Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases

Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs () across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of  from imputed SNPs (5.1× enrichment; p = 3.7 × 10⁻¹⁷) and 38% (SE = 4%) of  from genotyped SNPs (1.6× enrichment, p = 1.0 × 10⁻⁴). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of  despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease.

Challenges in secondary prevention of cardiovascular diseases: A review of the current practice

With the changing demography of populations and increasing prevalence of co-morbidity, frail patients and more complex cardiac conditions, the modern medicine is facing novel challenges leading to rapid innovation where evidence and experiences are lacking. This scenario is also evident in cardiovascular disease prevention, which continuously needs to accommodate its ever changing strategies, settings, and goals. The present paper summarises actual challenges of secondary prevention, and discusses how this intervention should not only be effective but also efficient. By this way the paper tries to bridge the gaps between research and real-world findings and thereby may find ways to improve standard care.

The Role of Peptidyl Prolyl Isomerases in Aging and Vascular Diseases

Peptidyl prolyl isomerases (PPIases) are proteins belonging to the immunophilin family and are characterised by their cis-trans isomerization activity at the X-Pro peptide bond, in addition to their tetratricopeptide repeat (TPR) domain, important for interaction with the molecular chaperone, Hsp90. Due to this unique structure these proteins are able to facilitate protein-protein interactions which can impact significantly on a range of cellular processes such as cell signalling, differentiation, cell cycle progression, metabolic activity and apoptosis. Malfunction and/or dysregulation of most members of this class of proteins promotes cellular damage and tissue/organ failure, predisposing to ageing and age-related diseases. Many individual genes within the PPIase family are associated with several age-related diseases including cardiovascular diseases (CVDs), atherosclerosis, type II diabetes (T2D), chronic kidney disease (CDK), neurodegeneration, cancer and age-related macular degeneration (AMD), in addition to the ageing process itself. This review will focus on the different roles of PPIases, and their therapeutic/biomarker potential in these age-related vascular diseases.

Appointment keeping for medical review among patients with selected chronic diseases in an urban area of Uganda

Introduction: proper management of chronic diseases is important for prevention of disease complications and yet some patients miss appointments for medical review thereby missing the opportunity for proper monitoring of their disease conditions. There is limited information on missed appointments among chronic disease patients in resource limited settings. This study aimed to determine the prevalence of missed appointments for medical review and associated factors among chronic disease patients in an urban area of Uganda.

Methods: patients or caregivers of children with chronic diseases were identified as they bought medicines from a community pharmacy. They were visited at home to access their medical documents and those whose chronic disease status was ascertained were enrolled. The data was collected using: questionnaires, review of medical documents, and in-depth interviews with chronic disease patients.

Results: the prevalence of missed appointments was 42% (95%CI=35-49%). The factors associated with missed appointments were: monthly income ?30US Dollars (OR=2.56, CI=1.25–5.26), affording less than half of prescribed drugs (OR=3.92, CI=1.64–9.40), not experiencing adverse events (OR=2.66, CI=1.26–5.61), not sure if treatment helps (OR=2.84, CI=1.047.77), not having a medicines administration schedule (OR=6.77, CI=2.11–21.68), and increasing number of drugs (OR=0.72, CI=0.53–0.98). Conclusion: patients missed appointments mainly due to: financial and health system barriers, conflicting commitments with appointments, and perceptions of the disease condition. Patients should be supported with accessible and affordable health services.

Measurement method and apparatus for analysing the metal or metal ion conten of a sample

2. K. Gow, P.K.J Robertson, P.M. Pollard, and K. Christidis

Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative

BACKGROUND: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research.

SETTINGS: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed.

RESULTS: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design.

INTERPRETATION: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.

Ultrastructure of head organs (anterior adhesive apparatus) and posterior secretory systems of Caballeria liewi Lim, 1995 (Monogenea, Ancyrocephalidae)

Caballeria liewi Lim, 1995, uses adhesive secretions from the head organs and posterior secretory systems to assist in locomotion and attachment. Ultrastructural investigations show that the head organs of C. liewi consist of three pairs of antero-lateral pit-like openings bearing microvilli and ducts leading from two types of uninucleated gland cells (located lateral to the pharynx), one type producing rod-like (S1) bodies with an electron-dense matrix containing less electron-dense vesicles and the second type producing oval (S2) bodies with a homogeneous electron-dense matrix. Interlinking band-like structures are observed between S1 bodies and between S2 bodies. S1 body is synthesised in the granular endoplasmic reticulum, transported to a Golgi complex to be packaged into vesicles and routed into ducts for exudation. The synthesis of the S2 body is unresolved. Haptoral secretions manifested externally as net-like structures are derived from dual electron-dense (DED) secretory body produced in the peduncular gland cells. The DED body consists of a less electron-dense oval core in a homogeneous electron-dense matrix. On exocytosis into the pyriform haptoral reservoir, DED bodies are transformed into a secretion with two types of inclusions (less electron-dense oval and electron-dense spherical inclusions) in an electron-dense matrix. The secretions are further transformed (as small, oval, electron-dense bodies) when transported to the superficial anchor grooves, and on exudation into the gill tissues, the secretions become an electron-dense matrix. Secretory bodies associated with uniciliated structures, anchor sleeves and marginal hooks are also observed.

Investigation of organic xenobiotic transfers, partitioning and processing in air-soil-plant systems using a microcosm apparatus. Part I:Microcosm development

A microcosm system was developed to investigate transfers of organic xenobiotics in air-soil-plant systems. This was validated using ¹⁴C labelled 1,2-dichlorobenzene (DCB) as a model compound. Trapping efficiency was 106 ± 3% for volatile compounds and 93.0 ± 2.2% for carbon dioxide in a blank microcosm arrangement. Recovery of 1,2-dichlorobenzene spiked to grassed and unplanted soils was > 90% after 1 week. The predominant DCB loss process was volatilisation with no evidence for mineralisation over 1 week and 20-30% of the added spike remained in soil. Although there was no evidence for root uptake and translocation of added label, foliar uptake of soil volatilised compound was detected. The microcosm showed good potential for study of ¹⁴C labelled and unlabelled organic xenobiotic transfers in air-soil-plant systems with single plants and also intact planted cores.

The macroeconomic impact of non-communicable diseases in China and India: Estimates, projections, and comparisons

This study provides estimates of the macroeconomic impact of non-communicable diseases (NCDs) inChina and India for the period 2012–2030. Our estimates are derived using the World Health Organization’sEPIC model of economic growth, which focuses on the negative effects of NCDs on labor supply andcapital accumulation. We present results for the five main NCDs (cardiovascular disease, cancer, chronicrespiratory disease, diabetes, and mental health). Our undiscounted estimates indicate that the cost ofthe five main NCDs will total USD 23.03 trillion for China and USD 4.58 trillion for India (in 2010 USD).For both countries, the most costly domain is cardiovascular disease. Our analyses also reveal that thecosts are much larger in China than in India mainly because of China’s higher and steeper income trajectory,and to a lesser extent its older population. Rough calculations also indicate that WHO’s best buys foraddressing the challenge of NCDs are highly cost-beneficial