RESUMO
BACKGROUND: Melamine and cyanuric acid, which are currently used in a variety of common consumer products and present in foods, have been implicated in the development of urolithiasis and acute kidney injury in Chinese children. To determine whether US children have measurable concentrations of these chemicals in their bodies and whether they are at greater risk of acute kidney injury, we measured melamine and cyanuric acid exposure in a cohort of US children and determined their relationship with markers of kidney injury. METHODS: We measured urinary melamine and cyanuric acid in a convenience sample of 109 children (4 months - 8 years) from Seattle, WA and New York City, NY using liquid chromatography with tandem mass spectrometry. We measured several urinary markers of kidney injury: fatty acid binding protein 3 (FABP3), kidney injury molecule 1 (KIM1), neutrophil gelatinase-associated lipocalin (NGAL) using Luminex xMAP methods, and urine urea was measured using standard laboratory methods. We described urinary melamine and cyanuric acid concentrations and assessed predictors of the exposures. We used multivariable linear regression to assess relationships between melamine/cyanuric acid and kidney injury markers in unadjusted and adjusted (creatinine, age, sex) analyses. RESULTS: Melamine and cyanuric acid were above the limit of detection (LOD) in 78% and 95% of all samples, respectively. The mean concentrations (SD) for melamine and cyanuric acid were 27.4â¯ng/ml (141.9â¯ng/ml) and 35.3â¯ng/ml (42.4â¯ng/ml). In unadjusted analyses, we observed statistically significant increases in the percentages of FABP3 and KIM1 in relation to a one log unit change in melamine and cyanuric acid, respectively. In adjusted analyses, we observed a 55% (95% CI 0, 141) increase in KIM1 in relation to a one log unit increase in cyanuric acid. CONCLUSIONS: US children have detectable concentrations of melamine and cyanuric acid in urine, and these concentrations are higher than those reported in children from other countries. This is a novel finding that improves upon previous exposure estimates using questionnaires only and suggests widespread exposure in the population. Cyanuric acid is associated with increased KIM 1 concentrations, suggesting kidney injury. Given the potential widespread exposure, future analyses should examine melamine and cyanuric acid in relation to chronic kidney disease and markers of kidney injury in a larger cohort that is representative of the general population.
Assuntos
Rim , Insuficiência Renal/induzido quimicamente , Triazinas , Criança , Humanos , Insuficiência Renal/epidemiologia , Estados Unidos/epidemiologiaRESUMO
Contact sensitizers are a major cause of inflammatory skin disease and as topical immunomodulators also have the potential for treating cancer, viral diseases and certain autoimmune disorders. In the present study, the authors identify the upregulation of the TH17 lymphocyte subset transcription factor retinoid orphan receptor gamma T (RORgammaT) and the CD70 costimulatory pathway in human contact sensitivity (CS) using molecular techniques. Identification of this important new subset of T lymphocytes and a recognized costimulatory pathway offers potential for ameliorating CS and insight into antitumor and antiviral mechanism of haptens as topical immunomodulators.
Assuntos
Ligante CD27/biossíntese , Ligante CD27/genética , Dermatite de Contato/genética , Dermatite de Contato/metabolismo , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Receptores dos Hormônios Tireóideos/genética , Receptores dos Hormônios Tireóideos/metabolismo , Subpopulações de Linfócitos T/metabolismo , Eletroforese em Gel de Ágar , Humanos , Fatores Imunológicos/fisiologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fixação de TecidosRESUMO
BACKGROUND: Inflammatory cytokines are at the intersection of tumor cell biology and host immune response. Peripheral cytokine expression levels may reflect the microscopic tumor milieu, and specific cytokines play an integral role in tumor initiation, growth, and metastasis. High-throughput cytokine analysis may identify panels for early-stage non-small cell lung cancer (NSCLC) diagnosis and identify individuals at high-risk for lung cancer with indeterminate lung nodules 8-20 mm in size. METHODS: Thirteen serum cytokines from the NYU Lung Cancer Biomarker Center cohort with early-stage NSCLC were analyzed using bead-based immunoassay technology. RESULTS: In the NYU cohort, a one unit increase in interferon-γ increased risk of lung cancer by 3% (OR = 1.03, 95% CI, 1.02-1.05) and a one unit increase in TNF-α decreased the risk of lung cancer by 53% (OR = 0.47, 95% Cl, 0.31-0.71) when both cytokines were included in a logistic regression model with adjustments for age and pack-years of smoking. The resulting AUC for the Receiver Operating Characteristic (ROC) curve was 0.88; the sensitivity and specificity at the optimal cutpoint were 78.9% and 90.3%, respectively. CONCLUSIONS: Cytokines have limited value in the early diagnosis of early-stage NSCLC. Our review of the literature suggests that although inflammation is important for the development of NSCLC, that cytokines are increased in more advanced lung cancer than when the diagnosis occurs at presentation.