Population genomics of cardiometabolic traits: design of the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium.

Substantial advances have been made in identifying common genetic variants influencing cardiometabolic traits and disease outcomes through genome wide association studies. Nevertheless, gaps in knowledge remain and new questions have arisen regarding the population relevance, mechanisms, and applications for healthcare. Using a new high-resolution custom single nucleotide polymorphism (SNP) array (Metabochip) incorporating dense coverage of genomic regions linked to cardiometabolic disease, the University College-London School-Edinburgh-Bristol (UCLEB) consortium of highly-phenotyped population-based prospective studies, aims to: (1) fine map functionally relevant SNPs; (2) precisely estimate individual absolute and population attributable risks based on individual SNPs and their combination; (3) investigate mechanisms leading to altered risk factor profiles and CVD events; and (4) use Mendelian randomisation to undertake studies of the causal role in CVD of a range of cardiovascular biomarkers to inform public health policy and help develop new preventative therapies.

The impact of implementing a 24/7 open trauma bed protocol in the surgical intensive care unit on throughput and outcomes.

Background: Increased emergency department (ED) length of stay (LOS) has been associated with increased mortality in trauma patients. In 2010, we implemented a 24/7 open trauma bed protocol in our designated trauma intensive care units (TICUs) to facilitate rapid admission from the ED. This required maintenance of a daily bump list and timely transferring of patients out of the TICU.

Nicaraguan surgical and anesthesia infrastructure: survey of Ministry of Health hospitals.

Background: Developing countries have surgical and anesthesia needs that are unique and disparate compared to those of developed countries. However, the extent of these disparities and the specific country-based needs are, for the most part, unknown. The goal of this study was to assess the surgical capacity of Nicaragua's public hospitals as part of a multinational study.

Intestinal alkaline phosphatase prevents metabolic syndrome in mice.

Metabolic syndrome comprises a cluster of related disorders that includes obesity, glucose intolerance, insulin resistance, dyslipidemia, and fatty liver. Recently, gut-derived chronic endotoxemia has been identified as a primary mediator for triggering the low-grade inflammation responsible for the development of metabolic syndrome. In the present study we examined the role of the small intestinal brush-border enzyme, intestinal alkaline phosphatase (IAP), in preventing a high-fat-diet-induced metabolic syndrome in mice.

Peripheral blood natural killer (NK) cell function in healthy adults assessed using the target-induced NK loss (TINKL) assay.

In this technical note we provide data useful for the clinical application of the target-induced Natural Killer (NK) loss (TINKL) assay. The TINKL assay is a sensitive flow cytometry-based assay for measuring NK cell function. Loss of NK cells from the lymphocyte gate occurs following culture with K562 (the prototypic target cell for natural killing) and antibody-coated target cells (for antibody-dependent killing).

Target-induced natural killer cell loss as a measure of NK cell responses.

Natural killer (NK) cells are an important effector cell of innate immunity. Their interaction with susceptible target cells triggers NK cell cytotoxicity and the release of cytokines. Immunofluorescence flow cytometry-based assays are now the preferred methods for measuring NK cell responses.

Genome-wide association studies identify four ER negative-specific breast cancer risk loci.

Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS).

Genomic responses in mouse models poorly mimic human inflammatory diseases.

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another.

Development of a genomic metric that can be rapidly used to predict clinical outcome in severely injured trauma patients.

Objective: Many patients have complicated recoveries following severe trauma due to the development of organ injury. Physiological and anatomical prognosticators have had limited success in predicting clinical trajectories. We report on the development and retrospective validation of a simple genomic composite score that can be rapidly used to predict clinical outcomes.

Intestinal alkaline phosphatase inhibits the proinflammatory nucleotide uridine diphosphate.

Uridine diphosphate (UDP) is a proinflammatory nucleotide implicated in inflammatory bowel disease. Intestinal alkaline phosphatase (IAP) is a gut mucosal defense factor capable of inhibiting intestinal inflammation. We used the malachite green assay to show that IAP dephosphorylates UDP.

Prevalence and outcomes of antimicrobial treatment for Staphylococcus aureus bacteremia in outpatients with ESRD.

Staphylococcus bacteremia is a common and life-threatening medical emergency, but it is treatable with appropriate antibiotic therapy. To identify opportunities that may reduce morbidity and mortality associated with S. aureus, we analyzed data from 293,094 chronic hemodialysis outpatients to characterize practices of antibiotic selection.

Cerebrospinal fluid proteome of patients with acute Lyme disease.

During acute Lyme disease, bacteria can disseminate to the central nervous system (CNS), leading to the development of meningitis and other neurologic symptoms. Here we have analyzed pooled cerebrospinal fluid (CSF) allowing a deep view into the proteome for patients diagnosed with early disseminated Lyme disease and CSF inflammation. Additionally, we analyzed individual patient samples and quantified differences in protein abundance employing label-free quantitative mass spectrometry-based methods.

9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: evidence from the Breast Cancer Association Consortium.

Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).

Methods: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls).

Identification of hemopexin as an anti-inflammatory factor that inhibits synergy of hemoglobin with HMGB1 in sterile and infectious inflammation.

