Question: In young and middle-aged adults, current or remote uses of ADHD medications increase the risk of serious cardiovascular events.

ADHD medications and risk of serious cardiovascular events in young and middle-aged adults.
CONTEXT More than 1.5 million US adults use stimulants and other medications labeled for treatment of attention-deficit/hyperactivity disorder (ADHD). These agents can increase heart rate and blood pressure, raising concerns about their cardiovascular safety. OBJECTIVE To examine whether current use of medications prescribed primarily to treat ADHD is associated with increased risk of serious cardiovascular events in young and middle-aged adults. DESIGN, SETTING, AND PARTICIPANTS Retrospective, population-based cohort study using electronic health care records from 4 study sites (OptumInsight Epidemiology, Tennessee Medicaid, Kaiser Permanente California, and the HMO Research Network), starting in 1986 at 1 site and ending in 2005 at all sites, with additional covariate assessment using 2007 survey data. Participants were adults aged 25 through 64 years with dispensed prescriptions for methylphenidate, amphetamine, or atomoxetine at baseline. Each medication user (n = 150,359) was matched to 2 nonusers on study site, birth year, sex, and calendar year (443,198 total users and nonusers). MAIN OUTCOME MEASURES Serious cardiovascular events, including myocardial infarction (MI), sudden cardiac death (SCD), or stroke, with comparison between current or new users and remote users to account for potential healthy-user bias. RESULTS During 806,182 person-years of follow-up (median, 1.3 years per person), 1357 cases of MI, 296 cases of SCD, and 575 cases of stroke occurred. There were 107,322 person-years of current use (median, 0.33 years), with a crude incidence per 1000 person-years of 1.34 (95% CI, 1.14-1.57) for MI, 0.30 (95% CI, 0.20-0.42) for SCD, and 0.56 (95% CI, 0.43-0.72) for stroke. The multivariable-adjusted rate ratio (RR) of serious cardiovascular events for current use vs nonuse of ADHD medications was 0.83 (95% CI, 0.72-0.96). Among new users of ADHD medications, the adjusted RR was 0.77 (95% CI, 0.63-0.94). The adjusted RR for current use vs remote use was 1.03 (95% CI, 0.86-1.24); for new use vs remote use, the adjusted RR was 1.02 (95% CI, 0.82-1.28); the upper limit of 1.28 corresponds to an additional 0.19 events per 1000 person-years at ages 25-44 years and 0.77 events per 1000 person-years at ages 45-64 years. CONCLUSIONS Among young and middle-aged adults, current or new use of ADHD medications, compared with nonuse or remote use, was not associated with an increased risk of serious cardiovascular events. Apparent protective associations likely represent healthy-user bias.

Anti-obesity drugs: past, present and future
The ideal anti-obesity drug would produce sustained weight loss with minimal side effects. The mechanisms that regulate energy balance have substantial built-in redundancy, overlap considerably with other physiological functions, and are influenced by social, hedonic and psychological factors that limit the effectiveness of pharmacological interventions. It is therefore unsurprising that anti-obesity drug discovery programmes have been littered with false starts, failures in clinical development, and withdrawals due to adverse effects that were not fully appreciated at the time of launch. Drugs that target pathways in metabolic tissues, such as adipocytes, liver and skeletal muscle, have shown potential in preclinical studies but none has yet reached clinical development. Recent improvements in the understanding of peptidergic signalling of hunger and satiety from the gastrointestinal tract mediated by ghrelin, cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), and of homeostatic mechanisms related to leptin and its upstream pathways in the hypothalamus, have opened up new possibilities. Although some have now reached clinical development, it is uncertain whether they will meet the strict regulatory hurdles required for licensing of an anti-obesity drug. However, GLP-1 receptor agonists have already succeeded in diabetes treatment and, owing to their attractive body-weight-lowering effects in humans, will perhaps also pave the way for other anti-obesity agents. To succeed in developing drugs that control body weight to the extent seen following surgical intervention, it seems obvious that a new paradigm is needed. In other therapeutic arenas, such as diabetes and hypertension, lower doses of multiple agents targeting different pathways often yield better results than strategies that modify one pathway alone. Some combination approaches using peptides and small molecules have now reached clinical trials, although recent regulatory experience suggests that large challenges lie ahead. In future, this polytherapeutic strategy could possibly rival surgery in terms of efficacy, safety and sustainability of weight loss.

Inhibition of mammalian target of rapamycin potentiates thrombin-induced intercellular adhesion molecule-1 expression by accelerating and stabilizing NF-kappa B activation in endothelial cells.
We addressed the regulatory function of mammalian target of rapamycin (mTOR) in the mechanism of thrombin-induced ICAM-1 gene expression in endothelial cells. Pretreatment of HUVECs with rapamycin, an inhibitor of mTOR, augmented thrombin-induced ICAM-1 expression. Inhibition of mTOR by this approach promoted whereas over-expression of mTOR inhibited thrombin-induced transcriptional activity of NF-kappaB, an essential regulator of ICAM-1 transcription. Analysis of the NF-kappaB signaling pathway revealed that inhibition of mTOR potentiated IkappaB kinase activation resulting in a rapid and persistent phosphorylation of IkappaBalpha on Ser32 and Ser36, a requirement for IkappaBalpha degradation. Consistent with these data, we observed a more efficient and stable nuclear localization of RelA/p65 and, subsequently, the DNA binding activity of NF-kappaB by thrombin following mTOR inhibition. These data define a novel role of mTOR in down-regulating thrombin-induced ICAM-1 expression in endothelial cells by controlling a delayed and transient activation of NF-kappaB.

At the gates of death.
Apoptosis that proceeds via the mitochondrial pathway involves mitochondrial outer membrane permeabilization (MOMP), responsible for the release of cytochrome c and other proteins of the mitochondrial intermembrane space. This essential step is controlled and mediated by proteins of the Bcl-2 family. The proapoptotic proteins Bax and Bak are required for MOMP, while the antiapoptotic Bcl-2 proteins, including Bcl-2, Bcl-xL, Mcl-1, and others, prevent MOMP. Different proapoptotic BH3-only proteins act to interfere with the function of the antiapoptotic Bcl-2 members and/or activate Bax and Bak. Here, we discuss an emerging view, proposed by Certo et al. in this issue of Cancer Cell, on how these interactions result in MOMP and apoptosis.

Large-Scale Profiling Reveals the Influence of Genetic Variation on Gene Expression in Human Induced Pluripotent Stem Cells.
In this study, we used whole-genome sequencing and gene expression profiling of 215 human induced pluripotent stem cell (iPSC) lines from different donors to identify genetic variants associated with RNA expression for 5,746 genes. We were able to predict causal variants for these expression quantitative trait loci (eQTLs) that disrupt transcription factor binding and validated a subset of them experimentally. We also identified copy-number variant (CNV) eQTLs, including some that appear to affect gene expression by altering the copy number of intergenic regulatory regions. In addition, we were able to identify effects on gene expression of rare genic CNVs and regulatory single-nucleotide variants and found that reactivation of gene expression on the X chromosome depends on gene chromosomal position. Our work highlights the value of iPSCs for genetic association analyses and provides a unique resource for investigating the genetic regulation of gene expression in pluripotent cells.

To err is human. Building a safer health system
Human beings, make errors Healthcare Services is a complex industry prone to accidents. The IOM Report [1] points out that some systems are more prone to accidents than others. When a system fails there are often multiple faults. In healthcare,human errors are the greatest contributors to accidents,however when human error is to blame it often depends upon failures within the system. These failures exists in the system before the error occurs, the same as with latent errors which are difficult to identify since they may be hidden in computers or within the various managerial layers. Most of the errors can be prevented by designing systems that make it hard for people to do the wrong thing and easy for people to do the right thing. In healthcare, this means designing processes that are able to ensure that patients are safe from accidental injury. As healthcare and the system that delivers it become more complex, the opportunities for errors abound. The IOM report “To Err is Human” proposes an approach for reducing medical errors and improving patient safety. The environment within which this occurs has a critical influence on quality. This influence may contain two dimensions; the first consists of the domain of quality which includes the practice that is consistent with current medical knowledge. The second dimension consists of forces in the external environment that can drive quality improvement in the delivery system. Although the risk of dying as a result of a medical error, far surpasses the risk of dying in an airline accident, public attention has been more focused on improving safety in the airline industry than in healthcare systems. Because of the absence of standardized nomenclature, it is important to define what an error is and what is an adverse event, the IOM Report defines them in the following way: “An error is the failure of a planned action to be completed as intended or the use of a wrong plan to achieve an aim. ” An adverse event is an injury caused by medical management rather than the underlying condition of the patient. An adverse event attributable to error is a “preventable adverse event”.

The role of regulatory variation in complex traits and disease
We are in a phase of unprecedented progress in identifying genetic loci that cause variation in traits ranging from growth and fitness in simple organisms to disease in humans. However, a mechanistic understanding of how these loci influence traits is lacking for the majority of loci. Studies of the genetics of gene expression have emerged as a key tool for linking DNA sequence variation to phenotypes. Here, we review recent insights into the molecular nature of regulatory variants and describe their influence on the transcriptome and the proteome. We discuss conceptual advances from studies in model organisms and present examples of complete chains of causality that link individual polymorphisms to changes in gene expression, which in turn result in physiological changes and, ultimately, disease risk.

