Validity of chronic obstructive pulmonary disease diagnoses in a large administrative database,”

H ealth authorities (often the payers of health care) create and maintain administrative databases by compiling claims data sets. Claims data include the patient diagnosis that motivated the provision of services and the charges paid for the services provided. Typically, the database includes patient demographics and patient-level data about their use of health care resources. Administrators and health care researchers can access the information in these databases to ascertain resource use, even if it involved several providers and health care centres (1-3). When one payer reimburses all health care provisions, these databases afford the opportunity to conduct large populationbased observational studies with minimal referral bias, nonresponse and drop-outs. Similar to other investigators, we were interested in exploiting such a database for a series of studies that could answer health services questions (eg, utilization or quality of care) and clinical questions related to chronic obstructive pulmonary disease (COPD). Before doing so, we considered the underlying validity of the diagnoses included in the database. The objective of the present study was, therefore, to determine the extent to which the principal diagnoses of COPD made in hospitalized patients and recorded in a large administrative database were valid, ie, corroborated by clinical history (including smoking status) and pulmonary function tests

Quality of care for older adults with chronic obstructive pulmonary disease and asthma based on comparisons to practice guidelines and smoking status

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to describe the prevalence of respiratory diseases in older adults and compare the demographic, health and smoking characteristics of those with and without these diseases. Furthermore, we evaluate the association between smoking status and patterns in health care and how concordant this care is with guidelines.</p> <p>Methods</p> <p>Using a nationally representative sample of 29,902 older adults who participated in the Medicare Current Beneficiary Survey (1992–2002), we compared guideline recommendations on the treatment and prevention of chronic obstructive pulmonary disease and asthma with survey utilization data, including the use of bronchodilators, spirometry and influenza vaccine.</p> <p>Results</p> <p>26% to 30% of older adults were diagnosed with or self-reported chronic respiratory diseases; however 69% received no pharmacological treatment and 30% of patients reporting use of pharmacological treatments did not receive short-acting bronchodilator inhalers. Current smokers appeared to receive significantly less care for respiratory diseases than non-smokers or former smokers.</p> <p>Conclusion</p> <p>Disparities between recommended and actual care for older adults with chronic lung disease require further research. The needs of older adults with co-morbidities and nicotine addiction deserve special attention in care as well as guideline development and implementation.</p

The Death Effector Domains of Caspase-8 Induce Terminal Differentiation

The differentiation and senescence programs of metazoans play key roles in regulating normal development and preventing aberrant cell proliferation, such as cancer. These programs are intimately associated with both the mitotic and apoptotic pathways. Caspase-8 is an apical apoptotic initiator that has recently been appreciated to coordinate non-apoptotic roles in the cell. Most of these functions are attributed to the catalytic domain, however, the amino-terminal death effector domains (DED)s, which belong to the death domain superfamily of proteins, can also play key roles during development. Here we describe a novel role for caspase-8 DEDs in regulating cell differentiation and senescence. Caspase-8 DEDs accumulate during terminal differentiation and senescence of epithelial, endothelial and myeloid cells; genetic deletion or shRNA suppression of caspase-8 disrupts cell differentiation, while re-expression of DEDs rescues this phenotype. Among caspase-8 deficient neuroblastoma cells, DED expression attenuated tumor growth in vivo and proliferation in vitro via disruption of mitosis and cytokinesis, resulting in upregulation of p53 and induction of differentiation markers. These events occur independent of caspase-8 catalytic activity, but require a critical lysine (K156) in a microtubule-binding motif in the second DED domain. The results demonstrate a new function for the DEDs of caspase-8, and describe an unexpected mechanism that contributes to cell differentiation and senescence

Active nuclear import and cytoplasmic retention of activation-induced deaminase

The enzyme activation-induced deaminase (AID) triggers antibody diversification in B cells by catalyzing deamination and consequently mutation of immunoglobulin genes. To minimize off-target deamination, AID is restrained by several regulatory mechanisms including nuclear exclusion, thought to be mediated exclusively by active nuclear export. Here we identify two other mechanisms involved in controlling AID subcellular localization. AID is unable to passively diffuse into the nucleus, despite its small size, and its nuclear entry requires active import mediated by a conformational nuclear localization signal. We also identify in its C terminus a determinant for AID cytoplasmic retention, which hampers diffusion to the nucleus, competes with nuclear import and is crucial for maintaining the predominantly cytoplasmic localization of AID in steady-state conditions. Blocking nuclear import alters the balance between these processes in favor of cytoplasmic retention, resulting in reduced isotype class switching.This work was supported by the Canadian Institutes of Health Research (MOP 84543) and a Canada Research Chair (to J.M.D.). A.O. was supported by a fellowship from the Canadian Institutes of Health Research Cancer Training Program at the IRCM. V.A.C. was supported in part by a Michel Saucier fellowship from the Louis-Pasteur Canadian Fund through the University of Montreal

