RESUMO
BACKGROUND AND PURPOSE: Reduced cardiac contractility has been associated with disrupted myocardial Ca(2+) signalling. The 1,4 benzothiazepine K201 (JTV-519) acts on several Ca(2+) handling proteins and improves cardiac contractility in vivo in a variety of animal models of myocardial dysfunction. However, it is unclear whether this improvement depends on the systemic effects of K201 or if K201 reverses the effects of Ca(2+) dysregulation, regardless of the cause. EXPERIMENTAL APPROACH: The effect of K201 on cardiac mechanical function was assessed in isolated working hearts from adult rabbits, using a ventricular pressure-volume catheter. In separate experiments, the effect of K201 was investigated in hearts following pharmacologically induced Ca(2+) overload using elevated extracellular [Ca(2+) ] ([Ca(2+) ](o) ) and ß-adrenoceptor stimulation. KEY RESULTS: K201 induced a concentration-dependent decline in systolic function (peak pressure, dP/dt(max) and preload recruitable stroke work), lusitropy (reduced dP/dt(min) and increased end diastolic pressure) and stroke volume, independent of decreased heart rate. In separate experiments, mechanical function in hearts exposed to 4.5 mmol·L(-1) [Ca(2+) ](o) and 150 nmol·L(-1) isoprenaline declined until cessation of aortic flow (in 6 out of 11 hearts). However, all hearts perfused with the addition of 1 µmol·L(-1) K201 maintained aortic flow and demonstrated significantly improved peak systolic pressures, dP/dt(max) and dP/dt(min) . CONCLUSIONS AND IMPLICATIONS: K201 significantly improved mechanical function of the heart during Ca(2+) overload. This suggests that K201 can limit the detrimental effects of elevated intracellular Ca(2+) and exert beneficial effects on cardiac contractile function, independent of systemic effects previously observed in vivo.
Assuntos
Cardiotônicos/farmacologia , Coração/efeitos dos fármacos , Tiazepinas/farmacologia , Animais , Cálcio/fisiologia , Coração/fisiologia , Técnicas In Vitro , Masculino , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Coelhos , Receptores Adrenérgicos beta/fisiologiaRESUMO
AIM: Flow-mediated dilation (FMD) is a surrogate marker of endothelial function, which has been proposed as a barometer of vascular health. Impaired microvascular response to reactive hyperaemia is thought to be the mechanism behind reduced shear stress and subsequently impaired FMD, which has been associated with cardiovascular events. This study aims to assess the effect of pioglitazone on the vasculature of patients with impaired glucose tolerance (IGT). MATERIALS AND METHODS: Forty IGT patients with no cardiovascular disease were compared with 24 healthy age- and sex-matched controls. Endothelial function was assessed using FMD of the brachial artery. Adiponectin (ADN) levels were measured and insulin sensitivity was calculated using homeostasis model assessment of insulin resistance (HOMA-IR). A randomised double-blind placebo-controlled trial of the IGT subjects was then performed, with subjects receiving either pioglitazone 30 mg od or matched placebo for 12 weeks before the measurements were repeated. RESULTS: The IGT subjects had a significantly impaired FMD compared with the controls (p < 0.001). Diastolic shear stress (DSS) was also significantly reduced in IGT (p = 0.04). High molecular weight (HMW) ADN was significantly lower in the IGT group than in controls (p = 0.03). On analysis of the IGT group after 12 weeks treatment, FMD was significantly increased in the pioglitazone group compared with placebo (p = 0.03) as was endothelium-independent dilation (EID) (p = 0.03). A significant increase in total ADN (p < 0.001), HMW ADN (p < 0.001) and HMW/total ratio (p = 0.001) occurred in the pioglitazone group compared with placebo. CONCLUSIONS: Pioglitazone improved endothelial function in IGT. Treatment with pioglitazone may reduce the risk of cardiovascular disease in this patient group.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Endotélio Vascular/efeitos dos fármacos , Intolerância à Glucose/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Tiazolidinedionas/uso terapêutico , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Endotélio Vascular/fisiopatologia , Feminino , Intolerância à Glucose/fisiopatologia , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/farmacologia , Masculino , Pessoa de Meia-Idade , Pioglitazona , Tiazolidinedionas/farmacologiaRESUMO
