RESUMO
BACKGROUND: dyslipidemia is common and is often treated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins). Little is known about the comparative effectiveness of statins among human immunodeficiency virus (HIV)-infected patients. This study compared the effectiveness and toxicity of statins among HIV-infected patients in clinical care. METHODS: we conducted a retrospective cohort study of patients starting their initial statin medications at 2 large HIV clinics (N = 700). The primary observation was change in lipid levels during statin therapy. Secondary observations included whether individualized National Cholesterol Education Program (NCEP) goals for low density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein cholesterol (non-HDL-C) levels were reached, and toxicity rates. We used linear regression to examine change in lipid levels, controlling for baseline lipid values and demographic and clinical characteristics. We conducted secondary analyses using propensity scores to address confounding by indication. RESULTS: the most commonly prescribed statins were atorvastatin (N = 303), pravastatin (N = 280), and rosuvastatin (N = 95). One year after starting a statin therapy, patients who received atorvastatin or rosuvastatin had significantly greater decreases in total cholesterol, LDL-C, and non-HDL-C than patients on pravastatin. The likelihood of reaching NCEP goals for LDL-C levels was higher with the use of rosuvastatin (OR 2.1; P = .03) and atorvastatin (odds ratio [OR], 2.1; P = .001) compared with that of pravastatin. The likelihood of reaching NCEP goals for non-HDL-C levels was higher for rosuvastatin (OR 2.3; P = .045) but not atorvastatin (OR, 1.5; P = .1) compared with pravastatin. Toxicity rates were similar for all 3 statins: 7.3% for atorvastatin, 6.1% for pravastatin, and 5.3% for rosuvastatin. CONCLUSIONS: our findings suggest that atorvastatin and rosuvastatin are preferable to pravastatin for treatment of HIV-infected patients with dyslipidemia, due to greater declines in total cholesterol, LDL-C, and non-HDL-C, with similar lower toxicity rates.
Assuntos
Dislipidemias/tratamento farmacológico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Atorvastatina , Colesterol/sangue , Estudos de Coortes , Feminino , Fluorbenzenos/efeitos adversos , Fluorbenzenos/farmacologia , Fluorbenzenos/uso terapêutico , Ácidos Heptanoicos/efeitos adversos , Ácidos Heptanoicos/farmacologia , Ácidos Heptanoicos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/efeitos adversos , Pirróis/farmacologia , Pirróis/uso terapêutico , Estudos Retrospectivos , Rosuvastatina Cálcica , Soro/química , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêuticoRESUMO
OBJECTIVE: To determine whether obesity and insulin resistance associate with changes in the protein content of high-density lipoprotein (HDL) in 2 different groups of men by using targeted proteomics. METHODS AND RESULTS: Insulin resistance and obesity are hallmarks of type 2 diabetes mellitus and the metabolic syndrome, which confer an increased risk of cardiovascular disease. Recent studies suggest that the protein cargo of HDL makes important contributions to the lipoprotein's cardioprotective effects. In a discovery study, we used isotope dilution mass spectrometry to quantify the relative concentrations of 5 proteins previously implicated in HDL's cardioprotective effects in 3 groups of healthy subjects: lean insulin-sensitive, lean insulin-resistant, and obese insulin-resistant individuals. We validated our findings in a different group of subjects. The clusterin concentration in HDL strongly and negatively associated with insulin resistance and body mass index in both populations. HDL clusterin levels were lower in subjects with low HDL and high triglycerides, key components of the metabolic syndrome. There was an inverse correlation between clusterin levels in HDL and very-low-density lipoprotein/low-density lipoprotein. CONCLUSIONS: Clusterin levels in HDL are lower in men with reduced insulin sensitivity, higher body mass index, and an unfavorable lipid profile. Our observations raise the possibility that clusterin depletion contributes to the loss of HDL's cardioprotective properties.
Assuntos
Clusterina/sangue , Diabetes Mellitus Tipo 2/sangue , Dislipidemias/sangue , Resistência à Insulina , Lipoproteínas HDL/sangue , Síndrome Metabólica/sangue , Obesidade/sangue , Adulto , Biomarcadores/sangue , Índice de Massa Corporal , Estudos de Casos e Controles , Cromatografia Líquida , Diabetes Mellitus Tipo 2/fisiopatologia , Regulação para Baixo , Dislipidemias/fisiopatologia , Humanos , Técnicas de Diluição do Indicador , Masculino , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Oklahoma , Proteômica/métodos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Triglicerídeos/sangue , WashingtonRESUMO
HDL lowers the risk for atherosclerotic cardiovascular disease by promoting cholesterol efflux from macrophage foam cells. However, other antiatherosclerotic properties of HDL are poorly understood. To test the hypothesis that the lipoprotein carries proteins that might have novel cardioprotective activities, we used shotgun proteomics to investigate the composition of HDL isolated from healthy subjects and subjects with coronary artery disease (CAD). Unexpectedly, our analytical strategy identified multiple complement-regulatory proteins and a diverse array of distinct serpins with serine-type endopeptidase inhibitor activity. Many acute-phase response proteins were also detected, supporting the proposal that HDL is of central importance in inflammation. Mass spectrometry and biochemical analyses demonstrated that HDL3 from subjects with CAD was selectively enriched in apoE, raising the possibility that HDL carries a unique cargo of proteins in humans with clinically significant cardiovascular disease. Collectively, our observations suggest that HDL plays previously unsuspected roles in regulating the complement system and protecting tissue from proteolysis and that the protein cargo of HDL contributes to its antiinflammatory and antiatherogenic properties.
