Showing papers by "University of Alabama at Birmingham published in 2009"
University of Alabama at Birmingham1, University of Michigan2, University of Wisconsin-Madison3, Duke University4, University of Lausanne5, University of California, Los Angeles6, Georgia Regents University7, Radboud University Nijmegen8, University of Texas at Austin9, Rowan University10, AstraZeneca11, National Institutes of Health12, Wayne State University13
TL;DR: These updated guidelines replace the previous guidelines published in the 15 January 2004 issue of Clinical Infectious Diseases and are intended for use by health care providers who care for patients who either have or are at risk of these infections.
Abstract: Guidelines for the management of patients with invasive candidiasis and mucosal candidiasis were prepared by an Expert Panel of the Infectious Diseases Society of America. These updated guidelines replace the previous guidelines published in the 15 January 2004 issue of Clinical Infectious Diseases and are intended for use by health care providers who care for patients who either have or are at risk of these infections. Since 2004, several new antifungal agents have become available, and several new studies have been published relating to the treatment of candidemia, other forms of invasive candidiasis, and mucosal disease, including oropharyngeal and esophageal candidiasis. There are also recent prospective data on the prevention of invasive candidiasis in high-risk neonates and adults and on the empiric treatment of suspected invasive candidiasis in adults. This new information is incorporated into this revised document.
3,016 citations
TL;DR: Findings of a 20-year longitudinal adult-onset CR study in rhesus monkeys aimed at filling this critical gap in aging research demonstrate that CR slows aging in a primate species.
Abstract: Caloric restriction (CR), without malnutrition, delays aging and extends life span in diverse species; however, its effect on resistance to illness and mortality in primates has not been clearly established We report findings of a 20-year longitudinal adult-onset CR study in rhesus monkeys aimed at filling this critical gap in aging research In a population of rhesus macaques maintained at the Wisconsin National Primate Research Center, moderate CR lowered the incidence of aging-related deaths At the time point reported, 50% of control fed animals survived as compared with 80% of the CR animals Furthermore, CR delayed the onset of age-associated pathologies Specifically, CR reduced the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy These data demonstrate that CR slows aging in a primate species
2,114 citations
Ohio State University1, National Institutes of Health2, George Washington University3, Brown University4, University of Texas Health Science Center at Houston5, University of Texas Southwestern Medical Center6, Columbia University7, University of Utah8, University of Alabama at Birmingham9, University of North Carolina at Chapel Hill10, Drexel University11, Case Western Reserve University12, Wake Forest University13, University of Texas Medical Branch14, University of Pittsburgh15, Wayne State University16, Northwestern University17, Oregon Health & Science University18
TL;DR: Treatment of mild gestational diabetes mellitus did not significantly reduce the frequency of a composite outcome that included stillbirth or perinatal death and several neonatal complications, but it did reduce the risks of fetal overgrowth, shoulder dystocia, cesarean delivery, and hypertensive disorders.
Abstract: Background It is uncertain whether treatment of mild gestational diabetes mellitus improves pregnancy outcomes. Methods Women who were in the 24th to 31st week of gestation and who met the criteria for mild gestational diabetes mellitus (i.e., an abnormal result on an oral glucose-tolerance test but a fasting glucose level below 95 mg per deciliter [5.3 mmol per liter]) were randomly assigned to usual prenatal care (control group) or dietary intervention, self-monitoring of blood glucose, and insulin therapy, if necessary (treatment group). The primary outcome was a composite of stillbirth or perinatal death and neonatal complications, including hyperbilirubinemia, hypoglycemia, hyperinsulinemia, and birth trauma. Results A total of 958 women were randomly assigned to a study group — 485 to the treatment group and 473 to the control group. We observed no significant difference between groups in the frequency of the composite outcome (32.4% and 37.0% in the treatment and control groups, respectively; P=0.1...
1,587 citations
TL;DR: An epigenetic molecular mechanism potentially underlying lifelong and transgenerational perpetuation of changes in gene expression and behavior incited by early abuse and neglect is highlighted.
1,176 citations
University of Washington1, Johns Hopkins University2, University of Alabama at Birmingham3, Yale University4, Simon Fraser University5, University of California, San Francisco6, University of North Carolina at Chapel Hill7, Centers for Disease Control and Prevention8, University of Toronto9, University of Calgary10, Harvard University11, McGill University12, Case Western Reserve University13, Vanderbilt University14, Kaiser Permanente15, National Institutes of Health16, University of California, San Diego17
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.
