Medizin - Open Access LMU - Teil 20/22 Archiv

Large randomized trials on critically ill patients have related the use of hydroxyethyl starch (HES) to negative outcomes. In a recent comment we explained in detail why, from our point of view, transferring the results of VISEP, 6S and CHEST into daily ICU practice is as difficult as their extrapolation to perioperative treatment. Haase, Muller and Perner lately challenged this analysis. However, after having carefully read their letter to the editor we are happy to demonstrate that all points we made were absolutely correct. We agree with Haase et al. that a debate on HES safety is important, but has to be based on facts. The difference might be that we like to thoroughly discuss all of them, including the main one: VISEP, 6S and CHEST do not capture the initial stabilization of their hemodynamically instable patients. The vast majority, including those patients later assigned to the "crystalloid" groups, had been stabilized with colloids before study onset. This is not a big problem, but has to be discussed carefully and honestly to prevent the data from being misinterpreted by users and official authorities.

Background: Giardia-infection in cattle is often subclinical or asymptomatic, but it can also cause diarrhoea. The livestock-specific species Giardia bovis is the most frequently observed in cattle, however, the two zoonotic species Giardia duodenalis and Giardia enterica have also been found. Therefore calves are thought to be of public health significance. The aim of this study was to obtain current data about the frequency of the different Giardia-species in calves in Southern Germany. Findings: Faecal samples of calves (diarrhoeic and healthy) in Southern Germany, diagnosed Giardia-positive by microscopy, were characterised by multi-locus PCR and sequencing. Of 152 microscopically Giardia-positive samples 110 (72.4%) were positive by PCR and successfully sequenced. G. bovis (Assemblage E) was detected in 101/110 (91.8%) PCR-positive samples, whilst G. duodenalis (Assemblage A) was detected in 8/110 (7.3%) samples and a mixed infection with G. duodenalis and G. bovis (Assemblage A+E) was identified in 1/110 (0.9%) samples. The sub-genotypes A1, E2 and E3 were identified with the beta-giardin and the glutamate dehydrogenase genes. In the majority of diarrhoeic faecal samples a co-infection with Cryptosporidium spp. or Eimeria spp. was present, however, there were some in which G. bovis was the only protozoan pathogen found. Conclusions: The results suggest that there is potentially a risk for animal handlers as calves in Southern Germany are, at a low percentage, infected with the zoonotic species G. duodenalis. In addition, it was found that G. bovis was the only pathogen identified in some samples of diarrhoeic calves, indicating that this parasite may be a contributing factor to diarrhoea in calves.

Background: Re-irradiation is a reasonable second treatment option for patients with recurrent malignant glioma (MG) after previous radio(chemo) therapy. However, only limited data is available allowing for a precise selection of patients suitable for re-treatment in regard to safety and efficacy. Methods: Using the department database, 58 patients with two courses of percutaneous radiation were identified. Besides classical dose-volume histogram (DVH) parameters equivalent uniform dose (EUD) values were calculated for the tumor and organs at risk (OARs), retrospectively analyzed and correlated to survival outcome parameters. Cumulative EUD values were also calculated in all cases where previous OAR DVHs were available. Results: Median follow-up was 265 days and no relevant toxicity was observed after re-irradiation in our patient cohort during follow-up. Time interval between first and second irradiation was regularly above 6 months. As a conservative estimation of the cumulative EUD to the OARs, the EUDs of first and second irradiation were added. Median cumulative EUD to the optic chiasm was 48.8 Gy (range, 2.5-76.5 Gy), 57.4 Gy (range, 2.7-75.3 Gy) to the brainstem, 20.9/22.1 Gy (range, 0.0-68.3 Gy) to the right/left optic nerve and 73.8 Gy (range, 64.9-77.3 Gy) to the brain. No correlation between treated volume and survival was seen. Conclusions: This study provides retrospective estimates on cumulative doses at the OARs. EUD values are derived and may serve as reference for further studies, including planning studies where specific constraints are needed.