Assuntos
Ativação do Complemento , Doença da Artéria Coronariana/imunologia , Lipoproteínas HDL/metabolismo , Peptídeo Hidrolases/metabolismo , Proteômica , Sequência de Aminoácidos , Cromatografia Líquida , Doença da Artéria Coronariana/enzimologia , Humanos , Inflamação/metabolismo , Metabolismo dos Lipídeos , Lipoproteínas HDL/sangue , Lipoproteínas HDL/isolamento & purificação , Espectrometria de Massas , Microscopia Eletrônica de Varredura , Dados de Sequência MolecularRESUMO
BACKGROUND: Boosting low high-density lipoprotein (HDL) levels is a current strategy for preventing clinical events that result from cardiovascular disease. We previously showed that HDL(3) of subjects with coronary artery disease is enriched in apolipoprotein E and that the lipoprotein carries a distinct protein cargo. This observation suggests that altered protein composition might affect the antiatherogenic and antiinflammatory properties of HDL. We hypothesized that an intervention that increases HDL levels-combined statin and niacin therapy-might reverse these changes. METHODS AND RESULTS: HDL(3) isolated from 6 coronary artery disease subjects before and 1 year after combination therapy was analyzed by liquid chromatography-Fourier transform-mass spectrometry. Alterations in protein composition were detected by spectral counting and confirmed with extracted ion chromatograms. We found that combination therapy decreased the abundance of apolipoprotein E in HDL(3) while increasing the abundance of other macrophage proteins implicated in reverse cholesterol transport. Treatment-induced decreases in apolipoprotein E levels of HDL(3) were validated biochemically in a second group of 18 coronary artery disease subjects. Interestingly, the changes in HDL(3) proteome with niacin/statin treatment resulted in a protein composition that more closely resembled that of HDL(3) in healthy control subjects. CONCLUSIONS: Combined statin and niacin therapy partially reverses the changes in the protein composition seen in HDL(3) in coronary artery disease subjects. Our observations raise the possibility that quantifying the HDL proteome could provide insights into the therapeutic efficacy of antiatherosclerotic interventions.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Lipoproteínas HDL/efeitos dos fármacos , Lipoproteínas HDL/genética , Niacina/administração & dosagem , Proteoma/genética , Adulto , Idoso , Sequência de Aminoácidos , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/genética , Quimioterapia Combinada , Humanos , Lipoproteínas HDL/sangue , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteoma/metabolismoRESUMO
Five lines of evidence justify comprehensive lipoprotein management over aggressive low-density lipoprotein (LDL) lowering alone in most cases of cardiovascular disease (CVD) prevention. First, lipoprotein lipid transport consists of a single, recycling system involving very-low-density lipoprotein, LDL, and high-density lipoprotein (HDL). Single lipid interventions affect all lipoprotein classes to varying degrees. These effects can be expanded by using different drug classes in combination. Second, observational studies support the unitary nature of lipoprotein risk. A family of curves describes increasing CVD risk from increasing LDL as other risk factors are present. Conversely, a family of curves describes increasing CVD risk from decreasing levels of HDL in mirror image to LDL. The LDL and HDL risks are additive. Third, clinical trials that raise HDL and lower triglyceride ameliorate CVD, as does lowering LDL. Lowering LDL prevents heart disease, but by only 22%-36% with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor therapy. Studies indicate that better CVD prevention is obtained when drugs for triglyceride and HDL reduction are combined with LDL reduction. Fourth, HDL and its apolipoprotein (apo), apo A-I, as well as apo A-I analogues, decrease atherosclerosis. Each modality decreases atherosclerosis in animal models, and apo A-I Milano acutely decreases human coronary luminal stenosis. Apo A-I analogues have similar promise. Fifth, combined hyperlipidemia is the most common lipid disorder, has the strongest risk for CVD, and combines elevated LDL, hypertriglyceridemia, and low HDL. This condition requires the comprehensive treatment approach described above. In conclusion, 5 lines of evidence justify comprehensive diet and drug treatment for combined hyperlipidemia and, at lesser LDL elevations, the atherogenic dyslipidemias of obesity, diabetes mellitus, and the metabolic syndrome.
Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/efeitos dos fármacos , Dislipidemias/tratamento farmacológico , Niacina/uso terapêutico , Apolipoproteína A-I/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , HDL-Colesterol/efeitos dos fármacos , LDL-Colesterol/sangue , Ácido Clofíbrico/uso terapêutico , Quimioterapia Combinada , Dislipidemias/complicações , Humanos , Hiperlipidemias/complicações , Hiperlipidemias/tratamento farmacológico , Hipertrigliceridemia/tratamento farmacológico , Fatores de RiscoRESUMO
OBJECTIVE: The majority of graduating US medical students reported inadequate nutrition training over the past decade. This trend could in part be due to the lack of valid measures to assess the relationship between adequacy of nutrition training and proficiency on nutrition topics deemed essential. The study's objective was to test the hypothesis that self-reported nutrition proficiency is positively correlated with the perceived adequacy (quality, quantity, coverage and importance) of nutrition training of University of Washington medical students. METHOD: Cross-sectional e-mail survey of 1st to 4th year medical students (n = 708), including a survey prompt and three e-mail follow-up measures. To reduce and interpret the survey data, principal components analysis was employed, followed by Varimax rotation with Kaiser normalization. To assess internal consistency reliability, alpha (alpha) of nutrition proficiency items and factors was determined. RESULTS: A 44.5% response rate was achieved (n = 315 respondents). The 31-item questionnaire was reduced to 6 factors, explaining 60.2% of the total variance (alpha = 0.947). Self reported nutrition proficiency was positively correlated with the perceived quality, quantity and coverage of nutrition training in all 6 essential nutrition factors or topics determined after factor analysis (P < 0.01). CONCLUSION: Quality and coverage may be effective gauges of adequacy of nutrition training and related nutrition proficiency in medical education. Current national medical education evaluation measures focus on the quantity of nutrition instruction. The lowest reported proficiency topics; nutrition and disease management, micronutrients and complementary and alternative medicine are recommended for particular curricular emphasis.
Assuntos
Educação Médica/normas , Conhecimentos, Atitudes e Prática em Saúde , Ciências da Nutrição/educação , Estudantes de Medicina/psicologia , Adulto , Estudos Transversais , Análise Fatorial , Feminino , Humanos , Internet , Masculino , Análise de Componente Principal , Estudantes de Medicina/estatística & dados numéricos , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: High-dose HMG-CoA reductase inhibitors (statins) fail to prevent approximately two-thirds of cardiovascular events. This fact has focused increased attention on treating abnormalities of non-high-density lipoprotein-cholesterol (non-HDL-C), HDL-C, and triglycerides in national guidelines and has intensified interest in combination therapy. METHODS: The OCEANS study (Open-label evaluation of the safety and efficacy of a Combination of niacin ER and simvAstatin in patieNts with dySlipidemia; ClinicalTrials.gov identifier: NCT00080275) evaluated the safety and efficacy of a combination of niacin extended release and simvastatin (NER/S; SIMCOR) over 52 weeks in 520 patients with mixed dyslipidemia. After a >or=4-week run-in phase of diet modification and simvastatin 40 mg/day, median baseline values (mg/dL) were: non-HDL-C = 141, low-density lipoprotein-cholesterol (LDL-C) = 110, HDL-C = 45, and triglyceride = 151. Patients were randomized to an 8- or 12-week niacin titration scheme to a maximum NER/S dosage of 2,000/40 mg/day. RESULTS: Differences between titration groups in tolerability, safety, and efficacy were minimal; therefore, all results are for pooled titration groups. The safety of NER/S was consistent with the safety profile of each individual component. Treatment with NER/S was well tolerated: 71% of patients experienced flushing and 92% of flushing episodes were mild or moderate in intensity. Overall, 61% of patients experienced flushing episodes that were rated as mild or moderate in intensity. Flushing decreased over time: <40% of those who had flushing during titration experienced flushing during the final 12 weeks. A total of 20% of patients discontinued treatment because of a treatment-related adverse event, including 7% who discontinued because of flushing. Median changes from baseline (following the simvastatin 40 mg/day run-in phase) to 24 weeks were: non-HDL-C = -27.3%, LDL-C = -25.0%, HDL-C = +23.9%, and triglycerides = -35.9% (all p < 0.0001 vs baseline). In lipid-treatment-naive patients, NER/S 2,000/40 mg/day decreased non-HDL-C, LDL-C, and triglycerides by approximately 50% and increased HDL-C by approximately 25% when week-24 lipid values were compared with lipid values obtained prior to the simvastatin 40 mg/day run-in. All three therapeutic lipid targets (LDL-C [risk-adjusted goal], HDL-C >or=40 mg/dL, and triglycerides <150 mg/dL) were achieved concurrently by 65% of patients treated with NER/S. CONCLUSION: Treatment with NER/S 2,000/40 mg/day is well tolerated, has no unanticipated adverse events, and provides additional, clinically relevant improvements in multiple lipid parameters beyond statin monotherapy.
