Medizin - Open Access LMU - Teil 14/22 Archiv

Aim: To prospectively assess the antibacterial resistance rate in Helicobacter pylori strains obtained from symptomatic children in Europe.Methods: During a 4-year period, 17 paediatric centres from 14 European countries reported prospectively on patients infected with H pylori, for whom antibiotic susceptibility was tested.Results: A total of 1233 patients were reported from Northern (3%), Western (70%), Eastern (9%) and Southern Europe (18%); 41% originated from outside Europe as indicated by mother's birth-country; 13% were 11 years of age. Testing was carried out before the first treatment (group A, n = 1037), and after treatment failure (group B, n = 196). Overall resistance to clarithromycin was detected in 24% (mean, A: 20%, B: 42%). The primary clarithromycin resistance rate was higher in boys (odds ratio (OR) 1.58; 1.12 to 2.24, p = 0.01), in children 12 years (OR 1.82, 1.10 to 3.03, p = 0.020) and in patients living in Southern Europe compared with those living in Northern Europe (OR 2.25; 1.52 to 3.30, p

Objective To evaluate two commercial stool tests for detection of secretory IgA antibodies against gliadin and human tissue transglutaminase for diagnosis of coeliac disease in children with symptoms.Setting Tertiary care children's hospital.Participants Coded stool samples from 20 children with newly diagnosed coeliac disease and 64 controls. Six children with coeliac disease had stool tests every two weeks for three months after starting a gluten-free diet.Main outcome measures Secretory IgA antibodies against gliadin and human tissue transglutaminase in stool samples, determined in duplicate by using recommended cut-off limits.Results Sensitivity of faecal antibodies against human tissue transglutaminase was 10% (95% confidence interval 1% to 32%), and specificity was 98% (91% to 100%). For antibodies against gliadin, sensitivity was 6% (0% to 29%) and specificity was 97% (89% to 100%). Optimisation of cut-off limits by receiver operating characteristic analysis and use of results of both tests increased sensitivity to 82%, but specificity decreased to 58%. All follow-up stool tests remained negative, except for two positive anti-gliadin results in one patient, six and 10 weeks after the gluten-free diet was started.Conclusions Neither stool test was suitable for screening for coeliac disease in children with symptoms.

Background: Golabi, Ito, and Hall reported a family with X linked mental retardation (XLMR), microcephaly, postnatal growth deficiency, and other anomalies, including atrial septal defect, in 1984.Methods: This family was restudied as part of our ongoing study of XLMR, but significant linkage to X chromosome markers could not be found. Extreme short stature and microcephaly as well as other new clinical findings were observed. Mutations in the polyglutamine tract binding protein 1 gene (PQBP1) have recently been reported in four XLMR disorders (Renpenning, Hamel cerebro-palato-cardiac, Sutherland-Haan, and Porteous syndromes) as well as in several other families. The clinical similarity of our family to these patients with mutations in PQBP1, particularly the presence of microcephaly, short stature, and atrial septal defect, prompted examination of this gene.Results: A missense mutation in PQBP1 was identified which changed the conserved tyrosine residue in the WW domain at position 65 to a cysteine (p.Y65C).Conclusions: This is the first missense mutation identified in PQBP1 and the first mutation in the WW domain of the gene. The WW domain has been shown to play an important role in the regulation of transcription by interacting with the PPxY motif found in transcription factors. The p.Y65C mutation may affect the proper functioning of the PQBP1 protein as a transcriptional co-activator.

