Medizin - Open Access LMU - Teil 21/22

Conventional sciences have brought forth a wealth of knowledge and benefits, but they have not always been clear and precise about their legitimate scope and methodological limitations. In contrast, new and critical approaches in modern sciences question and reflect their own presuppositions, dependencies, and constraints. Examples are quantum physics, theory and history of science, as well as theory and history of medicine, sociology, and economics. In this way, deprecative dogmatism and animosity amongst sciences ought to be lessened, while the field opens up for each science to redefine its appropriate place in society. This would appear to be a chance for homeopathy, as new approaches, especially within the social and economic sciences, suggest that being a follower of Samuel Hahnemann (1755–1843) may have advantages and privileges that conventional medicine seems to be lacking and whose relevance was overlooked during the rise of economic thinking in the last two centuries.

Numerous high-throughput sequencing studies have focused on detecting conventionally spliced mRNAs in RNA-seq data. However, non-standard RNAs arising through gene fusion, circularization or trans-splicing are often neglected. We introduce a novel, unbiased algorithm to detect splice junctions from single-end cDNA sequences. In contrast to other methods, our approach accommodates multi-junction structures. Our method compares favorably with competing tools for conventionally spliced mRNAs and, with a gain of up to 40% of recall, systematically outperforms them on reads with multiple splits, trans-splicing and circular products.

We studied seven Itokawa particles provided by the Japan Aerospace Exploration Agency (JAXA) as first International Announcement of Opportunity (AO) study mainly using electron and synchrotron radiation X-ray beam techniques. All the analyzed particles were collected from the first-touchdown site and composed of olivine and plagioclase with traces of Ca phosphate and chromite, and do not contain pyroxenes. Optical microscopy of these particles shows minor undulatory extinction of olivine and plagioclase, suggesting minor shock metamorphism (shock stage: S2). The electron microprobe analysis shows that olivine is Fo(70-73) and plagioclase is An(13-10)Or(5-7). The synchrotron radiation X-ray diffraction (SR-XRD) analysis of olivine crystals gives cell dimensions of a = 4.708 to 4.779 angstrom, b = 10.271 to 10.289 angstrom, c = 6.017 to 6.024 angstrom, corresponding to the Fo content of Fo(similar to 70) by Vegard's law. This composition matches the result obtained by the electron microprobe analysis. The olivine compositions of the analyzed particles are consistent with those of LL chondrites. The cell dimensions of two plagioclase crystals (a = 8.180 to 8.194 angstrom, b = 12.53 to 12.893 angstrom, c = 7.125 to 7.23 angstrom, a = 92.6 degrees to 93.00 degrees, beta = 116.36 degrees to 116.75 degrees, gamma = 90.03 degrees to 90.17 degrees) indicate that their equilibration temperatures are 800 degrees C +/- 10 degrees C. This temperature is near the peak metamorphic temperature recorded by equilibrated ordinary chondrites. The size of plagioclase crystals and the homogeneity of olivine compositions indicate that their petrologic type is >= 5. We also analyzed plagioclase by SR iron X-ray absorption near-edge structure (SR-XANES) and found that its Fe3+/(Fe2+ + Fe3+) ratio is approximately 0.5. Such high Fe3+ abundance indicates the formation under a relatively oxidizing environment. Thus, all these analyses have reconfirmed that the Itokawa particles returned by the Hayabusa spacecraft are very weakly shocked equilibrated LL chondrites, which matches the results of the preliminary examination team.

Background: Hepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data. Methods: Via questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications. Results: Early treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 mu M) and NTBC-levels in the therapeutic range (20-40 mu M). Side effects of NTBC are mild and often transient. Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood). Conclusion: Based on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.

