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1.
JAMA Ophthalmol ; 139(8): 896-897, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34196670

RESUMO

Importance: Emerging vision scientists who have yet to be awarded their first independent funding may have their research careers disproportionately affected by early COVID-19-related disruptions. In September 2020, the Alliance for Eye and Vision Research convened a panel of 22 such scientists (nominated by their academic institutions) to communicate to the US Congress about the importance of vision research. As part of the effort, interviews were conducted with scientists about the effect of the pandemic on their research. Observations: Qualitative areas of adverse consequences from the early months of COVID-19 disruptions included striking interruptions of patient-based research, limits on other types of clinical research, loss of research time for scientists with young children (especially women), challenges with animal colonies and cell cultures, impediments to research collaborations, and loss of training time. Conclusions and Relevance: The early months during the COVID-19 pandemic increased career stress on many early-stage investigators in the vision field and delayed (and may potentially derail) their ability to attract their first independent research funding grant. As a result, federal and private granting agencies may need to take these factors into account to retain talented, early-stage vision researchers.


Assuntos
Pesquisa Biomédica/organização & administração , COVID-19/complicações , Escolha da Profissão , Oftalmologia/organização & administração , Pesquisadores/educação , SARS-CoV-2 , Estresse Psicológico/etiologia , Pesquisa Biomédica/educação , Pré-Escolar , Feminino , Humanos , Masculino , Oftalmologia/educação , Quarentena/psicologia , Pesquisadores/psicologia , Apoio à Pesquisa como Assunto/organização & administração , Estresse Psicológico/psicologia , Inquéritos e Questionários , Estados Unidos
2.
Eur Respir J ; 58(1)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33542049

RESUMO

The lung clearance index (LCI) measured by the multiple breath washout (MBW) test is sensitive to early lung disease in children with cystic fibrosis. While LCI worsens during the preschool years in cystic fibrosis, there is limited evidence to clarify whether this continues during the early school age years, and whether the trajectory of disease progression as measured by LCI is modifiable.A cohort of children (healthy and cystic fibrosis) previously studied for 12 months as preschoolers were followed during school age (5-10 years). LCI was measured every 3 months for a period of 24 months using the Exhalyzer D MBW nitrogen washout device. Linear mixed effects regression was used to model changes in LCI over time.A total of 582 MBW measurements in 48 healthy subjects and 845 measurements in 64 cystic fibrosis subjects were available. The majority of children with cystic fibrosis had elevated LCI at the first preschool and first school age visits (57.8% (37 out of 64)), whereas all but six had normal forced expiratory volume in 1 s (FEV1) values at the first school age visit. During school age years, the course of disease was stable (-0.02 units·year-1 (95% CI -0.14-0.10). LCI measured during preschool years, as well as the rate of LCI change during this time period, were important determinants of LCI and FEV1, at school age.Preschool LCI was a major determinant of school age LCI; these findings further support that the preschool years are critical for early intervention strategies.


Assuntos
Fibrose Cística , Testes Respiratórios , Criança , Pré-Escolar , Progressão da Doença , Volume Expiratório Forçado , Humanos , Pulmão , Testes de Função Respiratória
3.
Am J Respir Crit Care Med ; 203(8): 977-986, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33030967

RESUMO

Rationale: The lung clearance index (LCI) is responsive to acute respiratory events in preschool children with cystic fibrosis (CF), but its utility to identify and manage these events in school-age children with CF is not well defined.Objectives: To describe changes in LCI with acute respiratory events in school-age children with CF.Methods: In a multisite prospective observational study, the LCI and FEV1 were measured quarterly and during acute respiratory events. Linear regression was used to compare relative changes in LCI and FEV1% predicted at acute respiratory events. Logistic regression was used to compare the odds of a significant worsening in LCI and FEV1% predicted at acute respiratory events. Generalized estimating equation models were used to account for repeated events in the same subject.Measurements and Main Results: A total of 98 children with CF were followed for 2 years. There were 265 acute respiratory events. Relative to a stable baseline measure, LCI (+8.9%; 95% confidence interval, 6.5 to 11.3) and FEV1% predicted (-6.6%; 95% confidence interval, -8.3 to -5.0) worsened with acute respiratory events. A greater proportion of events had a worsening in LCI compared with a decline in FEV1% predicted (41.7% vs. 30.0%; P = 0.012); 53.9% of events were associated with worsening in LCI or FEV1. Neither LCI nor FEV1 recovered to baseline values at the next follow-up visit.Conclusions: In school-age children with CF, the LCI is a sensitive measure to assess lung function worsening with acute respiratory events and incomplete recovery at follow-up. In combination, the LCI and FEV1 capture a higher proportion of events with functional impairment.


