Integration of the Duke Activity Status Index into preoperative risk evaluation: a multicentre prospective cohort study.

BACKGROUND: The Duke Activity Status Index (DASI) questionnaire might help incorporate self-reported functional capacity into preoperative risk assessment. Nonetheless, prognostically important thresholds in DASI scores remain unclear. We conducted a nested cohort analysis of the Measurement of Exercise Tolerance before Surgery (METS) study to characterise the association of preoperative DASI scores with postoperative death or complications. METHODS: The analysis included 1546 participants (≥40 yr of age) at an elevated cardiac risk who had inpatient noncardiac surgery. The primary outcome was 30-day death or myocardial injury. The secondary outcomes were 30-day death or myocardial infarction, in-hospital moderate-to-severe complications, and 1 yr death or new disability. Multivariable logistic regression modelling was used to characterise the adjusted association of preoperative DASI scores with outcomes. RESULTS: The DASI score had non-linear associations with outcomes. Self-reported functional capacity better than a DASI score of 34 was associated with reduced odds of 30-day death or myocardial injury (odds ratio: 0.97 per 1 point increase above 34; 95% confidence interval [CI]: 0.96-0.99) and 1 yr death or new disability (odds ratio: 0.96 per 1 point increase above 34; 95% CI: 0.92-0.99). Self-reported functional capacity worse than a DASI score of 34 was associated with increased odds of 30-day death or myocardial infarction (odds ratio: 1.05 per 1 point decrease below 34; 95% CI: 1.00-1.09), and moderate-to-severe complications (odds ratio: 1.03 per 1 point decrease below 34; 95% CI: 1.01-1.05). CONCLUSIONS: A DASI score of 34 represents a threshold for identifying patients at risk for myocardial injury, myocardial infarction, moderate-to-severe complications, and new disability.

Molecular epidemiological analysis to assess the influence of pet-ownership in the biodiversity of Staphylococcus aureus and MRSA in dog- and non-dog-owning healthy households.

It has been suggested that zoonotic transmission of Staphylococcus aureus (SA) and methicillin-resistant S. aureus (MRSA) can occur between owners and their pets within the same household. However, the influence that pet-ownership could have in the biodiversity of SA/MRSA strains circulating among owners is not fully understood. The objective of this study was to perform a molecular epidemiological analysis to evaluate and compare the biodiversity of SA/MRSA strains in dog-owning and non-dog-owning healthy households within the same community. Antimicrobial resistance, SCCmec type, USA type and clonality were assessed. Overall, 33·1% (165/499) of human subjects carried SA and 2·8% (14/499) carried MRSA. Among dogs, 7·1% (8/113) carried SA but none were MRSA positive. No difference was detected in the diversity index of SA/MRSA pulsotypes between dog-owning and non-dog-owning households; but, a marked variation was still observed in the pulsotypes circulating in each type of household. Additionally, simultaneous carriage of the same SA pulsotype in owner(s) and dog was observed in 57% of households with positive humans and pets. These results demonstrate that dogs can indeed participate in the circulation of SA/MRSA pulsotypes within a home and that the presence of a pet does not seem to favour certain strains within their household.

Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication.

Advances in genome technology have facilitated a new understanding of the historical and genetic processes crucial to rapid phenotypic evolution under domestication. To understand the process of dog diversification better, we conducted an extensive genome-wide survey of more than 48,000 single nucleotide polymorphisms in dogs and their wild progenitor, the grey wolf. Here we show that dog breeds share a higher proportion of multi-locus haplotypes unique to grey wolves from the Middle East, indicating that they are a dominant source of genetic diversity for dogs rather than wolves from east Asia, as suggested by mitochondrial DNA sequence data. Furthermore, we find a surprising correspondence between genetic and phenotypic/functional breed groupings but there are exceptions that suggest phenotypic diversification depended in part on the repeated crossing of individuals with novel phenotypes. Our results show that Middle Eastern wolves were a critical source of genome diversity, although interbreeding with local wolf populations clearly occurred elsewhere in the early history of specific lineages. More recently, the evolution of modern dog breeds seems to have been an iterative process that drew on a limited genetic toolkit to create remarkable phenotypic diversity.

A genome-wide perspective on the evolutionary history of enigmatic wolf-like canids.

