Showing papers by "Yale University published in 2005"
TL;DR: Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone.
Abstract: background The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study. methods A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments. results Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects. conclusions The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism.
5,437 citations
TL;DR: It is shown that the let-7 family negatively regulates let-60/RAS, a regulatory RNAs found in multicellular eukaryotes, including humans, where they are implicated in cancer.
3,676 citations
TL;DR: The obstructive sleep apnea syndrome significantly increases the risk of stroke or death from any cause, and the increase is independent of other risk factors, including hypertension.
Abstract: background Previous studies have suggested that the obstructive sleep apnea syndrome may be an important risk factor for stroke. It has not been determined, however, whether the syndrome is independently related to the risk of stroke or death from any cause after adjustment for other risk factors, including hypertension. methods In this observational cohort study, consecutive patients underwent polysomnography, and subsequent events (strokes and deaths) were verified. The diagnosis of the obstructive sleep apnea syndrome was based on an apnea–hypopnea index of 5 or higher (five or more events per hour); patients with an apnea–hypopnea index of less than 5 served as the comparison group. Proportional-hazards analysis was used to determine the independent effect of the obstructive sleep apnea syndrome on the composite outcome of stroke or death from any cause. results Among 1022 enrolled patients, 697 (68 percent) had the obstructive sleep apnea syndrome. At baseline, the mean apnea–hypopnea index in the patients with the syndrome was 35, as compared with a mean apnea–hypopnea index of 2 in the comparison group. In an unadjusted analysis, the obstructive sleep apnea syndrome was associated with stroke or death from any cause (hazard ratio, 2.24; 95 percent confidence interval, 1.30 to 3.86; P=0.004). After adjustment for age, sex, race, smoking status, alcohol-consumption status, body-mass index, and the presence or absence of diabetes mellitus, hyperlipidemia, atrial fibrillation, and hypertension, the obstructive sleep apnea syndrome retained a statistically significant association with stroke or death (hazard ratio, 1.97; 95 percent confidence interval, 1.12 to 3.48; P=0.01). In a trend analysis, increased severity of sleep apnea at baseline was associated with an increased risk of the development of the composite end point (P=0.005). conclusions The obstructive sleep apnea syndrome significantly increases the risk of stroke or death from any cause, and the increase is independent of other risk factors, including hypertension.
2,766 citations
TL;DR: In this paper, the most important experimental results from the first three years of nucleus-nucleus collision studies at RHIC were reviewed, with emphasis on results of the STAR experiment.
2,750 citations
University of Rochester1, University of Washington2, University of Pennsylvania3, Johns Hopkins University4, Harvard University5, Yale University6, Ludwig Maximilian University of Munich7, AstraZeneca8, University of Queensland9, Tufts University10, Merck & Co.11, National Institutes of Health12, Endo International plc13, Food and Drug Administration14, University of Toronto15, Purdue Pharma16
2,441 citations
TL;DR: In this article, the authors measure the effect of Catholic high school attendance on educational attainment and test scores, and find that Catholic high schools substantially increase the probability of graduating from high school and, more tentatively, attending college.
Abstract: In this paper we measure the effect of Catholic high school attendance on educational attainment and test scores. Because we do not have a good instrumental variable for Catholic school attendance, we develop new estimation methods based on the idea that the amount of selection on the observed explanatory variables in a model provides a guide to the amount of selection on the unobservables. We also propose an informal way to assess selectivity bias based on measuring the ratio of selection on unobservables to selection on observables that would be required if one is to attribute the entire effect of Catholic school attendance to selection bias. We use our methods to estimate the effect of attending a Catholic high school on a variety of outcomes. Our main conclusion is that Catholic high schools substantially increase the probability of graduating from high school and, more tentatively, attending college. We find little evidence of an effect on test scores.
2,411 citations
Wayne State University1, Yale University2, University of Texas at Austin3, RTI International4, University of Cincinnati5, Case Western Reserve University6, National Institutes of Health7, University of California, San Diego8, University of Alabama9, University of Miami10, Duke University11, Stanford University12, Emory University13, Indiana University – Purdue University Indianapolis14, University of Rochester15
TL;DR: Whole-body hypothermia reduces the risk of death or disability in infants with moderate or severe hypoxic–ischemic encephalopathy and there was no increase in major disability among survivors.
