RESUMO
This study aims to investigate the effects of treatments on the quality of life for patients with esophageal squamous cell carcinoma patients diagnosed at early and late stages. From a medical center in central Taiwan, patients who had been diagnosed with esophageal squamous cell carcinoma from February 2007 and March 2011 were recruited. Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Quality of Life Questionnaire Oesophageal 18 (QLQ-OES18), quality of life scores for 105 esophageal squamous cell carcinoma patients were obtained and assessed. Multivariate analysis was performed on the quality of life scores after stratification by cancer stage. Among early-stage esophageal squamous cell carcinoma patients, those received only surgery (S-only) performed better in physical and social functioning compared with patients who underwent surgery and concurrent chemoradiotherapy (S+CCRT) (ß = 9.0, P = 0.03; ß = 12.1, P = 0.04, respectively). For those that received only concurrent chemoradiotherapy (CCRT-only), they performed worse in role and emotional functioning relative to S+CCRT patients (ß = -17.2, P = 0.02; ß = -15.7, P = 0.05, respectively). Among late-stage patients, CCRT-only treatment gave insignificantly better global health status and functional scale scores and less severe symptoms compared to the S+CCRT option. Better functional scores and less aggravated symptoms are observed in early-stage esophageal squamous cell carcinoma patients who received surgery-only treatment relative to those that underwent both surgery and chemoradiotherapy. For late-stage esophageal cancer patients, the measured difference of quality of life is not significant between CCRT-only and S+CCRT treatments.
Assuntos
Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/terapia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Esofagectomia , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia Adjuvante/efeitos adversos , Esofagectomia/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Inquéritos e QuestionáriosRESUMO
BACKGROUND: (131)I-meta-iodobenzylguanidine ((131)I-MIBG) has been in therapeutic use since 1980s. Newer treatment modalities are emerging for neuroendocrine tumours (NETs) and chromaffin cell tumours (CCTs), but many of these do not yet have adequate long-term follow-up to determine their longer term efficacy and sequelae. METHODS: Fifty-eight patients with metastatic NETs and CCTs who had received (131)I-MIBG therapy between 2000 and 2011 were analysed. Survival and any long-term haematological or renal sequelae were investigated. RESULTS: In the NET group, the overall median survival and median survival following the diagnosis of metastatic disease was 124 months. The median survival following the commencement of (131)I-MIBG was 66 months. For the CCT group, median survival had not been reached. The 5-year survival from diagnosis and following the diagnosis of metastatic disease was 67% and 67.5% for NETs and CCTs, respectively. The 5-year survival following the commencement of (131)I-MIBG therapy was 68%. Thirty-two patients had long-term haematological sequelae: 5 of these 32 patients developed haematological malignancies. Two patients developed a mild deterioration in renal function. CONCLUSION: Long follow up of (131)I-MIBG therapy reveals a noteable rate of bone marrow toxicities and malignancy and long term review of all patients receiving radionuclide therapies is recommended.
Assuntos
3-Iodobenzilguanidina/uso terapêutico , Neoplasias das Glândulas Suprarrenais/radioterapia , Células Cromafins/patologia , Células Cromafins/efeitos da radiação , Radioisótopos do Iodo/uso terapêutico , Tumores Neuroendócrinos/radioterapia , Compostos Radiofarmacêuticos/uso terapêutico , 3-Iodobenzilguanidina/efeitos adversos , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Estudos de Coortes , Feminino , Humanos , Radioisótopos do Iodo/efeitos adversos , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/efeitos adversos , Estudos RetrospectivosRESUMO
AIM: The purpose of this study is to investigate the impact of breast cancer awareness on the attendance for screening among women with breast cancer prior to diagnoses of breast cancer. BACKGROUND: Breast cancer is the most commonly diagnosed cancer for women in Taiwan and its incidence rate continues to increase. However, screening for breast cancer is still not common even if the incidence rate has topped the list from 2003 to 2010. METHODS: A cross-sectional study was conducted among women diagnosed with breast cancer. Subjects (535 women) were recruited from two medical centres in central Taiwan. Information on attendance for breast cancer screening was collected by self-report. Chi-square test and logistic regression were utilized to analyse the relationships between awareness of breast cancer and attendance at screening. FINDINGS: The results indicated that pre-diagnostic awareness of 'the concept of early treatment relating to higher cure rate'[odds ratio (OR): 4.09; 95% confidence interval (CI): 1.12-14.9], 'various breast cancer screening methods' (OR:3.00; 95% CI: 1.23-7.30), 'the coverage of breast cancer screening programme in the National Health Insurance' (OR:1.76; 95% CI: 1.03-3.02) and 'breast self-examination after each menstrual cycle' (OR:3.42; 95% CI: 1.99-5.87) were all significantly associated with the screening procedures performed. CONCLUSIONS: Findings of this study indicated that particular attention should be paid towards enhancement of women's knowledge for prevention and early detection of breast cancer through educational efforts by nurse professionals, medical institutions and/or civil organizations.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Mamografia/estatística & dados numéricos , Educação de Pacientes como Assunto , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Fatores Socioeconômicos , Adulto JovemRESUMO
The ATM protein, encoded by the gene responsible for the human genetic disorder ataxia telangiectasia (A-T), regulates several cellular responses to DNA breaks. ATM shares a phosphoinositide 3-kinase-related domain with several proteins, some of them protein kinases. A wortmannin-sensitive protein kinase activity was associated with endogenous or recombinant ATM and was abolished by structural ATM mutations. In vitro substrates included the translation repressor PHAS-I and the p53 protein. ATM phosphorylated p53 in vitro on a single residue, serine-15, which is phosphorylated in vivo in response to DNA damage. This activity was markedly enhanced within minutes after treatment of cells with a radiomimetic drug; the total amount of ATM remained unchanged. Various damage-induced responses may be activated by enhancement of the protein kinase activity of ATM.
