RESUMO
BACKGROUND: Same-day HIV testing and antiretroviral therapy (ART) initiation is being widely implemented. However, the optimal timing of ART among patients with tuberculosis (TB) symptoms is unknown. We hypothesized that same-day treatment (TB treatment for those diagnosed with TB; ART for those not diagnosed with TB) would be superior to standard care in this population. METHODS AND FINDINGS: We conducted an open-label trial among adults with TB symptoms at initial HIV diagnosis at GHESKIO in Haiti; participants were recruited and randomized on the same day. Participants were randomized in a 1:1 ratio to same-day treatment (same-day TB testing with same-day TB treatment if TB diagnosed; same-day ART if TB not diagnosed) versus standard care (initiating TB treatment within 7 days and delaying ART to day 7 if TB not diagnosed). In both groups, ART was initiated 2 weeks after TB treatment. The primary outcome was retention in care with 48-week HIV-1 RNA <200 copies/mL, with intention to treat (ITT) analysis. From November 6, 2017 to January 16, 2020, 500 participants were randomized (250/group); the final study visit occurred on March 1, 2021. Baseline TB was diagnosed in 40 (16.0%) in the standard and 48 (19.2%) in the same-day group; all initiated TB treatment. In the standard group, 245 (98.0%) initiated ART at median of 9 days; 6 (2.4%) died, 15 (6.0%) missed the 48-week visit, and 229 (91.6%) attended the 48-week visit. Among all who were randomized, 220 (88.0%) received 48-week HIV-1 RNA testing; 168 had <200 copies/mL (among randomized: 67.2%; among tested: 76.4%). In the same-day group, 249 (99.6%) initiated ART at median of 0 days; 9 (3.6%) died, 23 (9.2%) missed the 48-week visit, and 218 (87.2%) attended the 48-week visit. Among all who were randomized, 211 (84.4%) received 48-week HIV-1 RNA; 152 had <200 copies/mL (among randomized: 60.8%; among tested: 72.0%). There was no difference between groups in the primary outcome (60.8% versus 67.2%; risk difference: -0.06; 95% CI [-0.15, 0.02]; p = 0.14). Two new grade 3 or 4 events were reported per group; none were judged to be related to the intervention. The main limitation of this study is that it was conducted at a single urban clinic, and the generalizability to other settings is uncertain. CONCLUSIONS: In patients with TB symptoms at HIV diagnosis, we found that same-day treatment was not associated with superior retention and viral suppression. In this study, a short delay in ART initiation did not appear to compromise outcomes. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov NCT03154320.
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Fármacos Anti-HIV , Infecções por HIV , Tuberculose , Adulto , Humanos , Fármacos Anti-HIV/uso terapêutico , Haiti/epidemiologia , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Tuberculose/complicações , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , RNARESUMO
In this consensus statement, we provide updated recommendations on multiple sclerosis (MS) management during the COVID-19 crisis and the post-pandemic period applicable to neurology services around the world. Statements/recommendations were generated based on available literature and the experience of 13 MS expert panelists using a modified Delphi approach online. The statements/recommendations give advice regarding implementation of telemedicine; use of disease-modifying therapies and management of MS relapses; management of people with MS at highest risk from COVID-19; management of radiological monitoring; use of remote pharmacovigilance; impact on MS research; implications for lowest income settings, and other key issues.
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COVID-19/epidemiologia , COVID-19/terapia , Internacionalidade , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/terapia , Guias de Prática Clínica como Assunto/normas , Gerenciamento Clínico , Humanos , Pandemias/prevenção & controle , Farmacovigilância , Telemedicina/normas , Telemedicina/tendênciasRESUMO
OBJECTIVES: To determine how continuous spike and wave during slow wave sleep (CSWS) is currently managed and to compare the effectiveness of current treatment strategies using a database from 11 pediatric epilepsy centers in the US. STUDY DESIGN: This retrospective study gathered information on baseline clinical characteristics, CSWS etiology, and treatment(s) in consecutive patients seen between 2014 and 2016 at 11 epilepsy referral centers. Treatments were categorized as benzodiazepines, steroids, other antiseizure medications (ASMs), or other therapies. Two measures of treatment response (clinical improvement as noted by the treating physician; and electroencephalography improvement) were compared across therapies, controlling for baseline variables. RESULTS: Eighty-one children underwent 153 treatment trials during the study period (68 trials of benzodiazepines, 25 of steroids, 45 of ASMs, 14 of other therapies). Children most frequently received benzodiazepines (62%) or ASMs (27%) as first line therapy. Treatment choice did not differ based on baseline clinical variables, nor did these variables correlate with outcome. After adjusting for baseline variables, children had a greater odds of clinical improvement with benzodiazepines (OR 3.32, 95%CI 1.57-7.04, P = .002) or steroids (OR 4.04, 95%CI 1.41-11.59, P = .01) than with ASMs and a greater odds of electroencephalography improvement after steroids (OR 3.36, 95% CI 1.09-10.33, P = .03) than after ASMs. CONCLUSIONS: Benzodiazepines and ASMs are the most frequent initial therapy prescribed for CSWS in the US. Our data suggests that ASMs are inferior to benzodiazepines and steroids and support earlier use of these therapies. Multicenter prospective studies that rigorously assess treatment protocols and outcomes are needed.
