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[ "Chronic feeding on high-calorie diets causes obesity and type 2 diabetes mellitus (T2DM), illnesses that affect hundreds of millions.", "Thus, understanding the pathways protecting against diet-induced metabolic imbalance is of paramount medical importance.", "Here, we show that mice lacking SIRT1 in steroidogenic factor 1 (SF1) neurons are hypersensitive to dietary obesity owing to maladaptive energy expenditure.", "Also, mutant mice have increased susceptibility to developing dietary T2DM due to insulin resistance in skeletal muscle.", "Mechanistically, these aberrations arise, in part, from impaired metabolic actions of the neuropeptide orexin-A and the hormone leptin.", "Conversely, mice overexpressing SIRT1 in SF1 neurons are more resistant to diet-induced obesity and insulin resistance due to increased energy expenditure and enhanced skeletal muscle insulin sensitivity.", "Our results unveil important protective roles of SIRT1 in SF1 neurons against dietary metabolic imbalance." ]

[ 2, 3, 5 ]

[ "Chronic feeding on high-calorie diets causes obesity and type 2 diabetes mellitus (T2DM), illnesses that affect hundreds of millions.", "Thus, understanding the pathways protecting against diet-induced metabolic imbalance is of paramount medical importance.", "Here, we show that mice lacking SIRT1 in steroidogenic factor 1 (SF1) neurons are hypersensitive to dietary obesity owing to maladaptive energy expenditure.", "Also, mutant mice have increased susceptibility to developing dietary T2DM due to insulin resistance in skeletal muscle.", "Mechanistically, these aberrations arise, in part, from impaired metabolic actions of the neuropeptide orexin-A and the hormone leptin.", "Conversely, mice overexpressing SIRT1 in SF1 neurons are more resistant to diet-induced obesity and insulin resistance due to increased energy expenditure and enhanced skeletal muscle insulin sensitivity.", "Our results unveil important protective roles of SIRT1 in SF1 neurons against dietary metabolic imbalance." ]

[ 2, 3, 5 ]

[ "BACKGROUND Interleukin (IL)-12 exerts a potent proinflammatory effect by stimulating T-helper (Th) 1 responses.", "This effect is believed to be mediated primarily through the activation of STAT4 and subsequent production of interferon (IFN)-gamma.", "Methods and Results- We examined the role of IL-12 receptor (IL-12R) signaling in the development of murine experimental autoimmune myocarditis (EAM) induced by cardiac myosin immunization.", "Both IL-12Rbeta1-deficient mice and STAT4-deficient mice were resistant to the induction of myocarditis.", "Treatment with exogenous IL-12 exacerbated disease.", "We questioned whether IFN-gamma is required for the disease-promoting activity of IL-12.", "On the contrary, we found that IFN-gamma suppresses EAM.", "Lack of IFN-gamma due to either depletion with an antibody or a genetic deficiency exacerbated myocarditis.", "Spleens from IFN-gamma-deficient mice immunized with cardiac myosin showed increased cellularity; greater numbers of CD3+, CD4+, CD8+, and IL-2-producing cells; and heightened ability to produce cytokines on stimulation in vitro.", "Treatment of mice with recombinant IFN-gamma suppressed the development of myocarditis.", "CONCLUSIONS IL-12/IL-12R/STAT4 signaling promotes the development of EAM.", "In contrast, IFN-gamma plays a protective role.", "The disease-limiting effects of IFN-gamma might be explained by its ability to control the expansion of activated T lymphocytes." ]

[ 7, 11 ]

[ "BACKGROUND Interferon-gamma (IFN-gamma) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases.", "Little is known about its role in inflammatory heart disease.", "METHODS AND RESULTS We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality.", "Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease.", "The persistent inflammation was accompanied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-gammaR(-/-) hearts.", "Treatment of wild-type mice with the nitric oxide synthetase inhibitor N:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis.", "CONCLUSIONS Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses." ]

[ 2, 3, 6 ]

[ "BACKGROUND Interleukin (IL)-12 exerts a potent proinflammatory effect by stimulating T-helper (Th) 1 responses.", "This effect is believed to be mediated primarily through the activation of STAT4 and subsequent production of interferon (IFN)-gamma.", "Methods and Results- We examined the role of IL-12 receptor (IL-12R) signaling in the development of murine experimental autoimmune myocarditis (EAM) induced by cardiac myosin immunization.", "Both IL-12Rbeta1-deficient mice and STAT4-deficient mice were resistant to the induction of myocarditis.", "Treatment with exogenous IL-12 exacerbated disease.", "We questioned whether IFN-gamma is required for the disease-promoting activity of IL-12.", "On the contrary, we found that IFN-gamma suppresses EAM.", "Lack of IFN-gamma due to either depletion with an antibody or a genetic deficiency exacerbated myocarditis.", "Spleens from IFN-gamma-deficient mice immunized with cardiac myosin showed increased cellularity; greater numbers of CD3+, CD4+, CD8+, and IL-2-producing cells; and heightened ability to produce cytokines on stimulation in vitro.", "Treatment of mice with recombinant IFN-gamma suppressed the development of myocarditis.", "CONCLUSIONS IL-12/IL-12R/STAT4 signaling promotes the development of EAM.", "In contrast, IFN-gamma plays a protective role.", "The disease-limiting effects of IFN-gamma might be explained by its ability to control the expansion of activated T lymphocytes." ]

[ 7, 11 ]

[ "The antibacterial peptide microcin J25 (MccJ25) inhibits transcription by bacterial RNA polymerase (RNAP).", "Biochemical results indicate that inhibition of transcription occurs at the level of NTP uptake or NTP binding by RNAP.", "Genetic results indicate that inhibition of transcription requires an extensive determinant, comprising more than 50 amino acid residues, within the RNAP secondary channel (also known as the \"NTP-uptake channel\" or \"pore\").", "Biophysical results indicate that inhibition of transcription involves binding of MccJ25 within the RNAP secondary channel.", "Molecular modeling indicates that binding of MccJ25 within the RNAP secondary channel obstructs the RNAP secondary channel.", "We conclude that MccJ25 inhibits transcription by binding within and obstructing the RNAP secondary channel--acting essentially as a \"cork in a bottle.", "\"", "Obstruction of the RNAP secondary channel represents an attractive target for drug discovery." ]

[ 1 ]

[ "The antibacterial peptide microcin J25 (MccJ25) inhibits transcription by bacterial RNA polymerase (RNAP).", "Biochemical results indicate that inhibition of transcription occurs at the level of NTP uptake or NTP binding by RNAP.", "Genetic results indicate that inhibition of transcription requires an extensive determinant, comprising more than 50 amino acid residues, within the RNAP secondary channel (also known as the \"NTP-uptake channel\" or \"pore\").", "Biophysical results indicate that inhibition of transcription involves binding of MccJ25 within the RNAP secondary channel.", "Molecular modeling indicates that binding of MccJ25 within the RNAP secondary channel obstructs the RNAP secondary channel.", "We conclude that MccJ25 inhibits transcription by binding within and obstructing the RNAP secondary channel--acting essentially as a \"cork in a bottle.", "\"", "Obstruction of the RNAP secondary channel represents an attractive target for drug discovery." ]

[ 1 ]

[ "Recent findings challenge the concept that microglia solely function in disease states in the central nervous system (CNS).", "Rather than simply reacting to CNS injury, infection, or pathology, emerging lines of evidence indicate that microglia sculpt the structure of the CNS, refine neuronal circuitry and network connectivity, and contribute to plasticity.", "These physiological functions of microglia in the normal CNS begin during development and persist into maturity.", "Here, we develop a conceptual framework for functions of microglia beyond neuroinflammation and discuss the rich repertoire of signaling and communication motifs in microglia that are critical both in pathology and for the normal physiology of the CNS." ]

[ 2, 3 ]

[ "Recent findings challenge the concept that microglia solely function in disease states in the central nervous system (CNS).", "Rather than simply reacting to CNS injury, infection, or pathology, emerging lines of evidence indicate that microglia sculpt the structure of the CNS, refine neuronal circuitry and network connectivity, and contribute to plasticity.", "These physiological functions of microglia in the normal CNS begin during development and persist into maturity.", "Here, we develop a conceptual framework for functions of microglia beyond neuroinflammation and discuss the rich repertoire of signaling and communication motifs in microglia that are critical both in pathology and for the normal physiology of the CNS." ]

[ 2, 3 ]

[ "OBJECTIVE To evaluate the association between migraine and cardiovascular disease, including stroke, myocardial infarction, and death due to cardiovascular disease.", "DESIGN Systematic review and meta-analysis.", "DATA SOURCES Electronic databases (PubMed, Embase, Cochrane Library) and reference lists of included studies and reviews published until January 2009.", "Selection criteria Case-control and cohort studies investigating the association between any migraine or specific migraine subtypes and cardiovascular disease.", "Review methods Two investigators independently assessed eligibility of identified studies in a two step approach.", "Disagreements were resolved by consensus.", "Studies were grouped according to a priori categories on migraine and cardiovascular disease.", "DATA EXTRACTION Two investigators extracted data.", "Pooled relative risks and 95% confidence intervals were calculated.", "RESULTS Studies were heterogeneous for participant characteristics and definition of cardiovascular disease.", "Nine studies investigated the association between any migraine and ischaemic stroke (pooled relative risk 1.73, 95% confidence interval 1.31 to 2.29).", "Additional analyses indicated a significantly higher risk among people who had migraine with aura (2.16, 1.53 to 3.03) compared with people who had migraine without aura (1.23, 0.90 to 1.69; meta-regression for aura status P=0.02).", "Furthermore, results suggested a greater risk among women (2.08, 1.13 to 3.84) compared with men (1.37, 0.89 to 2.11).", "Age less than 45 years, smoking, and oral contraceptive use further increased the risk.", "Eight studies investigated the association between migraine and myocardial infarction (1.12, 0.95 to 1.32) and five between migraine and death due to cardiovascular disease (1.03, 0.79 to 1.34).", "Only one study investigated the association between women who had migraine with aura and myocardial infarction and death due to cardiovascular disease, showing a twofold increased risk.", "CONCLUSION Migraine is associated with a twofold increased risk of ischaemic stroke, which is only apparent among people who have migraine with aura.", "Our results also suggest a higher risk among women and risk was further magnified for people with migraine who were aged less than 45, smokers, and women who used oral contraceptives.", "We did not find an overall association between any migraine and myocardial infarction or death due to cardiovascular disease.", "Too few studies are available to reliably evaluate the impact of modifying factors, such as migraine aura, on these associations." ]

[ 11, 16 ]

[ "OBJECTIVES To identify and describe misunderstandings between patients and doctors associated with prescribing decisions in general practice.", "DESIGN Qualitative study.", "SETTING 20 general practices in the West Midlands and south east England.", "PARTICIPANTS 20 general practitioners and 35 consulting patients.", "MAIN OUTCOME MEASURES Misunderstandings between patients and doctors that have potential or actual adverse consequences for taking medicine.", "RESULTS 14 categories of misunderstanding were identified relating to patient information unknown to the doctor, doctor information unknown to the patient, conflicting information, disagreement about attribution of side effects, failure of communication about doctor's decision, and relationship factors.", "All the misunderstandings were associated with lack of patients' participation in the consultation in terms of the voicing of expectations and preferences or the voicing of responses to doctors' decisions and actions.", "They were all associated with potential or actual adverse outcomes such as non-adherence to treatment.", "Many were based on inaccurate guesses and assumptions.", "In particular doctors seemed unaware of the relevance of patients' ideas about medicines for successful prescribing.", "CONCLUSIONS Patients' participation in the consultation and the adverse consequences of lack of participation are important.", "The authors are developing an educational intervention that builds on these findings." ]

[ 6, 7 ]

[ "Mitochondria are the primary energy-generating system in most eukaryotic cells.", "Additionally, they participate in intermediary metabolism, calcium signaling, and apoptosis.", "Given these well-established functions, it might be expected that mitochondrial dysfunction would give rise to a simple and predictable set of defects in all tissues.", "However, mitochondrial dysfunction has pleiotropic effects in multicellular organisms.", "Clearly, much about the basic biology of mitochondria remains to be understood.", "Here we discuss recent work that suggests that the dynamics (fusion and fission) of these organelles is important in development and disease." ]

[ 1 ]

[ "Mitochondria are the primary energy-generating system in most eukaryotic cells.", "Additionally, they participate in intermediary metabolism, calcium signaling, and apoptosis.", "Given these well-established functions, it might be expected that mitochondrial dysfunction would give rise to a simple and predictable set of defects in all tissues.", "However, mitochondrial dysfunction has pleiotropic effects in multicellular organisms.", "Clearly, much about the basic biology of mitochondria remains to be understood.", "Here we discuss recent work that suggests that the dynamics (fusion and fission) of these organelles is important in development and disease." ]

[ 0 ]

[ "Mitochondria are the primary energy-generating system in most eukaryotic cells.", "Additionally, they participate in intermediary metabolism, calcium signaling, and apoptosis.", "Given these well-established functions, it might be expected that mitochondrial dysfunction would give rise to a simple and predictable set of defects in all tissues.", "However, mitochondrial dysfunction has pleiotropic effects in multicellular organisms.", "Clearly, much about the basic biology of mitochondria remains to be understood.", "Here we discuss recent work that suggests that the dynamics (fusion and fission) of these organelles is important in development and disease." ]

[ 1 ]

[ "Our attitude towards candy—“if it tastes that good, it can't be healthy”—betrays society's puritanical stance towards pleasure.", "Candy has been blamed for various ills, including hyperactivity in children; however, clinical trials have not supported this.1 Candy—sugar confectionery and chocolate—is not a recent invention: the ancient Arabs, Chinese, and Egyptians candied fruits and nuts in honey, and the Aztecs made a chocolate drink from the bean of the cacao tree.", "Today, Americans gratify themselves with, on average, 5.4 kg of sugar candy and 6.5 kg of chocolate per person annually.2 Since candy has existed for centuries, we surmised that it cannot be totally unhealthy.", "We decided to investigate whether candy consumption was associated with longevity.", "Subjects were from the Harvard alumni health study, an ongoing study of men entering Harvard University as undergraduates between 1916 and 1950.", "We included 7841 men, free of cardiovascular disease and cancer, who responded to a health survey …" ]

[]

[ "The transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is a lethal event of uncertain molecular etiology.", "Comparing gene expression in isogenic androgen-dependent and CRPC xenografts, we found a reproducible increase in N-cadherin expression, which was also elevated in primary and metastatic tumors of individuals with CRPC.", "Ectopic expression of N-cadherin in nonmetastatic, androgen-dependent prostate cancer models caused castration resistance, invasion and metastasis.", "Monoclonal antibodies against the ectodomain of N-cadherin reduced proliferation, adhesion and invasion of prostate cancer cells in vitro.", "In vivo, these antibodies slowed the growth of multiple established CRPC xenografts, blocked local invasion and metastasis and, at higher doses, led to complete regression.", "N-cadherin–specific antibodies markedly delayed the time to emergence of castration resistance, markedly affected tumor histology and angiogenesis, and reduced both AKT serine-threonine kinase activity and serum interleukin-8 (IL-8) secretion.", "These data indicate that N-cadherin is a major cause of both prostate cancer metastasis and castration resistance.", "Therapeutic targeting of this factor with monoclonal antibodies may have considerable clinical benefit." ]

[ 5 ]

[ "The transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is a lethal event of uncertain molecular etiology.", "Comparing gene expression in isogenic androgen-dependent and CRPC xenografts, we found a reproducible increase in N-cadherin expression, which was also elevated in primary and metastatic tumors of individuals with CRPC.", "Ectopic expression of N-cadherin in nonmetastatic, androgen-dependent prostate cancer models caused castration resistance, invasion and metastasis.", "Monoclonal antibodies against the ectodomain of N-cadherin reduced proliferation, adhesion and invasion of prostate cancer cells in vitro.", "In vivo, these antibodies slowed the growth of multiple established CRPC xenografts, blocked local invasion and metastasis and, at higher doses, led to complete regression.", "N-cadherin–specific antibodies markedly delayed the time to emergence of castration resistance, markedly affected tumor histology and angiogenesis, and reduced both AKT serine-threonine kinase activity and serum interleukin-8 (IL-8) secretion.", "These data indicate that N-cadherin is a major cause of both prostate cancer metastasis and castration resistance.", "Therapeutic targeting of this factor with monoclonal antibodies may have considerable clinical benefit." ]

[ 4, 7 ]

[ "The transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is a lethal event of uncertain molecular etiology.", "Comparing gene expression in isogenic androgen-dependent and CRPC xenografts, we found a reproducible increase in N-cadherin expression, which was also elevated in primary and metastatic tumors of individuals with CRPC.", "Ectopic expression of N-cadherin in nonmetastatic, androgen-dependent prostate cancer models caused castration resistance, invasion and metastasis.", "Monoclonal antibodies against the ectodomain of N-cadherin reduced proliferation, adhesion and invasion of prostate cancer cells in vitro.", "In vivo, these antibodies slowed the growth of multiple established CRPC xenografts, blocked local invasion and metastasis and, at higher doses, led to complete regression.", "N-cadherin–specific antibodies markedly delayed the time to emergence of castration resistance, markedly affected tumor histology and angiogenesis, and reduced both AKT serine-threonine kinase activity and serum interleukin-8 (IL-8) secretion.", "These data indicate that N-cadherin is a major cause of both prostate cancer metastasis and castration resistance.", "Therapeutic targeting of this factor with monoclonal antibodies may have considerable clinical benefit." ]