Assuntos
Proteínas de Transporte , Dano ao DNA , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases , Proteínas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Androstadienos/farmacologia , Ataxia Telangiectasia/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular , Linhagem Celular , Proteínas de Ligação a DNA , Inibidores Enzimáticos/farmacologia , Humanos , Mutação , Fosfatidilinositol 3-Quinases/química , Fosfoproteínas/metabolismo , Fosforilação , Inibidores de Proteínas Quinases , Proteínas Quinases/química , Proteínas/antagonistas & inibidores , Proteínas/química , Proteínas/genética , Proteínas Recombinantes/metabolismo , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor , Wortmanina , Zinostatina/farmacologiaRESUMO
Both fission yeast and mammalian cells require the function of the checkpoint kinase CHK1 for G2 arrest after DNA damage. The tumor suppressor p53, a well-studied stress response factor, has also been shown to play a role in DNA damage G2 arrest, although in a manner that is probably independent of CHK1. p53, however, can be phosphorylated and regulated by both CHK1 as well as another checkpoint kinase, hCds1 (also called CHK2). It was therefore of interest to determine whether reciprocally, p53 affects either CHK1 or CHK2. We found that induction of p53 either by diverse stress signals or ectopically using a tetracycline-regulated promoter causes a marked reduction in CHK1 protein levels. CHK1 downregulation by p53 occurs as a result of reduced CHK1 RNA accumulation, indicating that repression occurs at the level of transcription. Repression of CHK1 by p53 requires p21, since p21 alone is sufficient for this to occur and cells lacking p21 cannot downregulate CHK1. Interestingly, pRB is also required for CHK1 downregulation, suggesting the possible involvement of E2F-dependent transcription in the regulation of CHK1. Our results identify a new repression target of p53 and suggest that p53 and CHK1 play interdependent and complementary roles in regulating both the arrest and resumption of G2 after DNA damage.
Assuntos
Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases , Proteína do Retinoblastoma/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Linhagem Celular , Quinase 1 do Ponto de Checagem , Quinase do Ponto de Checagem 2 , Dano ao DNA , Regulação para Baixo , Fase G2/genética , Fase G2/fisiologia , Marcação de Genes , Genes p53 , Humanos , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estresse Fisiológico/genética , Estresse Fisiológico/metabolismo , Proteína Supressora de Tumor p53/genética , Proteínas rho de Ligação ao GTP/genéticaRESUMO
The tumor suppressor protein p53 acts as a transcriptional activator that can mediate cellular responses to DNA damage by inducing apoptosis and cell cycle arrest. p53 is a nuclear phosphoprotein, and phosphorylation has been proposed to be a means by which the activity of p53 is regulated. The cyclin-dependent kinase (CDK)-activating kinase (CAK) was originally identified as a cellular kinase required for the activation of a CDK-cyclin complex, and CAK is comprised of three subunits: CDK7, cyclin H, and p36MAT1. CAK is part of the transcription factor IIH multiprotein complex, which is required for RNA polymerase II transcription and nucleotide excision repair. Because of the similarities between p53 and CAK in their involvement in the cell cycle, transcription, and repair, we investigated whether p53 could act as a substrate for phosphorylation by CAK. While CDK7-cyclin H is sufficient for phosphorylation of CDK2, we show that p36MAT1 is required for efficient phosphorylation of p53 by CDK7-cyclin H, suggesting that p36MAT1 can act as a substrate specificity-determining factor for CDK7-cyclin H. We have mapped a major site of phosphorylation by CAK to Ser-33 of p53 and have demonstrated as well that p53 is phosphorylated at this site in vivo. Both wild-type and tumor-derived mutant p53 proteins are efficiently phosphorylated by CAK. Furthermore, we show that p36 and p53 can interact both in vitro and in vivo. These studies reveal a potential mechanism for coupling the regulation of p53 with DNA repair and the basal transcriptional machinery.
