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1.
Pathogens ; 11(8)2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-36015018

RESUMO

Trypanosoma cruzi, the causative agent of Chagas disease, faces changes in redox status and nutritional availability during its life cycle. However, the influence of oxygen fluctuation upon the biology of T. cruzi is unclear. The present work investigated the response of T. cruzi epimastigotes to hypoxia. The parasites showed an adaptation to the hypoxic condition, presenting an increase in proliferation and a reduction in metacyclogenesis. Additionally, parasites cultured in hypoxia produced more reactive oxygen species (ROS) compared to parasites cultured in normoxia. The analyses of the mitochondrial physiology demonstrated that hypoxic condition induced a decrease in both oxidative phosphorylation and mitochondrial membrane potential (ΔΨm) in epimastigotes. In spite of that, ATP levels of parasites cultivated in hypoxia increased. The hypoxic condition also increased the expression of the hexokinase and NADH fumarate reductase genes and reduced NAD(P)H, suggesting that this increase in ATP levels of hypoxia-challenged parasites was a consequence of increased glycolysis and fermentation pathways. Taken together, our results suggest that decreased oxygen levels trigger a shift in the bioenergetic metabolism of T. cruzi epimastigotes, favoring ROS production and fermentation to sustain ATP production, allowing the parasite to survive and proliferate in the insect vector.

2.
Genet Mol Biol ; 43(4): e20200160, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33270074

RESUMO

Early age acute leukemia (EAL) shows a high frequency of KMT2A-rearrangements (KMT2A-r). Previous investigations highlighted double-strand breaks arising from maternal exposure to xenobiotics during pregnancy as a risk factor for EAL and KMT2A-r. In this case-control study, we investigated the relationship between EAL and genetic variants of the nonhomologous end-joining (XRCC6 rs5751129, XRCC4 rs6869366 and rs28360071), since they might affect DNA repair capacity, leading to KMT2A-r and leukemogenesis. Samples from 577 individuals (acute lymphoblastic leukemia-ALL, n=164; acute myeloid leukemia-AML, n=113; controls, n=300) were genotyped. No significant association was found for rs5751129 and rs6869366, whereas rs28360071 was associated with an increased risk for ALL with KMT2A-r (IIxID: OR - Odds ratio 2.23, CI 1.17-4.25, p=0.014). Bone marrow samples from ALL patients showed a higher expression of XRCC4 compared to AML patients (p=0.025). Human Splicing Finder 3.1 predicted that the deleted allele of rs28360071 is potentially associated with the activation of a 5' cryptic splice site in intron 3 of XRCC4. The sequencing of cDNA did not show any differences on the splicing process for the rs28360071 genotypes. Our results suggest that the deleted allele for rs28360071 increases the risk for ALL with KMT2A-r, but not by modifying the XRCC4 expression levels or its structure.

3.
Biochim Biophys Acta Mol Basis Dis ; 1866(12): 165951, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32861766

RESUMO

Trypanosoma cruzi has a complex life cycle involving four life stages: the replicative epimastigotes and metacyclic trypomastigotes in the invertebrate host digestive tract, and intracellular amastigotes and bloodstream trypomastigotes in the mammalian host. Trypomastigotes can invade any nucleated cell, including macrophages, which produce ROS that enhance intracellular infection. However, how ROS modulate T. cruzi infection in the mammalian cell remains unclear. Therefore, the present work aimed to investigate the role of ROS during the stimulation of amastigogenesis in vitro. Our results showed that H2O2 improves the differentiation process in vitro and that it was impaired by Peg-Catalase. However, the antioxidants GSH and NAC had no influence on induced amastigogenesis, which suggests the specificity of H2O2 to increase intracellular differentiation. Amastigogenesis physiologically occurs in low pH, thus we investigated whether parasites are able to produce ROS during amastigogenesis. Interestingly, after 60 min of differentiation induction in vitro, we observed an increase in H2O2 production, which was inhibited by the mitochondrial-targeted antioxidant, mitoTEMPO and Cyclosporine A (a mitochondrial permeability transition pore -mPTP- inhibitor), suggesting mitochondrion as a H2O2 source. Indeed, quantitative real time (qPCR) showed an increase of the mitochondrial superoxide dismutase (FeSODA) gene expression after 60 min of induced amastigogenesis, reinforcing the hypothesis of mitochondrial ROS induction during intracellular differentiation of T. cruzi. The reduction of cellular respiration and the decreased ΔΨm observed during amastigogenesis can explain the increased mitochondrial ROS through mPTP opening. In conclusion, our results suggest that H2O2 is involved in the amastigogenesis of T. cruzi.