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Anticonvulsivantes/uso terapêutico , Benzodiazepinas/uso terapêutico , Síndromes Epilépticas/tratamento farmacológico , Padrões de Prática Médica/estatística & dados numéricos , Sono de Ondas Lentas/efeitos dos fármacos , Esteroides/uso terapêutico , Adolescente , Anticonvulsivantes/farmacologia , Benzodiazepinas/farmacologia , Criança , Pré-Escolar , Esquema de Medicação , Eletroencefalografia , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Esteroides/farmacologia , Resultado do Tratamento , Estados UnidosRESUMO
Moniliophthora perniciosa is a fungal pathogen and causal agent of the witches' broom disease of cocoa, a threat to the chocolate industry and to the economic and social security in cocoa-planting countries. The membrane-bound enzyme alternative oxidase (MpAOX) is crucial for pathogen survival; however a lack of information on the biochemical properties of MpAOX hinders the development of novel fungicides. In this study, we purified and characterised recombinant MpAOX in dose-response assays with activators and inhibitors, followed by a kinetic characterization both in an aqueous environment and in physiologically-relevant proteoliposomes. We present structure-activity relationships of AOX inhibitors such as colletochlorin B and analogues which, aided by an MpAOX structural model, indicates key residues for protein-inhibitor interaction. We also discuss the importance of the correct hydrophobic environment for MpAOX enzymatic activity. We envisage that such results will guide the future development of AOX-targeting antifungal agents against M. perniciosa, an important outcome for the chocolate industry.
Assuntos
Agaricales/efeitos dos fármacos , Agaricales/genética , Fungicidas Industriais/farmacologia , Proteínas Mitocondriais/genética , Oxirredutases/genética , Proteínas de Plantas/genética , Terpenos/farmacologia , Agaricales/química , Agaricales/enzimologia , Relação Dose-Resposta a Droga , Cinética , Proteínas Mitocondriais/antagonistas & inibidores , Proteínas Mitocondriais/química , Proteínas Mitocondriais/metabolismo , Oxirredutases/antagonistas & inibidores , Oxirredutases/química , Oxirredutases/metabolismo , Proteínas de Plantas/antagonistas & inibidores , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMO
BACKGROUND: Although there are theoretical reasons for believing that asthma and atopy may be negatively correlated with tuberculosis, epidemiological studies have had conflicting findings. OBJECTIVE: To determine if people with confirmed tuberculosis were less likely to be atopic and less likely to have atopic disease including asthma compared to those with no previous tuberculosis. METHODS: Patients in Lima, Peru with a prior history of tuberculosis were identified from clinic records in this cohort study. A representative sample of individuals without a prior tuberculosis diagnosis was recruited from the same community. Allergen skin prick testing was performed to classify atopic status. Allergic rhinitis was identified by history. Asthma was defined by symptoms and spirometry. Eosinophilic airway inflammation was measured using exhaled nitric oxide levels. RESULTS: We evaluated 177 patients with, and 161 individuals without, previous tuberculosis. There was a lower prevalence of atopy among people with prior tuberculosis on univariate analysis (odds ratio 0.57; 95% confidence interval 0.37-0.88) but, after adjustment for potential confounders, this was no longer statistically significant (aOR 0.64, 95% CI 0.41-1.01). The prevalence of allergic rhinitis (aOR 0.76, 95% CI 0.47 to 1.24 and asthma (aOR 1.18, 95% CI 0.69 to 2.00) did not differ significantly between the two groups. We also found no significant difference in the prevalence of elevated exhaled nitric oxide (aOR 1.30, 95% CI 0.78 to 2.17) or a combined index of atopic disease (aOR 0.86, 95% CI 0.54 to 1.36). CONCLUSION: In this urban environment in a middle-income country, prior tuberculosis may be associated with a reduced risk of atopy but does not protect against asthma and atopic disease.