Assuntos
Dislipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Niacina/uso terapêutico , Sinvastatina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Colesterol/sangue , HDL-Colesterol/sangue , Preparações de Ação Retardada , Combinação de Medicamentos , Feminino , Rubor/induzido quimicamente , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipolipemiantes/efeitos adversos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Niacina/efeitos adversos , Sinvastatina/efeitos adversos , Triglicerídeos/sangueRESUMO
International guidelines recommend lower target cholesterol levels and treatment of low high-density lipoprotein cholesterol (HDL-C) and elevated triglycerides for patients at moderately high to high coronary heart disease (CHD) risk. Combination therapy is often required to achieve multiple lipid treatment goals, and > or =50% reduction in low-density lipoprotein cholesterol (LDL-C) is needed in some patients to achieve aggressive LDL-C targets. In this context, we evaluated comparative effects on lipid levels of combination therapy at low to moderate doses with a statin plus extended-release niacin (niacin ER), a statin plus ezetimibe, and a highly potent statin alone. This was an open-label, multicenter, 12-week study in 292 patients (50% women) who qualified for drug therapy based on number of CHD risk factors. Patients were randomized to four parallel arms, titrated from low to moderate or high doses: atorvastatin/niacin ER, rosuvastatin/niacin ER, simvastatin/ezetimibe, or rosuvastatin alone. Baseline mean values were, for LDL-C 197 mg/dL (5.1 mmol/L), HDL-C 49 mg/dL (1.3 mmol/L), triglycerides 168 mg/dL (1.9 mmol/L). There were no significant differences among treatment groups in the change from baseline in LDL-C at pre-specified timepoints during treatment. All groups lowered LDL-C by approximately 50% or more (range -49 to -57%), achieving mean levels of 82-98 mg/dL (2.1-2.5 mmol/L). Changes in non-HDL-C (range -46 to -55%) mirrored those for LDL-C and did not differ among treatment groups. Statin/niacin ER combination regimens also increased HDL-C and large HDL (HDL2) and lowered triglycerides and lipoprotein (a) significantly more than other regimens. No drug-related myopathy or hepatotoxicity was observed. In this study, low to moderate dose combination therapy with a statin and niacin ER provided broad control of lipids and lipoproteins independently associated with CHD.
Assuntos
Fluorbenzenos/administração & dosagem , Ácidos Heptanoicos/administração & dosagem , Niacina/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Sinvastatina/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Atorvastatina , LDL-Colesterol/sangue , Preparações de Ação Retardada , Combinação de Medicamentos , Feminino , Humanos , Masculino , Rosuvastatina Cálcica , Resultado do TratamentoRESUMO
OBJECTIVE: To describe strategies for enhancing recruitment of African Americans to a longterm intervention study requiring frequent blood draws and follow-up visits, in a city with relatively few African Americans. DESIGN: The intervention study was a 14-month, double-blind, crossover study evaluating the effects of three oral folic acid doses on blood homocysteine levels. The goal was to have 40 African Americans complete the study, in addition to 160 participants from other races and ethnicities. RESULTS: Of 707 healthy, adult men and women recruited, 57 were African Americans. Recruitment advice was sought from African American community leaders interested in health research and the advice can be attributable to the success of recruitment. As suggested by the community leaders, our female African American project manager made oral presentations to select community groups. Word-of-mouth support from community leaders and study participants helped recruitment. Although the adult Seattle population is 7.4% African American, the group completing the study comprised 15% African Americans. Retention in the dietary intervention was 74% (31 out of 42) among African Americans, 81% (158 out of 196) among non-African Americans--a statistically non-significant difference. CONCLUSIONS: Advice from African American community leaders about targeting appropriate civic/professional groups, churches, and community organizations can lead to effective recruitment of African Americans. Advice should be sought before beginning recruitment and endorsement for the study should be obtained. Effective retention of African American participants is possible for intervention studies requiring multiple blood draws and follow-up visits.
