Asthma and COPD in cystic fibrosis intron-8 5T carriers. A population-based study

BACKGROUND: Carriers of cystic fibrosis intron-8 5T alleles with high exon-9 skipping could have increased annual lung function decline and increased risk for asthma or chronic obstructive pulmonary disease (COPD). METHODS: We genotyped 9131 individuals from the adult Danish population for cystic fibrosis 5T, 7T, 9T, and F508del alleles, and examined associations between 11 different genotype combinations, and annual FEV(1 )decline and risk of asthma or COPD. RESULTS: 5T heterozygotes vs. 7T homozygous controls had no increase in annual FEV(1 )decline, self-reported asthma, spirometry-defined COPD, or incidence of hospitalization from asthma or COPD. In 5T/7T heterozygotes vs. 7T homozygous controls we had 90% power to detect an increase in FEV(1 )decline of 8 ml, an odds ratio for self-reported asthma and spirometry-defined COPD of 1.9 and 1.7, and a hazard ratio for asthma and COPD hospitalization of 1.8 and 1.6, respectively. Both 5T homozygotes identified in the study showed evidence of asthma, while none of four 5T/F508del compound heterozygotes had severe pulmonary disease. 7T/9T individuals had annual decline in FEV(1 )of 19 ml compared with 21 ml in 7T homozygous controls (t-test:P = 0.03). 6.7% of 7T homozygotes without an F508del allele in the cystic fibrosis transmembrane conductance regulator gene reported asthma vs. 11% of 7T/9T individuals with an F508del allele (χ(2):P = 0.01) and 40% of 7T homozygotes with an F508del allele (P = 0.04). 7T homozygotes with vs. without an F508del allele also had higher incidence of asthma hospitalization (log-rank:P = 0.003); unadjusted and adjusted equivalent hazard ratios for asthma hospitalization were 11 (95%CI:1.5–78) and 6.3 (0.84–47) in 7T homozygotes with vs. without an F508del allele. CONCLUSION: Polythymidine 5T heterozygosity is not associated with pulmonary dysfunction or disease in the adult Caucasian population. Furthermore, our results support that F508del heterozygosity is associated with increased asthma risk independently of the 5T allele

The evolution of tooth wear indices

Tooth wear—attrition, erosion and abrasion—is perceived internationally as an ever-increasing problem. Clinical and epidemiological studies, however, are difficult to interpret and compare due to differences in terminology and the large number of indices that have been developed for diagnosing, grading and monitoring dental hard tissue loss. These indices have been designed to identify increasing severity and are usually numerical. Some record lesions on an aetiological basis (e.g. erosion indices), others record lesions irrespective of aetiology (tooth wear indices); none have universal acceptance, complicating the evaluation of the true increase in prevalence reported. This article considers the ideal requirements for an erosion index. It reviews the literature to consider how current indices have evolved and discusses if these indices meet the clinical and research needs of the dental profession

Etoricoxib - preemptive and postoperative analgesia (EPPA) in patients with laparotomy or thoracotomy - design and protocols

<p>Abstract</p> <p>Background and Objective</p> <p>Our objective was to report on the design and essentials of the <it>Etoricoxib </it>protocol<it>- Preemptive and Postoperative Analgesia (EPPA) </it>Trial, investigating whether preemptive analgesia with cox-2 inhibitors is more efficacious than placebo in patients who receive either laparotomy or thoracotomy.</p> <p>Design and Methods</p> <p>The study is a 2 × 2 factorial armed, double blinded, bicentric, randomised placebo-controlled trial comparing (a) etoricoxib and (b) placebo in a pre- and postoperative setting. The total observation period is 6 months. According to a power analysis, 120 patients scheduled for abdominal or thoracic surgery will randomly be allocated to either the preemptive or the postoperative treatment group. These two groups are each divided into two arms. Preemptive group patients receive etoricoxib prior to surgery and either etoricoxib again or placebo postoperatively. Postoperative group patients receive placebo prior to surgery and either placebo again or etoricoxib after surgery (2 × 2 factorial study design). The Main Outcome Measure is the cumulative use of morphine within the first 48 hours after surgery (measured by patient controlled analgesia PCA). Secondary outcome parameters include a broad range of tests including sensoric perception and genetic polymorphisms.</p> <p>Discussion</p> <p>The results of this study will provide information on the analgesic effectiveness of etoricoxib in preemptive analgesia and will give hints on possible preventive effects of persistent pain.</p> <p>Trial registration</p> <p>NCT00716833</p

Phosphorylation of Serine 248 of C/EBPα Is Dispensable for Myelopoiesis but Its Disruption Leads to a Low Penetrant Myeloid Disorder with Long Latency

BACKGROUND: Transcription factors play a key role in lineage commitment and differentiation of stem cells into distinct mature cells. In hematopoiesis, they regulate lineage-specific gene expression in a stage-specific manner through various physical and functional interactions with regulatory proteins that are simultanously recruited and activated to ensure timely gene expression. The transcription factor CCAAT/enhancer binding protein α (C/EBPα) is such a factor and is essential for the development of granulocytic/monocytic cells. The activity of C/EBPα is regulated on several levels including gene expression, alternative translation, protein interactions and posttranslational modifications, such as phosphorylation. In particular, the phosphorylation of serine 248 of the transactivation domain has been shown to be of crucial importance for granulocytic differentiation of 32Dcl3 cells in vitro. METHODOLOGY/PRINCIPAL FINDINGS: Here, we use mouse genetics to investigate the significance of C/EBPα serine 248 in vivo through the construction and analysis of Cebpa(S248A/S248A) knock-in mice. Surprisingly, 8-week old Cebpa(S248A/S248A) mice display normal steady-state hematopoiesis including unaltered development of mature myeloid cells. However, over time some of the animals develop a hematopoietic disorder with accumulation of multipotent, megakaryocytic and erythroid progenitor cells and a mild impairment of differentiation along the granulocytic-monocytic lineage. Furthermore, BM cells from Cebpa(S248A/S248A) animals display a competitive advantage compared to wild type cells in a transplantation assay. CONCLUSIONS/SIGNIFICANCE: Taken together, our data shows that the substitution of C/EBPα serine 248 to alanine favors the selection of the megakaryocytic/erythroid lineage over the monocytic/granulocytic compartment in old mice and suggests that S248 phosphorylation may be required to maintain proper hematopoietic homeostasis in response to changes in the wiring of cellular signalling networks. More broadly, the marked differences between the phenotype of the S248A variant in vivo and in vitro highlight the need to exert caution when extending in vitro phenotypes to the more appropriate in vivo context

A Climate Change Vulnerability Assessment of California's At-Risk Birds

Conservationists must develop new strategies and adapt existing tools to address the consequences of anthropogenic climate change. To support statewide climate change adaptation, we developed a framework for assessing climate change vulnerability of California's at-risk birds and integrating it into the existing California Bird Species of Special Concern list. We defined climate vulnerability as the amount of evidence that climate change will negatively impact a population. We quantified climate vulnerability by scoring sensitivity (intrinsic characteristics of an organism that make it vulnerable) and exposure (the magnitude of climate change expected) for each taxon. Using the combined sensitivity and exposure scores as an index, we ranked 358 avian taxa, and classified 128 as vulnerable to climate change. Birds associated with wetlands had the largest representation on the list relative to other habitat groups. Of the 29 state or federally listed taxa, 21 were also classified as climate vulnerable, further raising their conservation concern. Integrating climate vulnerability and California's Bird Species of Special Concern list resulted in the addition of five taxa and an increase in priority rank for ten. Our process illustrates a simple, immediate action that can be taken to inform climate change adaptation strategies for wildlife