Time and phenotype-dependent transcriptome analysis in AAV-TGFβ1 and Bleomycin-induced lung fibrosis models

We have previously established a novel mouse model of lung fibrosis based on Adeno-associated virus (AAV)-mediated pulmonary overexpression of TGFβ1. Here, we provide an in-depth characterization of phenotypic and transcriptomic changes (mRNA and miRNA) in a head-to-head comparison with Bleomycin-induced lung injury over a 4-week disease course. The analyses delineate the temporal state of model-specific and commonly altered pathways, thereby providing detailed insights into the processes underlying disease development. They further guide appropriate model selection as well as interventional study design. Overall, Bleomycin-induced fibrosis resembles a biphasic process of acute inflammation and subsequent transition into fibrosis (with partial resolution), whereas the TGFβ1-driven model is characterized by pronounced and persistent fibrosis with concomitant inflammation and an equally complex disease phenotype as observed upon Bleomycin instillation. Finally, based on an integrative approach combining lung function data, mRNA/miRNA profiles, their correlation and miRNA target predictions, we identify putative drug targets and miRNAs to be explored as therapeutic candidates for fibrotic diseases. Taken together, we provide a comprehensive analysis and rich data resource based on RNA-sequencing, along with a strategy for transcriptome-phenotype coupling. The results will be of value for TGFβ research, drug discovery and biomarker identification in progressive fibrosing interstitial lung diseases

Effect of maternal panic disorder on mother-child interaction and relation to child anxiety and child self-efficacy

To determine whether mothers with panic disorder with or without agoraphobia interacted differently with their children than normal control mothers, 86 mothers and their adolescents (aged between 13 and 23 years) were observed during a structured play situation. Maternal as well as adolescent anxiety status was assessed according to a structured diagnostic interview. Results showed that mothers with panic disorder/agoraphobia showed more verbal control, were more criticizing and less sensitive during mother-child interaction than mothers without current mental disorders. Moreover, more conflicts were observed between mother and child dyadic interactions when the mother suffered from panic disorder. The comparison of parenting behaviors among anxious and non-anxious children did not reveal any significant differences. These findings support an association between parental over-control and rejection and maternal but not child anxiety and suggest that particularly mother anxiety status is an important determinant of parenting behavior. Finally, an association was found between children’s perceived self-efficacy, parental control and child anxiety symptoms

Single-Nucleotide Polymorphism Genotyping Identifies a Locally Endemic Clone of Methicillin-Resistant Staphylococcus aureus

We developed, tested, and applied a TaqMan real-time PCR assay for interrogation of three single-nucleotide polymorphisms that differentiate a clade (termed ‘t003-X’) within the radiation of methicillin-resistant Staphylococcus aureus (MRSA) ST225. The TaqMan assay achieved 98% typeability and results were fully concordant with DNA sequencing. By applying this assay to 305 ST225 isolates from an international collection, we demonstrate that clade t003-X is endemic in a single acute-care hospital in Germany at least since 2006, where it has caused a substantial proportion of infections. The strain was also detected in another hospital located 16 kilometers away. Strikingly, however, clade t003-X was not found in 62 other hospitals throughout Germany nor among isolates from other countries, and, hence, displayed a very restricted geographical distribution. Consequently, our results show that SNP-typing may be useful to identify and track MRSA clones that are specific to individual healthcare institutions. In contrast, the spatial dissemination pattern observed here had not been resolved by other typing procedures, including multilocus sequence typing (MLST), spa typing, DNA macrorestriction, and multilocus variable-number tandem repeat analysis (MLVA)

Morbidity and Risk of Subsequent Diagnosis of HIV: A Population Based Case Control Study Identifying Indicator Diseases for HIV Infection