Assuntos
Fibrose Cística/complicações , Fibrose Cística/fisiopatologia , Volume Expiratório Forçado/fisiologia , Pneumopatias/etiologia , Pneumopatias/terapia , Adolescente , Criança , Feminino , Humanos , Indiana , Masculino , Ontário , Estudos Prospectivos , Testes de Função Respiratória
4.
Ann Am Thorac Soc ; 17(9): 1085-1093, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32603187

RESUMO

Rationale: In cystic fibrosis (CF), the lung clearance index (LCI), derived from multiple breath washout (MBW), is more sensitive in detecting early lung disease than FEV1; MBW has been less thoroughly evaluated in young patients with primary ciliary dyskinesia (PCD).Objectives: Our objectives were 1) to evaluate the sensitivity of MBW and spirometry for the detection of mild lung disease in young children with PCD and CF compared with healthy control (HC) subjects and 2) to compare patterns of airway obstruction between disease populations.Methods: We used a multicenter, single-visit, observational study in children with PCD and CF with a forced expiratory volume in 1 second (FEV1) greater than 60% predicted and HC subjects, ages 3-12 years. Nitrogen MBW and spirometry were performed and overread for acceptability. χ2 and Kruskall-Wallis tests compared demographics and lung function measures between groups, linear regression evaluated the effect of disease state, and Spearman's rank correlation coefficient compared the LCI and spirometric measurements.Results: Twenty-five children with PCD, 49 children with CF, and 80 HC children were enrolled, among whom 17 children with PCD (68%), 36 children with CF (73%), and 53 (66%) HC children performed both acceptable spirometry and MBW; these children made up the analytic cohort. The median age was 9.0 years (interquartile range [IQR], 6.8-11.1). The LCI was abnormal (more than 7.8) in 10 of 17 (59%) patients with PCD and 21 of 36 (58%) patients with CF, whereas FEV1 was abnormal in three of 17 (18%) patients with PCD and six of 36 (17%) patients with CF. The LCI was significantly elevated in patients with PCD and CF compared with HC subjects (ratio of geometric mean vs. HC: PCD 1.27; 95% confidence interval [CI], 1.15-1.39; and CF 1.24; 95% CI, 1.15-1.33]). Children with PCD had lower midexpiratory-phase forced expiratory flow % predicted compared with children with CF (62% [IQR, 50-78%] vs. 85% [IQR, 68-99%]; P = 0.05). LCI did not correlate with FEV1.Conclusions: The LCI is more sensitive than FEV1 in detecting lung disease in young patients with PCD, similar to CF. LCI holds promise as a sensitive endpoint for the assessment of early PCD lung disease.

5.
PLoS One ; 15(5): e0232327, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401806

RESUMO

This exploratory mixed methods study describes skills required to be an effective peer reviewer as a member of review panels conducted for federal agencies that fund research, and examines how reviewer experience and the use of technology within such panels impacts reviewer skill development. Two specific review panel formats are considered: in-person face-to-face and virtual video conference. Data were collected through interviews with seven program officers and five expert peer review panelists, and surveys from 51 respondents. Results include the skills reviewers' consider necessary for effective review panel participation, their assessment of the relative importance of these skills, how they are learned, and how review format affects skill development and improvement. Results are discussed relative to the peer review literature and with consideration of the importance of professional skills needed by successful scientists and peer reviewers.


