G-Proteins in N.I.D.D.M. and Hypertension

G-proteins are guanine-nucleotide-binding regulatory proteins which couple receptors to effector mechanisms; G-protein associated 'second messengers' include cAMP and the phospho-inositides, while other G-proteins are coupled to calcium and potassium channels. The expanding G-protein family (all of which share a common trimeric structure) currently includes at least 12 distinct G-proteins some of which can be identified in plasma membranes using specific antibodies (Western immuno-blotting): antibodies are available against several a subunits (Gsa, Gia1, Gia2, Gia3 and Goa)(which possess receptor and effector binding sites) as well as against B subunits. Function has not yet been ascribed to all G-proteins, but Gsa and Gia2 are concerned with the dual regulation (respectively stimulating and inhibiting) of adenylyl cyclase (AC) catalytic unit activity (A)

Reduced mortality and subsequent fracture risk associated with oral bisphosphonate recommendation in a fracture liaison service setting: A prospective cohort study

Objective: Osteoporotic fragility fractures, that are common in men and women, signal increased risk of future fractures and of premature mortality. Less than one-third of postmenopausal women and fewer men are prescribed active treatments to reduce fracture risk. Therefore, in this study the association of oral bisphosphonate recommendation with subsequent fracture and mortality over eight years in a fracture liaison service setting was analysed. Materials and methods: In this prospective cohort study, 5011 men and women aged \u3e50 years, who sustained a clinical fracture, accepted the invitation to attend the fracture liaison service of the West Glasgow health service between 1999 and 2007. These patients were fully assessed and all were recommended calcium and vitamin D. Based on pre-defined fracture risk criteria, 2534 (50.7%) patients were additionally also recommended oral bisphosphonates. Mortality and subsequent fracture risk were the pre-defined outcomes analysed using Cox proportional hazard models. Results: Those recommended bisphosphonates were more often female (82.9 vs. 72.4%), were older (73.4 vs. 64.4 years), had lower bone mineral density T-score (-3.1 vs. -1.5) and more had sustained hip fractures (21.7 vs. 6.2%; p \u3c 0.001). After adjustments, patients recommended bisphosphonates had lower subsequent fracture risk (Hazard Ratio (HR): 0.60; 95% confidence interval (CI): 0.49±0.73) and lower mortality risk (HR: 0.79, 95%CI: 0.64±0.97). Conclusion: Of the patients, who are fully assessed after a fracture at the fracture liaison service, those with higher fracture risk and a recommendation for bisphosphonates had worse baseline characteristics. However, after adjusting for these differences, those recommended bisphosphonate treatment had a substantially lower risk for subsequent fragility fracture and lower risk for mortality. These community-based data indicate the adverse public health outcomes and mortality impacts of the current low treatment levels post fracture could be improved by bisphosphonate recommendation for both subsequent fracture and mortality

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Co-developing end-of-life resources: an equal and reciprocal relationship

Involving people with dementia (PwD) in the development of new resources to help support their care at end-of-life requires a sensitive approach recognizing not only disability but also empowering and supporting capability. Some models of patient and public involvement (PPI) identify a spectrum of participation modes (e.g. Arnstein, 1969; Savory, 2010). Indeed there has been a discernable shift in PPI thinking from ‘doing to’, through ‘doing for’ to ‘doing with’ patients, i.e., from ‘coercion’ to ‘co-production’ (The New Economics Foundation, 2014). However, a recent review of PPI models currently being deployed concluded these were still too narrow, indeed often tokenistic, not acknowledging equality and diversity issues (Ocloo & Matthews, 2016). In the SEED study, concerned with the development of an intervention to increase the chances of a good death for PwD (SEED), designers joined the more traditional dementia, palliative and nursing care specialisms in the research team. The designers introduced methods and tools to involve all the key stakeholders (i.e., the PwD, family carers, the healthcare team and nurse specialists) in the design of new resources concerned with facilitating discussion and improving shared decision-making around key end-of-life plans. Specifically, through the nature and design of the workshops and use of participative tools these approaches were intended to better empower PwD and their family carers in this co-development process, to help open up their agendas in this very sensitive area. This presentation highlights key findings arising from this co-development process which enabled the PwD and family carers to voice their particular issues. Rather than outcomes being determined through a top-down ‘consultation’ model, the authors debate the value of a ground-up ‘collaborative’ model where new resources can be developed in a more equal and reciprocal partnership with PwD and their family carers