Assuntos
Peróxido de Hidrogênio/metabolismo , Trypanosoma cruzi/metabolismo , Animais , Chlorocebus aethiops , Concentração de Íons de Hidrogênio , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Trypanosoma cruzi/citologia , Células Vero
4.
PLoS Negl Trop Dis ; 14(1): e0007945, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31895927

RESUMO

Chagas disease, also known as American trypanosomiasis, is a potentially life-threatening illness caused by the protozoan parasite, Trypanosoma cruzi, and is transmitted by triatomine insects during its blood meal. Proliferative epimastigotes forms thrive inside the insects in the presence of heme (iron protoporphyrin IX), an abundant product of blood digestion, however little is known about the metabolic outcome of this signaling molecule in the parasite. Trypanosomatids exhibit unusual gene transcription employing a polycistronic transcription mechanism through trans-splicing that regulates its life cycle. Using the Deep Seq transcriptome sequencing we characterized the heme induced transcriptome of epimastigotes and determined that most of the upregulated genes were related to glucose metabolism inside the glycosomes. These results were supported by the upregulation of glycosomal isoforms of PEPCK and fumarate reductase of heme-treated parasites, implying that the fermentation process was favored. Moreover, the downregulation of mitochondrial gene enzymes in the presence of heme also supported the hypothesis that heme shifts the parasite glycosomal glucose metabolism towards aerobic fermentation. These results are examples of the environmental metabolic plasticity inside the vector supporting ATP production, promoting epimastigotes proliferation and survival.


Assuntos
Perfilação da Expressão Gênica , Heme/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/metabolismo , Animais , Doença de Chagas/metabolismo , Genes Mitocondriais , Glucose/metabolismo , Insetos Vetores/parasitologia , Microcorpos/metabolismo , Transdução de Sinais , Transcrição Gênica , Triatominae/parasitologia , Trypanosoma cruzi/genética , Trypanosoma cruzi/crescimento & desenvolvimento
5.
World J Gastroenterol ; 22(31): 7146-56, 2016 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-27610024

RESUMO

AIM: To compare expression of nicotinic cholinergic receptors (CHRNs) in healthy and squamous cell carcinoma-affected esophagus and determine the prognostic value. METHODS: We performed RT-qPCR to measure the expression of CHRNs in 44 esophageal samples from healthy individuals and in matched normal surrounding mucosa, and in tumors from 28 patients diagnosed with esophageal squamous cell carcinoma (ESCC). Next, we performed correlation analysis for the detected expression of these receptors with the habits and clinico-pathological characteristics of all study participants. In order to investigate the possible correlations between the expression of the different CHRN subunits in both healthy esophagus and tissues from ESCC patients, correlation matrices were generated. Subsequently, we evaluated whether the detected alterations in expression of the various CHRNs could precede histopathological modifications during the esophageal carcinogenic processes by using receiver operating characteristic curve analysis. Finally, we evaluated the impact of CHRNA5 and CHRNA7 expression on overall survival by using multivariate analysis. RESULTS: CHRNA3, CHRNA5, CHRNA7 and CHRNB4, but not CHRNA1, CHRNA4, CHRNA9 or CHRNA10, were found to be expressed in normal (healthy) esophageal mucosa. In ESCC, CHRNA5 and CHRNA7 were overexpressed as compared with patient-matched surrounding non-tumor mucosa (ESCC-adjacent mucosa; P < 0.0001 and P = 0.0091, respectively). Positive correlations were observed between CHRNA3 and CHRNB4 expression in all samples analyzed. Additionally, CHRNB4 was found to be differentially expressed in the healthy esophagus and the normal-appearing ESCC-adjacent mucosa, allowing for distinguishment between these tissues with a sensitivity of 75.86% and a specificity of 78.95% (P = 0.0002). Finally, CHRNA5 expression was identified as an independent prognostic factor in ESCC; patients with high CHRNA5 expression showed an increased overall survival, in comparison with those with low expression. The corresponding age- and tumor stage-adjusted hazard ratio was 0.2684 (95%CI: 0.075-0.97, P = 0.0448). CONCLUSION: Expression of CHRNs is homogeneous along healthy esophagus and deregulated in ESCC, suggesting a pathogenic role for these receptors in ESCC development and progression.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Esôfago/química , Receptores Nicotínicos/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/análise , Receptores Nicotínicos/genética
6.
Exp Mol Pathol ; 101(1): 66-73, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27260309

RESUMO

Esophageal squamous cell carcinoma (ESCC) is the most frequent esophageal tumor in the world. ESCC presents late diagnosis, highly aggressive behavior and poor survival. Changes in tumor cell energy metabolism appear to have a prominent role in malignant transformation. Tumor cells consume glucose avidly and produce lactic acid, even under normoxia. Among the factors that may contribute to the stimulation of glycolysis in tumor cells, there are changes in the glycolytic pathway enzymes such as: pyruvate kinase M1 and M2 (PKM2 and PKM1), hexokinase II (HKII), glucose transporter isoform 1 (GLUT-1), and transcription factor induced by hypoxia (HIF1α), responsible for the transcription of proteins cited. The objective of this study is to evaluate the alterations of these proteins and their association with clinicopathological data in ESCC. We performed immunohistochemistry to determine HIF-1α, GLUT-1, PKM1, PKM2, HK2 and Ki67-expression in ESCC patients and controls. Also, we used RT-qPCR to evaluated mRNA expression of GLUT-1 in esophageal mucosa of individuals without cancer, but are alcohol drinkers and tobacco smokers. Our results showed the exclusively expression of GLUT-1 in tumors cells and dysplastic samples. We also observed a compartmentalization of the expression of PKM1 and PKM2 in relation to tumor cells and stroma associated to tumor areas. All of the proteins evaluated, excepted GLUT-1, were frequently detected in normal mucosa. No correlations between clinicopathological features and protein expressions were observed. GLUT-1 expression appears in initial tumor lesions and is maintained through ESCC evolution. We reported for the first time PKM1 staining in normal esophagus and ESCC, being mostly present in more differentiated cells.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Glucose/metabolismo , Glicólise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Epitélio/enzimologia , Epitélio/patologia , Neoplasias Esofágicas/enzimologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Regulação Neoplásica da Expressão Gênica , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Hexoquinase/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Mucosa/enzimologia , Mucosa/patologia , Piruvato Quinase/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Risco , Microambiente Tumoral , Adulto Jovem
7.
PLoS One ; 10(5): e0127308, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25992585