Assuntos
Competência Mental , Revisão da Pesquisa por Pares , Feminino , Humanos , Masculino , Inquéritos e Questionários
6.
ERJ Open Res ; 4(1)2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29707562

RESUMO

The lung clearance index (LCI) from the multiple-breath washout (MBW) test is a promising surveillance tool for pre-school children with cystic fibrosis (CF). Current guidelines for MBW testing recommend that three acceptable trials are required. However, success rates to achieve these criteria are low in children aged <7 years and feasibility may improve with modified pre-school criteria that accepts tests with two acceptable trials. This study aimed to determine if relationships between LCI and clinical outcomes of CF lung disease differ when only two acceptable MBW trials are assessed. Healthy children and children with CF aged 3-6 years were recruited for MBW testing. Children with CF also underwent bronchoalveolar lavage fluid collection and a chest computed tomography scan. MBW feasibility increased from 46% to 75% when tests with two trials were deemed acceptable compared with tests where three acceptable trials were required. Relationships between MBW outcomes and markers of pulmonary inflammation, infection and structural lung disease were not different between tests with three acceptable trials compared with tests with two acceptable trials. This study indicates that pre-school MBW data from two acceptable trials may provide sufficient information on ventilation distribution if three acceptable trials are not possible.

7.
Ann Am Thorac Soc ; 14(10): 1548-1555, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28708417

RESUMO

RATIONALE: The underlying defect in the cystic fibrosis (CF) airway leads to defective mucociliary clearance and impaired bacterial killing, resulting in endobronchial infection and inflammation that contributes to progressive lung disease. Little is known about the respiratory microbiota in the early CF airway and its relationship to inflammation. OBJECTIVES: To examine the bacterial microbiota and inflammatory profiles in bronchoalveolar lavage fluid and oropharyngeal secretions in infants with CF. METHODS: Infants with CF from U.S. and Australian centers were enrolled in a prospective, observational study examining the bacterial microbiota and inflammatory profiles of the respiratory tract. Bacterial diversity and density (load) were measured. Lavage samples were analyzed for inflammatory markers (interleukin 8, unbound neutrophil elastase, and absolute neutrophil count) in the epithelial lining fluid. RESULTS: Thirty-two infants (mean age, 4.7 months) underwent bronchoalveolar lavage and oropharyngeal sampling. Shannon diversity strongly correlated between upper and lower airway samples from a given subject, although community compositions differed. Microbial diversity was lower in younger subjects and in those receiving daily antistaphylococcal antibiotic prophylaxis. In lavage samples, reduced diversity correlated with lower interleukin 8 concentration and absolute neutrophil count. CONCLUSIONS: In infants with CF, reduced bacterial diversity in the upper and lower airways was strongly associated with the use of prophylactic antibiotics and younger age at the time of sampling; less diversity in the lower airway correlated with lower inflammation on bronchoalveolar lavage. Our findings suggest modification of the respiratory microbiome in infants with CF may influence airway inflammation.


Assuntos
Antibioticoprofilaxia , Fibrose Cística/complicações , Microbiota , Sistema Respiratório/microbiologia , Austrália , Bactérias/isolamento & purificação , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/microbiologia , Fibrose Cística/microbiologia , Feminino , Humanos , Lactente , Inflamação , Interleucina-8/metabolismo , Contagem de Leucócitos , Elastase de Leucócito/metabolismo , Modelos Lineares , Masculino , Missouri , Neutrófilos/metabolismo , Estudos Prospectivos
8.
Ann Am Thorac Soc ; 14(9): 1436-1442, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28481640

RESUMO

RATIONALE: The lung clearance index is a measure of ventilation distribution derived from the multiple-breath washout technique. The lung clearance index is increased in the presence of lower respiratory tract inflammation and infection in infants with cystic fibrosis; however, the associations during the preschool years are unknown. OBJECTIVES: We assessed the ability of the lung clearance index to detect the presence and extent of lower respiratory tract inflammation and infection in preschool children with cystic fibrosis. METHODS: Ventilation distribution outcomes were assessed at 82 visits with 58 children with cystic fibrosis and at 38 visits with 31 healthy children aged 3-6 years. Children with cystic fibrosis also underwent bronchoalveolar lavage fluid collection for detection of lower respiratory tract inflammation and infection. Associations between multiple-breath washout indices and the presence and extent of airway inflammation and infection were assessed using linear mixed effects models. RESULTS: Lung clearance index was elevated in children with cystic fibrosis (mean [SD], 8.00 [1.45]) compared with healthy control subjects (6.67 [0.56]). In cystic fibrosis, the lung clearance index was elevated in individuals with lower respiratory tract infections (difference compared with uninfected [95% confidence interval], 0.62 [0.06, 1.18]) and correlated with the extent of airway inflammation. CONCLUSIONS: These data suggest that the lung clearance index may be a useful surveillance tool for monitoring the presence and extent of lower airway inflammation and infection in preschool children with cystic fibrosis.


Assuntos
Testes Respiratórios , Fibrose Cística/complicações , Fibrose Cística/fisiopatologia , Infecções Respiratórias/epidemiologia , Líquido da Lavagem Broncoalveolar/microbiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Modelos Lineares , Estudos Longitudinais , Pulmão/fisiopatologia , Masculino , Monitorização Fisiológica , Ventilação Pulmonar
9.
Am J Respir Crit Care Med ; 195(9): 1216-1225, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-27943680

RESUMO

RATIONALE: Implementation of intervention strategies to prevent lung damage in early cystic fibrosis (CF) requires objective outcome measures that capture and track lung disease. OBJECTIVES: To define the utility of the Lung Clearance Index (LCI), measured by multiple breath washout, as a means to track disease progression in preschool children with CF. METHODS: Children with CF between the ages of 2.5 and 6 years with a confirmed diagnosis of CF and age-matched healthy control subjects were enrolled at three North American CF centers. Multiple breath washout tests were performed at baseline, 1, 3, 6, and 12 months to mimic time points chosen in clinical care and interventional trials; spirometry was also conducted. A generalized linear mixed-effects model was used to distinguish LCI changes associated with normal growth and development (i.e., healthy children) from the progression of CF lung disease. MEASUREMENTS AND MAIN RESULTS: Data were collected on 156 participants with 800 LCI measurements. Although both LCI and spirometry discriminated health from disease, only the LCI identified significant deterioration of lung function in CF over time. The LCI worsened during cough episodes and pulmonary exacerbations, whereas similar symptoms in healthy children were not associated with increased LCI values. CONCLUSIONS: LCI is a useful marker to track early disease progression and may serve as a tool to guide therapies in young patients with CF.


Assuntos
Fibrose Cística/complicações , Pneumopatias/etiologia , Criança , Pré-Escolar , Fibrose Cística/patologia , Progressão da Doença , Feminino , Volume Expiratório Forçado , Humanos , Estudos Longitudinais , Pulmão/patologia , Pneumopatias/patologia , Masculino , Testes de Função Respiratória , Espirometria
10.
Environ Manage ; 53(3): 690-701, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24435878

RESUMO

Biodiversity information is essential for understanding and managing the environment. However, identifying and providing the forms and types of biodiversity information most needed for research and decision-making is a significant challenge. While research needs and data gaps within particular topics or regions have received substantial attention, other information aspects such as data formats, sources, metadata, and information tools have received little. Focusing on the US southeast, a region of global biodiversity importance, this paper assesses the biodiversity information needs of environmental researchers, managers, and decision makers. Survey results of biodiversity information users' information needs, information-seeking behaviors and preferred information source attributes support previous conclusions that useful biodiversity information must be easily and quickly accessible, available in forms that allow integration and visualization and appropriately matched to users' needs. Survey results concerning additional information aspects suggest successful participation in both the creation and provision of biodiversity information include an increased focus on information search and other tools for data management, discovery, and description.