Hemoglobin is released from lysed RBCs in numerous clinical settings. High mobility group box 1 (HMGB1) is a nuclear and cytosolic DNA-binding protein released from injured cells that has been shown to play an important role in inducing inflammation. Because both of these endogenous molecules are frequently present in sites of necrosis and inflammation, we studied their interaction on the activation of macrophages.

Transfusion of stored autologous blood does not alter reactive hyperemia index in healthy volunteers.

Background: Transfusion of human blood stored for more than 2 weeks is associated with increased mortality and morbidity. During storage, packed erythrocytes progressively release hemoglobin, which avidly binds nitric oxide. We hypothesized that the nitric oxide mediated hyperemic response after ischemia would be reduced after transfusion of packed erythrocytes stored for 40 days.

Target-induced natural killer cell loss as a measure of NK cell responses.

Natural killer (NK) cells are an important effector cell of innate immunity. Their interaction with susceptible target cells triggers NK cell cytotoxicity and the release of cytokines. Immunofluorescence flow cytometry-based assays are now the preferred methods for measuring NK cell responses.

Benchmarking outcomes in the critically injured trauma patient and the effect of implementing standard operating procedures.

Objective: To determine and compare outcomes with accepted benchmarks in trauma care at 7 academic level I trauma centers in which patients were treated on the basis of a series of standard operating procedures (SOPs).

Background: Injury remains the leading cause of death for those younger than 45 years. This study describes the baseline patient characteristics and well-defined outcomes of persons hospitalized in the United States for severe blunt trauma.

Advancing the health and quality-of-life of girls and women after traumatic brain injury: workshop summary and recommendations.

Purpose: To disseminate findings from an international workshop regarding priority issues for girls' and women's health and quality-of-life after sustaining a traumatic brain injury (TBI).

Methods: A workshop was held prior to the American Congress of Rehabilitation Medicine Conference 2010. The purpose of the workshop was to highlight the unique health issues experienced by women after a TBI, to identify research, education and policy gaps and to develop strategies to promote women's health.

A genomic storm in critically injured humans.

Human survival from injury requires an appropriate inflammatory and immune response. We describe the circulating leukocyte transcriptome after severe trauma and burn injury, as well as in healthy subjects receiving low-dose bacterial endotoxin, and show that these severe stresses produce a global reprioritization affecting >80% of the cellular functions and pathways, a truly unexpected "genomic storm." In severe blunt trauma, the early leukocyte genomic response is consistent with simultaneously increased expression of genes involved in the systemic inflammatory, innate immune, and compensatory antiinflammatory responses, as well as in the suppression of genes involved in adaptive immunity.

Utility of cardiovascular magnetic resonance in identifying substrate for malignant ventricular arrhythmias.

Background: Sudden cardiac death (SCD) and sustained monomorphic ventricular tachycardia (SMVT) are frequently associated with prior or acute myocardial injury. Cardiovascular magnetic resonance (CMR) provides morphological, functional, and tissue characterization in a single setting. We sought to evaluate the diagnostic yield of CMR-based imaging versus non-CMR-based imaging in patients with resuscitated SCD or SMVT.

Myocardial ischemia activates an injurious innate immune signaling via cardiac heat shock protein 60 and Toll-like receptor 4.

Innate immune response after transient ischemia is the most common cause of myocardial inflammation and may contribute to injury, yet the detailed signaling mechanisms leading to such a response are not well understood. Herein we tested the hypothesis that myocardial ischemia activates interleukin receptor-associated kinase-1 (IRAK-1), a kinase critical for the innate immune signaling such as that of Toll-like receptors (TLRs), via a mechanism that involves heat shock proteins (HSPs) and TLRs. Coronary artery occlusion induced a rapid myocardial IRAK-1 activation within 30 min in wild-type (WT), TLR2(-/-), or Trif(-/-) mice, but not in TLR4(def) or MyD88(-/-) mice.

Target-induced natural killer cell loss as a measure of NK cell responses.

The interaction of natural killer cells with susceptible target cells triggers NK cell activation, eliciting not only NK cell cytotoxicity and cytokine secretion, but also NK cell death. This study shows that following target cell interaction there is a substantial loss of NK cells, the extent of which correlates with measures of NK cell cytotoxicity assessed by the target cell release of (51)Cr and by the externalisation of the lysosomal marker LAMP-1 (CD107a) which is assessed on the remaining NK cells. This is the case for the killing of K562 (natural killing) and the CD20 mAb (Rituximab)-mediated killing of RAJI cells and autologous B cells (antibody-dependent cell cytotoxicity).

Films, Buckypapers and Fibers from Clay, Chitosan and Carbon Nanotubes.

The mechanical and electrical characteristics of films, buckypapers and fiber materials from combinations of clay, carbon nanotubes (CNTs) and chitosan are described. The rheological time-dependent characteristics of clay are maintained in clay-carbon nanotube-chitosan composite dispersions. It is demonstrated that the addition of chitosan improves their mechanical characteristics, but decreases electrical conductivity by three-orders of magnitude compared to clay-CNT materials.