Showing papers by "Research Triangle Park published in 2002"
Emory University1, Research Triangle Park2, Case Western Reserve University3, National Institutes of Health4, University of Alabama at Birmingham5, Yale University6, Indiana University7, University of Cincinnati8, Boston Children's Hospital9, University of Texas Health Science Center at Houston10, Brown University11, University of Miami12, University of Tennessee Health Science Center13, Wayne State University14, University of Texas Southwestern Medical Center15, Stanford University16, University of New Mexico17
TL;DR: Infants who developed late-onset sepsis had a significantly prolonged hospital stay and were significantly more likely to die than those who were uninfected, especially if they were infected with Gram-negative organisms or fungi.
Abstract: Objective. Late-onset sepsis (occurring after 3 days of age) is an important problem in very low birth weight (VLBW) infants. To determine the current incidence of late-onset sepsis, risk factors for disease, and the impact of late-onset sepsis on subsequent hospital course, we evaluated a cohort of 6956 VLBW (401–1500 g) neonates admitted to the clinical centers of the National Institute of Child Health and Human Development Neonatal Research Network over a 2-year period (1998–2000). Methods. The National Institute of Child Health and Human Development Neonatal Research Network maintains a prospective registry of all VLBW neonates admitted to participating centers within 14 days of birth. Expanded infection surveillance was added in 1998. Results. Of 6215 infants who survived beyond 3 days, 1313 (21%) had 1 or more episodes of blood culture-proven late-onset sepsis. The vast majority of infections (70%) were caused by Gram-positive organisms, with coagulase-negative staphylococci accounting for 48% of infections. Rate of infection was inversely related to birth weight and gestational age. Complications of prematurity associated with an increased rate of late-onset sepsis included patent ductus arteriosus, prolonged ventilation, prolonged intravascular access, bronchopulmonary dysplasia, and necrotizing enterocolitis. Infants who developed late-onset sepsis had a significantly prolonged hospital stay (mean length of stay: 79 vs 60 days). They were significantly more likely to die than those who were uninfected (18% vs 7%), especially if they were infected with Gram-negative organisms (36%) or fungi (32%). Conclusions. Late-onset sepsis remains an important risk factor for death among VLBW preterm infants and for prolonged hospital stay among VLBW survivors. Strategies to reduce late-onset sepsis and its medical, social, and economic toll need to be addressed urgently.
2,102 citations
TL;DR: The SAC's current conceptualization of eight key attributes of health status and QoL instruments and the criteria by which instruments would be reviewed on each of those attributes are offered.
Abstract: The field of health status and quality of life (QoL) measurement – as a formal discipline with a cohesive theoretical framework, accepted methods, and diverse applications – has been evolving for the better part of 30 years. To identify health status and QoL instruments and review them against rigorous criteria as a precursor to creating an instrument library for later dissemination, the Medical Outcomes Trust in 1994 created an independently functioning Scientific Advisory Committee (SAC). In the mid-1990s, the SAC defined a set of attributes and criteria to carry out instrument assessments; 5 years later, it updated and revised these materials to take account of the expanding theories and technologies upon which such instruments were being developed. This paper offers the SAC's current conceptualization of eight key attributes of health status and QoL instruments (i.e., conceptual and measurement model; reliability; validity; responsiveness; interpretability; respondent and administrative burden; alternate forms; and cultural and language adaptations) and the criteria by which instruments would be reviewed on each of those attributes. These are suggested guidelines for the field to consider and debate; as measurement techniques become both more familiar and more sophisticated, we expect that experts will wish to update and refine these criteria accordingly.
1,965 citations
TL;DR: Readers of medical literature need to consider two types of validity, internal and external: external validity is the ability to generalise from the study to the reader's patients, and internal validity means that the study measured what it set out to.
1,260 citations
TL;DR: Assessment of psychological symptom levels in the United States following the events of September 11 found probable PTSD was associated with direct exposure to the terrorist attacks among adults, and the prevalence in the New York City metropolitan area was substantially higher than elsewhere in the country.