Thrombocytopenia as an Indicator of Malaria in Adult Population
Objectives. To evaluate the predictive value of thrombocytopenia in malaria. Patients and Methods. It was a prospective observational study on all febrile patients with thrombocytopenia presenting to the Medical Unit of Hayat Abad Medical Complex during November 2008 to November 2010. Results. Of the total of 228 patients with fever and thrombocytopenia, 121 patients (53%) proved to be suffering from malaria. Of them 82 patients (68%) had falciparum malaria while 39 patients (32%) had vivax infection. Of these 121 patients, platelet counts ranged between 25,000 and 150,000/dL with a mean value of 101,000/dL (SD ± 47, 500) and a median of 75,000/dL. Of the 107 patients who were not suffering from malaria, the counts ranged between 10,000 and 150,000/dL with a mean value of 58,000/dL (SD ± 54, 000) and median of 50,000/dL. Conclusions. The presence of thrombocytopenia may be a predictor of malaria in adult population.

Margination of white blood cells in microcapillary flow.
Margination of white blood cells (WBCs) towards vessel walls is an essential precondition for their efficient adhesion to the vascular endothelium. We perform numerical simulations with a two-dimensional blood flow model to investigate the dependence of WBC margination on hydrodynamic interactions of blood cells with the vessel walls, as well as on their collective behavior and deformability. We find WBC margination to be optimal in intermediate ranges of red blood cell (RBC) volume fractions and flow rates, while, beyond these ranges, it is substantially attenuated. RBC aggregation enhances WBC margination, while WBC deformability reduces it. These results are combined in state diagrams, which identify WBC margination for a wide range of flow and cell suspension conditions.

A role for mitochondria in NLRP3 inflammasome activation
An inflammatory response initiated by the NLRP3 inflammasome is triggered by a variety of situations of host ‘danger’, including infection and metabolic dysregulation. Previous studies suggested that NLRP3 inflammasome activity is negatively regulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from an uncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome. Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. This indicates that NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.

Transcriptome analysis reveals human cytomegalovirus reprograms monocyte differentiation toward an M1 macrophage.
Monocytes are primary targets for human CMV (HCMV) infection and are proposed to be responsible for hematogenous dissemination of the virus. Monocytes acquire different functional traits during polarization to the classical proinflammatory M1 macrophage or the alternative antiinflammatory M2 macrophage. We hypothesized that HCMV induced a proinflammatory M1 macrophage following infection to promote viral dissemination because, biologically, a proinflammatory state provides the tools to drive infected monocytes from the blood into the tissue. To test this hypothesis of monocyte conversion from a normal quiescent phenotype to an inflammatory phenotype, we used Affymetrix Microarray to acquire a transcriptional profile of infected monocytes at a time point our data emphasized is a key temporal regulatory point following infection. We found that HCMV significantly up-regulated 583 (5.2%) of the total genes and down-regulated 621 (5.5%) of the total genes>or=1.5-fold at 4 h postinfection. Further ontology analysis revealed that genes implicated in classical M1 macrophage activation were stimulated by HCMV infection. We found that 65% of genes strictly associated with M1 polarization were up-regulated, while only 4% of genes solely associated with M2 polarization were up-regulated. Analysis of the monocyte chemokinome at the transcriptional level showed that 44% of M1 and 33% of M2 macrophage chemokines were up-regulated. Proteomic analysis using chemokine Ab arrays confirmed the secretion of these chemotactic proteins from HCMV-infected monocytes. Overall, the results identify that the HCMV-infected monocyte transcriptome displayed a unique M1/M2 polarization signature that was skewed toward the classical M1 activation phenotype.

Instruction: Given a scientific claim, retrieve documents that support or refute the claim


Question: Incidence of 10/66 dementia is higher than the incidence of DSM-IV dementia.

Dementia incidence and mortality in middle-income countries, and associations with indicators of cognitive reserve: a 10/66 Dementia Research Group population-based cohort study
BACKGROUND Results of the few cohort studies from countries with low incomes or middle incomes suggest a lower incidence of dementia than in high-income countries. We assessed incidence of dementia according to criteria from the 10/66 Dementia Research Group and Diagnostic and Statistical Manual of Mental Disorders (DSM) IV, the effect of dementia at baseline on mortality, and the independent effects of age, sex, socioeconomic position, and indicators of cognitive reserve. METHODS We did a population-based cohort study of all people aged 65 years and older living in urban sites in Cuba, the Dominican Republic, and Venezuela, and rural and urban sites in Peru, Mexico, and China, with ascertainment of incident 10/66 and DSM-IV dementia 3-5 years after cohort inception. We used questionnaires to obtain information about age in years, sex, educational level, literacy, occupational attainment, and number of household assets. We obtained information about mortality from all sites. For participants who had died, we interviewed a friend or relative to ascertain the likelihood that they had dementia before death. FINDINGS 12,887 participants were interviewed at baseline. 11,718 were free of dementia, of whom 8137 (69%) were reinterviewed, contributing 34,718 person-years of follow-up. Incidence for 10/66 dementia varied between 18·2 and 30·4 per 1000 person-years, and were 1·4-2·7 times higher than were those for DSM-IV dementia (9·9-15·7 per 1000 person-years). Mortality hazards were 1·56-5·69 times higher in individuals with dementia at baseline than in those who were dementia-free. Informant reports suggested a high incidence of dementia before death; overall incidence might be 4-19% higher if these data were included. 10/66 dementia incidence was independently associated with increased age (HR 1·67; 95% CI 1·56-1·79), female sex (0·72; 0·61-0·84), and low education (0·89; 0·81-0·97), but not with occupational attainment (1·04; 0·95-1·13). INTERPRETATION Our results provide supportive evidence for the cognitive reserve hypothesis, showing that in middle-income countries as in high-income countries, education, literacy, verbal fluency, and motor sequencing confer substantial protection against the onset of dementia. FUNDING Wellcome Trust Health Consequences of Population Change Programme, WHO, US Alzheimer's Association, FONACIT/ CDCH/ UCV.

Choosing appropriate substitution models for the phylogenetic analysis of protein-coding sequences.
Although phylogenetic inference of protein-coding sequences continues to dominate the literature, few analyses incorporate evolutionary models that consider the genetic code. This problem is exacerbated by the exclusion of codon-based models from commonly employed model selection techniques, presumably due to the computational cost associated with codon models. We investigated an efficient alternative to standard nucleotide substitution models, in which codon position (CP) is incorporated into the model. We determined the most appropriate model for alignments of 177 RNA virus genes and 106 yeast genes, using 11 substitution models including one codon model and four CP models. The majority of analyzed gene alignments are best described by CP substitution models, rather than by standard nucleotide models, and without the computational cost of full codon models. These results have significant implications for phylogenetic inference of coding sequences as they make it clear that substitution models incorporating CPs not only are a computationally realistic alternative to standard models but may also frequently be statistically superior.

Single-cell proteomic analysis of S. cerevisiae reveals the architecture of biological noise
A major goal of biology is to provide a quantitative description of cellular behaviour. This task, however, has been hampered by the difficulty in measuring protein abundances and their variation. Here we present a strategy that pairs high-throughput flow cytometry and a library of GFP-tagged yeast strains to monitor rapidly and precisely protein levels at single-cell resolution. Bulk protein abundance measurements of >2,500 proteins in rich and minimal media provide a detailed view of the cellular response to these conditions, and capture many changes not observed by DNA microarray analyses. Our single-cell data argue that noise in protein expression is dominated by the stochastic production/destruction of messenger RNAs. Beyond this global trend, there are dramatic protein-specific differences in noise that are strongly correlated with a protein's mode of transcription and its function. For example, proteins that respond to environmental changes are noisy whereas those involved in protein synthesis are quiet. Thus, these studies reveal a remarkable structure to biological noise and suggest that protein noise levels have been selected to reflect the costs and potential benefits of this variation.

Changes in white blood cells and platelets in children with falciparum malaria: relationship to disease outcome.
Little is known about the changes in white blood cells and platelets in children with falciparum malaria in endemic areas. We measured the white cell count (WCC) and platelets of 230 healthy children from the community, 1369 children admitted to hospital with symptomatic malaria, and 1461 children with other medical conditions. Children with malaria had a higher WCC compared with community controls, and leucocytosis was strongly associated with younger age, deep breathing, severe anaemia, thrombocytopenia and death. The WCC was not associated with a positive blood culture. In children with malaria, high lymphocyte and low monocyte counts were independently associated with mortality. A platelet count of less than 150 x 109/l was found in 56.7% of children with malaria, and was associated with age, prostration and parasite density, but not with bleeding problems or mortality. The mean platelet volume was also higher in children with malaria compared with other medical conditions. This may reflect early release from the bone marrow in response to peripheral platelet destruction. Thus, leucocytosis was associated with both severity and mortality in children with falciparum malaria, irrespective of bacteraemia, whereas thrombocytopenia, although very common, was not associated with adverse outcome.