Abstract: background Hypothermia is protective against brain injury after asphyxiation in animal models. However, the safety and effectiveness of hypothermia in term infants with encephalopathy is uncertain. methods We conducted a randomized trial of hypothermia in infants with a gestational age of at least 36 weeks who were admitted to the hospital at or before six hours of age with either severe acidosis or perinatal complications and resuscitation at birth and who had moderate or severe encephalopathy. Infants were randomly assigned to usual care (control group) or whole-body cooling to an esophageal temperature of 33.5°C for 72 hours, followed by slow rewarming (hypothermia group). Neurodevelopmental outcome was assessed at 18 to 22 months of age. The primary outcome was a combined end point of death or moderate or severe disability. results Of 239 eligible infants, 102 were assigned to the hypothermia group and 106 to the control group. Adverse events were similar in the two groups during the 72 hours of cooling. Primary outcome data were available for 205 infants. Death or moderate or severe disability occurred in 45 of 102 infants (44 percent) in the hypothermia group and 64 of 103 infants (62 percent) in the control group (risk ratio, 0.72; 95 percent confidence interval, 0.54 to 0.95; P=0.01). Twenty-four infants (24 percent) in the hypothermia group and 38 (37 percent) in the control group died (risk ratio, 0.68; 95 percent confidence interval, 0.44 to 1.05; P=0.08). There was no increase in major disability among survivors; the rate of cerebral palsy was 15 of 77 (19 percent) in the hypothermia group as compared with 19 of 64 (30 percent) in the control group (risk ratio, 0.68; 95 percent confidence interval, 0.38 to 1.22; P=0.20). conclusions Whole-body hypothermia reduces the risk of death or disability in infants with moderate or severe hypoxic–ischemic encephalopathy.
2,311 citations
TL;DR: The molecular relationships and physiological functions of these calcium channel proteins are presented and comprehensive information on their molecular, genetic, physiological, and pharmacological properties is provided.
Abstract: The family of voltage-gated sodium channels initiates action potentials in all types of excitable cells. Nine members of the voltage-gated sodium channel family have been characterized in mammals, and a 10th member has been recognized as a related protein. These distinct sodium channels have similar structural and functional properties, but they initiate action potentials in different cell types and have distinct regulatory and pharmacological properties. This article presents the molecular relationships and physiological roles of these sodium channel proteins and provides comprehensive information on their molecular, genetic, physiological, and pharmacological properties.
2,199 citations
TL;DR: A theoretical framework is presented to guide research and theory examining informant discrepancies in the clinic setting and theoretically driven attention to conceptualizing informant discrepancies across informant pairs is focused on.
Abstract: Discrepancies often exist among different informants' (e.g., parents, children, teachers) ratings of child psychopathology. Informant discrepancies have an impact on the assessment, classification, and treatment of childhood psychopathology. Empirical work has identified informant characteristics that may influence informant discrepancies. Limitations of previous work include inconsistent measurement of informant discrepancies and, perhaps most importantly, the absence of a theoretical framework to guide research. In this article, the authors present a theoretical framework (the Attribution Bias Context Model) to guide research and theory examining informant discrepancies in the clinic setting. Needed directions for future research and theory include theoretically driven attention to conceptualizing informant discrepancies across informant pairs (e.g., parent-teacher, mother-father, parent-child, teacher-child) as well as developing experimental approaches to decrease informant discrepancies in the clinic setting.
2,092 citations
TL;DR: Emerging evidence supports the potentially unifying hypothesis that both of these prominent features of type 2 diabetes are caused by mitochondrial dysfunction.
Abstract: Maintenance of normal blood glucose levels depends on a complex interplay between the insulin responsiveness of skeletal muscle and liver and glucose-stimulated insulin secretion by pancreatic β cells. Defects in the former are responsible for insulin resistance, and defects in the latter are responsible for progression to hyperglycemia. Emerging evidence supports the potentially unifying hypothesis that both of these prominent features of type 2 diabetes are caused by mitochondrial dysfunction.
1,868 citations
TL;DR: The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2,FGFR3 and FGFR4.
TL;DR: It is shown that protective immunity mediated by Nod2 recognition of bacterial muramyl dipeptide is abolished in Nod1-deficient mice, providing a possible mechanism for Nod 2 mutations in CD.
Abstract: The gene encoding the Nod2 protein is frequently mutated in Crohn's disease (CD) patients, although the physiological function of Nod2 in the intestine remains elusive. Here we show that protective immunity mediated by Nod2 recognition of bacterial muramyl dipeptide is abolished in Nod2-deficient mice. These animals are susceptible to bacterial infection via the oral route but not through intravenous or peritoneal delivery. Nod2 is required for the expression of a subgroup of intestinal anti-microbial peptides, known as cryptdins. The Nod2 protein is thus a critical regulator of bacterial immunity within the intestine, providing a possible mechanism for Nod2 mutations in CD.
TL;DR: Vitamin E had no benefit in patients with mild cognitive impairment and donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, a finding supported by the secondary outcome measures.
Abstract: background Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer’s disease. methods In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer’s disease; secondary outcomes were cognition and function. results A total of 769 subjects were enrolled, and possible or probable Alzheimer’s disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer’s disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer’s disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P=0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer’s disease during the first 12 months of the study (P=0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E e 4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer’s disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E e 4 carriers. conclusions Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer’s disease during the first 12 months of treatment, the rate of progression to Alzheimer’s disease after three years was not lower among patients treated with donepezil than among those given placebo.
TL;DR: The mesenchymal stromal cells (MSC) as mentioned in this paper have been proposed as a more scientifically correct nomenclature for the fibroblast-like cells, regardless of the tissue from which they are isolated.
TL;DR: The process of iterating or diffusing the Markov matrix is seen as a generalization of some aspects of the Newtonian paradigm, in which local infinitesimal transitions of a system lead to global macroscopic descriptions by integration.
Abstract: We provide a framework for structural multiscale geometric organization of graphs and subsets of R(n). We use diffusion semigroups to generate multiscale geometries in order to organize and represent complex structures. We show that appropriately selected eigenfunctions or scaling functions of Markov matrices, which describe local transitions, lead to macroscopic descriptions at different scales. The process of iterating or diffusing the Markov matrix is seen as a generalization of some aspects of the Newtonian paradigm, in which local infinitesimal transitions of a system lead to global macroscopic descriptions by integration. We provide a unified view of ideas from data analysis, machine learning, and numerical analysis.
Wellcome Trust Sanger Institute1, J. Craig Venter Institute2, George Washington University3, University of Glasgow4, University of Oxford5, Newcastle University6, University of Bordeaux7, University of Cambridge8, Oregon Health & Science University9, University of Dundee10, Imperial College London11, Case Western Reserve University12, Yale University13, Université catholique de Louvain14, University of Iowa15, Wellcome Trust16
TL;DR: Comparisons of the cytoskeleton and endocytic trafficking systems of Trypanosoma brucei with those of humans and other eukaryotic organisms reveal major differences.
Abstract: African trypanosomes cause human sleeping sickness and livestock trypanosomiasis in sub-Saharan Africa. We present the sequence and analysis of the 11 megabase-sized chromosomes of Trypanosoma brucei. The 26-megabase genome contains 9068 predicted genes, including ∼900 pseudogenes and ∼1700 T. brucei–specific genes. Large subtelomeric arrays contain an archive of 806 variant surface glycoprotein (VSG) genes used by the parasite to evade the mammalian immune system. Most VSG genes are pseudogenes, which may be used to generate expressed mosaic genes by ectopic recombination. Comparisons of the cytoskeleton and endocytic trafficking systems with those of humans and other eukaryotic organisms reveal major differences. A comparison of metabolic pathways encoded by the genomes of T. brucei, T. cruzi, and Leishmania major reveals the least overall metabolic capability in T. brucei and the greatest in L. major. Horizontal transfer of genes of bacterial origin has contributed to some of the metabolic differences in these parasites, and a number of novel potential drug targets have been identified.
TL;DR: Between-group differences in prefrontal cortical thickness were most pronounced in older participants, suggesting that meditation might offset age-related cortical thinning, and data provide the first structural evidence for experience-dependent cortical plasticity associated with meditation practice.
Abstract: Previous research indicates that long-term meditation practice is associated with altered resting electroencephalogram patterns, suggestive of long lasting changes in brain activity. We hypothesized that meditation practice might also be associated with changes in the brain’s physical structure. Magnetic resonance imaging was used to assess cortical thickness in 20 participants with extensive Insight meditation experience, which involves focused attention to internal experiences. Brain regions associated with attention, interoception and sensory processing were thicker in meditation participants than matched controls, including the prefrontal cortex and right anterior insula. Between-group diierences in prefrontal cortical thickness were most pronounced in older participants, suggesting that meditation might oiset age-related cortical thinning. Finally, the thickness of two regions correlated with meditation experience. These data provide the ¢rst structural evidence for experience-dependent cortical plasticity associated with meditation practice. NeuroReport 16:1893^1897 � c 2005 Lippincott Williams & Wilkins.
TL;DR: The fMRI results suggest that the functional contrasts within this single task differentially activate three separable anatomical networks related to the components of attention.
TL;DR: It is suggested that MITF represents a distinct class of ‘ lineage survival’ or ‘lineage addiction’ oncogenes required for both tissue-specific cancer development and tumour progression, and Targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic avenue into melanoma, a highly chemotherapy-resistant neoplasm.
Abstract: Systematic analyses of cancer genomes promise to unveil patterns of genetic alterations linked to the genesis and spread of human cancers. High-density single-nucleotide polymorphism (SNP) arrays enable detailed and genome-wide identification of both loss-of-heterozygosity events and copy-number alterations in cancer. Here, by integrating SNP array-based genetic maps with gene expression signatures derived from NCI60 cell lines, we identified the melanocyte master regulator MITF (microphthalmia-associated transcription factor) as the target of a novel melanoma amplification. We found that MITF amplification was more prevalent in metastatic disease and correlated with decreased overall patient survival. BRAF mutation and p16 inactivation accompanied MITF amplification in melanoma cell lines. Ectopic MITF expression in conjunction with the BRAF(V600E) mutant transformed primary human melanocytes, and thus MITF can function as a melanoma oncogene. Reduction of MITF activity sensitizes melanoma cells to chemotherapeutic agents. Targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic avenue into melanoma, a highly chemotherapy-resistant neoplasm. Together, these data suggest that MITF represents a distinct class of 'lineage survival' or 'lineage addiction' oncogenes required for both tissue-specific cancer development and tumour progression.
TL;DR: It is found that application of amyloid-β promoted endocytosis of NMDA receptors in cortical neurons, indicating a new mechanism by which amyloids-β can cause synaptic dysfunction and contribute to Alzheimer disease pathology.
Abstract: Amyloid-beta peptide is elevated in the brains of patients with Alzheimer disease and is believed to be causative in the disease process. Amyloid-beta reduces glutamatergic transmission and inhibits synaptic plasticity, although the underlying mechanisms are unknown. We found that application of amyloid-beta promoted endocytosis of NMDA receptors in cortical neurons. In addition, neurons from a genetic mouse model of Alzheimer disease expressed reduced amounts of surface NMDA receptors. Reducing amyloid-beta by treating neurons with a gamma-secretase inhibitor restored surface expression of NMDA receptors. Consistent with these data, amyloid-beta application produced a rapid and persistent depression of NMDA-evoked currents in cortical neurons. Amyloid-beta-dependent endocytosis of NMDA receptors required the alpha-7 nicotinic receptor, protein phosphatase 2B (PP2B) and the tyrosine phosphatase STEP. Dephosphorylation of the NMDA receptor subunit NR2B at Tyr1472 correlated with receptor endocytosis. These data indicate a new mechanism by which amyloid-beta can cause synaptic dysfunction and contribute to Alzheimer disease pathology.
TL;DR: A constant supply of oxygen is indispensable for cardiac viability and function, and oxygen is a major determinant of cardiac gene expression, and a critical participant in the formation of ROS and numerous other cellular processes.
Abstract: A constant supply of oxygen is indispensable for cardiac viability and function. However, the role of oxygen and oxygen-associated processes in the heart is complex, and they and can be either beneficial or contribute to cardiac dysfunction and death. As oxygen is a major determinant of cardiac gene expression, and a critical participant in the formation of ROS and numerous other cellular processes, consideration of its role in the heart is essential in understanding the pathogenesis of cardiac dysfunction.
TL;DR: The authors used a global climate model to compare the effectiveness of many climate forcing agents for producing climate change and found that replacing traditional instantaneous and adjusted forcings with an easily computed alternative, Fs, yields a better predictor of climate change, i.e., its efficacies are closer to unity.
Abstract: [1] We use a global climate model to compare the effectiveness of many climate forcing agents for producing climate change. We find a substantial range in the “efficacy” of different forcings, where the efficacy is the global temperature response per unit forcing relative to the response to CO2 forcing. Anthropogenic CH4 has efficacy ∼110%, which increases to ∼145% when its indirect effects on stratospheric H2O and tropospheric O3 are included, yielding an effective climate forcing of ∼0.8 W/m2 for the period 1750–2000 and making CH4 the largest anthropogenic climate forcing other than CO2. Black carbon (BC) aerosols from biomass burning have a calculated efficacy ∼58%, while fossil fuel BC has an efficacy ∼78%. Accounting for forcing efficacies and for indirect effects via snow albedo and cloud changes, we find that fossil fuel soot, defined as BC + OC (organic carbon), has a net positive forcing while biomass burning BC + OC has a negative forcing. We show that replacement of the traditional instantaneous and adjusted forcings, Fi and Fa, with an easily computed alternative, Fs, yields a better predictor of climate change, i.e., its efficacies are closer to unity. Fs is inferred from flux and temperature changes in a fixed-ocean model run. There is remarkable congruence in the spatial distribution of climate change, normalized to the same forcing Fs, for most climate forcing agents, suggesting that the global forcing has more relevance to regional climate change than may have been anticipated. Increasing greenhouse gases intensify the Hadley circulation in our model, increasing rainfall in the Intertropical Convergence Zone (ITCZ), Eastern United States, and East Asia, while intensifying dry conditions in the subtropics including the Southwest United States, the Mediterranean region, the Middle East, and an expanding Sahel. These features survive in model simulations that use all estimated forcings for the period 1880–2000. Responses to localized forcings, such as land use change and heavy regional concentrations of BC aerosols, include more specific regional characteristics. We suggest that anthropogenic tropospheric O3 and the BC snow albedo effect contribute substantially to rapid warming and sea ice loss in the Arctic. As a complement to a priori forcings, such as Fi, Fa, and Fs, we tabulate the a posteriori effective forcing, Fe, which is the product of the forcing and its efficacy. Fe requires calculation of the climate response and introduces greater model dependence, but once it is calculated for a given amount of a forcing agent it provides a good prediction of the response to other forcing amounts.
TL;DR: The purpose of this document is to provide a single resource on current standards of care pertaining specifically to children and adolescents with type 1 diabetes.
Abstract: During recent years, the American Diabetes Association (ADA) has published detailed guidelines and recommendations for the management of diabetes in the form of technical reviews, position statements, and consensus statements. Recommendations regarding children and adolescents have generally been included as only a minor portion of these documents. For example, the most recent ADA position statement on “Standards of Medical Care for Patients With Diabetes Mellitus” (last revised October 2003) included “special considerations” for children and adolescents (1). Other position statements included age-specific recommendations for screening for nephropathy (2) and retinopathy (3) in children with diabetes. In addition, the ADA has published guidelines pertaining to certain aspects of diabetes that apply exclusively to children and adolescents, including care of children with diabetes at school (4) and camp (5) and a consensus statement on type 2 diabetes in children and adolescents (6).
The purpose of this document is to provide a single resource on current standards of care pertaining specifically to children and adolescents with type 1 diabetes. It is not meant to be an exhaustive compendium on all aspects of the management of pediatric diabetes. However, relevant references are provided and current works in progress are indicated as such. The information provided is based on evidence from published studies whenever possible and, when not, supported by expert opinion or consensus (7). Several excellent detailed guidelines and chapters on type 1 diabetes in pediatric endocrinology texts exist, including those by the International Society of Pediatric and Adolescent Diabetes (ISPAD) (8), by the Australian Pediatric Endocrine Group (www.chw.edu/au/prof/services/endocrinology/apeg), in Lifshitz’s Pediatric Endocrinology (9–11), and by Plotnick and colleagues (12,13).
Children have characteristics and needs that dictate different standards of care. The management of diabetes in children must take the major differences between children of various ages and …
TL;DR: It is reported that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury and epithelial cell apoptosis after lung injury.
Abstract: Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88(-/-) and Tlr4(-/-)Tlr2(-/-) mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell-specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell-surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-kappaB. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.
TL;DR: The conversion of truly naive CD4+ T cells into suppressor cells expressing Foxp3 is reported by targeting of peptide-agonist ligands to dendritic cells and by analysis of Foxp 3 expression at the level of single cells, showing that conversion was achieved by minute antigen doses with suboptimal dendrite cell activation.
Abstract: Evidence suggests that regulatory T cells expressing the transcription factor Foxp3 develop extrathymically and intrathymically. Mechanisms of extrathymic induction require further scrutiny, especially as proliferation and/or phenotypic changes of preexisting suppressor cells must be distinguished from true de novo generation. Here we report the conversion of truly naive CD4+ T cells into suppressor cells expressing Foxp3 by targeting of peptide-agonist ligands to dendritic cells and by analysis of Foxp3 expression at the level of single cells. We show that conversion was achieved by minute antigen doses with suboptimal dendritic cell activation. The addition of transforming growth factor-β or the absence of interleukin 2 production, which reduces proliferation, enhanced the conversion rate. In addition, regulatory T cell populations induced in subimmunogenic conditions could subsequently be expanded by delivery of antigen in immunogenic conditions. The extrathymic generation and proliferation of regulatory T cells may contribute to self-tolerance as well as the poor immunogenicity of tumors and may be exploited clinically to prevent or reverse unwanted immunity.
TL;DR: Emerging evidence suggests that strategies that exploit regional differences in upstream factors or that target specific CREB-regulated genes, rather than CREB itself, could make a promising contribution to the treatment of neuropsychiatric conditions.
TL;DR: In this paper, the authors analyze the strategic interaction between machines and voters as an iterated prisoners' dilemma game with one-sided uncertainty and generate hypotheses about the impact of the machine's capacity to monitor voters, and of voters' incomes and ideological stances, on the effectiveness of machine politics.
Abstract: Political machines (or clientelist parties) mobilize electoral support by trading particularistic benefits to voters in exchange for their votes. But if the secret ballot hides voters' actions from the machine, voters are able to renege, accepting benefits and then voting as they choose. To explain how machine politics works, I observe that machines use their deep insertion into voters' social networks to try to circumvent the secret ballot and infer individuals' votes. When parties influence how people vote by threatening to punish them for voting for another party, I call this accountability. I analyze the strategic interaction between machines and voters as an iterated prisoners' dilemma game with one-sided uncertainty. The game generates hypotheses about the impact of the machine's capacity to monitor voters, and of voters' incomes and ideological stances, on the effectiveness of machine politics. I test these hypotheses with data from Argentina.
TL;DR: These key transcription factors T-bet and eomesodermin link the long-term renewal of memory CD8+ T cells to their characteristic effector potency, and are responsible for inducing enhanced expression of CD122, the receptor specifying interleukin 15 responsiveness.
Abstract: Two seemingly unrelated hallmarks of memory CD8(+) T cells are cytokine-driven proliferative renewal after pathogen clearance and a latent effector program in anticipation of rechallenge. Memory CD8(+) T cells and natural killer cells share cytotoxic potential and dependence on the growth factor interleukin 15. We now show that mice with compound mutations of the genes encoding the transcription factors T-bet and eomesodermin were nearly devoid of several lineages dependent on interleukin 15, including memory CD8(+) T cells and mature natural killer cells, and that their cells had defective cytotoxic effector programming. Moreover, T-bet and eomesodermin were responsible for inducing enhanced expression of CD122, the receptor specifying interleukin 15 responsiveness. Therefore, these key transcription factors link the long-term renewal of memory CD8(+) T cells to their characteristic effector potency.
