Identification of the genomic mutation in Epha4rb-2J/rb-2J mice

The EphA4 receptor tyrosine kinase is involved in numerous cell-signalling activities during embryonic development. EphA4 has the ability to bind to both types of ephrin ligands, the ephrinAs and ephrinBs. The C57BL/6J-Epha4rb-2J/GrsrJ strain, denoted Epha4rb-2J/rb-2J, is a spontaneous mouse mutant that arose at The Jackson Laboratory. These mutants exhibited a synchronous hind limb locomotion defect or “hopping gait” phenotype, which is also characteristic of EphA4 null mice. Genetic complementation experiments suggested that Epha4rb-2J corresponds to an allele of EphA4, but details of the genomic defect in this mouse mutant are currently unavailable. We found a single base-pair deletion in exon 9 resulting in a frame shift mutation that subsequently resulted in a premature stop codon. Analysis of the predicted structure of the truncated protein suggests that both the kinase and sterile α motif (SAM) domains are absent. Definitive determination of genotype is needed for experimental studies of mice carrying the Epha4rb-2J allele, and we have also developed a method to ease detection of the mutation through RFLP. Eph-ephrin family members are reportedly expressed as numerous isoforms. Hence, delineation of the specific mutation in EphA4 in this strain is important for further functional studies, such as protein–protein interactions, immunostaining and gene compensatory studies, investigating the mechanism underlying the effects of altered function of Eph family of receptor tyrosine kinases on phenotype

The place and barriers of evidence based practice: knowledge and perceptions of medical, nursing and allied health practitioners in malaysia

<p>Abstract</p> <p>Background</p> <p>Despite a recent increase in activities to promote evidence-based practice (EBP), it was unclear how Malaysian hospital practitioners received this new approach in medicine. This study examines their confidence and perceptions on EBP.</p> <p>Findings</p> <p>We conducted cross-sectional surveys using a self-administered questionnaire during two EBP training courses in two Malaysian hospitals in January and June 2007. Our subjects (n = 144) were doctors and nursing and allied health staff (NAH) participating in the EBP courses. Our questionnaire covered three domains: confidence and understanding (six items), attitude (five items) and barriers to practice (four items). We presented simple descriptive statistics, including the sum ratings and the proportions with different responses for each item, and compared different groups using Mann-Whitney U test for scaled ratings and Chi-square test for dichotomous responses.</p> <p>Ninety-two doctors and 52 NAH staff completed the surveys. Overall, doctors expressed slightly higher confidence on EBP compared to NAH staff. Out of a maximum sum rating of 27 over six items, doctors reported an average of 18.3 (SD 3.2) and NAH staff reported an average of 16.0 (SD 3.4), p = 0.002. Doctors were also more positive in their views on EBP. For example, 67.4% of doctors disagreed, but 61% of NAH staff agreed that "the importance of EBP in patient care is exaggerated", and 79.3% of doctors disagreed, but 46.2% of NAH staff agreed that "EBP is too tedious and impractical". Similar responses were observed for other items in the domain.</p> <p>Doctors and NAH staff shared similar concerns on barriers to evidence-based practice. The highest proportions considered poor facilities to access evidence a barrier (76% of doctors and 90% of NAH), followed by poor awareness of evidence (62% of doctors and 70% of NAH) and time constraints (63% of doctors and 68% of NAH), p = 0.09 for the combined rating of four items in the domain.</p> <p>Conclusions</p> <p>The findings of our survey suggest a need for greater efforts in promoting EBP among Malaysian hospital practitioners especially for NAH staff. From the responses based on the barriers to EBP, improving facilities for accessing evidence and promoting more user-friendly resources to address time constraints appear to be the priorities.</p

Analysis of sequence variations in low-density lipoprotein receptor gene among Malaysian patients with familial hypercholesterolemia