Abstract: ContextThe terrorist attacks of September 11, 2001, represent an unprecedented
exposure to trauma in the United States.ObjectivesTo assess psychological symptom levels in the United States following
the events of September 11 and to examine the association between postattack
symptoms and a variety of indices of exposure to the events.DesignWeb-based epidemiological survey of a nationally representative cross-sectional
sample using the Posttraumatic Stress Disorder (PTSD) Checklist and the Brief
Symptom Inventory, administered 1 to 2 months following the attacks.Setting and ParticipantsSample of 2273 adults, including oversamples of the New York, NY, and
Washington, DC, metropolitan areas.Main Outcome MeasuresSelf-reports of the symptoms of PTSD and of clinically significant nonspecific
psychological distress; adult reports of symptoms of distress among children
living in their households.ResultsThe prevalence of probable PTSD was significantly higher in the New
York City metropolitan area (11.2%) than in Washington, DC (2.7%), other major
metropolitan areas (3.6%), and the rest of the country (4.0%). A broader measure
of clinically significant psychological distress suggests that overall distress
levels across the country, however, were within expected ranges for a general
community sample. In multivariate models, sex, age, direct exposure to the
attacks, and the amount of time spent viewing TV coverage of the attacks on
September 11 and the few days afterward were associated with PTSD symptom
levels; sex, the number of hours of television coverage viewed, and an index
of the content of that coverage were associated with the broader distress
measure. More than 60% of adults in New York City households with children
reported that 1 or more children were upset by the attacks.ConclusionsOne to 2 months following the events of September 11, probable PTSD
was associated with direct exposure to the terrorist attacks among adults,
and the prevalence in the New York City metropolitan area was substantially
higher than elsewhere in the country. However, overall distress levels in
the country were within normal ranges. Further research should document the
course of symptoms and recovery among adults following exposure to the events
of September 11 and further specify the types and severity of distress in
children.
1,091 citations
TL;DR: In this paper, the authors used mRNA profiles generated from microarray experiments to deduce the functions of genes encoding known and putative Arabidopsis transcription factors, showing that transcription factors are important in regulating plant responses to environmental stress.
Abstract: Numerous studies have shown that transcription factors are important in regulating plant responses to environmental stress. However, specific functions for most of the genes encoding transcription factors are unclear. In this study, we used mRNA profiles generated from microarray experiments to deduce the functions of genes encoding known and putative Arabidopsis transcription factors. The mRNA levels of 402 distinct transcription factor genes were examined at different developmental stages and under various stress conditions. Transcription factors potentially controlling downstream gene expression in stress signal transduction pathways were identified by observed activation and repression of the genes after certain stress treatments. The mRNA levels of a number of previously characterized transcription factor genes were changed significantly in connection with other regulatory pathways, suggesting their multifunctional nature. The expression of 74 transcription factor genes responsive to bacterial pathogen infection was reduced or abolished in mutants that have defects in salicylic acid, jasmonic acid, or ethylene signaling. This observation indicates that the regulation of these genes is mediated at least partly by these plant hormones and suggests that the transcription factor genes are involved in the regulation of additional downstream responses mediated by these hormones. Among the 43 transcription factor genes that are induced during senescence, 28 of them also are induced by stress treatment, suggesting extensive overlap responses to these stresses. Statistical analysis of the promoter regions of the genes responsive to cold stress indicated unambiguous enrichment of known conserved transcription factor binding sites for the responses. A highly conserved novel promoter motif was identified in genes responding to a broad set of pathogen infection treatments. This observation strongly suggests that the corresponding transcription factors play general and crucial roles in the coordinated regulation of these specific regulons. Although further validation is needed, these correlative results provide a vast amount of information that can guide hypothesis-driven research to elucidate the molecular mechanisms involved in transcriptional regulation and signaling networks in plants.
991 citations
TL;DR: It is discovered that physical dispersion of nonporous, nanoscale, fumed silica particles in glassy amorphous poly(4-methyl-2-pentyne) simultaneously and surprisingly enhances both membrane permeability and selectivity for large organic molecules over small permanent gases.