Margination of white blood cells in microcapillary flow.
Margination of white blood cells (WBCs) towards vessel walls is an essential precondition for their efficient adhesion to the vascular endothelium. We perform numerical simulations with a two-dimensional blood flow model to investigate the dependence of WBC margination on hydrodynamic interactions of blood cells with the vessel walls, as well as on their collective behavior and deformability. We find WBC margination to be optimal in intermediate ranges of red blood cell (RBC) volume fractions and flow rates, while, beyond these ranges, it is substantially attenuated. RBC aggregation enhances WBC margination, while WBC deformability reduces it. These results are combined in state diagrams, which identify WBC margination for a wide range of flow and cell suspension conditions.

Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2
Deregulated redox metabolism in cancer leads to oxidative damage to cellular components including deoxyribonucleoside triphosphates (dNTPs). Targeting dNTP pool sanitizing enzymes, such as MTH1, is a highly promising anticancer strategy. The MTH2 protein, known as NUDT15, is described as the second human homologue of bacterial MutT with 8-oxo-dGTPase activity. We present the first NUDT15 crystal structure and demonstrate that NUDT15 prefers other nucleotide substrates over 8-oxo-dGTP. Key structural features are identified that explain different substrate preferences for NUDT15 and MTH1. We find that depletion of NUDT15 has no effect on incorporation of 8-oxo-dGTP into DNA and does not impact cancer cell survival in cell lines tested. NUDT17 and NUDT18 were also profiled and found to have far less activity than MTH1 against oxidized nucleotides. We show that NUDT15 is not a biologically relevant 8-oxo-dGTPase, and that MTH1 is the most prominent sanitizer of the cellular dNTP pool known to date.

Non-coding RNAs: Functions and applications in endocrine-related cancer.
A significant fraction of the human genome is transcribed as non-coding RNAs (ncRNAs). This non-coding transcriptome has challenged the notion of the central dogma and its involvement in transcriptional and post-transcriptional regulation of gene expression is well established. Interestingly, several ncRNAs are dysregulated in cancer and current non-coding transcriptome research aims to use our increasing knowledge of these ncRNAs for the development of cancer biomarkers and anti-cancer drugs. In endocrine-related cancers, for which survival rates can be relatively low, there is a need for such advancements. In this review, we aimed to summarize the roles and clinical implications of recently discovered ncRNAs, including long ncRNAs, PIWI-interacting RNAs, tRNA- and Y RNA-derived ncRNAs, and small nucleolar RNAs, in endocrine-related cancers affecting both sexes. We focus on recent studies highlighting discoveries in ncRNA biology and expression in cancer, and conclude with a discussion on the challenges and future directions, including clinical application. ncRNAs show great promise as diagnostic tools and therapeutic targets, but further work is necessary to realize the potential of these unconventional transcripts.

Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer.
Circadian rhythms are daily oscillations in various biological processes, generated by the feedback loops of eight core circadian genes: Period1 (Per1), Period2 (Per2), Period3 (Per3), Cryptochrome1 (Cry1), Cryptochrome2 (Cry2), Clock, Bmal1 and Casein Kinase I ε (CKIε). Recent studies have suggested that circadian genes participate in the growth and development of various cancers. This study examined the relations of circadian gene expression to clinicopathological factors and outcomes in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 202 patients with untreated colorectal cancer. The relative expression levels of the circadian genes in the specimens were measured by quantitative real-time, reverse-transcription polymerase chain reaction. Expression of the Clock gene and the CKIε gene in cancer tissue were significantly higher compared to that in adjacent normal mucosa. Expression of the Per1 and Per3 genes in cancer tissue was significantly lower compared to that in adjacent normal mucosa. Analysis of the relations between clinicopathological features and expression of the eight circadian genes in cancer tissue showed that high expression of the Bmal1 gene and low expression of the Per1 gene correlated with liver metastasis. On analysis of the relations between outcomes and gene expression, high expression of the Per2 gene was associated with significantly better outcomes than low expression of the Per2 gene. Overexpression of the Bmal1 gene and reduced expression of the Per1 gene may thus be useful predictors of liver metastasis. Moreover, reduced expression of the Per2 gene may be a predictor of outcomes in patients with colorectal cancer.

Antibodies specific for Epstein-Barr virus nuclear antigen-1 cross-react with human heterogeneous nuclear ribonucleoprotein L.
Epstein-Barr virus (EBV) is associated with multiple sclerosis (MS), and antibodies to the EBV nuclear antigen-1 (EBNA-1) are consistently increased in MS patients. The hypothesis of this study is that anti-EBNA-1 antibodies cross-react with a self antigen in MS patients. We affinity purified anti-EBNA-1 antibodies from human plasma, used the anti-EBNA-1 to immunoprecipitate antigens from human brain, and identified bound antigens with mass spectrometry. Anti-EBNA-1 consistently bound heterogeneous nuclear ribonucleoprotein L (HNRNPL). We expressed both the long and short isoforms of this protein, and verified with Western blots and ELISA that the long isoform cross-reacts with EBNA-1. Immunohistochemistry demonstrated that anti-EBNA-1 bound to an antigen in the nucleus of cultured rat central nervous system cells. ELISA demonstrated the presence of antibodies to HNRNPL in the plasma of both healthy controls and MS patients, but anti-HNRNPL was not increased in MS patients. We conclude that HNRNPL is an autoantigen which cross-reacts with EBNA-1. The relevance of this autoantigen to MS and other autoimmune diseases remains to be investigated.

Patient preferences and expectations for care: determinants in patients with lumbar intervertebral disc herniation.
STUDY DESIGN Prospective observational cohort. OBJECTIVE To describe the baseline characteristics of patients with a diagnosis of intervertebral disc herniation who had different treatment preferences and the relationship of specific expectations with those preferences. SUMMARY OF BACKGROUND DATA Data were gathered from the observational cohort of the Spine Patient Outcomes Research Trial (SPORT). Patients in the observational cohort met eligibility requirements identical to those of the randomized cohort, but declined randomization, receiving instead the treatment of their choice. METHODS Baseline preference and expectation data were acquired at the time of enrollment of the patient, before exposure to the informed consent process. Univariate analyses were performed using a t test for continuous variables and chi for categorical variables. Multivariate analyses were also performed with ANCOVA for continuous variables and logistic regression for categorical variables. Multiple logistic regression models were developed in a forward stepwise fashion using blocks of variables. RESULTS More patients preferred operative care: 67% preferred surgery, 28% preferred nonoperative treatment, and 6% were unsure; 53% of those preferring surgery stated a definite preference, whereas only 18% of those preferring nonoperative care had a definite preference. Patients preferring surgery were younger, had lower levels of education, and higher levels of unemployment/disability. This group also reported higher pain, worse physical and mental functioning, more back pain related disability, a longer duration of symptoms, and more opiate use. Gender, race, comorbidities, and use of other therapies did not differ significantly across preference groups. Patients' expectations regarding improvement with nonoperative care was the strongest predictor of preference. CONCLUSION Patient expectations, particularly regarding the benefit of nonoperative treatment, are the primary determinant of surgery preference among patients with lumbar intervertebral disc herniation. Demographic, functional status, and prior treatment experience had significant associations with patients' expectations and preferences.

Serum amyloid A: An acute-phase protein involved in tumour pathogenesis
The synthesis of acute-phase protein serum amyloid A (SAA) is largely regulated by inflammation- associated cytokines and a high concentration of circulating SAA may represent an ideal marker for acute and chronic inflammatory diseases. However, SAA is also synthesized in extrahepatic tissues, e.g. human carcinoma metastases and cancer cell lines. An increasing body of in vitro data supports the concept of involvement of SAA in carcinogenesis and neoplastic diseases. Accumulating evidence suggests that SAA might be included in a group of biomarkers to detect a pattern of physiological events that reflect the growth of malignancy and host response. This review is meant to provide a broad overview of the many ways that SAA could contribute to tumour development, and accelerate tumour progression and metastasis, and to gain a better understanding of this acute-phase reactant as a possible link between chronic inflammation and neoplasia.

Instruction: Given a scientific claim, retrieve documents that support or refute the claim


Question: Incidence of 10/66 dementia is lower than the incidence of DSM-IV dementia.

Dementia incidence and mortality in middle-income countries, and associations with indicators of cognitive reserve: a 10/66 Dementia Research Group population-based cohort study
BACKGROUND Results of the few cohort studies from countries with low incomes or middle incomes suggest a lower incidence of dementia than in high-income countries. We assessed incidence of dementia according to criteria from the 10/66 Dementia Research Group and Diagnostic and Statistical Manual of Mental Disorders (DSM) IV, the effect of dementia at baseline on mortality, and the independent effects of age, sex, socioeconomic position, and indicators of cognitive reserve. METHODS We did a population-based cohort study of all people aged 65 years and older living in urban sites in Cuba, the Dominican Republic, and Venezuela, and rural and urban sites in Peru, Mexico, and China, with ascertainment of incident 10/66 and DSM-IV dementia 3-5 years after cohort inception. We used questionnaires to obtain information about age in years, sex, educational level, literacy, occupational attainment, and number of household assets. We obtained information about mortality from all sites. For participants who had died, we interviewed a friend or relative to ascertain the likelihood that they had dementia before death. FINDINGS 12,887 participants were interviewed at baseline. 11,718 were free of dementia, of whom 8137 (69%) were reinterviewed, contributing 34,718 person-years of follow-up. Incidence for 10/66 dementia varied between 18·2 and 30·4 per 1000 person-years, and were 1·4-2·7 times higher than were those for DSM-IV dementia (9·9-15·7 per 1000 person-years). Mortality hazards were 1·56-5·69 times higher in individuals with dementia at baseline than in those who were dementia-free. Informant reports suggested a high incidence of dementia before death; overall incidence might be 4-19% higher if these data were included. 10/66 dementia incidence was independently associated with increased age (HR 1·67; 95% CI 1·56-1·79), female sex (0·72; 0·61-0·84), and low education (0·89; 0·81-0·97), but not with occupational attainment (1·04; 0·95-1·13). INTERPRETATION Our results provide supportive evidence for the cognitive reserve hypothesis, showing that in middle-income countries as in high-income countries, education, literacy, verbal fluency, and motor sequencing confer substantial protection against the onset of dementia. FUNDING Wellcome Trust Health Consequences of Population Change Programme, WHO, US Alzheimer's Association, FONACIT/ CDCH/ UCV.