1,116 citations
University of Hertfordshire1, University of Alabama at Birmingham2, University of Helsinki3, University of South Florida4, University of Glasgow5, University of Kentucky6, Leiden University Medical Center7, Institute for Animal Health8, University of Guelph9, Katholieke Universiteit Leuven10, Pasteur Institute11, Agriculture and Agri-Food Canada12, University of Bristol13, University of Edinburgh14, Queen's University15
TL;DR: Changes to virus taxonomy approved and ratified by the International Committee on Taxonomy of Viruses in February 2015 are listed.
Abstract: Changes to virus taxonomy approved and ratified by the International Committee on Taxonomy of Viruses in February 2015 are listed.
1,039 citations
TL;DR: Mice deficient for STAT4 and T-bet-two prototypical Th1 transcription factors are protected from autoimmunity associated with Th17 pathogenesis and support a model of late Th17 developmental plasticity with implications for autoIMmunity and host defense.
1,033 citations
University of Toronto1, University of Turin2, Imperial College London3, Leicester General Hospital4, John Radcliffe Hospital5, Université de Montréal6, University of Washington7, LSU Health Sciences Center Shreveport8, Leiden University9, Columbia University10, Case Western Reserve University11, Mayo Clinic12, University of Amsterdam13, Vanderbilt University14, Western Infirmary15, German Cancer Research Center16, Johns Hopkins University17, St. Vincent's Health System18, Scott & White Hospital19, University of Florida20, University of North Carolina at Chapel Hill21, University of Alabama at Birmingham22, Jikei University School of Medicine23, The Chinese University of Hong Kong24, Nanjing University25, Austral University of Chile26, Juntendo University27, Peking University28, Erasmus University Rotterdam29, Wakayama Medical University30
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.
994 citations
TL;DR: It is shown using in vitro and in vivo models that active TGF-β1 released during bone resorption coordinates bone formation by inducing migration of bone marrow stromal cells, also known as bone mesenchymal stem cells, to theBone resorptive sites and that this process is mediated through a SMAD signaling pathway.
Abstract: Bone remodeling depends on the precise coordination of bone resorption and subsequent bone formation. Disturbances of this process are associated with skeletal diseases, such as Camurati-Engelmann disease (CED). We show using in vitro and in vivo models that active TGF-beta1 released during bone resorption coordinates bone formation by inducing migration of bone marrow stromal cells, also known as bone mesenchymal stem cells, to the bone resorptive sites and that this process is mediated through a SMAD signaling pathway. Analyzing mice carrying a CED-derived mutant TGFB1 (encoding TGF-beta1), which show the typical progressive diaphyseal dysplasia seen in the human disease, we found high levels of active TGF-beta1 in the bone marrow. Treatment with a TGF-beta type I receptor inhibitor partially rescued the uncoupled bone remodeling and prevented the fractures. Thus, as TGF-beta1 functions to couple bone resorption and formation, modulation of TGF-beta1 activity could be an effective treatment for bone remodeling diseases.
962 citations
Columbia University1, University of Miami2, University of North Carolina at Chapel Hill3, SUNY Downstate Medical Center4, University College London5, Cambridge University Hospitals NHS Foundation Trust6, University of California, San Francisco7, University of California, Los Angeles8, University of Alabama at Birmingham9, Rio de Janeiro State University10, University of Guadalajara11, University of Düsseldorf12, New York University13, University of Barcelona14, Shanghai Jiao Tong University15, University of Lisbon16, Stellenbosch University17, Guy's and St Thomas' NHS Foundation Trust18, Oregon Health & Science University19, University of Padua20, University of Leeds21, North Shore-LIJ Health System22, Northwestern University23, Medical University of South Carolina24, University of Birmingham25, Sun Yat-sen University26, Lille University of Science and Technology27, Charité28, Rutgers University29, Federal University of São Paulo30, University of Debrecen31, Imperial College London32, Emory University33, University of Liège34, University of Pittsburgh35, University of Paris36, University of the Witwatersrand37, California State University, Long Beach38, Royal Melbourne Hospital39, University of Texas Southwestern Medical Center40, Autonomous University of Barcelona41, Pennsylvania State University42, Johns Hopkins University43, University of Szeged44, Duke University45, University of Colorado Denver46, Harvard University47, University of Cape Town48, University of Malaya49, Peking Union Medical College50
TL;DR: Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis.
