Showing papers by "Boston Children's Hospital published in 2009"
TL;DR: The goal is to combine kinetic and kinematic data to examine translational motions during microgravity adaptations to encourage fine-control motions as these reduce the risk of injury and increase controllability.
Abstract: Introduction: Astronauts soaring through space modules with the grace of birds seems counterintuitive. How do they adapt to the weightless environment? Previous spaceflights have shown that astronauts in orbit adapt their motor strategies to each change in their gravitational environment. During adaptation, performance is degraded and can lead to mission-threatening injuries. If adaptation can occur before a mission, productivity during the mission might improve, minimizing risk. The goal is to combine kinetic and kinematic data to examine translational motions during microgravity adaptations. Methods: Experiments were performed during parabolic flights aboard NASA's C-9. Five subjects used their legs to push off from a sensor, landing on a target 3.96 m (13 ft) away. The sensor quantified the kinetics during contact, while four cameras recorded kinematics during push-off. Joint torques were calculated for a subset of traverses (N = 50) using the forces, moments, and joint angles. Results: During the 149 traverses, the average peak force exerted onto the sensor was 224.6 ± 74.6 N, with peak values ranging between 65.8―461.9 N. Two types of force profiles were observed, some having single, strong peaks (N = 64) and others having multiple, weaker peaks (N = 86). Conclusions: The force data were consistent with values recorded previously in sustained microgravity aboard Mir and the Space Shuttle. A training program for astronauts might be designed to encourage fine-control motions (i.e., multiple, weaker peaks) as these reduce the risk of injury and increase controllability. Additionally, a kinematic and kinetic sensor suite was successfully demonstrated in the weightless environment onboard the C-9 aircraft.
5,639 citations
TL;DR: Some key aspects of Wnt/beta-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis are highlighted, and potential therapeutic implications are discussed.
4,926 citations
Tufts Medical Center1, Boston Children's Hospital2, University of California, San Diego3, University of California, Los Angeles4, Los Angeles Biomedical Research Institute5, Providence Portland Medical Center6, Case Western Reserve University7, United States Department of Veterans Affairs8, University of Virginia9, Johns Hopkins University School of Medicine10
TL;DR: An update on potentially effective antibacterial drugs in the late-stage development pipeline is provided, in the hope of encouraging collaboration between industry, academia, the National Institutes of Health, the Food and Drug Administration, and the Centers for Disease Control and Prevention work productively together.
Abstract: The Infectious Diseases Society of America (IDSA) continues to view with concern the lean pipeline for novel therapeutics to treat drug-resistant infections, especially those caused by gram-negative pathogens. Infections now occur that are resistant to all current antibacterial options. Although the IDSA is encouraged by the prospect of success for some agents currently in preclinical development, there is an urgent, immediate need for new agents with activity against these panresistant organisms. There is no evidence that this need will be met in the foreseeable future. Furthermore, we remain concerned that the infrastructure for discovering and developing new antibacterials continues to stagnate, thereby risking the future pipeline of antibacterial drugs. The IDSA proposed solutions in its 2004 policy report, “Bad Bugs, No Drugs: As Antibiotic R&D Stagnates, a Public Health Crisis Brews,” and recently issued a “Call to Action” to provide an update on the scope of the problem and the proposed solutions. A primary objective of these periodic reports is to encourage a community and legislative response to establish greater financial parity between the antimicrobial development and the development of other drugs. Although recent actions of the Food and Drug Administration and the 110th US Congress present a glimmer of hope, significant uncertainly remains. Now, more than ever, it is essential to create a robust and sustainable antibacterial research and development infrastructure—one that can respond to current antibacterial resistance now and anticipate evolving resistance. This challenge requires that industry, academia, the National Institutes of Health, the Food and Drug Administration, the Centers for Disease Control and Prevention, the US Department of Defense, and the new Biomedical Advanced Research and Development Authority at the Department of Health and Human Services work productively together. This report provides an update on potentially effective antibacterial drugs in the late-stage development pipeline, in the hope of encouraging such collaborative action.
4,256 citations
Imperial College London1, National Institutes of Health2, Boston Children's Hospital3, University of Alberta4, Royal Prince Alfred Hospital5, University of Sydney6, University of Giessen7, Amrita Institute of Medical Sciences and Research Centre8, University of Illinois at Urbana–Champaign9, Medical University of Graz10, Vanderbilt University Medical Center11, University of São Paulo12
TL;DR: In this paper, a clinical classification of pulmonary hypertension (PH) was established, categorizing PH into groups which share similar pathological and hemodynamic characteristics and therapeutic approaches, and the main change was to withdraw persistent pulmonary hypertension of the newborn (PPHN) from Group 1 because this entity carries more differences than similarities with other PAH subgroups.
4,135 citations
TL;DR: The results lend empirical support for the validity and reliability of this set of facial expressions as determined by accurate identification of expressions and high intra-participant agreement across two testing sessions, respectively.
Abstract: A set of face stimuli called the NimStim Set of Facial Expressions is described. The goal in creating this set was to provide facial expressions that untrained individuals, characteristic of research participants, would recognize. This set is large in number, multiracial, and available to the scientific community online. The results of psychometric evaluations of these stimuli are presented. The results lend empirical support for the validity and reliability of this set of facial expressions as determined by accurate identification of expressions and high intra-participant agreement across two testing sessions, respectively.
3,040 citations
TL;DR: The guidelines reiterate the importance of nutrition assessment-particularly, the detection of malnourished patients who are most vulnerable and therefore may benefit from timely intervention and there is a need for renewed focus on accurate estimation of energy needs and attention to optimizing protein intake.
Abstract: This document represents the first collaboration between 2 organizations-the American Society for Parenteral and Enteral Nutrition and the Society of Critical Care Medicine-to describe best practices in nutrition therapy in critically ill children. The target of these guidelines is intended to be the pediatric critically ill patient (>1 month and 2-3 days in a PICU admitting medical, surgical, and cardiac patients. In total, 2032 citations were scanned for relevance. The PubMed/MEDLINE search resulted in 960 citations for clinical trials and 925 citations for cohort studies. The EMBASE search for clinical trials culled 1661 citations. In total, the search for clinical trials yielded 1107 citations, whereas the cohort search yielded 925. After careful review, 16 randomized controlled trials and 37 cohort studies appeared to answer 1 of the 8 preidentified question groups for this guideline. We used the GRADE criteria (Grading of Recommendations, Assessment, Development, and Evaluation) to adjust the evidence grade based on assessment of the quality of study design and execution. These guidelines are not intended for neonates or adult patients. The guidelines reiterate the importance of nutrition assessment-particularly, the detection of malnourished patients who are most vulnerable and therefore may benefit from timely intervention. There is a need for renewed focus on accurate estimation of energy needs and attention to optimizing protein intake. Indirect calorimetry, where feasible, and cautious use of estimating equations and increased surveillance for unintended caloric underfeeding and overfeeding are recommended. Optimal protein intake and its correlation with clinical outcomes are areas of great interest. The optimal route and timing of nutrient delivery are areas of intense debate and investigations. Enteral nutrition remains the preferred route for nutrient delivery. Several strategies to optimize enteral nutrition during critical illness have emerged. The role of supplemental parenteral nutrition has been highlighted, and a delayed approach appears to be beneficial. Immunonutrition cannot be currently recommended. Overall, the pediatric critical care population is heterogeneous, and a nuanced approach to individualizing nutrition support with the aim of improving clinical outcomes is necessary.
2,947 citations
TL;DR: In a test set of 168 CKiD patients at 1 yr of follow-up, this formula compared favorably with previously published estimating equations for children, and with height measured in cm, a bedside calculation provides a good approximation to the estimated GFR formula.
Abstract: The Schwartz formula was devised in the mid-1970s to estimate GFR in children. Recent data suggest that this formula currently overestimates GFR as measured by plasma disappearance of iohexol, likely a result of a change in methods used to measure creatinine. Here, we developed equations to estimate GFR using data from the baseline visits of 349 children (aged 1 to 16 yr) in the Chronic Kidney Disease in Children (CKiD) cohort. Median iohexol-GFR (iGFR) was 41.3 ml/min per 1.73 m(2) (interquartile range 32.0 to 51.7), and median serum creatinine was 1.3 mg/dl. We performed linear regression analyses assessing precision, goodness of fit, and accuracy to develop improvements in the GFR estimating formula, which was based on height, serum creatinine, cystatin C, blood urea nitrogen, and gender. The best equation was: GFR(ml/min per 1.73 m(2))=39.1[height (m)/Scr (mg/dl)](0.516) x [1.8/cystatin C (mg/L)](0.294)[30/BUN (mg/dl)](0.169)[1.099](male)[height (m)/1.4](0.188). This formula yielded 87.7% of estimated GFR within 30% of the iGFR, and 45.6% within 10%. In a test set of 168 CKiD patients at 1 yr of follow-up, this formula compared favorably with previously published estimating equations for children. Furthermore, with height measured in cm, a bedside calculation of 0.413*(height/serum creatinine), provides a good approximation to the estimated GFR formula. Additional studies of children with higher GFR are needed to validate these formulas for use in screening all children for CKD.
2,816 citations
French Institute of Health and Medical Research1, University of Paris-Sud2, Institut Gustave Roussy3, Icahn School of Medicine at Mount Sinai4, University of Texas Southwestern Medical Center5, Thomas Jefferson University6, McMaster University7, University of Massachusetts Medical School8, LSU Health Sciences Center New Orleans9, Roswell Park Cancer Institute10, Boston Children's Hospital11, University of Gothenburg12, University of Freiburg13, University of California, San Francisco14, Buck Institute for Research on Aging15, Centre national de la recherche scientifique16, National Institutes of Health17, Technion – Israel Institute of Technology18, University of Leicester19, University of Chieti-Pescara20, Istituto Superiore di Sanità21, University of North Carolina at Chapel Hill22, New York University23, University of Pennsylvania24, Howard Hughes Medical Institute25, Yale University26, University of Ulm27, University of Burgundy28, Aix-Marseille University29, Pasteur Institute30, University of Strasbourg31, Johns Hopkins University32, University of Zurich33, University of Tokyo34, Weizmann Institute of Science35, University of Michigan36, University College London37, Duke University38, University of Graz39, Ghent University40, Trinity College, Dublin41, University of Amsterdam42, University of Lyon43, University of Rome Tor Vergata44, Stony Brook University45, University of Göttingen46, Kyoto University47, Merck & Co.48, Austrian Academy of Sciences49, National University of Singapore50, University of Chicago51, Royal College of Surgeons in Ireland52, La Trobe University53, University of Buenos Aires54, University of Padua55, University of Lisbon56, University of Cambridge57, University of Würzburg58, University of Geneva59, University of Bern60, Rockefeller University61, University of Lausanne62, Osaka University63, University of California, San Diego64, University of Glasgow65, Harvard University66, Karolinska Institutet67
TL;DR: A nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls is provided and the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells is emphasized.
Abstract: Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios Thus far, dozens of methods have been proposed to quantify cell death-related parameters However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells
2,218 citations
University of Washington1, University of Paris2, Queen Mary University of London3, McMaster University4, Cornell University5, University of Pennsylvania6, University of New South Wales7, Medical University of Vienna8, Sapienza University of Rome9, Scripps Research Institute10, Boston Children's Hospital11, University of Toronto12, University of Oklahoma Health Sciences Center13
TL;DR: An International Working Group of recognized expert clinicians convened a 2-day structured meeting to define standard terminology and definitions for primary ITP and its different phases and criteria for the grading of severity, and clinically meaningful outcomes and response.
2,127 citations
TL;DR: It is shown that exhausted CD8+ T cells are subject to complex layers of negative regulation resulting from the coexpression of multiple inhibitory receptors, and regulation of T cell exhaustion by various inhibitory pathways was nonredundant.
Abstract: T cell exhaustion often occurs during chronic infection and prevents optimal viral control. The molecular pathways involved in T cell exhaustion remain poorly understood. Here we show that exhausted CD8+ T cells are subject to complex layers of negative regulation resulting from the coexpression of multiple inhibitory receptors. Exhausted CD8+ T cells expressed up to seven inhibitory receptors. Coexpression of multiple distinct inhibitory receptors was associated with greater T cell exhaustion and more severe infection. Regulation of T cell exhaustion by various inhibitory pathways was nonredundant, as blockade of the T cell inhibitory receptors PD-1 and LAG-3 simultaneously and synergistically improved T cell responses and diminished viral load in vivo. Thus, CD8+ T cell responses during chronic viral infections are regulated by complex patterns of coexpressed inhibitory receptors.
1,775 citations
TL;DR: It is the view of the AE-PCOS Society Task Force that PCOS should be defined by the presence of hyperandrogenism, ovarian dysfunction, and/or polycystic ovaries, and the exclusion of related disorders.
TL;DR: Very preterm and/or VLBW children have moderate-to-severe deficits in academic achievement, attention problems, and internalizing behavioral problems and poor EF, which are adverse outcomes that were strongly correlated to their immaturity at birth.
Abstract: OBJECTIVE: Sequelae of academic underachievement, behavioral problems, and poor executive function (EF) have been extensively reported for very preterm (≤33 weeks9 gestation) and/or very low birth weight (VLBW) (≤1500 g) children. Great variability in the published results, however, hinders the field in studying underlying dysfunctions and developing intervention strategies. We conducted a quantitative meta-analysis of studies published between 1998 and 2008 on academic achievement, behavioral functioning, and EF with the aim of providing aggregated measures of effect size for these outcome domains. METHODS: Suitable for inclusion were 14 studies on academic achievement, 9 studies on behavioral problems, and 12 studies on EF, which compared a total of 4125 very preterm and/or VLBW children with 3197 term-born controls. Combined effect sizes for the 3 outcome domains were calculated in terms of Cohen9s d. Q-test statistics were performed to test homogeneity among the obtained effect sizes. Pearson9s correlation coefficients were calculated to examine the impact of mean birth weight and mean gestational age, as well as the influence of mean age at assessment on the effect sizes for academic achievement, behavioral problems, and EF. RESULTS: Combined effect sizes show that very preterm and/or VLBW children score 0.60 SD lower on mathematics tests, 0.48 SD on reading tests, and 0.76 SD on spelling tests than term-born peers. Of all behavioral problems stacked, attention problems were most pronounced in very preterm and/or VLBW children, with teacher and parent ratings being 0.43 to 0.59 SD higher than for controls, respectively. Combined effect sizes for parent and teacher ratings of internalizing behavior problems were small ( 0.51). CONCLUSIONS: Very preterm and/or VLBW children have moderate-to-severe deficits in academic achievement, attention problems, and internalizing behavioral problems and poor EF, which are adverse outcomes that were strongly correlated to their immaturity at birth. During transition to young adulthood these children continue to lag behind term-born peers.
TL;DR: The demographic characteristics, pathogenesis, evaluation, and treatment of moyamoya disease and syndrome, and patients with characteristic moysamoya vasculopathy plus associated conditions are categorized as having moy amoya syndrome.
Abstract: Moyamoya disease is a cerebrovascular condition predisposing affected patients to stroke in association with progressive stenosis of the intracranial internal carotid arteries and their proximal branches. Patients with characteristic moyamoya vasculopathy plus associated conditions are categorized as having moyamoya syndrome. This review describes the demographic characteristics, pathogenesis, evaluation, and treatment of moyamoya disease and syndrome.
TL;DR: This paper seeks to advance implementation science in mental health services by over viewing the emergence of implementation as an issue for research, by addressing key issues of language and conceptualization, and by presenting a heuristic skeleton model for the study of implementation processes.
Abstract: One of the most critical issues in mental health services research is the gap between what is known about effective treatment and what is provided to consumers in routine care. Concerted efforts are required to advance implementation science and produce skilled implementation researchers. This paper seeks to advance implementation science in mental health services by over viewing the emergence of implementation as an issue for research, by addressing key issues of language and conceptualization, by presenting a heuristic skeleton model for the study of implementation processes, and by identifying the implications for research and training in this emerging field.
TL;DR: Current models of the mechanisms that cause copy number variation focus on perturbation of DNA replication and replication of non-contiguous DNA segments and cellular stress might induce repair of broken replication forks to switch from high-fidelity homologous recombination to non-homologous repair, thus promoting copy number change.
Abstract: Deletions and duplications of chromosomal segments (copy number variants, CNVs) are a major source of variation between individual humans and are an underlying factor in human evolution and in many diseases, including mental illness, developmental disorders and cancer CNVs form at a faster rate than other types of mutation, and seem to do so by similar mechanisms in bacteria, yeast and humans Here we review current models of the mechanisms that cause copy number variation Non-homologous end-joining mechanisms are well known, but recent models focus on perturbation of DNA replication and replication of non-contiguous DNA segments For example, cellular stress might induce repair of broken replication forks to switch from high-fidelity homologous recombination to non-homologous repair, thus promoting copy number change
Boston Children's Hospital1, Vrije Universiteit Brussel2, University of California, San Francisco3, Nationwide Children's Hospital4, University of Illinois at Urbana–Champaign5, University of Amsterdam6, University of Naples Federico II7, Great Ormond Street Hospital8, University of Mississippi Medical Center9
TL;DR: This document serves as an update of the North American and European societies for Pediatric Gastroenterology, Hepatology, and Nutrition 2009 clinical guidelines for the diagnosis and management of gastroesophageal reflux disease in infants and children and is intended to be applied in daily practice and as a basis for clinical trials.
Abstract: Objective: T o de v elop a North American Society for Pediatric Ga str oen te rol og y , He pat olo gy , and Nut ri tio n (N ASP GH AN) and Eu rop ea n Soc ie ty fo r Pe di atr ic Gas tr oen te ro log y , Hep at ol og y , and Nut rit io n (ES PGH AN ) int er nat io nal con se ns us on th e di agn os is an d ma nag em ent of gas tr oes op hag eal refl ux and gas tr oes op hag eal re flu x di sea se in th e ped ia tr ic po pu la tio n. Methods: An international panel of 9 pediatric gastroenterologists and 2 epidemiologists were selected by both societies, which de v eloped these guidelines based on the Delphi principle. Statements were based on systematic literature searches using the best-av ailable e vidence from PubMed, Cumulati ve Index to Nursing and Allied Health Literature, and bibliographies. The committee con v ened in face-to-face meetings 3 times. Consensus was achie v ed for all recommendations through nominal group technique, a structured, quantitati v e method. Articles were e v aluated using the Oxford Centre for Evidence-based Medicine Le vels of Evidence. Using the Oxford Grades of Recommendation, the quality of e vidence of each of the recommendations made by the committee was determined and is summarized in appendices. Results: More than 600 articles were re vie wed for this work. The document provides e vidence-based guidelines for the diagnosis and management of gastroesophageal reflux and gastroesophageal reflux disease in the pediatric population. Conclusions: Th is do cum ent is int end ed to be us ed in dai ly pra cti ce fo r th e de v el op me nt of fut ure cli ni cal pra ct ic e gu ide lin es and as a bas is for cli ni cal tr ia ls . JP GN 49 :49 8 – 54 7, 20 09 . Ke y Wo rd s: Cli nic al pra ct ic e gu id el ine s — Di agn os tic te sts — Ga str oes op hag ea l refl ux (GE R) — Ga str oes op hag ea l refl ux di sea se (GE RD ) — The rap eut ic mod al iti es. # 20 09 by Eu rop ea n Soc ie ty fo r Pe di atr ic Gas tr oen te ro log y , Hep at ol og y , and Nut rit io n and No rt h Am er ica n So ci ety for Pe dia tri c Ga str oen te rol og y , Hep at ol og y , an d Nu tr iti on
University of Porto1, The Catholic University of America2, Sheba Medical Center3, Rambam Health Care Campus4, University of Palermo5, Boston Children's Hospital6, University College Dublin7, University of Barcelona8, Western General Hospital9, Guy's and St Thomas' NHS Foundation Trust10, McMaster University11, Université de Montréal12, Mount Sinai Hospital13
TL;DR: The treatment of inflammatory bowel disease has been revolutionised over the past decade by the increasing use of immunomodulators, mainly azathioprine/6-mercaptopurine and methotrexate, together with the advent of biological therapy.
St Thomas' Hospital1, University of California, San Francisco2, University of Maryland Medical Center3, Baylor University Medical Center4, Mayo Clinic5, Harvard University6, Boston Children's Hospital7, Osaka University8, Toronto General Hospital9, Cleveland Clinic10, Duke University11, Washington University in St. Louis12, MedStar Washington Hospital Center13
TL;DR: A Report From the American Society of Echocardiography’s Guidelines and Standards Committee and the Task Force on Prosthetic Valves, developed in Conjunction with the American College of Cardiology Cardiovascular Imaging Committee.
Abstract: A Report From the American Society of Echocardiography’s Guidelines and Standards Committee and the Task Force on Prosthetic Valves, Developed in Conjunction With the American College of Cardiology Cardiovascular Imaging Committee, Cardiac Imaging Committee of the American Heart Association, the European Association of Echocardiography, a registered branch of the European Society of Cardiology, the Japanese Society of Echocardiography and the Canadian Society of Echocardiography, Endorsed by the American College of Cardiology Foundation, American Heart Association, European Association of Echocardiography, a registered branch of the European Society of Cardiology, the Japanese Society of Echocardiography, and Canadian Society of Echocardiography
TL;DR: In lipoatrophic A-ZIP/F1 ‘fatless’ mice, and in mice treated with the peroxisome proliferator-activated receptor-γ inhibitor bisphenol A diglycidyl ether, marrow engraftment after irradiation is accelerated relative to wild-type or untreated mice, suggesting that antagonizing marrow adipogenesis may enhance haematopoietic recovery in clinical bone-marrow transplantation.
Abstract: Osteoblasts and endothelium constitute functional niches that support haematopoietic stem cells in mammalian bone marrow. Adult bone marrow also contains adipocytes, the number of which correlates inversely with the haematopoietic activity of the marrow. Fatty infiltration of haematopoietic red marrow follows irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia. To explore whether adipocytes influence haematopoiesis or simply fill marrow space, we compared the haematopoietic activity of distinct regions of the mouse skeleton that differ in adiposity. Here we show, by flow cytometry, colony-forming activity and competitive repopulation assay, that haematopoietic stem cells and short-term progenitors are reduced in frequency in the adipocyte-rich vertebrae of the mouse tail relative to the adipocyte-free vertebrae of the thorax. In lipoatrophic A-ZIP/F1 'fatless' mice, which are genetically incapable of forming adipocytes, and in mice treated with the peroxisome proliferator-activated receptor-gamma inhibitor bisphenol A diglycidyl ether, which inhibits adipogenesis, marrow engraftment after irradiation is accelerated relative to wild-type or untreated mice. These data implicate adipocytes as predominantly negative regulators of the bone-marrow microenvironment, and indicate that antagonizing marrow adipogenesis may enhance haematopoietic recovery in clinical bone-marrow transplantation.
TL;DR: In patients with pulmonary arterial hypertension, tadalafil 40 mg was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening.
Abstract: Background— Treatment options for pulmonary arterial hypertension target the prostacyclin, endothelin, or nitric oxide pathways. Tadalafil, a phosphodiesterase type-5 inhibitor, increases cGMP, the final mediator in the nitric oxide pathway. Methods and Results— In this 16-week, double-blind, placebo-controlled study, 405 patients with pulmonary arterial hypertension (idiopathic or associated), either treatment-naive or on background therapy with the endothelin receptor antagonist bosentan, were randomized to placebo or tadalafil 2.5, 10, 20, or 40 mg orally once daily. The primary end point was the change from baseline to week 16 in the distance walked in 6 minutes. Changes in World Health Organization functional class, clinical worsening, and health-related quality of life were also assessed. Patients completing the 16-week study could enter a long-term extension study. Tadalafil increased the distance walked in 6 minutes in a dose-dependent manner; only the 40-mg dose met the prespecified level of statistical significance ( P P =0.041), incidence of clinical worsening (68% relative risk reduction; P =0.038), and health-related quality of life. The changes in World Health Organization functional class were not statistically significant. The most common treatment-related adverse events reported with tadalafil were headache, myalgia, and flushing. Conclusions— In patients with pulmonary arterial hypertension, tadalafil 40 mg was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening.
TL;DR: A portion of this large body of work including the environmental signals and signaling pathways that regulate biofilm formation, the components of the biofilm matrix, and the mechanisms and regulation of biofilm dispersal are reviewed.
Abstract: Biofilms are communities of microorganisms that live attached to surfaces. Biofilm formation has received much attention in the last decade, as it has become clear that virtually all types of bacteria can form biofilms and that this may be the preferred mode of bacterial existence in nature. Our current understanding of biofilm formation is based on numerous studies of myriad bacterial species. Here, we review a portion of this large body of work including the environmental signals and signaling pathways that regulate biofilm formation, the components of the biofilm matrix, and the mechanisms and regulation of biofilm dispersal.
TL;DR: It is shown that differentiated heart muscle cells, cardiomyocytes, can be induced to proliferate and regenerate and an underlying molecular mechanism for controlling this process that involves the growth factor neuregulin1 (NRG1) and its tyrosine kinase receptor, ErbB4 is identified.
TL;DR: The 2009 H1N1 virus had a substantial effect on ICUs during the winter in Australia and New Zealand, and the data can assist planning for the treatment of patients during theWinter in the Northern Hemisphere.
Abstract: BACKGROUND: Planning for the treatment of infection with the 2009 pandemic influenza A (H1N1) virus through health care systems in developed countries during winter in the Northern Hemisphere is hampered by a lack of information from similar health care systems. METHODS: We conducted an inception-cohort study in all Australian and New Zealand intensive care units (ICUs) during the winter of 2009 in the Southern Hemisphere. We calculated, per million inhabitants, the numbers of ICU admissions, bed-days, and days of mechanical ventilation due to infection with the 2009 H1N1 virus. We collected data on demographic and clinical characteristics of the patients and on treatments and outcomes. RESULTS: From June 1 through August 31, 2009, a total of 722 patients with confirmed infection with the 2009 H1N1 virus (28.7 cases per million inhabitants; 95% confidence interval [CI], 26.5 to 30.8) were admitted to an ICU in Australia or New Zealand. Of the 722 patients, 669 (92.7%) were under 65 years of age and 66 (9.1%) were pregnant women; of the 601 adults for whom data were available, 172 (28.6%) had a body-mass index (the weight in kilograms divided by the square of the height in meters) greater than 35. Patients infected with the 2009 H1N1 virus were in the ICU for a total of 8815 bed-days (350 per million inhabitants). The median duration of treatment in the ICU was 7.0 days (interquartile range, 2.7 to 13.4); 456 of 706 patients (64.6%) with available data underwent mechanical ventilation for a median of 8 days (interquartile range, 4 to 16). The maximum daily occupancy of the ICU was 7.4 beds (95% CI, 6.3 to 8.5) per million inhabitants. As of September 7, 2009, a total of 103 of the 722 patients (14.3%; 95% CI, 11.7 to 16.9) had died, and 114 (15.8%) remained in the hospital. CONCLUSIONS: The 2009 H1N1 virus had a substantial effect on ICUs during the winter in Australia and New Zealand. Our data can assist planning for the treatment of patients during the winter in the Northern Hemisphere. 2009 Massachusetts Medical Society
TL;DR: Mediation analyses showed that perceived discrimination accounted for increased depressive symptomatology amongLGBT males and females, and accounted for an elevated risk of self-harm and suicidal ideation among LGBT males.
Abstract: The authors evaluated emotional distress among 9th-12th grade students, and examined whether the association between being lesbian, gay, bisexual, and/or transgendered (i.e., "LGBT") and emotional distress was mediated by perceptions of having been treated badly or discriminated against because others thought they were gay or lesbian. Data come from a school-based survey in Boston, Massachusetts (n = 1,032); 10% were LGBT, 58% were female, and ages ranged from 13 to 19 years. About 45% were Black, 31% were Hispanic, and 14% were White. LGBT youth scored significantly higher on the scale of depressive symptomatology. They were also more likely than heterosexual, non-transgendered youth to report suicidal ideation (30% vs. 6%, p < 0.0001) and self-harm (21% vs. 6%, p < 0.0001). Mediation analyses showed that perceived discrimination accounted for increased depressive symptomatology among LGBT males and females, and accounted for an elevated risk of self-harm and suicidal ideation among LGBT males. Perceived discrimination is a likely contributor to emotional distress among LGBT youth.
TL;DR: It is shown that increased endoplasmic reticulum stress and activation of the unfolded protein response in the hypothalamus of obese mice inhibits leptin receptor signaling and chemical chaperones, 4-phenyl butyric acid, and tauroursodeoxycholic acid, act as leptin-sensitizing agents, which may provide the basis for a novel treatment of obesity.
TL;DR: Hip arthroscopy for femoroacetabular impingement, accompanied by suitable rehabilitation, gives a good short-term outcome and high patient satisfaction and the predictors of a better outcome were the pre-operative modified HHS, joint space narrowing >or= 2 mm, and repair of labral pathology instead of debridement.
Abstract: Over an eight-month period we prospectively enrolled 122 patients who underwent arthroscopic surgery of the hip for femoroacetabular impingement and met the inclusion criteria for this study. Patients with bilateral hip arthroscopy, avascular necrosis and previous hip surgery were excluded. Ten patients refused to participate leaving 112 in the study. There were 62 women and 50 men. The mean age of the patients was 40.6 yrs (95% confidence interval (CI) 37.7 to 43.5). At arthroscopy, 23 patients underwent osteoplasty only for cam impingement, three underwent rim trimming only for pincer impingement, and 86 underwent both procedures for mixed-type impingement. The mean follow-up was 2.3 years (2.0 to 2.9). The mean modified Harris hip score (HHS) improved from 58 to 84 (mean difference = 24 (95% CI 19 to 28)) and the median patient satisfaction was 9 (1 to 10). Ten patients underwent total hip replacement at a mean of 16 months (8 to 26) after arthroscopy. The predictors of a better outcome were the pre-operative modified HHS (p = 0.018), joint space narrowing >or= 2 mm (p = 0.005), and repair of labral pathology instead of debridement (p = 0.032). Hip arthroscopy for femoroacetabular impingement, accompanied by suitable rehabilitation, gives a good short-term outcome and high patient satisfaction.
TL;DR: It is shown that kinesin is present on all axonal mitochondria, including those that are stationary or moving retrograde, and that the EF-hand motifs of Miro mediate Ca(2+)-dependent arrest of mitochondria and elucidate the regulatory mechanism.
TL;DR: A genome-wide study to improve prognostic classification of ALL in children revealed a new ALL subtype, the underlying genetic abnormalities of which were characterised by comparative genomic hybridisation-arrays and molecular cytogenetics.
Abstract: Summary Background Genetic subtypes of acute lymphoblastic leukaemia (ALL) are used to determine risk and treatment in children. 25% of precursor B-ALL cases are genetically unclassified and have intermediate prognosis. We aimed to use a genome-wide study to improve prognostic classification of ALL in children. Methods We constructed a classifier based on gene expression in 190 children with newly diagnosed ALL (German Cooperative ALL [COALL] discovery cohort) by use of double-loop cross-validation and validated this in an independent cohort of 107 newly diagnosed patients (Dutch Childhood Oncology Group [DCOG] independent validation cohort). Hierarchical cluster analysis with classifying gene-probe sets revealed a new ALL subtype, the underlying genetic abnormalities of which were characterised by comparative genomic hybridisation-arrays and molecular cytogenetics. Findings Our classifier predicted ALL subtype with a median accuracy of 90·0% (IQR 88·3–91·7) in the discovery cohort and correctly identified 94 of 107 patients (accuracy 87·9%) in the independent validation cohort. Without our classifier, 44 children in the COALL cohort and 33 children in the DCOG cohort would have been classified as B-other. However, hierarchical clustering showed that many of these genetically unclassified cases clustered with BCR–ABL1 -positive cases: 30 (19%) of 154 children with precursor B-ALL in the COALL cohort and 14 (15%) of 92 children with precursor B-ALL in the DCOG cohort had this BCR–ABL1 -like disease. In the COALL cohort, these patients had unfavourable outcome (5-year disease-free survival 59·5%, 95% CI 37·1–81·9) compared with patients with other precursor B-ALL (84·4%, 76·8–92·1%; p=0·012), a prognosis similar to that of patients with BCR–ABL1 -positive ALL (51·9%, 23·1–80·6%). In the DCOG cohort, the prognosis of BCR–ABL1 -like disease (57·1%, 31·2–83·1%) was worse than that of other precursor B-ALL (79·2%, 70·2–88·3%; p=0.026), and similar to that of BCR–ABL1 -positive ALL (32·5%, 2·3–62·7%). 36 (82%) of the patients with BCR–ABL1 -like disease had deletions in genes involved in B-cell development, including IKZF1, TCF3, EBF1, PAX5, and VPREB1 ; only nine (36%) of 25 patients with B-other ALL had deletions in these genes (p=0·0002). Compared with other precursor B-ALL cells, BCR–ABL1 -like cells were 73 times more resistant to L-asparaginase (p=0·001) and 1·6 times more resistant to daunorubicin (p=0·017), but toxicity of prednisolone and vincristine did not differ. Interpretation New treatment strategies are needed to improve outcome for this newly identified high-risk subtype of ALL. Funding Dutch Cancer Society, Sophia Foundation for Medical Research, Paediatric Oncology Foundation Rotterdam, Centre of Medical Systems Biology of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research, American National Institute of Health, American National Cancer Institute, and American Lebanese Syrian Associated Charities.
TL;DR: The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain.
TL;DR: The matrix metalloproteinase (MMP) family of enzymes is comprised of critically important extracellular matrix remodeling proteases whose activity has been implicated in a number of key normal and pathologic processes.
Abstract: The matrix metalloproteinase (MMP) family of enzymes is comprised of critically important extracellular matrix remodeling proteases whose activity has been implicated in a number of key normal and pathologic processes. The latter include tumor growth, progression, and metastasis as well as the dysregulated angiogenesis that is associated with these events. As a result, these proteases have come to represent important therapeutic and diagnostic targets for the treatment and detection of human cancers. In this review, we summarize the literature that establishes these enzymes as important clinical targets, discuss the complexity surrounding their choice as such, and chronicle the development strategies and outcomes of their clinical testing to date. The status of the MMP inhibitors currently in US Food and Drug Administration approved clinical trials is presented and reviewed. We also discuss the more recent and successful targeting of this enzyme family as diagnostic and prognostic predictors of human cancer, its status, and its stage. This analysis includes a wide variety of human cancers and a number of human sample types including tissue, plasma, serum, and urine.