Assuntos
Negro ou Afro-Americano , Suplementos Nutricionais , Seleção de Pacientes , Adolescente , Adulto , Idoso , Estudos Cross-Over , Método Duplo-Cego , Feminino , Ácido Fólico/farmacologia , Ácido Fólico/uso terapêutico , Homocisteína/análise , Homocisteína/sangue , Homocisteína/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , WashingtonRESUMO
OBJECTIVE: Cardiovascular disease (CVD) risk is increased in type 2 diabetes. The purpose of this study was to assess the effect of 10 mg of atorvastatin versus placebo on CVD prevention in subjects with type 2 diabetes and LDL cholesterol levels below contemporary guideline targets. RESEARCH DESIGN AND METHODS: Subjects were randomly assigned to receive 10 mg of atorvastatin or placebo in a 4-year, double-blind, parallel-group study. The composite primary end point comprised cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, recanalization, coronary artery bypass surgery, resuscitated cardiac arrest, and worsening or unstable angina requiring hospitalization. RESULTS: A total of 2,410 subjects with type 2 diabetes were randomized. Mean LDL cholesterol reduction in the atorvastatin group over 4 years was 29% versus placebo (P < 0.0001). When we compared atorvastatin versus placebo, composite primary end point rates were 13.7 and 15.0%, respectively (hazard ratio 0.90 [95% CI 0.73-1.12]). In the subset of 1,905 subjects without prior myocardial infarction or interventional procedure, 10.4% of atorvastatin- and 10.8% of placebo-treated subjects experienced a primary end point (0.97 [0.74-1.28]). In the 505 subjects with prior myocardial infarction or interventional procedure, 26.2% of atorvastatin- and 30.8% of placebo-treated subjects experienced a primary end point (0.82 [0.59-1.15]). Relative risk reductions in fatal and nonfatal myocardial infarction were 27% overall (P = 0.10) and 19% (P = 0.41) and 36% (P = 0.11) for subjects without and with prior myocardial infarction or interventional procedure, respectively. CONCLUSIONS: Composite end point reductions were not statistically significant. This result may relate to the overall study design, the types of subjects recruited, the nature of the primary end point, and the protocol changes required because of changing treatment guidelines. For these reasons, the results of the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) did not confirm the benefit of therapy but do not detract from the imperative that the majority of diabetic patients are at risk of coronary heart disease and deserve LDL cholesterol lowering to the currently recommended targets.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ácidos Heptanoicos/uso terapêutico , Pirróis/uso terapêutico , Adulto , Idoso , Atorvastatina , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Ácidos Heptanoicos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Pirróis/efeitos adversos , Medição de Risco , Resultado do TratamentoRESUMO
OBJECTIVE: To determine whether the hyperbolic relationship between insulin sensitivity and the acute insulin response to glucose (AIRg) exists in subjects with impaired fasting glucose (IFG) or decreased glucose tolerance. RESEARCH DESIGN AND METHODS: We studied 219 healthy subjects (88 male and 131 female subjects, aged 26-75 years) with fasting plasma glucose (FPG) <6.11 mmol/l. Subjects underwent an intravenous glucose tolerance test to determine the insulin sensitivity index (Si), AIRg, and the glucose disappearance constant (Kg), the latter a measure of intravenous glucose tolerance. RESULTS: Si and AIRg were inversely related for the entire cohort, and this relationship was not significantly different from hyperbolic. The inverse relationship between Si and AIRg was not significantly different when compared between groups based on fasting glucose (normal fasting glucose [NFG], FPG <5.56 mmol/l vs. IFG, FPG 5.56-6.11 mmol/l) or by the Kg quartile. However, the curve relating Si and AIRg was left shifted in the IFG compared with NFG group (P < 0.001) and was progressively more left shifted with decreasing Kg (P < 0.001), consistent with decreasing beta-cell function. These changes were not observed for the curves relating Si and fasting insulin, suggesting that in the fasting state beta-cell function is maintained even in patients with mild IFG. Finally, the disposition index (DI) (Si x AIRg) was calculated as a measure of beta-cell function. The DI progressively decreased with increasing FPG, even in the group of subjects classified as NFG. CONCLUSIONS: The inverse relationship between insulin sensitivity and AIRg is consistent with a hyperbola not only in subjects with normal glucose tolerance but also with mild IFG or decreased Kg. Based on a hyperbolic relationship, a decrease in beta-cell function can be detected as FPG increases, even in patients who are normal glucose tolerant.