Assuntos
Quinases Ciclina-Dependentes , Ciclinas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação/genética , Ciclina H , Ciclinas/química , Reparo do DNA , Humanos , Dados de Sequência Molecular , Mutação , Fosforilação , Conformação Proteica , Proteínas Serina-Treonina Quinases/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transcrição Gênica , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/genética , Quinase Ativadora de Quinase Dependente de CiclinaRESUMO
BACKGROUND: Discriminative drug level thresholds for disease activity endpoints in patients with Crohn's disease. have been consistently demonstrated with infliximab, but not adalimumab. AIMS: To identify threshold concentrations for infliximab and adalimumab in Crohn's disease according to different disease endpoints, and factors that influence drug levels. METHODS: We performed a cross-sectional service evaluation of patients receiving maintenance infliximab or adalimumab for Crohn's disease. Serum drug levels were at trough for infliximab and at any time point for adalimumab. Endpoints included Harvey-Bradshaw index, C-reactive protein and faecal calprotectin. 6-tioguanine nucleotide (TGN) concentrations were measured in patients treated with thiopurines. RESULTS: A total of 191 patients (96 infliximab, 95 adalimumab) were included. Differences in infliximab levels were observed for clinical (P=.081) and biochemical remission (P=.003) and faecal calprotectin normalisation (P<.0001) with corresponding thresholds identified on ROC analysis of 1.5, 3.4 and 5.7 µg/mL. Adalimumab levels were similar between active disease and remission regardless of the endpoint assessed. Modelling identified that higher infliximab dose, body mass index and colonic disease independently accounted for 31% of the variation in infliximab levels, and weekly dosing, albumin and weight accounted for 23% of variation in adalimumab levels. TGN levels did not correlate with drug levels. CONCLUSIONS: Infliximab drug levels are associated with the depth of response/remission in patients with Crohn's disease, but no such relationship was observed for adalimumab. More data are needed to explain the variation in drug levels.
Assuntos
Adalimumab/uso terapêutico , Doença de Crohn/tratamento farmacológico , Infliximab/uso terapêutico , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Adulto , Anticorpos Monoclonais/uso terapêutico , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Estudos Transversais , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Infliximab/administração & dosagem , Infliximab/efeitos adversos , Complexo Antígeno L1 Leucocitário/análise , Masculino , Pessoa de Meia-IdadeRESUMO
Oxidatively modified low-density lipoprotein may be involved in the adherence of blood monocytes to arterial endothelium in the early atherosclerotic lesion. The present study employed static assays and flow-chamber technique to investigate the adhesive interactions between isolated human blood monocytes and cultured human umbilical vein endothelial cell (EC) monolayer pretreated with Cu(2+)-oxidized human plasma LDL (Ox-LDL) and native LDL (N-LDL). The cell-cell binding force was estimated by the intensity of wall shear stress needed to detach monocytes from an EC monolayer. The number of monocytes attached to EC monolayer was quantitated by microscopic observation, measurement of myeloperoxidase (MPO) activity in monocyte and cellular uptake of Rose Bengal stain. The results show that the proadhesive activity of EC surface for monocytes was strongly induced by Ox-LDL and weakly modulated by N-LDL. Pretreatment of an EC monolayer with Ox-LDL (25 micrograms/ml) for 6 h induced a 2.2-fold increase in the number and an 8-fold increase in the force of monocyte binding to EC monolayer as compared to untreated control. A significant number of monocytes (4.4-times control) were able to maintain their adhesion to Ox-LDL-pretreated EC monolayer under high shear stress (30 dyn/cm2). The cell surface expression of intercellular adhesion molecule 1 (ICAM-1), but not vascular cell adhesion molecule 1 (VCAM-1), in umbilical vein EC was increased by 2.6-fold after treatment of EC with Ox-LDL (50 micrograms/ml) for 6 h compared with non-treated control. On prolonged (> 12 h) incubation, Ox-LDL (> 100 micrograms/ml) was found to have cytotoxic effect on EC as reflected by the loss of EC integrity and detachment at low shear stress. It indicates that a sublethal dose of oxidized LDL may alter vascular endothelium physiology, up-regulate expression of ICAM-1 in EC, enhance monocytes binding against shear-stress-induced detachment, and thus may contribute to atherogenesis.