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Asma/epidemiologia , Hipersensibilidade Imediata/epidemiologia , Rinite Alérgica/epidemiologia , Tuberculose/epidemiologia , Adulto , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Peru/epidemiologia , Prevalência , Testes Cutâneos , Espirometria , Adulto JovemRESUMO
OBJECTIVE: Family conflict is related to depression, difficulties with treatment adherence and glycemic control, in adolescents with type 1 diabetes (T1D). We examined the psychometric properties of a parent-rated family conflict measure and the most frequent behaviors endorsed by caregivers of these youths. METHODS: Participants were 51 caregivers (86.27% women) of adolescents (aged 12-17) with T1D, recruited during a psychotherapy study for youth depression. Both (caregivers and youths) completed questionnaires during the eligibility evaluation. Caregivers completed the Conflict subscale of the Family Environment Scale, considering to what extent its items described their whole family or its majority. RESULTS: The most frequent indicators of conflict where becoming upset, displaying anger openly, believing that something can be achieved by speaking loudly, and criticizing and fighting, although not physically. Internal consistency for the subscale when rating conflict indicators in a dichotomous format was .69 and .76 when rated in an ordinal format. Conflict scores correlated moderately and significantly (p less than or equal .05) with other measures completed by youths and caregivers. Caregivers of youths with the worst glycemic control reported the highest levels of conflict. The subscale also showed a satisfactory sensitivity to change by reflecting a significant reduction in caregivers' reports of family conflict after adolescent group treatment. CONCLUSION: Our results confirm the frequent occurrence of conflict (especially verbal conflict) in these families and document the psychometric properties of a measure for its assessment, which may be useful in studies that examine the impact of family conflict in both youth depression and diabetes.
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Depressão/epidemiologia , Diabetes Mellitus Tipo 1/psicologia , Conflito Familiar/psicologia , Hispânico ou Latino/psicologia , Adolescente , Adulto , Glicemia/metabolismo , Cuidadores/psicologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pais/psicologia , Psicometria , Inquéritos e QuestionáriosRESUMO
Ectothermic species are particularly sensitive to changes in temperature and may adapt to changes in thermal environments through evolutionary shifts in thermal physiology or thermoregulatory behaviour. Nevertheless, the heritability of thermal traits, which sets a limit on evolutionary potential, remains largely unexplored. In this study, we captured brown anole lizards (Anolis sagrei) from two populations that occur in contrasting thermal environments. We raised offspring from these populations in a laboratory common garden and compared the shape of their thermal performance curves to test for genetic divergence in thermal physiology. Thermal performance curves differed between populations in a common garden in ways partially consistent with divergent patterns of natural selection experienced by the source populations, implying that they had evolved in response to selection. Next, we estimated the heritability of thermal performance curves and of several traits related to thermoregulatory behaviour. We did not detect significant heritability in most components of the thermal performance curve or in several aspects of thermoregulatory behaviour, suggesting that contemporary selection is unlikely to result in rapid evolution. Our results indicate that the response to selection may be slow in the brown anole and that evolutionary change is unlikely to keep pace with current rates of environmental change.
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Regulação da Temperatura Corporal/genética , Deriva Genética , Lagartos/fisiologia , Animais , Bahamas , Feminino , Lagartos/genética , Masculino , Seleção GenéticaRESUMO
BACKGROUND: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease. METHODS: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants...
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Aspirina , Doença da Artéria Coronariana , Estudos de Casos e Controles , RivaroxabanaRESUMO
Predicting wildfire under future conditions is complicated by complex interrelated drivers operating across large spatial scales. Annual area burned (AAB) is a useful index of global wildfire activity. Current and antecedent seasonal climatic conditions, and the timing of snowpack melt, have been suggested as important drivers of AAB. As climate warms, seasonal climate and snowpack co-vary in intricate ways, influencing fire at continental and sub-continental scales. We used independent records of seasonal climate and snow cover duration (last date of permanent snowpack, LDPS) and cell-based Structural Equation Models (SEM) to separate direct (climatic) and indirect (snow cover) effects on relative changes in AAB under future climatic scenarios across western and boreal North America. To isolate seasonal climate variables with the greatest effect on AAB, we ran multiple regression models of log-transformed AAB on seasonal climate variables and LDPS. We used the results of multiple regressions to project future AAB using GCM ensemble climate variables and LDPS, and validated model predictions with recent AAB trends. Direct influences of spring and winter temperatures on AAB are larger and more widespread than the indirect effect mediated by changes in LDPS in most areas. Despite significant warming trends and reductions in snow cover duration, projected responses of AAB to early-mid 21st century are heterogeneous across the continent. Changes in AAB range from strongly increasing (one order of magnitude increases in AAB) to moderately decreasing (more than halving of baseline AAB). Annual wildfire area burned in coming decades is likely to be highly geographically heterogeneous, reflecting interacting regional and seasonal climate drivers of fire occurrence and spread.
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Modelos Estatísticos , Tempo (Meteorologia) , Incêndios Florestais/estatística & dados numéricos , Clima , Previsões , Humanos , Análise de Regressão , Árvores/crescimento & desenvolvimento , Estados UnidosRESUMO
BACKGROUND: Most analyses of gaps in human resources for health (HRH) do not consider training and the transition of graduates into the labour market. This study aims to explore the labour market for Peru's recent medical, nursing, and midwifery graduates as well as their transition into employment in the Ministry of Health's (MOH) system. METHODS: Data from four different datasets, covering 2007-2013, was used to characterize the patterns of recently trained physicians, nurses, midwives, and postgraduate-trained physicians that enter employment in the MOH system, and scenario analyses were used to describe how this rate of entry needs to adapt in order to fill current HRH shortages. RESULTS: HRH graduates have been increasing from 2007 to 2011, but the proportions that enter employment in the MOH system 2 years later range from 8 to 45% and less than 10% of newly trained medical specialists. Scenario analyses indicate that the gap for physicians and nurses will be met in 2027 and 2024, respectively, while midwives in 2017. However, if the number of HRH graduates entering the MOH system doubles, these gaps could be filled as early as 2020 for physicians and 2019 for nurses. In this latter scenario, the MOH system would still only utilize 56% of newly qualified physicians, 74% of nurses, and 66% of midwives available in the labour market. CONCLUSION: At 2013 training rates, Peru has the number of physicians, nurses, and midwives it needs to address HRH shortages and meet estimated HRH gaps in the national MOH system during the next decade. However, a significant number of newly qualified health professionals do not work for the MOH system within 2 years of graduation. These analyses highlight the importance of building adequate incentive structures to improve the entry and retention of HRH into the public sector.
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Atenção à Saúde , Emprego/tendências , Enfermeiras e Enfermeiros/provisão & distribuição , Médicos/provisão & distribuição , Setor Público , Atenção à Saúde/tendências , Países em Desenvolvimento , Feminino , Pessoal de Saúde , Necessidades e Demandas de Serviços de Saúde , Humanos , Tocologia , Motivação , Enfermeiros Obstétricos/provisão & distribuição , Peru , Gravidez , Recursos HumanosRESUMO
The bacterium Burkholderia ubonensis is commonly co-isolated from environmental specimens harbouring the melioidosis pathogen, Burkholderia pseudomallei. B. ubonensis has been reported in northern Australia and Thailand but not North America, suggesting similar geographic distribution to B. pseudomallei. Unlike most other Burkholderia cepacia complex (Bcc) species, B. ubonensis is considered non-pathogenic, although its virulence potential has not been tested. Antibiotic resistance in B. ubonensis, particularly towards drugs used to treat the most severe B. pseudomallei infections, has also been poorly characterised. This study examined the population biology of B. ubonensis, and includes the first reported isolates from the Caribbean. Phylogenomic analysis of 264 B. ubonensis genomes identified distinct clades that corresponded with geographic origin, similar to B. pseudomallei. A small proportion (4%) of strains lacked the 920kb chromosome III replicon, with discordance of presence/absence amongst genetically highly related strains, demonstrating that the third chromosome of B. ubonensis, like other Bcc species, probably encodes for a nonessential pC3 megaplasmid. Multilocus sequence typing using the B. pseudomallei scheme revealed that one-third of strains lack the "housekeeping" narK locus. In comparison, all strains could be genotyped using the Bcc scheme. Several strains possessed high-level meropenem resistance (≥32 µg/mL), a concern due to potential transmission of this phenotype to B. pseudomallei. In silico analysis uncovered a high degree of heterogeneity among the lipopolysaccharide O-antigen cluster loci, with at least 35 different variants identified. Finally, we show that Asian B. ubonensis isolate RF23-BP41 is avirulent in the BALB/c mouse model via a subcutaneous route of infection. Our results provide several new insights into the biology of this understudied species.
