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Showing papers by "Vanderbilt University published in 2009"


Journal ArticleDOI
TL;DR: Research electronic data capture (REDCap) is a novel workflow methodology and software solution designed for rapid development and deployment of electronic data Capture tools to support clinical and translational research.

29,988 citations


Journal ArticleDOI
08 Oct 2009-Nature
TL;DR: This paper examined potential sources of missing heritability and proposed research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
Abstract: Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

7,797 citations


Journal ArticleDOI
TL;DR: A series of improvements to the spectroscopic reductions are described, including better flat fielding and improved wavelength calibration at the blue end, better processing of objects with extremely strong narrow emission lines, and an improved determination of stellar metallicities.
Abstract: This paper describes the Seventh Data Release of the Sloan Digital Sky Survey (SDSS), marking the completion of the original goals of the SDSS and the end of the phase known as SDSS-II. It includes 11,663 deg^2 of imaging data, with most of the ~2000 deg^2 increment over the previous data release lying in regions of low Galactic latitude. The catalog contains five-band photometry for 357 million distinct objects. The survey also includes repeat photometry on a 120° long, 2°.5 wide stripe along the celestial equator in the Southern Galactic Cap, with some regions covered by as many as 90 individual imaging runs. We include a co-addition of the best of these data, going roughly 2 mag fainter than the main survey over 250 deg^2. The survey has completed spectroscopy over 9380 deg^2; the spectroscopy is now complete over a large contiguous area of the Northern Galactic Cap, closing the gap that was present in previous data releases. There are over 1.6 million spectra in total, including 930,000 galaxies, 120,000 quasars, and 460,000 stars. The data release includes improved stellar photometry at low Galactic latitude. The astrometry has all been recalibrated with the second version of the USNO CCD Astrograph Catalog, reducing the rms statistical errors at the bright end to 45 milliarcseconds per coordinate. We further quantify a systematic error in bright galaxy photometry due to poor sky determination; this problem is less severe than previously reported for the majority of galaxies. Finally, we describe a series of improvements to the spectroscopic reductions, including better flat fielding and improved wavelength calibration at the blue end, better processing of objects with extremely strong narrow emission lines, and an improved determination of stellar metallicities.

5,665 citations


Journal ArticleDOI
TL;DR: A conservative strategy of fluid management using explicit protocols applied for seven days in 1000 patients with acute lung injury improved the chances of death at 60 days and the conservative strategy improved fluid balance during the first seven days.
Abstract: Background Optimal fluid management in patients with acute lung injury is unknown. Diuresis or fluid restriction may improve lung function but could jeopardize extrapulmonary-organ perfusion. Methods In a randomized study, we compared a conservative and a liberal strategy of fluid management using explicit protocols applied for seven days in 1000 patients with acute lung injury. The primary end point was death at 60 days. Secondary end points included the number of ventilator-free days and organ-failure–free days and measures of lung physiology. Results The rate of death at 60 days was 25.5 percent in the conservative-strategy group and 28.4 percent in the liberal-strategy group (P=0.30; 95 percent confidence interval for the difference, −2.6 to 8.4 percent). The mean (±SE) cumulative fluid balance during the first seven days was –136±491 ml in the conservative-strategy group and 6992±502 ml in the liberal-strategy group (P<0.001). As compared with the liberal strategy, the conservative strategy improved ...

2,733 citations


Journal ArticleDOI
27 Feb 2009-Science
TL;DR: Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder Ten percent of cases are inherited; most involve unidentified genes We report here 13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders

2,387 citations


Journal ArticleDOI
TL;DR: It is believed that context and various changes in plasticity biomarkers can help identify at least three types of EMT and that using a collection of criteria for EMT increases the likelihood that everyone is studying the same phenomenon - namely, the transition of epithelial and endothelial cells to a motile phenotype.
Abstract: In the early 19th century, building on observations of microscopists now ancient, Schleiden and Schwann formulated the doctrine that cells are building blocks for plant and animal tissues (1). By the mid-19th century, Raspail, Remak, and Virchow expanded this hypothesis by suggesting that all cells come from preexisting cells — the so-called cell theory. Although referring to cell division, this now classic notion is prescient of another contemporary twist in the biology of cell maturation: beyond lineage development and normal differentiation, mature epithelial cells under new environmental pressures exhibit a local plasticity that allows them to morph into other mature phenotypes with or without proliferation (2, 3). Growing interest in the biology of these cellular transitions helped both establish epithelial cell plasticity as a field of study in the late 20th century and fashion much of the current thinking regarding morphogenesis in early embryonic development, tissue repair, and cancer metastasis (4–6). The details of some of these processes are not discussed here, as they are outlined in other articles in this Review Series on epithelial-mesenchymal transition (EMT) (7, 8). Instead, we offer a personal view gathered from our own experience and the literature regarding an approach documenting EMT events in culture or tissue. We hope this serves to stimulate other points of view as new data emerge.