Abstract: Recent studies have suggested that mycophenolate mofetil (MMF) may offer advantages over intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis, but these therapies have not been compared in an international randomized, controlled trial. Here, we report the comparison of MMF and IVC as induction treatment for active lupus nephritis in a multinational, two-phase (induction and maintenance) study. We randomly assigned 370 patients with classes III through V lupus nephritis to open-label MMF (target dosage 3 g/d) or IVC (0.5 to 1.0 g/m(2) in monthly pulses) in a 24-wk induction study. Both groups received prednisone, tapered from a maximum starting dosage of 60 mg/d. The primary end point was a prespecified decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine. Secondary end points included complete renal remission, systemic disease activity and damage, and safety. Overall, we did not detect a significantly different response rate between the two groups: 104 (56.2%) of 185 patients responded to MMF compared with 98 (53.0%) of 185 to IVC. Secondary end points were also similar between treatment groups. There were nine deaths in the MMF group and five in the IVC group. We did not detect significant differences between the MMF and IVC groups with regard to rates of adverse events, serious adverse events, or infections. Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis.
909 citations
TL;DR: The prognostic factors for BM patients varied by diagnosis, and two new DS-GPA indexes were designed for breast/gastrointestinal cancer and melanoma/renal cell carcinoma.
Abstract: Purpose Controversy endures regarding the optimal treatment of patients with brain metastases (BMs). Debate persists, despite many randomized trials, perhaps because BM patients are a heterogeneous population. The purpose of the present study was to identify significant diagnosis-specific prognostic factors and indexes (Diagnosis-Specific Graded Prognostic Assessment [DS-GPA]). Methods and Materials A retrospective database of 5,067 patients treated for BMs between 1985 and 2007 was generated from 11 institutions. After exclusion of the patients with recurrent BMs or incomplete data, 4,259 patients with newly diagnosed BMs remained eligible for analysis. Univariate and multivariate analyses of the prognostic factors and outcomes by primary site and treatment were performed. The significant prognostic factors were determined and used to define the DS-GPA prognostic indexes. The DS-GPA scores were calculated and correlated with the outcomes, stratified by diagnosis and treatment. Results The significant prognostic factors varied by diagnosis. For non–small-cell lung cancer and small-cell lung cancer, the significant prognostic factors were Karnofsky performance status, age, presence of extracranial metastases, and number of BMs, confirming the original GPA for these diagnoses. For melanoma and renal cell cancer, the significant prognostic factors were Karnofsky performance status and the number of BMs. For breast and gastrointestinal cancer, the only significant prognostic factor was the Karnofsky performance status. Two new DS-GPA indexes were thus designed for breast/gastrointestinal cancer and melanoma/renal cell carcinoma. The median survival by GPA score, diagnosis, and treatment were determined. Conclusion The prognostic factors for BM patients varied by diagnosis. The original GPA was confirmed for non–small-cell lung cancer and small-cell lung cancer. New DS-GPA indexes were determined for other histologic types and correlated with the outcome, and statistical separation between the groups was confirmed. These data should be considered in the design of future randomized trials and in clinical decision-making.
TL;DR: Questions remain about which groups of patients benefit from therapy and at which point in the course of disease this therapy should be initiated, and limited rigorous evidence exists demonstrating the effect of these therapies on important long-term clinical outcomes.