Background: In up to 30% of patients with ischemic stroke no definite etiology can be established. A significant proportion of cryptogenic stroke cases may be due to non-stenosing atherosclerotic plaques or low grade carotid artery stenosis not fulfilling common criteria for atherothrombotic stroke. The aim of the CAPIAS study is to determine the frequency, characteristics, clinical and radiological long-term consequences of ipsilateral complicated American Heart Association lesion type VI (AHA-LT VI) carotid artery plaques in patients with cryptogenic stroke. Methods/Design: 300 patients (age > 49 years) with unilateral DWI-positive lesions in the anterior circulation and non- or moderately stenosing (

Background: Chronic pain is a common reason for consultation in general practice. Current research distinguishes between chronic localized pain (CLP) and chronic widespread pain (CWP). The aim of this study was to identify differences between CWP and chronic low back pain (CLBP), a common type of CLP, in primary care settings. Methods: Fifty-eight German general practitioners (GPs) consecutively recruited all eligible patients who consulted for chronic low back pain during a 5 month period. All patients received a questionnaire on sociodemographic data, pain characteristics, comorbidities, psychosomatic symptoms, and previous therapies. Results: GPs recruited 647 eligible patients where of a quarter (n = 163, 25.2\%) met the CWP criteria according to the American College of Rheumatology. CWP patients had significantly more comorbidities and psychosomatic symptoms, showed longer pain duration, and suffered predominantly from permanent pain instead of distinguishable pain attacks. CWP patients were more often females, are less working and reported a current pension application or a state-approved grade of disability more frequently. We found no other differences in demographic parameters such as age, nationality, marital status, number of persons in household, education, health insurance status, or in health care utilization data. Conclusions: This project is the largest study performed to date which analyzes differences between CLBP and CWP in primary care settings. Our results showed that CWP is a frequent and particularly severe pain syndrome.

Gravity has been a constant force throughout the Earth's evolutionary history. Thus, one of the fundamental biological questions is if and how complex cellular and molecular functions of life on Earth require gravity. In this study, we investigated the influence of gravity on the oxidative burst reaction in macrophages, one of the key elements in innate immune response and cellular signaling. An important step is the production of superoxide by the NADPH oxidase, which is rapidly converted to H2O2 by spontaneous and enzymatic dismutation. The phagozytosis-mediated oxidative burst under altered gravity conditions was studied in NR8383 rat alveolar macrophages by means of a luminol assay. Ground-based experiments in "functional weightlessness" were performed using a 2 D clinostat combined with a photomultiplier (PMT clinostat). The same technical set-up was used during the 13th DLR and 51st ESA parabolic flight campaign. Furthermore, hypergravity conditions were provided by using the Multi-Sample Incubation Centrifuge (MuSIC) and the Short Arm Human Centrifuge (SAHC). The results demonstrate that release of reactive oxygen species (ROS) during the oxidative burst reaction depends greatly on gravity conditions. ROS release is 1.) reduced in microgravity, 2.) enhanced in hypergravity and 3.) responds rapidly and reversible to altered gravity within seconds. We substantiated the effect of altered gravity on oxidative burst reaction in two independent experimental systems, parabolic flights and 2D clinostat / centrifuge experiments. Furthermore, the results obtained in simulated microgravity (2D clinorotation experiments) were proven by experiments in real microgravity as in both cases a pronounced reduction in ROS was observed. Our experiments indicate that gravity-sensitive steps are located both in the initial activation pathways and in the final oxidative burst reaction itself, which could be explained by the role of cytoskeletal dynamics in the assembly and function of the NADPH oxidase complex.

Background: Diabetes affects both individuals and their families and has an impact on economic and social development of a country. Information on the availability, cost, and quality of medical care for diabetes is mostly not available for many low-and middle-income countries including Bangladesh. Complications from diabetes, which can be devastating, could largely be prevented by wider use of several inexpensive generic medicines, simple tests and monitoring and can be a cost saving intervention. This study will provide an in-depth and comprehensive picture of social and economic impacts of diabetes in Bangladesh and propose clear recommendations for improving prevention and management of diabetes. The objectives of the study are: 1) To study the association between diabetes and other health problems and its social impacts 2) To estimate the economic impact of diabetes including total direct and indirect costs 3) To measure the impact of diabetes on quality of life among diabetes patients in Bangladesh 4) To study the impact of diabetes on the health care system Methods: This is a case-control study comparing cases with type 2 diabetes to controls without diabetes matched on age, sex and place of residence. 564 cases and 564 controls will be selected from the outpatient department of a tertiary hospital in Dhaka, Bangladesh. Data on socioeconomic status, health utility index, direct and indirect costs for diabetes, medication adherence, quality of life, treatment satisfaction, diet, physical activity, mental state examination, weight, height, hip and waist circumference, blood pressure, pulse, medication history, laboratory data and physical examination will be conducted. Outcome measures: The primary outcome measures will be association between diabetes and other health problems, cost of diabetes, impact of diabetes on quality of life and secondary outcome measures are impact of diabetes on healthcare systems in Bangladesh. Discussion: This study will provide an in-depth and comprehensive picture of social and economic impacts of diabetics in Bangladesh and propose clear recommendations for improving prevention and management of diabetics. It will help to develop programs and policies for better management of Diabetics and cost effective strategies in Bangladesh context.