2,016 citations


Journal ArticleDOI
TL;DR: The importance of spatial ability in educational pursuits and the world of work was examined in this article, with particular attention devoted to STEM (science, technology, engineering, and mathematics) domains.
Abstract: The importance of spatial ability in educational pursuits and the world of work was examined, with particular attention devoted to STEM (science, technology, engineering, and mathematics) domains. Participants were drawn from a stratified random sample of U.S. high schools (Grades 9–12, N 400,000) and were tracked for 11 years; their longitudinal findings were aligned with pre-1957 findings and with contemporary data from the Graduate Record Examination and the Study of Mathematically Precocious Youth. For decades, spatial ability assessed during adolescence has surfaced as a salient psychological attribute among those adolescents who subsequently go on to achieve advanced educational credentials and occupations in STEM. Results solidify the generalization that spatial ability plays a critical role in developing expertise in STEM and suggest, among other things, that including spatial ability in modern talent searches would identify many adolescents with potential for STEM who are currently being missed.

1,407 citations


Journal ArticleDOI
22 May 2009-Science
TL;DR: A detailed genetic analysis of most major groups of African populations is provided, suggesting that Africans represent 14 ancestral populations that correlate with self-described ethnicity and shared cultural and/or linguistic properties.
Abstract: Africa is the source of all modern humans, but characterization of genetic variation and of relationships among populations across the continent has been enigmatic. We studied 121 African populations, four African American populations, and 60 non-African populations for patterns of variation at 1327 nuclear microsatellite and insertion/deletion markers. We identified 14 ancestral population clusters in Africa that correlate with self-described ethnicity and shared cultural and/or linguistic properties. We observed high levels of mixed ancestry in most populations, reflecting historical migration events across the continent. Our data also provide evidence for shared ancestry among geographically diverse hunter-gatherer populations (Khoesan speakers and Pygmies). The ancestry of African Americans is predominantly from Niger-Kordofanian (approximately 71%), European (approximately 13%), and other African (approximately 8%) populations, although admixture levels varied considerably among individuals. This study helps tease apart the complex evolutionary history of Africans and African Americans, aiding both anthropological and genetic epidemiologic studies.

1,376 citations


Journal ArticleDOI
TL;DR: Laparoscopic liver surgery is a safe and effective approach to the management of surgical liver disease in the hands of trained surgeons with experience in hepatobiliary and laparoscopic surgery, and national and international societies should become involved in the goal of establishing training standards and credentialing.
Abstract: Objective:To summarize the current world position on laparoscopic liver surgery.Summary Background Data:Multiple series have reported on the safety and efficacy of laparoscopic liver surgery. Small and medium sized procedures have become commonplace in many centers, while major laparoscopic liver re

1,366 citations


Journal ArticleDOI
TL;DR: The prevalence of chronic, impairing LBP has risen significantly in North Carolina, with continuing high levels of disability and health care use, and a substantial portion of the rise in LBP care costs over the past 2 decades may be related to this rising prevalence.
Abstract: Background National or state-level estimates on trends in the prevalence of chronic low back pain (LBP) are lacking. The objective of this study was to determine whether the prevalence of chronic LBP and the demographic, health-related, and health care–seeking characteristics of individuals with the condition have changed over the last 14 years. Methods A cross-sectional, telephone survey of a representative sample of North Carolina households was conducted in 1992 and repeated in 2006. A total of 4437 households were contacted in 1992 and 5357 households in 2006 to identify noninstitutionalized adults 21 years or older with chronic (>3 months), impairing LBP or neck pain that limits daily activities. These individuals were interviewed in more detail about their health and health care seeking. Results The prevalence of chronic, impairing LBP rose significantly over the 14-year interval, from 3.9% (95% confidence interval [CI], 3.4%-4.4%) in 1992 to 10.2% (95% CI, 9.3%-11.0%) in 2006. Increases were seen for all adult age strata, in men and women, and in white and black races. Symptom severity and general health were similar for both years. The proportion of individuals who sought care from a health care provider in the past year increased from 73.1% (95% CI, 65.2%-79.8%) to 84.0% (95% CI, 80.8%-86.8%), while the mean number of visits to all health care providers were similar (19.5 [1992] vs 19.4 [2006]). Conclusions The prevalence of chronic, impairing LBP has risen significantly in North Carolina, with continuing high levels of disability and health care use. A substantial portion of the rise in LBP care costs over the past 2 decades may be related to this rising prevalence.