Assuntos
Acesso à Informação , Biodiversidade , Coleta de Dados , Bases de Dados como Assunto , Humanos , Sudeste dos Estados Unidos
11.
Front Immunol ; 4: 478, 2013 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-24391650

RESUMO

THE REGULATORY CYTOKINE TUMOR NECROSIS FACTOR (TNF) EXERTS ITS EFFECTS THROUGH TWO RECEPTORS: TNFR1 and TNFR2. Defects in TNFR2 signaling are evident in a variety of autoimmune diseases. One new treatment strategy for autoimmune disease is selective destruction of autoreactive T cells by administration of TNF, TNF inducers, or TNFR2 agonism. A related strategy is to rely on TNFR2 agonism to induce T-regulatory cells (Tregs) that suppress cytotoxic T cells. Targeting TNFR2 as a treatment strategy is likely superior to TNFR1 because of its more limited cellular distribution on T cells, subsets of neurons, and a few other cell types, whereas TNFR1 is expressed throughout the body. This review focuses on TNFR2 expression, structure, and signaling; TNFR2 signaling in autoimmune disease; treatment strategies targeting TNFR2 in autoimmunity; and the potential for TNFR2 to facilitate end organ regeneration.

12.
J Pediatr Gastroenterol Nutr ; 53(6): 651-8, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21694637

RESUMO

BACKGROUND AND AIMS: Eosinophilic esophagitis (EE) continues to present clinical challenges, including a need for noninvasive tools to manage the disease. To identify a marker able to assess disease status in lieu of repeated endoscopies, we examined 3 noninvasive biomarkers, serum interleukin (IL)-5, serum eosinophil-derived neurotoxin (EDN), and stool EDN, and examined possible correlations of these with disease phenotype and activity (symptoms and histology) in a longitudinal study of children with EE. SUBJECTS AND METHODS: Children with EE were studied for up to 24 weeks (12 weeks on 1 of 2 corticosteroid therapies and 12 weeks off therapy). Twenty children with normal esophagogastroduodenoscopies with biopsies were enrolled as controls. Serum IL-5, serum EDN, and stool EDN were measured at weeks 0, 4, 12, 18, and 24 in children with EE, and at baseline alone for controls. Primary and secondary statistical analyses (excluding and including outlier values of the biomarkers, respectively) were performed. RESULTS: Sixty subjects with EE (46 [75%] boys, mean age 7.5 ±â€Š4.4 years) and 20 normal controls (10 [50%] boys, mean age 6.7 ±â€Š4.1 years) were included. Significant changes in serum EDN (significant decrease from baseline to week 4, and then rebound from week 4 to week 12) occurred. Serum EDN levels were stable after week 12. Serum IL-5 and stool EDN levels in subjects with EE were not statistically different from those of the control subjects when each time point for the cases was compared with the controls' 1-time measurement. CONCLUSIONS: Serum EDN levels were significantly higher in subjects with EE than in controls, and the results suggest a possible role, after additional future studies, for serum EDN in establishing EE diagnosis, assessing response to therapy, and/or monitoring for relapse or quiescence.


Assuntos
Biomarcadores/sangue , Esofagite Eosinofílica/diagnóstico , Esofagite Eosinofílica/fisiopatologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Endoscopia do Sistema Digestório/métodos , Neurotoxina Derivada de Eosinófilo/sangue , Eosinófilos/metabolismo , Feminino , Humanos , Interleucina-5/sangue , Estudos Longitudinais , Masculino , Fenótipo , Estudos Prospectivos
13.
J Pediatr Gastroenterol Nutr ; 53(4): 404-8, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21519281

RESUMO

AIM: The aim of the present study was to report the global experience with placement, complication rate, and recording of esophageal pH using the BRAVO capsule at our institution. PATIENTS AND METHODS: We recorded the rate of any technical problems and complications during placement in all of the patients (ages 4-22 years) who received this device during a 2-year period. All of the patients undergoing esophagogastroduodenoscopy with the placement of BRAVO pH capsule were included in this analysis. We also examined the pH data recorded on days 1 and 2 for significant day-to-day variability during 2 days of pH monitoring. RESULTS: Two hundred eighty-nine BRAVO pH probes were placed from January 1, 2006 to December 31, 2008. At least 1 day of data was obtained in 278 patients (96.2%). Two days of data were obtained in 274 patients (94.8%). Of all of the reported complications, 1% occurred before deployment of the capsule, 4% occurred during deployment of the capsule, and 9% occurred after successful deployment of the capsule. One patient experienced a superficial esophageal tear that was associated with failure of the capsule to release from the delivery system. No patient requested removal of the capsule and all of the capsules detached within 14 days. In 9.12% of our patients, reflux index was normal on day 1 and abnormal on day 2. There was no statistically significant difference between reflux index recorded on day 1 versus day 2 (P = 0.686). CONCLUSIONS: The BRAVO pH capsule is easy to place, safe, and well tolerated by children. Performing a 48-hour study detected abnormal reflux in an additional 9% of our patients.