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Citocinas/sangue , Mediadores da Inflamação/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico , Tomografia Computadorizada por Raios X , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Comorbidade , Humanos , Neoplasias Pulmonares/cirurgia , Estadiamento de Neoplasias , Curva ROC , Fatores de RiscoRESUMO
RATIONALE: The World Trade Center (WTC) collapse generated caustic airborne particulates that caused chronic rhinosinusitis in exposed Fire Department of New York firefighters. Surgery was performed when symptoms remained uncontrolled despite medical management. OBJECTIVES: To identify predictors of surgical intervention for chronic rhinosinusitis in firefighters exposed to airborne irritants at the WTC collapse site. METHODS: We assessed in 8,227 firefighters with WTC exposure between September 11, 2001 (9/11), and September 25, 2001, including WTC-site arrival time, months of rescue and recovery work, and eosinophil concentration measured between 9/11 and March 10, 2003. We assessed the association of serum cytokines and immunoglobulins with eosinophil concentration and surgery for rhinosinusitis in 112 surgical cases and 376 control subjects with serum available from the first 6 months after exposure to the WTC collapse site. MEASUREMENTS AND MAIN RESULTS: Between 9/11 and March 10, 2015, the surgery rate was 0.47 cases per 100 person-years. In the first 18 months post-9/11, surgical patients had higher mean blood eosinophil levels than study cohort patients (219 ± 155 vs. 191 ± 134; P < 0.0001). Increased surgery risk was associated with increasing blood eosinophil counts (hazard ratio [HR], 1.12 per 100 cells/µl; 95% confidence interval [CI], 1.07-1.17; P < 0.001); arriving at the WTC site on 9/11 or September 12, 2001 (HR, 1.43; 95% CI, 1.04-1.99; P = 0.03); and working 6 months or longer at the WTC site (HR, 1.48; 95% CI, 1.14-1.93; P < 0.01). Median blood eosinophil levels for surgical patients were above levels for the cohort in all 18-month intervals March 11, 2000, through March 10, 2015, using 51,163 measurements representing 97,733 person-years of observation. Increasing age, increasing IL-17A, and low IgA in serum from 2001 to 2002 predicted blood eosinophil concentration in surgical patients but not in control subjects (R(2) = 0.26, P < 0.0001; vs. R(2) = 0.008, P = 0.56). CONCLUSIONS: Increasing blood eosinophil concentration predicts surgical intervention for chronic rhinosinusitis, particularly in those with intense acute and prolonged exposure to airborne irritants. WTC-exposed Fire Department of New York firefighters who underwent irritant-associated sinus surgery are immunologically different from the cohort. Surgical patients have a higher blood eosinophil levels that is associated with mediators of mucosal immunity.
Assuntos
Eosinófilos/citologia , Bombeiros/estatística & dados numéricos , Material Particulado/efeitos adversos , Ataques Terroristas de 11 de Setembro , Sinusite/sangue , Sinusite/cirurgia , Adulto , Biomarcadores/sangue , Doença Crônica , Humanos , Imunoglobulina A/sangue , Interleucina-17/sangue , Contagem de Leucócitos , Modelos Lineares , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Cidade de Nova Iorque , Exposição Ocupacional , Modelos de Riscos Proporcionais , Sinusite/etiologia , Fatores de TempoRESUMO
Glycogen storage disease type II is an autosomal recessive muscle disorder due to deficiency of lysosomal acid alpha-glucosidase and the resulting intralysosomal accumulation of glycogen. We found six novel mutations in three Spanish classic infantile onset glycogen storage disease type II patients with involvement of both cardiac and skeletal muscle; three missense mutations (G219R, E262K, M408V), a nonsense mutation (Y191X), a donor splice site mutation (IVS18 +2gt>ga) and an in frame deletion of an asparagine residue (nt1408-1410). The missense mutations were not found in 100 normal chromosomes and therefore are not normal polymorphic variants. The splice site mutation was subsequently detected in an additional 'Spanish' infantile onset glycogen storage disease type II patient from El Salvador. Further studies will be required to determine if the IVS18 +2gt>ga splice site mutation might in fact be a relatively common Spanish mutation. Mutations among Spanish glycogen storage disease type II patients appear to be genetically heterogeneous and differ from common mutations in neighboring countries.