1,346 citations


Journal ArticleDOI
Brian J. Haas1, Sophien Kamoun2, Sophien Kamoun3, Michael C. Zody1, Michael C. Zody4, Rays H. Y. Jiang1, Rays H. Y. Jiang5, Robert E. Handsaker1, Liliana M. Cano3, Manfred Grabherr1, Chinnappa D. Kodira1, Chinnappa D. Kodira6, Sylvain Raffaele3, Trudy Torto-Alalibo2, Trudy Torto-Alalibo6, Tolga O. Bozkurt3, Audrey M. V. Ah-Fong7, Lucia Alvarado1, Vicky L. Anderson8, Miles R. Armstrong9, Anna O. Avrova9, Laura Baxter10, Jim Beynon10, Petra C. Boevink9, Stephanie R. Bollmann11, Jorunn I. B. Bos2, Vincent Bulone12, Guohong Cai13, Cahid Cakir2, James C. Carrington14, Megan Chawner15, Lucio Conti16, Stefano Costanzo11, Richard Ewan16, Noah Fahlgren14, Michael A. Fischbach17, Johanna Fugelstad12, Eleanor M. Gilroy9, Sante Gnerre1, Pamela J. Green18, Laura J. Grenville-Briggs8, John Griffith15, Niklaus J. Grünwald11, Karolyn Horn15, Neil R. Horner8, Chia-Hui Hu19, Edgar Huitema2, Dong-Hoon Jeong18, Alexandra M. E. Jones3, Jonathan D. G. Jones3, Richard W. Jones11, Elinor K. Karlsson1, Sridhara G. Kunjeti20, Kurt Lamour21, Zhenyu Liu2, Li-Jun Ma1, Dan MacLean3, Marcus C. Chibucos22, Hayes McDonald23, Jessica McWalters15, Harold J. G. Meijer5, William Morgan24, Paul Morris25, Carol A. Munro8, Keith O'Neill1, Keith O'Neill6, Manuel D. Ospina-Giraldo15, Andrés Pinzón, Leighton Pritchard9, Bernard H Ramsahoye26, Qinghu Ren27, Silvia Restrepo, Sourav Roy7, Ari Sadanandom16, Alon Savidor28, Sebastian Schornack3, David C. Schwartz29, Ulrike Schumann8, Ben Schwessinger3, Lauren Seyer15, Ted Sharpe1, Cristina Silvar3, Jing Song2, David J. Studholme3, Sean M. Sykes1, Marco Thines3, Marco Thines30, Peter J. I. van de Vondervoort5, Vipaporn Phuntumart25, Stephan Wawra8, R. Weide5, Joe Win3, Carolyn A. Young2, Shiguo Zhou29, William E. Fry13, Blake C. Meyers18, Pieter van West8, Jean B. Ristaino19, Francine Govers5, Paul R. J. Birch31, Stephen C. Whisson9, Howard S. Judelson7, Chad Nusbaum1 
17 Sep 2009-Nature
TL;DR: The sequence of the P. infestans genome is reported, which at ∼240 megabases (Mb) is by far the largest and most complex genome sequenced so far in the chromalveolates and probably plays a crucial part in the rapid adaptability of the pathogen to host plants and underpins its evolutionary potential.
Abstract: Phytophthora infestans is the most destructive pathogen of potato and a model organism for the oomycetes, a distinct lineage of fungus-like eukaryotes that are related to organisms such as brown algae and diatoms. As the agent of the Irish potato famine in the mid-nineteenth century, P. infestans has had a tremendous effect on human history, resulting in famine and population displacement(1). To this day, it affects world agriculture by causing the most destructive disease of potato, the fourth largest food crop and a critical alternative to the major cereal crops for feeding the world's population(1). Current annual worldwide potato crop losses due to late blight are conservatively estimated at $6.7 billion(2). Management of this devastating pathogen is challenged by its remarkable speed of adaptation to control strategies such as genetically resistant cultivars(3,4). Here we report the sequence of the P. infestans genome, which at similar to 240 megabases (Mb) is by far the largest and most complex genome sequenced so far in the chromalveolates. Its expansion results from a proliferation of repetitive DNA accounting for similar to 74% of the genome. Comparison with two other Phytophthora genomes showed rapid turnover and extensive expansion of specific families of secreted disease effector proteins, including many genes that are induced during infection or are predicted to have activities that alter host physiology. These fast-evolving effector genes are localized to highly dynamic and expanded regions of the P. infestans genome. This probably plays a crucial part in the rapid adaptability of the pathogen to host plants and underpins its evolutionary potential.

