Pathway-based variant enrichment analysis on the example of dilated cardiomyopathy.

Genome-wide association (GWA) studies have significantly contributed to the understanding of human genetic variation and its impact on clinical traits. Frequently only a limited number of highly significant associations were considered as biologically relevant. Increasingly, network analysis of affected genes is used to explore the potential role of the genetic background on disease mechanisms.

Quantitative acylcarnitine determination by UHPLC-MS/MS--Going beyond tandem MS acylcarnitine "profiles".

Tandem MS "profiling" of acylcarnitines and amino acids was conceived as a first-tier screening method, and its application to expanded newborn screening has been enormously successful. However, unlike amino acid screening (which uses amino acid analysis as its second-tier validation of screening results), acylcarnitine "profiling" also assumed the role of second-tier validation, due to the lack of a generally accepted second-tier acylcarnitine determination method. In this report, we present results from the application of our validated UHPLC-MS/MS second-tier method for the quantification of total carnitine, free carnitine, butyrobetaine, and acylcarnitines to patient samples with known diagnoses: malonic acidemia, short-chain acyl-CoA dehydrogenase deficiency (SCADD) or isobutyryl-CoA dehydrogenase deficiency (IBD), 3-methyl-crotonyl carboxylase deficiency (3-MCC) or ß-ketothiolase deficiency (BKT), and methylmalonic acidemia (MMA).

Growth, Yield and Fruit Quality of Grapevines under Organic and Biodynamic Management.

The main objective of this study was to determine growth, yield and fruit quality of grapevines under organic and biodynamic management in relation to integrated viticultural practices. Furthermore, the mechanisms for the observed changes in growth, yield and fruit quality were investigated by determining nutrient status, physiological performance of the plants and disease incidence on bunches in three consecutive growing seasons. A field trial (Vitis vinifera L.

Unemployment, health, and education of HIV-infected males in Germany.

Objectives: The present study on people living with HIV/AIDS (PLWHA) identifies socio-demographic and health-related factors corresponding with their labour market participation.

Methods: The study sample bases on a German observational sub-study of 527 male PLWHA. The present analysis is restricted to male PLWHA in working age.

Immunity comes first: the effect of parasite genotypes on adaptive immunity and immunization in three-spined sticklebacks.

Adaptive immunity in vertebrates can confer increased resistance against invading pathogens upon re-infection. But how specific parasite genotypes affect the temporal transition from innate to adaptive immunity under continual exposure to parasites is poorly understood. Here, we investigated the effects of homologous and heterologous exposures of genetically distinct parasite lineages of the eye fluke Diplostomum pseudospathaceum on gene expression patterns of adaptive immunity in sticklebacks (Gasterosteus aculeatus).

Magnetic Resonance Imaging Findings following Intraarticular Infliximab Therapy for Refractory Temporomandibular Joint Arthritis among Children with Juvenile Idiopathic Arthritis.

Objective: To evaluate the involvement of intraarticular (IA) infliximab (IFX) in the management of temporomandibular joint (TMJ) arthritis associated with juvenile idiopathic arthritis (JIA) that is refractory to systemic treatment and IA corticosteroid therapy.

Methods: Ours was a retrospective study of children with JIA who received IA IFX into the TMJ. The effectiveness of treatment on the progression of acute and chronic changes was assessed by a quantitative magnetic resonance imaging scoring system.

Validated method for the quantification of free and total carnitine, butyrobetaine, and acylcarnitines in biological samples.

A validated quantitative method for the determination of free and total carnitine, butyrobetaine, and acylcarnitines is presented. The versatile method has four components: (1) isolation using strong cation-exchange solid-phase extraction, (2) derivatization with pentafluorophenacyl trifluoromethanesulfonate, (3) sequential ion-exchange/reversed-phase (ultra) high-performance liquid chromatography [(U)HPLC] using a strong cation-exchange trap in series with a fused-core HPLC column, and (4) detection with electrospray ionization multiple reaction monitoring (MRM) mass spectrometry (MS). Standardized carnitine along with 65 synthesized, standardized acylcarnitines (including short-chain, medium-chain, long-chain, dicarboxylic, hydroxylated, and unsaturated acyl moieties) were used to construct multiple-point calibration curves, resulting in accurate and precise quantification.