RESUMO

Based on observational studies, early age leukemia (EAL) was associated with maternal hormone exposure during pregnancy. We studied the association between genetic polymorphisms of estrogen metabolism and EAL. Using data from the Brazilian Collaborative Study Group of Infant Acute Leukemia (2000-2012), 350 cases and 404 age-matched controls and 134 mothers of cases and controls were genotyped to explore polymorphisms in genes of the estrogen metabolism pathway: CYP1B1 (c.1294C>G, rs1056836), CYP3A4 (c.-392A>G, rs2740574), CYP3A5 (c.219-237G>A, rs776746), GSTM1/GSTT1 deletions, and SULT1A1 (c.638G>A, rs9282861; and c.667A>G, rs1801030). Logistic regression was used to calculate the odds ratios (OR) with 95% confidence intervals (CIs), and unconditional logistic regression was used to estimate adjusted odds ratios (aORs) by ethnicity. Because of multiple testing, p values < 0.01 were significant after Bonferroni correction. SULT1A1 (c.638G>A) was associated to infant acute lymphoblastic leukemia and acute myeloid leukemia (AML) risk in males (additive model: aOR = 0.52; 95% CI: 0.29-0.95, p = 0.03; dominant model: aOR = 2.18; 95% CI: 1.17-4.05, p = 0.01, respectively). CYP1B1 polymorphism was associated with a decreased risk of AML either for non-white or female children (additive model: OR = 0.24; 95% CI: 0.08-0.76, p < 0.01; additive model: aOR = 0.27; 95% CI: 0.08-0.89, p = 0.03, respectively). Since polymorphisms of Cytochrome P450 genes presented gender-specific risk associations, we also investigated their expression. CYP1B1 was not expressed in 57.1% of EAL cases, and its expression varied by genotype, gender, and leukemia subtype. Maternal-fetal GSTT1 null genotype was associated with risk of EAL. This study shows that polymorphisms in genes of estrogen metabolism confer genetic susceptibility to EAL, mainly in males, and maternal susceptibility genes modify the risk for developing EAL in newborns.


Assuntos
Arilsulfotransferase/genética , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP3A/genética , Glutationa Transferase/genética , Leucemia Mieloide Aguda/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Idade de Início , Brasil/etnologia , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lactente , Leucemia Mieloide Aguda/etnologia , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/etnologia , Fatores Sexuais
8.
PLoS One ; 10(2): e0116712, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25671543

RESUMO

Trypanosoma cruzi proliferate and differentiate inside different compartments of triatomines gut that is the first environment encountered by T. cruzi. Due to its complex life cycle, the parasite is constantly exposed to reactive oxygen species (ROS). We tested the influence of the pro-oxidant molecules H2O2 and the superoxide generator, Paraquat, as well as, metabolism products of the vector, with distinct redox status, in the proliferation and metacyclogenesis. These molecules are heme, hemozoin and urate. We also tested the antioxidants NAC and GSH. Heme induced the proliferation of epimastigotes and impaired the metacyclogenesis. ß-hematin, did not affect epimastigote proliferation but decreased parasite differentiation. Conversely, we show that urate, GSH and NAC dramatically impaired epimastigote proliferation and during metacyclogenesis, NAC and urate induced a significant increment of trypomastigotes and decreased the percentage of epimastigotes. We also quantified the parasite loads in the anterior and posterior midguts and in the rectum of the vector by qPCR. The treatment with the antioxidants increased the parasite loads in all midgut sections analyzed. In vivo, the group of vectors fed with reduced molecules showed an increment of trypomastigotes and decreased epimastigotes when analyzed by differential counting. Heme stimulated proliferation by increasing the cell number in the S and G2/M phases, whereas NAC arrested epimastigotes in G1 phase. NAC greatly increased the percentage of trypomastigotes. Taken together, these data show a shift in the triatomine gut microenvironment caused by the redox status may also influence T. cruzi biology inside the vector. In this scenario, oxidants act to turn on epimastigote proliferation while antioxidants seem to switch the cycle towards metacyclogenesis. This is a new insight that defines a key role for redox metabolism in governing the parasitic life cycle.