Abstract: Polymer nanocomposites continue to receive tremendous attention for application in areas such as microelectronics, organic batteries, optics, and catalysis. We have discovered that physical dispersion of nonporous, nanoscale, fumed silica particles in glassy amorphous poly(4-methyl-2-pentyne) simultaneously and surprisingly enhances both membrane permeability and selectivity for large organic molecules over small permanent gases. These highly unusual property enhancements, in contrast to results obtained in conventional filled polymer systems, reflect fumed silica-induced disruption of polymer chain packing and an accompanying subtle increase in the size of free volume elements through which molecular transport occurs, as discerned by positron annihilation lifetime spectroscopy. Such nanoscale hybridization represents an innovative means to tune the separation properties of glassy polymeric media through systematic manipulation of molecular packing.
979 citations
TL;DR: A collection of Arabidopsis lines with T-DNA insertions in known sites was generated to increase the efficiency of functional genomics and showed a bias against predicted coding sequences.
Abstract: A collection of Arabidopsis lines with T-DNA insertions in known sites was generated to increase the efficiency of functional genomics. A high-throughput modified thermal asymetric interlaced (TAIL)-PCR protocol was developed and used to amplify DNA fragments flanking the T-DNA left borders from ∼100,000 transformed lines. A total of 85,108 TAIL-PCR products from 52,964 T-DNA lines were sequenced and compared with the Arabidopsis genome to determine the positions of T-DNAs in each line. Predicted T-DNA insertion sites, when mapped, showed a bias against predicted coding sequences. Predicted insertion mutations in genes of interest can be identified using Arabidopsis Gene Index name searches or by BLAST (Basic Local Alignment Search Tool) search. Insertions can be confirmed by simple PCR assays on individual lines. Predicted insertions were confirmed in 257 of 340 lines tested (76%). This resource has been named SAIL (Syngenta Arabidopsis Insertion Library) and is available to the scientific community at www.tmri.org.
978 citations
TL;DR: It is demonstrated that MRP2 is regulated by three distinct nuclear receptor signaling pathways that converge on a common response element in the 5′-flanking region of this gene.
900 citations
TL;DR: The diverse toxic actions and pharmacological effects of pyrethroids suggest that simple additivity models based on combined actions at a single target are not appropriate to assess the risks of cumulative exposure to multiple pyre Throids.
849 citations
TL;DR: Although double blinding (blinding investigators, participants, and outcome assessors) indicates a strong design, trials that are not double blinded should not automatically be deemed inferior, and researchers should explicitly state who was blinded, and how.
790 citations
TL;DR: The lower sensitivity of HLA-B57 for predicting hypersensitivity to abacavir identified in this study compared with a previous report highlights that predictive values for markers will vary across populations.
TL;DR: Investigators must effectively immunise trials against selection and confounding biases with proper allocation concealment, andHypothesis tests of baseline characteristics, however, are superfluous and could be harmful if they lead investigators to suppress reporting any baseline imbalances.
TL;DR: The crystal structure of the human GR ligand binding domain (LBD) bound to dexamethasone and a coactivator motif derived from the transcriptional intermediary factor 2 is reported to establish a framework for understanding the roles of protein-hormone and protein-protein interactions in GR signaling pathways.
TL;DR: It is demonstrated that in addition to tandem SREBP sites, the FASpromoter contains a high affinity binding site for the LXR/RXR heterodimer that is conserved in diverse animal species including birds, rodents, and humans.
TL;DR: 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA) was shown to be a very potent and selective FXR agonist and to be endowed with anticholeretic activity in an in vivo rat model of cholestasis.
Abstract: A series of 6α-alkyl-substituted analogues of chenodeoxycholic acid (CDCA) were synthesized and evaluated as potential farnesoid X receptor (FXR) ligands. Among them, 6α-ethyl-chenodeoxycholic acid (6-ECDCA) was shown to be a very potent and selective FXR agonist (EC50 = 99 nM) and to be endowed with anticholeretic activity in an in vivo rat model of cholestasis.