<p>Abstract</p> <p>Background</p> <p>Familial hypercholesterolemia is a genetic disorder mainly caused by defects in the low-density lipoprotein receptor gene. Few and limited analyses of familial hypercholesterolemia have been performed in Malaysia, and the underlying mutations therefore remain largely unknown.</p> <p>We studied a group of 154 unrelated FH patients from a northern area of Malaysia (Kelantan). The promoter region and exons 2-15 of the LDLR gene were screened by denaturing high-performance liquid chromatography to detect short deletions and nucleotide substitutions, and by multiplex ligation-dependent probe amplification to detect large rearrangements.</p> <p>Results</p> <p>A total of 29 gene sequence variants were reported in 117(76.0%) of the studied subjects. Eight different mutations (1 large rearrangement, 1 short deletion, 5 missense mutations, and 1 splice site mutation), and 21 variants. Eight gene sequence variants were reported for the first time and they were noticed in familial hypercholesterolemic patients, but not in controls (p.Asp100Asp, p.Asp139His, p.Arg471Gly, c.1705+117 T>G, c.1186+41T>A, 1705+112C>G, Dup exon 12 and p.Trp666ProfsX45). The incidence of the p.Arg471Gly variant was 11%. Patients with pathogenic mutations were younger, had significantly higher incidences of cardiovascular disease, xanthomas, and family history of hyperlipidemia, together with significantly higher total cholesterol and low density lipoprotein levels than patients with non-pathogenic variants.</p> <p>Conclusions</p> <p>Twenty-nine gene sequence variants occurred among FH patients; those with predicted pathogenicity were associated with higher incidences of cardiovascular diseases, tendon xanthomas, and higher total and low density lipoprotein levels compared to the rest. These results provide preliminary information on the mutation spectrum of this gene among patients with FH in Malaysia.</p

Functional Desaturase Fads1 (Δ5) and Fads2 (Δ6) Orthologues Evolved before the Origin of Jawed Vertebrates

Long-chain polyunsaturated fatty acids (LC-PUFAs) such as arachidonic (ARA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids are essential components of biomembranes, particularly in neural tissues. Endogenous synthesis of ARA, EPA and DHA occurs from precursor dietary essential fatty acids such as linoleic and α-linolenic acid through elongation and Δ5 and Δ6 desaturations. With respect to desaturation activities some noteworthy differences have been noted in vertebrate classes. In mammals, the Δ5 activity is allocated to the Fads1 gene, while Fads2 is a Δ6 desaturase. In contrast, teleosts show distinct combinations of desaturase activities (e.g. bifunctional or separate Δ5 and Δ6 desaturases) apparently allocated to Fads2-type genes. To determine the timing of Fads1-Δ5 and Fads2-Δ6 evolution in vertebrates we used a combination of comparative and functional genomics with the analysis of key phylogenetic species. Our data show that Fads1 and Fads2 genes with Δ5 and Δ6 activities respectively, evolved before gnathostome radiation, since the catshark Scyliorhinus canicula has functional orthologues of both gene families. Consequently, the loss of Fads1 in teleosts is a secondary episode, while the existence of Δ5 activities in the same group most likely occurred through independent mutations into Fads2 type genes. Unexpectedly, we also establish that events of Fads1 gene expansion have taken place in birds and reptiles. Finally, a fourth Fads gene (Fads4) was found with an exclusive occurrence in mammalian genomes. Our findings enlighten the history of a crucially important gene family in vertebrate fatty acid metabolism and physiology and provide an explanation of how observed lineage-specific gene duplications, losses and diversifications might be linked to habitat-specific food web structures in different environments and over geological timescales

Rheumatoid arthritis and the role of oral bacteria

Rheumatoid arthritis (RA) and periodontal disease (PD) have shown similar physiopathologic mechanisms such as chronic inflammation with adjacent bone resorption in an immunogenetically susceptible host; however, PD has a well-recognized bacterial etiology while the cause of RA is unclear. Some reports have indicated that an infectious agent in a susceptible host could be one possible trigger factor for RA, and it has been suggested that oral microorganisms, specialty periodontal bacteria could be the infectious agent (mainly Porphyromonas gingivalis). It has been reported that PD is more frequent and more severe in patients with RA, suggesting a positive association between both diseases. There have been reports regarding the detection of antibodies against periodontal bacteria while other studies have identified periodontal bacterial DNA in serum and synovial fluid of RA patients and have explored the possible pathways of transport of periodontal bacterial DNA. In conclusion, there is no question that RA and PD have pathologic features in common and there is strong evidence of an association between both diseases, but further studies, including experimental models, are needed to demonstrate the arthritogenicity of oral microorganisms

A new design for friction stir spot joining of Al alloys and carbon fibre reinforced composites