Assuntos
Insetos Vetores/parasitologia , Trypanosoma cruzi/citologia , Trypanosoma cruzi/fisiologia , Acetilcisteína/farmacologia , Animais , Antioxidantes/farmacologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Heme/farmacologia , Peróxido de Hidrogênio/farmacologia , Oxirredução/efeitos dos fármacos , Rhodnius/parasitologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/metabolismo , Ácido Úrico/farmacologia
9.
PLoS One ; 9(7): e103444, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25077953

RESUMO

Cardiovascular benefits from estradiol activation of nitric oxide endothelial production may depend on vascular wall and on estrogen receptor alpha (ESR1) and nitric oxide synthase (NOS3) polymorphisms. We have evaluated the microcirculation in vivo through nailfold videocapillaroscopy, before and after acute nasal estradiol administration at baseline and after increased sheer stress (postocclusive reactive hyperemia response) in 100 postmenopausal women, being 70 controls (healthy) and 30 simultaneously hypertensive and diabetic (HD), correlating their responses to PvuII and XbaI ESR1 polymorphisms and to VNTR, T-786C and G894T NOS3 variants. In HD women, C variant allele of ESR1 Pvull was associated to higher vasodilatation after estradiol (1.72 vs 1.64 mm/s, p = 0.01 compared to TT homozygotes) while G894T and T-786C NOS3 polymorphisms were connected to lower increment after shear stress (15% among wild type and 10% among variant alleles, p = 0.02 and 0.04). The G variant allele of ESR1 XbaI polymorphism was associated to higher HOMA-IR (3.54 vs. 1.64, p = 0.01) in HD and higher glucose levels in healthy women (91.8 vs. 87.1 mg/dl, p = 0.01), in which increased waist and HOMA-IR were also related to the G allele in NOS3 G894T (waist 93.5 vs 88.2 cm, p = 0.02; HOMA-IR 2.89 vs 1.48, p = 0.05). ESR1 Pvull, NOS3 G894T and T-786C polymorphism analysis may be considered in HD postmenopausal women for endothelial response prediction following estrogen therapy but were not discriminatory for endothelial response in healthy women. ESR1 XbaI and G894T NOS3 polymorphisms may be useful in accessing insulin resistance and type 2 diabetes risks in all women, even before menopause and occurrence of metabolic disease.


Assuntos
Doenças Cardiovasculares/fisiopatologia , Endotélio Vascular/fisiologia , Receptor alfa de Estrogênio/fisiologia , Resistência à Insulina , Óxido Nítrico Sintase Tipo III/fisiologia , Pós-Menopausa , Doenças Cardiovasculares/genética , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo III/genética , Fatores de Risco
10.
Arq. bras. cardiol ; 100(6): 561-570, jun. 2013. ilus, tab
Artigo em Português | LILACS | ID: lil-679140

RESUMO

FUNDAMENTO: Já foi demonstrado o uso do NT-proBNP pré-operatório para prever resultado cardíaco adverso, embora estudos recentes tenham sugerido que a determinação do NT-proBNP pós-operatório possa fornecer um valor adicional em pacientes submetidos à cirurgia não cardíaca. OBJETIVO: Avaliar o valor prognóstico perioperatório do NT-proBNP em pacientes de intermediário e alto risco cardiovascular submetidos à cirurgia não cardíaca. MÉTODOS: Este estudo incluiu prospectivamente 145 pacientes com idade > 45 anos, com pelo menos um fator de risco do Índice de Risco Cardíaco Revisado e submetidos à cirurgia de médio ou alto risco não-cardíaca. Os níveis de NTproBNP foram medidos no pré e pós-operatório. Preditores cardíacos de curto prazo foram avaliados por modelos de regressão logística. RESULTADOS: Durante uma mediana de acompanhamento de 29 dias, 17 pacientes (11,7%) apresentaram eventos cardíacos adversos importantes (MACE - 14 infartos do miocárdio não fatais, 2 paradas cardíacas não-fatais e 3 mortes cardíacas). Os níveis ótimos de limiar discriminatório para o NT-proBNP pré e pós-operatório foram 917 e 2962 pg/ mL, respectivamente. O NT-proBNP pré e pós-operatório (OR = 4,7, IC 95%: 1,62-13,73, p = 0,005 e OR 4,5, IC 95%: 1,53-13,16, p = 0,006) foram associados de forma significativa com MACE (eventos cardíacos adversos maiores). O NTproBNP pré-operatório foi significativa e independentemente associado com eventos cardíacos adversos em análise de regressão multivariada (OR ajustado 4,2, IC 95%: 1,38-12,62, p = 0,011). CONCLUSÃO: O NT-proBNP é um importante marcador de curto prazo de eventos cardiovasculares perioperatórios em pacientes de alto risco. Os níveis pós-operatórios foram menos informativos do que os níveis pré-operatórios. Uma única medição de NT-proBNP pré-operatório deve ser considerada na avaliação de risco pré-operatório.