Background: The proteasome system has a pivotal role in the control of the immune response, which suggests that it might be involved in the pathogenesis of autoimmune disorders.Objective: To investigate the expression profile of selected proteasomal genes in human peripheral blood mononuclear cells in patients with a variety of autoimmune diseases compared with healthy subjects.Methods: Real time quantitative RT-PCR was used to analyse the mRNA expression pattern of the proteasome activator subunits PA28\textgreeka and PA28\textgreekb and of constitutive proteasome and interferon-\textgreekg-inducible immunoproteasome subunits in peripheral blood mononuclear cells. Simultaneously, protein expression of selected proteasome subunits was quantified by immunoblotting.Results: Under systemic inflammatory conditions the proteasome subunits LMP2 (\textgreekb1i), LMP7 (\textgreekb5i), MECL1 (\textgreekb2i), and PA28\textgreeka were expressed abundantly at the protein level in the vast majority of systemic autoimmune disorders. However, simultaneous mRNA and protein quantification showed a characteristic proteasome expression signature in primary Sjögren's syndrome. At the transcript level, the interferon-\textgreekg-responsive subunits LMP2 (\textgreekb1i), MECL1 (\textgreekb2i), and the proteasome activator subunit PA28\textgreeka were markedly up regulated. In contrast, LMP2 (\textgreekb1i) deficiency was evident at the protein level, indicating deregulation of proteasome expression in Sjögren's syndrome.Conclusions: These data provide evidence for a regulatory defect in the proteasome system in human autoimmune disorders, pointing to a unique role for LMP2 (\textgreekb1i) in the pathogenesis of primary Sjögren's syndrome.

Background: Recently, the entity of retinal angiomatous proliferation (RAP) as a subtype of exudative age-related macular degeneration was described, but no treatment options have been established as yet. The only two therapeutic modalities being discussed are surgical lysis of the feeding arteriole and draining venule, and the use of photodynamic therapy combined with intravitreal triamcinolone injection.Aim: To examine focal laser treatment of early extrafoveal intraretinal neovascularisation of RAP.Methods: Prospective case series. We included 13 consecutive patients with an extrafoveal RAP stage I lesion. All patients underwent a complete ophthalmic examination, including fluorescein angiography and optical coherence tomography (OCT) III before treatment and at 2 weeks, 1, 2 and 4 months afterwards. In cases with marked macular oedema (>350 \textgreekmm retinal thickening in OCT III, r = 12), intravitreal injection of 4 mg triamcinolone was given before focal laser treatment to reduce the oedema.Results: This case series indicates anatomical improvement or stabilisation in patients with an extrafoveal RAP lesion after treatment. Initial visual acuity ranged from 0.1 to 0.6 on the Snellen chart. By calculating logarithmic values, visual acuity was seen to be improved in five cases (2 to 5 log lines), deteriorated in four cases (-2 to 5 log lines) and stabilised in four cases (-1 to +1 log line change). Exudation on fluorescein angiography was stopped in 11 cases.Conclusions: This preliminary case series suggests laser photocoagulation combined with prior intravitreal triamcinolone injection as a viable treatment option for RAP stage I. In cases with marked macular oedema, intravitreal triamcinolone injection improved visual acuity. For long-term stabilisation, additional laser treatment is mandatory. These preliminary results warrant a more detailed prospective clinical trial.

Detailed clinical, neuroradiological, histological, biochemical, and genetic investigations were undertaken in a child suffering from Leigh syndrome. The clinical symptoms started at age five months and led to a severe progressive neurodegenerative disorder causing epilepsy, psychomotor retardation, and tetraspasticity. Biochemical measurement of skeletal muscle showed a severe decrease in mitochondrial complex II. Sequencing of SDHA revealed compound heterozygosity for a nonsense mutation in exon 4 (W119X) and a missense mutation in exon 3 (A83V), both absent in normal controls. In six additional patients---five with Leigh or Leigh-like syndrome and one with neuropathy and ataxia associated with isolated deficiency of complex II---mutations in SDHA were not detected, indicating genetic heterogeneity.