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Antibacterianos/farmacologia , Burkholderia/classificação , Burkholderia/efeitos dos fármacos , Microbiologia Ambiental , Variação Genética , Filogeografia , Tienamicinas/farmacologia , Animais , Austrália , Burkholderia/genética , Burkholderia/isolamento & purificação , Infecções por Burkholderia/microbiologia , Infecções por Burkholderia/patologia , Modelos Animais de Doenças , Genótipo , Meropeném , Camundongos Endogâmicos BALB C , Tipagem de Sequências Multilocus , Antígenos O/genética , Papua Nova Guiné , Porto Rico , Tailândia , VirulênciaRESUMO
BACKGROUND: A trial involving adults 50 years of age or older (ZOE-50) showed that the herpes zoster subunit vaccine (HZ/su) containing recombinant varicella-zoster virus glycoprotein E and the AS01B adjuvant system was associated with a risk of herpes zoster that was 97.2% lower than that associated with placebo. A second trial was performed concurrently at the same sites and examined the safety and efficacy of HZ/su in adults 70 years of age or older (ZOE-70). METHODS: This randomized, placebo-controlled, phase 3 trial was conducted in 18 countries and involved adults 70 years of age or older. Participants received two doses of HZ/su or placebo (assigned in a 1:1 ratio) administered intramuscularly 2 months apart. Vaccine efficacy against herpes zoster and postherpetic neuralgia was assessed in participants from ZOE-70 and in participants pooled from ZOE-70 and ZOE-50. RESULTS: In ZOE-70, 13,900 participants who could be evaluated (mean age, 75.6 years) received either HZ/su (6950 participants) or placebo (6950 participants). During a mean follow-up period of 3.7 years, herpes zoster occurred in 23 HZ/su recipients and in 223 placebo recipients (0.9 vs. 9.2 per 1000 person-years). Vaccine efficacy against herpes zoster was 89.8% (95% confidence interval [CI], 84.2 to 93.7; P<0.001) and was similar in participants 70 to 79 years of age (90.0%) and participants 80 years of age or older (89.1%). In pooled analyses of data from participants 70 years of age or older in ZOE-50 and ZOE-70 (16,596 participants), vaccine efficacy against herpes zoster was 91.3% (95% CI, 86.8 to 94.5; P<0.001), and vaccine efficacy against postherpetic neuralgia was 88.8% (95% CI, 68.7 to 97.1; P<0.001). Solicited reports of injection-site and systemic reactions within 7 days after injection were more frequent among HZ/su recipients than among placebo recipients (79.0% vs. 29.5%). Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two study groups. CONCLUSIONS: In our trial, HZ/su was found to reduce the risks of herpes zoster and postherpetic neuralgia among adults 70 years of age or older. (Funded by GlaxoSmithKline Biologicals; ZOE-50 and ZOE-70 ClinicalTrials.gov numbers, NCT01165177 and NCT01165229 .).
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Vacina contra Herpes Zoster , Herpes Zoster/prevenção & controle , Neuralgia Pós-Herpética/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Herpes Zoster/imunologia , Vacina contra Herpes Zoster/efeitos adversos , Vacina contra Herpes Zoster/imunologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neuralgia Pós-Herpética/epidemiologia , Risco , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
STUDY OBJECTIVES: In addition to enhancing sleep onset and maintenance, a desirable insomnia therapeutic agent would preserve healthy sleep's ability to wake and respond to salient situations while maintaining sleep during irrelevant noise. Dual orexin receptor antagonists (DORAs) promote sleep by selectively inhibiting wake-promoting neuropeptide signaling, unlike global inhibition of central nervous system excitation by gamma-aminobutyric acid (GABA)-A receptor (GABAaR) modulators. We evaluated the effect of DORA versus GABAaR modulators on underlying sleep architecture, ability to waken to emotionally relevant stimuli versus neutral auditory cues, and performance on a sleepiness-sensitive cognitive task upon awakening. METHODS: DORA-22 and GABAaR modulators (eszopiclone, diazepam) were evaluated in adult male rhesus monkeys (n = 34) with continuous polysomnography recordings in crossover studies of sleep architecture, arousability to a classically conditioned salient versus neutral acoustical stimulus, and psychomotor vigilance task (PVT) performance if awakened. RESULTS: All compounds decreased wakefulness, but only DORA-22 sleep resembled unmedicated sleep in terms of underlying sleep architecture, preserved ability to awaken to salient-conditioned acoustic stimuli while maintaining sleep during neutral acoustic stimuli, and no congnitive impairment in PVT performance. Although GABAaR modulators induced lighter sleep, monkeys rarely woke to salient stimuli and PVT performance was impaired if monkeys were awakened. CONCLUSIONS: In nonhuman primates, DORAs' targeted mechanism for promoting sleep protects the ability to selectively arouse to salient stimuli and perform attentional tasks unimpaired, suggesting meaningful differentiation between a hypnotic agent that works through antagonizing orexin wake signaling versus the sedative hypnotic effects of the GABAaR modulator mechanism of action.
Assuntos
Macaca mulatta/fisiologia , Antagonistas dos Receptores de Orexina/farmacologia , Orexinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sono/efeitos dos fármacos , Sono/fisiologia , Vigília/efeitos dos fármacos , Vigília/fisiologia , Animais , Nível de Alerta/efeitos dos fármacos , Condicionamento Clássico , Estudos Cross-Over , Diazepam/farmacologia , Zopiclona/farmacologia , GABAérgicos/farmacologia , Hipnóticos e Sedativos/farmacologia , Masculino , Piperidinas/farmacologia , Polissonografia , Fases do Sono/efeitos dos fármacos , Fases do Sono/fisiologia , Triazóis/farmacologiaRESUMO
Cryptic population structure can increase both type I and type II errors. This is particularly problematic in case-control association studies of unrelated individuals. Some researchers believe that these problems are obviated in families. We argue here that this may not be the case, especially if families are drawn from a known admixed population such as Mexican Americans. We use a principal component approach to evaluate and visualize the results of three different approaches to searching for cryptic structure in the 20 multigenerational families of the Genetic Analysis Workshop 18 (GAW18). Approach 1 uses all family members in the sample to identify what might be considered "outlier" kindreds. Because families are likely to differ in size (in the GAW18 families, there is about a 4-fold difference in the number of typed individuals), approach 2 uses a weighting system that equalizes pedigree size. Approach 3 concentrates on the founders and the "marry-ins" because, in principle, the entire pedigree can be reconstructed with knowledge of the sequence of these unrelated individuals and genome-wide association study (GWAS) data on everyone else (to identify the position of recombinations). We demonstrate that these three approaches can yield very different insights about cryptic structure in a sample of families.
RESUMO
In a recent study, we have shown that in mammary tumors from mice lacking the Cav-1 gene, there are alterations in specific heat shock proteins as well as in tumor development. With this in mind, we have now investigated other proteins in the same mammary mouse tumor model (Her-2/neu expressing mammary tumors from Cav-1 wild type and Cav-1 null mice), to further comprehend the complex tumor-stroma mechanisms involved in regulating stress responses during tumor development. In this tumor model the cancer cells always lacked of Cav-1, so the KO influenced the Cav-1 in the stroma. By immunohistochemistry, we have found a striking co-expression of ß-catenin and Her-2/neu in the tumor cells. The absence of Cav-1 in the tumor stroma had no effect on expression or localization of ß-catenin and Her-2/neu. Both proteins appeared co-localized at the cell surface during tumor development and progression. Since Her-2/neu activation induces MTA1, we next evaluated MTA1 in the mouse tumors. Although this protein was found in numerous nuclei, the absence of Cav-1 did not alter its expression level. In contrast, significantly more PTEN protein was noted in the tumors lacking Cav-1 in the stroma, with the protein localized mainly in the nuclei. P-Akt levels were relatively low in tumors from both Cav-1 WT and Cav-1 KO mice. There was also an increase in nuclear NHERF1 expression levels in the tumors arising from Cav-1 KO mice. The data obtained in the MMTV-neu model are consistent with a role for Cav-1 in adjacent breast cancer stromal cells in modulating the expression and localization of important proteins implicated in tumor cell behavior.
Assuntos
Caveolina 1/metabolismo , Neoplasias Mamárias Animais/metabolismo , Vírus do Tumor Mamário do Camundongo/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfoproteínas/metabolismo , Receptor ErbB-2/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismo , beta Catenina/metabolismo , Animais , Caveolina 1/genética , Feminino , Humanos , Imuno-Histoquímica , Células MCF-7 , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/genética , beta Catenina/genéticaRESUMO
In a previous study, we measured caveolin-1 protein levels, both in the normal breast and in breast cancer. The study revealed no association between caveolin-1 expression in the epithelial compartment and clinical disease outcome. However, high levels of caveolin-1 in the stromal tissue surrounding the tumor associated strongly with reduced metastasis and improved survival. Using an animal model, we found that the onset of mammary tumors driven by Her-2/neu expression was accelerated in mice lacking caveolin-1. We have analysed the heat shock protein (Hsp) response in the tumors of mice lacking caveolin-1. In all cases, the mammary tumors were estrogen and progesterone receptor negative, and the levels of Her-2/neu (evaluated by immunohistochemistry) were not different between the caveolin-1 +/+ (n = 8) and the caveolin-1 -/- (n = 7) tumors. However, a significant reduction in the extent of apoptosis was observed in mammary tumors from animals lacking caveolin-1. While Bcl-2, Bax, and survivin levels in the tumors were not different, the amount of HSPA (Hsp70) was almost double in the caveolin-1 -/- tumors. In contrast, HSPB1 (Hsp27/Hsp25) levels were significantly lower in the caveolin-1 -/- tumors. The mammary tumors from caveolin-1 null mice expressed more HSPC4 (gp96 or grp94), but HSPC1 (Hsp90), HSPA5 (grp78), HSPD1 (Hsp60), and CHOP were not altered. No significant changes in these proteins were found in the stroma surrounding these tumors. These results demonstrate that the disruption of the Cav-1 gene can cause alterations of specific Hsps as well as tumor development.
Assuntos
Adenocarcinoma/metabolismo , Caveolina 1/metabolismo , Proteínas de Choque Térmico/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Animais , Apoptose , Chaperona BiP do Retículo Endoplasmático , Feminino , Imuno-Histoquímica , Camundongos , Receptor ErbB-2/metabolismoRESUMO
PURPOSE: Diarrheal disease is one of the leading causes of morbidity in developing countries. To further understand the epidemiology of diarrheal disease among a rural population surrounding Robillard, Haiti, fecal swabs from patients with diarrhea were screened for the presence of enteropathogenic bacteria. PATIENTS AND METHODS: Fecal swabs were collected from 34 patients with signs and symptoms of diarrhea and stored in BBL™ Cary-Blair transport medium (Becton, Dickinson and Company, Sparks, MD) until transit to the USA. Swab material was inoculated on to different enrichment and selective agars for incubation. Fermenting and nonfermenting bacteria that grew on the enteric selection media were identified by the BBL™ Crystal™ Enteric/Nonferementing Identification system (Becton, Dickinson and Company). Organisms identified as Escherichia coli were further screened for the presence of virulence factors by polymerase chain reaction (PCR). RESULTS: Of 34 patients, no Campylobacter, Shigella, Salmonella, or Vibrio spp. were isolated from swabs transported to the USA for culture. Of 73 E. coli isolates cultured from the swabs, one enteropathogenic strain of E. coli was identified by multiplex PCR. Escherichia fergusonii and Cronobacter sakazakii, both potential gastrointestinal pathogens, were also isolated from patient stools. CONCLUSION: This study was undertaken to determine if bacterial enteropathogens could be detected in the stools of patients suffering from diarrhea or dysentery and, in the absence of sufficient facilities, rectal swabs could be transported to the USA for culture. Although several genera of overt enteropathogens were not detected, one enteropathogenic E. coli and other pathogenic enterobacteriaceae were successfully cultured and identified.
