Genetic studies of osteoporosis: A rethink required

It has been 10 years since the seminal paper by Morrison and colleagues reporting the association of alleles of the vitamin D receptor and bone density [1], a paper which arguably kick-started the study of osteoporosis genetics. Since that report there have been literally thousands of osteoporosis genetic studies published, and large numbers of genes have been reported to be associated with the condition [2]. Although some of these reported associations are undoubtedly true, this snow-storm of papers and abstracts has clouded the field to such a great extent that it is very difficult to be certain of the veracity of most genetic associations reported hereto. The field needs to take stock and reconsider the best way forward, taking into account the biology of skeletal development and technological and statistical advances in human genetics, before more effort and money is wasted on continuing a process in which the primary achievement could be said to be a massive paper mountain. I propose in this review that the primary reasons for the paucity of success in osteoporosis genetics has been: •the absence of a major gene effect on bone mineral density (BMD), the most commonly studied bone phenotype; •failure to consider issues such as genetic heterogeneity, gene–environment interaction, and gene–gene interaction; •small sample sizes and over-optimistic data interpretation; and •incomplete assessment of the genetic variation in candidate genes studied.

Genetic studies of chondrocalcinosis

Purpose of review Our understanding of the causation of the chondrocalcinosis and other disorders characterized by ectopic mineralization is rapidly increasing, and genetic studies have contributed substantially to recent major advances in the field. This review will discuss what is known about the genetics of chondrocalcinosis and what we have learned from genetic studies to date. Recent findings: Chondrocalcinosis is one of a family of conditions associated with ectopic mineralization. This family also includes disorders of mineralization of bone and spinal and other ligaments, and vascular calcification. There has been increasing evidence of the key role of transport and metabolism of inorganic pyrophosphate (PPi) in control of mineralization, and as the likely explanation for the association of a variety of genetic variants with chondrocalcinosis and ectopic mineralization elsewhere. This may be an overly simplistic view of this family of conditions, with recent evidence suggesting that, for example, ANKH variants may not all predispose to chondrocalcinosis by effects on PPi transport, but may also influence chondrocyte maturation. Summary: Understanding the control of the process of mineralization and its tissue specificity are important steps in the search for rational therapies for these conditions.

Comparative studies of how living circumstances influence medication adherence in ≥ 65 year olds

Background Resources to help the older aged (≥65 year olds) manage their medicines should probably target those in greatest need. The older-aged have many different types of living circumstances. There are different locations (urban, rural), different types of housing (in the community or in retirement villages), different living arrangements (living alone or with others), and different socioeconomic status (SES) circumstances. However, there has been limited attention to whether these living circumstances affect adherence to medicines in the ≥65 year olds. Aim of the review The aim was to determine whether comparative studies, including logistic regression studies, show that living circumstances affect adherence to medicines by the ≥65 year olds. Methods A literature search of Medline, CINAHL and the Internet (Google) was undertaken. Results Four comparative studies have not shown differences in adherence to medicines between the ≥65 year olds living in rural and urban locations, but one study shows lower adherence to medicines for osteoporosis in rural areas compared to metropolitan, and another study shows greater adherence to antihypertensive medicines in rural than urban areas. There are no comparative studies of adherence to medicines in the older-aged living in indigenous communities compared to other communities. There is conflicting evidence as to whether living alone, being unmarried, or having a low income/worth is associated with nonadherence. Preliminary studies have suggested that the older-aged living in rental, low SES retirement villages or leasehold, middle SES retirement villages have a lower adherence to medicines than those living in freehold, high SES retirement villages. Conclusions The ≥65 year olds living in rural communities may need extra help with adherence to medicines for osteoporosis. The ≥65 year olds living in rental or leasehold retirement villages may require extra assistance/resources to adhere to their medicines. Further research is needed to clarify whether living under certain living circumstances (e.g. living alone, being unmarried, low income) has an effect on adherence, and to determine whether the ≥65 year olds living in indigenous communities need assistance to be adherent to prescribed medicines.