Assuntos
Glicemia/metabolismo , Jejum/metabolismo , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/fisiologia , Insulina/metabolismo , Adulto , Idoso , Feminino , Intolerância à Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Informed consent (IC) is an essential component of shared medical decision making between patients and providers in emergency medicine (EM). The basic components required for adequate consent are well described, yet little is published investigating whether EM residents demonstrate adequate IC skills. OBJECTIVE: The objectives were to assess the ability of EM residents to obtain IC for an invasive emergency procedure using a novel assessment tool and to assess reliability and validity of the tool. METHODS: This was an observational study in which participants were initially blinded to the primary objectives of the study. Each participant conducted a video-recorded history and physical examination with a standardized patient, requiring tube thoracostomy due to spontaneous pneumothorax. Two faculty EM physicians independently reviewed the videos and evaluated the participants' IC skills. First, they gave an overall impression of whether IC was obtained; they then evaluated the participants using a 30-point scoring tool based on the five elements of IC (decision-making capacity, disclosure, voluntariness, understanding, and physician recommendation). Upon all participants' case completion, we revealed the primary objectives and gave participants the option to withdraw from the study. Descriptive statistics and kappa coefficient were generated from the data collected. RESULTS: Twenty-two residents completed the study. None withdrew from the study after the primary objectives were revealed. Twenty residents (91%) obtained adequate IC based on both reviewers' overall impression. One disagreement occurred between reviewers (κ = 0.64). The mean IC score on a 30-point scale was 18.5 ± 0.5. CONCLUSIONS: In a simulated setting, most EM residents at this training program possess the knowledge and skills necessary to obtain IC prior to an invasive procedure. The assessment tool appears reliable and demonstrates construct validity.
RESUMO
BACKGROUND: Inflammatory markers associated with elevated cardiovascular risk are increased by cholesterol feeding in animal models. However, whether dietary cholesterol increases inflammatory marker levels in humans is not known. METHODS AND RESULTS: C-reactive protein (CRP), serum amyloid A (SAA), and lipoprotein levels were compared in 201 healthy subjects on an American Heart Association-National Cholesterol Education Program step 1 diet at baseline and after addition of 4 eggs per day for 4 weeks. Subjects were classified a priori into 3 groups based on their body mass index (BMI) and insulin sensitivity index (SI): lean insulin sensitive (LIS), mean+/-SEM BMI, 23.2+/-0.3 kg/m2, and SI, 6.7+/-0.3x10(-4)min(-1)/(microU/mL), n=66; lean insulin resistant (LIR), BMI, 24.5+/-0.2 kg/m2 and SI, 2.9+/-0.1x10(-4)min(-1)/(microU/mL), n=76; or obese insulin resistant (OIR), BMI, 31.4+/-0.5 kg/m2 and SI, 2.1+/-0.1x10(-4)min(-1)/(microU/mL), n=59. Insulin resistance and obesity each were associated with increased baseline levels of both CRP (P for trend, <0.001) and SAA (P for trend=0.015). Egg feeding was associated with significant increases in both CRP and SAA in the LIS group (both P<0.01) but not in the LIR or OIR groups. Egg feeding also was associated with a significant increase in non-HDL cholesterol (P<0.001) in LIS subjects; however, there was no correlation between the change in non-HDL cholesterol or changes in either CRP or SAA in this group. CONCLUSIONS: A high-cholesterol diet leads to significant increases in both inflammatory markers and non-HDL cholesterol levels in insulin-sensitive individuals but not in lean or obese insulin-resistant subjects.
Assuntos
Proteínas de Fase Aguda/análise , Peso Corporal , Colesterol na Dieta/farmacologia , Resistência à Insulina , Proteína C-Reativa/análise , Colesterol na Dieta/administração & dosagem , Feminino , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Obesidade , Proteína Amiloide A Sérica/análise , Magreza , Regulação para Cima/efeitos dos fármacosRESUMO
Two drug classes act in the intestine to lower cholesterol. Ezetimibe inhibits cholesterol absorption, whereas bile acid-binding resins enhance cholesterol excretion via enhanced conversion to bile acids. Combining these 2 classes may be beneficial, but cholestyramine binds ezetimibe, and the combined effect of colesevelam hydrochloride and ezetimibe was little studied. The aim of the study was to determine if adding colesevelam HCl to ezetimibe provides additional lowering of low-density lipoprotein- and apolipoprotein B-containing lipoproteins or alters ezetimibe levels. Twenty subjects with low-density lipoprotein cholesterol (LDL-C) levels of 130 mg/dL or higher were enrolled and taught a National Cholesterol Education Program Step I diet. At a second baseline visit, lipoproteins were measured and subjects were randomly allocated to (1) ezetimibe 10 mg daily with placebo colesevelam HCl twice daily (E) or (2) ezetimibe 10 mg daily with 1.875 g colesevelam HCl twice daily (E + C). Lipoproteins were measured 6 and 12 weeks after initiating treatment. Baseline characteristics (mean +/- SD) were statistically indistinguishable in E vs E + C: LDL-C (mg/dL), 167 +/- 26 and 158 +/- 27; triglyceride, 134 +/- 75 and 140 +/- 67; and BMI, 29.4 +/- 4.9 and 27.8 +/- 6.6 kg/m(2), respectively. Percent changes after 12 weeks in E vs E + C were as follows: LDL-C, -24 +/- 12 vs -30 +/- 11 (P = .102); triglyceride, -19 +/- 34 vs 36 +/- 85 (P = .054; at 6 weeks, P = .009); total cholesterol, -19 +/- 9 vs -15 +/- 8 (P = .50); non-high-density lipoprotein cholesterol, -25 +/- 10 vs -21 +/- 11 (P = .70); apolipoprotein B, -31 +/- 14 vs -22 +/- 14 (P = .41). Plasma ezetimibe levels at 12 weeks were 21% lower in E + C vs E, a nonsignificant difference (P = .54). In conclusion, in the short term, colesevelam HCl may not consistently add cholesterol-lowering benefit to ezetimibe. This observation requires confirmation.