Journal ArticleDOI
28 May 2009-Nature
TL;DR: Several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls, and duplications 55 kilobases upstream of complementary DNA AK123120 indicate that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
Abstract: Several lines of evidence point to genetic involvement in autism spectrum disorders (ASDs), neurodevelopmental and neuropsychiatric disorders characterized by impaired verbal communication and social interaction. The clinical and genetic complexities of the condition make it difficult to identify susceptibility factors, but two related studies now present robust evidence for a genetic involvement. The first, a genome-wide association study, identifies six single-nucleotide polymorphisms strongly associated with autism. These variants lie between two genes encoding neuronal cell-adhesion molecules (cadherins 9 and 10), suggesting possible involvement in ASD pathogenesis. The second study used copy number variation screens to identify genetic variants in two major gene pathways in children with ASDs. The changes are in the ubiquitin pathway, which has previously been associated with neurological disease, and in genes for neuronal cell-adhesion molecules.

Journal ArticleDOI
04 Feb 2009-JAMA
TL;DR: At comparable sedation levels, dexmedetomidine-treated patients spent less time on the ventilator, experienced less delirium, and developed less tachycardia and hypertension.
Abstract: Context γ-Aminobutyric acid receptor agonist medications are the most commonly used sedatives for intensive care unit (ICU) patients, yet preliminary evidence indicates that the α 2 agonist dexmedetomidine may have distinct advantages Objective To compare the efficacy and safety of prolonged sedation with dexmedetomidine vs midazolam for mechanically ventilated patients Design, Setting, and Patients Prospective, double-blind, randomized trial conducted in 68 centers in 5 countries between March 2005 and August 2007 among 375 medical/surgical ICU patients with expected mechanical ventilation for more than 24 hours Sedation level and delirium were assessed using the Richmond Agitation-Sedation Scale (RASS) and the Confusion Assessment Method for the ICU Interventions Dexmedetomidine (02-14 μg/kg per hour [n = 244]) or midazolam (002-01 mg/kg per hour [n = 122]) titrated to achieve light sedation (RASS scores between −2 and +1) from enrollment until extubation or 30 days Main Outcome Measures Percentage of time within target RASS range Secondary end points included prevalence and duration of delirium, use of fentanyl and open-label midazolam, and nursing assessments Additional outcomes included duration of mechanical ventilation, ICU length of stay, and adverse events Results There was no difference in percentage of time within the target RASS range (773% for dexmedetomidine group vs 751% for midazolam group; difference, 22% [95% confidence interval {CI}, −32% to 75%]; P = 18) The prevalence of delirium during treatment was 54% (n = 132/244) in dexmedetomidine-treated patients vs 766% (n = 93/122) in midazolam-treated patients (difference, 226% [95% CI, 14% to 33%]; P Conclusions There was no difference between dexmedetomidine and midazolam in time at targeted sedation level in mechanically ventilated ICU patients At comparable sedation levels, dexmedetomidine-treated patients spent less time on the ventilator, experienced less delirium, and developed less tachycardia and hypertension The most notable adverse effect of dexmedetomidine was bradycardia Trial Registration clinicaltrialsgov Identifier: NCT00216190Published online February 2, 2009 (doi:101001/jama200956)

Journal ArticleDOI
TL;DR: This work uses a behavioral approach to examine the reasonably achievable potential for near-term reductions by altered adoption and use of available technologies in US homes and nonbusiness travel and estimates the plasticity of 17 household action types in 5 behaviorally distinct categories.
Abstract: Most climate change policy attention has been addressed to long-term options, such as inducing new, low-carbon energy technologies and creating cap-and-trade regimes for emissions. We use a behavioral approach to examine the reasonably achievable potential for near-term reductions by altered adoption and use of available technologies in US homes and nonbusiness travel. We estimate the plasticity of 17 household action types in 5 behaviorally distinct categories by use of data on the most effective documented interventions that do not involve new regulatory measures. These interventions vary by type of action and typically combine several policy tools and strong social marketing. National implementation could save an estimated 123 million metric tons of carbon per year in year 10, which is 20% of household direct emissions or 7.4% of US national emissions, with little or no reduction in household well-being. The potential of household action deserves increased policy attention. Future analyses of this potential should incorporate behavioral as well as economic and engineering elements.