TL;DR: The randomised controlled trial sets the gold standard of clinical research, but randomisation persists as perhaps the least-understood aspect of a trial because anything short of proper randomisation courts selection and confounding biases.
TL;DR: Analysis of real data comprised of a dense map of single nucleotide polymorphisms spaced along a 12-cM chromosomal region allows us to confirm the utility of the haplotype approach as well as the validity and usefulness of the proposed statistical technique.
Abstract: There have been increasing efforts to relate drug efficacy and disease predisposition with genetic polymorphisms. We present statistical tests for association of haplotype frequencies with discrete and continuous traits in samples of unrelated individuals. Haplotype frequencies are estimated through the expectation-maximization algorithm, and each individual in the sample is expanded into all possible haplotype configurations with corresponding probabilities, conditional on their genotype. A regression-based approach is then used to relate inferred haplotype probabilities to the response. The relationship of this technique to commonly used approaches developed for case-control data is discussed. We confirm the proper size of the test under H(0) and find an increase in power under the alternative by comparing test results using inferred haplotypes with single-marker tests using simulated data. More importantly, analysis of real data comprised of a dense map of single nucleotide polymorphisms spaced along a 12-cM chromosomal region allows us to confirm the utility of the haplotype approach as well as the validity and usefulness of the proposed statistical technique. The method appears to be successful in relating data from multiple, correlated markers to response.
TL;DR: Inhibition of activated AKT in EGFR or erbB2-dependent tumors by GW572016 may lead to tumor regressions when used as a monotherapy, or may enhance the anti-tumor activity of chemotherapeutics, since constitutive activation of AKT has been linked to chemo-resistance.
Abstract: Dual EGFR/erbB2 inhibition is an attractive therapeutic strategy for epithelial tumors, as ligand-induced erbB2/EGFR heterodimerization triggers potent proliferative and survival signals. Here we show that a small molecule, GW572016, potently inhibits both EGFR and erbB2 tyrosine kinases leading to growth arrest and/or apoptosis in EGFR and erbB2-dependent tumor cell lines. GW572016 markedly reduced tyrosine phosphorylation of EGFR and erbB2, and inhibited activation of Erk1/2 and AKT, downstream effectors of proliferation and cell survival, respectively. Complete inhibition of activated AKT in erbB2 overexpressing cells correlated with a 23-fold increase in apoptosis compared with vehicle controls. EGF, often elevated in cancer patients, did not reverse the inhibitory effects of GW572016. These observations were reproduced in vivo, where GW572016 treatment inhibited activation of EGFR, erbB2, Erk1/2 and AKT in human tumor xenografts. Erk1/2 and AKT represent potential biomarkers to assess the clinical activity of GW572016. Inhibition of activated AKT in EGFR or erbB2-dependent tumors by GW572016 may lead to tumor regressions when used as a monotherapy, or may enhance the anti-tumor activity of chemotherapeutics, since constitutive activation of AKT has been linked to chemo-resistance.
TL;DR: Evidence is provided that PXR regulates a similar program of genes involved in xenobiotic metabolism in human liver, and the importance of these two nuclear receptors in defending the body against a broad array of potentially harmful xenobiotics is underscore.
Abstract: The nuclear pregnane X receptor (PXR) and constitutive androstane receptor (CAR) play central roles in protecting the body against environmental chemicals (xenobiotics). PXR and CAR are activated by a wide range of xenobiotics and regulate cytochrome P450 and other genes whose products are involved in the detoxification of these chemicals. In this report, we have used receptor-selective agonists together with receptor-null mice to identify PXR and CAR target genes in the liver and small intestine. Our results demonstrate that PXR and CAR regulate overlapping but distinct sets of genes involved in all phases of xenobiotic metabolism, including oxidative metabolism, conjugation, and transport. Among the murine genes regulated by PXR were those encoding PXR and CAR. We provide evidence that PXR regulates a similar program of genes involved in xenobiotic metabolism in human liver. Among the genes regulated by PXR in primary human hepatocytes were the aryl hydrocarbon receptor and its target genes CYP1A1 and CYP1A2. These findings underscore the importance of these two nuclear receptors in defending the body against a broad array of potentially harmful xenobiotics.