BACKGROUND: Preoperative NT-proBNP has been shown to predict adverse cardiac outcomes, although recent studies suggested that postoperative NT-proBNP determination could provide additional information in patients submitted to noncardiac surgery. OBJECTIVE: To evaluate the prognostic value of perioperative NT-proBNP in intermediate and high risk cardiovascular patients undergoing noncardiac surgery. METHODS: This study prospectively enrolled 145 patients aged >45 years, with at least one Revised Cardiac Risk Index risk factor and submitted to intermediate or high risk noncardiac surgery. NT-proBNP levels were measured pre- and postoperatively. Short-term cardiac outcome predictors were evaluated by logistic regression models. RESULTS: During a median follow-up of 29 days, 17 patients (11.7%) experienced major adverse cardiac events (MACE- 14 nonfatal myocardial infarctions, 2 nonfatal cardiac arrests and 3 cardiac deaths). The optimum discriminatory threshold levels for pre- and postoperative NT-proBNP were 917 and 2962 pg/mL, respectively. Pre- and postoperative NT-proBNP (OR 4.7; 95% CI 1.62-13.73; p=0.005 and OR 4.5; 95% CI 1.53-13.16; p=0.006) were significantly associated with MACE. Preoperative NT-proBNP was significantly and independently associated with adverse cardiac events in multivariate regression analysis (adjusted OR 4.2; 95% CI 1.38-12.62; p=0.011). CONCLUSION: NT-proBNP is a powerful short-term marker of perioperative cardiovascular events in high risk patients. Postoperative levels were less informative than preoperative levels. A single preoperative NT-proBNP measurement should be considered in the preoperative risk assessment.


Assuntos
Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Cardiovasculares/sangue , Peptídeo Natriurético Encefálico/sangue , Período Perioperatório , Fragmentos de Peptídeos/sangue , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Métodos Epidemiológicos , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de Risco , Procedimentos Cirúrgicos Operatórios/mortalidade , Fatores de Tempo
11.
Arq Bras Cardiol ; 100(6): 561-70, 2013 Jun.
Artigo em Inglês, Português | MEDLINE | ID: mdl-23657264

RESUMO

BACKGROUND: Preoperative NT-proBNP has been shown to predict adverse cardiac outcomes, although recent studies suggested that postoperative NT-proBNP determination could provide additional information in patients submitted to noncardiac surgery. OBJECTIVE: To evaluate the prognostic value of perioperative NT-proBNP in intermediate and high risk cardiovascular patients undergoing noncardiac surgery. METHODS: This study prospectively enrolled 145 patients aged ≥ 45 years, with at least one Revised Cardiac Risk Index risk factor and submitted to intermediate or high risk noncardiac surgery. NT-proBNP levels were measured pre- and postoperatively. Short-term cardiac outcome predictors were evaluated by logistic regression models. RESULTS: During a median follow-up of 29 days, 17 patients (11.7%) experienced major adverse cardiac events (MACE- 14 nonfatal myocardial infarctions, 2 nonfatal cardiac arrests and 3 cardiac deaths). The optimum discriminatory threshold levels for pre- and postoperative NT-proBNP were 917 and 2962 pg/mL, respectively. Pre- and postoperative NT-proBNP (OR 4.7; 95% CI 1.62-13.73; p=0.005 and OR 4.5; 95% CI 1.53-13.16; p=0.006) were significantly associated with MACE. Preoperative NT-proBNP was significantly and independently associated with adverse cardiac events in multivariate regression analysis (adjusted OR 4.2; 95% CI 1.38-12.62; p=0.011). CONCLUSION: NT-proBNP is a powerful short-term marker of perioperative cardiovascular events in high risk patients. Postoperative levels were less informative than preoperative levels. A single preoperative NT-proBNP measurement should be considered in the preoperative risk assessment.


Assuntos
Doenças Cardiovasculares/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Período Perioperatório , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Métodos Epidemiológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de Risco , Procedimentos Cirúrgicos Operatórios/mortalidade , Fatores de Tempo
12.
Dis Markers ; 35(6): 945-53, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24489430

RESUMO

BACKGROUND: Cardiac troponin levels have been reported to add value in the detection of cardiovascular complications in noncardiac surgery. A sensitive cardiac troponin I (cTnI) assay could provide more accurate prognostic information. METHODS: This study prospectively enrolled 142 patients with at least one Revised Cardiac Risk Index risk factor who underwent noncardiac surgery. cTnI levels were measured postoperatively. Short-term cardiac outcome predictors were evaluated. RESULTS: cTnI elevation was observed in 47 patients, among whom 14 were diagnosed as having myocardial infarction (MI). After 30 days, 16 patients had major adverse cardiac events (MACE). Excluding patients with a final diagnosis of MI, predictors of cTnI elevation included dialysis, history of heart failure, transoperative major bleeding, and elevated levels of pre- and postoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP). Maximal cTnI values showed the highest sensitivity (94%), specificity (75%), and overall accuracy (AUC 0.89; 95% CI 0.80-0.98) for postoperative MACE. Postoperative cTnI peak level (OR 9.4; 95% CI 2.3-39.2) and a preoperative NT-proBNP level ≥917 pg/mL (OR 3.47; 95% CI 1.05-11.6) were independent risk factors for MACE. CONCLUSIONS: cTnI was shown to be an independent prognostic factor for cardiac outcomes and should be considered as a component of perioperative risk assessment.