[ 5 ]

[ "The transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is a lethal event of uncertain molecular etiology.", "Comparing gene expression in isogenic androgen-dependent and CRPC xenografts, we found a reproducible increase in N-cadherin expression, which was also elevated in primary and metastatic tumors of individuals with CRPC.", "Ectopic expression of N-cadherin in nonmetastatic, androgen-dependent prostate cancer models caused castration resistance, invasion and metastasis.", "Monoclonal antibodies against the ectodomain of N-cadherin reduced proliferation, adhesion and invasion of prostate cancer cells in vitro.", "In vivo, these antibodies slowed the growth of multiple established CRPC xenografts, blocked local invasion and metastasis and, at higher doses, led to complete regression.", "N-cadherin–specific antibodies markedly delayed the time to emergence of castration resistance, markedly affected tumor histology and angiogenesis, and reduced both AKT serine-threonine kinase activity and serum interleukin-8 (IL-8) secretion.", "These data indicate that N-cadherin is a major cause of both prostate cancer metastasis and castration resistance.", "Therapeutic targeting of this factor with monoclonal antibodies may have considerable clinical benefit." ]

[ 3 ]

[ "Many fundamental aspects of DNA replication, such as the exact locations where DNA synthesis is initiated and terminated, how frequently origins are used, and how fork progression is influenced by transcription, are poorly understood.", "Via the deep sequencing of Okazaki fragments, we comprehensively document replication fork directionality throughout the S. cerevisiae genome, which permits the systematic analysis of initiation, origin efficiency, fork progression, and termination.", "We show that leading-strand initiation preferentially occurs within a nucleosome-free region at replication origins.", "Using a strain in which late origins can be induced to fire early, we show that replication termination is a largely passive phenomenon that does not rely on cis-acting sequences or replication fork pausing.", "The replication profile is predominantly determined by the kinetics of origin firing, allowing us to reconstruct chromosome-wide timing profiles from an asynchronous culture." ]

[ 4 ]

[ "Haploid cells are amenable for genetic analysis.", "Recent success in the derivation of mouse haploid embryonic stem cells (haESCs) via parthenogenesis has enabled genetic screening in mammalian cells.", "However, successful generation of live animals from these haESCs, which is needed to extend the genetic analysis to the organism level, has not been achieved.", "Here, we report the derivation of haESCs from androgenetic blastocysts.", "These cells, designated as AG-haESCs, partially maintain paternal imprints, express classical ESC pluripotency markers, and contribute to various tissues, including the germline, upon injection into diploid blastocysts.", "Strikingly, live mice can be obtained upon injection of AG-haESCs into MII oocytes, and these mice bear haESC-carried genetic traits and develop into fertile adults.", "Furthermore, gene targeting via homologous recombination is feasible in the AG-haESCs.", "Our results demonstrate that AG-haESCs can be used as a genetically tractable fertilization agent for the production of live animals via injection into oocytes." ]

[ 5 ]

[ "The only proven requirement for ascorbic acid (vitamin C) is in preventing scurvy, presumably because it is a cofactor for hydroxylases required for post-translational modifications that stabilize collagen.", "We have created mice deficient in the mouse ortholog (solute carrier family 23 member 1 or Slc23a1) of a rat ascorbic-acid transporter, Svct2 (ref.", "4).", "Cultured embryonic fibroblasts from homozygous Slc23a1−/− mice had less than 5% of normal ascorbic-acid uptake.", "Ascorbic-acid levels were undetectable or markedly reduced in the blood and tissues of Slc23a1−/− mice.", "Prenatal supplementation of pregnant females did not elevate blood ascorbic acid in Slc23a1−/− fetuses, suggesting Slc23a1 is important in placental ascorbic-acid transport.", "Slc23a1−/− mice died within a few minutes of birth with respiratory failure and intraparenchymal brain hemorrhage.", "Lungs showed no postnatal expansion but had normal surfactant protein B levels.", "Brain hemorrhage was unlikely to be simply a form of scurvy since Slc23a1−/− mice showed no hemorrhage in any other tissues and their skin had normal skin 4-hydroxyproline levels despite low ascorbic-acid content.", "We conclude that Slc23a1 is required for transport of ascorbic acid into many tissues and across the placenta.", "Deficiency of the transporter is lethal in newborn mice, thereby revealing a previously unrecognized requirement for ascorbic acid in the perinatal period." ]

[ 4, 6, 8 ]

[ "Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gβ subunits have not been defined.", "Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling.", "Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gβγ dimer.", "Different mutations in Gβ proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms.", "Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies.", "In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival.", "In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF.", "Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context.", "Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling." ]

[]

[ "In the yeast Saccharomyces cerevisiae, genetic studies suggest that the RIM1 gene encodes a positive regulator of meiosis.", "rim1 mutations cause reduced expression of IME1, which is required for expression of many meiotic genes, and thus lead to a partial defect in meiosis and spore formation.", "We report the sequence of RIM1 and functional analysis of its coding region.", "The RIM1 gene product (RIM1) contains three regions similar to C2H2 zinc fingers.", "Serine substitutions for cysteine in each of the putative zinc fingers abolish RIM1 function.", "The carboxyl-terminus of RIM1 is enriched in acidic amino acids and is required for full RIM1 activity.", "RIM1 also contains two putative cAMP-dependent protein kinase (cAPK) phosphorylation sites.", "At one site, substitution of alanine for serine does not affect RIM1 activity; at the other site, this substitution impairs activity.", "This analysis of RIM1 suggests that the protein may function as a transcriptional activator.", "We have used the cloned RIM1 gene to create a complete rim1 deletion.", "This null allele, like previously isolated rim1 mutations, causes a partial meiotic defect.", "In addition to RIM1, maximum IME1 expression requires the MCK1 and IME4 gene products.", "Defects associated with rim1, mck1, and ime4 mutations in expression of a meiotic reporter gene (ime2-lacZ) and in sporulation are additive.", "These findings suggest that RIM1 acts independently of MCK1 and IME4 to stimulate IME1 expression." ]

[ 1, 13 ]

[ "In the yeast Saccharomyces cerevisiae, genetic studies suggest that the RIM1 gene encodes a positive regulator of meiosis.", "rim1 mutations cause reduced expression of IME1, which is required for expression of many meiotic genes, and thus lead to a partial defect in meiosis and spore formation.", "We report the sequence of RIM1 and functional analysis of its coding region.", "The RIM1 gene product (RIM1) contains three regions similar to C2H2 zinc fingers.", "Serine substitutions for cysteine in each of the putative zinc fingers abolish RIM1 function.", "The carboxyl-terminus of RIM1 is enriched in acidic amino acids and is required for full RIM1 activity.", "RIM1 also contains two putative cAMP-dependent protein kinase (cAPK) phosphorylation sites.", "At one site, substitution of alanine for serine does not affect RIM1 activity; at the other site, this substitution impairs activity.", "This analysis of RIM1 suggests that the protein may function as a transcriptional activator.", "We have used the cloned RIM1 gene to create a complete rim1 deletion.", "This null allele, like previously isolated rim1 mutations, causes a partial meiotic defect.", "In addition to RIM1, maximum IME1 expression requires the MCK1 and IME4 gene products.", "Defects associated with rim1, mck1, and ime4 mutations in expression of a meiotic reporter gene (ime2-lacZ) and in sporulation are additive.", "These findings suggest that RIM1 acts independently of MCK1 and IME4 to stimulate IME1 expression." ]

[ 1, 13 ]

[ "We report a newly developed technique for high-resolution in vivo imaging of myelinated axons in the brain, spinal cord and peripheral nerve that requires no fluorescent labeling.", "This method, based on spectral confocal reflectance microscopy (SCoRe), uses a conventional laser-scanning confocal system to generate images by merging the simultaneously reflected signals from multiple lasers of different wavelengths.", "Striking color patterns unique to individual myelinated fibers are generated that facilitate their tracing in dense axonal areas.", "These patterns highlight nodes of Ranvier and Schmidt-Lanterman incisures and can be used to detect various myelin pathologies.", "Using SCoRe we carried out chronic brain imaging up to 400 μm deep, capturing de novo myelination of mouse cortical axons in vivo.", "We also established the feasibility of imaging myelinated axons in the human cerebral cortex.", "SCoRe adds a powerful component to the evolving toolbox for imaging myelination in living animals and potentially in humans." ]

[]

[ "We report a newly developed technique for high-resolution in vivo imaging of myelinated axons in the brain, spinal cord and peripheral nerve that requires no fluorescent labeling.", "This method, based on spectral confocal reflectance microscopy (SCoRe), uses a conventional laser-scanning confocal system to generate images by merging the simultaneously reflected signals from multiple lasers of different wavelengths.", "Striking color patterns unique to individual myelinated fibers are generated that facilitate their tracing in dense axonal areas.", "These patterns highlight nodes of Ranvier and Schmidt-Lanterman incisures and can be used to detect various myelin pathologies.", "Using SCoRe we carried out chronic brain imaging up to 400 μm deep, capturing de novo myelination of mouse cortical axons in vivo.", "We also established the feasibility of imaging myelinated axons in the human cerebral cortex.", "SCoRe adds a powerful component to the evolving toolbox for imaging myelination in living animals and potentially in humans." ]

[ 0, 2 ]

[ "Background The catalytically active 66-kDa subunit of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) consists of DNA polymerase, connection, and ribonuclease H (RNase H) domains.", "Almost all known RT inhibitor resistance mutations identified to date map to the polymerase domain of the enzyme.", "However, the connection and RNase H domains are not routinely analysed in clinical samples and none of the genotyping assays available for patient management sequence the entire RT coding region.", "The British Columbia Centre for Excellence in HIV/AIDS (the Centre) genotypes clinical isolates up to codon 400 in RT, and our retrospective statistical analyses of the Centre’s database have identified an N348I mutation in the RT connection domain in treatment-experienced individuals.", "The objective of this multidisciplinary study was to establish the in vivo relevance of this mutation and its role in drug resistance.", "Methods and Findings The prevalence of N348I in clinical isolates, the time taken for it to emerge under selective drug pressure, and its association with changes in viral load, specific drug treatment, and known drug resistance mutations was analysed from genotypes, viral loads, and treatment histories from the Centre’s database.", "N348I increased in prevalence from below 1% in 368 treatmentnao ¨ve individuals to 12.1% in 1,009 treatment-experienced patients (p ¼ 7.7 3 10 � 12 ).", "N348I appeared early in therapy and was highly associated with thymidine analogue mutations (TAMs) M41L and T215Y/F (p , 0.001), the lamivudine resistance mutations M184V/I (p , 0.001), and non-nucleoside RTI (NNRTI) resistance mutations K103N and Y181C/I (p , 0.001).", "The association with TAMs and NNRTI resistance mutations was consistent with the selection of N348I in patients treated with regimens that included both zidovudine and nevirapine (odds ratio 2.62, 95% confidence interval 1.43–4.81).", "The appearance of N348I was associated with a significant increase in viral load (p , 0.001), which was as large as the viral load increases observed for any of the TAMs.", "However, this analysis did not account for the simultaneous selection of other RT or protease inhibitor resistance mutations on viral load.", "To delineate the role of this mutation in RT inhibitor resistance, N348I was introduced into HIV-1 molecular clones containing different genetic backbones.", "N348I decreased zidovudine susceptibility 2- to 4-fold in the context of wildtype HIV-1 or when combined with TAMs.", "N348I also decreased susceptibility to nevirapine (7.4fold) and efavirenz (2.5-fold) and significantly potentiated resistance to these drugs when combined with K103N.", "Biochemical analyses of recombinant RT containing N348I provide supporting evidence for the role of this mutation in zidovudine and NNRTI resistance and give some insight into the molecular mechanism of resistance.", "Conclusions" ]

[ 13 ]

[ "Background The catalytically active 66-kDa subunit of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) consists of DNA polymerase, connection, and ribonuclease H (RNase H) domains.", "Almost all known RT inhibitor resistance mutations identified to date map to the polymerase domain of the enzyme.", "However, the connection and RNase H domains are not routinely analysed in clinical samples and none of the genotyping assays available for patient management sequence the entire RT coding region.", "The British Columbia Centre for Excellence in HIV/AIDS (the Centre) genotypes clinical isolates up to codon 400 in RT, and our retrospective statistical analyses of the Centre’s database have identified an N348I mutation in the RT connection domain in treatment-experienced individuals.", "The objective of this multidisciplinary study was to establish the in vivo relevance of this mutation and its role in drug resistance.", "Methods and Findings The prevalence of N348I in clinical isolates, the time taken for it to emerge under selective drug pressure, and its association with changes in viral load, specific drug treatment, and known drug resistance mutations was analysed from genotypes, viral loads, and treatment histories from the Centre’s database.", "N348I increased in prevalence from below 1% in 368 treatmentnao ¨ve individuals to 12.1% in 1,009 treatment-experienced patients (p ¼ 7.7 3 10 � 12 ).", "N348I appeared early in therapy and was highly associated with thymidine analogue mutations (TAMs) M41L and T215Y/F (p , 0.001), the lamivudine resistance mutations M184V/I (p , 0.001), and non-nucleoside RTI (NNRTI) resistance mutations K103N and Y181C/I (p , 0.001).", "The association with TAMs and NNRTI resistance mutations was consistent with the selection of N348I in patients treated with regimens that included both zidovudine and nevirapine (odds ratio 2.62, 95% confidence interval 1.43–4.81).", "The appearance of N348I was associated with a significant increase in viral load (p , 0.001), which was as large as the viral load increases observed for any of the TAMs.", "However, this analysis did not account for the simultaneous selection of other RT or protease inhibitor resistance mutations on viral load.", "To delineate the role of this mutation in RT inhibitor resistance, N348I was introduced into HIV-1 molecular clones containing different genetic backbones.", "N348I decreased zidovudine susceptibility 2- to 4-fold in the context of wildtype HIV-1 or when combined with TAMs.", "N348I also decreased susceptibility to nevirapine (7.4fold) and efavirenz (2.5-fold) and significantly potentiated resistance to these drugs when combined with K103N.", "Biochemical analyses of recombinant RT containing N348I provide supporting evidence for the role of this mutation in zidovudine and NNRTI resistance and give some insight into the molecular mechanism of resistance.", "Conclusions" ]

[ 13 ]

[ "CONTEXT The antioxidant acetylcysteine prevents acute contrast nephrotoxicity in patients with impaired renal function who undergo computed tomography scanning.", "However, its role in coronary angiography is unclear.", "OBJECTIVE To determine whether oral acetylcysteine prevents acute deterioration in renal function in patients with moderate renal insufficiency who undergo elective coronary angiography.", "DESIGN AND SETTING Prospective, randomized, double-blind, placebo-controlled trial conducted from May 2000 to December 2001 at the Grantham Hospital at the University of Hong Kong.", "PARTICIPANTS Two hundred Chinese patients aged mean (SD) 68 (6.5) years with stable moderate renal insufficiency (creatinine clearance <60 mL/min [1.00 mL/s]) who were undergoing elective coronary angiography with or without intervention.", "INTERVENTION Participants were randomly assigned to receive oral acetylcysteine(600 mg twice per day; n = 102) or matching placebo tablets (n = 98) on the day before and the day of angiography.", "All patients received low-osmolality contrast agent.", "MAIN OUTCOME MEASURES Occurrence of more than a 25% increase in serum creatinine level within 48 hours after contrast administration; change in creatinine clearance and serum creatinine level.", "RESULTS Twelve control patients (12%) and 4 acetylcysteine patients (4%) developed a more than 25% increase in serum creatinine level within 48 hours after contrast administration (relative risk, 0.32; 95% confidence interval [CI], 0.10-0.96; P =.03).", "Serum creatinine was lower in the acetylcysteine group (1.22 mg/dL [107.8 micromol/L]; 95% CI, 1.11-1.33 mg/dL vs 1.38 mg/dL [122.9 micromol/L]; 95% CI, 1.27-1.49 mg/dL; P =.006) during the first 48 hours after angiography.", "Acetylcysteine treatment significantly increased creatinine clearance from 44.8 mL/min (0.75 mL/s) (95% CI, 42.7-47.6 mL/min) to 58.9 mL/min (0.98 mL/s) (95% CI, 55.6-62.3 mL/min) 2 days after the contrast administration (P<.001).", "The increase was not significant in the control group (from 42.1 to 44.1 mL/min [0.70 to 0.74 mL/s]; P =.15).", "The benefit of acetylcysteine was consistent among various patient subgroups and persistent for at least 7 days.", "There were no major treatment-related adverse events.", "CONCLUSION Acetylcysteine protects patients with moderate chronic renal insufficiency from contrast-induced deterioration in renal function after coronary angiographic procedures, with minimal adverse effects and at a low cost." ]