Assuntos
Alilamina/análogos & derivados , Anticolesterolemiantes/uso terapêutico , Azetidinas/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alilamina/administração & dosagem , Azetidinas/administração & dosagem , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Cloridrato de Colesevelam , Método Duplo-Cego , Quimioterapia Combinada , Ezetimiba , Feminino , Humanos , Hipercolesterolemia/sangue , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Triglicerídeos/sangueRESUMO
OBJECTIVE: Early pregnancy losses increase with marked hyperglycemia in diabetic pregnancy. However, mean loss rates do not differ from those of nondiabetic pregnancy. This observation might be explained by increased fetal losses at the extremes of glycemia in diabetic and nondiabetic pregnancy. To test this hypothesis, we examined relationships of proximate measures of prior glycemia, glycated protein and fructosamine, to pregnancy loss. RESEARCH DESIGN AND METHODS: A total of 389 diabetic and 429 nondiabetic pregnant subjects participated in the Diabetes In Early Pregnancy study. Glycated protein and fructosamine measurements were standardized as multiples of control values for each center (Z score). The logarithm of odds of pregnancy loss were plotted against Z scores and tested by logistic models. RESULTS: Mean pregnancy loss rates were 12% in diabetic and 13% in normal pregnancies. However, over six intervals of glycated protein in diabetic pregnancy, fetal loss rates at the upper and lower extremes (24 and 33%, respectively) were approximately threefold higher than the four intervening rates (8-14%). The odds ratio of pregnancy loss for these extreme intervals to the intervening intervals is 3.0 (P = 0.01). Nondiabetic losses showed a similar pattern. In confirmation, logit pregnancy losses were increased in a J-shaped curve at the glycemic extremes in normal (P < 0.019) and diabetic (P < 0.015) pregnancy. The upper glycemic extreme in diabetic pregnancy was two- to fivefold higher than in control pregnancy. CONCLUSIONS: Pregnancy losses are increased at the extremes of glycemia in both normal and diabetic pregnancy but at higher levels in diabetic pregnancy. The data suggest defensive adaptations against hyperglycemia in diabetic pregnancy.
Assuntos
Aborto Espontâneo/sangue , Glicemia/metabolismo , Hiperglicemia/sangue , Gravidez em Diabéticas/sangue , Aborto Espontâneo/epidemiologia , Feminino , Frutosamina/sangue , Humanos , Hiperglicemia/epidemiologia , Modelos Logísticos , Valor Preditivo dos Testes , Gravidez , Resultado da Gravidez/epidemiologia , Primeiro Trimestre da Gravidez , Gravidez em Diabéticas/epidemiologia , Fatores de RiscoRESUMO
OBJECTIVE: Raloxifene hydrochloride is a selective estrogen receptor modulator that to date has not been shown to cause hypertriglyceridemia in normal, diabetic, or hypertriglyceridemic women. This study was designed to assess the effect of raloxifene on serum triglycerides in postmenopausal women who have a history of increased hypertriglyceridemia with oral estrogen therapy. RESEARCH DESIGN AND METHODS: This was a single-center, uncontrolled, open-label study investigating the effects of 8 weeks of raloxifene (60 mg/day) therapy on plasma lipids. The study subjects were 12 postmenopausal women, ages 49-73 years, with a documented history of oral estrogen-induced hypertriglyceridemia (serum triglycerides > or =3.39 mmol/l [> or =300 mg/dl]). RESULTS: At week 2 of the study, three (25%) of the subjects withdrew from the trial because they developed marked hypertriglyceridemia (>or =11.3 mmol/l [> or =1,000 mg/dl]) during raloxifene therapy. These three women had higher baseline triglyceride and glucose levels, were not being treated with lipid-lowering agents, and were more likely to have diabetes than the other study subjects. The remaining nine patients (75%) completed the 8-week trial and experienced a nonsignificant increase in mean triglyceride levels from baseline to end point. Raloxifene treatment also resulted in a significant 16% decrease in hepatic lipase activity and a 26% increase in HDL(2) levels (P = 0.013 and 0.03, respectively). CONCLUSIONS: Patients with a previous history of hypertriglyceridemia on oral estrogen therapy should have serum triglyceride levels monitored closely after beginning raloxifene therapy and may even require fibrate therapy before beginning raloxifene.