Background: Although the number of child laborers in Latin America is generally high, data on occupational hazards and injuries is insufficient. The objective of this study was therefore to determine the lifetime prevalence of and risk factors for occupational injuries among working students (10-17 years old) in Cusco Province. Methods: A cross-sectional study was conducted at five public night schools. 375 students (response 91.5%) completed an interview-based questionnaire on socio-demographics, work-related factors, and lifetime prevalence of occupational injuries. Multiple logistic regression analyses were performed to estimate risk factors for different types and causes of occupational injuries. Results: Falls (11%), car accidents (9%) and physical violence (3%) were common causes of injuries in this population. Severe injuries (fractures, luxation or amputations) were reported by 3% of the population. A high daily income (>= 20 PEN, similar to 15 USD) was a statistically significant predictor for injuries caused by falls [OR 2.8; 95% CI 1.2-6.5] and physical violence at work [12.1; 1.3-115.9] whereas children born in Cusco and those working in the service sector were at higher risk of injuries caused by car accidents [3.7; 1.5-9.3 and 4.2; 1.2-15.3]. Conclusions: Occupational accidents among child workers attending public night schools are common in Cusco with a lifetime prevalence of 3% for severe injuries. High income seems to convince child laborers to accept poor working conditions.

Background: Musculus gastrocnemius tightness (MGT) can be diagnosed by comparing ankle dorsiflexion (ADF) with the knee extended and flexed. Although various measurement techniques exist, the degree of knee flexion needed to eliminate the effect of the gastrocnemius on ADF is still unknown. The aim of this study was to identify the minimal degree of knee flexion required to eliminate the restricting effect of the musculus gastrocnemius on ADF. Methods: Bilateral ADF of 20 asymptomatic volunteers aged 18-40 years (50% female) was assessed prospectively at six different degrees of knee flexion (0 degrees, 20 degrees, 30 degrees, 45 degrees, 60 degrees, 75 degrees, Lunge). Tests were performed following a standardized protocol, non weightbearing and weightbearing, by two observers. Statistics comprised of descriptive statistics, t-tests, repeated measurement ANOVA and ICC. Results: 20 individuals with a mean age of 27 +/- 4 years were tested. No significant side to side differences were observed. The average ADF [95% confidence interval] for non weightbearing was 4 degrees{[}1 degrees-8 degrees] with the knee extended and 20 degrees [16 degrees-24 degrees] for the knee 75 flexed. Mean weightbearing ADF was 25 degrees[22 degrees-28 degrees] for the knee extended and 39 degrees[36 degrees-42 degrees] for the knee 75 degrees flexed. The mean differences between 20 degrees knee flexion and full extension were 15 degrees[12 degrees-18 degrees] non weightbearing and 13 degrees[11 degrees-16 degrees] weightbearing. Significant differences of ADF were only found between full extension and 20 degrees of knee flexion. Further knee flexion did not increase ADF. Conclusion: Knee flexion of 20 degrees fully eliminates the ADF restraining effect of the gastrocnemius. This knowledge is essential to design a standardized clinical examination assessing MGT.

Background: Genome wide association studies (GWAS) are applied to identify genetic loci, which are associated with complex traits and human diseases. Analogous to the evolution of gene expression analyses, pathway analyses have emerged as important tools to uncover functional networks of genome-wide association data. Usually, pathway analyses combine statistical methods with a priori available biological knowledge. To determine significance thresholds for associated pathways, correction for multiple testing and over-representation permutation testing is applied. Results: We systematically investigated the impact of three different permutation test approaches for over-representation analysis to detect false positive pathway candidates and evaluate them on genome-wide association data of Dilated Cardiomyopathy (DCM) and Ulcerative Colitis (UC). Our results provide evidence that the gold standard - permuting the case-control status - effectively improves specificity of GWAS pathway analysis. Although permutation of SNPs does not maintain linkage disequilibrium (LD), these permutations represent an alternative for GWAS data when case-control permutations are not possible. Gene permutations, however, did not add significantly to the specificity. Finally, we provide estimates on the required number of permutations for the investigated approaches. Conclusions: To discover potential false positive functional pathway candidates and to support the results from standard statistical tests such as the Hypergeometric test, permutation tests of case control data should be carried out. The most reasonable alternative was case-control permutation, if this is not possible, SNP permutations may be carried out. Our study also demonstrates that significance values converge rapidly with an increasing number of permutations. By applying the described statistical framework we were able to discover axon guidance, focal adhesion and calcium signaling as important DCM-related pathways and Intestinal immune network for IgA production as most significant UC pathway.