Genetic association and gene expression studies suggest that genetic variants in the SYNE1 and TNF genes are related to menstrual migraine

BACKGROUND: Menstrual migraine (MM) encompasses pure menstrual migraine (PMM) and menstrually-related migraine (MRM). This study was aimed at investigating genetic variants that are potentially related to MM, specifically undertaking genotyping and mRNA expression analysis of the ESR1, PGR, SYNE1 and TNF genes in MM cases and non-migraine controls. METHODS: A total of 37 variants distributed across 14 genes were genotyped in 437 DNA samples (282 cases and 155 controls). In addition levels of gene expression were determined in 74 cDNA samples (41 cases and 33 controls). Association and correlation analysis were performed using Plink and RStudio. RESULTS: SNPs rs3093664 and rs9371601 in TNF and SYNE1 genes respectively, were significantly associated with migraine in the MM population (p = 0.008; p = 0.009 respectively). Analysis of qPCR results found no significant difference in levels of gene expression between cases and controls. However, we found a significant correlation between the expression of ESR1 and SYNE1, ESR1 and PGR and TNF and SYNE1 in samples taken during the follicular phase of the menstrual cycle. CONCLUSIONS: Our results show that SNPs rs9371601 and rs3093664 in the SYNE1 and TNF genes respectively, are associated with MM. The present study also provides strong evidence to support the correlation of ESR1, PGR, SYNE1 and TNF gene expression in MM.

Reproducibility of fatmax and fat oxidation rates during exercise in recreationally trained males

Aerobic exercise training performed at the intensity eliciting maximal fat oxidation (Fatmax) has been shown to improve the metabolic profile of obese patients. However, limited information is available on the reproducibility of Fatmax and related physiological measures. The aim of this study was to assess the intra-individual variability of: a) Fatmax measurements determined using three different data analysis approaches and b) fat and carbohydrate oxidation rates at rest and at each stage of an individualized graded test. Fifteen healthy males [body mass index 23.1±0.6 kg/m2, maximal oxygen consumption () 52.0±2.0 ml/kg/min] completed a maximal test and two identical submaximal incremental tests on ergocycle (30-min rest followed by 5-min stages with increments of 7.5% of the maximal power output). Fat and carbohydrate oxidation rates were determined using indirect calorimetry. Fatmax was determined with three approaches: the sine model (SIN), measured values (MV) and 3rd polynomial curve (P3). Intra-individual coefficients of variation (CVs) and limits of agreement were calculated. CV for Fatmax determined with SIN was 16.4% and tended to be lower than with P3 and MV (18.6% and 20.8%, respectively). Limits of agreement for Fatmax were −2±27% of with SIN, −4±32 with P3 and −4±28 with MV. CVs of oxygen uptake, carbon dioxide production and respiratory exchange rate were <10% at rest and <5% during exercise. Conversely, CVs of fat oxidation rates (20% at rest and 24–49% during exercise) and carbohydrate oxidation rates (33.5% at rest, 8.5–12.9% during exercise) were higher. The intra-individual variability of Fatmax and fat oxidation rates was high (CV>15%), regardless of the data analysis approach employed. Further research on the determinants of the variability of Fatmax and fat oxidation rates is required.

Experimental studies on the performance of rail joints with modified wheel/railhead contact

Rail joints are provided with a gap to account for thermal movement and to maintain electrical insulation for the control of signals and/or broken rail detection circuits. The gap in the rail joint is regarded as a source of significant problems for the rail industry since it leads to a very short rail service life compared with other track components due to the various, and difficult to predict, failure modes – thus increasing the risk for train operations. Many attempts to improve the life of rail joints have led to a large number of patents around the world; notable attempts include strengthening through larger-sized joint bars, an increased number of bolts and the use of high yield materials. Unfortunately, no design to date has shown the ability to prolong the life of the rail joints to values close to those for continuously welded rail (CWR). This paper reports the results of a fundamental study that has revealed that the wheel contact at the free edge of the railhead is a major problem since it generates a singularity in the contact pressure and railhead stresses. A design was therefore developed using an optimisation framework that prevents wheel contact at the railhead edge. Finite element modelling of the design has shown that the contact pressure and railhead stress singularities are eliminated, thus increasing the potential to work as effectively as a CWR that does not have a geometric gap. An experimental validation of the finite element results is presented through an innovative non-contact measurement of strains. Some practical issues related to grinding rails to the optimal design are also discussed.

Plantar pressure in diabetic peripheral neuropathy patients with active foot ulceration, previous ulceration and no history of ulceration: A meta-analysis of observational studies