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[ "CONTEXT The antioxidant acetylcysteine prevents acute contrast nephrotoxicity in patients with impaired renal function who undergo computed tomography scanning.", "However, its role in coronary angiography is unclear.", "OBJECTIVE To determine whether oral acetylcysteine prevents acute deterioration in renal function in patients with moderate renal insufficiency who undergo elective coronary angiography.", "DESIGN AND SETTING Prospective, randomized, double-blind, placebo-controlled trial conducted from May 2000 to December 2001 at the Grantham Hospital at the University of Hong Kong.", "PARTICIPANTS Two hundred Chinese patients aged mean (SD) 68 (6.5) years with stable moderate renal insufficiency (creatinine clearance <60 mL/min [1.00 mL/s]) who were undergoing elective coronary angiography with or without intervention.", "INTERVENTION Participants were randomly assigned to receive oral acetylcysteine(600 mg twice per day; n = 102) or matching placebo tablets (n = 98) on the day before and the day of angiography.", "All patients received low-osmolality contrast agent.", "MAIN OUTCOME MEASURES Occurrence of more than a 25% increase in serum creatinine level within 48 hours after contrast administration; change in creatinine clearance and serum creatinine level.", "RESULTS Twelve control patients (12%) and 4 acetylcysteine patients (4%) developed a more than 25% increase in serum creatinine level within 48 hours after contrast administration (relative risk, 0.32; 95% confidence interval [CI], 0.10-0.96; P =.03).", "Serum creatinine was lower in the acetylcysteine group (1.22 mg/dL [107.8 micromol/L]; 95% CI, 1.11-1.33 mg/dL vs 1.38 mg/dL [122.9 micromol/L]; 95% CI, 1.27-1.49 mg/dL; P =.006) during the first 48 hours after angiography.", "Acetylcysteine treatment significantly increased creatinine clearance from 44.8 mL/min (0.75 mL/s) (95% CI, 42.7-47.6 mL/min) to 58.9 mL/min (0.98 mL/s) (95% CI, 55.6-62.3 mL/min) 2 days after the contrast administration (P<.001).", "The increase was not significant in the control group (from 42.1 to 44.1 mL/min [0.70 to 0.74 mL/s]; P =.15).", "The benefit of acetylcysteine was consistent among various patient subgroups and persistent for at least 7 days.", "There were no major treatment-related adverse events.", "CONCLUSION Acetylcysteine protects patients with moderate chronic renal insufficiency from contrast-induced deterioration in renal function after coronary angiographic procedures, with minimal adverse effects and at a low cost." ]

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[ "Successful pregnancy requires coordination of an array of signals and factors from multiple tissues.", "One such element, liver receptor homolog-1 (Lrh-1), is an orphan nuclear receptor that regulates metabolism and hormone synthesis.", "It is strongly expressed in granulosa cells of ovarian follicles and in the corpus luteum of rodents and humans.", "Germline ablation of Nr5a2 (also called Lrh-1), the gene coding for Lrh-1, in mice is embryonically lethal at gastrulation.", "Depletion of Lrh-1 in the ovarian follicle shows that it regulates genes required for both steroid synthesis and ovulation.", "To study the effects of Lrh-1 on mouse gestation, we genetically disrupted its expression in the corpus luteum, resulting in luteal insufficiency.", "Hormone replacement permitted embryo implantation but was followed by gestational failure with impaired endometrial decidualization, compromised placental formation, fetal growth retardation and fetal death.", "Lrh-1 is also expressed in the mouse and human endometrium, and in a primary culture of human endometrial stromal cells, reduction of NR5A2 transcript abundance by RNA interference abrogated decidualization.", "These findings show that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for formation of the placenta.", "It therefore has multiple, indispensible roles in establishing and sustaining pregnancy." ]

[ 5, 6, 7 ]

[ "Successful pregnancy requires coordination of an array of signals and factors from multiple tissues.", "One such element, liver receptor homolog-1 (Lrh-1), is an orphan nuclear receptor that regulates metabolism and hormone synthesis.", "It is strongly expressed in granulosa cells of ovarian follicles and in the corpus luteum of rodents and humans.", "Germline ablation of Nr5a2 (also called Lrh-1), the gene coding for Lrh-1, in mice is embryonically lethal at gastrulation.", "Depletion of Lrh-1 in the ovarian follicle shows that it regulates genes required for both steroid synthesis and ovulation.", "To study the effects of Lrh-1 on mouse gestation, we genetically disrupted its expression in the corpus luteum, resulting in luteal insufficiency.", "Hormone replacement permitted embryo implantation but was followed by gestational failure with impaired endometrial decidualization, compromised placental formation, fetal growth retardation and fetal death.", "Lrh-1 is also expressed in the mouse and human endometrium, and in a primary culture of human endometrial stromal cells, reduction of NR5A2 transcript abundance by RNA interference abrogated decidualization.", "These findings show that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for formation of the placenta.", "It therefore has multiple, indispensible roles in establishing and sustaining pregnancy." ]

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[ "BACKGROUND Genetic and epidemiological evidence suggests an inverse association between B-type natriuretic peptide (BNP) levels in blood and risk of type 2 diabetes (T2D), but the prospective association of BNP with T2D is uncertain, and it is unclear whether the association is confounded.", "METHODS AND FINDINGS We analysed the association between levels of the N-terminal fragment of pro-BNP (NT-pro-BNP) in blood and risk of incident T2D in a prospective case-cohort study and genotyped the variant rs198389 within the BNP locus in three T2D case-control studies.", "We combined our results with existing data in a meta-analysis of 11 case-control studies.", "Using a Mendelian randomization approach, we compared the observed association between rs198389 and T2D to that expected from the NT-pro-BNP level to T2D association and the NT-pro-BNP difference per C allele of rs198389.", "In participants of our case-cohort study who were free of T2D and cardiovascular disease at baseline, we observed a 21% (95% CI 3%-36%) decreased risk of incident T2D per one standard deviation (SD) higher log-transformed NT-pro-BNP levels in analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking, family history of T2D, history of hypertension, and levels of triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol.", "The association between rs198389 and T2D observed in case-control studies (odds ratio = 0.94 per C allele, 95% CI 0.91-0.97) was similar to that expected (0.96, 0.93-0.98) based on the pooled estimate for the log-NT-pro-BNP level to T2D association derived from a meta-analysis of our study and published data (hazard ratio = 0.82 per SD, 0.74-0.90) and the difference in NT-pro-BNP levels (0.22 SD, 0.15-0.29) per C allele of rs198389.", "No significant associations were observed between the rs198389 genotype and potential confounders.", "CONCLUSIONS Our results provide evidence for a potential causal role of the BNP system in the aetiology of T2D.", "Further studies are needed to investigate the mechanisms underlying this association and possibilities for preventive interventions.", "Please see later in the article for the Editors' Summary." ]

[ 4, 7 ]

[ "BACKGROUND Genetic and epidemiological evidence suggests an inverse association between B-type natriuretic peptide (BNP) levels in blood and risk of type 2 diabetes (T2D), but the prospective association of BNP with T2D is uncertain, and it is unclear whether the association is confounded.", "METHODS AND FINDINGS We analysed the association between levels of the N-terminal fragment of pro-BNP (NT-pro-BNP) in blood and risk of incident T2D in a prospective case-cohort study and genotyped the variant rs198389 within the BNP locus in three T2D case-control studies.", "We combined our results with existing data in a meta-analysis of 11 case-control studies.", "Using a Mendelian randomization approach, we compared the observed association between rs198389 and T2D to that expected from the NT-pro-BNP level to T2D association and the NT-pro-BNP difference per C allele of rs198389.", "In participants of our case-cohort study who were free of T2D and cardiovascular disease at baseline, we observed a 21% (95% CI 3%-36%) decreased risk of incident T2D per one standard deviation (SD) higher log-transformed NT-pro-BNP levels in analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking, family history of T2D, history of hypertension, and levels of triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol.", "The association between rs198389 and T2D observed in case-control studies (odds ratio = 0.94 per C allele, 95% CI 0.91-0.97) was similar to that expected (0.96, 0.93-0.98) based on the pooled estimate for the log-NT-pro-BNP level to T2D association derived from a meta-analysis of our study and published data (hazard ratio = 0.82 per SD, 0.74-0.90) and the difference in NT-pro-BNP levels (0.22 SD, 0.15-0.29) per C allele of rs198389.", "No significant associations were observed between the rs198389 genotype and potential confounders.", "CONCLUSIONS Our results provide evidence for a potential causal role of the BNP system in the aetiology of T2D.", "Further studies are needed to investigate the mechanisms underlying this association and possibilities for preventive interventions.", "Please see later in the article for the Editors' Summary." ]

[ 4, 7 ]

[ "Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs).", "Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO).", "Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV." ]

[ 1 ]

[ "How the number of immune cells recruited to sites of infection is determined and adjusted to differences in the cellular stoichiometry between host and pathogen is unknown.", "Here, we have uncovered a role for reactive oxygen species (ROS) as sensors of microbe size.", "By sensing the differential localization of ROS generated in response to microbes of different size, neutrophils tuned their interleukin (IL)-1β expression via the selective oxidation of NF-κB, in order to implement distinct inflammatory programs.", "Small microbes triggered ROS intracellularly, suppressing IL-1β expression to limit neutrophil recruitment as each phagocyte eliminated numerous pathogens.", "In contrast, large microbes triggered ROS extracellularly, amplifying IL-1β expression to recruit numerous neutrophils forming cooperative clusters.", "Defects in ROS-mediated microbe size sensing resulted in large neutrophil infiltrates and clusters in response to small microbes that contribute to inflammatory disease.", "These findings highlight the impact of ROS localization on signal transduction." ]

[ 4 ]

[ "BACKGROUND The large-scale emigration of physicians from sub-Saharan Africa (SSA) to high-income nations is a serious development concern.", "Our objective was to determine current emigration trends of SSA physicians found in the physician workforce of the United States.", "METHODS AND FINDINGS We analyzed physician data from the World Health Organization (WHO) Global Health Workforce Statistics along with graduation and residency data from the 2011 American Medical Association Physician Masterfile (AMA-PM) on physicians trained or born in SSA countries who currently practice in the US.", "We estimated emigration proportions, year of US entry, years of practice before emigration, and length of time in the US.", "According to the 2011 AMA-PM, 10,819 physicians were born or trained in 28 SSA countries.", "Sixty-eight percent (n = 7,370) were SSA-trained, 20% (n = 2,126) were US-trained, and 12% (n = 1,323) were trained outside both SSA and the US.", "We estimated active physicians (age ≤ 70 years) to represent 96% (n = 10,377) of the total.", "Migration trends among SSA-trained physicians increased from 2002 to 2011 for all but one principal source country; the exception was South Africa whose physician migration to the US decreased by 8% (-156).", "The increase in last-decade migration was >50% in Nigeria (+1,113) and Ghana (+243), >100% in Ethiopia (+274), and >200% (+244) in Sudan.", "Liberia was the most affected by migration to the US with 77% (n = 175) of its estimated physicians in the 2011 AMA-PM.", "On average, SSA-trained physicians have been in the US for 18 years.", "They practiced for 6.5 years before US entry, and nearly half emigrated during the implementation years (1984-1999) of the structural adjustment programs.", "CONCLUSION Physician emigration from SSA to the US is increasing for most SSA source countries.", "Unless far-reaching policies are implemented by the US and SSA countries, the current emigration trends will persist, and the US will remain a leading destination for SSA physicians emigrating from the continent of greatest need.", "Please see later in the article for the Editors' Summary." ]

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[ "Traditionally, vaccine development involves tradeoffs between immunogenicity and safety.", "Live-attenuated vaccines typically offer rapid and durable immunity but have reduced safety when compared to inactivated vaccines.", "In contrast, the inability of inactivated vaccines to replicate enhances safety at the expense of immunogenicity, often necessitating multiple doses and boosters.", "To overcome these tradeoffs, we developed the insect-specific alphavirus, Eilat virus (EILV), as a vaccine platform.", "To address the chikungunya fever (CHIKF) pandemic, we used an EILV cDNA clone to design a chimeric virus containing the chikungunya virus (CHIKV) structural proteins.", "The recombinant EILV/CHIKV was structurally identical at 10 Å to wild-type CHIKV, as determined by single-particle cryo-electron microscopy, and it mimicked the early stages of CHIKV replication in vertebrate cells from attachment and entry to viral RNA delivery.", "Yet the recombinant virus remained completely defective for productive replication, providing a high degree of safety.", "A single dose of EILV/CHIKV produced in mosquito cells elicited rapid (within 4 d) and long-lasting (>290 d) neutralizing antibodies that provided complete protection in two different mouse models.", "In nonhuman primates, EILV/CHIKV elicited rapid and robust immunity that protected against viremia and telemetrically monitored fever.", "Our EILV platform represents the first structurally native application of an insect-specific virus in preclinical vaccine development and highlights the potential application of such viruses in vaccinology." ]

[ 7, 8 ]

[ "CONTEXT The long-term risk for developing hypertension is best described by the lifetime risk statistic.", "The lifetime risk for hypertension and trends in this risk over time are unknown.", "OBJECTIVES To estimate the residual lifetime risk for hypertension in older US adults and to evaluate temporal trends in this risk.", "DESIGN, SETTING, AND PARTICIPANTS Community-based prospective cohort study of 1298 participants from the Framingham Heart Study who were aged 55 to 65 years and free of hypertension at baseline (1976-1998).", "MAIN OUTCOME MEASURES Residual lifetime risk (lifetime cumulative incidence not adjusted for competing causes of mortality) for hypertension, defined as blood pressure of 140/90 mm Hg or greater or use of antihypertensive medications.", "RESULTS The residual lifetime risks for developing hypertension and stage 1 high blood pressure or higher (greater-than-or-equal to 140/90 mm Hg regardless of treatment) were 90% in both 55- and 65-year-old participants.", "The lifetime probability of receiving antihypertensive medication was 60%.", "The risk for hypertension remained unchanged for women, but it was approximately 60% higher for men in the contemporary 1976-1998 period compared with an earlier 1952-1975 period.", "In contrast, the residual lifetime risk for stage 2 high blood pressure or higher (greater-than-or-equal to 160/100 mm Hg regardless of treatment) was considerably lower in both sexes in the recent period (35%-57% in 1952-1975 vs 35%-44% in 1976-1998), likely due to a marked increase in treatment of individuals with substantially elevated blood pressure.", "CONCLUSION The residual lifetime risk for hypertension for middle-aged and elderly individuals is 90%, indicating a huge public health burden.", "Although the decline in lifetime risk for stage 2 high blood pressure or higher represents a major achievement, efforts should be directed at the primary prevention of hypertension." ]

[ 5, 9 ]

[ "CONTEXT Noninvasive ventilation (NIV) has been associated with lower rates of endotracheal intubation in populations of patients with acute respiratory failure.", "OBJECTIVE To compare NIV with standard treatment using supplemental oxygen administration to avoid endotracheal intubation in recipients of solid organ transplantation with acute hypoxemic respiratory failure.", "DESIGN AND SETTING Prospective randomized study conducted at a 14-bed, general intensive care unit of a university hospital.", "PATIENTS Of 238 patients who underwent solid organ transplantation from December 1995 to October 1997, 51 were treated for acute respiratory failure.", "Of these, 40 were eligible and 20 were randomized to each group.", "INTERVENTION Noninvasive ventilation vs standard treatment with supplemental oxygen administration.", "MAIN OUTCOME MEASURES The need for endotracheal intubation and mechanical ventilation at any time during the study, complications not present on admission, duration of ventilatory assistance, length of hospital stay, and intensive care unit mortality.", "RESULTS The 2 groups were similar at study entry.", "Within the first hour of treatment, 14 patients (70%) in the NIV group, and 5 patients (25%) in the standard treatment group improved their ratio of the PaO2 to the fraction of inspired oxygen (FIO2).", "Over time, a sustained improvement in PaO2 to FIO2 was noted in 12 patients (60%) in the NIV group, and in 5 patients (25%) randomized to standard treatment (P = .03).", "The use of NIV was associated with a significant reduction in the rate of endotracheal intubation (20% vs 70%; P = .002), rate of fatal complications (20% vs 50%; P = .05), length of stay in the intensive care unit by survivors (mean [SD] days, 5.5 [3] vs 9 [4]; P = .03), and intensive care unit mortality (20% vs 50%; P = .05).", "Hospital mortality did not differ.", "CONCLUSIONS These results indicate that transplantation programs should consider NIV in the treatment of selected recipients of transplantation with acute respiratory failure." ]

[ 8, 9, 10, 12 ]

[ "IMPORTANCE Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer.", "OBJECTIVE To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer.", "DESIGN, SETTING, AND PARTICIPANTS Case-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011.", "Participants were all of European descent.", "EXPOSURES Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors.", "MAIN OUTCOMES AND MEASURES Colorectal cancer.", "RESULTS Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64-0.74]; P = 6.2 × 10(-28)) compared with nonregular use.", "In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6 × 10(-9) for interaction).", "Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P = 7.7 × 10(-33)) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P = .002).", "In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2 × 10(-9) for interaction).", "Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P = 1.9 × 10(-30)) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P = .76).", "CONCLUSIONS AND RELEVANCE In this genome-wide investigation of gene × environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15.", "Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies." ]

[ 6, 8, 10 ]

