Medizin - Open Access LMU - Teil 19/22

Background: A recent large-scale analysis of Gene Expression Omnibus (GEO) data found frequent evidence for spatial defects in a substantial fraction of Affymetrix microarrays in the GEO. Nevertheless, in contrast to quality assessment, artefact detection is not widely used in standard gene expression analysis pipelines. Furthermore, although approaches have been proposed to detect diverse types of spatial noise on arrays, the correction of these artefacts is mostly left to either summarization methods or the corresponding arrays are completely discarded. Results: We show that state-of-the-art robust summarization procedures are vulnerable to artefacts on arrays and cannot appropriately correct for these. To address this problem, we present a simple approach to detect artefacts with high recall and precision, which we further improve by taking into account the spatial layout of arrays. Finally, we propose two correction methods for these artefacts that either substitute values of defective probes using probeset information or filter corrupted probes. We show that our approach can identify and correct defective probe measurements appropriately and outperforms existing tools. Conclusions: While summarization is insufficient to correct for defective probes, this problem can be addressed in a straightforward way by the methods we present for identification and correction of defective probes. As these methods output CEL files with corrected probe values that serve as input to standard normalization and summarization procedures, they can be easily integrated into existing microarray analysis pipelines as an additional pre-processing step. An R package is freely available from http://www.bio.ifi.lmu.de/artefact-correction.

Systemic autoimmune diseases are characterized by the presence of antinuclear autoantibodies (ANAs). Diluted patient sera are typically used to screen for the presence of ANAs by immunofluorescence microscopy with fixed HEp-2 cells. Despite high quality test kits, reports of different laboratories frequently present controversial results. This study presents a recommendation for a unified processing and interpretation of HEp-2 based screening for autoantibodies. We provide suggestions for selection of high quality test kits, optimized processing, and diagnostic procedures. For good laboratory practice, in addition to a relevant clinical diagnosis and an experienced laboratory specialist, the following procedure is highly recommended: initial HEp-2 based screening by indirect immunofluorescence, starting with a 1:80 serum dilution and evaluation in a bright fluorescence microscope, pathological values from a titer of 1:160, internal quality checks, and unified interpretation. We aim to improve diagnostics and care for patients with autoimmune diseases as a central focus of the European Autoimmunity Standardization Initiative (EASI).

Background: Chronic localized pain syndromes, especially chronic low back pain (CLBP), are common reasons for consultation in general practice. In some cases chronic localized pain syndromes can appear in combination with chronic widespread pain (CWP). Numerous studies have shown a strong association between CWP and several physical and psychological factors. These studies are population-based cross-sectional and do not allow for assessing chronology. There are very few prospective studies that explore the predictors for the onset of CWP, where the main focus is identifying risk factors for the CWP incidence. Until now there have been no studies focusing on preventive factors keeping patients from developing CWP. Our aim is to perform a cross sectional study on the epidemiology of CLBP and CWP in general practice and to look for distinctive features regarding resources like resilience, self-efficacy and coping strategies. A subsequent cohort study is designed to identify the risk and protective factors of pain generalization (development of CWP) in primary care for CLBP patients. Methods/Design: Fifty-nine general practitioners recruit consecutively, during a 5 month period, all patients who are consulting their family doctor because of chronic low back pain (where the pain is lasted for 3 months). Patients are asked to fill out a questionnaire on pain anamnesis, pain-perception, co-morbidities, therapy course, medication, socio demographic data and psychosomatic symptoms. We assess resilience, coping resources, stress management and self-efficacy as potential protective factors for pain generalization. Furthermore, we raise risk factors for pain generalization like anxiety, depression, trauma and critical life events. During a twelve months follow up period a cohort of CLBP patients without CWP will be screened on a regular basis (3 monthly) for pain generalization (outcome: incident CWP). Discussion: This cohort study will be the largest study which prospectively analyzes predictors for transition from CLBP to CWP in primary care setting. In contrast to the typically researched risk factors, which increase the probability of pain generalization, this study also focus intensively on protective factors, which decrease the probability of pain generalization.

The symptoms of growth hormone deficiency and growth hormone excess manifest themselves clinically in different ways, before and after the completion of longitudinal growth. Always, however, biochemical diagnostics is based on the measurement of circulating concentrations of growth hormone and insulin-like growth factor I (IGF-I). Immunoassays are practical, sensitive, and mostly specific methods for measuring either hormone. Still, there are serious discrepancies between the measured results of different assays. These discrepancies are mainly due to differences in the isoform specificity of assays, the use of different standard preparations, as well as the interference of binding proteins. The method-related differences in measured results make the general application of published diagnostic decision limits more difficult. At an interdisciplinary consensus conference, with the participation of the Growth Hormone Research Society, the IGF Society, and the International Federal of Clinical Chemistry and Laboratory Medicine (IFCC), the existing problems were analyzed and possible strategies were highlighted to improve the comparability of the measured results of different GH and IFG-I assays. Currently, however, the use of method-specific reference ranges obtained from well-characterized cohorts continues to be essential in clinical practice.

Purpose: This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras (KRAS) gene on treatment efficacy in patients with metastatic colorectal cancer (mCRC). Patients: Overall, 119 patients bearing a KRAS mutation in codon 12 were evaluated. All patients received cetuximab-based first-line chemotherapy within the Central European Cooperative Oncology Group (CECOG), AIO KRK-0104 or AIO KRK-0306 trials. Results: Patients with KRAS codon 12 mutant mCRC showed a broad range of outcome when treated with cetuximab-based first-line regimens. Patients with tumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations (overall survival 23.3 vs. 14-18 months; hazard ratio 0.66, range 0.43-1.03). An interaction model illustrated that KRAS p.G12C was associated with unfavorable outcome when treated with oxaliplatin plus cetuximab. Conclusion: The present analysis suggests that KRAS codon 12 mutation may not represent a homogeneous entity in mCRC when treated with cetuximab-based first-line therapy. Copyright (C) 2012 S. Karger AG, Basel

Background: There is general consent that empathy is crucial for the physician-patient relationship and thus an important issue in medical education. This comparative study was designed to examine the differences in empathy between first year and final year medical students in Jimma University, Ethiopia. Methods: A comparative cross-sectional study among 131 first year and 106 final year medical students was conducted in Jimma University, Ethiopia on academic year 2010/11. The study subjects were selected using simple random sampling technique from the list of the students. Study participation was voluntary. The Balanced Emotional Empathy Scale (BEES) was used for the detection of "heart-reading"

The CIAO Study is a multicenter observational study currently underway in 66 European medical institutions over the course of a six-month study period (January-June 2012). This preliminary report overviews the findings of the first half of the study, which includes all data from the first three months of the six-month study period. Patients with either community-acquired or healthcare-associated complicated intra-abdominal infections (IAIs) were included in the study. 912 patients with a mean age of 54.4 years (range 4-98) were enrolled in the study during the first three-month period. 47.7% of the patients were women and 52.3% were men. Among these patients, 83.3% were affected by community-acquired IAIs while the remaining 16.7% presented with healthcare-associated infections. Intraperitoneal specimens were collected from 64.2% of the enrolled patients, and from these samples, 825 microorganisms were collectively identified. The overall mortality rate was 6.4% (58/912). According to univariate statistical analysis of the data, critical clinical condition of the patient upon hospital admission (defined by severe sepsis and septic shock) as well as healthcare-associated infections, non-appendicular origin, generalized peritonitis, and serious comorbidities such as malignancy and severe cardiovascular disease were all significant risk factors for patient mortality. White Blood Cell counts (WBCs) greater than 12,000 or less than 4,000 and core body temperatures exceeding 38 degrees C or less than 36 degrees C by the third post-operative day were statistically significant indicators of patient mortality.