TL;DR: In this article, the authors examined the chondrogenic potential of adipose tissue-derived stromal cells and found that these cells abundantly synthesized cartilage matrix molecules including collagen type II, VI, and chondroitin 4-sulfate.
TL;DR: A primer of clinical research is provided for clinicians and researchers alike, based on whether the investigator assigns the exposures or not, and measures of association are the preferred way of expressing results of dichotomous outcomes.
TL;DR: This study on a large, diverse set of marketed compounds clearly demonstrates that permeability, Pgp-mediated efflux, and certain physicochemical properties are factors that differentiate CNS and non-CNS drugs.
Abstract: Membrane permeability and P-glycoprotein (Pgp) can be limiting factors for blood-brain barrier penetration. The objectives of this study were to determine whether there are differences in the in vitro permeability, Pgp substrate profiles, and physicochemical properties of drugs for central nervous system (CNS) and non-CNS indications, and whether these differences are useful criteria in selecting compounds for drug development. Apparent permeability (P(app)) and Pgp substrate profiles for 93 CNS (n = 48) and non-CNS (n = 45) drugs were determined by monolayer efflux. Calcein-AM inhibition assays were used to supplement the efflux results. The CNS set (2 of 48, 4.2%) had a 7-fold lower incidence of passive permeability values 150 nm/s and not be a good (B --> A/A --> B ratio <2.5) Pgp substrate.
University of Cincinnati Academic Health Center1, University of Colorado Hospital2, University of Manitoba3, Boston Children's Hospital4, University of North Carolina at Chapel Hill5, University of Dayton6, University of Rochester7, Montana State University8, Research Triangle Park9, Wake Forest University10, University of British Columbia11, Northwestern University12
TL;DR: P. aeruginosa formed robust anaerobic biofilms, the viability of which requires rhl quorum sensing and nitric oxide reductase to modulate or prevent accumulation of toxic NO, a byproduct of anaerilic respiration.
Research Triangle Park1, Brown University2, University of Washington3, California Environmental Protection Agency4, Lovelace Respiratory Research Institute5, Health Canada6, United States Environmental Protection Agency7, Duke University8, Food and Drug Administration9, Harvard University10, Michigan State University11
TL;DR: This poster presents a probabilistic procedure to evaluate the phytochemical properties of anthrax, and the results have shown to be safe and beneficial for human health and the environment.
TL;DR: Data from Barrow, AK, at 71 degrees N show that rapid, photochemically driven oxidation of boundary-layer Hg0 after polar sunrise creates a rapidly depositing species of oxidized gaseous mercury in the remote Arctic troposphere at concentrations in excess of 900 pg m(-3).
Abstract: Gaseous elemental mercury (Hg0) is a globally distributed air toxin with a long atmospheric residence time. Any process that reduces its atmospheric lifetime increases its potential accumulation in the biosphere. Our data from Barrow, AK, at 71 degrees N show that rapid, photochemically driven oxidation of boundary-layer Hg0 after polar sunrise, probably by reactive halogens, creates a rapidly depositing species of oxidized gaseous mercury in the remote Arctic troposphere at concentrations in excess of 900 pg m(-3). This mercury accumulates in the snowpack during polar spring at an accelerated rate in a form that is bioavailable to bacteria and is released with snowmelt during the summer emergence of the Arctic ecosystem. Evidence suggests that this is a recent phenomenon that may be occurring throughout the earth's polar regions.
TL;DR: This is the first study to assess sexual dysfunction across the newer antidepressants using consistent methodology and a validated rating scale and overall, SSRIs and venlafaxine XR were associated with higher rates of sexual dysfunction than bupropion or nefazodone.