Abstract: National Institutes of Health (NIH) consensus and stateof-the-science statements are prepared by independent panels of health professionals and public representatives on the basis of 1) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality (AHRQ); 2) presentations by investigators working in areas relevant to the conference questions during a 2-day public session; 3) questions and statements from conference attendees during open discussion periods that are part of the public session; and 4) closed deliberations by the panel during the remainder of the second day and morning of the third. This statement is an independent report of the panel and is not a policy statement of the National Institutes of Health or the U.S. government. The statement reflects the panel’s assessment of medical knowledge available at the time the statement was written. Thus, it provides a “snapshot in time” of the state of knowledge on the conference topic. When reading the statement, keep in mind that new knowledge is inevitably accumulating through medical research. Hepatitis B is a major cause of liver disease worldwide, ranking as a substantial cause of cirrhosis and hepatocellular carcinoma. The development and use of a vaccine for hepatitis B virus (HBV) has resulted in a substantial decline in the number of new cases of acute hepatitis B among children, adolescents, and adults in the United States. However, this success has not yet been duplicated worldwide, and both acute and chronic HBV infection continue to represent important global health problems. Seven treatments are currently approved for adult patients with chronic HBV infection in the United States: interferon-, pegylated interferon-, lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate. Interferon- and lamivudine have been approved for children with HBV infection. Although available randomized, controlled trials (RCTs) show encouraging short-term results— demonstrating the favorable effect of these agents on such intermediate markers of disease as HBV DNA level, liver enzyme tests, and liver histology— limited rigorous evidence exists demonstrating the effect of these therapies on important long-term clinical outcomes, such as the development of hepatocellular carcinoma or a reduction in deaths. Questions therefore remain about which groups of patients benefit from therapy and at which point in the course of disease this therapy should be initiated.
TL;DR: Prolonged initial empirical antibiotic therapy may be associated with increased risk of necrotizing enterocolitis or death and should be used with caution.
Abstract: OBJECTIVES. Our objectives were to identify factors associated with the duration of the first antibiotic course initiated in the first 3 postnatal days and to assess associations between the duration of the initial antibiotic course and subsequent necrotizing enterocolitis or death in extremely low birth weight infants with sterile initial postnatal culture results. METHODS. We conducted a retrospective cohort analysis of extremely low birth weight infants admitted to tertiary centers in 1998–2001. We defined initial empirical antibiotic treatment duration as continuous days of antibiotic therapy started in the first 3 postnatal days with sterile culture results. We used descriptive statistics to characterize center practice, bivariate analyses to identify factors associated with prolonged empirical antibiotic therapy (≥5 days), and multivariate analyses to evaluate associations between therapy duration, prolonged empirical therapy, and subsequent necrotizing enterocolitis or death. RESULTS. Of 5693 extremely low birth weight infants admitted to 19 centers, 4039 (71%) survived >5 days, received initial empirical antibiotic treatment, and had sterile initial culture results through the first 3 postnatal days. The median therapy duration was 5 days (range: 1–36 days); 2147 infants (53%) received prolonged empirical therapy (center range: 27%–85%). Infants who received prolonged therapy were less mature, had lower Apgar scores, and were more likely to be black. In multivariate analyses adjusted for these factors and center, prolonged therapy was associated with increased odds of necrotizing enterocolitis or death and of death. Each empirical treatment day was associated with increased odds of death, necrotizing enterocolitis, and the composite measure of necrotizing enterocolitis or death. CONCLUSION. Prolonged initial empirical antibiotic therapy may be associated with increased risk of necrotizing enterocolitis or death and should be used with caution.
University of Oxford1, Imperial College London2, Université de Montréal3, University of Washington4, University of Turin5, Leicester General Hospital6, LSU Health Sciences Center Shreveport7, Leiden University8, University of Toronto9, Columbia University10, Case Western Reserve University11, Mayo Clinic12, University of Amsterdam13, Vanderbilt University14, Western Infirmary15, German Cancer Research Center16, Johns Hopkins University17, St. Vincent's Health System18, Scott & White Hospital19, University of Florida20, University of North Carolina at Chapel Hill21, University of Alabama at Birmingham22, Jikei University School of Medicine23, The Chinese University of Hong Kong24, Nanjing University25, Austral University of Chile26, Juntendo University27, Peking University28, Erasmus University Rotterdam29, Wakayama Medical University30
TL;DR: A unique approach for the pathological classification of a glomerular disease, IgA nephropathy, is developed, in which renal pathologists first undertook extensive iterative work to define pathologic variables with acceptable inter-observer reproducibility.
TL;DR: Viral properties associated with mucosal HIV-1 transmission and a limited set of rapidly evolving adaptive mutations driven primarily, but not exclusively, by early cytotoxic T cell responses are revealed.