Assuntos
Cápsulas , Monitoramento do pH Esofágico/instrumentação , Telemetria/instrumentação , Adolescente , Criança , Pré-Escolar , Endoscopia do Sistema Digestório/métodos , Feminino , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/fisiopatologia , Humanos , Concentração de Íons de Hidrogênio , Masculino , Estudos Prospectivos , Telemetria/métodos , Adulto Jovem
14.
Int J Biochem Cell Biol ; 42(10): 1576-9, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20601088

RESUMO

The view of the spleen as an unnecessary organ has been shattered. The evidence shows the spleen to be a source of naturally-occurring multipotent stem cells with possibly pluripotent potential. The stem cells are sequestered in the spleen of not only of animals but also of normal human adults. The reservoir of cells is set for differentiation and they need not be manipulated in vitro or ex vivo before autologous or heterologous use. Splenic stem cells, of Hox11 lineage, have been found in disease or injury to differentiate into pancreatic islets, salivary epithelial cells and osteoblast-like cells, cranial neurons, cochlea, lymphocytes, and more differentiated immune cells that repair injured heart cells. Injury or disease in target tissues induces these stem cells, still in the spleen, to upregulate the same embryonic transcription factors artificially introduced into induced pluripotent stem cells (iPS). Splenic stem cells may have broad pluripotent potential, but unlike iPS cells, possess low oncogenic risk.


Assuntos
Células-Tronco Adultas/metabolismo , Diabetes Mellitus Tipo 1/terapia , Células-Tronco Pluripotentes Induzidas/metabolismo , Síndrome de Sjogren/terapia , Baço/citologia , Nicho de Células-Tronco/citologia , Transplante de Células-Tronco , Células-Tronco Adultas/citologia , Animais , Diferenciação Celular , Linhagem da Célula , Proteínas de Homeodomínio/biossíntese , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Proteínas Proto-Oncogênicas/biossíntese
15.
J Pediatr Gastroenterol Nutr ; 51(4): 425-8, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20562721

RESUMO

OBJECTIVES: Fecal lactoferrin (FL) is a noninvasive biomarker that is elevated in Crohn disease (CD) compared to irritable bowel syndrome. The purpose of this study was to evaluate FL in identifying children with active versus inactive CD. PATIENTS AND METHODS: Fresh stool samples were collected from children with CD scheduled for endoscopy or a clinic visit, and from new outpatients who were scheduled for colonoscopy. FL was determined using a polyclonal antibody-based enzyme-linked immunosorbent assay. Physical global assessment, endoscopic findings, erythrocyte sedimentation rate (ESR), and the Pediatric CD Activity Index (PCDAI) were recorded for patients with CD. The PCDAI scores symptoms, laboratory parameters, physical examination, and extraintestinal manifestations. A score of ≤10 is inactive disease, 11 to 30 is mild active, and ≤31 is moderate to severe active. RESULTS: Of 101 study patients (4- to 20-year-old, 66 boys), 31 had active CD, 23 had inactive CD, and 37 had noninflammatory bowel disease (non-IBD) conditions. Four patients with ulcerative colitis and 6 patients with polyposis were excluded from analysis. FL was significantly elevated in CD versus non-IBD (P < 0.001) and in active versus inactive CD (P < 0.001). The PCDAI and ESR were higher in active CD than in inactive CD (both P < 0.001). Using an FL cutoff of 7.25 µg/g, FL has 100% sensitivity and 100% negative predictive value in detecting active CD. Using an FL cutoff level of 60 µg/g, FL had 84% sensitivity, 74% specificity, 81% positive predictive value, and 77% negative predictive value for detecting active CD. CONCLUSIONS: FL is a promising biomarker of active CD and may be more practical to use when it is not feasible to obtain all of the necessary clinical information for the PCDAI.