Assuntos
Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Troponina I/metabolismo , Idoso , Biomarcadores/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/cirurgia , Seleção de Pacientes , Período Pós-Operatório , Prognóstico , Estudos Prospectivos , Curva ROC , Medição de Risco , Fatores de Risco , Resultado do Tratamento
13.
Cancer Lett ; 326(1): 52-8, 2012 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-22819941

RESUMO

The role of HPV in esophageal squamous cell carcinoma (ESCCs) is controversial. Therefore, we determined, through different methodologies, the prevalence of HPV in 264 ESCC samples from Brazil, and correlated it with the presence of surrogate markers and clinicopathological characteristics. HPV is present in 13% of ESCC, and with a 3-fold variation between high and medium incidence areas. Most HPV positive tumors were infected with HPV16, but this was not associated with p16 expression, TP53 mutation status, patient age, amount of tobacco or alcohol consumption, or overall survival. We conclude that HPV infection may not have a role in ESCC.


Assuntos
Carcinoma de Células Escamosas/virologia , Neoplasias Esofágicas/virologia , Infecções por Papillomavirus/complicações , Fatores Etários , Idoso , Consumo de Bebidas Alcoólicas , Brasil/epidemiologia , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Feminino , Genes p16 , Genes p53 , Papillomavirus Humano 16/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prevalência , Fumar
14.
Rev Bras Ginecol Obstet ; 33(2): 99-103, 2011 Feb.
Artigo em Português | MEDLINE | ID: mdl-21779653

RESUMO

Dunnigan-type familial partial lipodystrophy (FPLD) is an autosomal dominant disease that results from heterozygous missense mutations in LMNA, the gene that encodes nuclear lamin A/C. FPLD is characterized by a progressive disappearance of subcutaneous adipose tissue in the limbs, gluteal region, abdomen and trunk, beginning at the time of or after puberty, and excessive amount of fat in the face, chin, labia majora, and intra-abdominal region, leading to a Cushingoid appearance and increased muscularity phenotype. Affected women are particularly predisposed to insulin resistance and its complications, including features of polycystic ovary syndrome. To emphasize the importance of an early FPLD diagnosis, which is necessary to prevent serious metabolic disturbances, we report a woman diagnosed at about 50 years of age. Increased muscularity and significant labia majora fat deposit made the diagnosis possible by gynecologists.


Assuntos
Lipodistrofia Parcial Familiar/diagnóstico , Diagnóstico Precoce , Feminino , Humanos , Pessoa de Meia-Idade , Fenótipo
15.
Rev. bras. ginecol. obstet ; 33(2): 99-103, fev. 2011. ilus
Artigo em Português | LILACS | ID: lil-593314

RESUMO

A lipodistrofia parcial familiar tipo Dunnigan é uma doença autossômica dominante rara. Em sua forma clássica, é resultante de uma mutação missense heterozigótica no gene LMNA, que codifica a proteína nuclear denominada lâmina tipo A/C. Caracteriza-se pelo desaparecimento progressivo do tecido adiposo subcutâneo nos membros, região glútea, abdome e tronco, que se inicia na puberdade, acompanhado de acúmulo de gordura em outras áreas, como a face, queixo, grandes lábios e região intra-abdominal, conferindo o aspecto de hipertrofia muscular e simulando o fenótipo de síndrome de Cushing. Mulheres afetadas são particularmente predispostas à resistência à insulina e suas complicações, incluindo sinais da síndrome dos ovários policísticos. Com o objetivo de alertar para o diagnóstico precoce, que possibilita a adoção de medidas que minimizam os graves distúrbios metabólicos vinculados à desordem, relatamos o caso de uma paciente em que a investigação foi realizada somente ao final da quinta década de vida. A aparente hipertrofia muscular e o acentuado depósito de gordura nos grandes lábios possibilitam aos médicos ginecologistas a suspeita diagnóstica.


Dunnigan-type familial partial lipodystrophy (FPLD) is an autosomal dominant disease that results from heterozygous missense mutations in LMNA, the gene that encodes nuclear lamin A/C. FPLD is characterized by a progressive disappearance of subcutaneous adipose tissue in the limbs, gluteal region, abdomen and trunk, beginning at the time of or after puberty, and excessive amount of fat in the face, chin, labia majora, and intra-abdominal region, leading to a Cushingoid appearance and increased muscularity phenotype. Affected women are particularly predisposed to insulin resistance and its complications, including features of polycystic ovary syndrome. To emphasize the importance of an early FPLD diagnosis, which is necessary to prevent serious metabolic disturbances, we report a woman diagnosed at about 50 years of age. Increased muscularity and significant labia majora fat deposit made the diagnosis possible by gynecologists.


Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Heterozigoto , Resistência à Insulina , Laminas , Lipodistrofia Parcial Familiar/genética , Mutação de Sentido Incorreto/genética , Fenótipo
16.
J Emerg Med ; 40(5): 557-64, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-20022199

RESUMO

BACKGROUND: Different strategies have been described to increase promptness and efficiency in the assessment and management of patients with acute chest pain and acute coronary syndrome (ACS) in the emergency department (ED). OBJECTIVE: The objective of this study is to evaluate the results of implementing a Chest Pain Unit (CPU) to assist patients with ACS, and to determine its impact on quality of health care indexes and clinical outcomes. METHODS: A study was conducted with a prospective cohort of patients admitted to the ED with a chief complaint of acute chest pain or suspected ACS at two different time periods: before (n = 663) and after (n = 450) introducing a CPU as part of the ED. Quality-of-care indexes analyzed in this study were adherence to a critical pathway, length of hospital stay, and hospital mortality. RESULTS: There was increased adherence to a critical pathway during the CPU period compared to the period with no designated CPU area, including compliance with prescribing aspirin, beta-blockers, and angiotensin-converting enzyme inhibitor, and performing coronary angiography in high-risk patients. After adjustment to baseline characteristics, admissions to a CPU resulted in a 65% reduction in mortality (odds ratio 0.35; 95% confidence interval 0.14-0.88; p = 0.03). There was no difference in median length of hospital stay, 7 days (interquartile range [IQR] 4-12) before CPU and 6 days (IQR 4-11) after introducing the CPU (p = 0.10). CONCLUSION: In the scenario of a crowded ED, implementation of a CPU was associated with greater adherence to a critical pathway for patients with ACS, with a concomitant reduction in mortality rates.


Assuntos
Síndrome Coronariana Aguda/diagnóstico , Dor no Peito/diagnóstico , Serviço Hospitalar de Emergência/organização & administração , Unidades Hospitalares/organização & administração , Síndrome Coronariana Aguda/mortalidade , Síndrome Coronariana Aguda/terapia , Algoritmos , Dor no Peito/mortalidade , Dor no Peito/terapia , Procedimentos Clínicos , Feminino , Fidelidade a Diretrizes , Mortalidade Hospitalar , Humanos , Tempo de Internação/estatística & dados numéricos , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Qualidade da Assistência à Saúde , Estatísticas não Paramétricas , Inquéritos e Questionários
17.
Coron Artery Dis ; 21(3): 129-36, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20305551

RESUMO

BACKGROUND: Atherosclerosis is a chronic inflammatory process, and myeloperoxidase (MPO) seems to contribute directly to the pathogenesis of acute coronary syndrome (ACS). OBJECTIVE: To compare MPO levels among the patients with stable and unstable ischemic heart disease and to evaluate their independent prognostic value for cardiovascular events. METHODS: MPO and C-reactive protein (CRP) were assessed in two cohorts of coronary artery disease patients, including 178 patients with stable angina and 130 patients with ACS evaluated at the emergency department. RESULTS: MPO and CRP levels were significantly higher among patients with ACS [MPO 93 (54-127) vs. 9.9 pmol/l (5-21) and high sensitivity-CRP 11 (3-27) vs. 2.6 mg/l (1-5)]. Among patients with stable angina, high sensitivity-CRP levels greater than 3 mg/l were associated with a three-fold risk of further cardiovascular events during a mean follow-up period of 13+/-4 months, although there was no significant association between MPO levels and outcomes. Among patients with ACS, baseline MPO level was an independent predictor of major adverse cardiac events during hospitalization, odds ratio of 3.8 (95% confidence interval: 1.2-12) for the combined endpoint (death, recurrent angina, heart failure, and arrhythmia). CRP levels were associated with hospital mortality in patients with ACS, but were not independently related to cardiovascular events. CONCLUSION: Elevated MPO levels among the ACS patients suggest that this marker may participate in plaque vulnerability and instability process, whereas higher CRP levels were predictive of cardiac events only among the stable angina patients. These findings suggest distinct role of the inflammatory markers studied in the pathophysiology of coronary artery disease.


Assuntos
Síndrome Coronariana Aguda/etiologia , Angina Pectoris/etiologia , Angina Instável/etiologia , Doença da Artéria Coronariana/enzimologia , Mediadores da Inflamação/sangue , Peroxidase/sangue , Síndrome Coronariana Aguda/enzimologia , Síndrome Coronariana Aguda/mortalidade , Idoso , Angina Pectoris/enzimologia , Angina Pectoris/mortalidade , Angina Instável/enzimologia , Angina Instável/mortalidade , Arritmias Cardíacas/enzimologia , Arritmias Cardíacas/etiologia , Biomarcadores/sangue , Proteína C-Reativa/análise , Distribuição de Qui-Quadrado , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/mortalidade , Feminino , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/etiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Recidiva , Medição de Risco , Fatores de Risco , Fatores de Tempo , Regulação para Cima
18.
Mutat Res ; 696(1): 10-5, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19944185