TL;DR: This review concentrates on the properties of antigen-presenting cells, especially those aspects of their overall organization, regulation, and intracellular transport that both facilitate and modulate the processing of protein antigens.
Abstract: The conversion of exogenous and endogenous proteins into immunogenic peptides recognized by T lymphocytes involves a series of proteolytic and other enzymatic events culminating in the formation of peptides bound to MHC class I or class II molecules. Although the biochemistry of these events has been studied in detail, only in the past few years has similar information begun to emerge describing the cellular context in which these events take place. This review thus concentrates on the properties of antigen-presenting cells, especially those aspects of their overall organization, regulation, and intracellular transport that both facilitate and modulate the processing of protein antigens. Emphasis is placed on dendritic cells and the specializations that help account for their marked efficiency at antigen processing and presentation both in vitro and, importantly, in vivo. How dendritic cells handle antigens is likely to be as important a determinant of immunogenicity and tolerance as is the nature of the antigens themselves.
TL;DR: As the severity of BPD identified by the consensus definition worsened, the incidence of those outcomes and of selected adverse neurodevelopmental outcomes increased in the infants who were seen at follow-up, and the consensus BPD definition was identified more accurately than other definitions.
Abstract: Objective. A number of definitions of bronchopulmonary dysplasia (BPD), or chronic lung dis- ease, have been used. A June 2000 National Institute of Child Health and Human Development/National Heart, Lung, and Blood Institute Workshop proposed a severity- based definition of BPD for infants 28 days but not at 36 weeks' postmenstrual age (PMA) or discharge, moderate BPD as O2 for >28 days plus treatment with 28 days plus >30% O2 and/or positive pressure at 36 weeks' PMA. The objective of this study was to determine the predictive validity of the severity-based, consensus definition of BPD. Methods. Data from 4866 infants (birth weight <1000 g, GA <32 weeks, alive at 36 weeks' PMA) who were entered into the National Institute of Child Health and Human Development Neonatal Research Network Very Low Birth weight (VLBW) Infant Registry between Jan- uary 1, 1995 and December 31, 1999, were linked to data from the Network Extremely Low Birth Weight (ELBW) Follow-up Program, in which surviving ELBW infants have a neurodevelopmental and health assessment at 18 to 22 months' corrected age. Linked VLBW Registry and Follow-up data were available for 3848 (79%) infants. Selected follow-up outcomes (use of pulmonary medica- tions, rehospitalization for pulmonary causes, receipt of respiratory syncytial virus prophylaxis, and neurodevel- opmental abnormalities) were compared among infants who were identified with BPD defined as O2 for 28 days (28 days definition), as O2 at 36 weeks' PMA (36 weeks' definition), and with the consensus definition of BPD. Results. A total of 77% of the neonates met the 28- days definition, and 44% met the 36-weeks definition. Using the consensus BPD definition, 77% of the infants had BPD, similar to the cohort identified by the 28-days definition. A total of 46% of the infants met the moderate (30%) or severe (16%) consensus definition criteria, iden- tifying a similar cohort of infants as the 36-weeks defi- nition. Of infants who met the 28-days definition and 36-weeks definition and were seen at follow-up at 18 to 22 months' corrected age, 40% had been treated with pulmonary medications and 35% had been rehospital- ized for pulmonary causes. In contrast, as the severity of BPD identified by the consensus definition worsened, the incidence of those outcomes and of selected adverse neurodevelopmental outcomes increased in the infants who were seen at follow-up. Conclusion. The consensus BPD definition identifies a spectrum of risk for adverse pulmonary and neurode- velopmental outcomes in early infancy more accurately than other definitions. Pediatrics 2005;116:1353-1360; bronchopulmonary dysplasia, chronic lung disease, ex- tremely preterm infants, neurodevelopmental.