Background: Since the times of domestication, cattle have been continually shaped by the influence of humans. Relatively recent history, including breed formation and the still enduring enormous improvement of economically important traits, is expected to have left distinctive footprints of selection within the genome. The purpose of this study was to map genome-wide selection signatures in ten cattle breeds and thus improve the understanding of the genome response to strong artificial selection and support the identification of the underlying genetic variants of favoured phenotypes. We analysed 47,651 single nucleotide polymorphisms (SNP) using Cross Population Extended Haplotype Homozygosity (XP-EHH). Results: We set the significance thresholds using the maximum XP-EHH values of two essentially artificially unselected breeds and found up to 229 selection signatures per breed. Through a confirmation process we verified selection for three distinct phenotypes typical for one breed (polledness in Galloway, double muscling in Blanc-Bleu Belge and red coat colour in Red Holstein cattle). Moreover, we detected six genes strongly associated with known QTL for beef or dairy traits (TG, ABCG2, DGAT1, GH1, GHR and the Casein Cluster) within selection signatures of at least one breed. A literature search for genes lying in outstanding signatures revealed further promising candidate genes. However, in concordance with previous genome-wide studies, we also detected a substantial number of signatures without any yet known gene content. Conclusions: These results show the power of XP-EHH analyses in cattle to discover promising candidate genes and raise the hope of identifying phenotypically important variants in the near future. The finding of plausible functional candidates in some short signatures supports this hope. For instance, MAP2K6 is the only annotated gene of two signatures detected in Galloway and Gelbvieh cattle and is already known to be associated with carcass weight, back fat thickness and marbling score in Korean beef cattle. Based on the confirmation process and literature search we deduce that XP-EHH is able to uncover numerous artificial selection targets in subpopulations of domesticated animals.

Background: Recently, individualized or personalized medicine (PM) has become a buzz word in the academic as well as public debate surrounding health care. However, PM lacks a clear definition and is open to interpretation. This conceptual vagueness complicates public discourse on chances, risks and limits of PM. Furthermore, stakeholders might use it to further their respective interests and preferences. For these reasons it is important to have a shared understanding of PM. In this paper, we present a sufficiently precise as well as adequate definition of PM with the potential of wide acceptance. Methods: For this purpose, in a first step a systematic literature review was conducted to understand how PM is actually used in scientific practice. PubMed was searched using the keywords "individualized medicine"

Background: Nepal has made substantial progress in reducing under-five mortality and is on track to achieve Millennium Development Goal 4, but advances in neonatal health are less encouraging. The objectives of this study were to assess relative and absolute inequalities in neonatal mortality over time, and to review experience with major programs to promote neonatal health. Methods: Using four nationally representative surveys conducted in 1996, 2001, 2006 and 2011, we calculated neonatal mortality rates for Nepal and for population groups based on child sex, geographical and socio-economic variables using a true cohort log probability approach. Inequalities based on different variables and years were assessed using rate differences (rd) and rate ratios (rr); time trends in neonatal mortality were measured using the annual rate of reduction. Through literature searches and expert consultation, information on Nepalese policies and programs implemented since 1990 and directly or indirectly attempting to reduce neonatal mortality was compiled. Data on timeline, coverage and effectiveness were extracted for major programs. Results: The annual rate of reduction for neonatal mortality between 1996 and 2011 (2.8 percent per annum) greatly lags behind the achievements in under-five and infant mortality, and varies across population groups. For the year 2011, stark absolute and relative inequalities in neonatal mortality exist in relation to wealth status (rd = 21.4, rr = 2.2); these are less pronounced for other measures of socio-economic status, child sex and urban-rural residence, ecological and development region. Among many efforts to promote child and maternal health, three established programs and two pilot programs emerged as particularly relevant to reducing neonatal mortality. While these were designed based on national and international evidence, information about coverage of different population groups and effectiveness is limited. Conclusion: Neonatal mortality varies greatly by socio-demographic variables. This study clearly shows that much remains to be achieved in terms of reducing neonatal mortality across different socio-economic, ethnic and geographical population groups in Nepal. In moving forward it will be important to scale up programs of proven effectiveness, conduct in-depth evaluation of promising new approaches, target unreached and hard-to-reach populations, and maximize use of financial and personnel resources through integration across programs.