Objective: The common single nucleotide polymorphism (SNP) rs9939609 in the fat mass and obesity-associated gene (FTO) is associated with obesity. As genetic variants associated with weight regulation might also be implicated in the etiology of eating disorders, we evaluated whether SNP rs9939609 is associated with bulimia nervosa (BN) and anorexia nervosa (AN). Methods: Association of rs9939609 with BN and AN was assessed in 689 patients with AN, 477 patients with BN, 984 healthy non-population-based controls, and 3,951 population-based controls (KORA-S4). Based on the familial and premorbid occurrence of obesity in patients with BN, we hypothesized an association of the obesity risk A-allele with BN. Results: In accordance with our hypothesis, we observed evidence for association of the rs9939609 A-allele with BN when compared to the non-population-based controls (unadjusted odds ratio (OR) = 1.142, one-sided 95% confidence interval (CI) 1.001-infinity; one-sided p = 0.049) and a trend in the population-based controls (OR = 1.124, one-sided 95% CI 0.932-infinity; one-sided p = 0.056). Interestingly, compared to both control groups, we further detected a nominal association of the rs9939609 A-allele to AN (OR = 1.181, 95% CI 1.027-1.359, two-sided p = 0.020 or OR = 1.673, 95% CI 1.101-2.541, two-sided p = 0.015,). Conclusion: Our data suggest that the obesity-predisposing FTO allele might be relevant in both AN and BN. Copyright (C) 2012 S. Karger GmbH, Freiburg

The mechanical complications of osteosyntheses after hip fractures are previously investigated by mostly static or dynamic uniaxial loading test systems. However, the physiologic loading of the hip joint during a normal gait is a multiplanar, dynamic movement. Therefore, we constructed a system to test osteosyntheses for hip fractures under physiologic multiplanar loading representative of normal gait. To evaluate the testing system, 12 femora pairs were tested under 25,000 cycles with two standard osteosyntheses (Proximal Femoral Nail Antirotation/Gamma3 Nail). For angular movement, the varus collapse to cut out (proportional to(CO)) (proportional to(CO) = 4.8 degrees +/- 2.1 degrees for blade and proportional to(CO) = 7.8 degrees +/- 3.8 degrees for screw) was the dominant failure mode, and only slight rotational angle shifts (proportional to(Rot)) (proportional to(Rot) = 1.7 degrees +/- 0.4 degrees for blade and proportional to(Rot) = 2.4 degrees +/- 0.3 degrees for screw) of the femoral head around the implant axis were observed. Angular displacements in varus direction and rotation were higher in specimens reinforced with screws. Hence, the cut out model and the migration directions showed a distinction between helical blade and hip screw. However, there were no significant differences between the different implants. The new setup is able to create clinical failures and allows to give evidence about the anchorage stability of different implant types under dynamic gait motion pattern.

Background: Consumer surveys provide information on effectiveness and side effects of medical interventions in routine clinical care. A report of fibromyalgia syndrome (FMS) consumers has not been carried out in Europe. Methods: The study was carried out from November 2010 to April 2011. Participants diagnosed with FMS rated the effectiveness and side effects of pharmacological and non-pharmacological FMS interventions on a 0 to 10 scale, with 10 being most efficacious (harmful). The questionnaire was distributed by the German League for people with Arthritis and Rheumatism and the German Fibromyalgia Association to their members and to all consecutive FMS patients of nine clinical centers of different levels of care. Results: 1661 questionnaires (95% women, mean age 54 years, mean duration since FMS diagnosis 6.8 years) were analysed. The most frequently used therapies were self-management strategies, prescription pain medication and aerobic exercise. The highest average effectiveness was attributed to whole body and local warmth therapies, thermal bathes, FMS education and resting. The highest average side effects were attributed to strong opioids, local cold therapy, gamma-amino-butyric acid analogues (pregabalin and gabapentin), tramadol and opioid transdermal systems. Conclusion: The German fibromyalgia consumer reports highlight the importance of non-pharmcological therapies in the long-term management of FMS, and challenges the strong recommendations for drug therapies given by FMS-guidelines.

The extent of porous coating of cementless total hip stems is held responsible for radiological periprosthetic changes, the rate of thigh pain, and even its long-term success. However, there is only sparse knowledge on how the biomechanical loading conditions of the femur are influenced by the extent of porous coating in the early phase after implantation of a cementless hip stem. Aiming to evaluate the effect of surface structuring on the strain pattern of the femur, we implanted three anatomic hip stems with different extents of porous coating (full, two-thirds proximal, and penguin type) in second-generation composite femora coated with a photoelastic layer. A cortical strain mapping was conducted before and after insertion of the implants under standardized loading conditions considering relevant muscle forces. The results of the statistical analysis of three different implantation sequences proved that composite femora are suitable for repeated measurements within the applied experimental setup. Cortical strain changes including stress-shielding effects medially (-60%) and laterally (-50%) were validated with a cadaver femur. The extent of porous coating had no significant influence on the surface strain pattern for an immediate postoperative situation.

Background: Extensive sets of data are required to investigate the potential use of a therapeutic drug monitoring with individualization of dosage of the antimycotic compound caspofungin. The goal was to develop an improved liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for this aim. Methods: Following protein precipitation, on-line solid phase extraction was performed for sample preparation. As the internal standard compound the veterinary drug tylosin was used. A standard validation protocol was applied. Results: Good reproducibility and accuracy of the method were observed. On-line solid phase extraction resulted in a convenient work-flow and good robustness of the method. Conclusions: This improved LC-MS/MS method was found reliable and convenient. It can be suggested for further work on the clinical pharmacology of caspofungin in the setting of clinical research laboratories.