Assuntos
Endotélio Vascular/citologia , Lipoproteínas LDL/fisiologia , Monócitos/fisiologia , Adesão Celular/fisiologia , Moléculas de Adesão Celular/biossíntese , Células Cultivadas , Endotélio Vascular/metabolismo , Humanos , Molécula 1 de Adesão Intercelular , Contagem de Leucócitos , Oxirredução , Estresse Mecânico , Molécula 1 de Adesão de Célula VascularRESUMO
Plasma low density lipoproteins (LDL) of patients with coronary artery disease (CAD) may be qualitatively different from those of normal persons. To study the immunochemical difference in plasma LDL between CAD patients and normals, we employed competitive enzyme-linked immunosorbent assay (ELISA) using one polyclonal and five monoclonal anti-LDL antibodies to measure apolipoprotein B (apo B) epitope expression in whole plasma from 20 angiographically documented CAD patients and 7 healthy control subjects. The patient group had a significantly higher plasma concentration of apo B but showed decreased relative expression of the 4B11 epitope in plasma LDL. No significant difference in the expression of the other four epitopes was found between patients and controls. The 4B11 monoclonal anti-LDL antibody was demonstrated to inhibit the modification of native LDL by endothelial cells (EC) and to reduce subsequent uptake and degradation by J774 macrophages. In vitro oxidative modification of LDL by EC or Cu2+ was associated with a decrease in the 4B11 immunoreactivity on apo B. The results imply that plasma LDL may be somewhat oxidatively modified in vivo by vascular endothelium in patients with CAD. Competitive inhibition assay further showed that plasma LDL of CAD patients had greater ability to compete for scavenger receptor and less ability to compete for LDL receptor of J774 macrophages than those of controls. Pretreatment of EC with plasma LDL of CAD patients as compared to those of control subjects induced a significantly greater increase in U937 monocyte adhesion. In conclusion, plasma LDL of CAD patients demonstrated decreased expression of a particular apo B epitope related to scavenger receptor-binding site of EC-modified LDL and greater affinity for scavenger receptor, and caused enhanced adherence of monocytes to EC. The data support the existence of qualitative changes in plasma LDL of CAD patients.
Assuntos
Apolipoproteínas B/sangue , Doença das Coronárias/sangue , Epitopos/análise , Lipoproteínas LDL/sangue , Idoso , Apolipoproteínas B/química , Sítios de Ligação , Ligação Competitiva , Adesão Celular , Doença das Coronárias/complicações , Complicações do Diabetes , Endotélio Vascular/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Hipercolesterolemia/complicações , Hipertensão/complicações , Peróxidos Lipídicos/análise , Lipoproteínas LDL/química , Macrófagos/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
Oxidative modification of lipoproteins may play a crucial role in the pathogenesis of atherosclerosis. This study was designed to examine whether increased lipid peroxides and/or oxidative susceptibility of plasma lipoproteins occur in patients with coronary artery disease. The levels of lipid peroxides, estimated as thiobarbituric acid-reactive substances (TBARS), were significantly greater in the plasma and very low density lipoprotein (VLDL) of symptomatic patients with coronary artery disease than in those of healthy persons, but the TBARS levels of low density lipoprotein (LDL) and high density lipoprotein (HDL) showed insignificant difference between patients and normals. To evaluate the oxidative susceptibility of lipoproteins, we employed in vitro Cu2+ oxidation of lipoproteins monitored by changes in fluorescence, TBARS level, trinitrobenzene sulfonic acid (TNBS) reactivity, apolipoprotein immunoreactivity and agarose gel electrophoretic mobility. While pooled VLDL and LDL of normal controls were oxidized at 5-10 microM Cu2+, pooled VLDL and LDL of patients with coronary artery disease were oxidized at 1-2.5 microM Cu2+, i.e., at relatively lower oxidative stress. At 5 microM Cu2+, VLDL and LDL of patients with coronary artery disease still showed a faster oxidation rate, judged by the rate of fluorescence increase, higher TBARS level, less TNBS reactivity, greater change in apo B immunoreactivity and higher electrophoretic mobility than those of normal controls. However, the difference on the oxidizability of HDL was insignificant for patients vs. normals. In conclusion, we have shown that plasma VLDL and LDL of patients with coronary artery disease are more susceptible to in vitro oxidative modification than those of healthy persons. The data suggest that enhanced oxidizability of plasma lipoproteins may be an important factor influencing the development of coronary artery disease.
Assuntos
Doença das Coronárias/sangue , Lipoproteínas LDL/sangue , Adulto , Idoso , Apolipoproteínas/análise , Cobre , Eletroforese em Gel de Ágar , Feminino , Humanos , Peroxidação de Lipídeos , Lipoproteínas HDL/sangue , Lipoproteínas VLDL/sangue , Masculino , Pessoa de Meia-Idade , Oxirredução , Espectrometria de Fluorescência , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Ácido TrinitrobenzenossulfônicoRESUMO
Plasma glucose, insulin, and lipoprotein concentrations were determined in 20 men with hypertension, and compared with values in 20 normotensive men of comparable age and body mass index. The results demonstrated a significant increase in both the plasma glucose and insulin response to a 75-g oral glucose challenge (two-way analysis of variance). In addition, a significant correlation existed between the plasma blood pressure. Finally, the greater the plasma glucose insulin response to oral glucose and both systolic and diastolic and insulin responses to oral glucose, the lower the plasma high-density lipoprotein concentrations, and the higher the ratio of plasma low-density lipoprotein cholesterol to high-density lipoprotein cholesterol. Thus, abnormalities of plasma glucose, insulin, and lipoprotein metabolism exist in patients with untreated hypertension, and these changes may contribute to the increased risk for coronary artery disease associated with hypertension.