RESUMO

Esophageal cancer (EC) is among the 10 most common and fatal malignacies in the world, presenting a marked geographic variation in incidence rates between and within different countries. The TP53 tumor suppressor gene is highly mutated in esophageal tumors and its mutation pattern can offer clues to the etiopathology of the tumor. As Brazil presents one of the highest incidence areas in the West, a deeper knowledge of the molecular mechanisms related to EC development in the Brazilian population is needed. We analyzed the mutation profile of 110 esophageal squamous cell carcinomas (ESCC) of patients from Southeastern Brazil (Rio de Janeiro and São Paulo) and collected data regarding alcohol intake and tobacco smoking. We detected 41 mutations in tumor samples from 38 patients. There was no association between mutation frequency and tobacco smoking or alcohol drinking. The most frequently mutated codons were 179, 214, 220 and 248. Codons 179, 220 and 248 are hot-spots for ESCC, but codon 214 presents only 0.7% of the mutations registered in the IARC database. The mutation profile revealed a high percentage of mutations at A:T base pairs (34.1%) followed by deletions (17.1%). We concluded that the mutation profile detected in this study is different from that of patients from Southern Brazil but very similar to that previously seen in French patients, being characterized by a high frequency of mutations at A:T base pairs, which may be associated with acetaldehyde, the metabolic product of ethanol.


Assuntos
Carcinoma de Células Escamosas/genética , Genes p53 , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas , Brasil/epidemiologia , Neoplasias Esofágicas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fumar
19.
Coron Artery Dis ; 20(5): 327-331, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19593889

RESUMO

BACKGROUND: Interleukin-18 (IL-18), a proinflammatory cytokine, has been associated with atherogenesis and plaque rupture in acute coronary syndrome (ACS). Recent studies suggest that IL-18 may have a long-term prognostic value. The aim of this study was to evaluate the relationship between IL-18 levels and major adverse cardiovascular events within 6 months of follow-up in post-ACS patients. METHODS: One hundred and twelve consecutive patients admitted to a university hospital with ACS were included in the study. IL-18 and C-reactive protein were measured within the first 24 h of admission. Six months after hospital discharge, the incidence of major adverse cardiovascular events (cardiovascular death, new episode of ACS, and need for unplanned revascularization) was assessed. RESULTS: Mean age of patients was 64 +/- 11 years, and 58 (52%) were male. During the 6 months of follow-up, 33 patients (31.4%) experienced major adverse cardiovascular events. Median IL-18 serum levels were higher among patients who had events than among those who did not: 271.7 pg/ml (interquartile range: 172.9-389.6) and 139.7 pg/ml (interquartile range: 99.9-265.7), respectively (P < 0.01). In the Cox multivariate analysis, after adjustment for clinical risk factors and serum troponin, elevated levels of IL-18 were associated with higher incidence of events (hazard ratio: 2.5; 95% confidence interval: 1.14-5.52; P = 0.023). In this population, C-reactive protein was of borderline significance for events. CONCLUSION: Serum IL-18 levels in ACS patients were independent predictors of long-term cardiovascular events. These findings support the association between inflammation and prognosis of ACS patients, as well as the clinical impact of this biomarker.


Assuntos
Síndrome Coronariana Aguda/imunologia , Doenças Cardiovasculares/imunologia , Mediadores da Inflamação/sangue , Interleucina-18/sangue , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/mortalidade , Síndrome Coronariana Aguda/terapia , Idoso , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Recidiva , Medição de Risco , Fatores de Tempo , Resultado do Tratamento , Troponina/sangue
20.
Pharmacogenomics ; 9(11): 1737-52, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19018727

RESUMO

Tobacco consumption is the main identifiable risk to cancer, contributing to the majority of tumors in upper aerodigestive tissues. The psychoactive compound responsible for tobacco addiction, nicotine and the potent carcinogens present at high concentrations either in cigarette mainstream smoke or in smokeless tobacco products, 4-(methylnitrosamino)-1-(3-pyridyl)-butanone (NNK) and N-nitrosonornicotine (NNN) can be metabolized by CYP2A6. CYP2A6 is expressed in many aerodigestive tissues with high interindividual variability. The CYP2A6 gene is highly polymorphic and CYP2A6 alleles coding for enzymes with altered expression or metabolic capacity produce alterations in nicotine metabolism in vivo and seem to influence smoking behavior. These polymorphisms may change the rate of NNK and NNN activation and, therefore, may influence cancer risk associated with tobacco consumption. However, to date only a few and inconclusive studies have addressed the risk that a given CYP2A6 polymorphism presents for the development of tobacco-related tumors. Most, but not all, show a reduced risk associated with alleles that result in decreased enzyme activity. The overlapping substrate specificity and tissue expression between CYP2A6 and the highly similar CYP2A13 may add to the conflicting results observed. The intricate regulation of CYP2A6 and the variation of structurally different chemical compounds capable of inhibiting CYP2A enzymes also add to the complexity. Finally, the interaction between polymorphisms of genes that code for CYP2A6, CYP2A13 and other potent carcinogen-metabolizing CYP enzymes may help to determine individuals that are at higher risk of developing tumors associated with tobacco consumption.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Carcinógenos/toxicidade , Neoplasias/genética , Nicotiana/toxicidade , Polimorfismo Genético , Carcinógenos/farmacocinética , Citocromo P-450 CYP2A6 , Humanos , Neoplasias/induzido quimicamente , Neoplasias/enzimologia , Nicotina/farmacocinética , Nicotina/toxicidade , Risco , Especificidade por Substrato , Nicotiana/química
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