Background: Real-time quantitative nucleic acid sequence-based amplification (QT-NASBA) is a sensitive method for detection of sub-microscopic gametocytaemia by measuring gametocyte-specific mRNA. Performing analysis on fresh whole blood samples is often not feasible in remote and resource-poor areas. Convenient methods for sample storage and transport are urgently needed. Methods: Real-time QT-NASBA was performed on whole blood spiked with a dilution series of purified in-vitro cultivated gametocytes. The blood was either freshly processed or spotted on filter papers. Gametocyte detection sensitivity for QT-NASBA was determined and controlled by microscopy. Dried blood spot (DBS) samples were subjected to five different storage conditions and the loss of sensitivity over time was investigated. A formula to approximate the loss of Pfs25-mRNA due to different storage conditions and time was developed. Results: Pfs25-mRNA was measured in time to positivity (TTP) and correlated well with the microscopic counts and the theoretical concentrations of the dilution series. TTP results constantly indicated higher amounts of RNA in filter paper samples extracted after 24 hours than in immediately extracted fresh blood. Among investigated storage conditions freezing at -20 degrees C performed best with 98.7% of the Pfs25-mRNA still detectable at day 28 compared to fresh blood samples. After 92 days, the RNA detection rate was only slightly decreased to 92.9%. Samples stored at 37 degrees C showed most decay with only 64.5% of Pfs25-mRNA detectable after one month. The calculated theoretical detection limit for 24 h-old DBS filter paper samples was 0.0095 (95% CI: 0.0025 to 0.0380) per mu l. Conclusions: The results suggest that the application of DBS filter papers for quantification of Plasmodium falciparum gametocytes with real-time QT-NASBA is practical and recommendable. This method proved sensitive enough for detection of sub-microscopic densities even after prolonged storage. Decay rates can be predicted for different storage conditions as well as durations.

Background: Mental planning and carrying out a plan provoke specific cerebral hemodynamic responses. Gender aspects of hemispheric laterality using rapid cerebral hemodynamics have not been reported. Method: Here, we applied functional transcranial Doppler sonography to examine lateralization of cerebral hemodynamics of the middle cerebral arteries of 28 subjects (14 women and 14 men) performing a standard planning task. There were easy and difficult problems, and mental planning without motor activity was separated from movement execution. Results: Difficult mental planning elicited lateralization to the right hemisphere after 2 or more seconds, a feature that was not observed during movement execution. In females, there was a dominance to the left hemisphere during movement execution. Optimized problem solving yielded an increased laterality change to the right during mental planning. Conclusions: Gender-related hemispheric dominance appears to be condition-dependent, and change of laterality to the right may play a role in optimized performance. Results are of relevance when considering laterality from a perspective of performance enhancement of higher cognitive functions, and also of psychiatric disorders with cognitive dysfunctions and abnormal lateralization patterns such as schizophrenia. Copyright (C) 2012 S. Karger AG, Basel

Sun, 1 Jan 2012 12:00:00 +0100 http://jnnp.bmj.com/content/83/Suppl_2/A14.4.abstract?sid=ccc27018-25b8-4eae-8af8-c02e427d8cf0 https://epub.ub.uni-muenchen.de/20879/1/oa_20879.pdf Radunovic, A.; Page, S.; Early, M.; Bader, B.; Danek, A.; Mohiddin, S.; Chan, J.; Fiddes, B.; Williamson, J. ddc:610, Medizin

Background: Listeria monocytogenes is a food-borne pathogen that causes infections with a high-mortality rate and has served as an invaluable model for intracellular parasitism. Here, we report complete genome sequences for two L. monocytogenes strains belonging to serotype 4a (L99) and 4b (CLIP80459), and transcriptomes of representative strains from lineages I, II, and III, thereby permitting in-depth comparison of genome- and transcriptome -based data from three lineages of L. monocytogenes. Lineage III, represented by the 4a L99 genome is known to contain strains less virulent for humans. Results: The genome analysis of the weakly pathogenic L99 serotype 4a provides extensive evidence of virulence gene decay, including loss of several important surface proteins. The 4b CLIP80459 genome, unlike the previously sequenced 4b F2365 genome harbours an intact inlB invasion gene. These lineage I strains are characterized by the lack of prophage genes, as they share only a single prophage locus with other L. monocytogenes genomes 1/2a EGD-e and 4a L99. Comparative transcriptome analysis during intracellular growth uncovered adaptive expression level differences in lineages I, II and III of Listeria, notable amongst which was a strong intracellular induction of flagellar genes in strain 4a L99 compared to the other lineages. Furthermore, extensive differences between strains are manifest at levels of metabolic flux control and phosphorylated sugar uptake. Intriguingly, prophage gene expression was found to be a hallmark of intracellular gene expression. Deletion mutants in the single shared prophage locus of lineage II strain EGD-e 1/2a, the lma operon, revealed severe attenuation of virulence in a murine infection model. Conclusion: Comparative genomics and transcriptome analysis of L. monocytogenes strains from three lineages implicate prophage genes in intracellular adaptation and indicate that gene loss and decay may have led to the emergence of attenuated lineages.

Sun, 1 Jan 2012 12:00:00 +0100 http://jnnp.bmj.com/content/83/3/e1.79 https://epub.ub.uni-muenchen.de/21395/1/oa_21395_bmj.pdf Lochmüller, H.; Abicht, A.; Beeson, D.; Palace, J.; Straub, V.; Bushby, K.; Muntoni, F.; Guergueltcheva, V.; Mueller, J. S.; Chaouch, A. d

Background: Sequencing of mRNA (RNA-seq) by next generation sequencing technologies is widely used for analyzing the transcriptomic state of a cell. Here, one of the main challenges is the mapping of a sequenced read to its transcriptomic origin. As a simple alignment to the genome will fail to identify reads crossing splice junctions and a transcriptome alignment will miss novel splice sites, several approaches have been developed for this purpose. Most of these approaches have two drawbacks. First, each read is assigned to a location independent on whether the corresponding gene is expressed or not, i.e. information from other reads is not taken into account. Second, in case of multiple possible mappings, the mapping with the fewest mismatches is usually chosen which may lead to wrong assignments due to sequencing errors. Results: To address these problems, we developed ContextMap which efficiently uses information on the context of a read, i.e. reads mapping to the same expressed region. The context information is used to resolve possible ambiguities and, thus, a much larger degree of ambiguities can be allowed in the initial stage in order to detect all possible candidate positions. Although ContextMap can be used as a stand-alone version using either a genome or transcriptome as input, the version presented in this article is focused on refining initial mappings provided by other mapping algorithms. Evaluation results on simulated sequencing reads showed that the application of ContextMap to either TopHat or MapSplice mappings improved the mapping accuracy of both initial mappings considerably. Conclusions: In this article, we show that the context of reads mapping to nearby locations provides valuable information for identifying the best unique mapping for a read. Using our method, mappings provided by other state-of-the-art methods can be refined and alignment accuracy can be further improved.

