The medical student

The Medical Student was published from 1888-1921 by the students of Boston University School of Medicine

ENU Mutagenesis Reveals a Novel Phenotype of Reduced Limb Strength in Mice Lacking Fibrillin 2

Background: Fibrillins 1 (FBN1) and 2 (FBN2) are components of microfibrils, microfilaments that are present in many connective tissues, either alone or in association with elastin. Marfan's syndrome and congenital contractural arachnodactyly (CCA) result from dominant mutations in the genes FBN1 and FBN2 respectively. Patients with both conditions often present with specific muscle atrophy or weakness, yet this has not been reported in the mouse models. In the case of Fbn1, this is due to perinatal lethality of the homozygous null mice making measurements of strength difficult. In the case of Fbn2, four different mutant alleles have been described in the mouse and in all cases syndactyly was reported as the defining phenotypic feature of homozygotes.Methodology/Principal Findings: As part of a large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis screen, we identified a mouse mutant, Mariusz, which exhibited muscle weakness along with hindlimb syndactyly. We identified an amber nonsense mutation in Fbn2 in this mouse mutant. Examination of a previously characterised Fbn2-null mutant, Fbn2(fp), identified a similar muscle weakness phenotype. The two Fbn2 mutant alleles complement each other confirming that the weakness is the result of a lack of Fbn2 activity. Skeletal muscle from mutants proved to be abnormal with higher than average numbers of fibres with centrally placed nuclei, an indicator that there are some regenerating muscle fibres. Physiological tests indicated that the mutant muscle produces significantly less maximal force, possibly as a result of the muscles being relatively smaller in Mariusz mice.Conclusions: These findings indicate that Fbn2 is involved in integrity of structures required for strength in limb movement. As human patients with mutations in the fibrillin genes FBN1 and FBN2 often present with muscle weakness and atrophy as a symptom, Fbn2-null mice will be a useful model for examining this aspect of the disease process further

People of the British Isles: preliminary analysis of genotypes and surnames in a UK control population

There is a great deal of interest in fine scale population structure in the UK, both as a signature of historical immigration events and because of the effect population structure may have on disease association studies. Although population structure appears to have a minor impact on the current generation of genome-wide association studies, it is likely to play a significant part in the next generation of studies designed to search for rare variants. A powerful way of detecting such structure is to control and document carefully the provenance of the samples involved. Here we describe the collection of a cohort of rural UK samples (The People of the British Isles), aimed at providing a well-characterised UK control population that can be used as a resource by the research community as well as providing fine scale genetic information on the British population. So far, some 4,000 samples have been collected, the majority of which fit the criteria of coming from a rural area and having all four grandparents from approximately the same area. Analysis of the first 3,865 samples that have been geocoded indicates that 75% have a mean distance between grandparental places of birth of 37.3km, and that about 70% of grandparental places of birth can be classed as rural. Preliminary genotyping of 1,057 samples demonstrates the value of these samples for investigating fine scale population structure within the UK, and shows how this can be enhanced by the use of surnames

The feasibility of determining the impact of primary health care research projects using the Payback Framework

<p>Abstract</p> <p>Background</p> <p>Primary health care research is under pressure to be accountable to funders in terms of benefits for practice and policy. However, methods to assess the impact of primary health care research must be appropriate to use with the diverse topics, settings and approaches of this sector. This project explored the feasibility of using the Buxton and Hanney Payback Framework to determine the impact of a stratified random sample (n = 4) of competitively funded, primary health care research projects.</p> <p>Methods</p> <p>The project conducted telephone interviews based on the Payback Framework with leaders of the research teams and nominated users of their research, used bibliometric methods for assessing impact through publication outputs and obtained documentary evidence of impact where possible. The purpose was to determine the effectiveness of the data collection methods and the applicability of the Payback Framework, and any other issues which arose around the assessment of impact of primary health care research.</p> <p>Results and discussion</p> <p>The thirteen interviews were resource intensive to organise conduct and analyse but provided better information about impact than bibliometric analysis or documentary analysis. Bibliometric analysis of the papers published from the four projects was hampered by the inclusion of only one of the journals in major citation indexes. Document analysis provided more evidence of dissemination than of impact.</p> <p>The payback framework and logic model were a sound basis for assessing impact. Chief investigators and nominated users of research provided substantial information relevant to the impact categories closest to their spheres of influence and awareness, but less about the impact their research had on the wider health sector, population health or economic benefits. An additional category of impact emerged from the interviews, that of strengthening research networks which could enhance the impact of later work. The framework provided rich information about the pathways to impact, better understanding of which may enhance impact.</p> <p>Conclusion</p> <p>It is feasible to use the Buxton and Hanney Payback framework and logic model to determine the proximal impacts of primary health care research. Though resource intensive, telephone interviews of chief investigators and nominated users provided rich information.</p

Differences between immigrant and non-immigrant groups in the use of primary medical care; a systematic review

Background. Studies on differences between immigrant and non-immigrant groups in health care utilization vary with respect to the extent and direction of differences in use. Therefore, our study aimed to provide a systematic overview of the existing research on differences in primary care utilization between immigrant groups and the majority population. Methods. For this review PubMed, PsycInfo, Cinahl, Sociofile, Web of Science and Current Contents were consulted. Study selection and quality assessment was performed using a predefined protocol by 2 reviewers independently of each other. Only original, quantitative, peer-reviewed papers were taken into account. To account for this hierarchical structure, logistic multilevel analyses were performed to examine the extent to which differences are found across countries and immigrant groups. Differences in primary care use were related to study characteristics, strength of the primary care system and methodological quality. Results. A total of 37 studies from 7 countries met all inclusion criteria. Remarkably, studies performed within the US more often reported a significant lower use among immigrant groups as compared to the majority population than the other countries. As studies scored higher on methodological quality, the likelihood of reporting significant differences increased. Adjustment for health status and use of culture-/language-adjusted procedures during the data

What research impacts do Australian primary health care researchers expect and achieve?