Introduction: Circulating microRNAs (miRNAs) are easily accessible and have already proven to be useful as prognostic markers in cancer patients. However, their origin and function in the circulation is still under discussion. In the present study we analyzed changes in the miRNAs in blood plasma of head and neck squamous cell carcinoma (HNSCC) patients in response to radiochemotherapy and compared them to the changes in a cell culture model of primary HNSCC cells undergoing simulated anti-cancer therapy. Materials and methods: MiRNA-profiles were analyzed by qRT-PCR arrays in paired blood plasma samples of HNSCC patients before therapy and after two days of treatment. Candidate miRNAs were validated by single qRT-PCR assays. An in vitro radiochemotherapy model using primary HNSCC cell cultures was established to test the possible tumor origin of the circulating miRNAs. Microarray analysis was performed on primary HNSCC cell cultures followed by validation of deregulated miRNAs via qRT-PCR. Results: Unsupervised clustering of the expression profiles using the six most regulated miRNAs (miR-425-5p, miR-21-5p, miR-106b-5p, miR-590-5p, miR-574-3p, miR-885-3p) significantly (p = 0.012) separated plasma samples collected prior to treatment from plasma samples collected after two days of radiochemotherapy. MiRNA profiling of primary HNSCC cell cultures treated in vitro with radiochemotherapy revealed differentially expressed miRNAs that were also observed to be therapy-responsive in blood plasma of the patients (miR-425-5p, miR-21-5p, miR-106b-5p, miR-93-5p) and are therefore likely to stem from the tumor. Of these candidate marker miRNAs we were able to validate by qRT-PCR a deregulation of eight plasma miRNAs as well as miR-425-5p and miR-93-5p in primary HNSCC cultures after radiochemotherapy. Conclusion: Changes in the abundance of circulating miRNAs during radiochemotherapy reflect the therapy response of primary HNSCC cells after an in vitro treatment. Therefore, the responsive miRNAs (miR-425-5p, miR-93-5p) may represent novel biomarkers for therapy monitoring. The prognostic value of this exciting observation requires confirmation using an independent patient cohort that includes clinical follow-up data.

Background: Knowledge on immunosuppressive factors in the pathogenesis of endometrial cancer is scarce. The aim of this study was to assess Glycodelin (Gd) and its immunosuppressive isoform Glycodelin A (GdA) in endometrial cancer tissue and to analyze its impact on clinical and pathological features and patient outcome. Methods: 292 patients diagnosed and treated for endometrial cancer were included. Patient characteristics, histology and follow-up data were available. Gd and GdA was determined by immunohistochemistry and in situ hybridization was performed for Gd mRNA. Results: Endometrial cancer shows intermediate (52.2%) or high (20.6%) expression for Gd in 72.8%, and GdA in 71.6% (intermediate 62.6%, high 9.\%) of all cases. The glycosylation dependent staining of GdA is tumour specific and correlates with the peptide-specific Gd staining though neither of the two is associated with estrogen receptor, progesterone receptor or clinic-pathological features. Also Gd protein positively correlates with Gd mRNA as quantified by in situ hybridization. Gd positive cases have a favourable prognosis (p = 0.039), while GdA positive patients have a poor outcome (p = 0.003). Cox-regression analysis proofed GdA to be an independent prognostic marker for patient survival (p = 0.002), besides tumour stage, grade and the concomitant diagnosis of hypertension. Conclusion: Gd and GdA are commonly expressed in endometrial cancer tissue and seem to be of relevance in tumourigenesis. They differ not only in glycosylation but also in their biological activity, since only GdA holds prognostic significance for a poor overall survival in endometrial cancer patients. This finding might be explained by GdAs immunosuppressive capacity.