Assuntos
Glicemia/metabolismo , Hipertensão/sangue , Insulina/sangue , Lipídeos/sangue , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
BTG3 (B-cell translocation gene 3) is a p53 target that also binds and inhibits E2F1. Although it connects two major growth-regulatory pathways functionally and is downregulated in human cancers, whether and how BTG3 acts as a tumor suppressor remain largely uncharacterized. Here we present evidence that BTG3 binds and suppresses AKT, a kinase frequently deregulated in cancers. BTG3 ablation results in increased AKT activity that phosphorylates and inhibits glycogen synthase kinase 3ß. Consequently, we also observed elevated ß-catenin/T-cell factor activity, upregulation of mesenchymal markers, and enhanced cell migration. Consistent with these findings, BTG3 overexpression suppressed tumor growth in mouse xenografts, and was associated with diminished AKT phosphorylation and reduced ß-catenin in tissue specimens. Significantly, a short BTG3-derived peptide was identified, which recapitulates these effects in vitro and in cells. Thus, our study provides mechanistic insights into a previously unreported AKT inhibitory pathway downstream of p53. The identification of an AKT inhibitory peptide also unveils a new avenue for cancer therapeutics development.
Assuntos
Progressão da Doença , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Técnicas de Cultura de Células , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Membrana Celular/enzimologia , Proliferação de Células , Transição Epitelial-Mesenquimal , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Peptídeos/metabolismo , Fosforilação , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismoRESUMO
This study was initiated to 1) assess gemfibrozil's ability to lower plasma triglyceride (TG) concentration in patients with NIDDM, and 2) determine whether this effect was associated with any changes in glycemic control. Measurements were made of mean hourly plasma glucose, insulin, TG, and FFA concentrations from 1200-1600 h in response to a test meal; hepatic glucose production (HGP); insulin-stimulated glucose uptake during a hyperinsulinemic glucose clamp study (MCR); and fasting plasma lipoprotein TG and cholesterol concentrations in 12 patients with NIDDM before and 3 months after gemfibrozil treatment. Although ambient plasma TG and FFA concentrations fell significantly, plasma glucose, insulin, HGP, concentrations fell significantly, plasma glucose, insulin, HGP, and glucose MCR did not change. However, when patients were divided into two groups, those with fasting plasma glucose levels above 9 mmol/L (fair control) and those with levels below 9 mmol/L (good control), a different phenomenon was observed. Patients in fair control had significant decreases in mean hourly plasma concentrations of glucose (15.1 +/- 1.7 to 12.6 +/- 0.9 mmol/L; P less than 0.001), insulin (523 +/- 59 to 471 +/- 75 pmol/L; P less than 0.001), FFA (652 +/- 150 to 504 +/- 76 mumol/L), and HGP (9.5 0.4 to 8.1 +/- 0.4 mumol/kg.min; P less than 0.005), and an increase in glucose MCR (2.63 +/- 0.49 to 3.72 +/- 0.54 mL/kg.min; P less than 0.07) in association with a fall in TG from 6.9 +/- 1.3 to 3.5 +/- 0.9 mmol/L (P less than 0.001). Although fasting low density lipoprotein cholesterol increased (1.8 +/- 0.2 to 2.7 +/- 0.2 mmol/L; P less than 0.05), the ratio of total to high density lipoprotein cholesterol decreased (6.84 +/- 0.88 to 5.80 +/- 1.05; P less than 0.02). Despite a significant fall in mean hourly TG concentration (4.6 +/- 0.7 to 3.8 +/- 0.7 mmol/L; P less than 0.001), neither insulin, FFA, HGP, nor glucose MCR changed in patients in good control. Furthermore, the mean hourly plasma glucose concentration increased from 9.2 +/- 0.7 to 11.7 +/- 1.4 mmol/L (P less than 0.001). Low density lipoprotein cholesterol also increased in this group (1.9 +/- 0.2 to 2.7 +/- 0.2 mmol/L; P less than 0.02), but, as before, the ratio of total to high density lipoprotein cholesterol decreased (8.15 +/- 1.93 to 6.36 +/- 1.03; P less than 0.02).