Book
02 Jan 2009
TL;DR: Pending the prevention and cure of diabetes or the development of methods that provide glucose-regulated insulin replacement or secretion, the authors need to learn to replace insulin in a much more physiological fashion, to prevent, correct, or compensate for compromised glucose counterregulation, or both if they are to achieve near-euglycemia safely in most people with diabetes.
Abstract: Iatrogenic hypoglycemia causes recurrent morbidity in most people with type 1 diabetes and many with type 2 diabetes, and it is sometimes fatal. The barrier of hypoglycemia generally precludes maintenance of euglycemia over a lifetime of diabetes and thus precludes full realization of euglycemia’s long-term benefits. While the clinical presentation is often characteristic, particularly for the experienced individual with diabetes, the neurogenic and neuroglycopenic symptoms of hypoglycemia are nonspecific and relatively insensitive; therefore, many episodes are not recognized. Hypoglycemia can result from exogenous or endogenous insulin excess alone. However, iatrogenic hypoglycemia is typically the result of the interplay of absolute or relative insulin excess and compromised glucose counterregulation in type 1 and advanced type 2 diabetes. Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine stand high in the hierarchy of redundant glucose counterregulatory factors that normally prevent or rapidly correct hypoglycemia. In insulin-deficient diabetes (exogenous) insulin levels do not decrease as glucose levels fall, and the combination of deficient glucagon and epinephrine responses causes defective glucose counterregulation. Reduced sympathoadrenal responses cause hypoglycemia unawareness. The concept of hypoglycemia-associated autonomic failure in diabetes posits that recent antecedent hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness. By shifting glycemic thresholds for the sympathoadrenal (including epinephrine) and the resulting neurogenic responses to lower plasma glucose concentrations, antecedent hypoglycemia leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. Thus, short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in most affected patients. The clinical approach to minimizing hypoglycemia while improving glycemic control includes 1 ) addressing the issue, 2 ) applying the principles of aggressive glycemic therapy, including flexible and individualized drug regimens, and 3 ) considering the risk factors for iatrogenic hypoglycemia. The latter include factors that result in absolute or relative insulin excess: drug dose, timing, and type; patterns of food ingestion and exercise; interactions with alcohol and other drugs; and altered sensitivity to or clearance of insulin. They also include factors that are clinical surrogates of compromised glucose counterregulation: endogenous insulin deficiency; history of severe hypoglycemia, hypoglycemia unawareness, or both; and aggressive glycemic therapy per se, as evidenced by lower HbA 1c levels, lower glycemic goals, or both. In a patient with hypoglycemia unawareness (which implies recurrent hypoglycemia) a 2- to 3-week period of scrupulous avoidance of hypoglycemia is advisable. Pending the prevention and cure of diabetes or the development of methods that provide glucose-regulated insulin replacement or secretion, we need to learn to replace insulin in a much more physiological fashion, to prevent, correct, or compensate for compromised glucose counterregulation, or both if we are to achieve near-euglycemia safely in most people with diabetes.

Journal ArticleDOI

Journal ArticleDOI
TL;DR: It is concluded that divergent selection makes diverse contributions to heterogeneous genomic divergence, and the number, size, and distribution of genomic regions affected by selection varied substantially among studies, leading us to discuss the potential role of Divergent selection in the growth of regions of differentiation (i.e. genomic islands of divergence), a topic in need of future investigation.
Abstract: Levels of genetic differentiation between populations can be highly variable across the genome, with divergent selection contributing to such heterogeneous genomic divergence. For example, loci under divergent selection and those tightly physically linked to them may exhibit stronger differentiation than neutral regions with weak or no linkage to such loci. Divergent selection can also increase genome-wide neutral differentiation by reducing gene flow (e.g. by causing ecological speciation), thus promoting divergence via the stochastic effects of genetic drift. These consequences of divergent selection are being reported in recently accumulating studies that identify: (i) ‘outlier loci’ with higher levels of divergence than expected under neutrality, and (ii) a positive association between the degree of adaptive phenotypic divergence and levels of molecular genetic differentiation across population pairs [‘isolation by adaptation’ (IBA)]. The latter pattern arises because as adaptive divergence increases, gene flow is reduced (thereby promoting drift) and genetic hitchhiking increased. Here, we review and integrate these previously disconnected concepts and literatures. We find that studies generally report 5–10% of loci to be outliers. These selected regions were often dispersed across the genome, commonly exhibited replicated divergence across different population pairs, and could sometimes be associated with specific ecological variables. IBA was not infrequently observed, even at neutral loci putatively unlinked to those under divergent selection. Overall, we conclude that divergent selection makes diverse contributions to heterogeneous genomic divergence. Nonetheless, the number, size, and distribution of genomic regions affected by selection varied substantially among studies, leading us to discuss the potential role of divergent selection in the growth of regions of differentiation (i.e. genomic islands of divergence), a topic in need of future investigation.