Friction stir spot welding (FSSW) has been recently developed to join dissimilar materials. However, the traditional requirement for a rotating tool consists of a pin and shoulder in FSSW leads to a complex joining process and unpredictable defects. In this study, a new static-shoulder design in FSSW was proposed and developed to join Al alloys to carbon fiber-reinforced polymer (CFRP) composites. The main joining parameters, including pin rotational speed, pin feed rate and pin plunge depth, were varied to investigate their effects on the joining temperature, materials interaction and the strength of joints. The pin rotational speed had the largest influence on the joining temperature. Lap shear tensile testing was conducted to evaluate the performance of the joints. The joints exhibited the ultimate lap shear force from 230 to 260 N. A brittle fracture occurred with the displacement-at-fracture load of 0.35-0.41 mm. Cross-sectional images revealed the creation of undulations on the surface of Al alloys in the joining zone. The undulations created a macro-mechanical interlocking bonding between the materials, which determined the performance of the joints. For a flat pin, by increasing the plunge depth from 1.25 to 1.30 mm, the undulation size increased from 0.21 to 0.26 mm, which can enhance the macro-mechanical interlocking bonding between Al alloys and CFRP and accordingly increased the ultimate shear force of the joints from 230 to 241 N. Use of a fluted pin significantly influenced the flow of the plasticized Al alloy which created pronounced undulations and large Al alloy spikes of 0.46 mm. These features seemed to establish an efficient macro-mechanical interlocking bonding, which resulted in a noticeable improvement in the performance of the joint. For a plunge depth of 1.30 mm, the ultimate shear force increased to 261 N using the fluted pin

The Impact of eHealth on the Quality and Safety of Health Care: A Systematic Overview

Aziz Sheikh and colleagues report the findings of their systematic overview that assessed the impact of eHealth solutions on the quality and safety of health care

Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults.

BACKGROUND: Underweight, overweight, and obesity in childhood and adolescence are associated with adverse health consequences throughout the life-course. Our aim was to estimate worldwide trends in mean body-mass index (BMI) and a comprehensive set of BMI categories that cover underweight to obesity in children and adolescents, and to compare trends with those of adults. METHODS: We pooled 2416 population-based studies with measurements of height and weight on 128·9 million participants aged 5 years and older, including 31·5 million aged 5-19 years. We used a Bayesian hierarchical model to estimate trends from 1975 to 2016 in 200 countries for mean BMI and for prevalence of BMI in the following categories for children and adolescents aged 5-19 years: more than 2 SD below the median of the WHO growth reference for children and adolescents (referred to as moderate and severe underweight hereafter), 2 SD to more than 1 SD below the median (mild underweight), 1 SD below the median to 1 SD above the median (healthy weight), more than 1 SD to 2 SD above the median (overweight but not obese), and more than 2 SD above the median (obesity). FINDINGS: Regional change in age-standardised mean BMI in girls from 1975 to 2016 ranged from virtually no change (-0·01 kg/m2 per decade; 95% credible interval -0·42 to 0·39, posterior probability [PP] of the observed decrease being a true decrease=0·5098) in eastern Europe to an increase of 1·00 kg/m2 per decade (0·69-1·35, PP>0·9999) in central Latin America and an increase of 0·95 kg/m2 per decade (0·64-1·25, PP>0·9999) in Polynesia and Micronesia. The range for boys was from a non-significant increase of 0·09 kg/m2 per decade (-0·33 to 0·49, PP=0·6926) in eastern Europe to an increase of 0·77 kg/m2 per decade (0·50-1·06, PP>0·9999) in Polynesia and Micronesia. Trends in mean BMI have recently flattened in northwestern Europe and the high-income English-speaking and Asia-Pacific regions for both sexes, southwestern Europe for boys, and central and Andean Latin America for girls. By contrast, the rise in BMI has accelerated in east and south Asia for both sexes, and southeast Asia for boys. Global age-standardised prevalence of obesity increased from 0·7% (0·4-1·2) in 1975 to 5·6% (4·8-6·5) in 2016 in girls, and from 0·9% (0·5-1·3) in 1975 to 7·8% (6·7-9·1) in 2016 in boys; the prevalence of moderate and severe underweight decreased from 9·2% (6·0-12·9) in 1975 to 8·4% (6·8-10·1) in 2016 in girls and from 14·8% (10·4-19·5) in 1975 to 12·4% (10·3-14·5) in 2016 in boys. Prevalence of moderate and severe underweight was highest in India, at 22·7% (16·7-29·6) among girls and 30·7% (23·5-38·0) among boys. Prevalence of obesity was more than 30% in girls in Nauru, the Cook Islands, and Palau; and boys in the Cook Islands, Nauru, Palau, Niue, and American Samoa in 2016. Prevalence of obesity was about 20% or more in several countries in Polynesia and Micronesia, the Middle East and north Africa, the Caribbean, and the USA. In 2016, 75 (44-117) million girls and 117 (70-178) million boys worldwide were moderately or severely underweight. In the same year, 50 (24-89) million girls and 74 (39-125) million boys worldwide were obese. INTERPRETATION: The rising trends in children's and adolescents' BMI have plateaued in many high-income countries, albeit at high levels, but have accelerated in parts of Asia, with trends no longer correlated with those of adults. FUNDING: Wellcome Trust, AstraZeneca Young Health Programme