Macrophages Facilitate Electrical Conduction in the Heart
Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11bDTR mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction.

Interferon alpha for the treatment of chronic hepatitis C in patients infected with human immunodeficiency virus. Hepatitis-HIV Spanish Study Group.
Liver disease secondary to hepatitis C virus (HCV) infection is a rising cause of morbidity and mortality among individuals who have been infected parenterally with human immunodeficiency virus (HIV) such as injection drug users, hemophiliacs, and transfused patients. We analyzed both the efficacy of interferon (IFN) alpha therapy in these patients and the predictors of response to this agent. A total of 119 patients with chronic hepatitis C (90 of whom were infected with HIV and 29 of whom were not) were included in a multicenter, prospective, open, nonrandomized observational study. IFN-alpha was given subcutaneously in a dosage of 5 million units three times a week during a 3-month period; those patients who responded received a dose of 3 million units given subcutaneously three times a week for an additional 9 months. One hundred seven patients completed the study; the level of aminotransferases returned to normal and sera became negative (complete response) for HCV RNA in 26 (32.5%) of 80 HIV-infected patients and 10 (37.0%) of 27 non-HIV-infected patients (P = .666) after completion of the treatment. Two variables were independently associated with a response in HIV-infected patients: a CD4+ T lymphocyte count of > 500 x 10(6)/L and a baseline HCV viremia level of < 10(7) copies/mL. In the 12 months following treatment, relapses occurred in 30.8% of the HIV-infected patients and 12.5% of non-HIV-infected patients (P = .403).

Outcome of repeated radiosurgery for recurrent metastatic brain tumors.
OBJECTIVE We investigated the outcome of repeated gamma knife radiosurgery (GKS) for local or remote recurrence after initial radiosurgery. MATERIAL AND METHODS We retrospectively reviewed 204 patients who were treated with GKS. Among them 43 patients (21%) underwent GKS more than once. The second GKS was given for recurrence at the previously treated sites in 16 patients, new lesions at remote sites in 13, and both local recurrence and new lesions in 14. RESULTS The median survival from the first GKS was 36 (7-190) weeks in all patients and 68 (16-156) weeks in 43 patients with repeated GKS. The median time from the first GKS to the second was 37 weeks. The median survival from the second radiosurgical intervention was 32 (7-132) weeks. Local control rate at 6 months after salvage GKS was 90.7%. RPA class was the commonly dominant prognostic factor in both initial and salvage GKS. CONCLUSION Recurrence is common for patients with metastatic brain tumors after initial radiosurgery. Local control and survival time after salvage treatment are comparable with those after initial radiosurgery. GKS as a salvage treatment may provide additional survival benefit in selected patients.

The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.
The cyclin-dependent kinase Cdk2 associates with cyclins A, D, and E and has been implicated in the control of the G1 to S phase transition in mammals. To identify potential Cdk2 regulators, we have employed an improved two-hybrid system to isolate human genes encoding Cdk-interacting proteins (Cips). CIP1 encodes a novel 21 kd protein that is found in cyclin A, cyclin D1, cyclin E, and Cdk2 immunoprecipitates. p21CIP1 is a potent, tight-binding inhibitor of Cdks and can inhibit the phosphorylation of Rb by cyclin A-Cdk2, cyclin E-Cdk2, cyclin D1-Cdk4, and cyclin D2-Cdk4 complexes. Cotransfection experiments indicate that CIP1 and SV40 T antigen function in a mutually antagonistic manner to control cell cycle progression.

Lithium Therapy Improves Neurological Function and Hippocampal Dendritic Arborization in a Spinocerebellar Ataxia Type 1 Mouse Model
Background  Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disorder characterized by progressive motor and cognitive dysfunction. Caused by an expanded polyglutamine tract in ataxin 1 (ATXN1), SCA1 pathogenesis involves a multifactorial process that likely begins with misfolding of ATXN1, which has functional consequences on its interactions, leading to transcriptional dysregulation. Because lithium has been shown to exert neuroprotective effects in a variety of conditions, possibly by affecting gene expression, we tested the efficacy of lithium treatment in a knock-in mouse model of SCA1 (Sca1154Q/2Q mice) that replicates many features of the human disease. Methods and Findings  Sca1154Q/2Q mice and their wild-type littermates were fed either regular chow or chow that contained 0.2% lithium carbonate. Dietary lithium carbonate supplementation resulted in improvement of motor coordination, learning, and memory in Sca1154Q/2Q mice. Importantly, motor improvement was seen when treatment was initiated both presymptomatically and after symptom onset. Neuropathologically, lithium treatment attenuated the reduction of dendritic branching in mutant hippocampal pyramidal neurons. We also report that lithium treatment restored the levels of isoprenylcysteine carboxyl methyltransferase (Icmt; alternatively, Pccmt), down-regulation of which is an early marker of mutant ATXN1 toxicity. Conclusions  The effect of lithium on a marker altered early in the course of SCA1 pathogenesis, coupled with its positive effect on multiple behavioral measures and hippocampal neuropathology in an authentic disease model, make it an excellent candidate treatment for human SCA1 patients.

ERAAP synergizes with MHC class I molecules to make the final cut in the antigenic peptide precursors in the endoplasmic reticulum.
The major histocompatibility complex class I molecules display peptides (pMHC I) on the cell surface for immune surveillance by CD8(+) T cells. These peptides are generated by proteolysis of intracellular polypeptides by the proteasome in the cytoplasm and then in the endoplasmic reticulum (ER) by the ER aminopeptidase associated with antigen processing (ERAAP). To define the unknown mechanism of ERAAP function in vivo, we analyzed naturally processed peptides in cells with or without appropriate MHC I and ERAAP. In the absence of MHC I, ERAAP degraded the antigenic precursors in the ER. However, MHC I molecules could bind proteolytic intermediates and were essential for generation of the final peptide by ERAAP. Thus, ERAAP synergizes with MHC I to generate the final pMHC I repertoire.

Prevalence of Multiple Sclerosis in Isfahan, Iran
Background: The prevalence of multiple sclerosis (MS) shows considerable variability all over the world. According to Kurtzke, Iran is considered to have a low prevalence. Objective: To estimate the period prevalence and risk factors of MS in Isfahan, central part of Iran. Methods: A cross-sectional case register study conducted between 2004 and 2005. In the province of Isfahan, Iran, all patients known to have definite MS during 2004 and 2005, being alive and resident within Isfahan as well as being a member of the Isfahan MS Association were included in the study. Demographic and case-related information was recorded. 1,391 definite MS patients (308 men and 1,083 women) from the Isfahan MS Association, Iran, have been identified. The disease was confirmed using clinical information and MRI findings by a neurologist and radiologist. The patients were evaluated by interview and a questionnaire. Population data were obtained from the year 1999 Iran Census. The mean (SD) age of the participants was 32.5 (9.3) years with a mean (SD) duration of the disease of 6.4 (5.1) years for men and 6.9 (5.3) years for women. Results: The period prevalence of MS was 35.5 per 100,000 [95% confidence interval (CI) 33.6–37.3] in a population of 3,923,255, with a higher rate in women than men [54.5 (95% CI: 51.1–57.8) for women and 14.9 (95% CI: 13.3–16.6) for men]. The female/male ratio was 3.6 (95% CI: 3.2–4.1). The direct age-adjusted period prevalence was 59.5 per 100,000 (95% CI: 44.8–75.2) for women and 17.0 per 100,000 (95% CI: 8.9–25.1) for men. MS rates were highest among 30- to 39-year-olds and decreased with increasing age. Sensory and visual disturbances were the most common initial presentations with a prevalence of 51.1% (95% CI: 48.4–53.7) and 47.0% (95% CI: 44.4–49.7), respectively. Conclusion: Isfahan could be considered as an area with a medium to high risk of MS. This is in sharp contrast with the gradient hypothesis.

