Whole-cortex mapping of common genetic influences on depression and a social deficits dimension

Social processes are associated with depression, particularly understanding and responding to others, deficits in which can manifest as callousness/unemotionality (CU). Thus, CU may reflect some of the genetic risk to depression. Further, this vulnerability likely reflects the neurological substrates of depression, presenting biomarkers to capture genetic vulnerability of depression severity. However, heritability varies within brain regions, so a high-resolution genetic perspective is needed. We developed a toolbox that maps genetic and environmental associations between brain and behavior at high resolution. We used this toolbox to estimate brain areas that are genetically associated with both depressive symptoms and CU in a sample of 258 same-sex twin pairs from the Colorado Longitudinal Twin Study (LTS). We then overlapped the two maps to generate coordinates that allow for tests of downstream effects of genes influencing our clusters. Genetic variance influencing cortical thickness in the right dorsal lateral prefrontal cortex (DLFPC) sulci and gyri, ventral posterior cingulate cortex (PCC), pre-somatic motor cortex (PreSMA), medial precuneus, left occipital-temporal junction (OTJ), parietal-temporal junction (PTJ), ventral somatosensory cortex (vSMA), and medial and lateral precuneus were genetically associated with both depression and CU. Split-half replication found support for both DLPFC clusters. Meta-analytic term search identified "theory of mind", "inhibit", and "pain" as likely functions. Gene and transcript mapping/enrichment analyses implicated calcium channels. CU reflects genetic vulnerability to depression that likely involves executive and social functioning in a distributed process across the cortex. This approach works to unify neuroimaging, neuroinformatics, and genetics to discover pathways to psychiatric vulnerability.</p

Computed tomographic enterography adds information to clinical management in small bowel Crohn's disease

Background: CT enterography yields striking findings in the bowel wall in Crohn's disease. These images may help to evaluate whether small bowel narrowing results from active disease requiring anti-inflammatory therapy. However, the clinical relevance of these images is unknown. It is also not known if these radiologic findings correlate with objective biomarkers of inflammation. Methods: In a blinded and independent evaluation, IBD subspecialty gastroenterologists reviewed clinical data, and CT radiologists reviewed CT enterography scans of 67 consecutive patients with Crohn's disease and suspicion of either small bowel inflammation or stricture. Comparisons were made between (1) clinical and radiologic assessments of inflammation and stricture, (2) clinical assessments before and after computed tomographic enterography (CTE) reports were revealed, and (3) radiologic findings and objective biomarkers of inflammation. Results: (1) Individual CTE findings correlated poorly (Spearman's rho < 0.30) with clinical assessment; (2) clinicians did not suspect 16% of radiologic strictures, and more than half the cases of clinically suspected strictures did not have them on CTE; (3) CTE data changed clinicians' perceptions of the likelihood of steroid benefit in 41 of 67 cases; (4) specific CTE findings correlated with CRP, and a distinct set of CTE findings correlated with ESR in the subset of patients who had these biomarkers measured. Conclusions: CTE seems to add unique information to clinical assessment, both in detecting additional strictures and in changing clinicians' perceptions of the likelihood of steroids benefiting patients. The biomarker correlations suggest that CTE is measuring real biologic phenomena that correlate with inflammation, providing information distinct from that in a standard clinical assessment. (Inflamm Bowel Dis 2006)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55965/1/20013_ftp.pd

Pan-European early switch/early discharge opportunities exist for hospitalised patients with methicillin-resistant <em>Staphylococcus</em> <em>aureus</em> complicated skin and soft-tissue infections

AbstractThe objective of this study was to document pan-European real-world treatment patterns and healthcare resource use and estimate opportunities for early switch (ES) from intravenous (IV) to oral antibiotics and early discharge (ED) in hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft tissue infections (cSSTIs). This retrospective observational medical chart review study enrolled 342 physicians across 12 European countries who collected data from 1542 patients with documented MRSA cSSTI who were hospitalized (July 2010 to June 2011) and discharged alive (by July 2011). Data included clinical characteristics and outcomes, hospital length of stay (LOS), MRSA-targeted IV and oral antibiotic use, and ES and ED eligibility according to literature-based and expert-validated criteria. The most frequent initial MRSA-active antibiotics were vancomycin (50.2%), linezolid (15.1%), clindamycin (10.8%), and teicoplanin (10.4%). Patients discharged with MRSA-active antibiotics (n = 480) were most frequently prescribed linezolid (42.1%) and clindamycin (19.8%). IV treatment duration (9.3 ± 6.5 vs. 14.6 ± 9.9 days; p <0.001) and hospital LOS (19.1 ± 12.9 vs. 21.0 ± 18.2 days; p 0.162) tended to be shorter for patients switched from IV to oral treatment than for patients who received IV treatment only. Of the patients, 33.6% met ES criteria and could have discontinued IV treatment 6.0 ± 5.5 days earlier, and 37.9% met ED criteria and could have been discharged 6.2 ± 8.2 days earlier. More than one-third of European patients hospitalized for MRSA cSSTI could be eligible for ES and ED, resulting in substantial reductions in IV days and bed-days, with potential savings of €2000 per ED-eligible patient

