Eukaryotic initiation factor 6 regulates mechanical responses in endothelial cells

The repertoire of extratranslational functions of components of the protein synthesis apparatus is expanding to include control of key cell signaling networks. However, very little is known about noncanonical functions of members of the protein synthesis machinery in regulating cellular mechanics. We demonstrate that the eukaryotic initiation factor 6 (eIF6) modulates cellular mechanobiology. eIF6-depleted endothelial cells, under basal conditions, exhibit unchanged nascent protein synthesis, polysome profiles, and cytoskeleton protein expression, with minimal effects on ribosomal biogenesis. In contrast, using traction force and atomic force microscopy, we show that loss of eIF6 leads to reduced stiffness and force generation accompanied by cytoskeletal and focal adhesion defects. Mechanistically, we show that eIF6 is required for the correct spatial mechanoactivation of ERK1/2 via stabilization of an eIF6-RACK1-ERK1/2-FAK mechanocomplex, which is necessary for force-induced remodeling. These results reveal an extratranslational function for eIF6 and a novel paradigm for how mechanotransduction, the cellular cytoskeleton, and protein translation constituents are linked

Increased use of malaria rapid diagnostic tests improves targeting of anti-malarial treatment in rural Tanzania: implications for nationwide rollout of malaria rapid diagnostic tests.

ABSTRACT: BACKGROUND: The World Health Organization recommends parasitological confirmation of all malaria cases. Tanzania is implementing a phased rollout of malaria rapid diagnostic tests (RDTs) for routine use in all levels of care as one strategy to increase parasitological confirmation of malaria diagnosis. This study was carried out to evaluated artemisinin combination therapy (ACT) prescribing patterns in febrile patients with and without uncomplicated malaria in one pre-RDT implementation and one post-RDT implementation area. METHODS: A cross-sectional health facility surveys was conducted during high and low malaria transmission seasons in 2010 in both areas. Clinical information and a reference blood film on all patients presenting for an initial illness consultation were collected. Malaria was defined as a history of fever in the past 48 hours and microscopically confirmed parasitaemia. Routine diagnostic testing was defined as RDT or microscopy ordered by the health worker and performed at the health facility as part of the health worker-patient consultation. Correct diagnostic testing was defined as febrile patient tested with RDT or microscopy. Over-testing was defined as a febrile patient tested with RDT or microscopy. Correct treatment was defined as patient with malaria prescribed ACT. Over-treatment was defined as patient without malaria prescribed ACT. RESULTS: A total of 1,247 febrile patients (627 from pre-implementation area and 620 from post-implementation area) were included in the analysis. In the post-RDT implementation area, 80.9% (95% CI, 68.2-89.3) of patients with malaria received recommended treatment with ACT compared to 70.3% (95% CI, 54.7-82.2) of patients in the pre-RDT implementation area. Correct treatment was significantly higher in the post-implementation area during high transmission season (85.9% (95%CI, 72.0-93.6) compared to 58.3% (95%CI, 39.4-75.1) in pre-implementation area (p=0.01). Over-treatment with ACT of patients without malaria was less common in the post-RDT implementation area (20.9%; 95% CI, 14.7-28.8) compared to the pre-RDT implementation area (45.8%; 95% CI, 37.2-54.6) (p<0.01) in high transmission. The odds of overtreatment was significantly lower in post- RDT area (adjusted Odds Ratio (OR: 95%CI) 0.57(0.36-0.89); and much higher with clinical diagnosis adjusted OR (95%CI) 2.24(1.37-3.67) CONCLUSION: Implementation of RDTs increased use of RDTs for parasitological confirmation and reduced over-treatment with ACT during high malaria transmission season in one area in Tanzania. Continued monitoring of the national RDT rollout will be needed to assess whether these changes in case management practices will be replicated in other areas and sustained over time. Additional measures (such as refresher trainings, closer supervisions, etc) may be needed to improve ACT targeting during low transmission seasons

Prevalence and determinants of the use of self-tests by members of the public: a mixed methods study

Background Self-tests can be used by members of the public to diagnose conditions without involving a doctor, nurse or other health professional. As technologies to design and manufacture diagnostic tests have developed, a range of self-tests have become available to the public to buy over-the-counter and via the Internet. This study aims to describe how many people have used self-tests and identify factors associated with their use. Methods A postal questionnaire will elicit basic information, including sociodemographic characteristics, and whether the person has used or would use specified self-tests. Consent will be sought to recontact people who want to participate further in the study, and interviews and focus groups will be used to develop hypotheses about factors associated with self-test use. These hypotheses will be tested in a case-control study. An in-depth questionnaire will be developed incorporating the identified factors. This will be sent to: people who have used a self-test (cases); people who have not used a self-test but would use one in the future (controls); and people who have not used and would not use a self-test (controls). Logistic regression analysis will be used to establish which factors are associated with self-test use. Discussion Self-tests do have potential benefits, for example privacy and convenience, but also potential harms, for example delay seeking treatment after a true negative result when the symptoms are actually due to another condition. It is anticipated that the outcomes from this study will include recommendations about how to improve the appropriate use of self-tests and existing health services, as well as information to prepare health professionals for patients who have used self-tests