Assuntos
Doença de Depósito de Glicogênio Tipo II/genética , Mutação , alfa-Glucosidases/genética , Idade de Início , Processamento Alternativo , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Sequência de Bases , Éxons , Feminino , Humanos , Lisossomos/enzimologia , Masculino , Alinhamento de Sequência , EspanhaRESUMO
BACKGROUND: Tuberculosis (TB) causes 1.45 million deaths annually world wide, the majority of which occur in the developing world. Active TB disease represents immune failure to control latent infection from airborne spread. Acid-fast bacillus (AFB) seen on sputum smear is a biomarker for contagiousness. METHODS: We enrolled 73 tuberculosis patients with extensive infiltrates into a research study using bronchoalveolar lavage (BAL) to sample lung immune cells and assay BAL cell cytokine production. All patients had sputum culture demonstrating Mycobacterium tuberculosis and 59/73 (81%) had AFB identified by microscopy of the sputum. Compared with smear negative patients, smear positive patients at presentation had a higher proportion with smoking history, a higher proportion with temperature >38.5(0) C, higher BAL cells/ml, lower percent lymphocytes in BAL, higher IL-4 and IL-12p40 in BAL cell supernatants. There was no correlation between AFB smear and other BAL or serum cytokines. Increasing IL-4 was associated with BAL PMN and negatively associated with BAL lymphocytes. Each 10-fold increase in BAL IL-4 and IL-12p40 increased the odds of AFB smear positivity by 7.4 and 2.2-fold, respectively, in a multi-variable logistic model. CONCLUSION: Increasing IL-4 and IL-12p40 production by BAL cells are biomarkers for AFB in sputum of patients who present with radiographically advanced TB. They likely reflect less effective immune control of pathways for controlling TB, leading to patients with increased infectiousness.
Assuntos
Biomarcadores/metabolismo , Lavagem Broncoalveolar , Subunidade p40 da Interleucina-12/metabolismo , Interleucina-4/metabolismo , Mycobacterium tuberculosis/metabolismo , Escarro/metabolismo , Tuberculose/diagnóstico , Temperatura Corporal , Humanos , Modelos Logísticos , Fumar/metabolismo , Escarro/microbiologiaRESUMO
BACKGROUND: Current treatment regimens for pulmonary tuberculosis require at least 6 months of therapy. Immune adjuvant therapy with recombinant interferon-gamma1b (rIFN-gammab) may reduce pulmonary inflammation and reduce the period of infectivity by promoting earlier sputum clearance. METHODOLOGY/PRINCIPAL FINDINGS: We performed a randomized, controlled clinical trial of directly observed therapy (DOTS) versus DOTS supplemented with nebulized or subcutaneously administered rIFN-gamma1b over 4 months to 89 patients with cavitary pulmonary tuberculosis. Bronchoalveolar lavage (BAL) and blood were sampled at 0 and 4 months. There was a significant decline in levels of inflammatory cytokines IL-1beta, IL-6, IL-8, and IL-10 in 24-hour BAL supernatants only in the nebulized rIFN-gamma1b group from baseline to week 16. Both rIFN-gamma1b groups showed significant 3-fold increases in CD4+ lymphocyte response to PPD at 4 weeks. There was a significant (p = 0.03) difference in the rate of clearance of Mtb from the sputum smear at 4 weeks for the nebulized rIFN-gamma1b adjuvant group compared to DOTS or DOTS with subcutaneous rIFN-gamma1b. In addition, there was significant reduction in the prevalence of fever, wheeze, and night sweats at 4 weeks among patients receiving rFN-gamma1b versus DOTS alone. CONCLUSION: Recombinant interferon-gamma1b adjuvant therapy plus DOTS in cavitary pulmonary tuberculosis can reduce inflammatory cytokines at the site of disease, improve clearance of Mtb from the sputum, and improve constitutional symptoms. TRIAL REGISTRATION: ClinicalTrials.gov NCT00201123.
Assuntos
Imunomodulação , Imunoterapia/métodos , Interferon gama/metabolismo , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/terapia , Adulto , Líquido da Lavagem Broncoalveolar , Citocinas/sangue , Citocinas/metabolismo , Feminino , Humanos , Inflamação , Linfócitos/metabolismo , Masculino , Proteínas Recombinantes/uso terapêutico , Escarro/imunologia , Resultado do Tratamento , Tuberculose Pulmonar/imunologiaRESUMO
Current methods for detection of mutations by polymerase chain reaction (PCR) and sequence analysis frequently are not able to detect heterozygous large deletions. We report the successful use of a novel approach to identify such deletions, based on detection of apparent homozygosity of contiguous single-nucleotide polymorphisms (SNPs). The sequence analysis of genomic DNA PCR products containing all coding exons and flanking introns identified only a single heterozygous mutation (IVS18+2t-->a) in a patient with classic infantile-onset autosomal recessive glycogen storage disease type II (GSDII). Apparent homozygosity for multiple contiguous SNPs detected by this sequencing suggested presence of a large deletion as the second mutation; primers flanking the region of homozygous SNPs permitted identification and characterization by PCR of a large genomic deletion (8.26 kb) extending from IVS7 to IVS15. The data clearly demonstrate the utility of SNPs as markers for large deletions in autosomal recessive diseases when only a single mutation is found, thus complementing currently standard DNA PCR sequence methods for identifying the molecular basis of disease.