Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that 'low dose' theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of 'low dose' theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. METHOD/DESIGN: TWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either 'low dose' theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. DISCUSSION: The demonstration that 'low dose' theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014

Postcopulatory sexual selection

The female reproductive tract is where competition between the sperm of different males takes place, aided and abetted by the female herself. Intense postcopulatory sexual selection fosters inter-sexual conflict and drives rapid evolutionary change to generate a startling diversity of morphological, behavioural and physiological adaptations. We identify three main issues that should be resolved to advance our understanding of postcopulatory sexual selection. We need to determine the genetic basis of different male fertility traits and female traits that mediate sperm selection; identify the genes or genomic regions that control these traits; and establish the coevolutionary trajectory of sexes

Value of prominent flow voids without cord edema in the detection of spinal arteriovenous fistulae

Purpose: To determine the prevalence of spinal dural arteriovenous fistulae (SDAVF) in patients presenting with prominent vascular flow voids on imaging without other imaging findings suggestive of SDAVF. Methods: We retrospectively identified patients from January 1, 2005 to March 1, 2012 who underwent spinal angiography for suspected SDAVF with prominent vascular flow voids on prior imaging. We excluded patients with other major spinal pathology or other imaging findings of SDAVF including cord hyperintensity, enhancement, or expansion. We calculated the proportion of patients with positive findings for SDAVF on angiography and evaluated the prevalence of SDAVF for this finding alone and in correlation with clinical findings. Results: 18 patients underwent spinal angiography for prominent flow voids on imaging without other spinal pathology or imaging findings of SDAVF. Three had a SDAVF detected on angiography. The prevalence of SDAVF in this population was low, only 17% (95% CI 6-39%). All of the patients with positive angiography findings had myelopathy, increasing the prevalence to 100% if the additional clinical finding of myelopathy was present. Conclusions: Prominent flow voids without other imaging findings suggestive of SDAVF is poorly predictive of the presence of a SDAVF, unless myelopathy is present clinically. © 2014 Alhilali et al

Identification of Essential Sequences for Cellular Localization in BRMS1 Metastasis Suppressor

10 páginas, 5 figuras. PMID: 19649328 [PubMed] PMCID: PMC2713406BACKGROUND: Breast cancer metastasis suppressor 1 (BRMS1) reduces the number and the size of secondary tumours in a mouse model without affecting the growth of the primary foci upon its re-expression. Knockdown of BRMS1 expression associates with metastasis. The molecular details on BRMS1 mechanism of action include its ability to function as a transcriptional co-repressor and consistently BRMS1 has been described as a predominantly nuclear protein. Since cellular distribution could represent a potential mechanism of regulation, we wanted to characterize BRMS1 sequence motifs that might regulate its cellular distribution. According to its amino acids sequence, BRMS1 contain two putative nuclear localization signals, however none of them has been proved to work so far. METHODOLOGY/PRINCIPAL FINDINGS: By using well known in vivo assays to detect both nuclear import and export signal, we have characterized, in the present study, one functional nuclear localisation signal as necessary and sufficient to promote nuclear transport. Additionally, the outcome of a directed yeast two-hybrid assay identify importin alpha6 as a specific partner of BRMS1 thus speculating that BRMS1 nuclear import could be specifically mediated by the reported nuclear transporter. Besides, the combination of a computational searching approach along the utilization of a nuclear export assay, identified a functional motif within the BRMS1 sequence responsible for its nuclear export, that resulted not affected by the highly specific CRM1 inhibitor Leptomycin-B. Interspecies heterokaryon assay demonstrate the capability of BRMS1 to shuttle between the nuclear and cytosolic compartments CONCLUSIONS/SIGNIFICANCE: Our results show for the first time that BRMS1 contains both nuclear import and export signals enabling its nucleo-cytoplasmic shuttling. These findings contributes new data for the understanding of the BRMS1 functions and allow us to speculate that this phenomenon could represent a novel mechanism for regulating the activity of BRMS1 or its associated cytosolic partnersThis work was supported by Spanish Ministerio de Ciencia y Tecnología (Grant SAF2006-10269), Ministerio de Ciencia e Innovación (Grant SAF2008-04048-E) and by a grant from Fundación Mutua Madrileña.Peer reviewe

Capacity management of nursing staff as a vehicle for organizational improvement

<p>Abstract</p> <p>Background</p> <p>Capacity management systems create insight into required resources like staff and equipment. For inpatient hospital care, capacity management requires information on beds and nursing staff capacity, on a daily as well as annual basis. This paper presents a comprehensive capacity model that gives insight into required nursing staff capacity and opportunities to improve capacity utilization on a ward level.</p> <p>Methods</p> <p>A capacity model was developed to calculate required nursing staff capacity. The model used historical bed utilization, nurse-patient ratios, and parameters concerning contract hours to calculate beds and nursing staff needed per shift and the number of nurses needed on an annual basis in a ward. The model was applied to three different capacity management problems on three separate groups of hospital wards. The problems entailed operational, tactical, and strategic management issues: optimizing working processes on pediatric wards, predicting the consequences of reducing length of stay on nursing staff required on a cardiology ward, and calculating the nursing staff consequences of merging two internal medicine wards.</p> <p>Results</p> <p>It was possible to build a model based on easily available data that calculate the nursing staff capacity needed daily and annually and that accommodate organizational improvements. Organizational improvement processes were initiated in three different groups of wards. For two pediatric wards, the most important improvements were found to be improving working processes so that the agreed nurse-patient ratios could be attained. In the second case, for a cardiology ward, what-if analyses with the model showed that workload could be substantially lowered by reducing length of stay. The third case demonstrated the possible savings in capacity that could be achieved by merging two small internal medicine wards.</p> <p>Conclusion</p> <p>A comprehensive capacity model was developed and successfully applied to support capacity decisions on operational, tactical, and strategic levels. It appeared to be a useful tool for supporting discussions between wards and hospital management by giving objective and quantitative insight into staff and bed requirements. Moreover, the model was applied to initiate organizational improvements, which resulted in more efficient capacity utilization.</p