Background: The association between smoking and asthma or wheeze has been extensively studied in cross sectional studies, but evidence from large prospective cohort studies on the incidence of asthma during adolescence is scarce.Methods: We report data from a cohort study in two German cities, Dresden and Munich. The study population (n = 2936) was first studied in 1995/6 at age 9--11 years as part of phase II of the International Study of Asthma and Allergies in Childhood (ISAAC II) and followed up in 2002/3. At baseline the parents completed a questionnaire and children underwent clinical examination and blood sampling. At follow up the young adults completed questionnaires on respiratory health, living, and exposure conditions. Incidence risk ratios (IRR) were calculated and adjusted for potential confounders using a modified Poisson regression approach.Results: The adjusted IRR for incident wheeze for active smokers compared with non-smokers was 2.30 (95% confidence interval (CI) 1.88 to 2.82). The adjusted IRR was slightly higher for incident wheeze without a cold (2.76, 95% CI 1.99 to 3.84) and the incidence of diagnosed asthma (2.56, 95% CI 1.55 to 4.21). Analysis of duration and intensity of active smoking indicated dose dependent associations. Stratified analyses showed that the risk of incident wheeze without a cold in atopic smokers increased with decreasing plasma \textgreeka1-antitrypsin levels at baseline (1.64, 95% CI 1.22 to 2.20 per interquartile range).Conclusions: Active smoking is an important risk factor for the incidence of asthma during adolescence. Relatively lower plasma levels of \textgreeka1-antitrypsin, although well above currently accepted thresholds, may increase susceptibility to respiratory disease among atopic smokers.

Background: A single nucleotide polymorphism (SNP) in the coding region of the prion protein gene (PRNP) at codon 129 has been repeatedly shown to be an associated factor to sporadic Creutzfeldt-Jakob disease (sCJD), but additional major predisposing DNA variants for sCJD are still unknown. Several previous studies focused on the characterisation of polymorphisms in PRNP and the prion-like doppel gene (PRND), generating contradictory results on relatively small sample sets. Thus, extensive studies are required for validation of the polymorphisms in PRNP and PRND.Methods: We evaluated a set of nine SNPs of PRNP and one SNP of PRND in 593 German sCJD patients and 748 German healthy controls. Genotyping was performed using MALDI-TOF mass spectrometry.Results: In addition to PRNP 129, we detected a significant association between sCJD and allele frequencies of six further PRNP SNPs. No significant association of PRND T174M with sCJD was shown. We observed strong linkage disequilibrium within eight adjacent PRNP SNPs, including PRNP 129. However, the association of sCJD with PRNP 1368 and PRNP 34296 appeared to be independent on the genotype of PRNP 129. We additionally identified the most common haplotypes of PRNP to be over-represented or under-represented in our cohort of patients with sCJD.Conclusion: Our study evaluated previous findings of the association of SNPs in the PRNP and PRND genes in the largest cohorts for association study in sCJD to date, and extends previous findings by defining for the first time the haplotypes associated with sCJD in a large population of the German CJD surveillance study.

Objective: To analyse the psychometric properties of the EuroQol questionnaire (EQ-5D) applied to patients with acute coronary syndromes (ACS).Setting: Rehabilitation hospital.Patients and design: 106 consecutive patients with ACS (51% myocardial infarction, 42% coronary artery bypass grafting, 7% angina) completed the EQ-5D, the 36 item short form health survey (SF-36), and the MacNew questionnaire at admission, at discharge, and three months after inpatient cardiac rehabilitation. Acceptance, validity, reliability, and responsiveness of the EQ-5D were tested.Results: The EQ-5D was highly accepted. The EQ-5D index showed substantial ceiling effects after rehabilitation. As expected the EQ-5D visual analogue scale (VAS) score (70.3 v 57.1) and EQ-5D index (77.8 v 64.5) were significantly better for patients with myocardial infarction than for patients who underwent surgery (both p ⩽ 0.001). Significant correlations were found between the EQ-5D VAS score, EQ-5D index, and domains of the SF-36 (r = 0.21 to r = 0.74). The correlation with the MacNew subscores and with the global score ranged between 0.55 and 0.78. With repeated measurement the EQ-5D showed reasonable reliability in stable patients with intraclass correlation ranging between 0.91 and 0.54. EQ-5D was responsive in patients who indicated improvement in health states between admission and discharge (effect size 0.74--0.82).Conclusion: The psychometric properties of the EQ-5D were satisfying. It is a reasonably valid, reliable, and responsive instrument for patients with ACS. It may be useful in clinical research and epidemiological studies to generate preference based valuations of health related quality life.