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Genfibrozila/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Glicemia/metabolismo , Colesterol/metabolismo , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos não Esterificados/sangue , Genfibrozila/farmacologia , Humanos , Insulina/sangue , Lipoproteínas/metabolismo , Lipoproteínas HDL/sangue , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
The effects of exertional heat stroke (ExHS), with or without acute renal failure (ARF), on thyroid hormone metabolism were investigated. Eighteen ExHS patients were recruited and divided into two groups based on the presence or absence of ARF. Eleven age-matched healthy subjects served as a control group. Serum values of T3, T4, TSH, free T4 (FT4), rT3, and sulfated T3 (T3S) were measured in these groups during the acute and recovery stages of ExHS. Serum T3, T4, and FT4 levels were reduced, with reciprocal increases in rT3 and T3S levels as the severity of ExHS increased. The following mean levels of thyroid hormones were found (controls vs. ExHS without ARF vs. with ARF): T3, 1514 vs. 1164 vs. 393 pmol/L (P < 0.05 each); T4, 97 vs. 79 vs. 49 nmol/L (P = NS and P < 0.05, respectively); FT4, 20.5 vs. 19.5 vs. 19.0 pmol/L (P = NS each); rT3, 371 vs. 617 vs. 805 pmol/L (P < 0.05 and P = NS, respectively); and T3S, 30.1 vs. 34.2 vs. 71.1 pmol/L (P = NS and P < 0.05, respectively). The serum TSH levels were not significantly different among the three groups. Significantly negative correlations were found between serum creatinine and T3 (r = -0.75; P < 0.001) and T4 levels (r = -0.65; P < 0.001), whereas no relationship was noted between serum creatinine and rT3 values (r = 0.11; P < 0.05). In contrast, a correlation was observed between serum glutamic pyruvic transaminase and rT3 (r = 0.45; P < 0.01). Thyroid function tests returned to normal after patients recovered. In conclusion, our results show that patients suffering from ExHS, with or without ARF, displayed altered serum thyroid function in proportion to the severity of their condition. No significant changes in serum levels of rT3 were observed between the two groups, whereas a positive relationship was observed between serum rT3 and serum glutamic pyruvic transaminase values, suggesting that the changes in serum rT3 levels were more dependent on extrarenal illness than on renal disease per se. The moderate increase in serum T3S levels found in patients suffering from both ExHS and ARF may represent a decrease in tissue 5'-monodeiodinase activity as found in other nonthyroidal illnesses. A return of serum thyroid function tests to normal values after recovery from ExHS suggests that the low T3 state may play a protective role to prevent undesirable catabolic effects. Replacement therapy is thus not recommended.
Assuntos
Injúria Renal Aguda/etiologia , Golpe de Calor/sangue , Golpe de Calor/complicações , Militares , Esforço Físico , Hormônios Tireóideos/sangue , Adulto , Alanina Transaminase/sangue , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Humanos , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue , Tri-Iodotironina Reversa/sangueRESUMO
Plasma glucose and insulin responses to a glucose challenge and insulin-stimulated glucose uptake were measured in 24 age-, weight-, and sex-matched Chinese men (8 with normal blood pressure, 8 with untreated hypertension, and 8 patients with hypertension treated with thiazide and beta-adrenergic antagonist drugs). Plasma glucose and insulin responses were determined by measuring plasma glucose and insulin concentrations before and at 30-min intervals for 2 h after a 75-g oral glucose dose. Insulin-stimulated glucose uptake was estimated by measuring the steady state plasma glucose (SSPG) and insulin (SSPI) concentrations achieved during the last 60 min of a 180-min continuous infusion of somatostatin, insulin, and glucose (insulin suppression test). Under these conditions endogenous insulin secretion was suppressed, and similar SSPI concentrations were achieved in all men; thus, the differences in the resultant SSPG concentrations allowed direct comparison of insulin's ability to stimulate disposal of an identical glucose load in different individuals. The results indicated that the men with hypertension, whether treated or untreated, had significantly elevated plasma glucose (P less than 0.001) and insulin (P less than 0.001) responses to the oral glucose dose compared to the normal men. Mean (+/- SE) SSPG concentrations were also higher (P less than 0.001) in the men with either untreated hypertension [219 +/- 9 mg/dL (12.2 +/- 0.5 mmol/L)] or treated hypertension [211 +/- 18 mg/dL (11.7 +/- 1.0 mmol/L)] than in the normal men [134 +/- 13 mg/dL (7.4 +/- 0.7 mmol/L)]. Since the mean SSPI concentrations were similar in the 3 groups [approximately 70 microU/mL (502 pmol/L)], insulin was less effective in promoting glucose disposal in both groups with hypertension. These results document the fact that patients with hypertension, whether treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic compared to a well-matched control group.