Co-designing new resources to support better quality end of life care with people with dementia and family carers

As more people die with dementia, end of life care discussions are growing in importance. Alastair Macdonald and colleagues report on their study and explain how co-designing new resources could help to strengthen support at the end of lifeinfo:eu-repo/semantics/publishedVersio

Co-designing new resources to support better quality end of life care with people with dementia and family carers

Involving people with dementia (PwD) in the development of new resources to help support their care at end-of-life requires a sensitive approach recognizing not only disability but also empowering and supporting capability. Some models of patient and public involvement (PPI) identify a spectrum of participation modes (e.g. Arnstein, 1969; Savory, 2010). Indeed there has been a discernable shift in PPI thinking from ‘doing to’, through ‘doing for’ to ‘doing with’ patients, i.e., from ‘coercion’ to ‘co-production’ (The New Economics Foundation, 2014). However, a recent review of PPI models currently being deployed concluded these were still too narrow, indeed often tokenistic, not acknowledging equality and diversity issues (Ocloo & Matthews, 2016). In the SEED study, concerned with the development of an intervention to increase the chances of a good death for PwD (SEED), designers joined the more traditional dementia, palliative and nursing care specialisms in the research team. The designers introduced methods and tools to involve all the key stakeholders (i.e., the PwD, family carers, the healthcare team and nurse specialists) in the design of new resources concerned with facilitating discussion and improving shared decision-making around key end-of-life plans. Specifically, through the nature and design of the workshops and use of participative tools these approaches were intended to better empower PwD and their family carers in this co-development process, to help open up their agendas in this very sensitive area. This presentation highlights key findings arising from this co-development process which enabled the PwD and family carers to voice their particular issues. Rather than outcomes being determined through a top-down ‘consultation’ model, the authors debate the value of a ground-up ‘collaborative’ model where new resources can be developed in a more equal and reciprocal partnership with PwD and their family carers

Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study

Osteoporosis is a common disease with a strong genetic component, characterized by reduced bone mass and an increased risk of fracture. Bone mineral density (BMD) is a highly heritable trait and a key determinant of osteoporotic fracture risk, but the genes responsible are incompletely defined. Here, we identified quantitative trait loci (QTL) for regulation of BMD by a genome wide scan involving 3691 individuals from 715 families, who were selected because of reduced BMD values at the lumbar spine (LS-BMD) or femoral neck (FN-BMD) in probands. Linkage analysis was conducted in the study group as a whole with correction for age, gender, weight and height. Further analyses were conducted for men and women separately to identify gender-specific QTL and for those under and over the age of 50 years to distinguish QTL for peak bone mass from those that influence bone mass in older people. No regions of suggestive or significant linkage were identified when data from all subjects were analyzed together. On subgroup analysis, however, we identified a significant QTL for FN-BMD on chromosome 10q21 (LOD score +4.42; men 50 years) and two suggestive QTL for LS-BMD on chromosomes 18p11 (LOD score +2.83; women &gt;50 years) and 20q13 (LOD score +3.20; women 50 years). We identified five other QTL for BMD with LOD scores of greater than +2.20 on chromosomes 3q25, 4q25, 7p14, 16p13 and 16q23. This study provides evidence for gender-specific, site-specific and age-specific QTL, which regulate BMD in humans, and illustrates the importance of conducting subgroup analysis to detect these loci

Survival curves for subsequent fractures and mortality.

<p>The curves are based on multivariable Cox proportional hazard models for subsequent fractures and mortality expressed as (A) fracture-free probability and (B) cumulative survival. Results presented for vitamin D and calcium recommendation alone (dotted black) and for bisphosphonates plus calcium and vitamin D recommendation (solid grey).</p