RESUMO
OBJECTIVE: Mitral valve surgery can be performed through the trans-atrial or the trans-septal approach. Although the trans-atrial is the preferred method, the trans-septal approach has also been used recently and has a particular value in beating-heart mitral valve surgery. Herein we report our experience with beating-heart mitral valve surgery via trans-septal approach, and discuss its advantages and pitfalls. METHODS: Between 2000 and 2007, 214 consecutive patients were operated upon utilizing beating heart technique for mitral valve surgery. The operation was performed via transseptal approach with the aorta unclamped, the heart beating, with normal electrocardiogram and in sinus rhythm. RESULTS: Mean age was 56.03 +/- 13.93 years (range: 19-86 years; median: 56 years). There were 131 (61.2%) males and 83 (38.8%) females. Of the prostheses used, 108 (50.5%) were biological, and 39 (18.2%) were mechanical. Mitral repairs were performed in 67 (31.3%) patients. Mean hospital stay was 17.4 +/- 20.0 days (range: 3-135 days; median: 11 days). Intra-aortic balloon pump (IABP) utilization was required in 12 (5.6%) of 214 patients. One-month mortality was 7.4%, and re-operation for bleeding was needed in 15 (7%) patients. CONCLUSIONS: Beating-heart mitral valve surgery is an option for myocardial protection in patients undergoing mitral valve surgery. This technique is facilitated by the trans-septal approach due to reduced aortic insufficiency and improved visualization of the mitral apparatus.
Assuntos
Septos Cardíacos/cirurgia , Implante de Prótese de Valva Cardíaca/métodos , Valva Mitral/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Ponte de Artéria Coronária sem Circulação Extracorpórea/métodos , Feminino , Implante de Prótese de Valva Cardíaca/efeitos adversos , Implante de Prótese de Valva Cardíaca/mortalidade , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Reoperação/estatística & dados numéricos , Resultado do Tratamento , Adulto JovemRESUMO
OBJETIVO: A cirurgia da valva mitral pode ser feita via transatrial ou transeptal. Embora a transatrial seja a preferida, a via transeptal tem sido utilizada mais recentemente e tido um grande valor nas operações com o coração batendo. Mostramos a nossa experiência na cirurgia da valva mitral via transeptal com coração batendo e discutimos seus benefícios e problemas. MÉTODOS: Entre 2000 e 2007, 214 pacientes consecutivos foram operados com o coração batendo. A operação foi feita por via transeptal sem pinçamento da aorta, com o coração batendo e eletrocardiograma normal e em ritmo sinusal. RESULTADOS: A idade média foi de 56,03 ± 13,93 anos (intervalo: 19-86 anos; mediana: 56 anos). Havia 131 (61,2 por cento) pacientes do sexo masculino e 83 (38,8 por cento), do feminino. Foram utilizadas 108 (50,5 por cento) próteses biológicas e 39 (18,2 por cento) mecânicas. Reparo da valva foi feito em 67 (31,3 por cento) pacientes. A estadia hospitalar foi de 17,4 ± 20,0 dias (intervalo: 3-135 dias; mediana: 11 dias). Balão intra-aórtico foi utilizado em 12 (5,6 por cento) pacientes. A mortalidade hospitalar foi de 7,4 por cento. Reoperação para revisão de hemostasia foi necessária em 15 pacientes. CONCLUSÃO: A operação com o coração batendo é uma opção para proteção miocárdica em pacientes submetidos a cirurgia da valva mitral. A técnica é facilitada ao se usar a via transeptal, reduzindo a insuficiência aórtica e melhorando a visualização do aparato mitral.
OBJECTIVE: Mitral valve surgery can be performed through the trans-atrial or the trans-septal approach. Although the trans-atrial is the preferred method, the trans-septal approach has also been used recently and has a particular value in beating-heart mitral valve surgery. Herein we report our experience with beating-heart mitral valve surgery via trans-septal approach, and discuss its advantages and pitfalls. METHODS: Between 2000 and 2007, 214 consecutive patients were operated upon utilizing beating heart technique for mitral valve surgery. The operation was performed via transseptal approach with the aorta unclamped, the heart beating, with normal electrocardiogram and in sinus rhythm. RESULTS: Mean age was 56.03 ± 13.93 years (range: 19-86 years; median: 56 years). There were 131 (61.2 percent) males and 83 (38.8 percent) females. Of the prostheses used, 108 (50.5 percent) were biological, and 39 (18.2 percent) were mechanical. Mitral repairs were performed in 67 (31.3 percent) patients. Mean hospital stay was 17.4 ± 20.0 days (range: 3-135 days; median: 11 days). Intra-aortic balloon pump (IABP) utilization was required in 12 (5.6 percent) of 214 patients. One-month mortality was 7.4 percent, and re-operation for bleeding was needed in 15 (7 percent) patients. CONCLUSIONS: Beating-heart mitral valve surgery is an option for myocardial protection in patients undergoing mitral valve surgery. This technique is facilitated by the trans-septal approach due to reduced aortic insufficiency and improved visualization of the mitral apparatus.