Abstract: Identification of full-length transmitted HIV-1 genomes could be instrumental in HIV-1 pathogenesis, microbicide, and vaccine research by enabling the direct analysis of those viruses actually responsible for productive clinical infection. We show in 12 acutely infected subjects (9 clade B and 3 clade C) that complete HIV-1 genomes of transmitted/founder viruses can be inferred by single genome amplification and sequencing of plasma virion RNA. This allowed for the molecular cloning and biological analysis of transmitted/founder viruses and a comprehensive genome-wide assessment of the genetic imprint left on the evolving virus quasispecies by a composite of host selection pressures. Transmitted viruses encoded intact canonical genes ( gag-pol-vif-vpr-tat-rev-vpu-env-nef ) and replicated efficiently in primary human CD4+ T lymphocytes but much less so in monocyte-derived macrophages. Transmitted viruses were CD4 and CCR5 tropic and demonstrated concealment of coreceptor binding surfaces of the envelope bridging sheet and variable loop 3. 2 mo after infection, transmitted/founder viruses in three subjects were nearly completely replaced by viruses differing at two to five highly selected genomic loci; by 12–20 mo, viruses exhibited concentrated mutations at 17–34 discrete locations. These findings reveal viral properties associated with mucosal HIV-1 transmission and a limited set of rapidly evolving adaptive mutations driven primarily, but not exclusively, by early cytotoxic T cell responses.
Genentech1, Uppsala University2, University of California, San Francisco3, University of California, Davis4, Karolinska Institutet5, Lund University6, Umeå University7, University of Minnesota8, University of Alabama at Birmingham9, Northwestern University10, University of Texas Health Science Center at Houston11, University of Puerto Rico12, University of Pittsburgh13, Johns Hopkins University14, North Shore-LIJ Health System15
TL;DR: The results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.
Abstract: Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 x 10(-8)): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P< or = 1 x 10(-5). A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 x 10(-3)) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.
TL;DR: A role for the NOX4 isoform in tissue repair functions of myofibroblasts and fibrogenesis is reported and proof of concept for therapeutic targeting of NOX-4 in recalcitrant fibrotic disorders is provided.
Abstract: Members of the NADPH oxidase (NOX) family of enzymes, which catalyze the reduction of O(2) to reactive oxygen species, have increased in number during eukaryotic evolution. Seven isoforms of the NOX gene family have been identified in mammals; however, specific roles of NOX enzymes in mammalian physiology and pathophysiology have not been fully elucidated. The best established physiological role of NOX enzymes is in host defense against pathogen invasion in diverse species, including plants. The prototypical member of this family, NOX-2 (gp91(phox)), is expressed in phagocytic cells and mediates microbicidal activities. Here we report a role for the NOX4 isoform in tissue repair functions of myofibroblasts and fibrogenesis. Transforming growth factor-beta1 (TGF-beta1) induces NOX-4 expression in lung mesenchymal cells via SMAD-3, a receptor-regulated protein that modulates gene transcription. NOX-4-dependent generation of hydrogen peroxide (H(2)O(2)) is required for TGF-beta1-induced myofibroblast differentiation, extracellular matrix (ECM) production and contractility. NOX-4 is upregulated in lungs of mice subjected to noninfectious injury and in cases of human idiopathic pulmonary fibrosis (IPF). Genetic or pharmacologic targeting of NOX-4 abrogates fibrogenesis in two murine models of lung injury. These studies support a function for NOX4 in tissue fibrogenesis and provide proof of concept for therapeutic targeting of NOX-4 in recalcitrant fibrotic disorders.
Brigham and Women's Hospital1, University of Michigan2, Johns Hopkins University3, Leipzig University4, Beth Israel Deaconess Medical Center5, University of Alabama at Birmingham6, Cornell University7, University of Pennsylvania8, University of Miami9, Leiden University Medical Center10, Queen Mary University of London11, Loyola University Medical Center12
TL;DR: Etienne M. Aliot, MD, FESC, FHRS, William G. Stevenson, this article, Frank Bogun, MD4, C. Neal Kay, MD12, Karl-Heinz Kuck, Dr.
University of Alabama at Birmingham1, Ohio State University2, National Institutes of Health3, George Washington University4, University of Texas at Dallas5, University of Utah6, University of Chicago7, University of Pittsburgh8, Wake Forest University9, Thomas Jefferson University10, Wayne State University11, University of Cincinnati12, Columbia University13, Brown University14, Northwestern University15, University of Miami16, University of Tennessee Health Science Center17, University of Texas at San Antonio18, University of North Carolina at Chapel Hill19, University of Texas at Austin20, Case Western Reserve University21
TL;DR: Elective repeat cesarean delivery before 39 weeks of gestation is common and is associated with respiratory and other adverse neonatal outcomes.