Background and Aims: Time of onset of antipsychotic action is still a debated matter. We aimed to replicate and extend previous findings that early response can predict subsequent non-response. Methods: 86 acutely psychotic patients treated with haloperidol were studied. Results: A PANSS reduction = 23% at 1 week of treatment predicts response at 3 weeks, with a specificity of 84% and a sensitivity of 86%. Conclusion: Our results confirm that an early response to antipsychotic treatment accurately predicts the treatment effectiveness and extends it to a prediction performed as early as 1 week. Copyright (c) 2012 S. Karger AG, Basel

Sun, 1 Jan 2012 12:00:00 +0100 https://epub.ub.uni-muenchen.de/21831/1/Jubilaeumsband_BGGF_2012.pdf Unbekannter Autor ddc:943, ddc:610, Medizin 0

Brune's proposal that erstwhile `vulnerability' genes need to be reconsidered as `plasticity' genes, given the potential for certain environments to yield increased positive function in the same domain as potential dysfunction, has implications for psychiatric nosology as well as a more dynamic understanding of the relationship between genes and culture. In addition to validating neuropsychiatric spectrum disorder nosologies by calling for similar methodological shifts in gene-environment-interaction studies, Brune's position elevates the importance of environmental contexts - inclusive of socio-cultural variables - as mechanisms that contribute to clinical presentation. We assert that when models of susceptibility to plasticity and neuropsychiatric spectrum disorders are concomitantly considered, a new line of inquiry emerges into the co-evolution and co-determination of sociocultural contexts and endophenotypes. This presents potentially unique opportunities, benefits, challenges, and responsibilities for research and practice in psychiatry.

Satavaptan, a vasopressin V2 receptor antagonist, has been shown to improve the control of ascites in cirrhosis in short-term phase II studies. The aim of this study was to evaluate the efficacy and safety of satavaptan in three different populations of patients with cirrhosis and ascites.

Background and objectives: Treatment options for oesophageal cancer have changed considerably over the last decades with the introduction of multimodal treatment concepts dominating the progress in the field. However, it remains unclear in how far the documented scientific progress influenced and changed the daily routine practice. Since most patients with oesophageal cancer generally suffer from reduced overall health conditions it is uncertain how high the proportion of aggressive treatments is and whether outcomes are improved substantially. In order to gain insight into this we performed a retrospective analysis of patients treated at a larger tertiary referral centre over time course of 25 years. Patients and methods: Data of all patients diagnosed with squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the oesophagus, treated between 1983 and 2007 in the department of radiation oncology of the LMU, were obtained. The primary endpoint of the data collection was overall survival (calculated from the date of diagnosis until death or last follow up). Changes in basic clinical characteristics, treatment approach and the effect on survival were analysed after dividing the cohort into five subsequent time periods (I-V) with 5 years each. In a second analysis any pattern of change regarding the use of radio(chemo) therapy (R(C) T) with and without surgery was determined. Results: In total, 503 patients with SCC (78.5%) and AC (18.9%) of the oesophagus were identified. The average age was 60 years (range 35-91 years). 56.5% of the patients were diagnose with advanced UICC stages III-IV. R(C) T was applied to 353 (70.2%) patients; R(C)T+ surgery was performed in 134 (26.6%) patients, 63.8% of all received chemotherapy (platinum-based 5.8%, 5-fluorouracil (5-FU) 12.1%, 42.3% 5-FU and mitomycin C (MMC)). The median follow-up period was 4.3 years. The median overall survival was 21.4 months. Over the time, patients were older, the formal tumour stage was more advanced, the incidence of AC was higher and the intensified treatment had a higher prevalence. However there was only a trend for an improved OS over the years with no difference between RCT with or without surgery (p = 0.09). The use of radiation doses over 54 Gy and the addition of chemotherapy (p = 0.002) were associated with improved OS. Conclusion: Although more complex treatment protocols were introduced into clinical routine, only a minor progress in OS rates was detectable. Main predictors of outcome in this cohort was the addition of chemotherapy. The addition of surgery to radio-chemotherapy may only be of value for very limited patient groups.

Prion diseases in humans and animals comprise a group of invariably fatal neurodegenerative diseases characterized by the formation of a pathogenic protein conformer designated PrPSc and infectious particles denoted prions. The cellular prion protein (PrPC) has a central role in the pathogenesis of prion disease. First, it is the precursor of PrPSc and infectious prions and second, its expression on neuronal cells is required to mediate toxic effects of prions. To specifically study the role of PrPC as a mediator of toxic signaling, we have developed novel cell culture models, including primary neurons prepared from PrP-deficient mice. Using these approaches we have been able to show that PrPC can interact with and mediate toxic signaling of various beta-sheet-rich conformers of different origins, including amyloid beta, suggesting a pathophysiological role of the prion protein beyond prion diseases. Copyright (C) 2011 S. Karger AG, Basel

To develop prediction models that better estimate the pretest probability of coronary artery disease in low prevalence populations.

To develop prediction models that better estimate the pretest probability of coronary artery disease in low prevalence populations.

Background: 15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC. Methods/Design: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2: 1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m(2) cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 mu g once weekly for 8 weeks, followed by s.c. L-BLP25 930 mu g maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned. Discussion: The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion.

Since the nineteenth century the theory of conventional medicine has been developed in close alignment with the mechanistic paradigm of natural sciences. Only in the twentieth century occasional attempts were made to (re)introduce the ‘subject’ into medical theory, as by Thure von Uexküll (1908–2004) who elaborated the so-called biopsychosocial model of the human being, trying to understand the patient as a unit of organic, mental, and social dimensions of life. Although widely neglected by conventional medicine, it is one of the most coherent, significant, and up-to-date models of medicine at present. Being torn between strict adherence to Hahnemann’s original conceptualization and alienation caused by contemporary scientific criticism, homeopathy today still lacks a generally accepted, consistent, and definitive theory which would explain in scientific terms its strength, peculiarity, and principles without relapsing into biomedical reductionism. The biopsychosocial model of the human being implies great potential for a new theory of homeopathy, as may be demonstrated with some typical examples.

Background: Infections and immunological processes are likely to be involved in the pathogenesis of Tourette's syndrome (TS). To determine possible common underlying immunological mechanisms, we focused on innate immunity and studied markers of inflammation, monocytes, and monocyte-derived cytokines. Methods: In a cross-sectional study, we used current methods to determine the number of monocytes and levels of C-reactive protein (CRP) in 46 children, adolescents, and adult patients suffering from TS and in 43 healthy controls matched for age and sex. Tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), soluble CD14 (sCD14), IL1-receptor antagonist (IL1-ra), and serum neopterin were detected by immunoassays. Results: We found that CRP and neopterin levels and the number of monocytes were significantly higher in TS patients than in healthy controls. Serum concentrations of TNF-alpha, sIL1-ra, and sCD14 were significantly lower in TS patients. All measured values were within normal ranges and often close to detection limits. Conclusions: The present results point to a monocyte dysregulation in TS. This possible dysbalance in innate immunity could predispose to infections or autoimmune reactions.

For skull base meningiomas, several treatment paradigms are available: Observation with serial imaging, surgical resection, stereotactic radiosurgery, radiation therapy or some combination of both. The choice depends on several factors. In this review we evaluate different treatment options, the outcome of modern irradiation techniques as well as the clinical results available, and establish recommendations for the treatment of patients with skull-base meningiomas.