A generic measure of relationship satisfaction.
The variety of interpersonal relationships in contemporary society necessitates the development of brief, reliable measures of satisfaction that are applicable to many types of close relationships. This article describes the development of such a measure. In Study I, the 7-item Relationship Assessment Scale (RAS) was administered to 125 subjects who reported themselves to be "in love. " Analyses revealed a unifactorial scale structure, substantial factor loadings, and moderate intercorrelations among the items. The scale correlated significantly with measures of love, sexual attitudes, self-disclosure, commitment, and investment in a relationship. In Study II, the scale was administered to 57 couples in ongoing relationships. Analyses supported a single factor, alpha reliability of .86, and correlations with relevant relationship measures. The scale correlated .80 with a longer criterion measure, the Dyadic Adjustment Scale (Spanier, 1976), and both scales were effective (with a subsample) in discriminating couples who stayed together from couples who broke up. The RAS is a brief, psychometrically sound, generic measure of relationship satisfaction.

A neuroimaging investigation of the association between aerobic fitness, hippocampal volume, and memory performance in preadolescent children.
Because children are becoming overweight, unhealthy, and unfit, understanding the neurocognitive benefits of an active lifestyle in childhood has important public health and educational implications. Animal research has indicated that aerobic exercise is related to increased cell proliferation and survival in the hippocampus as well as enhanced hippocampal-dependent learning and memory. Recent evidence extends this relationship to elderly humans by suggesting that high aerobic fitness levels in older adults are associated with increased hippocampal volume and superior memory performance. The present study aimed to further extend the link between fitness, hippocampal volume, and memory to a sample of preadolescent children. To this end, magnetic resonance imaging was employed to investigate whether higher- and lower-fit 9- and 10-year-old children showed differences in hippocampal volume and if the differences were related to performance on an item and relational memory task. Relational but not item memory is primarily supported by the hippocampus. Consistent with predictions, higher-fit children showed greater bilateral hippocampal volumes and superior relational memory task performance compared to lower-fit children. Hippocampal volume was also positively associated with performance on the relational but not the item memory task. Furthermore, bilateral hippocampal volume was found to mediate the relationship between fitness level (VO(2) max) and relational memory. No relationship between aerobic fitness, nucleus accumbens volume, and memory was reported, which strengthens the hypothesized specific effect of fitness on the hippocampus. The findings are the first to indicate that aerobic fitness may relate to the structure and function of the preadolescent human brain.

Ecological analysis of ethnic differences in relation between tuberculosis and poverty.
OBJECTIVE To examine the effect of ethnicity on the relation between tuberculosis and deprivation. DESIGN Retrospective ecological study comparing incidence of tuberculosis in white and south Asian residents of the 39 electoral wards in Birmingham with ethnic specific indices of deprivation. SETTING Birmingham, 1989-93. SUBJECTS 1516 notified cases of tuberculosis. MAIN OUTCOME MEASURES Rates of tuberculosis and measures of deprivation. RESULTS Univariate analysis showed significant associations of tuberculosis rates for the whole population with several indices of deprivation (P<0.01) and with the proportion of the population of south Asian origin (P<0.01). All deprivation covariates were positively associated with each other but on multiple regression, higher level of overcrowding was independently associated with tuberculosis rates. For the white population, overcrowding was associated with tuberculosis rates independently of other variables (P=0.0036). No relation with deprivation was found for the south Asian population in either single or multivariable analyses. CONCLUSIONS Poverty is significantly associated with tuberculosis in the white population, but no such relation exists for those of Asian ethnicity. These findings suggest that causal factors, and therefore potential interventions, will also differ by ethnic group.

Instruction: Given a scientific claim, retrieve documents that support or refute the claim


Question: Incidence of heart failure increased by 10% in women since 1979.

Trends in heart failure incidence and survival in a community-based population.
CONTEXT The epidemic of heart failure has yet to be fully investigated, and data on incidence, survival, and sex-specific temporal trends in community-based populations are limited. OBJECTIVE To test the hypothesis that the incidence of heart failure has declined and survival after heart failure diagnosis has improved over time but that secular trends have diverged by sex. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study using the resources of the Rochester Epidemiology Project conducted in Olmsted County, Minnesota. Patients were 4537 Olmsted County residents (57% women; mean [SD] age, 74 [14] years) with a diagnosis of heart failure between 1979 and 2000. Framingham criteria and clinical criteria were used to validate the diagnosis   MAIN OUTCOME MEASURES Incidence of heart failure and survival after heart failure diagnosis. RESULTS The incidence of heart failure was higher among men (378/100 000 persons; 95% confidence interval [CI], 361-395 for men; 289/100 000 persons; 95% CI, 277-300 for women) and did not change over time among men or women. After a mean follow-up of 4.2 years (range, 0-23.8 years), 3347 deaths occurred, including 1930 among women and 1417 among men. Survival after heart failure diagnosis was worse among men than women (relative risk, 1.33; 95% CI, 1.24-1.43) but overall improved over time (5-year age-adjusted survival, 43% in 1979-1984 vs 52% in 1996-2000, P<.001). However, men and younger persons experienced larger survival gains, contrasting with less or no improvement for women and elderly persons. CONCLUSION In this community-based cohort, the incidence of heart failure has not declined during 2 decades, but survival after onset of heart failure has increased overall, with less improvement among women and elderly persons.

Pharmacological interventions for smoking cessation: an overview and network meta-analysis.
BACKGROUND Smoking is the leading preventable cause of illness and premature death worldwide. Some medications have been proven to help people to quit, with three licensed for this purpose in Europe and the USA: nicotine replacement therapy (NRT), bupropion, and varenicline. Cytisine (a treatment pharmacologically similar to varenicline) is also licensed for use in Russia and some of the former socialist economy countries. Other therapies, including nortriptyline, have also been tested for effectiveness. OBJECTIVES How do NRT, bupropion and varenicline compare with placebo and with each other in achieving long-term abstinence (six months or longer)? How do the remaining treatments compare with placebo in achieving long-term abstinence? How do the risks of adverse and serious adverse events (SAEs) compare between the treatments, and are there instances where the harms may outweigh the benefits? METHODS The overview is restricted to Cochrane reviews, all of which include randomised trials. Participants are usually adult smokers, but we exclude reviews of smoking cessation for pregnant women and in particular disease groups or specific settings. We cover nicotine replacement therapy (NRT), antidepressants (bupropion and nortriptyline), nicotine receptor partial agonists (varenicline and cytisine), anxiolytics, selective type 1 cannabinoid receptor antagonists (rimonabant), clonidine, lobeline, dianicline, mecamylamine, Nicobrevin, opioid antagonists, nicotine vaccines, and silver acetate. Our outcome for benefit is continuous or prolonged abstinence at least six months from the start of treatment. Our outcome for harms is the incidence of serious adverse events associated with each of the treatments. We searched the Cochrane Database of Systematic Reviews (CDSR) in The Cochrane Library, for any reviews with 'smoking' in the title, abstract or keyword fields. The last search was conducted in November 2012. We assessed methodological quality using a revised version of the AMSTAR scale. For NRT, bupropion and varenicline we conducted network meta-analyses, comparing each with the others and with placebo for benefit, and varenicline and bupropion for risks of serious adverse events. MAIN RESULTS We identified 12 treatment-specific reviews. The analyses covered 267 studies, involving 101,804 participants. Both NRT and bupropion were superior to placebo (odds ratios (OR) 1.84; 95% credible interval (CredI) 1.71 to 1.99, and 1.82; 95% CredI 1.60 to 2.06 respectively). Varenicline increased the odds of quitting compared with placebo (OR 2.88; 95% CredI 2.40 to 3.47). Head-to-head comparisons between bupropion and NRT showed equal efficacy (OR 0.99; 95% CredI 0.86 to 1.13). Varenicline was superior to single forms of NRT (OR 1.57; 95% CredI 1.29 to 1.91), and to bupropion (OR 1.59; 95% CredI 1.29 to 1.96). Varenicline was more effective than nicotine patch (OR 1.51; 95% CredI 1.22 to 1.87), than nicotine gum (OR 1.72; 95% CredI 1.38 to 2.13), and than 'other' NRT (inhaler, spray, tablets, lozenges; OR 1.42; 95% CredI 1.12 to 1.79), but was not more effective than combination NRT (OR 1.06; 95% CredI 0.75 to 1.48). Combination NRT also outperformed single formulations. The four categories of NRT performed similarly against each other, apart from 'other' NRT, which was marginally more effective than NRT gum (OR 1.21; 95% CredI 1.01 to 1.46). Cytisine (a nicotine receptor partial agonist) returned positive findings (risk ratio (RR) 3.98; 95% CI 2.01 to 7.87), without significant adverse events or SAEs. Across the 82 included and excluded bupropion trials, our estimate of six seizures in the bupropion arms versus none in the placebo arms was lower than the expected rate (1:1000), at about 1:1500. SAE meta-analysis of the bupropion studies demonstrated no excess of neuropsychiatric (RR 0.88; 95% CI 0.31 to 2.50) or cardiovascular events (RR 0.77; 95% CI 0.37 to 1.59). SAE meta-analysis of 14 varenicline trials found no difference between the varenicline and placebo arms (RR 1.06; 95% CI 0.72 to 1.55), and subgroup analyses detected no significant excess of neuropsychiatric events (RR 0.53; 95% CI 0.17 to 1.67), or of cardiac events (RR 1.26; 95% CI 0.62 to 2.56). Nortriptyline increased the chances of quitting (RR 2.03; 95% CI 1.48 to 2.78). Neither nortriptyline nor bupropion were shown to enhance the effect of NRT compared with NRT alone. Clonidine increased the chances of quitting (RR 1.63; 95% CI 1.22 to 2.18), but this was offset by a dose-dependent rise in adverse events. Mecamylamine in combination with NRT may increase the chances of quitting, but the current evidence is inconclusive. Other treatments failed to demonstrate a benefit compared with placebo. Nicotine vaccines are not yet licensed for use as an aid to smoking cessation or relapse prevention. Nicobrevin's UK license is now revoked, and the manufacturers of rimonabant, taranabant and dianicline are no longer supporting the development or testing of these treatments. AUTHORS' CONCLUSIONS NRT, bupropion, varenicline and cytisine have been shown to improve the chances of quitting. Combination NRT and varenicline are equally effective as quitting aids. Nortriptyline also improves the chances of quitting. On current evidence, none of the treatments appear to have an incidence of adverse events that would mitigate their use. Further research is warranted into the safety of varenicline and into cytisine's potential as an effective and affordable treatment, but not into the efficacy and safety of NRT.