High-throughput genotyping technologies developed for model species can potentially increase the resolution of demographic history and ancestry in wild relatives. We use a SNP genotyping microarray developed for the domestic dog to assay variation in over 48K loci in wolf-like species worldwide. Despite the high mobility of these large carnivores, we find distinct hierarchical population units within gray wolves and coyotes that correspond with geographic and ecologic differences among populations. Further, we test controversial theories about the ancestry of the Great Lakes wolf and red wolf using an analysis of haplotype blocks across all 38 canid autosomes. We find that these enigmatic canids are highly admixed varieties derived from gray wolves and coyotes, respectively. This divergent genomic history suggests that they do not have a shared recent ancestry as proposed by previous researchers. Interspecific hybridization, as well as the process of evolutionary divergence, may be responsible for the observed phenotypic distinction of both forms. Such admixture complicates decisions regarding endangered species restoration and protection.

Identification of recent hybridization between gray wolves and domesticated dogs by SNP genotyping.

The ability to detect recent hybridization between dogs and wolves is important for conservation and legal actions, which often require accurate and rapid resolution of ancestry. The availability of a genetic test for dog-wolf hybrids would greatly support federal and legal enforcement efforts, particularly when the individual in question lacks prior ancestry information. We have developed a panel of 100 unlinked ancestry-informative SNP markers that can detect mixed ancestry within up to four generations of dog-wolf hybridization based on simulations of seven genealogical classes constructed following the rules of Mendelian inheritance. We establish 95 % confidence regions around the spatial clustering of each genealogical class using a tertiary plot of allele dosage and heterozygosity. The first- and second-backcrossed-generation hybrids were the most distinct from parental populations, with >90 % correctly assigned to genealogical class. In this article we provide a tool kit with population-level statistical quantification that can detect recent dog-wolf hybridization using a panel of dog-wolf ancestry-informative SNPs with divergent allele frequency distributions.

Salivary uric acid across child development and associations with weight, height, and body mass index.

Introduction: Obesity during childhood is a serious and growing chronic disease with consequences for lifelong health. In an effort to advance research into the preclinical indicators of pediatric obesity, we examined longitudinal assessments of uric acid concentrations in saliva among a cohort of healthy children from age 6-months to 12-years (n's per assessment range from 294 to 727). Methods: Using data from a subsample of participants from the Family Life Project (an Environmental influences on Child Health Outcomes Program cohort), we: (1) characterized salivary uric acid (sUA) concentrations from infancy to early adolescence by sex and race; (2) assessed changes in sUA levels across development; and (3) evaluated associations between sUA concentrations and measures of child weight, height, and body mass index (BMI). Across four assessments conducted at 6-, 24-, 90-, and 154-months of age, 2,000 saliva samples were assayed for UA from 781 participants (217 participants had sUA data at all assessments). Results: There were no significant differences in sUA concentrations by sex at any assessment, and differences in sUA concentrations between White and non-White children varied by age. At the 90- and 154-month assessments, sUA concentrations were positively correlated with measures of child weight, height, and BMI (90-month: weight- ρ(610) = 0.13, p < 0.01; height- ρ(607) = 0.10, p < 0.05; BMI- ρ(604) = 0.13, p < 0.01; 154-month: weight- ρ(723) = 0.18, p < 0.0001; height- ρ(721) = 0.10, p < 0.01; BMI- ρ(721) = 0.17, p < 0.0001). Group based trajectory modeling identified two groups of children in our sample with distinct patterns of sUA developmental change. The majority (72%) of participants showed no significant changes in sUA across time ("Stable" group), while 28% showed increases in sUA across childhood with steep increases from the 90- to 154-month assessments ("Increasing" group). Children in the Increasing group exhibited higher sUA concentrations at all assessments (6-month: t(215) = -5.71, p < 0.001; 24-month: t(215) = -2.89, p < 0.01; 90-month: t(215) = -3.89, p < 0.001; 154-month: t(215) = -19.28, p < 0.001) and higher weight at the 24- and 90-month assessments (24-month: t(214) = -2.37, p < 0.05; 90-month: t(214) = -2.73, p < 0.01). Discussion: Our findings support the potential utility of sUA as a novel, minimally-invasive biomarker that may help advance understanding of the mechanisms underlying obesity as well as further surveillance and monitoring efforts for pediatric obesity on a large-scale.