Background: Surfactant protein C (SP-C) is important for the function of pulmonary surfactant. Heterozygous mutations in SFTPC, the gene encoding SP-C, cause sporadic and familial interstitial lung disease (ILD) in children and adults. Mutations mapping to the BRICHOS domain located within the SP-C proprotein result in perinuclear aggregation of the proprotein. In this study, we investigated the effects of the mutation A116D in the BRICHOS domain of SP-C on cellular homeostasis. We also evaluated the ability of drugs currently used in ILD therapy to counteract these effects. Methods: SP-C-A116D was expressed in MLE-12 alveolar epithelial cells. We assessed in vitro the consequences for cellular homeostasis, immune response and effects of azathioprine, hydroxychloroquine, methylprednisolone and cyclophosphamide. Results: Stable expression of SP-C-A116D in MLE-12 alveolar epithelial cells resulted in increased intracellular accumulation of proSP-C processing intermediates. SP-C-A116D expression further led to reduced cell viability and increased levels of the chaperones Hsp90, Hsp70, calreticulin and calnexin. Lipid analysis revealed decreased intracellular levels of phosphatidylcholine (PC) and increased lyso-PC levels. Treatment with methylprednisolone or hydroxychloroquine partially restored these lipid alterations. Furthermore, SP-C-A116D cells secreted soluble factors into the medium that modulated surface expression of CCR2 or CXCR1 receptors on CD4(+) lymphocytes and neutrophils, suggesting a direct paracrine effect of SP-C-A116D on neighboring cells in the alveolar space. Conclusions: We show that the A116D mutation leads to impaired processing of proSP-C in alveolar epithelial cells, alters cell viability and lipid composition, and also activates cells of the immune system. In addition, we show that some of the effects of the mutation on cellular homeostasis can be antagonized by application of pharmaceuticals commonly applied in ILD therapy. Our findings shed new light on the pathomechanisms underlying SP-C deficiency associated ILD and provide insight into the mechanisms by which drugs currently used in ILD therapy act.

Background: Signaling studies in cell lines are hampered by non-physiological alterations obtained in vitro. Physiologic primary tumor cells from patients with leukemia require passaging through immune-compromised mice for amplification. The aim was to enable molecular work in patients' ALL cells by establishing siRNA transfection into cells amplified in mice. Results: We established delivering siRNA into these cells without affecting cell viability. Knockdown of single or multiple genes reduced constitutive or induced protein expression accompanied by marked signaling alterations. Conclusion: Our novel technique allows using patient-derived tumor cells instead of cell lines for signaling studies in leukemia.

Background/Aims: Transcatheter aortic valve implantation (TAVI) has emerged as a new therapeutic option for high-risk patients. However, dialysis patients were excluded from all previous studies. The aim of this study is to compare the outcomes of TAVI for dialysis patients with those for patients with chronic kidney disease (CKD) stages 3 and 4 and to compare TAVI with open surgery in dialysis patients. Methods: Part I: comparison of 10 patients on chronic hemodialysis with 116 patients with non-dialysis-dependent CKD undergoing TAVI. Part II: comparison of transcatheter (n = 15) with open surgical (n = 24) aortic valve replacement in dialysis patients. Results: Part I: dialysis patients were significantly younger (72.3 vs. 82.0 years; p < 0.01). Hospital stay was significantly longer in dialysis patients (21.8 vs. 12.1 days; p = 0.01). Overall 30-day mortality was 3.17%, with no deaths among dialysis patients. Six-month survival rates were similar (log-rank p = 0.935). Part II: patient age was comparable (66.5 vs. 69.5 years; p = 0.42). Patients in the surgical group tended to stay longer in hospital than TAVI patients (29.5 vs. 22.5 days; p = 0.35). Conclusion: TAVI is a safe procedure in patients on chronic hemodialysis. Until new data become available, we find no compelling reason to refuse these patients TAVI. Copyright (C) 2012 S. Karger AG, Basel

Objective: To investigate the effect of chlorhexidine applications in various forms and concentrations on adhesion and failure modes of metal brackets in vitro. Material and methods: Ninety bovine enamel specimens were allocated to six groups (n=15). Metal brackets were bonded on all specimens after chlorhexidine pre-treatments forming the following groups: (1) untreated specimens (control); (2) 40% varnish (EC40, Biodent BV, Netherlands), remnants removed with brushing mimicking patient cleaning; (3) 40% varnish (EC40), remnants removed with brushing mimicking professional cleaning; (4) 1% varnish (Cervitec Plus, Ivoclar vivadent, Schaan, Liechtenstein), remnants not removed; (5) brushed with% 1 gel (Corsodyl, GlaxoSmithKline, Munchenbuchsee, Germany), remnants not removed; (6) immersed in 0.07% mouthrinse (Corsodyl, GlaxoSmithKline, Munchenbuchsee, Germany), remnant not rinsed. Debonding of brackets was performed using a universal testing machine. Data were analysed using one-way ANOVA and post-hoc Scheffe test. Results: Group 4 performed significantly inferior than all the other groups and the control. Group 4 presented the highest number of adhesive failures at the enamel-resin interface whereas in other groups no failures at adhesive-resin interface was observed. Conclusion: Presence of chlorhexidine varnish prior to bracket bonding adversely affects adhesion. Concentration of chlorhexidine pre-treatment has no influence on shear bond strength.

The human-animal bond has been a fundamental feature of mankind's history for millennia. The first, and strongest of these, man's relationship with the dog, is believed to pre-date even agriculture, going back as far as 30,000 years. It remains at least as powerful today. Fed by the changing nature of the interactions between people and their dogs worldwide and the increasing tendency towards close domesticity, the health of dogs has never played a more important role in family life. Thanks to developments in scientific understanding and diagnostic techniques, as well as changing priorities of pet owners, veterinarians are now able, and indeed expected, to play a fundamental role in the prevention and treatment of canine disease, including canine vector-borne diseases (CVBDs). The CVBDs represent a varied and complex group of diseases, including anaplasmosis, babesiosis, bartonellosis, borreliosis, dirofilariosis, ehrlichiosis, leishmaniosis, rickettsiosis and thelaziosis, with new syndromes being uncovered every year. Many of these diseases can cause serious, even life-threatening clinical conditions in dogs, with a number having zoonotic potential, affecting the human population. Today, CVBDs pose a growing global threat as they continue their spread far from their traditional geographical and temporal restraints as a result of changes in both climatic conditions and pet dog travel patterns, exposing new populations to previously unknown infectious agents and posing unprecedented challenges to veterinarians. In response to this growing threat, the CVBD World Forum, a multidisciplinary group of experts in CVBDs from around the world which meets on an annual basis, gathered in Nice (France) in 2011 to share the latest research on CVBDs and discuss the best approaches to managing these diseases around the world. As a result of these discussions, we, the members of the CVBD Forum have developed the following recommendations to veterinarians for the management of CVBDs.