Assuntos
Terapia de Reposição de Estrogênios , Hipertrigliceridemia/sangue , Cloridrato de Raloxifeno/uso terapêutico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Triglicerídeos/sangue , Idoso , Apolipoproteínas/sangue , Colesterol/sangue , Feminino , Humanos , Lipoproteínas/sangue , Pessoa de Meia-Idade , Cooperação do Paciente , Pós-MenopausaRESUMO
BACKGROUND: The relation of trans-fatty acid intake to life-threatening arrhythmias and primary cardiac arrest is unknown. METHODS AND RESULTS: We investigated the association of trans-fatty acid intake, assessed through a biomarker, with the risk of primary cardiac arrest in a population-based case-control study. Cases, aged 25 to 74 years, were out-of-hospital cardiac arrest patients attended by paramedics in Seattle, Washington from 1988 to 1999 (n=179). Controls, matched to cases by age and sex, were randomly identified from the community (n=285). Participants were free of previous clinically diagnosed heart disease. Blood was obtained at the time of cardiac arrest (cases) or at the time of an interview (controls) to assess trans-fatty acid intake. Higher total trans-fatty acids in red blood cell membranes was associated with a modest increase in the risk of primary cardiac arrest after adjustment for medical and lifestyle risk factors (odds ratio for interquintile range, 1.5; 95% CI, 1.0 to 2.1). However, trans isomers of oleic acid were not associated with risk (odds ratio for interquintile range, 0.8; 95% CI, 0.5 to 1.2), whereas higher levels of trans isomers of linoleic acid were associated with 3-fold increase in risk (odds ratio for interquintile range, 3.1; 95% CI, 1.7 to 5.4). CONCLUSIONS: These findings suggest that dietary intake of total trans-fatty acids is associated with modest increase and trans isomers of linoleic acid with a larger increase in the risk of primary cardiac arrest. These associations need to be confirmed in future studies that distinguish between trans isomers of linoleic acid and trans isomers of oleic acid.
Assuntos
Membrana Celular/metabolismo , Ácidos Graxos Insaturados/metabolismo , Parada Cardíaca/epidemiologia , Parada Cardíaca/metabolismo , Adulto , Distribuição por Idade , Idoso , Estudos de Casos e Controles , Gorduras Insaturadas na Dieta/metabolismo , Eritrócitos/química , Eritrócitos/metabolismo , Ácidos Graxos Insaturados/análise , Feminino , Humanos , Ácido Linoleico/análise , Ácido Linoleico/metabolismo , Masculino , Pessoa de Meia-Idade , Conformação Molecular , Razão de Chances , Ácido Oleico/análise , Ácido Oleico/metabolismo , Medição de Risco , Fatores de Risco , Distribuição por Sexo , Estereoisomerismo , Washington/epidemiologiaRESUMO
The prevalence of glucose intolerance and type 2 diabetes increases with age. To determine whether the hyperbolic relationship between insulin sensitivity and the insulin response is affected by age and whether the decline in beta-cell function with age is related to increases in intra-abdominal fat or age per se, we studied 220 healthy subjects with fasting glucose <6.1 mmol/l (89 men and 131 women, aged 26-75 years, BMI 18.7-40.4 kg/m(2)). The insulin sensitivity index (S(i)) and the acute insulin response to glucose (AIRg) were determined, and from these beta-cell function was estimated as the disposition index (S(i) x AIRg). Intra-abdominal fat and subcutaneous fat areas were quantified by computed tomography. S(i) (5.40 +/- 0.5 vs. 7.86 +/- 0.7 x10(-5) min(-1)/[pmol/l]), P < 0.01) was decreased and intra-abdominal fat (117 +/- 10 vs. 81 +/- 9 cm(2), P < 0.05) was increased in the oldest (age 60-75 years) versus the youngest (age 26-44 years) quartile. The hyperbolic relationship between S(i) and AIRg was present independent of age; thus, beta-cell function measured as the disposition index (1,412 +/- 120 vs. 2,125 +/- 150 x10(-5) min(-1), P < 0.01) was lower in the oldest versus the youngest quartile. In multiple regression, intra-abdominal fat (r = -0.470, P < 0.001) but not age was associated with S(i), but both intra-abdominal fat (r = -0.198, P = 0.003) and age (r = -0.131, P = 0.05) were correlated with the disposition index. These data suggest that although intra-abdominal fat is a strong determinant of insulin sensitivity and beta-cell function, age has an independent effect on beta-cell function that may contribute to the increased prevalence of type 2 diabetes in older populations.