Patient reported side-effects of prednisone and methotrexate in a real-world sarcoidosis population

Currently prednisone is the first-line pharmacological treatment option for pulmonary sarcoidosis. Methotrexate is used as second-line therapy and seems to have fewer side-effects. No prospective comparative studies of first-line treatment with methotrexate exist. In this study, we evaluated patient reported presence and bothersomeness of side-effects of prednisone and methotrexate in a sarcoidosis population to guide the design of a larger prospective study. During a yearly patient information meeting 67 patients completed a questionnaire on medication use; 11 patients never used prednisone or methotrexate and were excluded from further analysis. Of the remaining 56 patients, 89% used prednisone and 70% methotrexate (present or former). Significantly more side-effects were reported for prednisone than for methotrexate, 78% versus 49% (p = 0.006). In conclusion, methotrexate seems to have fewer and less bothersome side-effects than prednisone. These findings need to be confirmed in a prospective study

ModuleDigger: an itemset mining framework for the detection of cis-regulatory modules

Background: The detection of cis-regulatory modules (CRMs) that mediate transcriptional responses in eukaryotes remains a key challenge in the postgenomic era. A CRM is characterized by a set of co-occurring transcription factor binding sites (TFBS). In silico methods have been developed to search for CRMs by determining the combination of TFBS that are statistically overrepresented in a certain geneset. Most of these methods solve this combinatorial problem by relying on computational intensive optimization methods. As a result their usage is limited to finding CRMs in small datasets (containing a few genes only) and using binding sites for a restricted number of transcription factors (TFs) out of which the optimal module will be selected. Results: We present an itemset mining based strategy for computationally detecting cis-regulatory modules (CRMs) in a set of genes. We tested our method by applying it on a large benchmark data set, derived from a ChIP-Chip analysis and compared its performance with other well known cis-regulatory module detection tools. Conclusion: We show that by exploiting the computational efficiency of an itemset mining approach and combining it with a well-designed statistical scoring scheme, we were able to prioritize the biologically valid CRMs in a large set of coregulated genes using binding sites for a large number of potential TFs as input

In silico identification and experimental validation of PmrAB targets in Salmonella typhimurium by regulatory motif detection

BACKGROUND: The PmrAB (BasSR) two-component regulatory system is required for Salmonella typhimurium virulence. PmrAB-controlled modifications of the lipopolysaccharide (LPS) layer confer resistance to cationic antibiotic polypeptides, which may allow bacteria to survive within macrophages. The PmrAB system also confers resistance to Fe(3+)-mediated killing. New targets of the system have recently been discovered that seem not to have a role in the well-described functions of PmrAB, suggesting that the PmrAB-dependent regulon might contain additional, unidentified targets. RESULTS: We performed an in silico analysis of possible targets of the PmrAB system. Using a motif model of the PmrA binding site in DNA, genome-wide screening was carried out to detect PmrAB target genes. To increase confidence in the predictions, all putative targets were subjected to a cross-species comparison (phylogenetic footprinting) using a Gibbs sampling-based motif-detection procedure. As well as the known targets, we detected additional targets with unknown functions. Four of these were experimentally validated (yibD, aroQ, mig-13 and sseJ). Site-directed mutagenesis of the PmrA-binding site (PmrA box) in yibD revealed specific sequence requirements. CONCLUSIONS: We demonstrated the efficiency of our procedure by recovering most of the known PmrAB-dependent targets and by identifying unknown targets that we were able to validate experimentally. We also pinpointed directions for further research that could help elucidate the S. typhimurium virulence pathway

A home monitoring program including real-time wireless home spirometry in idiopathic pulmonary fibrosis

In idiopathic pulmonary fibrosis (IPF), home monitoring experiences are limited, not yet real-time available nor implemented in daily care. We evaluated feasibility and potential barriers of a new home monitoring program with real-time wireless home spirometry in IPF. Ten patients with IPF were asked to test this home monitoring program, including daily home spirometry, for four weeks. Measurements of home and hospital spirometry showed good agreement. All patients considered real-time wireless spirometry useful and highly feasible. Both patients and researchers suggested relatively easy solutions for the identified potential barriers regarding real-time home monitoring in IPF

Inferring transcriptional modules from ChIP-chip, motif and microarray data

'ReMoDiscovery' is an intuitive algorithm to correlate regulatory programs with regulators and corresponding motifs to a set of co-expressed genes. It exploits in a concurrent way three independent data sources: ChIP-chip data, motif information and gene expression profiles. When compared to published module discovery algorithms, ReMoDiscovery is fast and easily tunable. We evaluated our method on yeast data, where it was shown to generate biologically meaningful findings and allowed the prediction of potential novel roles of transcriptional regulators

Longitudinal relations between parenting stress and child internalizing and externalizing behaviors: Testing within-person changes, bidirectionality and mediating mechanisms

IntroductionParenthood can be experienced as a pleasant but challenging period for parents, possibly accompanied by parenting stress. Early parenthood in particular is a vulnerable period as many parents experience biological and psychosocial changes related to new parenthood. Previous studies have shown that parenting stress is related to child behavior problems, but few studies have investigated the transactional relations across time between parenting stress and child internalizing and externalizing outcomes separately, examining within-person changes. The first aim of this study was to examine the transactional within-person associations of parenting stress and child internalizing and externalizing behavior problems across childhood from age 9 months to 9 years. As a second aim, we examined parenting as a possible underlying mechanism of the transactional associations by testing whether parental warmth and hostility mediate within-person associations of parenting stress and child behavior across time.MethodData were analyzed from the Growing Up in Ireland longitudinal child cohort study including 7,208 caregiver-child dyads at wave 1 (child’s age 9 months), who were followed at child’s age three (wave 2), five (wave 3), and 9 years (wave 5). Primary caregiver’s and child’s age and gender, household income, occupational status, educational status, partner status, and cultural background were covariates assessed at all waves. Data were analyzed using a random intercept cross-lagged panel model (CLPM) in R-lavaan.ResultsBidirectional relations between parenting stress and child behavior were found for both internalizing and externalizing behavior from age 5 to 9, but not for earlier time points.DiscussionOur results did not indicate mediating effects of parental warmth or parental hostility in the associations between parenting stress and child behavior problems. Therefore, we conclude that parenting stress and child internalizing as well as parenting stress and child externalizing behaviors have transactional associations from child’s age 5 to 9 years. Future research examining transactional associations of parenting stress and child behaviors should investigate possible other mediations taking a within-person approach by utilizing the RI-CLPM