Mechanism of self-tolerance of gamma/delta T cells in epithelial tissue.

The present study examined mechanisms of tolerance for T cell receptor gamma/delta (TCR-gamma/delta) cells. Using a transgenic (Tg) model, we demonstrate that although alloantigen (Ag)-specific TCR-gamma/delta cells are deleted in the thymus and spleen of Ag-bearing mice, intraepithelial lymphocytes (IELs) expressing normal levels of the Tg TCR were present. However, Tg+ IELs from Ag-bearing mice were unresponsive to activation. Furthermore, self-reactive Tg+ IELs decreased in number over time. Thus, in epithelial tissue, Tg TCR-gamma/delta cells are eliminated subsequent to and most likely as a result of the induction of clonal anergy.

Control of inflammation, cytokine expression, and germinal center formation by BCL-6.

The gene encoding the BCL-6 transcriptional repressor is frequently translocated and mutated in diffuse large cell lymphoma. Mice with a disrupted BCL-6 gene developed myocarditis and pulmonary vasculitis, had no germinal centers, and had increased expression of T helper cell type 2 cytokines. The BCL-6 DNA recognition motif resembled sites bound by the STAT (signal transducers and activators of transcription) transcription factors, which mediate cytokine signaling. BCL-6 could repress interleukin-4 (IL-4)-induced transcription when bound to a site recognized by the IL-4-responsive transcription factor Stat6. Thus, dysregulation of STAT-responsive genes may underlie the inflammatory disease in BCL-6-deficient mice and participate in lymphoid malignancies.

Requirement for positive selection of gamma delta receptor-bearing T cells.

The alpha beta and gamma delta T cell receptors for antigen (TCR) delineate distinct T cell populations. TCR alpha beta-bearing thymocytes must be positively selected by binding of the TCR to major histocompatibility complex (MHC) molecules on thymic epithelium. To examine the requirement for positive selection of TCR gamma delta T cells, mice bearing a class I MHC-specific gamma delta transgene (Tg) were crossed to mice with disrupted beta 2 microglobulin (beta 2M) genes. The Tg+beta 2M- (class I MHC-) offspring had Tg+ thymocytes that did not proliferate to antigen or Tg-specific monoclonal antibody and few peripheral Tg+ cells. This is evidence for positive selection within the gamma delta T cell subset.

Extended-Spectrum ß-lactam Resistance in the Enteric Flora of Patients at a Tertiary Care Medical Centre.

The dissemination of Enterobacteriaceae expressing resistance to extended-spectrum cephalosporins, which are therapeutically used in both human and veterinary medicine, is of critical concern. The normal commensal flora of food animals may serve as an important reservoir for the zoonotic food-borne transmission of Enterobacteriaceae harbouring ß-lactam resistance. We hypothesized that the predominant AmpC and ESBL genes reported in US livestock and fresh retail meat products, blaCMY-2 and blaCTX-M , would also be predominant in human enteric flora. We recovered enteric flora from a convenience sample of patients included in a large tertiary medical centre's Clostridium difficile surveillance programme to screen for and estimate the frequency of carriage of AmpC and ESBL resistance genes. In- and outpatient diarrhoeic submissions (n = 692) received for C. difficile testing at the medical centre's clinical diagnostic laboratory from July to December, 2013, were included. Aliquoted to a transport swab, each submission was inoculated to MacConkey broth with cefotaxime, incubated at 37°C and then inoculated to MacConkey agars supplemented with cefoxitin and cefepime to select for the AmpC and ESBL phenotypes, with blaCMY and blaCTX-M genotypes confirmed by PCR and sequencing. From the 692 diarrhoeic submissions, our selective culture yielded 184 isolates (26.6%) with reduced susceptibility to cefotaxime. Of these, 46 (6.7%) samples harboured commensal isolates carrying the AmpC blaCMY . Another 21 (3.0%) samples produced isolates harbouring the ESBL blaCTX-M : 19 carrying CTX-M-15 and 2 with CTX-M-27. Our results indicate that ß-lactam resistance genes likely acquired through zoonotic food-borne transmission are present in the enteric flora of this hospital-associated population at lower levels than reported in livestock and fresh food products.