Background: Most studies on biodegradable magnesium implants published recently use magnesium-calcium-alloys or magnesium-aluminum-rare earth-alloys. However, since rare earths are a mixture of elements and their toxicity is unclear, a reduced content of rare earths is favorable. The present study assesses the in vivo biocompatibility of two new magnesium alloys which have a reduced content (ZEK100) or contain no rare earths at all (AX30). Methods: 24 rabbits were randomized into 4 groups (AX30 or ZEK100, 3 or 6 months, respectively) and cylindrical pins were inserted in their tibiae. To assess the biodegradation mu CT scans and histological examinations were performed. Results: The mu CT scans showed that until month three ZEK100 degrades faster than AX30, but this difference is leveled out after 6 months. Histology revealed that both materials induce adverse host reactions and high numbers of osteoclasts in the recipient bone. The mineral apposition rates of both materials groups were high. Conclusions: Both alloys display favorable degradation characteristics, but they induce adverse host reactions, namely an osteoclast-driven resorption of bone and a subsequent periosteal formation of new bone. Therefore, the biocompatibility of ZEK100 and AX30 is questionable and further studies, which should focus on the interactions on cellular level, are needed.

Background: Little is known as to how health-related quality of life (HRQoL) when measured by generic instruments such as EQ-5D differ across smokers, ex-smokers and never-smokers in the general population; whether the overall pattern of this difference remain consistent in each domain of HRQoL; and what implications this variation, if any, would have for economic evaluations of tobacco control interventions. Methods: Using the 2006 round of Health Survey for England data (n = 13,241), this paper aims to examine the impact of smoking status on health-related quality of life in English population. Depending upon the nature of the EQ-5D data (i.e. tariff or domains), linear or logistic regression models were fitted to control for biology, clinical conditions, socio-economic background and lifestyle factors that an individual may have regardless of their smoking status. Age-and gender-specific predicted values according to smoking status are offered as the potential `utility' values to be used in future economic evaluation models. Results: The observed difference of 0.1100 in EQ-5D scores between never-smokers (0.8839) and heavy-smokers (0.7739) reduced to 0.0516 after adjusting for biological, clinical, lifestyle and socioeconomic conditions. Heavy-smokers, when compared with never-smokers, were significantly more likely to report some/severe problems in all five domains - mobility (67%), self-care (70%), usual activity (42%), pain/discomfort (46%) and anxiety/depression (86%) -. `Utility' values by age and gender for each category of smoking are provided to be used in the future economic evaluations. Conclusion: Smoking is significantly and negatively associated with health-related quality of life in English general population and the magnitude of this association is determined by the number of cigarettes smoked. The varying degree of this association, captured through instruments such as EQ-5D, may need to be fed into the design of future economic evaluations where the intervention being evaluated affects (e. g. tobacco control) or is affected (e. g. treatment for lung cancer) by individual's (or patients') smoking status.

Background: Secondary sclerosing cholangitis is a severe disease of the biliary tract. Over the last decade, several cases of sclerosing cholangitis in critically ill patients (SC-CIP) were reported. Reports in the literature so far are characterized by a wide variety of underlying causes of critical illness, thereby hindering a risk-factor analysis. We report on a homogenous cohort of critically ill patients with influenza A (H1N1) pneumonia and severe acute respiratory distress syndrome (ARDS), of whom a subgroup developed sclerosing cholangitis, allowing for probing of risk factors associated with SC-CIP. Methods: Twenty-one patients (5 female, 16 male, 46.3 +/- 10.8 years) with severe ARDS due to H1N1 pneumonia were retrospectively divided into two groups, characterized by the presence (n = 5) and absence of SC-CIP (n = 16). A large array of clinical data, laboratory parameters, and multi-detector computed tomography-derived measures were compared. Results: Both patient groups showed severe pulmonary impairment. Severity of disease on admission day and during the first 14 days of treatment showed no difference. The patients developing SC-CIP had a higher body mass index (BMI) (37.4 +/- 6.0 kg/m(2) vs. 29.3 +/- 6.8 kg/m(2); P = 0.029) and a higher volume of intraperitoneal fat (8273 +/- 3659 cm(3) vs. 5131 +/- 2268 cm(3); P = 0.033) and spent a longer cumulative period in the prone position during the first 14 days (165 +/- 117 h vs. 78 +/- 61 h; P = 0.038). Conclusion: Our results suggest that obesity, intraperitoneal fat volume, and a longer cumulative duration spent in the prone position may put patients with ARDS at risk of developing SC-CIP. These results lead us to propose that the prone position should be carefully deployed, particularly in abdominally obese patients, and that frequent checks be made for early hepatic dysfunction.

Background: Global histone modifications have been implicated in the progression of various tumour entities. Our study was designed to assess global methylation levels of histone 4 lysine 20 (H4K20me1-3) at different stages of prostate cancer (PCA) carcinogenesis. Methods: Global H4K20 methylation levels were evaluated using a tissue microarray in patients with clinically localized PCA (n = 113), non-malignant prostate disease (n = 27), metastatic hormone-naive PCA (mPCA, n = 30) and castration-resistant PCA (CRPC, n = 34). Immunohistochemistry was performed to assess global levels of H4K20 methylation levels. Results: Similar proportions of the normal, PCA, and mPCA prostate tissues showed strong H4K20me3 staining. CRPC tissue analysis showed the weakest immunostaining levels of H4K20me1 and H4K20me2, compared to other prostate tissues. H4K20me2 methylation levels indicated significant differences in examined tissues except for normal prostate versus PCA tissue. H4K20me1 differentiates CRPC from other prostate tissues. H4K20me1 was significantly correlated with lymph node metastases, and H4K20me2 showed a significant correlation with the Gleason score. However, H4K20 methylation levels failed to predict PSA recurrence after radical prostatectomy. Conclusions: H4K20 methylation levels constitute valuable markers for the dynamic process of prostate cancer carcinogenesis.

Background: In recent years magnesium alloys have been intensively investigated as potential resorbable materials with appropriate mechanical and corrosion properties. Particularly in orthopedic research magnesium is interesting because of its mechanical properties close to those of natural bone, the prevention of both stress shielding and removal of the implant after surgery. Methods: ZEK100 plates were examined in this in vitro study with Hank's Balanced Salt Solution under physiological conditions with a constant laminar flow rate. After 14, 28 and 42 days of immersion the ZEK100 plates were mechanically tested via four point bending test. The surfaces of the immersed specimens were characterized by SEM, EDX and XRD. Results: The four point bending test displayed an increased bending strength after 6 weeks immersion compared to the 2 week group and 4 week group. The characterization of the surface revealed the presence of high amounts of O, P and Ca on the surface and small Mg content. This indicates the precipitation of calcium phosphates with low solubility on the surface of the ZEK100 plates. Conclusions: The results of the present in vitro study indicate that ZEK100 is a potential candidate for degradable orthopedic implants. Further investigations are needed to examine the degradation behavior.