Abstract: BACKGROUND: Sexual dysfunction commonly occurs during antidepressant treatment However, the reported rates of sexual dysfunction vary across antidepressants and are typically underreported in product literature The objectives of this study were (1) to estimate the prevalence of sexual dysfunction among patients taking newer antidepressants (bupropion immediate release [IR], bupropion sustained release [SR], citalopram, fluoxetine, mirtazapine, nefazodone, paroxetine, sertraline, venlafaxine, and venlafaxine extended release [XR]) and (2) to compare physician-perceived with patient-reported prevalence rates of antidepressant-associated sexual dysfunction METHOD: This cross-sectional, observational study was conducted in 1101 US primary care clinics Adult outpatients (4534 women and 1763 men) receiving antidepressant monotherapy were enrolled The prevalence of sexual dysfunction was measured using the Changes in Sexual Functioning Questionnaire
RESULTS: In the overall population, bupropion IR (22%) and SR (25%) and nefazodone (28%) were associated with the lowest risk for sexual dysfunction, whereas selective serotonin reuptake inhibitor (SSRI) antidepressants, mirtazapine, and venlafaxine XR were associated with higher rates (36%-43%) In a prospectively defined subpopulation unlikely to have predisposing factors for sexual dysfunction, the prevalence of sexual dysfunction ranged from 7% to 30%, with the odds of having sexual dysfunction 4 to 6 times greater with SSRIs or venlafaxine XR than with bupropion SR Physicians consistently underestimated the prevalence of antidepressant-associated sexual dysfunction
CONCLUSION: Ours is the first study to assess sexual dysfunction across the newer antidepressants using consistent methodology and a validated rating scale Overall, SSRIs and venlafaxine XR were associated with higher rates of sexual dysfunction than bupropion or nefazodone Because antidepressant-associated sexual dysfunction is considerably underestimated by physicians, greater recognition and education are imperative when prescribing antidepressant treatment
TL;DR: A new procedure to take the product of only those P‐values less than some specified cut‐off value and to evaluate the probability of such a product, or a smaller value, under the overall hypothesis that all L hypotheses are true is presented.
Abstract: We present a new procedure for combining P-values from a set of L hypothesis tests. Our procedure is to take the product of only those P-values less than some specified cut-off value and to evaluate the probability of such a product, or a smaller value, under the overall hypothesis that all L hypotheses are true. We give an explicit formulation for this P-value, and find by simulation that it can provide high power for detecting departures from the overall hypothesis. We extend the procedure to situations when tests are not independent. We present both real and simulated examples where the method is especially useful. These include exploratory analyses when L is large, such as genome-wide scans for marker-trait associations and meta-analytic applications that combine information from published studies, with potential for dealing with the "publication bias" phenomenon. Once the overall hypothesis is rejected, an adjustment procedure with strong family-wise error protection is available for smaller subsets of hypotheses, down to the individual tests.
TL;DR: The selective and irreversible nature of GW9662 treatment, and the observation that activity is maintained in cell culture experiments, suggests that this compound may be a useful tool for elucidation of the role of PPARgamma in biological processes.
Abstract: In the course of a high throughput screen to search for ligands of peroxisome proliferator activated receptor-γ (PPARγ), we identified GW9662 using a competition binding assay against the human ligand binding domain. GW9662 had nanomolar IC50 versus PPARγ and was 10- and 600-fold less potent in binding experiments using PPARα and PPARδ, respectively. Pretreatment of all three PPARs with GW9662 resulted in the irreversible loss of ligand binding as assessed by scintillation proximity assay. Incubation of PPAR with GW9662 resulted in a change in the absorbance spectra of the receptors consistent with covalent modification. Mass spectrometric analysis of the PPARγ ligand binding domain treated with GW9662 established Cys285 as the site of covalent modification. This cysteine is conserved among all three PPARs. In cell-based reporter assays, GW9662 was a potent and selective antagonist of full-length PPARγ. The functional activity of GW9662 as an antagonist of PPARγ was confirmed in an assay of adipocyte diff...
TL;DR: Screening tests are ubiquitous in contemporary practice, yet the principles of screening are widely misunderstood; lead-time and length biases distort the apparent value of screening programmes; randomised controlled trials are the only way to avoid these biases.
TL;DR: Three important uses of descriptive studies include trend analysis, health-care planning, and hypothesis generation, which represent the first scientific toe in the water in new areas of inquiry.