Heart development and regeneration in urodeles.

Classical fate mapping and transplantation studies have yielded a rich embryological understanding of heart development in urodeles. Recent advances in understanding the molecular nature of many early developmental events can be applied to urodele heart development. In this review we examine urodele heart development from both morphological and molecular viewpoints. We focus primarily on cardiac induction, early cardiogenesis, and heart regeneration.

The location of the third cleavage plane of Xenopus embryos partitions morphogenetic information in animal quartets.

Analysis of the developmental potential of animal quartets (the set of four animal blastomeres isolated from the 8-cell stage Xenopus embryo) provided insight into the manner in which morphogenetic information is distributed along the animal-vegetal axis. Gravity treatments were employed to alter the partitioning plane. Animal quartets isolated from embryos exposed to simulated weightlessness had larger animal blastomeres, and they formed structures such as a groove and a protrusion more often than 1g-control animal quartets. Animal quartets with an unusual non-horizontal third cleavage plane were also found to have a higher frequency of protrusion formation than animal quartets with a typical horizontal cleavage plane. The increase in the frequency seen in simulated weightlessness animal quartets was not due to their increased size. Fusing two animal quartets isolated from hypergravity (3g) exposed embryos (small blastomeres and low incidence of protrusions) did not affect the frequency of protrusion formation. Molecular analyses revealed that a partial induction was associated with the protrusion formation. Transcripts of the dorsal lip specific homeobox gene, goosecoid, and alpha-cardiac actin were detectable by PCR amplification in the animal quartet with a protrusion, and alpha-cardiac actin mRNA was found by whole-mount in situ hybridization to be localized in the protrusion. Taken together, all these results are consistent with the notion that both animal and vegetal information is necessary for normal development and the partitioning of morphogenetic information into animal quartets results in gravity-dependent differential morphogenesis and gene regulation.

Continuous monitoring of arterial pressure indicates sinoaortic denervated rats are not hypertensive.

The mean arterial pressure (MAP) of nine sinoaortic denervated (SAD) and eight control rats housed in standard-sized metabolic cages was determined continuously via aortic cannulae and computerized data collection over 24 hours. These continuous measurements were compared with direct, mean aortic pressure measurements and indirect, tail-cuff systolic pressure determinations made while these rats were resting in a Lucite restrainer. Denervated rats were studied 1 month after debuffering. Both types of measurements made during restraint indicated that the SAD rats were hypertensive; the MAP averaged 145 +/- 3.4 mm Hg (mean +/- SEM) in SAD rats compared with 119 +/- 2.8 mm Hg in the control group (p less than 0.001), and the tail-cuff pressure in SAD rats was 156 +/- 5.4 vs 121 +/- 2.7 mm Hg in control rats (p less than 0.001). In contrast, continuous monitoring showed that the SAD rats were normotensive; the MAP averaged 119 +/- 4.7 mm Hg in the SAD group and 119 +/- 3.1 mm Hg in the control group. Denervation increased pressure lability; the average 24-hour standard deviation of MAP was 19.0 +/- 1.2 mm Hg in SAD rats vs 8.0 +/- 0.7 mm Hg in control rats (p less than 0.001). Apparently, arterial pressure is elevated during restraint in SAD rats because buffering by the baroreceptor reflex is absent, and pressure measurements made under these conditions give a false indication of hypertension.

Control of self-reactivity in the intestine.

In the intestine maintenance of self-tolerance may involve tissue-specific self-Ags, APCs, 'second signals', and extrathymic pathways of T cell maturation. These factors combine to create a unique environment where autoimmune tissue destruction is prevented despite local inflammatory influences. In this review we summarize our findings using a TCR-gamma delta transgenic model where self-tolerance was maintained by clonal deletion for cells localizing to peripheral lymphoid tissue and by clonal anergy for cells localizing to the intraepithelial compartments. Several possible explanations exist for these results but in general, these findings have implications for the maintenance of self-tolerance of normal TCR-alpha beta and TCR-gamma delta IELs in epithelial tissues such as the intestine.

Regulation of lymphocyte cell fate decisions and lymphomagenesis by BCL-6.