Adrenergic Repression of the Epigenetic Reader MeCP2 Facilitates Cardiac Adaptation in Chronic Heart Failure.

Rationale: In chronic heart failure, increased adrenergic activation contributes to structural remodeling and altered gene expression. Although adrenergic signaling alters histone modifications, it is unknown, whether it also affects other epigenetic processes, including DNA methylation and its recognition.

Objective: The aim of this study was to identify the mechanism of regulation of the methyl-CpG-binding protein 2 (MeCP2) and its functional significance during cardiac pressure overload and unloading.

Deep Sequencing in Conjunction with Expression and Functional Analyses Reveals Activation of FGFR1 in Ewing Sarcoma.

Purpose: A low mutation rate seems to be a general feature of pediatric cancers, in particular in oncofusion gene-driven tumors. Genetically, Ewing sarcoma is defined by balanced chromosomal EWS/ETS translocations, which give rise to oncogenic chimeric proteins (EWS-ETS). Other contributing somatic mutations involved in disease development have only been observed at low frequency.

Treatment strategies for treatment naïve HIV patients in Germany: evidence from claims data.

A recent observational study of HIV patients in Germany suggests that treatment naïve patients that are in a more advanced stage of their disease are more likely to receive a treatment regimen based on a boosted protease inhibitor (PI/r) compared with a non-nucleoside reverse-transcriptase-inhibitor (NNRTI) base regimen. To validate those results we analysed claims data of seven German sickness funds from 2009 to 2012 with approximately 4 million beneficiaries. Patients in a more advanced disease state (CDC class C) had a higher likelihood to receive a PI/r based regime rather than a NNRTI based regimen as their initial treatment.

Cardiac Myocyte De Novo DNA Methyltransferases 3a/3b Are Dispensable for Cardiac Function and Remodeling after Chronic Pressure Overload in Mice.

Background: Recent studies reported altered DNA methylation in failing human hearts. This may suggest a role for de novo DNA methylation in the development of heart failure. Here, we tested whether cardiomyocyte-specific loss of de novo DNA methyltransferases Dnmt3a and Dnmt3b altered cardiac function and remodeling after chronic left ventricular pressure overload.

Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia.

Hereditary spastic paraplegias are heterogeneous neurological disorders characterized by a pyramidal syndrome with symptoms predominantly affecting the lower limbs. Some limited pyramidal involvement also occurs in patients with an autosomal recessive neurocutaneous syndrome due to ALDH18A1 mutations. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), an enzyme that catalyses the first and common step of proline and ornithine biosynthesis from glutamate.

Gut microbes, immunity, and spondyloarthritis.

The last decade has witnessed an explosion of studies evaluating the impact of the human microbiota on a variety of disease states. The microbiota can impact diseases in multiple ways, including through abnormalities in the diversity and contents of the microbiota, as well as by acting as targets of immunologic dysregulation. Herein, evidence that the microbiota in spondyloarthritis is both altered and abnormally targeted by the immune system will be presented.

From pills to patients: an evaluation of data sources to determine the number of people living with HIV who are receiving antiretroviral therapy in Germany.

Background: This study aimed to determine the number of people living with HIV receiving antiretroviral therapy (ART) between 2006 and 2013 in Germany by using the available numbers of antiretroviral drug prescriptions and treatment data from the ClinSurv HIV cohort (CSH).

Methods: The CSH is a multi-centre, open, long-term observational cohort study with an average number of 10.400 patients in the study period 2006-2013.

Regulation of alpha-1 acid glycoprotein synthesis by porcine hepatocytes in monolayer culture.

Alpha-1 acid glycoprotein (AGP, orosomucoid, ORM-1) is a highly glycosylated mammalian acute-phase protein, which is synthesized primarily in the liver and represents the major serum protein in newborn pigs. Recent data have suggested that the pig is unique in that AGP is a negative acute-phase protein in this species, and its circulating concentration appears to be associated with growth rate. The purpose of the present study was to investigate the regulation of AGP synthesis in hepatocytes prepared from suckling piglets and to provide a framework to compare its regulation with that of haptoglobin (HP), a positive acute-phase protein.