Background/Aims: Reduction of capillary network density occurs early in the development of metabolic syndrome and may be relevant for the precipitation of diabetes. Agonists of the peroxisome proliferator-activated receptor (PPAR)-gamma transcription factor are vasculoprotective, but their capacity for structural preservation of the microcirculation is unclear. Methods: Male Wistar rats were rendered diabetic by streptozotocin and treated with pioglitazone in chow for up to 12 weeks. Capillary density was determined in heart and skeletal muscle after platelet endothelial cell adhesion molecule-1 (PECAM-1) immunostaining. Hallmarks of apoptosis and angiogenesis were determined. Results: Capillary density deteriorated progressively in the presence of hyperglycemia (from 971/mm(2) to 475/mm(2) in quadriceps muscle during 13 weeks). Pioglitazone did not influence plasma glucose, left ventricular weight, or body weight but nearly doubled absolute and relative capillary densities compared to untreated controls (1.2 vs. 0.6 capillaries/myocyte in heart and 1.5 vs. 0.9 capillaries/myocyte in quadriceps muscle) after 13 weeks of diabetes. No antiapoptotic or angiogenic influence of pioglitazone was detected while a reduced expression of hypoxia-inducible factor-3 alpha and PPAR coactivator-1 alpha (PGC-1 alpha) mRNA as well as vascular endothelial growth factor (VEGF) protein possibly occurred as a consequence of improved vascularization. Conclusion: Pioglitazone preserves microvascular structure in diabetes independently of improvements in glycemic control and by a mechanism unrelated to VEGF-mediated angiogenesis. Copyright (C) 2012 S. Karger AG, Basel

Background: As differences in gas exchange between pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) have been demonstrated, we asked if cardiac output measurements determined by acetylene (C2H2) uptake significantly differed in these diseases when compared to the thermodilution technique. Method: Single-breath open-circuit C2H2 uptake, thermodilution, and cardiopulmonary exercise testing were performed in 72 PAH and 32 CTEPH patients. Results: In PAH patients the results for cardiac output obtained by the two methods showed an acceptable agreement with a mean difference of -0.16 L/min (95% CI -2.64 to 2.32 L/min). In contrast, the agreement was poorer in the CTEPH group with the difference being -0.56 L/min (95% CI -4.96 to 3.84 L/min). Functional dead space ventilation (44.5 +/- 1.6 vs. 32.2 +/- 1.4%, p < 0.001) and the mean arterial to end-tidal CO2 gradient (9.9 +/- 0.8 vs. 4.1 +/- 0.5 mmHg, p < 0.001) were significantly elevated among CTEPH patients. Conclusion: Cardiac output evaluation by the C2H2 technique should be interpreted with caution in CTEPH, as ventilation to perfusion mismatching might be more relevant than in PAH.

Background: Distal radius fractures (DRF) are one of the most common fractures and often need surgical treatment, which has been validated through biomechanical tests. Currently a number of different fracture models are used, none of which resemble the in vivo fracture location. The aim of the study was to develop a new standardized fracture model for DRF (AO-23.A3) and compare its biomechanical behavior to the current gold standard. Methods: Variable angle locking volar plates (ADAPTIVE, Medartis) were mounted on 10 pairs of fresh-frozen radii. The osteotomy location was alternated within each pair (New: 10 mm wedge 8 mm / 12 mm proximal to the dorsal / volar apex of the articular surface; Gold standard: 10 mm wedge 20 mm proximal to the articular surface). Each specimen was tested in cyclic axial compression (increasing load by 100 N per cycle) until failure or -3 mm displacement. Parameters assessed were stiffness, displacement and dissipated work calculated for each cycle and ultimate load. Significance was tested using a linear mixed model and Wald test as well as t-tests. Results: 7 female and 3 male pairs of radii aged 74 +/- 9 years were tested. In most cases (7/10), the two groups showed similar mechanical behavior at low loads with increasing differences at increasing loads. Overall the novel fracture model showed a significant different biomechanical behavior than the gold standard model (p < 0,001). The average final loads resisted were significantly lower in the novel model (860 N +/- 232 N vs. 1250 N +/- 341 N; p = 0.001). Conclusion: The novel biomechanical fracture model for DRF more closely mimics the in vivo fracture site and shows a significantly different biomechanical behavior with increasing loads when compared to the current gold standard.

Background: Hepatoblastoma (HB) is an embryonal liver neoplasm of early childhood with a poor prognosis for patients with distant metastases and vascular invasion. We and others have previously shown that the overexpression of insulin-like growth factor 2 (IGF2), loss of imprinting at the IGF2/H19 locus, and amplification of pleomorphic adenoma gene 1 (PLAG1) are common features in HB, suggesting a critical role of the IGF axis in hepatoblastomagenesis. In this study, we investigated the role of the insulin-like growth factor binding protein 3 (IGFBP3), a known competitor of the IGF axis, in pediatric liver cancers. Results: The IGFBP3 gene was highly expressed in normal pediatric livers but was heavily downregulated in four HB cell lines and the majority of HB primary tumors (26/36). Detailed methylation analysis of CpG sites in the IGFBP3 promoter region by bisulfite sequencing revealed a high degree of DNA methylation, which is causatively associated with the suppression of IGFBP3 in HB cell lines. Consequently, the treatment of HB cell lines with 5-aza-2'-deoxycytidine resulted in DNA demethylation and reactivation of the epigenetically silenced IGFBP3 expression. Interestingly, IGFBP3 promoter methylation predominantly occurred in metastatic HB with vascular invasion. Restoring IGFBP3 expression in HB cells resulted in reduced colony formation, migration, and invasion. Conclusion: This study provides the first direct evidence that the reactivation of IGFBP3 decreases aggressive properties of pediatric liver cancer cells and that IGFBP3 promoter methylation might be used as an indicator for vessel-invasive tumor growth in HB patients.

Iodine-125 brachytherapy has been applied to brain tumours since 1979. Even though the physical and biological characteristics make these implants particularly attractive for minimal invasive treatment, the place for stereotactic brachytherapy is still poorly defined. An extensive review of the literature has been performed, especially concerning indications, results and complications. Iodine-125 seeds have been implanted in astrocytomas I-III, glioblastomas, metastases and several other tumour entities. Outcome data given in the literature are summarized. Complications are rare in carefully selected patients. All in all, for highly selected patients with newly diagnosed or recurrent primary or metastatic tumours, this method provides encouraging survival rates with relatively low complication rates and a good quality of life.

Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and antiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more antiinflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. Copyright (C) 2012 S. Karger AG, Basel

Background: Mucin-1 is known to be over-expressed by various human carcinomas and is shed into the circulation where it can be detected in patient's serum by specific anti-Mucin-1 antibodies, such as the tumour marker assays CA 15-3 and CA 27.29. The prognostic value of Mucin-1 expression in ovarian carcinoma remains uncertain. One aim of this study was to compare the concentrations of Mucin-1 in a cohort of patients with either benign or malignant ovarian tumours detected by CA 15-3 and CA 27.29. Another aim of this study was to evaluate Mucin-1 expression by immunohistochemistry in a different cohort of ovarian carcinoma patients with respect to grade, stage and survival. Methods: Patients diagnosed with and treated for ovarian tumours were included in the study. Patient characteristics, histology including histological subtype, tumour stage, grading and follow-up data were available from patient records. Serum Mucin-1 concentrations were measured with ELISA technology detecting CA 15-3 and CA 27.29, Mucin-1 tissue expression was determined by immunohistochemistry using the VU4H5 and VU3C6 anti-Mucin-1 antibodies. Statistical analysis was performed by using SPSS 18.0. Results: Serum samples of 118 patients with ovarian tumours were obtained to determine levels of Mucin-1. Median CA 15-3 and CA 27.29 concentrations were significantly higher in patients with malignant disease (p < 0.001) than in patients with benign disease. Paraffin-embedded tissue of 154 patients with ovarian carcinoma was available to determine Mucin-1 expression. The majority of patients presented with advanced stage disease at primary diagnosis. Median follow-up time was 11.39 years. Immunohistochemistry results for VU4H5 showed significant differences with respect to tumour grade, FIGO stage and overall survival. Patients with negative expression had a mean overall survival of 9.33 years compared to 6.27 years for patients with positive Mucin-1 expression. Conclusions: This study found significantly elevated Mucin-1 serum concentrations in ovarian carcinoma patients as compared to those women suffering from benign ovarian diseases. However, it needs to be noted that Mucin-1 concentrations in carcinoma patients showed a rather high variability. Results from immunohistochemistry indicate that Mucin-1 has a prognostic relevance in ovarian carcinomas when evaluating the expression by VU4H5 antibody.

Background: In recent years inhibitors directed against the epidermal growth factor receptor (EGFR) have evolved as effective targeting cancer drugs. Characteristic papulopustular exanthemas, often described as acneiform rashes, are the most frequent adverse effect associated with this class of novel cancer drugs and develop in > 90% of patients. Notably, the rash may significantly compromise the patients' quality of life, thereby potentially leading to incompliance as well as dose reduction or even termination of the anti-EGFR therapy. Yet, an effective dermatologic management of cutaneous adverse effects can be achieved. Whereas various case reports, case series or expert opinions on the management of EGFR-inhibitor (EGFRI) induced rashes have been published, data on systematic management studies are sparse. Methods: Here, we present a retrospective, uncontrolled, comparative study in 49 patients on three established regimens for the management of EGFRI-associated rashes. Results: Strikingly, patients' rash severity improved significantly over three weeks of treatment with topical mometason furoate cream, topical prednicarbate cream plus nadifloxacin cream, as well as topical prednicarbate cream plus nadifloxacin cream plus systemic isotretinoin. Conclusions: In summary our results demonstrate that EGFRI-associated rashes can be effectively managed by specific dermatologic interventions. Whereas mild to moderate rashes should be treated with basic measures in combination with topical glucocorticosteroids or combined regiments using glucocorticosteroids and antiseptics/antibiotics, more severe or therapy-resistant rashes are likely to respond with the addition of systemic retinoids.

Background: Graphical models were identified as a promising new approach to modeling high-dimensional clinical data. They provided a probabilistic tool to display, analyze and visualize the net-like dependence structures by drawing a graph describing the conditional dependencies between the variables. Until now, the main focus of research was on building Gaussian graphical models for continuous multivariate data following a multivariate normal distribution. Satisfactory solutions for binary data were missing. We adapted the method of Meinshausen and Buhlmann to binary data and used the LASSO for logistic regression. Objective of this paper was to examine the performance of the Bolasso to the development of graphical models for high dimensional binary data. We hypothesized that the performance of Bolasso is superior to competing LASSO methods to identify graphical models. Methods: We analyzed the Bolasso to derive graphical models in comparison with other LASSO based method. Model performance was assessed in a simulation study with random data generated via symmetric local logistic regression models and Gibbs sampling. Main outcome variables were the Structural Hamming Distance and the Youden Index. We applied the results of the simulation study to a real-life data with functioning data of patients having head and neck cancer. Results: Bootstrap aggregating as incorporated in the Bolasso algorithm greatly improved the performance in higher sample sizes. The number of bootstraps did have minimal impact on performance. Bolasso performed reasonable well with a cutpoint of 0.90 and a small penalty term. Optimal prediction for Bolasso leads to very conservative models in comparison with AIC, BIC or cross-validated optimal penalty terms. Conclusions: Bootstrap aggregating may improve variable selection if the underlying selection process is not too unstable due to small sample size and if one is mainly interested in reducing the false discovery rate. We propose using the Bolasso for graphical modeling in large sample sizes.

Background: Ehrlichia species are the etiological agents of emerging and life-threatening tick-borne human zoonoses that inflict serious and fatal infections in companion animals and livestock. The aim of this paper was to phylogeneticaly characterise a new species of Ehrlichia isolated from Rhipicephalus (Boophilus) microplus from Minas Gerais, Brazil. Methods: The agent was isolated from the hemolymph of Rhipicephalus (B.) microplus engorged females that had been collected from naturally infested cattle in a farm in the state of Minas Gerais, Brazil. This agent was then established and cultured in IDE8 tick cells. The molecular and phylogenetic analysis was based on 16S rRNA, groEL, dsb, gltA and gp36 genes. We used the maximum likelihood method to construct the phylogenetic trees. Results: The phylogenetic trees based on 16S rRNA, groEL, dsb and gltA showed that the Ehrlichia spp isolated in this study falls in a clade separated from any previously reported Ehrlichia spp. The molecular analysis of the ortholog of gp36, the major immunoreactive glycoproteins in E. canis and ortholog of the E. chaffeensis gp47, showed a unique tandem repeat of 9 amino acids (VPAASGDAQ) when compared with those reported for E. canis, E. chaffeensis and the related mucin-like protein in E. ruminantium. Conclusions: Based on the molecular and phylogenetic analysis of the 16S rRNA, groEL, dsb and gltA genes we concluded that this tick-derived microorganism isolated in Brazil is a new species, named E. mineirensis (UFMG-EV), with predicted novel antigenic properties in the gp36 ortholog glycoprotein. Further studies on this new Ehrlichia spp should address questions about its transmissibility by ticks and its pathogenicity for mammalian hosts.

There is an ongoing debate concerning the risk benefit ratio of psychopharmacologic compounds. With respect to the benefit, recent reports and meta-analyses note only small effect sizes with comparably high placebo response rates in the psychiatric field. These reports together with others lead to a wider, general critique on psychotropic drugs in the scientific community and in the lay press. In a recently published article, Leucht and his colleagues compare the efficacy of psychotropic drugs with the efficacy of common general medicine drugs in different indications according to results from reviewed meta-analyses. The authors conclude that, overall, the psychiatric drugs were generally not less effective than most other medical drugs. This article will highlight some of the results of this systematic review and discuss the limitations and the impact of this important approach on the above mentioned debate.