cause was a secondary tethered cord syndrome due to dural adhesions which had developed 8 years after resection of a thoracic lymphoma and (2) an explorative neurosurgical procedure with complete untethering caused normalisation of the cerebrospinal fluid and stopped disease progression.

Objectives: To determine trends in the prevalence and aetiological distribution of genital ulcer syndrome (GUS) in a cohort of female bar workers and to assess factors associated with these trends.Methods: An open cohort of 600 women at high risk of HIV and sexually transmitted infection (STI) was offered screening and treatment for STI at 3-month intervals. The prevalence of GUS and associated aetiological agents (Herpes simplex virus (HSV), Treponema pallidum and Haemophilus ducreyi) were monitored over 27 months through clinical examination, dry lesion swabbing and multiplex polymerase chain reaction. The effects of HIV status and other factors on the prevalence trends of STI were assessed.Results: A total of 753 women were recruited into the cohort over 10 examination rounds. At recruitment, the seroprevalence was 67% for HIV and 89% for HSV type 2 (HSV-2). During follow-up, 57% of ulcers had unknown aetiology, 37% were due to genital herpes and 6% to bacterial aetiologies, which disappeared completely in later rounds. The absolute prevalence of genital herpes remained stable at around 2%. The proportion of GUS caused by HSV increased from 22% to 58%, whereas bacterial causes declined. These trends were observed in both HIV-negative and HIV-positive women.Conclusions: The changes observed in the frequency and proportional distribution of GUS aetiologies suggest that regular STI screening and treatment over an extended period can effectively reduce bacterial STI and should therefore be sustained. However, in populations with a high prevalence of HSV-2, there remains a considerable burden of genital herpes, which soon becomes the predominant cause of GUS. Given the observed associations between genital herpes and HIV transmission, high priority should be given to the evaluation of potential interventions to control HSV-2 either through a vaccine or through episodic or suppressive antiviral therapy and primary prevention.