Assuntos
Glicemia/metabolismo , Hipertensão/sangue , Resistência à Insulina , Adulto , Humanos , Hiperinsulinismo/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
Gemfibrozil or placebo was administered for 3 months to 24 individuals with endogenous hypertriglyceridemia and normal glucose tolerance. Mean ( +/- SEM) fasting plasma triglyceride (TG) concentrations decreased (4.01 +/- 0.55 to 1.34 +/- 0.12 mmol/L; P < 0.001) and high density lipoprotein cholesterol concentrations increased (0.54 +/- 0.03 to 0.67 +/- 0.04 mmol/L; P < 0.001) in gemfibrozil-treated patients, associated with lower (P < 0.01-0.001) plasma free fatty acid and TG concentrations when measured at hourly intervals in response to breakfast (0800 h) and lunch (1200 h). However, day-long plasma glucose and insulin responses to meals in the 2 groups were similar before and after treatment, as were the steady state plasma glucose and insulin concentrations at the end of a 180-min infusion of somatostatin, insulin, and glucose. Thus, marked decreases in both plasma TG and free fatty acid concentrations seen in association with gemfibrozil neither enhanced insulin-mediated glucose disposal nor lowered ambient plasma insulin concentrations in patients with endogenous hypertriglyceridemia.
Assuntos
Genfibrozila/uso terapêutico , Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Adulto , Idoso , Glicemia/metabolismo , HDL-Colesterol/sangue , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Ritmo Circadiano , Ácidos Graxos não Esterificados/sangue , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/complicações , Insulina/sangue , Resistência à Insulina , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
Pharmacokinetics and pharmacodynamics of pimobendan were studied in eight patients with dilated cardiomyopathy and chronic congestive heart failure after single dosing and after 2-week repeated dosing of 5 mg racemic pimobendan. Enantiomers of pimobendan and its demethylated metabolite in plasma and in red blood cells were measured. In the single-dose study, the peak plasma levels of 16.3 +/- 4.0 and 17.0 +/- 3.1 ng/ml of (+)- and (-)-pimobendan were observed at 0.9 hour after dosing. The concentration-time curves followed a two-compartment model, with terminal half-lives of 2.56 +/- 0.35 and 2.93 +/- 0.33 hours for (+)- and (-)-pimobendan (p > 0.05), respectively. The oral volumes of distribution after equilibrium were 3.26 +/- 0.74 and 3.13 +/- 0.75 L/kg, and oral clearances were 28.6 +/- 7.0 and 21.9 +/- 4.1 ml/min/kg for (+)- and (-)-pimobendan (p > 0.05), respectively. In red blood cells, the respective (+)- and (-)-pimobendan concentrations were 5.8 and 8.4 times higher than those in plasma, indicating a stereoselective partitioning of drugs between plasma and red blood cells. The pharmacodynamic effect of pimobendan was evaluated by echocardiography. The ejection fraction, mean velocity of circumferential fiber shortening, aortic flow peak velocity, cardiac index, and stroke volume index significantly increased 50% to 60%. The left ventricular end-systolic dimension, systolic blood pressure, and diastolic blood pressure significantly decreased 8% to 11%. These effects lasted for more than 8 hours. In a 2-week repeated-dose study, there was no significant dose accumulation in plasma and red blood cells. The pharmacokinetic parameters were similar to those in the single-dose study, except for significantly shorter absorption half-lives. The baseline levels of cardiac index and stroke volume index were significantly higher than the baseline levels in the single-dose study. This suggests an accumulation of pharmacodynamic effects despite a relatively short elimination half-life.
Assuntos
Cardiomiopatia Dilatada/metabolismo , Cardiotônicos/farmacocinética , Insuficiência Cardíaca/metabolismo , Hemodinâmica/efeitos dos fármacos , Piridazinas/farmacocinética , Vasodilatadores/farmacocinética , Administração Oral , Análise de Variância , Cardiomiopatia Dilatada/fisiopatologia , Cardiotônicos/administração & dosagem , Cardiotônicos/farmacologia , Ecocardiografia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Piridazinas/administração & dosagem , Piridazinas/farmacologia , Estereoisomerismo , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacologiaRESUMO
BACKGROUND: Childhood obesity increases the risk of obesity in adulthood and is associated with cardiovascular disease (CVD) risk factors such as hypertension, diabetes mellitus, and dyslipidemia. OBJECTIVE: We evaluated the clustering of CVD risk factors among obese schoolchildren in Taiwan. DESIGN: After multistage sampling of 85 junior high schools in Taipei, we randomly selected 1366 children (681 boys and 685 girls) aged 13.3 y (range: 12-16 y). Anthropometric, blood pressure (BP), and biochemical CVD risk factors (including blood glucose, lipid, and lipoprotein concentrations) were measured. RESULTS: Boys had a higher body mass index, systolic BP, and glucose concentrations than girls and girls had higher lipid and lipoprotein concentrations than boys. After adjustment for age, obese boys had a significantly higher BP, ratio of total to HDL cholesterol, and glucose, cholesterol, triacylglycerol, HDL cholesterol, LDL cholesterol, apolipoprotein A-I, and apolipoprotein B concentrations than nonobese boys. BP, HDL cholesterol, LDL cholesterol, and ratio of total to HDL cholesterol were significantly different between nonobese and obese girls. Approximately 70% of obese boys had one and 25% had two or more CVD risk factors other than obesity. Obese girls had a significantly higher prevalence of high BP and a higher prevalence of CVD risk factor clustering than nonobese girls. CONCLUSIONS: Boys had higher glucose concentrations and BP and lower lipid concentrations than girls. We found an association between obesity and higher BP and between obesity and blood glucose and lipid concentrations for both sexes. Clustering of CVD risk factors was especially apparent among the obese children. A clustering of CVD risk factors may begin during early adolescence among the obese.