Isolation and characterization of the cDNA encoding BKLF/TEF-2, a major CACCC-box-binding protein in erythroid cells and selected other cells.
CACCC boxes are among the critical sequences present in regulatory elements of genes expressed in erythroid cells, as well as in selected other cell types. While an erythroid cell-specific CACCC-box-binding protein, EKLF, has been shown to be required in vivo for proper expression of the adult beta-globin gene, it is dispensable for the regulation of several other globin and nonglobin erythroid cell-expressed genes. In the work described here, we searched for additional CACCC-box transcription factors that might be active in murine erythroid cells. We identified a major gel shift activity (termed BKLF), present in yolk sac and fetal liver erythroid cells, that could be distinguished from EKLF by specific antisera. Through relaxed-stringency hybridization, we obtained the cDNA encoding BKLF, a highly basic, novel zinc finger protein that is related to EKLF and other Krüppel-like members in its DNA-binding domain but unrelated elsewhere. BKLF, which is widely but not ubiquitously expressed in cell lines, is highly expressed in the midbrain region of embryonic mice and appears to correspond to the gel shift activity TEF-2, a transcriptional activator implicated in regulation of the simian virus 40 enhancer and other CACCC-box-containing regulatory elements. Because BKLF binds with high affinity and preferentially over Sp1 to many CACCC sequences of erythroid cell expressed genes, it is likely to participate in the control of many genes whose expression appears independent of the action of EKLF.

Structure of Actin-related protein 8 and its contribution to nucleosome binding
Nuclear actin-related proteins (Arps) are subunits of several chromatin remodelers, but their molecular functions within these complexes are unclear. We report the crystal structure of the INO80 complex subunit Arp8 in its ATP-bound form. Human Arp8 has several insertions in the conserved actin fold that explain its inability to polymerize. Most remarkably, one insertion wraps over the active site cleft and appears to rigidify the domain architecture, while active site features shared with actin suggest an allosterically controlled ATPase activity. Quantitative binding studies with nucleosomes and histone complexes reveal that Arp8 and the Arp8-Arp4-actin-HSA sub-complex of INO80 strongly prefer nucleosomes and H3-H4 tetramers over H2A-H2B dimers, suggesting that Arp8 functions as a nucleosome recognition module. In contrast, Arp4 prefers free (H3-H4)(2) over nucleosomes and may serve remodelers through binding to (dis)assembly intermediates in the remodeling reaction.

A core Klf circuitry regulates self-renewal of embryonic stem cells
Embryonic stem (ES) cells are unique in their ability to self-renew indefinitely and maintain pluripotency. These properties require transcription factors that specify the gene expression programme of ES cells. It has been possible to reverse the highly differentiated state of somatic cells back to a pluripotent state with a combination of four transcription factors: Klf4 is one of the reprogramming factors required, in conjunction with Oct4, Sox2 and c-Myc. Maintenance of self-renewal and pluripotency of ES cells requires Oct4, Sox2 and c-Myc, but Klf4 is dispensable. Here, we show that Krüppel-like factors are required for the self-renewal of ES cells. Simultaneous depletion of Klf2, Klf4 and Klf5 lead to ES cell differentiation. Chromatin immunoprecipitation coupled to microarray assay reveals that these Klf proteins share many common targets of Nanog, suggesting a close functional relationship between these factors. Expression analysis after triple RNA interference (RNAi) of the Klfs shows that they regulate key pluripotency genes, such as Nanog. Taken together, our study provides new insight into how the core Klf circuitry integrates into the Nanog transcriptional network to specify gene expression that is unique to ES cells.

Wedelolactone protects human bronchial epithelial cell injury against cigarette smoke extract-induced oxidant stress and inflammation responses through Nrf2 pathway.
Cigarette smoke is the leading cause of the development of various lung diseases including lung cancer through triggering oxidant stress and inflammatory responses which contributed to the lesions of normal human bronchial epithelial (NHBE) cell. Wedelolactone (WEL), a natural compound from Eclipta prostrata L., has been found to possess the inhibitive effects on the proliferation and growth of cancers. In the present study, we investigated the effects of WEL on NHBE cell injury induced by cigarette smoke extract (CSE) in vitro. It showed that the pretreatment WEL (2.5-20μM) resulted in a significant protective effect on 10% CSE-induced cell death in NHBE cells. The pretreatment with WEL dose-dependently and significantly reversed the activities of SOD, CAT, GSH and the level of MDA to normal level. We also found that the protein expression levels of COX-2 and ICAM-1 which are related to inflammatory response were remarkably reduced by WEL compared with 10% CSE treatment. Additionally, WEL also reduced the expressions of antioxidases including NAD(P)H dehydrogenase:Quinone 1 (NQO1) and heme oxygenase-1 (HO-1). Moreover, Nrf2 inhibitor all-trans-retinoic acid (ATRA) decreased remarkably their expressions. These results suggest that WEL protects NHBE cell against CSE-induced injury through modulating Nrf2 pathway. Our study indicates that WEL may be a new potential protective agent against CSE-induced lung injury.

The Association between Single-Nucleotide Polymorphisms of ORAI1 Gene and Breast Cancer in a Taiwanese Population
BACKGROUND Breast cancer is the most common malignancy in women. There is increasing evidence suggesting that ORAI1, components of store-operated calcium channel, play a pivotal role in breast cancer progression and metastasis. METHODS A total of 384 female patients with breast cancer were included in this study. We selected five representative tagging ORAI1 SNPs from HapMap database with minimum allele frequency (MAF) >10%. Genotyping was performed using TaqMan allelic discrimination assay. Chi-square (χ²) test was used to analyze statistical differences among control and patient groups in genotype and allelic frequencies. RESULTS Two of the ORAI1 SNPs (rs12320939 and rs12313273) were associated with estrogen receptors positive in breast cancer patients under the recessive model. When the Bonferroni correction was performed, the significance still existed. In addition, rs12320939 also associated with the lymph nodal involvement. CONCLUSION We showed that genetic polymorphisms of ORAI1 associated strongly with lymph nodal involvement and estrogen receptors (ERs) positive breast cancer patients in a Taiwanese population.

Polymorphism and ligand dependent changes in human glucagon-like peptide-1 receptor (GLP-1R) function: allosteric rescue of loss of function mutation.
The glucagon-like peptide-1 receptor (GLP-1R) is a key physiological regulator of insulin secretion and a major therapeutic target for the treatment of type II diabetes. However, regulation of GLP-1R function is complex with multiple endogenous peptides that interact with the receptor, including full-length (1-37) and truncated (7-37) forms of GLP-1 that can exist in an amidated form (GLP-1(1-36)NH₂ and GLP-1(7-36)NH₂) and the related peptide oxyntomodulin. In addition, the GLP-1R possesses exogenous agonists, including exendin-4, and the allosteric modulator, compound 2 (6,7-dichloro-2-methylsulfonyl-3-tert-butylaminoquinoxaline). The complexity of this ligand-receptor system is further increased by the presence of several single nucleotide polymorphisms (SNPs) that are distributed across the receptor. We have investigated 10 GLP-1R SNPs, which were characterized in three physiologically relevant signaling pathways (cAMP accumulation, extracellular signal-regulated kinase 1/2 phosphorylation, and intracellular Ca²⁺ mobilization); ligand binding and cell surface receptor expression were also determined. We demonstrate both ligand- and pathway-specific effects for multiple SNPs, with the most dramatic effect observed for the Met¹⁴⁹ receptor variant. At the Met¹⁴⁹ variant, there was selective loss of peptide-induced responses across all pathways examined, but preservation of response to the small molecule compound 2. In contrast, at the Cys³³³ variant, peptide responses were preserved but there was attenuated response to compound 2. Strikingly, the loss of peptide function at the Met¹⁴⁹ receptor variant could be allosterically rescued by compound 2, providing proof-of-principle evidence that allosteric drugs could be used to treat patients with this loss of function variant.

Signaling architectures that transmit unidirectional information despite retroactivity
A signaling pathway transmits information from an upstream system to downstream systems, ideally in a unidirectional fashion. A key obstacle to unidirectional transmission is retroactivity, the additional reaction flux that affects a system once its species interact with those of downstream systems. This raises the fundamental question of whether signaling pathways have developed specialized architectures that overcome retroactivity and transmit unidirectional signals. Here, we propose a general procedure based on mathematical analysis that provides an answer to this question. Using this procedure, we analyze the ability of a variety of signaling architectures to transmit one-way (from upstream to downstream) signals, as key biological parameters are tuned. We find that single stage phosphorylation and phosphotransfer systems that transmit signals from a kinase show a stringent design trade-off that hampers their ability to overcome retroactivity. Interestingly, cascades of these architectures, which are highly represented in nature, can overcome this trade-off and thus enable unidirectional transmission. By contrast, phosphotransfer systems, and single and double phosphorylation cycles that transmit signals from a substrate are unable to mitigate retroactivity effects, even when cascaded, and hence are not well suited for unidirectional information transmission. Our results identify signaling architectures that, allowing unidirectional transmission of signals, embody modular processes that conserve their input/output behavior across multiple contexts. These findings can be used to decompose natural signal transduction networks into modules, and, at the same time, they establish a library of devices that can be used in synthetic biology to facilitate modular circuit design.

TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function
Progressive kidney failure is a genetically and clinically heterogeneous group of disorders. Podocyte foot processes and the interposed glomerular slit diaphragm are essential components of the permeability barrier in the kidney. Mutations in genes encoding structural proteins of the podocyte lead to the development of proteinuria, resulting in progressive kidney failure and focal segmental glomerulosclerosis. Here, we show that the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm. We identified five families with autosomal dominant focal segmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 on chromosome 11q. Two of the TRPC6 mutants had increased current amplitudes. These data show that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function.

Relationship of ambulatory blood pressure and the heart rate profile with renal function parameters in hypertensive patients with chronic kidney disease.
Strict blood pressure (BP) control is reportedly important for the management of hypertensive patients with chronic kidney disease (CKD). The purpose of this cross-sectional study was to examine whether the variables of ambulatory BP and the heart rate (HR) profile, central hemodynamics, and arterial stiffness were closely related to the renal function parameters (urine albumin excretion rate [UACR] and estimated glomerular filtration rate [eGFR]) observed in 25 consecutive hospitalized hypertensive patients with CKD. There were significant positive relationships between UACR and 24-hour, daytime, and nighttime ambulatory systolic BP. In addition, there were significant negative relationships between UACR and 24-hour and daytime HR variability. The circulating B-type natriuretic peptide level and hemoglobin A1c were also positively related to UACR. With respect to eGFR, although the 24-hour and nighttime HR variability were positively associated with eGFR, the circulating pentosidine and nighttime HR had a negative relationship with eGFR. On the other hand, central hemodynamics and arterial stiffness did not exhibit any significant association with renal function parameters. These results indicate that ambulatory BP and the HR profile are closely modulated by renal function deterioration. Further studies are needed to investigate the causal relationship between ambulatory BP and the HR profile and renal function parameters in hypertensive patients with CKD.

Instruction: Given a scientific claim, retrieve documents that support or refute the claim


Question: Incidence of sepsis has fallen substantially from 2009 to 2014.

Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014
Importance Estimates from claims-based analyses suggest that the incidence of sepsis is increasing and mortality rates from sepsis are decreasing. However, estimates from claims data may lack clinical fidelity and can be affected by changing diagnosis and coding practices over time. Objective To estimate the US national incidence of sepsis and trends using detailed clinical data from the electronic health record (EHR) systems of diverse hospitals. Design, Setting, and Population Retrospective cohort study of adult patients admitted to 409 academic, community, and federal hospitals from 2009-2014. Exposures Sepsis was identified using clinical indicators of presumed infection and concurrent acute organ dysfunction, adapting Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria for objective and consistent EHR-based surveillance. Main Outcomes and Measures Sepsis incidence, outcomes, and trends from 2009-2014 were calculated using regression models and compared with claims-based estimates using International Classification of Diseases, Ninth Revision, Clinical Modification codes for severe sepsis or septic shock. Case-finding criteria were validated against Sepsis-3 criteria using medical record reviews. Results A total of 173 690 sepsis cases (mean age, 66.5 [SD, 15.5] y; 77 660 [42.4%] women) were identified using clinical criteria among 2 901 019 adults admitted to study hospitals in 2014 (6.0% incidence). Of these, 26 061 (15.0%) died in the hospital and 10 731 (6.2%) were discharged to hospice. From 2009-2014, sepsis incidence using clinical criteria was stable (+0.6% relative change/y [95% CI, −2.3% to 3.5%], P = .67) whereas incidence per claims increased (+10.3%/y [95% CI, 7.2% to 13.3%], P < .001). In-hospital mortality using clinical criteria declined (−3.3%/y [95% CI, −5.6% to −1.0%], P = .004), but there was no significant change in the combined outcome of death or discharge to hospice (−1.3%/y [95% CI, −3.2% to 0.6%], P = .19). In contrast, mortality using claims declined significantly (−7.0%/y [95% CI, −8.8% to −5.2%], P < .001), as did death or discharge to hospice (−4.5%/y [95% CI, −6.1% to −2.8%], P < .001). Clinical criteria were more sensitive in identifying sepsis than claims (69.7% [95% CI, 52.9% to 92.0%] vs 32.3% [95% CI, 24.4% to 43.0%], P < .001), with comparable positive predictive value (70.4% [95% CI, 64.0% to 76.8%] vs 75.2% [95% CI, 69.8% to 80.6%], P = .23). Conclusions and Relevance In clinical data from 409 hospitals, sepsis was present in 6% of adult hospitalizations, and in contrast to claims-based analyses, neither the incidence of sepsis nor the combined outcome of death or discharge to hospice changed significantly between 2009-2014. The findings also suggest that EHR-based clinical data provide more objective estimates than claims-based data for sepsis surveillance.

The Women's Interagency HIV Study
The Women's Interagency HIV Study comprises the largest U.S. cohort to date of human immunodeficiency virus (HIV)-seropositive women (N = 2,058) with a comparison cohort of seronegative women (N = 568). The methodology, training, and quality assurance activities employed are described. The study pop

Exon duplication and divergence in the human preproglucagon gene
Glucagon is a 29-amino acid pancreatic hormone which counteracts the blood glucose-lowering action of insulin by stimulating hepatic glycogenolysis and gluconeogenesis1. The structure of the hamster pancreatic glucagon precursor has recently been determined from the sequence of a cloned cDNA2. Hamster preproglucagon is a 180-amino acid protein which contains five functional regions; a signal or pre-peptide, an NH2-terminal peptide (also called glicentin-related pancreatic peptide, GRPP), glucagon, and two carboxy-terminal glucagon-like peptides (GLP-1 and GLP-2). The sequences of two non-allelic anglerfish pancreatic glucagon precursors3–5 have also been determined and their organization is similar but not identical to the hamster protein; they lack the polypeptide segment corresponding to hamster GLP-2. The presence of three regions possessing internal homology, that is, glucagon, GLP-1 and GLP-2, within proglucagon, and the absence of GLP-2 in the anglerfish precursors suggests that the structure of the preproglucagon gene might provide insight into the evolution of this polyprotein. We have isolated and sequenced the human preproglucagon gene and report here that the organization of the human precursor deduced from this sequence is identical to the hamster protein. The gene contains at least three intervening sequences which divide the protein-coding portion of the gene into four regions corresponding to the signal peptide and part of the NH2-terminal peptide, the remainder of the NH2-terminal peptide and glucagon, GLP-1, and GLP-2. The data suggest that triplication and subsequent sequence divergence of an exon encoding glucagon or a glucagon-like peptide produced this polyprotein precursor.

 DNA methylation and healthy human aging
The process of aging results in a host of changes at the cellular and molecular levels, which include senescence, telomere shortening, and changes in gene expression. Epigenetic patterns also change over the lifespan, suggesting that epigenetic changes may constitute an important component of the aging process. The epigenetic mark that has been most highly studied is DNA methylation, the presence of methyl groups at CpG dinucleotides. These dinucleotides are often located near gene promoters and associate with gene expression levels. Early studies indicated that global levels of DNA methylation increase over the first few years of life and then decrease beginning in late adulthood. Recently, with the advent of microarray and next-generation sequencing technologies, increases in variability of DNA methylation with age have been observed, and a number of site-specific patterns have been identified. It has also been shown that certain CpG sites are highly associated with age, to the extent that prediction models using a small number of these sites can accurately predict the chronological age of the donor. Together, these observations point to the existence of two phenomena that both contribute to age-related DNA methylation changes: epigenetic drift and the epigenetic clock. In this review, we focus on healthy human aging throughout the lifetime and discuss the dynamics of DNA methylation as well as how interactions between the genome, environment, and the epigenome influence aging rates. We also discuss the impact of determining 'epigenetic age' for human health and outline some important caveats to existing and future studies.