Abstract: BACKGROUND Because of increased rates of respiratory complications, elective cesarean delivery is discouraged before 39 weeks of gestation unless there is evidence of fetal lung maturity. We assessed associations between elective cesarean delivery at term (37 weeks of gestation or longer) but before 39 weeks of gestation and neonatal outcomes. METHODS We studied a cohort of consecutive patients undergoing repeat cesarean sections performed at 19 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network from 1999 through 2002. Women with viable singleton pregnancies delivered electively (i.e., before the onset of labor and without any recognized indications for delivery before 39 weeks of gestation) were included. The primary outcome was the composite of neonatal death and any of several adverse events, including respiratory complications, treated hypoglycemia, newborn sepsis, and admission to the neonatal intensive care unit (ICU). RESULTS Of 24,077 repeat cesarean deliveries at term, 13,258 were performed electively; of these, 35.8% were performed before 39 completed weeks of gestation (6.3% at 37 weeks and 29.5% at 38 weeks) and 49.1% at 39 weeks of gestation. One neonatal death occurred. As compared with births at 39 weeks, births at 37 weeks and at 38 weeks were associated with an increased risk of the primary outcome (adjusted odds ratio for births at 37 weeks, 2.1; 95% confidence interval [CI], 1.7 to 2.5; adjusted odds ratio for births at 38 weeks, 1.5; 95% CI, 1.3 to 1.7; P for trend <0.001). The rates of adverse respiratory outcomes, mechanical ventilation, newborn sepsis, hypoglycemia, admission to the neonatal ICU, and hospitalization for 5 days or more were increased by a factor of 1.8 to 4.2 for births at 37 weeks and 1.3 to 2.1 for births at 38 weeks. CONCLUSIONS Elective repeat cesarean delivery before 39 weeks of gestation is common and is associated with respiratory and other adverse neonatal outcomes.
TL;DR: In this contemporary study population of patients with diabetes, the cardiac event rates were low and were not significantly reduced by MPI screening for myocardial ischemia over 4.8 years.
Abstract: Context Coronary artery disease (CAD) is the major cause of mortality and morbidity in patients with type 2 diabetes. But the utility of screening patients with type 2 diabetes for asymptomatic CAD is controversial. Objective To assess whether routine screening for CAD identifies patients with type 2 diabetes as being at high cardiac risk and whether it affects their cardiac outcomes. Design, Setting, and Patients The Detection of Ischemia in Asymptomatic Diabetics (DIAD) study is a randomized controlled trial in which 1123 participants with type 2 diabetes and no symptoms of CAD were randomly assigned to be screened with adenosine-stress radionuclide myocardial perfusion imaging (MPI) or not to be screened. Participants were recruited from diabetes clinics and practices and prospectively followed up from August 2000 to September 2007. Main Outcome Measure Cardiac death or nonfatal myocardial infarction (MI). Results The cumulative cardiac event rate was 2.9% over a mean (SD) follow-up of 4.8 (0.9) years for an average of 0.6% per year. Seven nonfatal MIs and 8 cardiac deaths (2.7%) occurred among the screened group and 10 nonfatal MIs and 7 cardiac deaths (3.0%) among the not-screened group (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.44-1.88; P = .73). Of those in the screened group, 409 participants with normal results and 50 with small MPI defects had lower event rates than the 33 with moderate or large MPI defects; 0.4% per year vs 2.4% per year (HR, 6.3; 95% CI, 1.9-20.1; P = .001). Nevertheless, the positive predictive value of having moderate or large MPI defects was only 12%. The overall rate of coronary revascularization was low in both groups: 31 (5.5%) in the screened group and 44 (7.8%) in the unscreened group (HR, 0.71; 95% CI, 0.45-1.1; P = .14). During the course of study there was a significant and equivalent increase in primary medical prevention in both groups. Conclusion In this contemporary study population of patients with diabetes, the cardiac event rates were low and were not significantly reduced by MPI screening for myocardial ischemia over 4.8 years. Trial Registration clinicaltrials.gov Identifier: NCT00769275
TL;DR: Kinetic analysis and mathematical modeling of virus immune escape showed that the contribution of CD8 T cell–mediated killing of productively infected cells was earlier and much greater than previously recognized and that it contributed to the initial decline of plasma virus in acute infection.