Journal ArticleDOI
TL;DR: It is shown that in skeletal muscle of both rodents and humans, a diet high in fat increases the H(2)O(2)-emitting potential of mitochondria, shifts the cellular redox environment to a more oxidized state, and decreases the redox-buffering capacity in the absence of any change in mitochondrial respiratory function.
Abstract: High dietary fat intake leads to insulin resistance in skeletal muscle, and this represents a major risk factor for type 2 diabetes and cardiovascular disease. Mitochondrial dysfunction and oxidative stress have been implicated in the disease process, but the underlying mechanisms are still unknown. Here we show that in skeletal muscle of both rodents and humans, a diet high in fat increases the H2O2-emitting potential of mitochondria, shifts the cellular redox environment to a more oxidized state, and decreases the redox-buffering capacity in the absence of any change in mitochondrial respiratory function. Furthermore, we show that attenuating mitochondrial H2O2 emission, either by treating rats with a mitochondrial-targeted antioxidant or by genetically engineering the overexpression of catalase in mitochondria of muscle in mice, completely preserves insulin sensitivity despite a high-fat diet. These findings place the etiology of insulin resistance in the context of mitochondrial bioenergetics by demonstrating that mitochondrial H2O2 emission serves as both a gauge of energy balance and a regulator of cellular redox environment, linking intracellular metabolic balance to the control of insulin sensitivity.

Journal ArticleDOI
02 Apr 2009-Nature
TL;DR: It is shown that orientations held in working memory can be decoded from activity patterns in the human visual cortex, even when overall levels of activity are low, and early visual areas can retain specific information about visual features held inWorking memory, over periods of many seconds when no physical stimulus is present.
Abstract: Visual working memory provides an essential link between perception and higher cognitive functions, allowing for the active maintenance of information about stimuli no longer in view. Research suggests that sustained activity in higher-order prefrontal, parietal, inferotemporal and lateral occipital areas supports visual maintenance, and may account for the limited capacity of working memory to hold up to 3-4 items. Because higher-order areas lack the visual selectivity of early sensory areas, it has remained unclear how observers can remember specific visual features, such as the precise orientation of a grating, with minimal decay in performance over delays of many seconds. One proposal is that sensory areas serve to maintain fine-tuned feature information, but early visual areas show little to no sustained activity over prolonged delays. Here we show that orientations held in working memory can be decoded from activity patterns in the human visual cortex, even when overall levels of activity are low. Using functional magnetic resonance imaging and pattern classification methods, we found that activity patterns in visual areas V1-V4 could predict which of two oriented gratings was held in memory with mean accuracy levels upwards of 80%, even in participants whose activity fell to baseline levels after a prolonged delay. These orientation-selective activity patterns were sustained throughout the delay period, evident in individual visual areas, and similar to the responses evoked by unattended, task-irrelevant gratings. Our results demonstrate that early visual areas can retain specific information about visual features held in working memory, over periods of many seconds when no physical stimulus is present.

Journal ArticleDOI
TL;DR: The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.
Abstract: BACKGROUND The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain. METHODS We conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or >500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group). RESULTS In the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001). CONCLUSIONS The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.

Journal ArticleDOI
Sekar Kathiresan1, Benjamin F. Voight1, Shaun Purcell2, Kiran Musunuru1, Diego Ardissino, Pier Mannuccio Mannucci3, Sonia S. Anand4, James C. Engert5, Nilesh J. Samani6, Heribert Schunkert7, Jeanette Erdmann7, Muredach P. Reilly8, Daniel J. Rader8, Thomas M. Morgan9, John A. Spertus10, Monika Stoll11, Domenico Girelli12, Pascal P. McKeown13, Christopher Patterson13, David S. Siscovick14, Christopher J. O'Donnell15, Roberto Elosua, Leena Peltonen16, Veikko Salomaa17, Stephen M. Schwartz14, Olle Melander18, David Altshuler1, Pier Angelica Merlini, Carlo Berzuini19, Luisa Bernardinelli19, Flora Peyvandi3, Marco Tubaro, Patrizia Celli, Maurizio Ferrario, Raffaela Fetiveau, Nicola Marziliano, Giorgio Casari20, Michele Galli, Flavio Ribichini12, Marco Rossi, Francesco Bernardi21, Pietro Zonzin, Alberto Piazza22, Jean Yee14, Yechiel Friedlander23, Jaume Marrugat, Gavin Lucas, Isaac Subirana, Joan Sala24, Rafael Ramos, James B. Meigs1, Gordon H. Williams1, David M. Nathan1, Calum A. MacRae1, Aki S. Havulinna17, Göran Berglund18, Joel N. Hirschhorn1, Rosanna Asselta, Stefano Duga, Marta Spreafico25, Mark J. Daly1, James Nemesh2, Joshua M. Korn1, Steven A. McCarroll1, Aarti Surti2, Candace Guiducci2, Lauren Gianniny2, Daniel B. Mirel2, Melissa Parkin2, Noël P. Burtt2, Stacey Gabriel2, John R. Thompson6, Peter S. Braund6, Benjamin J. Wright6, Anthony J. Balmforth26, Stephen G. Ball26, Alistair S. Hall26, Patrick Linsel-Nitschke7, Wolfgang Lieb7, Andreas Ziegler7, Inke R. König7, Christian Hengstenberg27, Marcus Fischer27, Klaus Stark27, Anika Grosshennig7, Michael Preuss7, H-Erich Wichmann28, Stefan Schreiber29, Willem H. Ouwehand19, Panos Deloukas30, Michael Scholz, François Cambien31, Mingyao Li8, Zhen Chen8, Robert L. Wilensky8, William H. Matthai8, Atif Qasim8, Hakon Hakonarson8, Joe Devaney32, Mary-Susan Burnett32, Augusto D. Pichard32, Kenneth M. Kent32, Lowell F. Satler32, Joseph M. Lindsay32, Ron Waksman32, Stephen E. Epstein32, Thomas Scheffold, Klaus Berger11, Andreas Huge11, Nicola Martinelli12, Oliviero Olivieri12, Roberto Corrocher12, Hilma Holm33, Gudmar Thorleifsson33, Unnur Thorsteinsdottir34, Kari Stefansson34, Ron Do5, Changchun Xie4, David S. Siscovick14 
TL;DR: SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with my Cardiovascular Infarction risk.
Abstract: We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls We carried out replication in an independent sample with an effective sample size of up to 19,492 SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations1, 2, 3, 4 (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9) We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10-3) We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk

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TL;DR: A clear definition of pulmonary hypertension and the development of a rational approach to diagnostic assessment and follow-up using both conventional and new tools will be essential to deriving maximal benefit from the expanding therapeutic armamentarium.

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TL;DR: A growing body of data suggests that ED crowding is associated both with objective clinical endpoints, such as mortality, as well as clinically important processes of care,such as time to treatment for patients with time-sensitive conditions such as pneumonia.
Abstract: Background: An Institute of Medicine (IOM) report defines six domains of quality of care: safety, patient-centeredness, timeliness, efficiency, effectiveness, and equity. The effect of emergency department (ED) crowding on these domains of quality has not been comprehensively evaluated. Objectives: The objective was to review the medical literature addressing the effects of ED crowding on clinically oriented outcomes (COOs). Methods: We reviewed the English-language literature for the years 1989–2007 for case series, cohort studies, and clinical trials addressing crowding’s effects on COOs. Keywords searched included “ED crowding,”“ED overcrowding,”“mortality,”“time to treatment,”“patient satisfaction,”“quality of care,” and others. Results: A total of 369 articles were identified, of which 41 were kept for inclusion. Study quality was modest; most articles reflected observational work performed at a single institution. There were no randomized controlled trials. ED crowding is associated with an increased risk of in-hospital mortality, longer times to treatment for patients with pneumonia or acute pain, and a higher probability of leaving the ED against medical advice or without being seen. Crowding is not associated with delays in reperfusion for patients with ST-elevation myocardial infarction. Insufficient data were available to draw conclusions on crowding’s effects on patient satisfaction and other quality endpoints. Conclusions: A growing body of data suggests that ED crowding is associated both with objective clinical endpoints, such as mortality, as well as clinically important processes of care, such as time to treatment for patients with time-sensitive conditions such as pneumonia. At least two domains of quality of care, safety and timeliness, are compromised by ED crowding.

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TL;DR: Current users of typical and of atypical antipsychotic drugs had a similar, dose-related increased risk of sudden cardiac death.
Abstract: Methods We calculated the adjusted incidence of sudden cardiac death among current users of antipsychotic drugs in a retrospective cohort study of Medicaid enrollees in Tennessee. The primary analysis included 44,218 and 46,089 baseline users of single typical and atypical drugs, respectively, and 186,600 matched nonusers of antipsychotic drugs. To assess residual confounding related to factors associated with the use of antipsychotic drugs, we performed a secondary analysis of users of antipsychotic drugs who had no baseline diagnosis of schizophrenia or related psychoses and with whom nonusers were matched according to propensity score (i.e., the predicted probability that they would be users of antipsychotic drugs). Results Current users of typical and of atypical antipsychotic drugs had higher rates of sudden cardiac death than did nonusers of antipsychotic drugs, with adjusted incidencerate ratios of 1.99 (95% confidence interval [CI], 1.68 to 2.34) and 2.26 (95% CI, 1.88 to 2.72), respectively. The incidence-rate ratio for users of atypical antipsychotic drugs as compared with users of typical antipsychotic drugs was 1.14 (95% CI, 0.93 to 1.39). Former users of antipsychotic drugs had no significantly increased risk (incidencerate ratio, 1.13; 95% CI, 0.98 to 1.30). For both classes of drugs, the risk for current users increased significantly with an increasing dose. Among users of typical anti psychotic drugs, the incidence-rate ratios increased from 1.31 (95% CI, 0.97 to 1.77) for those taking low doses to 2.42 (95% CI, 1.91 to 3.06) for those taking high doses (P<0.001). Among users of atypical agents, the incidence-rate ratios increased from 1.59 (95% CI, 1 .03 to 2.46) for those taking low doses to 2.86 (95% CI, 2.25 to 3.65) for those taking high doses (P = 0.01). The findings were similar in the cohort that was matched for propensity score. Conclusions Current users of typical and of atypical antipsychotic drugs had a similar, dose-related increased risk of sudden cardiac death.