Assuntos
Doença de Crohn/diagnóstico , Doença de Crohn/metabolismo , Fezes/química , Lactoferrina/metabolismo , Adolescente , Adulto , Biomarcadores/metabolismo , Criança , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Enteropatias/diagnóstico , Enteropatias/metabolismo , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Adulto Jovem
16.
Nat Rev Drug Discov ; 9(6): 482-93, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20489699

RESUMO

Although drug development has advanced for autoimmune diseases, many current therapies are hampered by adverse effects and the frequent destruction or inactivation of healthy cells in addition to pathological cells. Targeted autoimmune therapies capable of eradicating the rare autoreactive immune cells that are responsible for the attack on the body's own cells are yet to be identified. This Review presents a new emerging approach aimed at selectively destroying autoreactive immune cells by specific activation of tumour necrosis factor receptor 2 (TNFR2), which is found on autoreactive and normal T lymphocytes, with the potential of avoiding or reducing the toxicity observed with existing therapies.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Receptores Tipo II do Fator de Necrose Tumoral/agonistas , Complexo CD3/imunologia , Humanos , NF-kappa B/fisiologia , Receptor Cross-Talk , Receptores Tipo I de Fatores de Necrose Tumoral/fisiologia , Receptores Tipo II do Fator de Necrose Tumoral/fisiologia , Transdução de Sinais
17.
J Mol Med (Berl) ; 87(12): 1173-8, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19693476

RESUMO

Type I diabetes (TID) is an autoimmune disease in which insulin-secreting beta cells of the pancreatic islets are destroyed by T lymphocytes. Until the 1990s, the prevailing dogma was that the attack was attributable to rogue T lymphocytes bearing CD4 markers on their surface (CD4 T helper lymphocytes). Today, the prevailing view is that rogue T cells bearing CD8 markers or cytotoxic CD8 T lymphocytes are also important and perhaps the foremost contributors to beta-cell death. Recognizing CD8 T-cell subsets as the prime culprits has helped to trace the disease's pathogenesis to abnormal T-cell education. Defective education can occur when antigen-presenting cells fail to assemble and present self-antigens to naïve T cells. The failure in that process, normally designed to prevent T cells' attack on the body's own antigens, enables self-reactive T cells to escape into the circulation. Once released, the self-reactive CD8 T cells kill specific self-antigens, which, in the case of TID, include insulin and other key proteins associated with beta cell functions. Abnormalities during T-cell education have been mapped in part to genetic defects in specific gene-encoding regions of the major histocompatibility complex class I region and to proteins that assemble self-peptides into the MHC class I structure that map within the MHC class II region. Two decades of research have led to understanding of genetic and functional defects in the immune system, placing us at the threshold of finding new therapeutic strategies aimed at eliminating autoreactive CD8 T cells, while preserving healthy immune cells.


Assuntos
Doenças Autoimunes , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Doenças Autoimunes/terapia , Autoimunidade , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 1/terapia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos NOD
18.
J Pediatr ; 154(1): 96-100, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18783791