Elimination of micropollutants in activated sludge reactors with a special focus on the effect of biomass concentration

This study aimed to investigate the effects of sludge retention time (SRT), hydraulic retention time (HRT), and biomass concentration (CTSS) in activated sludge systems on removal of various micropollutants (MPs), covering a wide spectrum of biodegradability. The influence of biomass concentration on the classical pseudo-first-order rate constant was verified. Results showed that the removal rate constants were affected by both the HRT and SRT. The enhancement of the SRT increased the removal of all the MPs except for two macrolide antibiotics. Application of a higher HRT also improved MP removal, as was expected from the measured removal rate constants. More interesting, our results indicated that, logically, the increase of biomass concentration (expressed as total suspended solids CTSS) from 3 to 5 gTSS L−1 significantly enhanced the removal rate of the highly and moderately degradable compounds. Conversely, a further increase to 8 gTSS L−1 produced only an unexpected moderate effect, showing that the rate was not proportional to biomass concentration, contrary to what is generally postulated. Therefore, the use of classical kinetic models is questionable, since they do not cover the entire range of boundary conditions in activated sludge systems. This work opens new research paths and suggests potential improvements to processe

Environmental Factors in the Relapse and Recurrence of Inflammatory Bowel Disease:A Review of the Literature

The causes of relapse in patients with Crohn's disease (CD) and ulcerative colitis (UC) are largely unknown. This paper reviews the epidemiological and clinical data on how medications (non-steroidal anti-inflammatory drugs, estrogens and antibiotics), lifestyle factors (smoking, psychological stress, diet and air pollution) may precipitate clinical relapses and recurrence. Potential biological mechanisms include: increasing thrombotic tendency, imbalances in prostaglandin synthesis, alterations in the composition of gut microbiota, and mucosal damage causing increased permeability

Recombination Phenotypes of Escherichia coli greA Mutants

<p>Abstract</p> <p>Background</p> <p>The elongation factor GreA binds to RNA polymerase and modulates transcriptional pausing. Some recent research suggests that the primary role of GreA may not be to regulate gene expression, but rather, to promote the progression of replication forks which collide with RNA polymerase, and which might otherwise collapse. Replication fork collapse is known to generate dsDNA breaks, which can be recombinogenic. It follows that GreA malfunction could have consequences affecting homologous recombination.</p> <p>Results</p> <p><it>Escherichia coli </it>mutants bearing substitutions of the active site acidic residues of the transcription elongation factor GreA, D41N and E44K, were isolated as suppressors of growth inhibition by a toxic variant of the bacteriophage lambda Red-beta recombination protein. These mutants, as well as a D41A <it>greA </it>mutant and a <it>greA </it>deletion, were tested for proficiency in recombination events. The mutations were found to increase the efficiency of RecA-RecBCD-mediated and RecA-Red-mediated recombination, which are replication-independent, and to decrease the efficiency of replication-dependent Red-mediated recombination.</p> <p>Conclusion</p> <p>These observations provide new evidence for a role of GreA in resolving conflicts between replication and transcription.</p

Multi-ancestry meta-analysis of tobacco use disorder prioritizes novel candidate risk genes and reveals associations with numerous health outcomes

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviors, and although strides have been made using genome-wide association studies (GWAS) to identify risk variants, the majority of variants identified have been for nicotine consumption, rather than TUD. We leveraged five biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records, EHR) in 898,680 individuals (739,895 European, 114,420 African American, 44,365 Latin American). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviors in children, and hundreds of medical outcomes, including HIV infection, heart disease, and pain. This work furthers our biological understanding of TUD and establishes EHR as a source of phenotypic information for studying the genetics of TUD