Bacteremia caused by a strain of Desulfovibrio related to the provisionally named Desulfovibrio fairfieldensis.
Eight isolates of Desulfovibrio spp. have been obtained over 5 years from abdominal or brain abscesses or blood. Seven isolates were part of a mixed flora [corrected]. One strain was isolated in pure culture from the blood of a patient with peritonitis of appendicular origin. According to the 16S rRNA gene sequences, this strain was close to Desulfovibrio fairfieldensis. The present report describes the fourth isolate of this recently described species to be isolated in pure culture or as a predominant part of the flora and to be associated with infectious processes. Thus, D. fairfieldensis may possess a higher pathogenic potential than other Desulfovibrio species.

Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care.
BACKGROUND Cancer survivors represent a growing population, heterogeneous in their need for medical care, psychosocial support, and practical assistance. To inform survivorship research and practice, this manuscript will describe the prevalent population of cancer survivors in terms of overall numbers and prevalence by cancer site and time since diagnosis. METHODS Incidence and survival data from 1975-2007 were obtained from the Surveillance, Epidemiology, and End Results Program and population projections from the United States Census Bureau. Cancer prevalence for 2012 and beyond was estimated using the Prevalence Incidence Approach Model, assuming constant future incidence and survival trends but dynamic projections of the U.S. population. RESULTS As of January 1, 2012, approximately 13.7 million cancer survivors were living in the United States with prevalence projected to approach 18 million by 2022. Sixty-four percent of this population have survived 5 years or more; 40% have survived 10 years or more; and 15% have survived 20 years or more after diagnosis. Over the next decade, the number of people who have lived 5 years or more after their cancer diagnosis is projected to increase approximately 37% to 11.9 million. CONCLUSIONS A coordinated agenda for research and practice is needed to address cancer survivors' long-term medical, psychosocial, and practical needs across the survivorship trajectory. IMPACT Prevalence estimates for cancer survivors across the survivorship trajectory will inform the national research agenda as well as future projections about the health service needs of this population.

Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial.
BACKGROUND Angiotensin receptor blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to reduce proteinuria. Their combination might be more effective than either treatment alone, but long-term data for comparative changes in renal function are not available. We investigated the renal effects of ramipril (an ACE inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage. METHODS The trial ran from 2001 to 2007. After a 3-week run-in period, 25 620 participants were randomly assigned to ramipril 10 mg a day (n=8576), telmisartan 80 mg a day (n=8542), or to a combination of both drugs (n=8502; median follow-up was 56 months), and renal function and proteinuria were measured. The primary renal outcome was a composite of dialysis, doubling of serum creatinine, and death. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00153101. FINDINGS 784 patients permanently discontinued randomised therapy during the trial because of hypotensive symptoms (406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of events for the composite primary outcome was similar for telmisartan (n=1147 [13.4%]) and ramipril (1150 [13.5%]; hazard ratio [HR] 1.00, 95% CI 0.92-1.09), but was increased with combination therapy (1233 [14.5%]; HR 1.09, 1.01-1.18, p=0.037). The secondary renal outcome, dialysis or doubling of serum creatinine, was similar with telmisartan (189 [2.21%]) and ramipril (174 [2.03%]; HR 1.09, 0.89-1.34) and more frequent with combination therapy (212 [2.49%]: HR 1.24, 1.01-1.51, p=0.038). Estimated glomerular filtration rate (eGFR) declined least with ramipril compared with telmisartan (-2.82 [SD 17.2] mL/min/1.73 m(2)vs -4.12 [17.4], p<0.0001) or combination therapy (-6.11 [17.9], p<0.0001). The increase in urinary albumin excretion was less with telmisartan (p=0.004) or with combination therapy (p=0.001) than with ramipril. INTERPRETATION In people at high vascular risk, telmisartan's effects on major renal outcomes are similar to ramipril. Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes.

2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.
OBJECTIVE The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. METHODS A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease--this being the appropriate current paradigm underlying the disease construct 'RA'. RESULTS In the new criteria set, classification as 'definite RA' is based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0-5), serological abnormality (range 0-3), elevated acute-phase response (range 0-1) and symptom duration (two levels; range 0-1). CONCLUSION This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct 'RA'.

Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough: diagnostic study
OBJECTIVES To quantify the diagnostic accuracy of selected inflammatory markers in addition to symptoms and signs for predicting pneumonia and to derive a diagnostic tool. DESIGN Diagnostic study performed between 2007 and 2010. Participants had their history taken, underwent physical examination and measurement of C reactive protein (CRP) and procalcitonin in venous blood on the day they first consulted, and underwent chest radiography within seven days. SETTING Primary care centres in 12 European countries. PARTICIPANTS Adults presenting with acute cough. MAIN OUTCOME MEASURES Pneumonia as determined by radiologists, who were blind to all other information when they judged chest radiographs. RESULTS Of 3106 eligible patients, 286 were excluded because of missing or inadequate chest radiographs, leaving 2820 patients (mean age 50, 40% men) of whom 140 (5%) had pneumonia. Re-assessment of a subset of 1675 chest radiographs showed agreement in 94% (κ 0.45, 95% confidence interval 0.36 to 0.54). Six published "symptoms and signs models" varied in their discrimination (area under receiver operating characteristics curve (ROC) ranged from 0.55 (95% confidence interval 0.50 to 0.61) to 0.71 (0.66 to 0.76)). The optimal combination of clinical prediction items derived from our patients included absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever, with an ROC area of 0.70 (0.65 to 0.75). Addition of CRP at the optimal cut off of >30 mg/L increased the ROC area to 0.77 (0.73 to 0.81) and improved the diagnostic classification (net reclassification improvement 28%). In the 1556 patients classified according to symptoms, signs, and CRP >30 mg/L as "low risk" (<2.5%) for pneumonia, the prevalence of pneumonia was 2%. In the 132 patients classified as "high risk" (>20%), the prevalence of pneumonia was 31%. The positive likelihood ratio of low, intermediate, and high risk for pneumonia was 0.4, 1.2, and 8.6 respectively. Measurement of procalcitonin added no relevant additional diagnostic information. A simplified diagnostic score based on symptoms, signs, and CRP >30 mg/L resulted in proportions of pneumonia of 0.7%, 3.8%, and 18.2% in the low, intermediate, and high risk group respectively. CONCLUSIONS A clinical rule based on symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough performed best in patients with mild or severe clinical presentation. Addition of CRP concentration at the optimal cut off of >30 mg/L improved diagnostic information, but measurement of procalcitonin concentration did not add clinically relevant information in this group.

Elevated red blood cell distribution width contributes to poor prognosis in patients undergoing resection for nonmetastatic rectal cancer
Several studies have reported that elevated red blood cell distribution width (RDW) was associated with the poor prognosis of different kinds of cancers. The aim of this study was to investigate the prognostic role of RDW in patients undergoing resection for nonmetastatic rectal cancer. We retrospectively reviewed a database of 625 consecutive patients who underwent curative resection for nonmetastatic rectal cancer at our institution from January 2009 to December 2014. The cutoff value of RDW was calculated by receiver-operating characteristic curve. The results demonstrated that patients in high RDW-cv group had a lower overall survival (OS) (P = .018) and disease-free survival (P = .004). We also observed that patients in high RDW-sd group were associated with significantly lower OS (P = .033), whereas the disease-free survival (DFS) was not significantly different (P = .179).In multivariate analysis, we found elevated RDW-cv was associated poor DFS (hazard ratio [HR] = 1.56, P = .010) and RDW-sd can predict a worse OS (HR = 1.70, P = .009).We confirmed that elevated RDW can be an independently prognostic factor in patients undergoing resection for nonmetastatic rectal cancer. So more intervention or surveillance might be paid to the patients with nonmetastatic rectal cancer and elevated RDW values in the future.

Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer.
Conditions related to chronic hyperinsulinemia, such as obesity, noninsulin dependent diabetes mellitus and polycystic ovary syndrome, are associated with an increased risk of endometrial cancer. Elevated plasma IGF-I and decreased levels of IGF-binding proteins have been shown to be associated with increased risk of several cancer types that are frequent in affluent societies. We investigated for the first time in a prospective study the association of pre-diagnostic blood concentrations of C-peptide (a marker of pancreatic insulin production), IGF-I, IGFBP-1, -2 and -3 with endometrial cancer risk. A case-control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). It included 166 women with primary invasive endometrial cancer and 315 matched controls, of which 44 case and 78 control subjects were premenopausal at recruitment. Endometrial cancer risk increased with increasing levels of C-peptide (ptrend = 0.0002), up to an odds ratio (OR) of 4.76 [95% confidence interval (CI) = 1.91-11.8] for the highest quintile. This association remained after adjustment for BMI and other confounders [OR for the top quintile = 4.40 (1.65-11.7)]. IGFBP-1 levels were inversely related to endometrial cancer [ptrend = 0.002; OR in the upper quintile = 0.30 (0.15-0.62)], but the association was weakened and lost statistical significance after adjustment for confounders [ptrend = 0.06; OR in the upper quintile = 0.49 (0.22-1.07)]. Risk was unrelated to levels of IGF-I, IGFBP-2 and IGFBP-3. Chronic hyperinsulinemia, as reflected by increased circulating C-peptide, is associated with increased endometrial cancer risk. Decrease in the prevalence of chronic hyperinsulinemia, through changes in lifestyle or medication, is expected to prevent endometrial cancer.

Instruction: Given a scientific claim, retrieve documents that support or refute the claim