High-resolution intravascular magnetic resonance quantification of atherosclerotic plaque at 3T

<p>Abstract</p> <p>Background</p> <p>The thickness of fibrous caps (FCT) of atherosclerotic lesions is a critical factor affecting plaque vulnerability to rupture. This study tests whether 3 Tesla high-resolution intravascular cardiovascular magnetic resonance (CMR) employing tiny loopless detectors can identify lesions and accurately measure FCT in human arterial specimens, and whether such an approach is feasible <it>in vivo </it>using animal models.</p> <p>Methods</p> <p>Receive-only 2.2 mm and 0.8 mm diameter intravascular loopless CMR detectors were fabricated for a clinical 3 Tesla MR scanner, and the absolute signal-to-noise ratio determined. The detectors were applied in a two-step protocol comprised of CMR angiography to identify atherosclerotic lesions, followed by high-resolution CMR to characterize FCT, lesion size, and/or vessel wall thickness. The protocol was applied in fresh human iliac and carotid artery specimens in a human-equivalent saline bath. Mean FCT measured by 80 μm intravascular CMR was compared with histology of the same sections. <it>In vivo </it>studies compared aortic wall thickness and plaque size in healthy and hyperlipidemic rabbit models, with post-mortem histology.</p> <p>Results</p> <p>Histology confirmed plaques in human specimens, with calcifications appearing as signal voids. Mean FCT agreed with histological measurements within 13% on average (correlation coefficient, <it>R </it>= 0.98; Bland-Altman analysis, -1.3 ± 68.9 μm). <it>In vivo </it>aortic wall and plaque size measured by 80 μm intravascular CMR agreed with histology.</p> <p>Conclusion</p> <p>Intravascular 3T CMR with loopless detectors can both locate atherosclerotic lesions, and accurately measure FCT at high-resolution in a strategy that appears feasible <it>in vivo</it>. The approach shows promise for quantifying vulnerable plaque for evaluating experimental therapies.</p

Positive Selection Shaped the Convergent Evolution of Independently Expanded Kallikrein Subfamilies Expressed in Mouse and Rat Saliva Proteomes

We performed proteomics studies of salivas from the genome mouse (C57BL/6 strain) and the genome rat (BN/SsNHsd/Mcwi strain). Our goal was to identify salivary proteins with one or more of three characteristics that may indicate that they have been involved in adaptation: 1) rapid expansion of their gene families; 2) footprints of positive selection; and/or 3) sex-limited expression. The results of our proteomics studies allow direct comparison of the proteins expressed and their levels between the sexes of the two rodent species. Twelve members of the Mus musculus species-specific kallikrein subfamily Klk1b showed sex-limited expression in the mouse saliva proteomes. By contrast, we did not find any of the Rattus norvegicus species-specific kallikrein subfamily Klk1c proteins in male or female genome rat, nor transcripts in their submandibular glands. On the other hand, we detected expression of this family as transcripts in the submandibular glands of both sexes of Sprague-Dawley rats. Using the CODEML program in the PAML package, we demonstrate that the two rodent kallikrein subfamilies have apparently evolved rapidly under the influence of positive selection that continually remodeled the amino acid sites on the same face in the members of the subfamilies. Thus, although their kallikrein subfamily expansions were independent, this evolutionary pattern has occurred in parallel in the two rodent species, suggesting a form of convergent evolution at the molecular level. On the basis of this new data, we suggest that the previous speculative function of the species-specific rodent kallikreins as important solely in wound healing in males be investigated further. In addition to or instead of that function, we propose that their sex-limited expression, coupled with their rapid evolution may be clues to an as-yet-undetermined interaction between the sexes

Development of a video-based education and process change intervention to improve advance cardiopulmonary resuscitation decision-making

Background: Advance cardiopulmonary resuscitation (CPR) decision-making and escalation of care discussions are variable in routine clinical practice. We aimed to explore physician barriers to advance CPR decision-making in an inpatient hospital setting and develop a pragmatic intervention to support clinicians to undertake and document routine advance care planning discussions. Methods: Two focus groups, which involved eight consultants and ten junior doctors, were conducted following a review of the current literature. A subsequent iterative consensus process developed two intervention elements: (i) an updated ‘Goals of Patient Care’ (GOPC) form and process; (ii) an education video and resources for teaching advance CPR decision-making and communication. A multidisciplinary group of health professionals and policymakers with experience in systems development, education and research provided critical feedback. Results: Three key themes emerged from the focus groups and the literature, which identified a structure for the intervention: (i) knowing what to say; (ii) knowing how to say it; (iii) wanting to say it. The themes informed the development of a video to provide education about advance CPR decision-making framework, improving communication and contextualising relevant clinical issues. Critical feedback assisted in refining the video and further guided development and evolution of a medical GOPC approach to discussing and recording medical treatment and advance care plans. Conclusion: Through an iterative process of consultation and review, video-based education and an expanded GOPC form and approach were developed to address physician and systemic barriers to advance CPR decisionmaking and documentation. Implementation and evaluation across hospital settings is required to examine utility and determine effect on quality of care