Genetic alterations of the BCL-6 gene in mice and man have established BCL-6 as a pivotal regulator of normal differentiation of B and T lymphocytes as well as one of the most frequently translocated oncogenes in human B cell lymphomas. As an oncogene, BCL-6 has not been easy to place into existing paradigms of cellular transformation. Rather, it is likely that the function of BCL-6 as a regulator of lymphocyte differentiation is subverted in BCL-6-induced lymphomas. The lymphomas in which BCL-6 is translocated are all suspected to arise from the germinal center B lymphocyte. Given the selective expression of BCL-6 protein in normal germinal center B lymphocytes and the requirement for BCL-6 in germinal center development, the functions of BCL-6 in normal and malignant B cells are probably intertwined. The BCL-6 protein is a potent transcriptional repressor which presumably controls lymphocyte differentiation and induces lymphomas by regulating the expression of key downstream target genes.

Screening for memory problems in multiple sclerosis.

OBJECTIVES: To assess the Brief, Repeatable Battery of Neuropsychological Tests (BRB-N) as a screening measure for memory problems in people with multiple sclerosis (MS). DESIGN: Sensitivity and specificity values were calculated and Receiver Operating Characteristic (ROC) curves plotted. METHODS: Patients were recruited from the regional MS Management Clinic. The BRB-N and WMS-R were administered. RESULTS: Using the Symbol Digit Modalities Test (SDMT) and 10/36 Spatial Recall Test (10/36 SRT) Total Immediate recall, the BRB-N had a sensitivity of 93% and specificity of 48%. CONCLUSION: The BRB-N is sensitive at detecting memory impairments, although its specificity is low.

Gastroscopy in a West African rural mission hospital.

The results of 1075 fibreoptic gastroscopies performed in the Northwest Province of Cameroon are presented. Three hundred and fifty-three examinations showed pyloroduodenal ulcer disease, 111 showed macroscopic gastritis, and 37 had gastric carcinoma. Sixteen other diagnosis were made, with a positive finding in 620 cases. The benefits of the 'high-technology' gastroscope in a low technology setting are discussed. Included are examinations of a series of 46 patients with haematemesis and/or melaena, and 43 who had previous gastric surgery.

Structural origin of light emission in germanium quantum dots.

We used a combination of optically-detected x-ray absorption spectroscopy with molecular dynamics simulations to explore the origins of light emission in small (5 nm to 9 nm) Ge nanoparticles. Two sets of nanoparticles were studied, with oxygen and hydrogen terminated surfaces. We show that optically-detected x-ray absorption spectroscopy shows sufficient sensitivity to reveal the different origins of light emission in these two sets of samples. We found that in oxygen terminated nanoparticles its the oxide-rich regions that are responsible for the light emission. In hydrogen terminated nanoparticles we established that structurally disordered Ge regions contribute to the luminescence. Using a combination of molecular dynamics simulations and optically-detected x-ray absorption spectroscopy we show that these disordered regions correspond to the disordered layer a few Šthick at the surface of the simulated nanoparticle.

Use of biogenic and abiotic elemental selenium nanospheres to sequester elemental mercury released from mercury contaminated museum specimens.

Mercuric chloride solutions have historically been used as pesticides to prevent bacterial, fungal and insect degradation of herbarium specimens. The University of Manchester museum herbarium contains over a million specimens from numerous collections, many preserved using HgCl(2) and its transformation to Hg(v)(0) represents a health risk to herbarium staff. Elevated mercury concentrations in work areas (∼ 1.7 µg m(-3)) are below advised safe levels (<25 µg m(-3)) but up to 90 µg m(-3) mercury vapour was measured in specimen boxes, representing a risk when accessing the samples. Mercury vapour release correlated strongly with temperature. Mercury salts were observed on botanical specimens at concentrations up to 2.85 wt% (bulk); XPS, SEM-EDS and XANES suggest the presence of residual HgCl(2) as well as cubic HgS and HgO. Bacterially derived, amorphous nanospheres of elemental selenium effectively sequestered the mercury vapour in the specimen boxes (up to 19 wt%), and analysis demonstrated that the Hg(v)(0) was oxidised by the selenium to form stable HgSe on the surface of the nanospheres. Biogenic Se(0) can be used to reduce Hg(v)(0) in long term, slow release environments.