Abstract: Identification of the transmitted/founder virus makes possible, for the first time, a genome-wide analysis of host immune responses against the infecting HIV-1 proteome. A complete dissection was made of the primary HIV-1–specific T cell response induced in three acutely infected patients. Cellular assays, together with new algorithms which identify sites of positive selection in the virus genome, showed that primary HIV-1–specific T cells rapidly select escape mutations concurrent with falling virus load in acute infection. Kinetic analysis and mathematical modeling of virus immune escape showed that the contribution of CD8 T cell–mediated killing of productively infected cells was earlier and much greater than previously recognized and that it contributed to the initial decline of plasma virus in acute infection. After virus escape, these first T cell responses often rapidly waned, leaving or being succeeded by T cell responses to epitopes which escaped more slowly or were invariant. These latter responses are likely to be important in maintaining the already established virus set point. In addition to mutations selected by T cells, there were other selected regions that accrued mutations more gradually but were not associated with a T cell response. These included clusters of mutations in envelope that were targeted by NAbs, a few isolated sites that reverted to the consensus sequence, and bystander mutations in linkage with T cell–driven escape.
TL;DR: Patients considered for mechanical circulatory support can now be classified using the 7 profiles plus 3 modifiers developed through INTERMACS, and understanding these profiles and their impact on outcome should help to better select patients and therapies in the advanced stages of disease.
Abstract: Background The current classification of patients with New York Heart Association Class IV symptoms does not offer adequate description to allow optimal selection of patients for the current options of medical and pacing therapies, cardiac transplantation and mechanical circulatory support. Methods Seven clinical profiles and an arrhythmia modifier were developed and implemented into the first year of data collection for the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). The INTERMACS Coordinators' Council provided ongoing feedback regarding the characterization of patients receiving implantable devices. Results The definition of 7 clinical profiles revealed that 80% of current devices are being used in the 2 profiles with the highest levels of clinical compromise. The INTERMACS Coordinators' Council helped to identify gaps in the characterization of hospitalized patients on temporary assist devices and of homebound patients with resting symptoms, which has led to revised definitions of Profile 3 and 4 and the addition of 2 new modifiers, for temporary circulatory support devices in the hospital, and for frequent rehospitalization of patients at home. Conclusions Patients considered for mechanical circulatory support can now be classified using the 7 profiles plus 3 modifiers developed through INTERMACS. Further understanding these profiles and their impact on outcome should help to better select patients and therapies in the advanced stages of disease.
Pennington Biomedical Research Center1, Thomas Jefferson University2, Cornell University3, University of Wisconsin-Madison4, University of Alabama at Birmingham5, Michigan State University6, Johns Hopkins University7, University of Auckland8, Louisiana State University9, University of Verona10, Wayne State University11, University of Louisville12, Baylor College of Medicine13
TL;DR: Evidence for microorganisms, epigenetics, increasing maternal age, greater fecundity among people with higher adiposity, assortative mating, sleep debt, endocrine disruptors, pharmaceutical iatrogenesis, reduction in variability of ambient temperatures, and intrauterine and intergenerational effects as contributing factors to the obesity epidemic are reviewed.
Abstract: The obesity epidemic is a global issue and shows no signs of abating, while the cause of this epidemic remains unclear. Marketing practices of energy-dense foods and institutionally-driven declines...
TL;DR: CMV glycoprotein B vaccine has the potential to decrease incident cases of maternal and congenital CMV infection and was more likely to remain uninfected during a 42-month period than the placebo group.
Abstract: Background Congenital infection with cytomegalovirus (CMV) is an important cause of hearing, cognitive, and motor impairments in newborns. Methods In this phase 2, placebo-controlled, randomized, double-blind trial, we evaluated a vaccine consisting of recombinant CMV envelope glycoprotein B with MF59 adjuvant, as compared with placebo. Three doses of the CMV vaccine or placebo were given at 0, 1, and 6 months to CMV-seronegative women within 1 year after they had given birth. We tested for CMV infection in the women in quarterly tests during a 42-month period, using an assay for IgG antibodies against CMV proteins other than glycoprotein B. Infection was confirmed by virus culture or immunoblotting. The primary end point was the time until the detection of CMV infection. Results We randomly assigned 234 subjects to receive the CMV vaccine and 230 subjects to receive placebo. A scheduled interim analysis led to a stopping recommendation because of vaccine efficacy. After a minimum of 1 year of follow-up, ...