Genomics of divergence along a continuum of parapatric population differentiation.

The patterns of genomic divergence during ecological speciation are shaped by a combination of evolutionary forces. Processes such as genetic drift, local reduction of gene flow around genes causing reproductive isolation, hitchhiking around selected variants, variation in recombination and mutation rates are all factors that can contribute to the heterogeneity of genomic divergence. On the basis of 60 fully sequenced three-spined stickleback genomes, we explore these different mechanisms explaining the heterogeneity of genomic divergence across five parapatric lake and river population pairs varying in their degree of genetic differentiation.

Fetal-adult cardiac transcriptome analysis in rats with contrasting left ventricular mass reveals new candidates for cardiac hypertrophy.

Reactivation of fetal gene expression patterns has been implicated in common cardiac diseases in adult life including left ventricular (LV) hypertrophy (LVH) in arterial hypertension. Thus, increased wall stress and neurohumoral activation are discussed to induce the return to expression of fetal genes after birth in LVH. We therefore aimed to identify novel potential candidates for LVH by analyzing fetal-adult cardiac gene expression in a genetic rat model of hypertension, i.

Safety and efficacy of rituximab in childhood-onset systemic lupus erythematosus and other rheumatic diseases.

Objective: Rituximab (RTX) has been used to treat many pediatric autoimmune conditions. We investigated the safety and efficacy of RTX in a variety of pediatric autoimmune diseases, especially systemic lupus erythematosus (SLE).

Methods: Retrospective study of children treated with RTX.

Transcriptome assessment reveals a dominant role for TLR4 in the activation of human monocytes by the alarmin MRP8.

The alarmins myeloid-related protein (MRP)8 and MRP14 are the most prevalent cytoplasmic proteins in phagocytes. When released from activated or necrotic phagocytes, extracellular MRP8/MRP14 promote inflammation in many diseases, including infections, allergies, autoimmune diseases, rheumatoid arthritis, and inflammatory bowel disease. The involvement of TLR4 and the multiligand receptor for advanced glycation end products as receptors during MRP8-mediated effects on inflammation remains controversial.

Extensive copy-number variation of young genes across stickleback populations.

Duplicate genes emerge as copy-number variations (CNVs) at the population level, and remain copy-number polymorphic until they are fixed or lost. The successful establishment of such structural polymorphisms in the genome plays an important role in evolution by promoting genetic diversity, complexity and innovation. To characterize the early evolutionary stages of duplicate genes and their potential adaptive benefits, we combine comparative genomics with population genomics analyses to evaluate the distribution and impact of CNVs across natural populations of an eco-genomic model, the three-spined stickleback.

Altered microbiota associated with abnormal humoral immune responses to commensal organisms in enthesitis-related arthritis.

Introduction: Prior studies have established altered microbiota and immunologic reactivity to enteric commensal organisms in inflammatory bowel disease (IBD). Since intestinal inflammation is present in a subset of patients with both pediatric and adult spondyloarthritis (SpA), we hypothesized that SpA patients may also have altered microbiota and immune responsiveness to enteric organisms.

Methods: Stool and blood specimens were collected from children with enthesitis-related arthritis (ERA) and non-inflammatory controls.

Transcription factor cAMP response element modulator (Crem) restrains Pdgf-dependent proliferation of vascular smooth muscle cells in mice.

Transcription factors of the cAMP response element-binding protein (Creb)/cAMP response element modulator (Crem) family were linked to the switch from a contractile to a proliferating phenotype in vascular smooth muscle cells (VSMCs). Here, we analyzed the vascular function of Crem in mice with a global inactivation of Crem (Crem(-/-)). CRE-mediated transcriptional activity was enhanced in primary Crem(-/-) VSMCs under nonstimulated conditions and under stimulation with Forskolin and platelet-derived growth factor (Pdgf) whereas stimulation with nitric oxide or cGMP showed no effect.