Background: Parkinson's disease is a genetically complex disease with mixed mode of inheritance. Recently, a haplotype across the sepiapterin reductase (SPR) gene, which is located in the PARK3 linkage region, was shown to modulate age of onset of Parkinson's disease in sibships from North America.Objective: To make a thorough assessment of the SPR gene region in sporadic Parkinson's disease.Methods: A linkage study in 122 European sibship families with five microsatellite and 17 single nucleotide polymorphism (SNP) markers in and around the SPR gene region, and an association analysis in 340 sporadic cases of Parkinson's disease and 680 control subjects from Germany with 40 SNPs. Linkage was evaluated by non-parametric linkage scores and genotypic or haplotype association was tested by regression analysis, assuming different risk effect models.Results: Significant LOD scores between 2 and 3 were obtained at the two SPR-flanking markers D2S2110 and D2S1394 and seven SNP markers around the SPR gene. We found the previously reported promoter SNP rs1876487 also significantly associated with age of onset in our sib pair families (p-value 0.02). One strong linkage disequilibrium (LD) block of 45 kb including the entire SPR gene was observed. Within this LD block all 14 inter-correlated SNPs were significantly associated with Parkinson's disease affection status (p-value 0.004).Conclusions: DNA polymorphisms in a highly intercorrelated LD block, which includes the SPR gene, appear to be associated with both sporadic and familial Parkinson's disease. This confirms a previous study showing that SPR potentially modulates the onset of or risk for Parkinson's disease.

Background and aims: A number of Helicobacter pylori outer membrane proteins (OMPs) undergo phase variations. This study examined the relation between OMP phase variations and clinical outcome.Methods: Expression of H pylori BabA, BabB, SabA, and OipA proteins was determined by immunoblot. Multiple regression analysis was performed to determine the relation among OMP expression, clinical outcome, and mucosal histology.Results:H pylori were cultured from 200 patients (80 with gastritis, 80 with duodenal ulcer (DU), and 40 with gastric cancer). The most reliable results were obtained using cultures from single colonies of low passage number. Stability of expression with passage varied with OipA > BabA > BabB > SabA. OipA positive status was significantly associated with the presence of DU and gastric cancer, high H pylori density, and severe neutrophil infiltration. SabA positive status was associated with gastric cancer, intestinal metaplasia, and corpus atrophy, and negatively associated with DU and neutrophil infiltration. The Sydney system underestimated the prevalence of intestinal metaplasia/atrophy compared with systems using proximal and distal corpus biopsies. SabA expression dramatically decreased following exposure of H pylori to pH 5.0 for two hours.Conclusions: SabA expression frequently switched on or off, suggesting that SabA expression can rapidly respond to changing conditions in the stomach or in different regions of the stomach. SabA positive status was inversely related to the ability of the stomach to secrete acid, suggesting that its expression may be regulated by changes in acid secretion and/or in antigens expressed by the atrophic mucosa.

Objective: To develop evidence based recommendations for the management of ankylosing spondylitis (AS) as a combined effort of the `ASsessment in AS' international working group and the European League Against Rheumatism.Methods: Each of the 22 participants was asked to contribute up to 15 propositions describing key clinical aspects of AS management. A Delphi process was used to select 10 final propositions. A systematic literature search was then performed to obtain scientific evidence for each proposition. Outcome data for efficacy, adverse effects, and cost effectiveness were abstracted. The effect size, relative risk, number needed to treat, and incremental cost effectiveness ratio were calculated. On the basis of the search results, 10 major recommendations for the management of AS were constructed. The strength of recommendation was assessed based on the strength of the literature evidence, risk-benefit trade-off, and clinical expertise.Results: The final recommendations considered the use of non-steroidal anti-inflammatory drugs (NSAIDs) (conventional NSAIDs, coxibs, and co-prescription of gastroprotective agents), disease modifying antirheumatic drugs, treatments with biological agents, simple analgesics, local and systemic steroids, non-pharmacological treatment (including education, exercise, and physiotherapy), and surgical interventions. Three general recommendations were also included. Research evidence (categories I--IV) supported 11 interventions in the treatment of AS. Strength of recommendation varied, depending on the category of evidence and expert opinion.Conclusion: Ten key recommendations for the treatment of AS were developed and assessed using a combination of research based evidence and expert consensus. Regular updating will be carried out to keep abreast of new developments in the management of AS.