TL;DR: Evidence is provided that the survival of BCR deficient mature B cells can be rescued by a single signaling pathway downstream of the BCR, namely PI3K signaling, with the FOXO1 transcription factor playing a central role.
TL;DR: A linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms in a common set of 1,031 multiplex autism families, implicating SEMA5A as an autism susceptibility gene.
Abstract: Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 x 10(-7)). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.
TL;DR: Many of the recent advances contributing to the ascendancy of the primary cilium are reviewed and how the extraordinary complexity of this organelle inevitably assures many more exciting future discoveries.
01 Nov 2009
TL;DR: This paper presents the results of a pilot study to assess the feasibility of using accelerometer data to estimate the severity of symptoms and motor complications in patients with Parkinson's disease, and a support vector machine (SVM) classifier was implemented to estimateThe severity of tremor, bradykinesia and dyskinesian symptoms from accelerometers data features.
Abstract: This paper presents the results of a pilot study to assess the feasibility of using accelerometer data to estimate the severity of symptoms and motor complications in patients with Parkinson's disease. A support vector machine (SVM) classifier was implemented to estimate the severity of tremor, bradykinesia and dyskinesia from accelerometer data features. SVM-based estimates were compared with clinical scores derived via visual inspection of video recordings taken while patients performed a series of standardized motor tasks. The analysis of the video recordings was performed by clinicians trained in the use of scales for the assessment of the severity of Parkinsonian symptoms and motor complications. Results derived from the accelerometer time series were analyzed to assess the effect on the estimation of clinical scores of the duration of the window utilized to derive segments (to eventually compute data features) from the accelerometer data, the use of different SVM kernels and misclassification cost values, and the use of data features derived from different motor tasks. Results were also analyzed to assess which combinations of data features carried enough information to reliably assess the severity of symptoms and motor complications. Combinations of data features were compared taking into consideration the computational cost associated with estimating each data feature on the nodes of a body sensor network and the effect of using such data features on the reliability of SVM-based estimates of the severity of Parkinsonian symptoms and motor complications.
TL;DR: A recurring interstitial deletion of the pseudoautosomal region 1 of chromosomes X and Y in B-progenitor ALL that juxtaposes the first, noncoding exon of P2RY8 with the coding region of CRLF2 is reported.
Abstract: Aneuploidy and translocations are hallmarks of B-progenitor acute lymphoblastic leukemia (ALL), but many individuals with this cancer lack recurring chromosomal alterations. Here we report a recurring interstitial deletion of the pseudoautosomal region 1 of chromosomes X and Y in B-progenitor ALL that juxtaposes the first, noncoding exon of P2RY8 with the coding region of CRLF2. We identified the P2RY8-CRLF2 fusion in 7% of individuals with B-progenitor ALL and 53% of individuals with ALL associated with Down syndrome. CRLF2 alteration was associated with activating JAK mutations, and expression of human P2RY8-CRLF2 together with mutated mouse Jak2 resulted in constitutive Jak-Stat activation and cytokine-independent growth of Ba/F3 cells overexpressing interleukin-7 receptor alpha. Our findings indicate that these two genetic lesions together contribute to leukemogenesis in B-progenitor ALL.
TL;DR: The clinical manifestations, recent molecular and genetic findings, and current and developing therapies for managing clinical problems associated with neurofibromatosis type 1 are described.
Abstract: Neurofibromatosis type 1 (NF1) is an autosomal dominant condition with a worldwide incidence of 1 per 2500 to 3000 individuals. Caused by a germ-line‐ inactivating mutation in the NF1 gene on chromosome 17, the disease is associated with increased morbidity and mortality. In the past several years, significant progress has been made in standardizing management of the major clinical features of neurofibromatosis type 1. Moreover, improved understanding of how the neurofibromatosis type 1 protein, neurofibromin, regulates cell growth recently provided insight into the pathogenesis of the disease and has led to the development of new therapies. In this review, we describe the clinical manifestations, recent molecular and genetic findings, and current and developing therapies for managing clinical problems associated with neurofibromatosis type 1. Pediatrics 2009;123:124‐133