BACKGROUND: Early identification of persons with undiagnosed HIV infection is an important health care issue. We examined associations between diseases diagnosed in hospitals and risk of subsequent HIV diagnosis. METHODS: In this population-based case control study, cases were persons with incident HIV infection diagnosed in Denmark between 1 January 1995 and 1 June 2008. Risk-set sampling was used to identify 19 age- and gender-matched population controls for each HIV case, using the HIV diagnosis date as the index date for both cases and controls. Prior hospital diagnoses obtained from Danish medical databases were first categorized into 22 major disease categories (excluding AIDS-defining diseases except tuberculosis) and then subdivided into 161 subcategories, allowing us to examine specific diseases as potential HIV indicators by conditional logistic regression. RESULTS: The study included 2,036 HIV cases and 35,718 controls. Persons with the following disease categories had a high risk of HIV diagnosis during the subsequent 5-year period: sexually transmitted infections and viral hepatitis (adjusted odds ratio [aOR] = 12.3, 95% CI: 9.60-15.7), hematological diseases (aOR = 4.28, 3.13-5.85), lower respiratory tract infections (aOR = 3.98, 3.14-5.04)), CNS infections (aOR = 3.44, 1.74-6.80), skin infections (aOR = 3.05, 2.47-3.75), other infections (aOR = 4.64, 3.89-5.54), and substance abuse (aOR = 2.60, 2.06-3.29). Several specific diseases were associated with aORs >20 including syphilis, hepatitis A, non "A" viral hepatitis, herpes zoster, candida infection, endocarditis, thrombocytopenia, and opioid abuse. CONCLUSIONS: Targeted testing for HIV in patients diagnosed with diseases associated with HIV may lead to earlier treatment and thereby reduced morbidity, mortality and HIV transmission

The working alliance in a randomized controlled trial comparing online with face-to-face cognitive-behavioral therapy for depression

Background: Although numerous efficacy studies in recent years have found internet-based interventions for depression to be effective, there has been scant consideration of therapeutic process factors in the online setting. In face-to face therapy, the quality of the working alliance explains variance in treatment outcome. However, little is yet known about the impact of the working alliance in internet-based interventions, particularly as compared with face-to-face therapy. Methods: This study explored the working alliance between client and therapist in the middle and at the end of a cognitive-behavioral intervention for depression. The participants were randomized to an internet-based treatment group (n = 25) or face-to-face group (n = 28). Both groups received the same cognitive behavioral therapy over an 8-week timeframe. Participants completed the Beck Depression Inventory (BDI) post-treatment and the Working Alliance Inventory at mid- and post- treatment. Therapists completed the therapist version of the Working Alliance Inventory at post-treatment. Results: With the exception of therapists' ratings of the tasks subscale, which were significantly higher in the online group, the two groups' ratings of the working alliance did not differ significantly. Further, significant correlations were found between clients' ratings of the working alliance and therapy outcome at post-treatment in the online group and at both mid- and post-treatment in the face-to-face group. Correlation analysis revealed that the working alliance ratings did not significantly predict the BDI residual gain score in either group. Conclusions: Contrary to what might have been expected, the working alliance in the online group was comparable to that in the face-to-face group. However, the results showed no significant relations between the BDI residual gain score and the working alliance ratings in either group

Strong Association of a Common Dihydropyrimidine Dehydrogenase Gene Polymorphism with Fluoropyrimidine-Related Toxicity in Cancer Patients

variations associated with enhanced drug toxicity. = 0.001; the attributable risk was 56.9%. Comparing tumor-type matched sets of samples, correlation of c.496A>G with toxicity was particularly present in patients with gastroesophageal and breast cancer, but did not reach significance in patients with colorectal malignancies. polymorphism strongly contributes to the occurrence of fluoropyrimidine-related drug adverse effects. Carriers of this variant could benefit from individual dose adjustment of the fluoropyrimidine drug or alternate therapies

The Roles of Standardization, Certification and Assurance Services in Global Commerce

In this article we examine the rapid emergence and expansion of standardized product and process frameworks and a private-sector compliance and enforcement infrastructure that we believe may increasingly be providing a substitute for public and legal regulatory infrastructure in global commerce. This infrastructure is provided by a proliferation of performance codes and standards, many of which define acceptable social and environmental behavior, and a rapidly-growing number of privately-trained and authorized inspectors and certifiers that we call the third-party assurance industry. We offer reasons for this development, evidence of its scope and scale, and then describe the phenomenon in more detail by examining supply chain arrangements in two industries, food products and apparel, where the use of third-party standards and assurance services has expanded especially rapidly. We conclude with a discussion of the implications for the make or buy decision at the core of the theory of the firm. We argue that as quasi-regulatory standards are developed within various industries, and as performance to these standards can be systematically evaluated using third-party inspectors and certifiers, the costs of moving production outside of vertical firm hierarchies drop. We believe this may be an important factor in accelerating the shift to outsourcing that has been observed over the last two decades

A Timescale for Evolution, Population Expansion, and Spatial Spread of an Emerging Clone of Methicillin-Resistant Staphylococcus aureus

Due to the lack of fossil evidence, the timescales of bacterial evolution are largely unknown. The speed with which genetic change accumulates in populations of pathogenic bacteria, however, is a key parameter that is crucial for understanding the emergence of traits such as increased virulence or antibiotic resistance, together with the forces driving pathogen spread. Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of hospital-acquired infections. We have investigated an MRSA strain (ST225) that is highly prevalent in hospitals in Central Europe. By using mutation discovery at 269 genetic loci (118,804 basepairs) within an international isolate collection, we ascertained extremely low diversity among European ST225 isolates, indicating that a recent population bottleneck had preceded the expansion of this clone. In contrast, US isolates were more divergent, suggesting they represent the ancestral population. While diversity was low, however, our results demonstrate that the short-term evolutionary rate in this natural population of MRSA resulted in the accumulation of measurable DNA sequence variation within two decades, which we could exploit to reconstruct its recent demographic history and the spatiotemporal dynamics of spread. By applying Bayesian coalescent methods on DNA sequences serially sampled through time, we estimated that ST225 had diverged since approximately 1990 (1987 to 1994), and that expansion of the European clade began in 1995 (1991 to 1999), several years before the new clone was recognized. Demographic analysis based on DNA sequence variation indicated a sharp increase of bacterial population size from 2001 to 2004, which is concordant with the reported prevalence of this strain in several European countries. A detailed ancestry-based reconstruction of the spatiotemporal dispersal dynamics suggested a pattern of frequent transmission of the ST225 clone among hospitals within Central Europe. In addition, comparative genomics indicated complex bacteriophage dynamics

16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65 046 European population controls (5/393 cases versus 32/65 046 controls; Fisher's exact test P = 2.83 × 10−6, odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10−4). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical R

Defining Quality Indicators for Breast Device Surgery: Using Registries for Global Benchmarking

Background: Breast device registries monitor devices encompassing breast implants, tissue expanders and dermal matrices, and the quality of care and patient outcomes for breast device surgery. Defining a standard set of quality indicators and risk adjustment factors will enable consistency and adjustment for case-mix in benchmarking quality of care across breast implant registries. This study aimed to develop a set of quality indicators to enable assessment and reporting of quality of care for breast device surgery which can be applied globally. Methods: A scoping literature review was undertaken, and potential quality indicators were identified. Consensus on the final list of quality indicators was obtained using a modified Delphi approach. This process involved a series of online surveys, and teleconferences over 6 months. The Delphi panel included participants from various countries and representation from surgical specialty groups including breast and general surgeons, plastic and reconstructive surgeons, cosmetic surgeons, a breast-care nurse, a consumer, a devices regulator (Therapeutic Goods Administration), and a biostatistician. A total of 12 candidate indicators were proposed: Intraoperative antibiotic wash, intraoperative antiseptic wash, preoperative antibiotics, nipple shields, surgical plane, volume of implant, funnels, immediate versus delayed reconstruction, time to revision, reoperation due to complications, patient satisfaction, and volume of activity. Results: Three of the 12 proposed indicators were endorsed by the panel: preoperative intravenous antibiotics, reoperation due to complication, and patient reported outcome measures. Conclusion: The 3 endorsed quality indicator measures will enable breast device registries to standardize benchmarking of care internationally for patients undergoing breast device surgery