RESUMO

OBJECTIVES: To determine predictors of histological response to proton pump inhibitor (PPI) therapy among children with significant esophageal eosinophilia (SEE), defined as >or=15 eosinophils per high powered field (eos/hpf) on esophageal mucosal biopsy (EMB). STUDY DESIGN: Response to PPI therapy among children with SEE treated with PPI who underwent repeat EMB was studied retrospectively. Response was defined as <5 eos/hpf on repeat EMB. Characteristics of responders and nonresponders were analyzed. RESULTS: Of 326 patients (ages 1 through 18 years) diagnosed with SEE over a 7-year period, 43 (mean age, 8.5 years; 67% males) met inclusion criteria. After PPI therapy, 17 patients (40%) were responders. There were no significant differences in demographics, presenting symptoms, endoscopic, or histological findings between responders and nonresponders. Among patients with 15 to 20 eos/hpf on EMB, 50% were responders; among patients with >20 eos/hpf on EMB, 29% were responders. Seven of 17 (41%) patients with abnormal pH monitoring and 5 of 11 (45%) patients with normal monitoring were responders. CONCLUSIONS: Forty percent of patients with SEE demonstrated histological response to PPI therapy. None of the clinical characteristics evaluated predicted response, and response was not dependent on results of pH study. The role of PPI therapy in treating SEE warrants further prospective investigation.


Assuntos
Eosinofilia/tratamento farmacológico , Doenças do Esôfago/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Adolescente , Criança , Pré-Escolar , Endoscopia do Sistema Digestório , Eosinofilia/patologia , Doenças do Esôfago/patologia , Monitoramento do pH Esofágico , Feminino , Humanos , Lactente , Masculino , Membrana Mucosa/patologia , Resultado do Tratamento
19.
Am J Psychiatry ; 166(1): 34-41, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19047323

RESUMO

Unlike most psychiatric diagnoses, posttraumatic stress disorder (PTSD) is defined in relation to a potentially etiologic event (the traumatic "stressor criterion") that is fundamental to its conceptualization. The diagnosis of PTSD thus inherently depends on two separate but confounded processes: exposure to trauma and development of a specific pattern of symptoms that appear following the trauma. Attempts to define the range of trauma exposure inherent in the diagnosis of PTSD have generated controversy, as reflected in successive revisions of the criterion from DSM-III onward. It is still not established whether or not there are specific types of traumatic events and levels of exposure to them that are associated with a syndrome that is cohesive in clinical characteristics, biological correlates, familial patterns, and longitudinal diagnostic stability. On the other hand, the symptomatic description of PTSD is becoming more clear. Of three categories of symptoms associated with PTSD--intrusive memories, avoidance and numbing, and hyperarousal--avoidance and numbing appear to be the most specific for identification of PTSD. Research is now poised to answer questions about the relevance of traumatic events based on their relationship to symptomatic outcome. The authors recommend that future research begin with existing diagnostic criteria, testing and further refining them in accordance with the classic Robins and Guze strategy for validation of psychiatric diagnoses. In this process, diligent adherence to the criteria under examination is paramount to successful PTSD research, and changes in criteria are driven by empirical data rather than theory. Collaborations among trauma research biologists, epidemiologists, and nosologists to map the correspondence between the clinical and biological indicators of psychopathology are necessary to advance validation and further understanding of PTSD.


Assuntos
Transtornos de Estresse Pós-Traumáticos/diagnóstico , Adaptação Psicológica , Diagnóstico Diferencial , Manual Diagnóstico e Estatístico de Transtornos Mentais , Humanos , Acontecimentos que Mudam a Vida , Fatores de Risco , Transtornos de Estresse Pós-Traumáticos/psicologia , Transtornos de Estresse Pós-Traumáticos/terapia
20.
Adv Physiol Educ ; 30(4): 152-8, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17108242

RESUMO

Sex hormones have long been implicated in autoimmune diseases because women account for 80% of cases. The mechanism of hormonal action in autoimmunity is unknown. Drawing on genetic studies of autoimmune disease, this article discusses how both genes and sex hormones may exert their effects through the same general mechanism, dysregulation of transcription factor NF-kappaB, an immunoregulatory protein. Gene and hormone alterations of the NF-kappaB signaling cascade provide a unifying hypothesis to explain the wide-ranging human and murine autoimmune disease phenotypes regulated by NF-kappaB, including cytokine balance, antigen presentation, lymphoid development, and lymphoid repertoire selection by apoptosis.


Assuntos
Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Animais , Formação de Anticorpos , Doenças Autoimunes/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Humanos , Modelos Imunológicos , NF-kappa B/metabolismo , Fenótipo , Fatores Sexuais , Transdução de Sinais
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