Mammography screening: views from women and primary care physicians in Crete

Background: Breast cancer is the most commonly diagnosed cancer among women and a leading cause of death from cancer in women in Europe. Although breast cancer incidence is on the rise worldwide, breast cancer mortality over the past 25 years has been stable or decreasing in some countries and a fall in breast cancer mortality rates in most European countries in the 1990s was reported by several studies, in contrast, in Greece have not reported these favourable trends. In Greece, the age-standardised incidence and mortality rate for breast cancer per 100.000 in 2006 was 81,8 and 21,7 and although it is lower than most other countries in Europe, the fall in breast cancer mortality that observed has not been as great as in other European countries. There is no national strategy for screening in this country. This study reports on the use of mammography among middleaged women in rural Crete and investigates barriers to mammography screening encountered by women and their primary care physicians. Methods: Design: Semi-structured individual interviews. Setting and participants: Thirty women between 45–65 years of age, with a mean age of 54,6 years, and standard deviation 6,8 from rural areas of Crete and 28 qualified primary care physicians, with a mean age of 44,7 years and standard deviation 7,0 serving this rural population. Main outcome measure: Qualitative thematic analysis. Results: Most women identified several reasons for not using mammography. These included poor knowledge of the benefits and indications for mammography screening, fear of pain during the procedure, fear of a serious diagnosis, embarrassment, stress while anticipating the results, cost and lack of physician recommendation. Physicians identified difficulties in scheduling an appointment as one reason women did not use mammography and both women and physicians identified distance from the screening site, transportation problems and the absence of symptoms as reasons for non-use. Conclusion: Women are inhibited from participating in mammography screening in rural Crete. The provision of more accessible screening services may improve this. However physician recommendation is important in overcoming women's inhibitions. Primary care physicians serving rural areas need to be aware of barriers preventing women from attending mammography screening and provide women with information and advice in a sensitive way so women can make informed decisions regarding breast caner screening

A Unique Resource Mutualism between the Giant Bornean Pitcher Plant, Nepenthes rajah, and Members of a Small Mammal Community

The carnivorous pitcher plant genus Nepenthes grows in nutrient-deficient substrates and produce jug-shaped leaf organs (pitchers) that trap arthropods as a source of N and P. A number of Bornean Nepenthes demonstrate novel nutrient acquisition strategies. Notably, three giant montane species are engaged in a mutualistic association with the mountain treeshrew, Tupaia montana, in which the treeshrew defecates into the pitchers while visiting them to feed on nectar secretions on the pitchers' lids

Sequencing and association analysis of the type 1 diabetes - linked region on chromosome 10p12-q11

Background: In an effort to locate susceptibility genes for type I diabetes (TID) several genome-wide linkage scans have been undertaken. A chromosomal region designated IDDM10 retained genome-wide significance in a combined analysis of the main linkage scans. Here, we studied sequence polymorphisms in 23 Mb on chromosome 10p12-q11, including the putative IDDM10 region, to identify genes associated with TID. Results: Initially, we resequenced the functional candidate genes, CREM and SDF1, located in this region, genotyped 13 tag single nucleotide polymorphisms (SNPs) and found no association with TID. We then undertook analysis of the whole 23 Mb region. We constructed and sequenced a contig tile path from two bacterial artificial clone libraries. By comparison with a clone library from an unrelated person used in the Human Genome Project, we identified 12,058 SNPs. We genotyped 303 SNPs and 25 polymorphic microsatellite markers in 765 multiplex TID families and followed up 22 associated polymorphisms in up to 2,857 families. We found nominal evidence of association in six loci (P = 0.05-0.0026), located near the PAPDI gene. Therefore, we resequenced 38.8 kb in this region, found 147 SNPs and genotyped 84 of them in the TID families. We also tested 13 polymorphisms in the PAPDI gene and in five other loci in 1,612 TID patients and 1,828 controls from the UK. Overall, only the D10S193 microsatellite marker located 28 kb downstream of PAPDI showed nominal evidence of association in both TID families and in the case-control sample (P = 0.037 and 0.03, respectively). Conclusion: We conclude that polymorphisms in the CREM and SDFI genes have no major effect on TID. The weak TID association that we detected in the association scan near the PAPDI gene may be either false or due to a small genuine effect, and cannot explain linkage at the IDDM10 region