[ "IMPORTANCE Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer.", "OBJECTIVE To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer.", "DESIGN, SETTING, AND PARTICIPANTS Case-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011.", "Participants were all of European descent.", "EXPOSURES Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors.", "MAIN OUTCOMES AND MEASURES Colorectal cancer.", "RESULTS Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64-0.74]; P = 6.2 × 10(-28)) compared with nonregular use.", "In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6 × 10(-9) for interaction).", "Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P = 7.7 × 10(-33)) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P = .002).", "In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2 × 10(-9) for interaction).", "Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P = 1.9 × 10(-30)) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P = .76).", "CONCLUSIONS AND RELEVANCE In this genome-wide investigation of gene × environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15.", "Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies." ]

[ 6, 8, 10 ]

[ "The TLX1 and TLX3 transcription factor oncogenes have a key role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL).", "Here we used reverse engineering of global transcriptional networks to decipher the oncogenic regulatory circuit controlled by TLX1 and TLX3.", "This systems biology analysis defined T cell leukemia homeobox 1 (TLX1) and TLX3 as master regulators of an oncogenic transcriptional circuit governing T-ALL.", "Notably, a network structure analysis of this hierarchical network identified RUNX1 as a key mediator of the T-ALL induced by TLX1 and TLX3 and predicted a tumor-suppressor role for RUNX1 in T cell transformation.", "Consistent with these results, we identified recurrent somatic loss-of-function mutations in RUNX1 in human T-ALL.", "Overall, these results place TLX1 and TLX3 at the top of an oncogenic transcriptional network controlling leukemia development, show the power of network analyses to identify key elements in the regulatory circuits governing human cancer and identify RUNX1 as a tumor-suppressor gene in T-ALL." ]

[ 3 ]

[ "Tumor necrosis factor (TNF), a key effector in controlling tuberculosis, is thought to exert protection by directing formation of granulomas, organized aggregates of macrophages and other immune cells.", "Loss of TNF signaling causes progression of tuberculosis in humans, and the increased mortality of Mycobacterium tuberculosis-infected mice is associated with disorganized necrotic granulomas, although the precise roles of TNF signaling preceding this endpoint remain undefined.", "We monitored transparent Mycobacterium marinum-infected zebrafish live to conduct a stepwise dissection of how TNF signaling operates in mycobacterial pathogenesis.", "We found that loss of TNF signaling caused increased mortality even when only innate immunity was operant.", "In the absence of TNF, intracellular bacterial growth and granuloma formation were accelerated and was followed by necrotic death of overladen macrophages and granuloma breakdown.", "Thus, TNF is not required for tuberculous granuloma formation, but maintains granuloma integrity indirectly by restricting mycobacterial growth within macrophages and preventing their necrosis." ]

[ 4, 5 ]

[ "Tumor necrosis factor (TNF), a key effector in controlling tuberculosis, is thought to exert protection by directing formation of granulomas, organized aggregates of macrophages and other immune cells.", "Loss of TNF signaling causes progression of tuberculosis in humans, and the increased mortality of Mycobacterium tuberculosis-infected mice is associated with disorganized necrotic granulomas, although the precise roles of TNF signaling preceding this endpoint remain undefined.", "We monitored transparent Mycobacterium marinum-infected zebrafish live to conduct a stepwise dissection of how TNF signaling operates in mycobacterial pathogenesis.", "We found that loss of TNF signaling caused increased mortality even when only innate immunity was operant.", "In the absence of TNF, intracellular bacterial growth and granuloma formation were accelerated and was followed by necrotic death of overladen macrophages and granuloma breakdown.", "Thus, TNF is not required for tuberculous granuloma formation, but maintains granuloma integrity indirectly by restricting mycobacterial growth within macrophages and preventing their necrosis." ]

[ 4, 5 ]

[ "While significant progress has been made in understanding the induction of tumor vasculature by secreted angiogenic factors, little is known regarding contact-dependent signals that promote tumor angiogenesis.", "Here, we report that the Notch ligand Jagged1 induced by growth factors via mitogen-activating protein kinase (MAPK) in head and neck squamous cell carcinoma (HNSCC) cells triggered Notch activation in neighboring endothelial cells (ECs) and promoted capillary-like sprout formation.", "Jagged1-expressing HNSCC cells significantly enhanced neovascularization and tumor growth in vivo.", "Moreover, the level of Jagged1 was significantly correlated with tumor blood vessel content and associated with HNSCC development.", "Our results elucidate a novel mechanism by which the direct interplay between tumor cells and ECs promotes angiogenesis through MAPK and Notch signaling pathways." ]

[ 1, 4 ]

[ "Notch receptors expressed on hematopoietic stem cells interact with their ligands on bone marrow stromal cells and thereby control cell fate decisions and survival.", "We recently demonstrated that Notch signaling is involved in proliferation and survival of B cell-derived tumor cells of classic Hodgkin disease and described a novel mechanism for the oncogenic capacity of Notch.", "In this study we investigated whether Notch signaling is involved in the tight interactions between neoplastic plasma cells and their bone marrow microenvironment, which are essential for tumor cell growth in multiple myeloma (MM).", "Here we demonstrate that Notch receptors and their ligand Jagged1 are highly expressed in cultured and primary MM cells, whereas nonneoplastic counterparts show low to undetectable levels of Notch.", "Functional data indicate that ligand-induced Notch signaling is a growth factor for MM cells and suggest that these interactions contribute to myelomagenesis in vivo." ]

[ 1 ]

[ "Derivation of patient-specific human pluripotent stem cells via somatic cell nuclear transfer (SCNT) has the potential for applications in a range of therapeutic contexts.", "However, successful SCNT with human cells has proved challenging to achieve, and thus far has only been reported with fetal or infant somatic cells.", "In this study, we describe the application of a recently developed methodology for the generation of human ESCs via SCNT using dermal fibroblasts from 35- and 75-year-old males.", "Our study therefore demonstrates the applicability of SCNT for adult human cells and supports further investigation of SCNT as a strategy for regenerative medicine." ]

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[ "Background Celiac disease is a small intestinal inflammatory disorder characterized by malabsorption, nutrient deficiency, and a range of clinical manifestations.", "It is caused by an inappropriate immune response to dietary gluten and is treated with a gluten-free diet.", "Recent feeding studies have indicated oats to be safe for celiac disease patients, and oats are now often included in the celiac disease diet.", "This study aimed to investigate whether oat intolerance exists in celiac disease and to characterize the cells and processes underlying this intolerance.", "Methods and Findings We selected for study nine adults with celiac disease who had a history of oats exposure.", "Four of the patients had clinical symptoms on an oats-containing diet, and three of these four patients had intestinal inflammation typical of celiac disease at the time of oats exposure.", "We established oats-avenin-specific and -reactive intestinal T-cell lines from these three patients, as well as from two other patients who appeared to tolerate oats.", "The avenin-reactive T-cell lines recognized avenin peptides in the context of HLA-DQ2.", "These peptides have sequences rich in proline and glutamine residues closely resembling wheat gluten epitopes.", "Deamidation (glutamine→glutamic acid conversion) by tissue transglutaminase was involved in the avenin epitope formation.", "Conclusions We conclude that some celiac disease patients have avenin-reactive mucosal T-cells that can cause mucosal inflammation.", "Oat intolerance may be a reason for villous atrophy and inflammation in patients with celiac disease who are eating oats but otherwise are adhering to a strict gluten-free diet.", "Clinical follow-up of celiac disease patients eating oats is advisable." ]

[ 6 ]

[ "BACKGROUND The main associations of body-mass index (BMI) with overall and cause-specific mortality can best be assessed by long-term prospective follow-up of large numbers of people.", "The Prospective Studies Collaboration aimed to investigate these associations by sharing data from many studies.", "METHODS Collaborative analyses were undertaken of baseline BMI versus mortality in 57 prospective studies with 894 576 participants, mostly in western Europe and North America (61% [n=541 452] male, mean recruitment age 46 [SD 11] years, median recruitment year 1979 [IQR 1975-85], mean BMI 25 [SD 4] kg/m(2)).", "The analyses were adjusted for age, sex, smoking status, and study.", "To limit reverse causality, the first 5 years of follow-up were excluded, leaving 66 552 deaths of known cause during a mean of 8 (SD 6) further years of follow-up (mean age at death 67 [SD 10] years): 30 416 vascular; 2070 diabetic, renal or hepatic; 22 592 neoplastic; 3770 respiratory; 7704 other.", "FINDINGS In both sexes, mortality was lowest at about 22.5-25 kg/m(2).", "Above this range, positive associations were recorded for several specific causes and inverse associations for none, the absolute excess risks for higher BMI and smoking were roughly additive, and each 5 kg/m(2) higher BMI was on average associated with about 30% higher overall mortality (hazard ratio per 5 kg/m(2) [HR] 1.29 [95% CI 1.27-1.32]): 40% for vascular mortality (HR 1.41 [1.37-1.45]); 60-120% for diabetic, renal, and hepatic mortality (HRs 2.16 [1.89-2.46], 1.59 [1.27-1.99], and 1.82 [1.59-2.09], respectively); 10% for neoplastic mortality (HR 1.10 [1.06-1.15]); and 20% for respiratory and for all other mortality (HRs 1.20 [1.07-1.34] and 1.20 [1.16-1.25], respectively).", "Below the range 22.5-25 kg/m(2), BMI was associated inversely with overall mortality, mainly because of strong inverse associations with respiratory disease and lung cancer.", "These inverse associations were much stronger for smokers than for non-smokers, despite cigarette consumption per smoker varying little with BMI.", "INTERPRETATION Although other anthropometric measures (eg, waist circumference, waist-to-hip ratio) could well add extra information to BMI, and BMI to them, BMI is in itself a strong predictor of overall mortality both above and below the apparent optimum of about 22.5-25 kg/m(2).", "The progressive excess mortality above this range is due mainly to vascular disease and is probably largely causal.", "At 30-35 kg/m(2), median survival is reduced by 2-4 years; at 40-45 kg/m(2), it is reduced by 8-10 years (which is comparable with the effects of smoking).", "The definite excess mortality below 22.5 kg/m(2) is due mainly to smoking-related diseases, and is not fully explained." ]

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[ "BACKGROUND The main associations of body-mass index (BMI) with overall and cause-specific mortality can best be assessed by long-term prospective follow-up of large numbers of people.", "The Prospective Studies Collaboration aimed to investigate these associations by sharing data from many studies.", "METHODS Collaborative analyses were undertaken of baseline BMI versus mortality in 57 prospective studies with 894 576 participants, mostly in western Europe and North America (61% [n=541 452] male, mean recruitment age 46 [SD 11] years, median recruitment year 1979 [IQR 1975-85], mean BMI 25 [SD 4] kg/m(2)).", "The analyses were adjusted for age, sex, smoking status, and study.", "To limit reverse causality, the first 5 years of follow-up were excluded, leaving 66 552 deaths of known cause during a mean of 8 (SD 6) further years of follow-up (mean age at death 67 [SD 10] years): 30 416 vascular; 2070 diabetic, renal or hepatic; 22 592 neoplastic; 3770 respiratory; 7704 other.", "FINDINGS In both sexes, mortality was lowest at about 22.5-25 kg/m(2).", "Above this range, positive associations were recorded for several specific causes and inverse associations for none, the absolute excess risks for higher BMI and smoking were roughly additive, and each 5 kg/m(2) higher BMI was on average associated with about 30% higher overall mortality (hazard ratio per 5 kg/m(2) [HR] 1.29 [95% CI 1.27-1.32]): 40% for vascular mortality (HR 1.41 [1.37-1.45]); 60-120% for diabetic, renal, and hepatic mortality (HRs 2.16 [1.89-2.46], 1.59 [1.27-1.99], and 1.82 [1.59-2.09], respectively); 10% for neoplastic mortality (HR 1.10 [1.06-1.15]); and 20% for respiratory and for all other mortality (HRs 1.20 [1.07-1.34] and 1.20 [1.16-1.25], respectively).", "Below the range 22.5-25 kg/m(2), BMI was associated inversely with overall mortality, mainly because of strong inverse associations with respiratory disease and lung cancer.", "These inverse associations were much stronger for smokers than for non-smokers, despite cigarette consumption per smoker varying little with BMI.", "INTERPRETATION Although other anthropometric measures (eg, waist circumference, waist-to-hip ratio) could well add extra information to BMI, and BMI to them, BMI is in itself a strong predictor of overall mortality both above and below the apparent optimum of about 22.5-25 kg/m(2).", "The progressive excess mortality above this range is due mainly to vascular disease and is probably largely causal.", "At 30-35 kg/m(2), median survival is reduced by 2-4 years; at 40-45 kg/m(2), it is reduced by 8-10 years (which is comparable with the effects of smoking).", "The definite excess mortality below 22.5 kg/m(2) is due mainly to smoking-related diseases, and is not fully explained." ]

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[ "Blind individuals often demonstrate enhanced nonvisual perceptual abilities.", "However, the neural substrate that underlies this improved performance remains to be fully understood.", "An earlier behavioral study demonstrated that some early-blind people localize sounds more accurately than sighted controls using monaural cues.", "In order to investigate the neural basis of these behavioral differences in humans, we carried out functional imaging studies using positron emission tomography and a speaker array that permitted pseudo-free-field presentations within the scanner.", "During binaural sound localization, a sighted control group showed decreased cerebral blood flow in the occipital lobe, which was not seen in early-blind individuals.", "During monaural sound localization (one ear plugged), the subgroup of early-blind subjects who were behaviorally superior at sound localization displayed two activation foci in the occipital cortex.", "This effect was not seen in blind persons who did not have superior monaural sound localization abilities, nor in sighted individuals.", "The degree of activation of one of these foci was strongly correlated with sound localization accuracy across the entire group of blind subjects.", "The results show that those blind persons who perform better than sighted persons recruit occipital areas to carry out auditory localization under monaural conditions.", "We therefore conclude that computations carried out in the occipital cortex specifically underlie the enhanced capacity to use monaural cues.", "Our findings shed light not only on intermodal compensatory mechanisms, but also on individual differences in these mechanisms and on inhibitory patterns that differ between sighted individuals and those deprived of vision early in life." ]

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[ "Intestinal microbiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO).", "We demonstrate here that metabolism by intestinal microbiota of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis in mice.", "Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism.", "The presence of specific bacterial taxa in human feces was associated with both plasma TMAO concentration and dietary status.", "Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predicted increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (myocardial infarction, stroke or death), but only among subjects with concurrently high TMAO levels.", "Chronic dietary L-carnitine supplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis, but this did not occur if intestinal microbiota was concurrently suppressed.", "In mice with an intact intestinal microbiota, dietary supplementation with TMAO or either carnitine or choline reduced in vivo reverse cholesterol transport.", "Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk." ]

[ 2 ]

[ "Intestinal microbiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO).", "We demonstrate here that metabolism by intestinal microbiota of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis in mice.", "Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism.", "The presence of specific bacterial taxa in human feces was associated with both plasma TMAO concentration and dietary status.", "Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predicted increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (myocardial infarction, stroke or death), but only among subjects with concurrently high TMAO levels.", "Chronic dietary L-carnitine supplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis, but this did not occur if intestinal microbiota was concurrently suppressed.", "In mice with an intact intestinal microbiota, dietary supplementation with TMAO or either carnitine or choline reduced in vivo reverse cholesterol transport.", "Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk." ]

[ 2 ]

[ "Intestinal microbiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO).", "We demonstrate here that metabolism by intestinal microbiota of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis in mice.", "Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism.", "The presence of specific bacterial taxa in human feces was associated with both plasma TMAO concentration and dietary status.", "Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predicted increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (myocardial infarction, stroke or death), but only among subjects with concurrently high TMAO levels.", "Chronic dietary L-carnitine supplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis, but this did not occur if intestinal microbiota was concurrently suppressed.", "In mice with an intact intestinal microbiota, dietary supplementation with TMAO or either carnitine or choline reduced in vivo reverse cholesterol transport.", "Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk." ]

[ 2 ]

[ "OBJECTIVE To determine the rate of early discontinuation and non-publication of randomised controlled trials involving patients undergoing surgery.", "DESIGN Cross sectional observational study of registered and published trials.", "SETTING Randomised controlled trials of interventions in patients undergoing a surgical procedure.", "DATA SOURCES The ClinicalTrials.gov database was searched for interventional trials registered between January 2008 and December 2009 using the keyword \"surgery\".", "Recruitment status was extracted from the ClinicalTrials.gov database.", "A systematic search for studies published in peer reviewed journals was performed; if they were not found, results posted on the ClinicalTrials.gov results database were sought.", "Email queries were sent to trial investigators of discontinued and unpublished completed trials if no reason for the respective status was disclosed.", "MAIN OUTCOME MEASURES Trial discontinuation before completion and non-publication after completion.", "Logistic regression was used to determine the effect of funding source on publication status, with adjustment for intervention type and trial size.", "RESULTS Of 818 registered trials found using the keyword \"surgery\", 395 met the inclusion criteria.", "Of these, 21% (81/395) were discontinued early, most commonly owing to poor recruitment (44%, 36/81).", "The remaining 314 (79%) trials proceeded to completion, with a publication rate of 66% (208/314) at a median time of 4.9 (interquartile range 4.0-6.0) years from study completion to publication search.", "A further 6% (20/314) of studies presented results on ClinicalTrials.gov without a corresponding peer reviewed publication.", "Industry funding did not affect the rate of discontinuation (adjusted odds ratio 0.91, 95% confidence interval 0.54 to 1.55) but was associated with a lower odds of publication for completed trials (0.43, 0.26 to 0.72).", "Investigators' email addresses for trials with an uncertain fate were identified for 71.4% (10/14) of discontinued trials and 83% (101/122) of unpublished studies.", "Only 43% (6/14) and 20% (25/122) replies were received.", "Email responses for completed trials indicated 11 trials in press, five published studies (four in non-indexed peer reviewed journals), and nine trials remaining unpublished.", "CONCLUSIONS One in five surgical randomised controlled trials are discontinued early, one in three completed trials remain unpublished, and investigators of unpublished studies are frequently not contactable.", "This represents a waste of research resources and raises ethical concerns regarding hidden clinical data and futile participation by patients with its attendant risks.", "To promote future efficiency and transparency, changes are proposed to research governance frameworks to overcome these concerns." ]

[ 10, 17 ]

[ "OBJECTIVE To determine the rate of early discontinuation and non-publication of randomised controlled trials involving patients undergoing surgery.", "DESIGN Cross sectional observational study of registered and published trials.", "SETTING Randomised controlled trials of interventions in patients undergoing a surgical procedure.", "DATA SOURCES The ClinicalTrials.gov database was searched for interventional trials registered between January 2008 and December 2009 using the keyword \"surgery\".", "Recruitment status was extracted from the ClinicalTrials.gov database.", "A systematic search for studies published in peer reviewed journals was performed; if they were not found, results posted on the ClinicalTrials.gov results database were sought.", "Email queries were sent to trial investigators of discontinued and unpublished completed trials if no reason for the respective status was disclosed.", "MAIN OUTCOME MEASURES Trial discontinuation before completion and non-publication after completion.", "Logistic regression was used to determine the effect of funding source on publication status, with adjustment for intervention type and trial size.", "RESULTS Of 818 registered trials found using the keyword \"surgery\", 395 met the inclusion criteria.", "Of these, 21% (81/395) were discontinued early, most commonly owing to poor recruitment (44%, 36/81).", "The remaining 314 (79%) trials proceeded to completion, with a publication rate of 66% (208/314) at a median time of 4.9 (interquartile range 4.0-6.0) years from study completion to publication search.", "A further 6% (20/314) of studies presented results on ClinicalTrials.gov without a corresponding peer reviewed publication.", "Industry funding did not affect the rate of discontinuation (adjusted odds ratio 0.91, 95% confidence interval 0.54 to 1.55) but was associated with a lower odds of publication for completed trials (0.43, 0.26 to 0.72).", "Investigators' email addresses for trials with an uncertain fate were identified for 71.4% (10/14) of discontinued trials and 83% (101/122) of unpublished studies.", "Only 43% (6/14) and 20% (25/122) replies were received.", "Email responses for completed trials indicated 11 trials in press, five published studies (four in non-indexed peer reviewed journals), and nine trials remaining unpublished.", "CONCLUSIONS One in five surgical randomised controlled trials are discontinued early, one in three completed trials remain unpublished, and investigators of unpublished studies are frequently not contactable.", "This represents a waste of research resources and raises ethical concerns regarding hidden clinical data and futile participation by patients with its attendant risks.", "To promote future efficiency and transparency, changes are proposed to research governance frameworks to overcome these concerns." ]

[ 10, 17 ]

[ "BACKGROUND Aedes aegypti, the major vector of dengue viruses, often breeds in water storage containers used by households without tap water supply, and occurs in high numbers even in dense urban areas.", "We analysed the interaction between human population density and lack of tap water as a cause of dengue fever outbreaks with the aim of identifying geographic areas at highest risk.", "METHODS AND FINDINGS We conducted an individual-level cohort study in a population of 75,000 geo-referenced households in Vietnam over the course of two epidemics, on the basis of dengue hospital admissions (n = 3,013).", "We applied space-time scan statistics and mathematical models to confirm the findings.", "We identified a surprisingly narrow range of critical human population densities between around 3,000 to 7,000 people/km² prone to dengue outbreaks.", "In the study area, this population density was typical of villages and some peri-urban areas.", "Scan statistics showed that areas with a high population density or adequate water supply did not experience severe outbreaks.", "The risk of dengue was higher in rural than in urban areas, largely explained by lack of piped water supply, and in human population densities more often falling within the critical range.", "Mathematical modeling suggests that simple assumptions regarding area-level vector/host ratios may explain the occurrence of outbreaks.", "CONCLUSIONS Rural areas may contribute at least as much to the dissemination of dengue fever as cities.", "Improving water supply and vector control in areas with a human population density critical for dengue transmission could increase the efficiency of control efforts.", "Please see later in the article for the Editors' Summary." ]

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[ "BACKGROUND Aedes aegypti, the major vector of dengue viruses, often breeds in water storage containers used by households without tap water supply, and occurs in high numbers even in dense urban areas.", "We analysed the interaction between human population density and lack of tap water as a cause of dengue fever outbreaks with the aim of identifying geographic areas at highest risk.", "METHODS AND FINDINGS We conducted an individual-level cohort study in a population of 75,000 geo-referenced households in Vietnam over the course of two epidemics, on the basis of dengue hospital admissions (n = 3,013).", "We applied space-time scan statistics and mathematical models to confirm the findings.", "We identified a surprisingly narrow range of critical human population densities between around 3,000 to 7,000 people/km² prone to dengue outbreaks.", "In the study area, this population density was typical of villages and some peri-urban areas.", "Scan statistics showed that areas with a high population density or adequate water supply did not experience severe outbreaks.", "The risk of dengue was higher in rural than in urban areas, largely explained by lack of piped water supply, and in human population densities more often falling within the critical range.", "Mathematical modeling suggests that simple assumptions regarding area-level vector/host ratios may explain the occurrence of outbreaks.", "CONCLUSIONS Rural areas may contribute at least as much to the dissemination of dengue fever as cities.", "Improving water supply and vector control in areas with a human population density critical for dengue transmission could increase the efficiency of control efforts.", "Please see later in the article for the Editors' Summary." ]

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[ "The bone marrow (BM) niche comprises multiple cell types that regulate hematopoietic stem/progenitor cell (HSPC) migration out of the niche and into the circulation.", "Here, we demonstrate that osteocytes, the major cellular component of mature bone, are regulators of HSPC egress.", "Granulocyte colony-stimulating factor (G-CSF), used clinically to mobilize HSPCs, induces changes in the morphology and gene expression of the osteocytic network that precedes changes in osteoblasts.", "This rapid response is likely under control of the sympathetic nervous system, since osteocytes express the β2-adrenergic receptor and surgical sympathectomy prevents it.", "Mice with targeted ablation of osteocytes or a disrupted osteocyte network have comparable numbers of HSPCs in the BM but fail to mobilize HSPCs in response to G-CSF.", "Taken together, these results indicate that the BM/bone niche interface is critically controlled from inside of the bone matrix and establish an important physiological role for skeletal tissues in hematopoietic function." ]

[ 2, 4 ]

[ "CONTEXT Chronic low back pain (LBP) with degenerative lumbar osteoarthritis (OA) is widespread in the adult population.", "Although glucosamine is increasingly used by patients with chronic LBP, little is known about its effect in this setting.", "OBJECTIVE To investigate the effect of glucosamine in patients with chronic LBP and degenerative lumbar OA.", "DESIGN, SETTING, AND PARTICIPANTS A double-blind, randomized, placebo-controlled trial conducted at Oslo University Hospital Outpatient Clinic, Oslo, Norway, with 250 patients older than 25 years of age with chronic LBP (>6 months) and degenerative lumbar OA.", "INTERVENTIONS Daily intake of 1500 mg of oral glucosamine (n = 125) or placebo (n = 125) for 6 months, with assessment of effect after the 6-month intervention period and at 1 year (6 months postintervention).", "MAIN OUTCOME MEASURES The primary outcome was pain-related disability measured with the Roland Morris Disability Questionnaire (RMDQ).", "Secondary outcomes were numerical scores from pain-rating scales of patients at rest and during activity, and the quality-of-life EuroQol-5 Dimensions (EQ-5D) instrument.", "Data collection occurred during the intervention period at baseline, 6 weeks, 3 and 6 months, and again 6 months following the intervention at 1 year.", "Group differences were analyzed using linear mixed models analysis.", "RESULTS At baseline, mean RMDQ scores were 9.2 (95% confidence interval [CI], 8.4-10.0) for glucosamine and 9.7 (95% CI, 8.9-10.5) for the placebo group (P = .37).", "At 6 months, the mean RMDQ score was the same for the glucosamine and placebo groups (5.0; 95% CI, 4.2-5.8).", "At 1 year, the mean RMDQ scores were 4.8 (95% CI, 3.9-5.6) for glucosamine and 5.5 (95% CI, 4.7-6.4) for the placebo group.", "No statistically significant difference in change between groups was found when assessed after the 6-month intervention period and at 1 year: RMDQ (P = .72), LBP at rest (P = .91), LBP during activity (P = .97), and quality-of-life EQ-5D (P = .20).", "Mild adverse events were reported in 40 patients in the glucosamine group and 46 in the placebo group (P = .48).", "CONCLUSIONS Among patients with chronic LBP and degenerative lumbar OA, 6-month treatment with oral glucosamine compared with placebo did not result in reduced pain-related disability after the 6-month intervention and after 1-year follow-up.", "TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00404079." ]

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[ "Background The degree of volume depletion in severe malaria is currently unknown, although knowledge of fluid compartment volumes can guide therapy.", "To assist management of severely ill children, and to test the hypothesis that volume changes in fluid compartments reflect disease severity, we measured body compartment volumes in Gabonese children with malaria.", "Methods and Findings Total body water volume (TBW) and extracellular water volume (ECW) were estimated in children with severe or moderate malaria and in convalescence by tracer dilution with heavy water and bromide, respectively.", "Intracellular water volume (ICW) was derived from these parameters.", "Bioelectrical impedance analysis estimates of TBW and ECW were calibrated against dilution methods, and bioelectrical impedance analysis measurements were taken daily until discharge.", "Sixteen children had severe and 19 moderate malaria.", "Severe childhood malaria was associated with depletion of TBW (mean [SD] of 37 [33] ml/kg, or 6.7% [6.0%]) relative to measurement at discharge.", "This is defined as mild dehydration in other conditions.", "ECW measurements were normal on admission in children with severe malaria and did not rise in the first few days of admission.", "Volumes in different compartments (TBW, ECW, and ICW) were not related to hyperlactataemia or other clinical and laboratory markers of disease severity.", "Moderate malaria was not associated with a depletion of TBW." ]

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[ "The mechanisms ensuring specific incorporation of CENP-A at centromeres are poorly understood.", "Mis16 and Mis18 are required for CENP-A localization at centromeres and form a complex that is conserved from fission yeast to human.", "Fission yeast sim1 mutants that alleviate kinetochore domain silencing are defective in Scm3(Sp), the ortholog of budding yeast Scm3(Sc).", "Scm3(Sp) depends on Mis16/18 for its centromere localization and like them is recruited to centromeres in late anaphase.", "Importantly, Scm3(Sp) coaffinity purifies with CENP-A(Cnp1) and associates with CENP-A(Cnp1) in vitro, yet localizes independently of intact CENP-A(Cnp1) chromatin and is differentially released from chromatin.", "While Scm3(Sc) has been proposed to form a unique hexameric nucleosome with CENP-A(Cse4) and histone H4 at budding yeast point centromeres, we favor a model in which Scm3(Sp) acts as a CENP-A(Cnp1) receptor/assembly factor, cooperating with Mis16 and Mis18 to receive CENP-A(Cnp1) from the Sim3 escort and mediate assembly of CENP-A(Cnp1) into subkinetochore chromatin." ]

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[ "The mechanisms ensuring specific incorporation of CENP-A at centromeres are poorly understood.", "Mis16 and Mis18 are required for CENP-A localization at centromeres and form a complex that is conserved from fission yeast to human.", "Fission yeast sim1 mutants that alleviate kinetochore domain silencing are defective in Scm3(Sp), the ortholog of budding yeast Scm3(Sc).", "Scm3(Sp) depends on Mis16/18 for its centromere localization and like them is recruited to centromeres in late anaphase.", "Importantly, Scm3(Sp) coaffinity purifies with CENP-A(Cnp1) and associates with CENP-A(Cnp1) in vitro, yet localizes independently of intact CENP-A(Cnp1) chromatin and is differentially released from chromatin.", "While Scm3(Sc) has been proposed to form a unique hexameric nucleosome with CENP-A(Cse4) and histone H4 at budding yeast point centromeres, we favor a model in which Scm3(Sp) acts as a CENP-A(Cnp1) receptor/assembly factor, cooperating with Mis16 and Mis18 to receive CENP-A(Cnp1) from the Sim3 escort and mediate assembly of CENP-A(Cnp1) into subkinetochore chromatin." ]

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[ "Immune sensing of DNA is critical for antiviral immunity but can also trigger autoimmune diseases such as lupus erythematosus (LE).", "Here we have provided evidence for the involvement of a damage-associated DNA modification in the detection of cytosolic DNA.", "The oxidized base 8-hydroxyguanosine (8-OHG), a marker of oxidative damage in DNA, potentiated cytosolic immune recognition by decreasing its susceptibility to 3' repair exonuclease 1 (TREX1)-mediated degradation.", "Oxidizative modifications arose physiologically in pathogen DNA during lysosomal reactive oxygen species (ROS) exposure, as well as in neutrophil extracellular trap (NET) DNA during the oxidative burst.", "8-OHG was also abundant in UV-exposed skin lesions of LE patients and colocalized with type I interferon (IFN).", "Injection of oxidized DNA in the skin of lupus-prone mice induced lesions that closely matched respective lesions in patients.", "Thus, oxidized DNA represents a prototypic damage-associated molecular pattern (DAMP) with important implications for infection, sterile inflammation, and autoimmunity." ]

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[ "The role of ataxia telangiectasia mutated (ATM), a DNA double-strand break recognition and response protein, in inflammation and inflammatory diseases is unclear.", "We have previously shown that high levels of systemic DNA damage are induced by intestinal inflammation in wild-type mice.", "To determine the effect of Atm deficiency in inflammation, we induced experimental colitis in Atm(-/-), Atm(+/-), and wild-type mice via dextran sulfate sodium (DSS) administration.", "Atm(-/-) mice had higher disease activity indices and rates of mortality compared with heterozygous and wild-type mice.", "Systemic DNA damage and immune response were characterized in peripheral blood throughout and after three cycles of treatment.", "Atm(-/-) mice showed increased sensitivity to levels of DNA strand breaks in peripheral leukocytes, as well as micronucleus formation in erythroblasts, compared with heterozygous and wild-type mice, especially during remission periods and after the end of treatment.", "Markers of reactive oxygen and nitrogen species-mediated damage, including 8-oxoguanine and nitrotyrosine, were present both in the distal colon and in peripheral leukocytes, with Atm(-/-) mice manifesting more 8-oxoguanine formation than wild-type mice.", "Atm(-/-) mice showed greater upregulation of inflammatory cytokines and significantly higher percentages of activated CD69+ and CD44+ T cells in the peripheral blood throughout treatment.", "ATM, therefore, may be a critical immunoregulatory factor dampening the deleterious effects of chronic DSS-induced inflammation, necessary for systemic genomic stability and homeostasis of the gut epithelial barrier." ]

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[ "Immune sensing of DNA is critical for antiviral immunity but can also trigger autoimmune diseases such as lupus erythematosus (LE).", "Here we have provided evidence for the involvement of a damage-associated DNA modification in the detection of cytosolic DNA.", "The oxidized base 8-hydroxyguanosine (8-OHG), a marker of oxidative damage in DNA, potentiated cytosolic immune recognition by decreasing its susceptibility to 3' repair exonuclease 1 (TREX1)-mediated degradation.", "Oxidizative modifications arose physiologically in pathogen DNA during lysosomal reactive oxygen species (ROS) exposure, as well as in neutrophil extracellular trap (NET) DNA during the oxidative burst.", "8-OHG was also abundant in UV-exposed skin lesions of LE patients and colocalized with type I interferon (IFN).", "Injection of oxidized DNA in the skin of lupus-prone mice induced lesions that closely matched respective lesions in patients.", "Thus, oxidized DNA represents a prototypic damage-associated molecular pattern (DAMP) with important implications for infection, sterile inflammation, and autoimmunity." ]

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[ "The role of ataxia telangiectasia mutated (ATM), a DNA double-strand break recognition and response protein, in inflammation and inflammatory diseases is unclear.", "We have previously shown that high levels of systemic DNA damage are induced by intestinal inflammation in wild-type mice.", "To determine the effect of Atm deficiency in inflammation, we induced experimental colitis in Atm(-/-), Atm(+/-), and wild-type mice via dextran sulfate sodium (DSS) administration.", "Atm(-/-) mice had higher disease activity indices and rates of mortality compared with heterozygous and wild-type mice.", "Systemic DNA damage and immune response were characterized in peripheral blood throughout and after three cycles of treatment.", "Atm(-/-) mice showed increased sensitivity to levels of DNA strand breaks in peripheral leukocytes, as well as micronucleus formation in erythroblasts, compared with heterozygous and wild-type mice, especially during remission periods and after the end of treatment.", "Markers of reactive oxygen and nitrogen species-mediated damage, including 8-oxoguanine and nitrotyrosine, were present both in the distal colon and in peripheral leukocytes, with Atm(-/-) mice manifesting more 8-oxoguanine formation than wild-type mice.", "Atm(-/-) mice showed greater upregulation of inflammatory cytokines and significantly higher percentages of activated CD69+ and CD44+ T cells in the peripheral blood throughout treatment.", "ATM, therefore, may be a critical immunoregulatory factor dampening the deleterious effects of chronic DSS-induced inflammation, necessary for systemic genomic stability and homeostasis of the gut epithelial barrier." ]

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[ "Fast axonal transport (FAT) requires consistent energy over long distances to fuel the molecular motors that transport vesicles.", "We demonstrate that glycolysis provides ATP for the FAT of vesicles.", "Although inhibiting ATP production from mitochondria did not affect vesicles motility, pharmacological or genetic inhibition of the glycolytic enzyme GAPDH reduced transport in cultured neurons and in Drosophila larvae.", "GAPDH localizes on vesicles via a huntingtin-dependent mechanism and is transported on fast-moving vesicles within axons.", "Purified motile vesicles showed GAPDH enzymatic activity and produced ATP.", "Finally, we show that vesicular GAPDH is necessary and sufficient to provide on-board energy for fast vesicular transport.", "Although detaching GAPDH from vesicles reduced transport, targeting GAPDH to vesicles was sufficient to promote FAT in GAPDH deficient neurons.", "This specifically localized glycolytic machinery may supply constant energy, independent of mitochondria, for the processive movement of vesicles over long distances in axons." ]

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[ "BACKGROUND Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowers plasma low-density lipoprotein (LDL) cholesterol and apolipoprotein B100 (apoB).", "Although studies in mice and cells have identified increased hepatic LDL receptors as the basis for LDL lowering by PCSK9 inhibitors, there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism.", "In particular, it is not known whether inhibition of PCSK9 has any effects on very low-density lipoprotein or intermediate-density lipoprotein (IDL) metabolism.", "Inhibition of PCSK9 also results in reductions of plasma lipoprotein (a) levels.", "The regulation of plasma Lp(a) levels, including the role of LDL receptors in the clearance of Lp(a), is poorly defined, and no mechanistic studies of the Lp(a) lowering by alirocumab in humans have been published to date.", "METHODS Eighteen (10 F, 8 mol/L) participants completed a placebo-controlled, 2-period study.", "They received 2 doses of placebo, 2 weeks apart, followed by 5 doses of 150 mg of alirocumab, 2 weeks apart.", "At the end of each period, fractional clearance rates (FCRs) and production rates (PRs) of apoB and apo(a) were determined.", "In 10 participants, postprandial triglycerides and apoB48 levels were measured.", "RESULTS Alirocumab reduced ultracentrifugally isolated LDL-C by 55.1%, LDL-apoB by 56.3%, and plasma Lp(a) by 18.7%.", "The fall in LDL-apoB was caused by an 80.4% increase in LDL-apoB FCR and a 23.9% reduction in LDL-apoB PR.", "The latter was due to a 46.1% increase in IDL-apoB FCR coupled with a 27.2% decrease in conversion of IDL to LDL.", "The FCR of apo(a) tended to increase (24.6%) without any change in apo(a) PR.", "Alirocumab had no effects on FCRs or PRs of very low-density lipoproteins-apoB and very low-density lipoproteins triglycerides or on postprandial plasma triglycerides or apoB48 concentrations.", "CONCLUSIONS Alirocumab decreased LDL-C and LDL-apoB by increasing IDL- and LDL-apoB FCRs and decreasing LDL-apoB PR.", "These results are consistent with increases in LDL receptors available to clear IDL and LDL from blood during PCSK9 inhibition.", "The increase in apo(a) FCR during alirocumab treatment suggests that increased LDL receptors may also play a role in the reduction of plasma Lp(a).", "CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov.", "Unique identifier: NCT01959971." ]

[ 3, 16 ]

[ "Viral replication and microbial translocation from the gut to the blood during HIV infection lead to hyperimmune activation, which contributes to the decline in CD4+ T cell numbers during HIV infection.", "Programmed death-1 (PD-1) and interleukin-10 (IL-10) are both upregulated during HIV infection.", "Blocking interactions between PD-1 and programmed death ligand-1 (PD-L1) and between IL-10 and IL-10 receptor (IL-10R) results in viral clearance and improves T cell function in animal models of chronic viral infections.", "Here we show that high amounts of microbial products and inflammatory cytokines in the plasma of HIV-infected subjects lead to upregulation of PD-1 expression on monocytes that correlates with high plasma concentrations of IL-10.", "Triggering of PD-1 expressed on monocytes by PD-L1 expressed on various cell types induced IL-10 production and led to reversible CD4+ T cell dysfunction.", "We describe a new function for PD-1 whereby microbial products inhibit T cell expansion and function by upregulating PD-1 levels and IL-10 production by monocytes after binding of PD-1 by PD-L1." ]

[ 4, 5 ]

[ "Although aberrant DNA methylation is considered to be one of the key ways by which tumor-suppressor and DNA-repair genes are silenced during tumor initiation and progression, the mechanisms underlying DNA methylation alterations in cancer remain unclear.", "Here we show that prostaglandin E(2) (PGE(2)) silences certain tumor-suppressor and DNA-repair genes through DNA methylation to promote tumor growth.", "These findings uncover a previously unrecognized role for PGE(2) in the promotion of tumor progression." ]

[]

[ "Synaptic long-term potentiation (LTP) at spinal neurons directly communicating pain-specific inputs from the periphery to the brain has been proposed to serve as a trigger for pain hypersensitivity in pathological states.", "Previous studies have functionally implicated the NMDA receptor-NO pathway and the downstream second messenger, cGMP, in these processes.", "Because cGMP can broadly influence diverse ion-channels, kinases, and phosphodiesterases, pre- as well as post-synaptically, the precise identity of cGMP targets mediating spinal LTP, their mechanisms of action, and their locus in the spinal circuitry are still unclear.", "Here, we found that Protein Kinase G1 (PKG-I) localized presynaptically in nociceptor terminals plays an essential role in the expression of spinal LTP.", "Using the Cre-lox P system, we generated nociceptor-specific knockout mice lacking PKG-I specifically in presynaptic terminals of nociceptors in the spinal cord, but not in post-synaptic neurons or elsewhere (SNS-PKG-I(-/-) mice).", "Patch clamp recordings showed that activity-induced LTP at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) was completely abolished in SNS-PKG-I(-/-) mice, although basal synaptic transmission was not affected.", "Analyses of synaptic failure rates and paired-pulse ratios indicated a role for presynaptic PKG-I in regulating the probability of neurotransmitter release.", "Inositol 1,4,5-triphosphate receptor 1 and myosin light chain kinase were recruited as key phosphorylation targets of presynaptic PKG-I in nociceptive neurons.", "Finally, behavioural analyses in vivo showed marked defects in SNS-PKG-I(-/-) mice in several models of activity-induced nociceptive hypersensitivity, and pharmacological studies identified a clear contribution of PKG-I expressed in spinal terminals of nociceptors.", "Our results thus indicate that presynaptic mechanisms involving an increase in release probability from nociceptors are operational in the expression of synaptic LTP on spinal-PAG projection neurons and that PKG-I localized in presynaptic nociceptor terminals plays an essential role in this process to regulate pain sensitivity." ]

[ 3, 9 ]

[ "Synaptic long-term potentiation (LTP) at spinal neurons directly communicating pain-specific inputs from the periphery to the brain has been proposed to serve as a trigger for pain hypersensitivity in pathological states.", "Previous studies have functionally implicated the NMDA receptor-NO pathway and the downstream second messenger, cGMP, in these processes.", "Because cGMP can broadly influence diverse ion-channels, kinases, and phosphodiesterases, pre- as well as post-synaptically, the precise identity of cGMP targets mediating spinal LTP, their mechanisms of action, and their locus in the spinal circuitry are still unclear.", "Here, we found that Protein Kinase G1 (PKG-I) localized presynaptically in nociceptor terminals plays an essential role in the expression of spinal LTP.", "Using the Cre-lox P system, we generated nociceptor-specific knockout mice lacking PKG-I specifically in presynaptic terminals of nociceptors in the spinal cord, but not in post-synaptic neurons or elsewhere (SNS-PKG-I(-/-) mice).", "Patch clamp recordings showed that activity-induced LTP at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) was completely abolished in SNS-PKG-I(-/-) mice, although basal synaptic transmission was not affected.", "Analyses of synaptic failure rates and paired-pulse ratios indicated a role for presynaptic PKG-I in regulating the probability of neurotransmitter release.", "Inositol 1,4,5-triphosphate receptor 1 and myosin light chain kinase were recruited as key phosphorylation targets of presynaptic PKG-I in nociceptive neurons.", "Finally, behavioural analyses in vivo showed marked defects in SNS-PKG-I(-/-) mice in several models of activity-induced nociceptive hypersensitivity, and pharmacological studies identified a clear contribution of PKG-I expressed in spinal terminals of nociceptors.", "Our results thus indicate that presynaptic mechanisms involving an increase in release probability from nociceptors are operational in the expression of synaptic LTP on spinal-PAG projection neurons and that PKG-I localized in presynaptic nociceptor terminals plays an essential role in this process to regulate pain sensitivity." ]

[ 5 ]

[ "Synaptic long-term potentiation (LTP) at spinal neurons directly communicating pain-specific inputs from the periphery to the brain has been proposed to serve as a trigger for pain hypersensitivity in pathological states.", "Previous studies have functionally implicated the NMDA receptor-NO pathway and the downstream second messenger, cGMP, in these processes.", "Because cGMP can broadly influence diverse ion-channels, kinases, and phosphodiesterases, pre- as well as post-synaptically, the precise identity of cGMP targets mediating spinal LTP, their mechanisms of action, and their locus in the spinal circuitry are still unclear.", "Here, we found that Protein Kinase G1 (PKG-I) localized presynaptically in nociceptor terminals plays an essential role in the expression of spinal LTP.", "Using the Cre-lox P system, we generated nociceptor-specific knockout mice lacking PKG-I specifically in presynaptic terminals of nociceptors in the spinal cord, but not in post-synaptic neurons or elsewhere (SNS-PKG-I(-/-) mice).", "Patch clamp recordings showed that activity-induced LTP at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) was completely abolished in SNS-PKG-I(-/-) mice, although basal synaptic transmission was not affected.", "Analyses of synaptic failure rates and paired-pulse ratios indicated a role for presynaptic PKG-I in regulating the probability of neurotransmitter release.", "Inositol 1,4,5-triphosphate receptor 1 and myosin light chain kinase were recruited as key phosphorylation targets of presynaptic PKG-I in nociceptive neurons.", "Finally, behavioural analyses in vivo showed marked defects in SNS-PKG-I(-/-) mice in several models of activity-induced nociceptive hypersensitivity, and pharmacological studies identified a clear contribution of PKG-I expressed in spinal terminals of nociceptors.", "Our results thus indicate that presynaptic mechanisms involving an increase in release probability from nociceptors are operational in the expression of synaptic LTP on spinal-PAG projection neurons and that PKG-I localized in presynaptic nociceptor terminals plays an essential role in this process to regulate pain sensitivity." ]

[ 5 ]

[ "The transcriptional status of a gene can be maintained through multiple rounds of cell division during development.", "This epigenetic effect is believed to reflect heritable changes in chromatin folding and histone modifications or variants at target genes, but little is known about how these chromatin features are inherited through cell division.", "A particular challenge for maintaining transcription states is DNA replication, which disrupts or dilutes chromatin-associated proteins and histone modifications.", "PRC1-class Polycomb group protein complexes are essential for development and are thought to heritably silence transcription by altering chromatin folding and histone modifications.", "It is not known whether these complexes and their effects are maintained during DNA replication or subsequently re-established.", "We find that when PRC1-class Polycomb complex-bound chromatin or DNA is replicated in vitro, Polycomb complexes remain bound to replicated templates.", "Retention of Polycomb proteins through DNA replication may contribute to maintenance of transcriptional silencing through cell division." ]

[]

[ "Vascular disease progression is associated with marked changes in vascular smooth muscle cell (SMC) phenotype and function.", "SMC contractile gene expression and, thus differentiation, is under direct transcriptional control by the transcription factor, serum response factor (SRF); however, the mechanisms dynamically regulating SMC phenotype are not fully defined.", "Here we report that the lipid and protein phosphatase, PTEN, has a novel role in the nucleus by functioning as an indispensible regulator with SRF to maintain the differentiated SM phenotype.", "PTEN interacts with the N-terminal domain of SRF and PTEN-SRF interaction promotes SRF binding to essential promoter elements in SM-specific genes.", "Factors inducing phenotypic switching promote loss of nuclear PTEN through nucleo-cytoplasmic translocation resulting in reduced myogenically active SRF, but enhanced SRF activity on target genes involved in proliferation.", "Overall decreased expression of PTEN was observed in intimal SMCs of human atherosclerotic lesions underlying the potential clinical importance of these findings." ]

[ 2, 3, 4 ]

[ "CONTEXT Many smokers are unable or unwilling to completely quit smoking.", "A proposed means of harm reduction is to reduce the number of cigarettes smoked per day.", "However, it is not clear whether this strategy decreases the risk for tobacco-related diseases.", "OBJECTIVE To assess the effects of smoking reduction on lung cancer incidence.", "DESIGN, SETTING, AND PARTICIPANTS Observational population-based cohort study with up to 31 years of follow-up from the Copenhagen Centre for Prospective Population Studies, which administrates data from 3 longitudinal studies conducted in Copenhagen and suburbs, the Copenhagen City Heart Study, the Copenhagen Male Study, and the Glostrup Population Studies, Denmark.", "Participants were 11,151 men and 8563 women (N = 19,714) aged 20 to 93 years, who attended 2 consecutive examinations with a 5- to 10-year interval between 1964 and 1988.", "Participants underwent a physical examination and completed self-filled questionnaires about lifestyle habits.", "The study population was divided into 6 groups according to smoking habits: continued heavy smokers (> or =15 cigarettes/d), reducers (reduced from > or =15 cigarettes/d by minimum of 50% without quitting), continued light smokers (1-14 cigarettes/d), quitters (stopped between first and second examination), stable ex-smokers, and never smokers.", "MAIN OUTCOME MEASURE Incident primary lung cancer cases assessed by record linkage with the National Cancer Registry until December 31, 2003.", "RESULTS There were 864 incident lung cancers during follow-up.", "Using Cox regression, the adjusted hazard ratio (HR) for lung cancer in reducers was 0.73 (95% confidence interval [CI], 0.54-0.98) compared with persistent heavy smokers.", "The HR for light smokers was 0.44 (95% CI, 0.35-0.56); for quitters, HR 0.50 (95% CI, 0.36-0.69), for stable ex-smokers, HR 0.17 (95% CI, 0.13-0.23), and for never smokers, HR 0.09 (95% CI, 0.06-0.13).", "CONCLUSION Among individuals who smoke 15 or more cigarettes per day, smoking reduction by 50% significantly reduces the risk of lung cancer." ]

[ 11 ]

[ "OBJECTIVES To explore the association between a stable partnership and clinical outcome in HIV infected patients receiving highly active antiretroviral therapy (HAART).", "DESIGN Prospective cohort study of adults with HIV (Swiss HIV cohort study).", "SETTING Seven outpatient clinics throughout Switzerland.", "PARTICIPANTS The 3736 patients in the cohort who started HAART before 2002 (median age 36 years, 29% female, median follow up 3.6 years).", "MAIN OUTCOME MEASURES Time to AIDS or death (primary endpoint), death alone, increases in CD4 cell count of at least 50 and 100 above baseline, optimal viral suppression (a viral load below 400 copies/ml), and viral rebound.", "RESULTS During follow up 2985 (80%) participants reported a stable partnership on at least one occasion.", "When starting HAART, 52% (545/1042) of participants reported a stable partnership; after five years of follow up 46% (190/412) of participants reported a stable partnership.", "In an analysis stratified by previous antiretroviral therapy and clinical stage when starting HAART (US Centers for Disease Control and Prevention group A, B, or C), the adjusted hazard ratio for progression to AIDS or death was 0.79 (95% confidence interval 0.63 to 0.98) for participants with a stable partnership compared with those without.", "Adjusted hazards ratios for other endpoints were 0.59 (0.44 to 0.79) for progression to death, 1.15 (1.06 to 1.24) for an increase in CD4 cells of 100 counts/microl or more, and 1.06 (0.98 to 1.14) for optimal viral suppression.", "CONCLUSIONS A stable partnership is associated with a slower rate of progression to AIDS or death in HIV infected patients receiving HAART." ]

[ 7, 9 ]

[ "OBJECTIVES To explore the association between a stable partnership and clinical outcome in HIV infected patients receiving highly active antiretroviral therapy (HAART).", "DESIGN Prospective cohort study of adults with HIV (Swiss HIV cohort study).", "SETTING Seven outpatient clinics throughout Switzerland.", "PARTICIPANTS The 3736 patients in the cohort who started HAART before 2002 (median age 36 years, 29% female, median follow up 3.6 years).", "MAIN OUTCOME MEASURES Time to AIDS or death (primary endpoint), death alone, increases in CD4 cell count of at least 50 and 100 above baseline, optimal viral suppression (a viral load below 400 copies/ml), and viral rebound.", "RESULTS During follow up 2985 (80%) participants reported a stable partnership on at least one occasion.", "When starting HAART, 52% (545/1042) of participants reported a stable partnership; after five years of follow up 46% (190/412) of participants reported a stable partnership.", "In an analysis stratified by previous antiretroviral therapy and clinical stage when starting HAART (US Centers for Disease Control and Prevention group A, B, or C), the adjusted hazard ratio for progression to AIDS or death was 0.79 (95% confidence interval 0.63 to 0.98) for participants with a stable partnership compared with those without.", "Adjusted hazards ratios for other endpoints were 0.59 (0.44 to 0.79) for progression to death, 1.15 (1.06 to 1.24) for an increase in CD4 cells of 100 counts/microl or more, and 1.06 (0.98 to 1.14) for optimal viral suppression.", "CONCLUSIONS A stable partnership is associated with a slower rate of progression to AIDS or death in HIV infected patients receiving HAART." ]

[ 7, 9 ]

[ "OBJECTIVES To determine the extent to which type of hospital admission (emergency compared with elective) and surgical procedure varied by socioeconomic circumstances, age, sex, and year of admission for colorectal, breast, and lung cancer.", "DESIGN Repeated cross sectional study with data from individual patients, 1 April 1999 to 31 March 2006.", "SETTING Hospital episode statistics (HES) dataset.", "PARTICIPANTS 564 821 patients aged 50 and over admitted with a diagnosis of colorectal, breast, or lung cancer.", "MAIN OUTCOME MEASURES Proportion of patients admitted as emergencies, and the proportion receiving the recommended surgical treatment.", "RESULTS Patients from deprived areas, older people, and women were more likely to be admitted as emergencies.", "For example, the adjusted odds ratio for patients with breast cancer in the least compared with most deprived fifth of deprivation was 0.63 (95% confidence interval 0.60 to 0.66) and the adjusted odds ratio for patients with lung cancer aged 80-89 compared with those aged 50-59 was 3.13 (2.93 to 3.34).", "There were some improvements in disparities between age groups but not for patients living in deprived areas over time.", "Patients from deprived areas were less likely to receive preferred procedures for rectal, breast, and lung cancer.", "These findings did not improve with time.", "For example, 67.4% (3529/5237) of patients in the most deprived fifth of deprivation had anterior resection for rectal cancer compared with 75.5% (4497/5959) of patients in the least deprived fifth (1.34, 1.22 to 1.47).", "Over half (54.0%, 11 256/20 849) of patients in the most deprived fifth of deprivation had breast conserving surgery compared with 63.7% (18 445/28 960) of patients in the least deprived fifth (1.21, 1.16 to 1.26).", "Men were less likely than women to undergo anterior resection and lung cancer resection and older people were less likely to receive breast conserving surgery and lung cancer resection.", "For example, the adjusted odds ratio for lung cancer patients aged 80-89 compared with those aged 50-59 was 0.52 (0.46 to 0.59).", "Conclusions Despite the implementation of the NHS Cancer Plan, social factors still strongly influence access to and the provision of care." ]

[ 6, 7, 10 ]

[ "OBJECTIVES To determine the extent to which type of hospital admission (emergency compared with elective) and surgical procedure varied by socioeconomic circumstances, age, sex, and year of admission for colorectal, breast, and lung cancer.", "DESIGN Repeated cross sectional study with data from individual patients, 1 April 1999 to 31 March 2006.", "SETTING Hospital episode statistics (HES) dataset.", "PARTICIPANTS 564 821 patients aged 50 and over admitted with a diagnosis of colorectal, breast, or lung cancer.", "MAIN OUTCOME MEASURES Proportion of patients admitted as emergencies, and the proportion receiving the recommended surgical treatment.", "RESULTS Patients from deprived areas, older people, and women were more likely to be admitted as emergencies.", "For example, the adjusted odds ratio for patients with breast cancer in the least compared with most deprived fifth of deprivation was 0.63 (95% confidence interval 0.60 to 0.66) and the adjusted odds ratio for patients with lung cancer aged 80-89 compared with those aged 50-59 was 3.13 (2.93 to 3.34).", "There were some improvements in disparities between age groups but not for patients living in deprived areas over time.", "Patients from deprived areas were less likely to receive preferred procedures for rectal, breast, and lung cancer.", "These findings did not improve with time.", "For example, 67.4% (3529/5237) of patients in the most deprived fifth of deprivation had anterior resection for rectal cancer compared with 75.5% (4497/5959) of patients in the least deprived fifth (1.34, 1.22 to 1.47).", "Over half (54.0%, 11 256/20 849) of patients in the most deprived fifth of deprivation had breast conserving surgery compared with 63.7% (18 445/28 960) of patients in the least deprived fifth (1.21, 1.16 to 1.26).", "Men were less likely than women to undergo anterior resection and lung cancer resection and older people were less likely to receive breast conserving surgery and lung cancer resection.", "For example, the adjusted odds ratio for lung cancer patients aged 80-89 compared with those aged 50-59 was 0.52 (0.46 to 0.59).", "Conclusions Despite the implementation of the NHS Cancer Plan, social factors still strongly influence access to and the provision of care." ]

[ 6, 7, 10 ]

[ "BACKGROUND The heritable haemoglobinopathy alpha(+)-thalassaemia is caused by the reduced synthesis of alpha-globin chains that form part of normal adult haemoglobin (Hb).", "Individuals homozygous for alpha(+)-thalassaemia have microcytosis and an increased erythrocyte count.", "Alpha(+)-thalassaemia homozygosity confers considerable protection against severe malaria, including severe malarial anaemia (SMA) (Hb concentration < 50 g/l), but does not influence parasite count.", "We tested the hypothesis that the erythrocyte indices associated with alpha(+)-thalassaemia homozygosity provide a haematological benefit during acute malaria.", "METHODS AND FINDINGS Data from children living on the north coast of Papua New Guinea who had participated in a case-control study of the protection afforded by alpha(+)-thalassaemia against severe malaria were reanalysed to assess the genotype-specific reduction in erythrocyte count and Hb levels associated with acute malarial disease.", "We observed a reduction in median erythrocyte count of approximately 1.5 x 10(12)/l in all children with acute falciparum malaria relative to values in community children (p < 0.001).", "We developed a simple mathematical model of the linear relationship between Hb concentration and erythrocyte count.", "This model predicted that children homozygous for alpha(+)-thalassaemia lose less Hb than children of normal genotype for a reduction in erythrocyte count of >1.1 x 10(12)/l as a result of the reduced mean cell Hb in homozygous alpha(+)-thalassaemia.", "In addition, children homozygous for alpha(+)-thalassaemia require a 10% greater reduction in erythrocyte count than children of normal genotype (p = 0.02) for Hb concentration to fall to 50 g/l, the cutoff for SMA.", "We estimated that the haematological profile in children homozygous for alpha(+)-thalassaemia reduces the risk of SMA during acute malaria compared to children of normal genotype (relative risk 0.52; 95% confidence interval [CI] 0.24-1.12, p = 0.09).", "CONCLUSIONS The increased erythrocyte count and microcytosis in children homozygous for alpha(+)-thalassaemia may contribute substantially to their protection against SMA.", "A lower concentration of Hb per erythrocyte and a larger population of erythrocytes may be a biologically advantageous strategy against the significant reduction in erythrocyte count that occurs during acute infection with the malaria parasite Plasmodium falciparum.", "This haematological profile may reduce the risk of anaemia by other Plasmodium species, as well as other causes of anaemia.", "Other host polymorphisms that induce an increased erythrocyte count and microcytosis may confer a similar advantage." ]

[ 2, 9, 10 ]

[ "BACKGROUND The heritable haemoglobinopathy alpha(+)-thalassaemia is caused by the reduced synthesis of alpha-globin chains that form part of normal adult haemoglobin (Hb).", "Individuals homozygous for alpha(+)-thalassaemia have microcytosis and an increased erythrocyte count.", "Alpha(+)-thalassaemia homozygosity confers considerable protection against severe malaria, including severe malarial anaemia (SMA) (Hb concentration < 50 g/l), but does not influence parasite count.", "We tested the hypothesis that the erythrocyte indices associated with alpha(+)-thalassaemia homozygosity provide a haematological benefit during acute malaria.", "METHODS AND FINDINGS Data from children living on the north coast of Papua New Guinea who had participated in a case-control study of the protection afforded by alpha(+)-thalassaemia against severe malaria were reanalysed to assess the genotype-specific reduction in erythrocyte count and Hb levels associated with acute malarial disease.", "We observed a reduction in median erythrocyte count of approximately 1.5 x 10(12)/l in all children with acute falciparum malaria relative to values in community children (p < 0.001).", "We developed a simple mathematical model of the linear relationship between Hb concentration and erythrocyte count.", "This model predicted that children homozygous for alpha(+)-thalassaemia lose less Hb than children of normal genotype for a reduction in erythrocyte count of >1.1 x 10(12)/l as a result of the reduced mean cell Hb in homozygous alpha(+)-thalassaemia.", "In addition, children homozygous for alpha(+)-thalassaemia require a 10% greater reduction in erythrocyte count than children of normal genotype (p = 0.02) for Hb concentration to fall to 50 g/l, the cutoff for SMA.", "We estimated that the haematological profile in children homozygous for alpha(+)-thalassaemia reduces the risk of SMA during acute malaria compared to children of normal genotype (relative risk 0.52; 95% confidence interval [CI] 0.24-1.12, p = 0.09).", "CONCLUSIONS The increased erythrocyte count and microcytosis in children homozygous for alpha(+)-thalassaemia may contribute substantially to their protection against SMA.", "A lower concentration of Hb per erythrocyte and a larger population of erythrocytes may be a biologically advantageous strategy against the significant reduction in erythrocyte count that occurs during acute infection with the malaria parasite Plasmodium falciparum.", "This haematological profile may reduce the risk of anaemia by other Plasmodium species, as well as other causes of anaemia.", "Other host polymorphisms that induce an increased erythrocyte count and microcytosis may confer a similar advantage." ]

[ 2, 9, 10 ]

[ "Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks.", "In individuals with panic disorder there is evidence of decreased central gamma-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate.", "In a rat model of panic disorder, chronic inhibition of GABA synthesis in the dorsomedial-perifornical hypothalamus of rats produces anxiety-like states and a similar vulnerability to sodium lactate-induced cardioexcitatory responses.", "The dorsomedial-perifornical hypothalamus is enriched in neurons containing orexin (ORX, also known as hypocretin), which have a crucial role in arousal, vigilance and central autonomic mobilization, all of which are key components of panic.", "Here we show that activation of ORX-synthesizing neurons is necessary for developing a panic-prone state in the rat panic model, and either silencing of the hypothalamic gene encoding ORX (Hcrt) with RNAi or systemic ORX-1 receptor antagonists blocks the panic responses.", "Moreover, we show that human subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety.", "Taken together, our results suggest that the ORX system may be involved in the pathophysiology of panic anxiety and that ORX antagonists constitute a potential new treatment strategy for panic disorder." ]

[ 5 ]

[ "CONTEXT Vaso-occlusion is central to the painful crises and acute and chronic organ damage in sickle cell disease.", "Abnormal nitric oxide-dependent regulation of vascular tone, adhesion, platelet activation, and inflammation contributes to the pathophysiology of vaso-occlusion.", "Nitric oxide may have promise as a mechanism-of-disease-based therapy for treatment of vaso-occlusion.", "OBJECTIVE To explore the efficacy and safety of inhaled nitric oxide (INO) for treatment of vaso-occlusive crisis in pediatric patients.", "DESIGN Prospective, double-blind, placebo-controlled, randomized clinical trial with enrollment between September 1999 and October 2001.", "SETTING Urban, tertiary care children's hospital in the United States.", "PARTICIPANTS Twenty patients aged 10 to 21 years with sickle cell disease and severe acute vaso-occlusive crisis.", "INTERVENTION Patients were randomly assigned to receive INO (80 ppm with 21% final concentration of inspired oxygen; n = 10), or placebo (21% inspired oxygen; n = 10) for 4 hours.", "MAIN OUTCOME MEASURES Change in pain at 4 hours of inhalation compared with preinhalation pain, measured on a 10-cm visual analog scale (VAS); secondary outcome measures were pain over 6 hours, parenteral narcotic use over 24 hours, duration of hospitalization, blood pressure, oxygen saturation, and methemoglobin concentration.", "RESULTS Preinhalation VAS pain scores were similar in the INO and placebo groups (P =.80).", "The decrease in VAS pain scores at 4 hours was 2.0 cm in the INO group and 1.2 cm in the placebo group (P =.37).", "Repeated-measures analysis of variance for hourly pain scores showed a 1-cm/h greater reduction in the INO group than the placebo group (P =.02).", "Morphine use over 6 hours was significantly less in the INO group (mean cumulative use, 0.29 vs 0.44 mg/kg; P =.03) but was not different over 4 hours (0.26 vs 0.32 mg/kg; P =.21) or 24 hours (0.63 vs 0.91 mg/kg; P =.15).", "Duration of hospitalization was 78 and 100 hours in the INO and placebo groups, respectively (P =.19).", "No INO toxicity was observed.", "CONCLUSIONS Results of this exploratory study suggest that INO may be beneficial for acute vaso-occlusive crisis.", "These preliminary results warrant further investigation." ]

[ 12 ]

[ "To explore the mechanism by which herpes simplex virus (HSV)-2 infection is related to HIV-1 acquisition, we conducted in situ analysis of the cellular infiltrate from sequential biopsies of HSV-2 lesions from patients on and off antiviral therapy.", "CD4(+) and CD8(+) T cells and a mixed population of plasmacytoid and myeloid dendritic cells (DCs), including cells expressing the C-type lectin receptor DC-SIGN, persisted at sites of HSV-2 reactivation for months after healing, even with daily antiviral therapy.", "The CD4(+) T cells that persisted reacted to HSV-2 antigen, were enriched for expression of the chemokine receptor CCR5, and were contiguous to DCs expressing the interleukin-3 receptor CD123 or DC-SIGN.", "Ex vivo infection with a CCR5-tropic strain of HIV-1 revealed greater concentrations of integrated HIV-1 DNA in cells derived from healed genital lesion biopsies than in cells from control skin biopsies.", "The persistence and enrichment of HIV receptor-positive inflammatory cells in the genitalia help explain the inability of anti-HSV-2 therapy to reduce HIV acquisition." ]

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[ "Antigen-specific CD8+ T-cell tolerance, induced by myeloid-derived suppressor cells (MDSCs), is one of the main mechanisms of tumor escape.", "Using in vivo models, we show here that MDSCs directly disrupt the binding of specific peptide–major histocompatibility complex (pMHC) dimers to CD8-expressing T cells through nitration of tyrosines in a T-cell receptor (TCR)-CD8 complex.", "This process makes CD8-expressing T cells unable to bind pMHC and to respond to the specific peptide, although they retain their ability to respond to nonspecific stimulation.", "Nitration of TCR-CD8 is induced by MDSCs through hyperproduction of reactive oxygen species and peroxynitrite during direct cell-cell contact.", "Molecular modeling suggests specific sites of nitration that might affect the conformational flexibility of TCR-CD8 and its interaction with pMHC.", "These data identify a previously unknown mechanism of T-cell tolerance in cancer that is also pertinent to many pathological conditions associated with accumulation of MDSCs." ]

[ 3, 5 ]

[ "Molecular targeted therapy has the potential to dramatically improve survival in patients with cancer.", "However, complete and durable responses to targeted therapy are rare in individuals with advanced-stage solid cancers.", "Even the most effective targeted therapies generally do not induce a complete tumor response, resulting in residual disease and tumor progression that limits patient survival.", "We discuss the emerging need to more fully understand the molecular basis of residual disease as a prelude to designing therapeutic strategies to minimize or eliminate residual disease so that we can move from temporary to chronic control of disease, or a cure, for patients with advanced-stage solid cancers.", "Ultimately, we propose a shift from the current reactive paradigm of analyzing and treating acquired drug resistance to a pre-emptive paradigm of defining the mechanisms that result in residual disease, to target and limit this disease reservoir." ]

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[ "Molecular targeted therapy has the potential to dramatically improve survival in patients with cancer.", "However, complete and durable responses to targeted therapy are rare in individuals with advanced-stage solid cancers.", "Even the most effective targeted therapies generally do not induce a complete tumor response, resulting in residual disease and tumor progression that limits patient survival.", "We discuss the emerging need to more fully understand the molecular basis of residual disease as a prelude to designing therapeutic strategies to minimize or eliminate residual disease so that we can move from temporary to chronic control of disease, or a cure, for patients with advanced-stage solid cancers.", "Ultimately, we propose a shift from the current reactive paradigm of analyzing and treating acquired drug resistance to a pre-emptive paradigm of defining the mechanisms that result in residual disease, to target and limit this disease reservoir." ]

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[ "CONTEXT Pharmacist review of medication orders in the intensive care unit (ICU) has been shown to prevent errors, and pharmacist consultation has reduced drug costs.", "However, whether pharmacist participation in the ICU at the time of drug prescribing reduces adverse events has not been studied.", "OBJECTIVE To measure the effect of pharmacist participation on medical rounds in the ICU on the rate of preventable adverse drug events (ADEs) caused by ordering errors.", "DESIGN Before-after comparison between phase 1 (baseline) and phase 2 (after intervention implemented) and phase 2 comparison with a control unit that did not receive the intervention.", "SETTING A medical ICU (study unit) and a coronary care unit (control unit) in a large urban teaching hospital.", "PATIENTS Seventy-five patients randomly selected from each of 3 groups: all admissions to the study unit from February 1, 1993, through July 31, 1993 (baseline) and all admissions to the study unit (postintervention) and control unit from October 1, 1994, through July 7, 1995.", "In addition, 50 patients were selected at random from the control unit during the baseline period.", "INTERVENTION A senior pharmacist made rounds with the ICU team and remained in the ICU for consultation in the morning, and was available on call throughout the day.", "MAIN OUTCOME MEASURES Preventable ADEs due to ordering (prescribing) errors and the number, type, and acceptance of interventions made by the pharmacist.", "Preventable ADEs were identified by review of medical records of the randomly selected patients during both preintervention and postintervention phases.", "Pharmacists recorded all recommendations, which were then analyzed by type and acceptance.", "RESULTS The rate of preventable ordering ADEs decreased by 66% from 10.4 per 1000 patient-days (95% confidence interval [CI], 7-14) before the intervention to 3.5 (95% CI, 1-5; P<.001) after the intervention.", "In the control unit, the rate was essentially unchanged during the same time periods: 10.9 (95% CI, 6-16) and 12.4 (95% CI, 8-17) per 1000 patient-days.", "The pharmacist made 366 recommendations related to drug ordering, of which 362 (99%) were accepted by physicians.", "CONCLUSIONS The presence of a pharmacist on rounds as a full member of the patient care team in a medical ICU was associated with a substantially lower rate of ADEs caused by prescribing errors.", "Nearly all the changes were readily accepted by physicians." ]

[ 11, 14 ]

[ "CONTEXT Pharmacist review of medication orders in the intensive care unit (ICU) has been shown to prevent errors, and pharmacist consultation has reduced drug costs.", "However, whether pharmacist participation in the ICU at the time of drug prescribing reduces adverse events has not been studied.", "OBJECTIVE To measure the effect of pharmacist participation on medical rounds in the ICU on the rate of preventable adverse drug events (ADEs) caused by ordering errors.", "DESIGN Before-after comparison between phase 1 (baseline) and phase 2 (after intervention implemented) and phase 2 comparison with a control unit that did not receive the intervention.", "SETTING A medical ICU (study unit) and a coronary care unit (control unit) in a large urban teaching hospital.", "PATIENTS Seventy-five patients randomly selected from each of 3 groups: all admissions to the study unit from February 1, 1993, through July 31, 1993 (baseline) and all admissions to the study unit (postintervention) and control unit from October 1, 1994, through July 7, 1995.", "In addition, 50 patients were selected at random from the control unit during the baseline period.", "INTERVENTION A senior pharmacist made rounds with the ICU team and remained in the ICU for consultation in the morning, and was available on call throughout the day.", "MAIN OUTCOME MEASURES Preventable ADEs due to ordering (prescribing) errors and the number, type, and acceptance of interventions made by the pharmacist.", "Preventable ADEs were identified by review of medical records of the randomly selected patients during both preintervention and postintervention phases.", "Pharmacists recorded all recommendations, which were then analyzed by type and acceptance.", "RESULTS The rate of preventable ordering ADEs decreased by 66% from 10.4 per 1000 patient-days (95% confidence interval [CI], 7-14) before the intervention to 3.5 (95% CI, 1-5; P<.001) after the intervention.", "In the control unit, the rate was essentially unchanged during the same time periods: 10.9 (95% CI, 6-16) and 12.4 (95% CI, 8-17) per 1000 patient-days.", "The pharmacist made 366 recommendations related to drug ordering, of which 362 (99%) were accepted by physicians.", "CONCLUSIONS The presence of a pharmacist on rounds as a full member of the patient care team in a medical ICU was associated with a substantially lower rate of ADEs caused by prescribing errors.", "Nearly all the changes were readily accepted by physicians." ]

[ 11, 14 ]

[ "Background Current criteria for the selection of unrelated donors for hematopoietic cell transplantation (HCT) include matching for the alleles of each human leukocyte antigen (HLA) locus within the major histocompatibility complex (MHC).", "Graft-versus-host disease (GVHD), however, remains a significant and potentially life-threatening complication even after HLA-identical unrelated HCT.", "The MHC harbors more than 400 genes, but the total number of transplantation antigens is unknown.", "Genes that influence transplantation outcome could be identified by using linkage disequilibrium (LD)-mapping approaches, if the extended MHC haplotypes of the unrelated donor and recipient could be defined." ]

[ 3 ]

[ "CONTEXT Many observational studies have shown that physical activity reduces the risk of cognitive decline; however, evidence from randomized trials is lacking.", "OBJECTIVE To determine whether physical activity reduces the rate of cognitive decline among older adults at risk.", "DESIGN AND SETTING Randomized controlled trial of a 24-week physical activity intervention conducted between 2004 and 2007 in metropolitan Perth, Western Australia.", "Assessors of cognitive function were blinded to group membership.", "PARTICIPANTS We recruited volunteers who reported memory problems but did not meet criteria for dementia.", "Three hundred eleven individuals aged 50 years or older were screened for eligibility, 89 were not eligible, and 52 refused to participate.", "A total of 170 participants were randomized and 138 participants completed the 18-month assessment.", "INTERVENTION Participants were randomly allocated to an education and usual care group or to a 24-week home-based program of physical activity.", "MAIN OUTCOME MEASURE Change in Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores (possible range, 0-70) over 18 months.", "RESULTS In an intent-to-treat analysis, participants in the intervention group improved 0.26 points (95% confidence interval, -0.89 to 0.54) and those in the usual care group deteriorated 1.04 points (95% confidence interval, 0.32 to 1.82) on the ADAS-Cog at the end of the intervention.", "The absolute difference of the outcome measure between the intervention and control groups was -1.3 points (95% confidence interval,-2.38 to -0.22) at the end of the intervention.", "At 18 months, participants in the intervention group improved 0.73 points (95% confidence interval, -1.27 to 0.03) on the ADAS-Cog, and those in the usual care group improved 0.04 points (95% confidence interval, -0.46 to 0.88).", "Word list delayed recall and Clinical Dementia Rating sum of boxes improved modestly as well, whereas word list total immediate recall, digit symbol coding, verbal fluency, Beck depression score, and Medical Outcomes 36-Item Short-Form physical and mental component summaries did not change significantly.", "CONCLUSIONS In this study of adults with subjective memory impairment, a 6-month program of physical activity provided a modest improvement in cognition over an 18-month follow-up period.", "TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12605000136606." ]

[ 9, 13 ]

[ "CONTEXT Physical inactivity contributes to weight gain in adults, but whether this relationship is true for children of different ethnic groups is not well established.", "OBJECTIVE To assess participation in vigorous activity and television watching habits and their relationship to body weight and fatness in US children.", "DESIGN Nationally representative cross-sectional survey with an in-person interview and medical examination.", "SETTING AND PARTICIPANTS Between 1988 and 1994, 4063 children aged 8 through 16 years were examined as part of the National Health and Nutrition Examination Survey III.", "Mexican Americans and non-Hispanic blacks were oversampled to produce reliable estimates for these groups.", "MAIN OUTCOME MEASURES Episodes of weekly vigorous activity and daily hours of television watched, and their relationship to body mass index and body fatness.", "RESULTS Eighty percent of US children reported performing 3 or more bouts of vigorous activity each week.", "This rate was lower in non-Hispanic black and Mexican American girls (69% and 73%, respectively).", "Twenty percent of US children participated in 2 or fewer bouts of vigorous activity perweek, and the rate was higher in girls (26%) than in boys (17%).", "Overall, 26% of US children watched 4 or more hours of television per day and 67% watched at least 2 hours per day.", "Non-Hispanic black children had the highest rates of watching 4 or more hours of television per day (42%).", "Boys and girls who watch 4 or more hours of television each day had greater body fat (P<.001) and had a greater body mass index (P<.001) than those who watched less than 2 hours per day.", "CONCLUSIONS Many US children watch a great deal of television and are inadequately vigorously active.", "Vigorous activity levels are lowest among girls, non-Hispanic blacks, and Mexican Americans.", "Intervention strategies to promote lifelong physical activity among US children are needed to stem the adverse health consequences of inactivity." ]

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[ "The purpose of this study was to examine differences in resting, submaximal, and maximal (VO2max) oxygen consumption (VO2) in African-American (n = 44) and Caucasian (n = 31) prepubertal children aged 5-10 yr.", "Resting VO2 was measured via indirect calorimetry in the fasted state.", "Submaximal VO2 and VO2max were determined during an all out, progressive treadmill exercise test appropriate for children.", "Dual-energy X-ray absorptiometry was used to determine total fat mass (FM), soft lean tissue mass (LTM), and leg soft LTM.", "Doubly labeled water was used to determine total energy expenditure (TEE) and activity energy expenditure (AEE).", "A significant effect of ethnicity (P < 0.01) was found for VO2max but not resting or submaximal VO2, with African-American children having absolute VO2max approximately 15% lower than Caucasian children (1.21 +/- 0.032 vs. 1.43 +/-", "0.031 l/min, respectively).", "The lower VO2max persisted in African-American children after adjustment for soft LTM (1.23 +/- 0.025 vs. 1.39 +/-", "0.031 l/min; P < 0.01), leg soft LTM (1.20 +/-", "0.031 vs. 1.43 +/-", "0.042 l/min; P < 0.01), and soft LTM and FM (1.23 +/-", "0.025 vs. 1.39 +/-", "0.031 l/min; P < 0.01).", "The lower VO2max persisted also after adjustment for TEE (1.20 +/-", "0.02 vs. 1.38 +/-", "0.0028 l/min P < 0.001) and AEE (1.20 +/- 0.024 vs. 1.38 +/-", "0.028 l/min; P < 0.001).", "In conclusion, our data indicate that African-American and Caucasian children have similar rates of VO2 at rest and during submaximal exercise, but VO2max is approximately 15% lower in African-American children, independent of soft LTM, FM, leg LTM, TEE, and AEE." ]

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[ "BACKGROUND Little is known about how the intensity of exercise influences cardiovascular fitness and body composition, especially in obese adolescents.", "OBJECTIVE Our goal was to determine the effects of physical training intensity on the cardiovascular fitness, percentage of body fat (%BF), and visceral adipose tissue (VAT) of obese adolescents.", "DESIGN Obese 13-16-y-olds (n = 80) were assigned to 1) biweekly lifestyle education (LSE), 2) LSE + moderate-intensity physical training, or 3) LSE + high-intensity physical training.", "The intervention lasted 8 mo.", "Physical training was offered 5 d/wk, and the target energy expenditure for all subjects in physical training groups was 1047 kJ (250 kcal)/session.", "Cardiovascular fitness was measured with a multistage treadmill test, %BF with dual-energy X-ray absorptiometry, and VAT with magnetic resonance imaging.", "RESULTS The increase in cardiovascular fitness in the high-intensity physical training group, but not in the moderate-intensity group, was significantly greater than that in the LSE alone group (P = 0.009); no other comparisons of the 3 groups were significant.", "Compared with the LSE alone group, a group composed of subjects in both physical training groups combined who attended training sessions >or=2 d/wk showed favorable changes in cardiovascular fitness (P < 0.001), %BF (P = 0.001), and VAT (P = 0.029).", "We found no evidence that the high-intensity physical training was more effective than the moderate-intensity physical training in enhancing body composition.", "CONCLUSIONS The cardiovascular fitness of obese adolescents was significantly improved by physical training, especially high-intensity physical training.", "The physical training also reduced both visceral and total-body adiposity, but there was no clear effect of the intensity of physical training." ]

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[ "OBJECTIVES Despite recognition of the important influence of environmental determinants on physical activity patterns, minimal empirical research has been done to assess the impact of environmental/contextual determinants of physical activity.", "This article aims to investigate environmental and sociodemographic determinants of physical activity and inactivity patterns among subpopulations of US adolescents.", "We define environmental determinants as modifiable factors in the physical environment that impose a direct influence on the opportunity to engage in physical activity.", "The present research examines environmental and sociodemographic determinants of physical activity and inactivity with the implication that these findings can point toward societal-level intervention strategies for increasing physical activity and decreasing inactivity among adolescents.", "STUDY DESIGN AND METHODOLOGY The study population consists of nationally representative data from the 1996 National Longitudinal Study of Adolescent Health on 17 766 US adolescents enrolled in US middle and high schools (including 3933 non-Hispanic blacks, 3148 Hispanics, and 1337 Asians).", "Hours/week of inactivity (TV/video viewing and video/computer games) and times/week of moderate to vigorous physical activity were collected by questionnaire.", "Outcome variables were moderate to vigorous physical activity and inactivity, which were broken into categories (physical activity: 0-2 times/week, 3-4 times/week, and >/=5 times/week; inactivity: 0-10 hours/week, 11-24 hours/week, and >/=25 hours/week).", "Sociodemographic and environmental correlates of physical activity and inactivity were used as exposure and control variables and included sex, age, urban residence, participation in school physical education program, use of community recreation center, total reported incidents of serious crime in neighborhood, socioeconomic status, ethnicity, generation of residence in the United States, presence of mother/father in household, pregnancy status, work status, in-school status, region, and month of interview.", "Logistic regression models of high versus low and medium physical activity and inactivity were used to investigate sex and ethnic interactions in relation to environmental and sociodemographic factors to examine evidence for the potential impact of physical education and recreation programs and sociodemographic factors on physical activity and inactivity patterns.", "RESULTS Moderate to vigorous physical activity was lower and inactivity higher for non-Hispanic black and Hispanic adolescents.", "Participation in school physical education programs was considerably low for these adolescents and decreased with age.", "Participation in daily school physical education (PE) program classes (adjusted odds ratio [AOR]: 2.21; confidence interval [CI]: 1.82-2.68) and use of a community recreation center (AOR: 1.75; CI: 1.56-1.96) were associated with an increased likelihood of engaging in high level moderate to vigorous physical activity.", "Maternal education was inversely associated with high inactivity patterns; for example, having a mother with a graduate or professional degree was associated with an AOR of.61 (CI:.48-.76) for high inactivity.", "High family income was associated with increased moderate to vigorous physical activity (AOR: 1.43; CI: 1.22-1.67) and decreased inactivity (AOR:.70; CI:.59-.82).", "High neighborhood serious crime level was associated with a decreased likelihood of falling in the highest category of moderate to vigorous physical activity (AOR:.77; CI:.66-.91).", "CONCLUSIONS These results show important associations between modifiable environmental factors, such as participation in school PE and community recreation programs, with activity patterns of adolescents.", "Despite the marked and significant impact of participation in school PE programs on physical activity patterns of US adolescents, few adolescents participated in such school PE programs; only 21.3% of all adolescents" ]

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[ "CONTEXT Physical inactivity contributes to weight gain in adults, but whether this relationship is true for children of different ethnic groups is not well established.", "OBJECTIVE To assess participation in vigorous activity and television watching habits and their relationship to body weight and fatness in US children.", "DESIGN Nationally representative cross-sectional survey with an in-person interview and medical examination.", "SETTING AND PARTICIPANTS Between 1988 and 1994, 4063 children aged 8 through 16 years were examined as part of the National Health and Nutrition Examination Survey III.", "Mexican Americans and non-Hispanic blacks were oversampled to produce reliable estimates for these groups.", "MAIN OUTCOME MEASURES Episodes of weekly vigorous activity and daily hours of television watched, and their relationship to body mass index and body fatness.", "RESULTS Eighty percent of US children reported performing 3 or more bouts of vigorous activity each week.", "This rate was lower in non-Hispanic black and Mexican American girls (69% and 73%, respectively).", "Twenty percent of US children participated in 2 or fewer bouts of vigorous activity perweek, and the rate was higher in girls (26%) than in boys (17%).", "Overall, 26% of US children watched 4 or more hours of television per day and 67% watched at least 2 hours per day.", "Non-Hispanic black children had the highest rates of watching 4 or more hours of television per day (42%).", "Boys and girls who watch 4 or more hours of television each day had greater body fat (P<.001) and had a greater body mass index (P<.001) than those who watched less than 2 hours per day.", "CONCLUSIONS Many US children watch a great deal of television and are inadequately vigorously active.", "Vigorous activity levels are lowest among girls, non-Hispanic blacks, and Mexican Americans.", "Intervention strategies to promote lifelong physical activity among US children are needed to stem the adverse health consequences of inactivity." ]

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