Background: We report on the design and implementation of a study protocol entitled Acupuncture randomised trial for post anaesthetic recovery and postoperative pain - a pilot study (ACUARP) designed to investigate the effectiveness of acupuncture therapy performed in the perioperative period on post anaesthetic recovery and postoperative pain. Methods/Design: The study is designed as a randomised controlled pilot trial with three arms and partial double blinding. We will compare (a) press needle acupuncture, (b) no treatment and (c) press plaster acupressure in a standardised anaesthetic setting. Seventy-five patients scheduled for laparoscopic surgery to the uterus or ovaries will be allocated randomly to one of the three trial arms. The total observation period will begin one day before surgery and end on the second postoperative day. Twelve press needles and press plasters are to be administered preoperatively at seven acupuncture points. The primary outcome measure will be time from extubation to `ready for discharge' from the post anaesthesia care unit (in minutes). The `ready for discharge' end point will be assessed using three different scores: the Aldrete score, the Post Anaesthetic Discharge Scoring System and an In-House score. Secondary outcome measures will comprise pre-, intra- and postoperative variables (which are anxiety, pain, nausea and vomiting, concomitant medication). Discussion: The results of this study will provide information on whether acupuncture may improve patient post anaesthetic recovery. Comparing acupuncture with acupressure will provide insight into potential therapeutic differences between invasive and non-invasive acupuncture techniques.

Evidence suggests that research protocols often lack important information on study design, which hinders external review. The study protocol should provide an adequate explanation for why the proposed study methodology is appropriate for the question posed, why the study design is likely to answer the research question, and why it is the best approach. It is especially important that researchers explain why the treatment difference sought is worthwhile to patients, and they should reference consultations with the public and patient groups and existing literature. Moreover, the study design should be underpinned by a systematic review of the existing evidence, which should be included in the research protocol. The Health Research Authority in collaboration with partners has published guidance entitled `Specific questions that need answering when considering the design of clinical trials'. The guidance will help those designing research and those reviewing it to address key issues.

Background: With the help of epigenome-wide association studies (EWAS), increasing knowledge on the role of epigenetic mechanisms such as DNA methylation in disease processes is obtained. In addition, EWAS aid the understanding of behavioral and environmental effects on DNA methylation. In terms of statistical analysis, specific challenges arise from the characteristics of methylation data. First, methylation beta-values represent proportions with skewed and heteroscedastic distributions. Thus, traditional modeling strategies assuming a normally distributed response might not be appropriate. Second, recent evidence suggests that not only mean differences but also variability in site-specific DNA methylation associates with diseases, including cancer. The purpose of this study was to compare different modeling strategies for methylation data in terms of model performance and performance of downstream hypothesis tests. Specifically, we used the generalized additive models for location, scale and shape (GAMLSS) framework to compare beta regression with Gaussian regression on raw, binary logit and arcsine square root transformed methylation data, with and without modeling a covariate effect on the scale parameter. Results: Using simulated and real data from a large population-based study and an independent sample of cancer patients and healthy controls, we show that beta regression does not outperform competing strategies in terms of model performance. In addition, Gaussian models for location and scale showed an improved performance as compared to models for location only. The best performance was observed for the Gaussian model on binary logit transformed beta-values, referred to as M-values. Our results further suggest that models for location and scale are specifically sensitive towards violations of the distribution assumption and towards outliers in the methylation data. Therefore, a resampling procedure is proposed as a mode of inference and shown to diminish type I error rate in practically relevant settings. We apply the proposed method in an EWAS of BMI and age and reveal strong associations of age with methylation variability that are validated in an independent sample. Conclusions: Models for location and scale are promising tools for EWAS that may help to understand the influence of environmental factors and disease-related phenotypes on methylation variability and its role during disease development.