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background Funding for research is under pressure to be accountable in terms of benefits and translation of research findings into practice and policy. Primary health care research has considerable potential to improve health care in a wide range of settings, but little is known about the extent to which these impacts actually occur. This study examines the impact of individual primary health care research projects on policy and practice from the perspective of Chief Investigators (CIs). Methods The project used an online survey adapted from the Buxton and Hanney Payback Framework to collect information about the impacts that CIs expected and achieved from primary health care research projects funded by Australian national competitive grants. Results and Discussion Chief Investigators (CIs) provided information about seventeen completed projects. While no CI expected their project to have an impact in every domain of the framework used in the survey, 76% achieved at least half the impacts they expected. Sixteen projects had published and/or presented their work, 10 projects included 11 doctorate awards in their research capacity domain. All CIs expected their research to lead to further research opportunities with 11 achieving this. Ten CIs achieved their expectation of providing information for policy making but only four reported their research had influenced policy making. However 11 CIs achieved their expectation of providing information for organizational decision making and eight reported their research had influenced organizational decision making. Conclusion CIs reported that nationally funded primary health care research projects made an impact on knowledge production, staff development and further research, areas within the realm of influence of the research team and within the scope of awareness of the CIs. Some also made an impact on policy and organizational decision-making, and on localized clinical practice and service delivery. CIs reported few broader economic benefits from their research. Routine use of an instrument of this type would facilitate primary health care research funders' determination of the payback for funding of research in this sector

Relevance of the JAK2V617F mutation in patients with deep vein thrombosis of the leg

Venous thromboembolism (VTE) can be the first presenting symptom in myeloproliferative neoplasms (MPN). Studies have demonstrated a high prevalence of the JAK2V617F mutation in patients with splanchnic vein thrombosis. Fewer studies have been done in patients with thrombosis outside the splanchnic area, showing a lower prevalence although the clinical relevance of the mutation in these patients, e.g., progression to overt MPN, remains unknown. The objective of this study was to determine the effect size of JAK2V617F in prospectively collected DNA samples of patients objectively diagnosed with deep vein thrombosis (DVT) of the leg and controls without DVT, with follow-up on JAK2V617F-positive patients to assess clinical relevance. Presence of JAK2V617F was determined in DNA samples from 187 patients with DVT and 201 controls, using quantitative RT-PCR. Hematological parameters were also analyzed. All initially JAK2V617F-positive patients were reassessed. Of 187 patients with DVT, 178 were analyzed for JAK2V617F, and in four (2.3%; 95% CI 0.1–4.4), JAK2V617F was present. Of 201 controls, 198 were analyzed; one was JAK2V617F positive (0.5%; 95% CI −0.5–1.5, OR 4.5; 95% CI 0.5–40.9). None had MPN features, nor upon reassessment after a median follow-up of 68.5 months. Four JAK2V617F-positive patients with DVT and one control without DVT did not develop overt MPN after a median follow-up of nearly 6 years. Thus, in patients with non-splanchnic venous thrombosis, JAK2V617F appears not to be clinically relevant

Effect of Anticholinergic Use for the Treatment of Overactive Bladder on Cognitive Function in Postmenopausal Women

Overactive bladder (OAB) is a common condition affecting the elderly. The mainstay of treatment for OAB is medical therapy with anticholinergics. However, adverse events have been reported with this class of drugs including cognitive changes

Vectorial secretion of interleukin-8 mediates autocrine signalling in intestinal epithelial cells via apically located CXCR1

BACKGROUND: In the intestinal mucosa, several adaptations of TLR signalling have evolved to avoid chronic inflammatory responses to the presence of commensal microbes. Here we investigated whether polarized monolayers of intestinal epithelial cells might regulate inflammatory responses by secreting IL-8 in a vectorial fashion (i.e. apical versus basolateral) depending on the location of the TLR stimulus. RESULTS: In the Caco-2 BBE model of polarized villus-like epithelium, apical stimulation with TLR2 and TLR5 ligands resulted in the apical secretion of IL-8. The CXCR1 receptor for IL-8 was expressed only on the apical membrane of Caco-2 BBE cells and differentiated epithelial cells in the human small intestine and colon. Transcriptome analyses revealed that Caco-2 BBE cells respond to stimulation with IL-8 supporting the hypothesis that IL-8 induces G protein-coupled receptor signalling. CONCLUSIONS: These results show that IL-8 induces autocrine signalling via an apical CXCR1 in Caco-2 BBE intestinal epithelial cells and that this receptor is also expressed on the apical surface of differentiated human intestinal epithelial cells in vivo, suggesting an autocrine function for IL-8 secreted in the lumen

The medical student

The Medical Student was published from 1888-1921 by the students of Boston University School of Medicine