Aims Elevated dynamic plantar pressures are a consistent finding in diabetes patients with peripheral neuropathy with implications for plantar foot ulceration. This meta-analysis aimed to compare the plantar pressures of diabetes patients that had peripheral neuropathy and those with neuropathy with active or previous foot ulcers. Methods Published articles were identified from Medline via OVID, CINAHL, SCOPUS, INFORMIT, Cochrane Central EMBASE via OVID and Web of Science via ISI Web of Knowledge bibliographic databases. Observational studies reporting barefoot dynamic plantar pressure in adults with diabetic peripheral neuropathy, where at least one group had a history of plantar foot ulcers were included. Interventional studies, shod plantar pressure studies and studies not published in English were excluded. Overall mean peak plantar pressure (MPP) and pressure time integral (PTI) were primary outcomes. The six secondary outcomes were MPP and PTI at the rear foot, mid foot and fore foot. The protocol of the meta-analysis was published with PROPSERO, (registration number CRD42013004310). Results Eight observational studies were included. Overall MPP and PTI were greater in diabetic peripheral neuropathy patients with foot ulceration compared to those without ulceration (standardised mean difference 0.551, 95% CI 0.290–0.811, p<0.001; and 0.762, 95% CI 0.303–1.221, p = 0.001, respectively). Sub-group analyses demonstrated no significant difference in MPP for those with neuropathy with active ulceration compared to those without ulcers. A significant difference in MPP was found for those with neuropathy with a past history of ulceration compared to those without ulcers; (0.467, 95% CI 0.181– 0.753, p = 0.001). Statistical heterogeneity between studies was moderate. Conclusions Plantar pressures appear to be significantly higher in patients with diabetic peripheral neuropathy with a history of foot ulceration compared to those with diabetic neuropathy without a history of ulceration. More homogenous data is needed to confirm these findings.

Comparing fat oxidation in an exercise test with moderate-intensity interval training

This study compared fat oxidation rate from a graded exercise test (GXT) with a moderate-intensity interval training session (MIIT) in obese men. Twelve sedentary obese males (age 29 ± 4.1 years; BMI 29.1 ± 2.4 kg·m-2; fat mass 31.7 ± 4.4 %body mass) completed two exercise sessions: GXT to determine maximal fat oxidation (MFO) and maximal aerobic power (VO2max), and an interval cycling session during which respiratory gases were measured. The 30-min MIIT involved 5-min repetitions of workloads 20% below and 20% above the MFO intensity. VO2max was 31.8 ± 5.5 ml·kg-1·min-1 and all participants achieved ≥ 3 of the designated VO2max test criteria. The MFO identified during the GXT was not significantly different compared with the average fat oxidation rate in the MIIT session. During the MIIT session, fat oxidation rate increased with time; the highest rate (0.18 ± 0.11 g·min- 1) in minute 25 was significantly higher than the rate at minute 5 and 15 (p ≤ 0.01 and 0.05 respectively). In this cohort with low aerobic fitness, fat oxidation during the MIIT session was comparable with the MFO determined during a GXT. Future research may consider if the varying workload in moderate-intensity interval training helps adherence to exercise without compromising fat oxidation.

Archiving primary data: Solutions for long-term studies

The recent trend for journals to require open access to primary data included in publications has been embraced by many biologists, but has caused apprehension amongst researchers engaged in long-term ecological and evolutionary studies. A worldwide survey of 73 principal investigators (Pls) with long-term studies revealed positive attitudes towards sharing data with the agreement or involvement of the PI, and 93% of PIs have historically shared data. Only 8% were in favor of uncontrolled, open access to primary data while 63% expressed serious concern. We present here their viewpoint on an issue that can have non-trivial scientific consequences. We discuss potential costs of public data archiving and provide possible solutions to meet the needs of journals and researchers.

Long-term effect of childhood liver transplantation on body cell mass

Malnutrition is common in end-stage liver disease, but a correction after transplantation is expected. Body cell mass (BCM) assessment using total body potassium (TBK) measurements is considered the gold standard for assessing nutritional status. The aim of this study was to examine the BCM and, therefore, nutritional status of long-term survivors after childhood liver transplantation. © 2014 American Association for the Study of Liver Diseases.

Media business studies as we see it: Why does it matter, for whom, and how do you get published? [editorial]

To the delight of the renewed editorial team, the Journal of Media Business Studies (JOMBS) receives an increasing number of submissions every week. Given the growing interest in the study of media business, whether from the angle of economics, management, strategy, organisation studies, marketing, consumer behaviour, innovation and entrepreneurship or other contributing disciplines, this editorial aims to clarify how we look at the field and wish to move the journal forward. In particular, we want to address a few questions that we believe are central for those who wish to publish their research with us and thereby contribute to the academic discussion. This article gives a more elaborate explanation to the aims and scope of JOMBS.

Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm

Background Forearm fractures affect 1.7 million individuals worldwide each year and most occur earlier in life than hip fractures. While the heritability of forearm bone mineral density (BMD) and fracture is high, their genetic determinants are largely unknown. Aim To identify genetic variants associated with forearm BMD and forearm fractures. Methods BMD at distal radius, measured by dualenergy x-ray absorptiometry, was tested for association with common genetic variants. We conducted a metaanalysis of genome-wide association studies for BMD in 5866 subjects of European descent and then selected the variants for replication in 715 Mexican American samples. Gene-based association was carried out to supplement the single-nucleotide polymorphism (SNP) association test. We then tested the BMD-associated SNPs for association with forearm fracture in 2023 cases and 3740 controls. Results We found that five SNPs in the introns of MEF2C were associated with forearm BMD at a genome-wide significance level (p<5×10-8) in meta-analysis (lead SNP, rs11951031[T] -0.20 SDs per allele, p=9.01×10-9). The gene-based association test suggested an association between MEF2C and forearm BMD ( p=0.003). The association between MEF2C variants and risk of fracture did not achieve statistical significance (SNP rs12521522[A]: OR=1.14 (95% CI 0.92 to 1.35), p=0.14). Meta-analysis also revealed two genome-wide suggestive loci at CTNNA2 and 6q23.2. Conclusions These findings demonstrate that variants at MEF2C were associated with forearm BMD, implicating this gene in the determination of BMD at forearm.

Genome-wide association studies

Genome-wide association studies (GWAS) are a powerful hypothesis-free tool for the dissection of susceptibility to common heritable human diseases, including osteoporosis. To date, more than 2000 loci for common human diseases have been identified by GWAS. Success using the GWAS model depends on genetic risk being determined by shared stretches of DNA carried with different frequencies in cases and controls, inherited from ancient ancestors, termed the “common disease–common variant” hypothesis. Not all disease risk is caused by common variants, however, and thus GWAS will not detect all variants involved. Successful GWAS performance requires careful quality control, especially as the effect sizes under study are modest, and there are multiple potential sources of error. Conservative interpretation, use of stringent significance thresholds, and replication in independent cohorts are required to ensure results are robust. Despite these challenging parameters, much has been learnt from GWAS and, as the approach matures and is modified to identify a wider range of variants, significantly more will be learnt about the etiopathogenesis of common diseases such as osteoporosis.

Assessment of body composition in Sri Lankan children: Validation of a bioelectrical impedance prediction equation

Objective: To develop bioelectrical impedance analysis (BIA) equations to predict total body water (TBW) and fat-free mass (FFM) of Sri Lankan children. Subjects/Methods: Data were collected from 5- to 15-year-old healthy children. They were randomly assigned to validation (M/F: 105/83) and cross-validation (M/F: 53/41) groups. Height, weight and BIA were measured. TBW was assessed using isotope dilution method (D2 O). Multiple regression analysis was used to develop preliminary equations and cross-validated on an independent group. Final prediction equation was constructed combining the two groups and validated by PRESS (prediction of sum of squares) statistics. Impedance index (height2/impedance; cm2/Ω), weight and sex code (male = 1; female = 0) were used as variables. Results: Independent variables of the final prediction equation for TBW were able to predict 86.3% of variance with root means-squared error (RMSE) of 2.1l. PRESS statistics was 2.1l with press residuals of 1.2l. Independent variables were able to predict 86.9% of variance of FFM with RMSE of 2.7 kg. PRESS statistics was 2.8 kg with press residuals of 1.4 kg. Bland Altman technique showed that the majority of the residuals were within mean bias±1.96 s.d. Conclusions: Results of this study provide BIA equation for the prediction of TBW and FFM in Sri Lankan children. To the best of our knowledge there are no published BIA prediction equations validated on South Asian populations. Results of this study need to be affirmed by more studies on other closely related populations by using multi-component body composition assessment.

Genome-wide association studies and musculoskeletal diseases

Bone and joint diseases are major causes of morbidity and mortality worldwide, and their prevalence is increasing as the average population age increases. Most common musculoskeletal diseases show significant heritability, and few have treatments that prevent disease or can induce true treatment-free, disease-free remission. Furthermore, despite valiant efforts of hypothesis-driven research, our understanding of the etiopathogenesis of these conditions is, with few exceptions, at best moderate. Therefore, there has been a long-standing interest in genetics research in musculoskeletal disease as a hypothesis-free method for investigating disease etiopathogenesis. Important contributions have been made through the identification of monogenic causes of disease, but the holy grail of human genetics research has been the identification of the genes responsible for common diseases. The development of genome-wide association (GWA) studies has revolutionized this field, and led to an explosion in the number of genes identified that are definitely involved in musculoskeletal disease pathogenesis. However, this approach will not identify all common disease genes, and although the current progress is exciting and proves the potential of this research discipline, other approaches will be required to identify many of the types of genetic variation likely to be involved.