Heel raises versus prefabricated orthoses in the treatment of posterior heel pain associated with calcaneal apophysitis (Sever's Disease): study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Posterior Heel pain can present in children of 8 to 14 years, associated with or clinically diagnosed as Sever's disease, or calcaneal apophysitis. Presently, there are no comparative randomised studies evaluating treatment options for posterior heel pain in children with the clinical diagnosis of calcaneal apophysitis or Sever's disease. This study seeks to compare the clinical efficacy of some currently employed treatment options for the relief of disability and pain associated with posterior heel pain in children.</p> <p>Method</p> <p>Design: Factorial 2 × 2 randomised controlled trial with monthly follow-up for 3 months.</p> <p>Participants: Children with clinically diagnosed posterior heel pain possibly associated with calcaneal apophysitis/Sever's disease (n = 124).</p> <p>Interventions: Treatment factor 1 will be two types of shoe orthoses: a heel raise or prefabricated orthoses. Both of these interventions are widely available, mutually exclusive treatment approaches that are relatively low in cost. Treatment factor 2 will be a footwear prescription/replacement intervention involving a shoe with a firm heel counter, dual density EVA midsole and rear foot control. The alternate condition in this factor is no footwear prescription/replacement, with the participant wearing their current footwear.</p> <p>Outcomes: Oxford Foot and Ankle Questionnaire and the Faces pain scale.</p> <p>Discussion</p> <p>This will be a randomised trial to compare the efficacy of various treatment options for posterior heel pain in children that may be associated with calcaneal apophysitis also known as Sever's disease.</p> <p>Trial Registration</p> <p>Trial Number: ACTRN12609000696291</p> <p>Ethics Approval Southern Health: HREC Ref: 09271B</p

Time spent with cats is never wasted: Lessons learned from feline acromegalic cardiomyopathy, a naturally occurring animal model of the human disease

<div><p>Background</p><p>In humans, acromegaly due to a pituitary somatotrophic adenoma is a recognized cause of increased left ventricular (LV) mass. Acromegalic cardiomyopathy is incompletely understood, and represents a major cause of morbidity and mortality. We describe the clinical, echocardiographic and histopathologic features of naturally occurring feline acromegalic cardiomyopathy, an emerging disease among domestic cats.</p><p>Methods</p><p>Cats with confirmed hypersomatotropism (IGF-1>1000ng/ml and pituitary mass; n = 67) were prospectively recruited, as were two control groups: diabetics (IGF-1<800ng/ml; n = 24) and healthy cats without known endocrinopathy or cardiovascular disease (n = 16). Echocardiography was performed in all cases, including after hypersomatotropism treatment where applicable. Additionally, tissue samples from deceased cats with hypersomatotropism, hypertrophic cardiomyopathy and age-matched controls (n = 21 each) were collected and systematically histopathologically reviewed and compared.</p><p>Results</p><p>By echocardiography, cats with hypersomatotropism had a greater maximum LV wall thickness (6.5mm, 4.1–10.1mm) than diabetic (5.9mm, 4.2–9.1mm; Mann Whitney, p<0.001) or control cats (5.2mm, 4.1–6.5mm; Mann Whitney, p<0.001). Left atrial diameter was also greater in cats with hypersomatotropism (16.6mm, 13.0–29.5mm) than in diabetic (15.4mm, 11.2–20.3mm; Mann Whitney, p<0.001) and control cats (14.0mm, 12.6–17.4mm; Mann Whitney, p<0.001). After hypophysectomy and normalization of IGF-1 concentration (n = 20), echocardiographic changes proved mostly reversible. As in humans, histopathology of the feline acromegalic heart was dominated by myocyte hypertrophy with interstitial fibrosis and minimal myofiber disarray.</p><p>Conclusions</p><p>These results demonstrate cats could be considered a naturally occurring model of acromegalic cardiomyopathy, and as such help elucidate mechanisms driving cardiovascular remodeling in this disease.</p></div

Cost-effectiveness of a national exercise referral programme for primary care patients in Wales: results of a randomised controlled trial

This article is published under license to BioMed Central Ltd. 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.The research was independent and funded by the Welsh Assembly Government. RTE is supported by Public Health Wales. Additional support for LM and SM during write up was provided by The Centre for the Development and Evaluation of Complex Interventions for Public Health Improvement (DECIPHer), a UKCRC Public Health Research: Centre of Excellence. Funding from the British Heart Foundation, Cancer Research UK, Economic and Social Research Council (RES-590-28-0005), Medical Research Council, the Welsh Assembly Government and the Wellcome Trust (WT087640MA), under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged