Proteomic-based approaches to cardiac development and disease

Congenital malformations, or structural birth defects, are now the leading cause of infant mortality in the United States and Europe (Dolk et al., 2010; Heron et al., 2009). Of the congenital malformations, congenital heart disease (CHD) is the most common (Dolk et al., 2010; Heron et al., 2009). Thus, a molecular understanding of heart development is an essential goal for improving clinical approaches to CHD. However, CHDs are commonly a result of genetic defects that manifest themselves in a spatial and temporal manner during the early stages of embryogenesis, leaving them mostly intractable to mass spectrometry-based analysis. Here, we describe the technologies and advancements in the field of mass spectrometry over the past few years that have begun to provide insights into the molecular and cellular basis of CHD and prospects for these types of approaches in the future

Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation

Sex disparities in cardiac homeostasis and heart disease are well documented, with differences attributed to actions of sex hormones. However, studies have indicated sex chromosomes act outside of the gonads to function without mediation by gonadal hormones. Here, we performed transcriptional and proteomics profiling to define differences between male and female mouse hearts. We demonstrate, contrary to current dogma, cardiac sex disparities are controlled not only by sex hormones but also through a sex-chromosome mechanism. Using Turner syndrome (XO) and Klinefelter (XXY) models, we find the sex-chromosome pathway is established by X-linked gene dosage. We demonstrate cardiac sex disparities occur at the earliest stages of heart formation, a period before gonad formation. Using these datasets, we identify and define a role for alpha-1B-glycoprotein (A1BG), showing loss of A1BG leads to cardiac defects in females, but not males. These studies provide resources for studying sex-biased cardiac disease states

Serum magnesium and calcium levels in relation to ischemic stroke : Mendelian randomization study

ObjectiveTo determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.MethodsAnalyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).ResultsIn standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 7 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 7 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.ConclusionsThis study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype

Empirical support for radiographic review: A follow-up study of total hip arthroplasty

Routine post surgery surveillance of total hip arthroplasty (THA) is widely recommended to identify asymptomatic failure but inclusion of an x-ray adds to service costs. Evidence is needed to support orthopaedic opinion in order to identify what should be included in surveillance. An investigation was conducted to establish whether an x-ray is needed in addition to patient reported outcome measures. One hundred and fifty-four THA had been assessed at 3 years and were reviewed again at 6 to 9 years (mid-term) when radiographic signs of deterioration commonly appear. Data were explored for associations between radiographic changes and changes in the participants' Oxford Hip Score, age, EuroQol 5-D score or comorbidities. Hierarchical multiple regression analysis showed that the number of radiographic changes could not be predicted by any of the other variables. This supports the inclusion of an x-ray in THA surveillance and suggests that the state of the THA cannot be determined by the use of patient reported outcome measures alone. This has implications for future arthroplasty surveillance. © 2012 Wichtig Editore - ISSN 1120-7000