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TL;DR: A multilaboratory study to assess reproducibility, recovery, linear dynamic range and limits of detection and quantification of multiplexed, MRM-based assays, conducted by NCI-CPTAC demonstrates that these assays can be highly reproducible within and across laboratories and instrument platforms.
Abstract: Verification of candidate biomarkers relies upon specific, quantitative assays optimized for selective detection of target proteins, and is increasingly viewed as a critical step in the discovery pipeline that bridges unbiased biomarker discovery to preclinical validation. Although individual laboratories have demonstrated that multiple reaction monitoring (MRM) coupled with isotope dilution mass spectrometry can quantify candidate protein biomarkers in plasma, reproducibility and transferability of these assays between laboratories have not been demonstrated. We describe a multilaboratory study to assess reproducibility, recovery, linear dynamic range and limits of detection and quantification of multiplexed, MRM-based assays, conducted by NCI-CPTAC. Using common materials and standardized protocols, we demonstrate that these assays can be highly reproducible within and across laboratories and instrument platforms, and are sensitive to low mug/ml protein concentrations in unfractionated plasma. We provide data and benchmarks against which individual laboratories can compare their performance and evaluate new technologies for biomarker verification in plasma.

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TL;DR: In this article, a new classification for IgA nephropathy is presented by an international consensus working group and the goal of this new system was to identify specific pathological features that more accurately predict risk of progression of renal disease.

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TL;DR: There have been tremendous advances in the discovery of novel ligands for GPCRs that act at allosteric sites to regulate receptor function that provide high selectivity, novel modes of efficacy and may lead to novel therapeutic agents for the treatment of multiple psychiatric and neurological human disorders.
Abstract: Despite G-protein-coupled receptors (GPCRs) being among the most fruitful targets for marketed drugs, intense discovery efforts for several GPCR subtypes have failed to deliver selective drug candidates. Historically, drug discovery programmes for GPCR ligands have been dominated by efforts to develop agonists and antagonists that act at orthosteric sites for endogenous ligands. However, in recent years, there have been tremendous advances in the discovery of novel ligands for GPCRs that act at allosteric sites to regulate receptor function. These compounds provide high selectivity, novel modes of efficacy and may lead to novel therapeutic agents for the treatment of multiple psychiatric and neurological human disorders.

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28 May 2009-Nature
TL;DR: The results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to the authors' knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.
Abstract: Several lines of evidence point to genetic involvement in autism spectrum disorders (ASDs), neurodevelopmental and neuropsychiatric disorders characterized by impaired verbal communication and social interaction. The clinical and genetic complexities of the condition make it difficult to identify susceptibility factors, but two related studies now present robust evidence for a genetic involvement. The first, a genome-wide association study, identifies six single-nucleotide polymorphisms strongly associated with autism. These variants lie between two genes encoding neuronal cell-adhesion molecules (cadherins 9 and 10), suggesting possible involvement in ASD pathogenesis. The second study used copy number variation screens to identify genetic variants in two major gene pathways in children with ASDs. The changes are in the ubiquitin pathway, which has previously been associated with neurological disease, and in genes for neuronal cell-adhesion molecules.

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TL;DR: This interim report and an online supplement detail the progress made toward a complete murine model of human diabetic kidney disease and the critical analysis of existing murine models, which substantially enhances the understanding of this disease process.
Abstract: Mice provide an experimental model of unparalleled flexibility for studying mammalian diseases. Inbred strains of mice exhibit substantial differences in their susceptibility to the renal complications of diabetes. Much remains to be established regarding the course of diabetic nephropathy (DN) in mice as well as defining those strains and/or mutants that are most susceptible to renal injury from diabetes. Through the use of the unique genetic reagents available in mice (including knockouts and transgenics), the validation of a mouse model reproducing human DN should significantly facilitate the understanding of the underlying genetic mechanisms that contribute to the development of DN. Establishment of an authentic mouse model of DN will undoubtedly facilitate testing of translational diagnostic and therapeutic interventions in mice before testing in humans.