Analysis of the piggyBac transposase reveals a functional nuclear targeting signal in the 94 c-terminal residues

<p>Abstract</p> <p>Background</p> <p>The <it>piggyBac</it> transposable element is a popular tool for germ-line transgenesis of eukaryotes. Despite this, little is known about the mechanism of transposition or the transposase (TPase) itself. A thorough understanding of just how <it>piggyBac</it> works may lead to more effective use of this important mobile element. A PSORTII analysis of the TPase amino acid sequence predicts a bipartite nuclear localization signal (NLS) near the c-terminus, just upstream of a putative ZnF (ZnF).</p> <p>Results</p> <p>We fused the <it>piggyBac</it> TPase upstream of and in-frame with the enhanced yellow fluorescent protein (EYFP) in the <it>Drosophila melanogaster</it> inducible metallothionein protein. Using Drosophila Schneider 2 (S2) cells and the deep red fluorescent nuclear stain Draq5, we were able to track the pattern of <it>piggyBac</it> localization with a scanning confocal microscope 48 hours after induction with copper sulphate.</p> <p>Conclusion</p> <p>Through n and c-terminal truncations, targeted internal deletions, and specific amino acid mutations of the <it>piggyBac</it> TPase open reading frame, we found that not only is the PSORTII-predicted NLS required for the TPase to enter the nucleus of S2 cells, but there are additional requirements for negatively charged amino acids a short length upstream of this region for nuclear localization.</p

The Intrinsic Antiviral Defense to Incoming HSV-1 Genomes Includes Specific DNA Repair Proteins and Is Counteracted by the Viral Protein ICP0

Cellular restriction factors responding to herpesvirus infection include the ND10 components PML, Sp100 and hDaxx. During the initial stages of HSV-1 infection, novel sub-nuclear structures containing these ND10 proteins form in association with incoming viral genomes. We report that several cellular DNA damage response proteins also relocate to sites associated with incoming viral genomes where they contribute to the cellular front line defense. We show that recruitment of DNA repair proteins to these sites is independent of ND10 components, and instead is coordinated by the cellular ubiquitin ligases RNF8 and RNF168. The viral protein ICP0 targets RNF8 and RNF168 for degradation, thereby preventing the deposition of repressive ubiquitin marks and counteracting this repair protein recruitment. This study highlights important parallels between recognition of cellular DNA damage and recognition of viral genomes, and adds RNF8 and RNF168 to the list of factors contributing to the intrinsic antiviral defense against herpesvirus infection

The Effect of Complex Interventions on Depression and Anxiety in Chronic Obstructive Pulmonary Disease: Systematic Review and Meta-Analysis

Background Depression and anxiety are very common in people with chronic obstructive pulmonary disease (COPD) and are associated with excess morbidity and mortality. Patients prefer non-drug treatments and clinical guidelines promote non-pharmacological interventions as first line therapy for depression and anxiety in people with long term conditions. However the comparative effectiveness of psychological and lifestyle interventions among COPD patients is not known. We assessed whether complex psychological and/or lifestyle interventions are effective in reducing symptoms of anxiety and depression in patients with COPD. We then determined what types of psychological and lifestyle interventions are most effective. Methods and Findings Systematic review of randomised controlled trials of psychological and/or lifestyle interventions for adults with COPD that measured symptoms of depression and/or anxiety. CENTRAL, Medline, Embase, PsychINFO, CINAHL, ISI Web of Science and Scopus were searched up to April 2012. Meta-analyses using random effects models were undertaken to estimate the average effect of interventions on depression and anxiety. Thirty independent comparisons from 29 randomised controlled trials (n = 2063) were included in the meta-analysis. Overall, psychological and/or lifestyle interventions were associated with small reductions in symptoms of depression (standardised mean difference −0.28, 95% confidence interval −0.41 to −0.14) and anxiety (standardised mean difference −0.23, 95% confidence interval −0.38 to −0.09). Multi-component exercise training was the only intervention subgroup associated with significant treatment effects for depression (standardised mean difference −0.47, 95% confidence interval −0.66 to −0.28), and for anxiety (standardised mean difference −0.45, 95% confidence interval −0.71 to −0.18). Conclusions Complex psychological and/or lifestyle interventions that include an exercise component significantly improve symptoms of depression and anxiety in people with COPD. Furthermore, multi-component exercise training effectively reduces symptoms of anxiety and depression in all people with COPD regardless of severity of depression or anxiety, highlighting the importance of promoting physical activity in this population