Assuntos
Doenças Cardiovasculares/epidemiologia , Obesidade/complicações , Adolescente , Antropometria , Doenças Cardiovasculares/etiologia , Criança , Análise por Conglomerados , Estudos Transversais , Feminino , Humanos , Hiperglicemia/complicações , Hiperglicemia/epidemiologia , Hiperlipidemias/complicações , Hiperlipidemias/epidemiologia , Hipertensão/complicações , Hipertensão/epidemiologia , Masculino , Obesidade/sangue , Prevalência , Distribuição Aleatória , Fatores de Risco , Fatores Sexuais , Inquéritos e Questionários , TaiwanRESUMO
Plasma lipid and lipoprotein concentrations were determined in 125 Chinese males with a medical history and electrocardiographic abnormalities consistent with the diagnosis of coronary artery disease (CAD). All subjects underwent coronary arteriography, and patients were divided into 3 groups based upon the results of the coronary arteriograms: 1) patients with a negative angiogram (CAD-, n = 30), without hypertension; 2) patients with a positive angiogram, without hypertension (CAD+, n = 70); and 3) patients with a positive angiogram, who had hypertension (CAD + HT, n = 25). Mean fasting plasma lipid and lipoprotein concentrations of these 3 groups of patients were compared to values in age and weight-matched groups of normal individuals (n = 80) and untreated patients with hypertension and no evidence of CAD (HT, n = 20). The results indicated that total plasma triglyceride, cholesterol, and LDL-cholesterol levels were significantly higher (P less than 0.001) than normal in patients with CAD+ and CAD + HT, whereas only plasma cholesterol levels were higher than normal in patients with HT. Although patients with CAD- had values intermediate between normal and CAD, the differences were not statistically significant. In addition, the ratio of LDL to HDL-cholesterol was significantly increased (P less than 0.05-0.001) above normal in patients with CAD+, CAD + HT, and HT. As before, the values in patients with CAD- were intermediate. These data document the presence of multiple abnormalities of lipid and lipoprotein concentration in patients with angiographic evidence of CAD, whether or not they were hypertensive. Furthermore, abnormalities in lipid and lipoprotein metabolism were seen in patients with hypertension alone.
Assuntos
Doença das Coronárias/sangue , Hipertensão/sangue , Lipídeos/sangue , Lipoproteínas/sangue , Idoso , China , Colesterol/sangue , Angiografia Coronária , Doença das Coronárias/complicações , Doença das Coronárias/diagnóstico por imagem , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The homozygote deletion (DD) genotype of the angiotensin I converting enzyme (ACE) gene has been shown to be associated with an increased risk of coronary heart disease independent of other risk factors. OBJECTIVE: To investigate the possible association of the insertion/deletion (I/D) polymorphism of the ACE gene with insulin resistance in a Chinese population with and without hypertension. SUBJECTS AND METHODS: The I/D polymorphism of the ACE gene was determined for 361 Chinese including 148 women and 96 men with normal blood pressures and 64 male and 53 female patients with mild-to-moderate hypertension. Insulin resistance was estimated by the insulin suppression test and glucose intolerance evaluated with an oral glucose-tolerance test for all of the subjects. RESULTS: Three hypertensive subgroups with DD, DI and II genotypes having similar ages and body mass indexes presented insignificantly different degrees of glucose intolerance and insulin resistance both among men and among women. Similar results were found for normotensive subjects. In addition, ACE genotypes were not significant predictors of insulin resistance and glucose intolerance either among men or among women after adjustment for age, body mass index, and hypertension. CONCLUSION: The present data indicated that the I/D polymorphism of the ACE gene was not related to insulin resistance for Chinese hypertensive and normotensive subjects. The increased risk of coronary heart disease associated with the DD genotype need not be mediated through the mechanism of insulin resistance and glucose intolerance for Chinese patients with hypertension.