OBJECTIVES: The drug K201 (JTV-519) increases inotropy and suppresses arrhythmias in failing hearts, but the effects of K201 on normal hearts is unknown. METHODS: The effect of K201 on excitation-contraction (E-C) coupling in normal myocardium was studied by using voltage-clamp and intracellular Ca(2+) measurements in intact cells. Sarcoplasmic reticulum (SR) function was assessed using permeabilised cardiomyocytes. RESULTS: Acute application of <1 micromol/L K201 had no significant effect on E-C coupling. K201 at 1 micromol/L decreased Ca(2+) transient amplitude (to 83+/-7%) without affecting I(Ca,L) or the SR Ca(2+) content. At 3 micromol/L K201 caused a larger reduction of Ca(2+) transient amplitude (to 60+/-7%) with accompanying reductions in I(Ca,L) amplitude (to 66+/-8%) and SR Ca(2+) content (74+/-9%). Spontaneous SR Ca(2+) release during diastole was induced by increasing intracellular [Ca(2+)]. At 1 micromol/L K201 reduced the frequency of spontaneous Ca(2+) release. The effect of K201 on SR-mediated Ca(2+) waves and Ca(2+) sparks was examined in beta-escin-permeabilised cardiomyocytes by confocal microscopy. K201 (1 micromol/L) reduced the frequency and velocity of SR Ca(2+) waves despite no change in SR Ca(2+) content. At 3 micromol/L K201 completely abolished Ca(2+) waves and reduced the SR Ca(2+) content (to approximately 73%). K201 at 1 micromol/L reduced Ca(2+) spark amplitude and frequency. Assays specific to SR Ca(2+)-ATPase and RyR2 activity indicated that K201 inhibited both SR Ca(2+) uptake and release. CONCLUSIONS: K201 modifies E-C coupling in normal cardiomyocytes. A dual inhibitory action on SERCA and RyR2 explains the ability of K201 to suppress spontaneous diastolic Ca(2+) release during Ca(2+) overload without significantly affecting Ca(2+) transient amplitude.
Assuntos
Cálcio/metabolismo , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Tiazepinas/farmacologia , Animais , Cafeína/farmacologia , Ventrículos do Coração/metabolismo , Humanos , Coelhos , Canal de Liberação de Cálcio do Receptor de Rianodina/fisiologia , Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismoRESUMO
Both the cardiac action potential duration (APD) (0.6-1 s) and resting heart rate (30-40 beats/min) in the horse are significantly different from humans and smaller mammals, including the rabbit. This would be anticipated to have consequences for excitation-contraction (EC) coupling and require adaptation of the individual processes involved. The sarcoplasmic reticulum (SR) is one of the main components involved in EC coupling. This study examines and compares the activity of this organelle in the horse with that of the rabbit. In particular, the study focuses on SR Ca2+ release via the Ca2+ release channel/ryanodine receptor (RyR2) and Ca2+ uptake via the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) pump. Isolated cardiomyocytes from both horse and rabbit hearts were permeabilized, bathed in a mock intracellular solution, and exposed to a specified [Ca2+]. Rabbit cardiomyocytes exposed to 260 nM [Ca2+] produced spontaneous Ca2+ release and propagated Ca2+ waves. Horse cells failed to produce Ca2+ waves; instead, only local release in the form of Ca2+ sparks was evident. However, at 550 nM [Ca2+], Ca2+ waves were produced in both species. Ca2+ waves were four times less frequent yet approximately 1.5 times greater in amplitude in the horse compared with the rabbit. Ca2+ wave velocity was comparable between the species. The reason for this disparity in Ca2+ wave characteristics is unknown. Separate measurements of oxalate-supported Ca2+ uptake into the SR suggest that both horse and rabbit cardiomyocytes have comparable levels SERCA activity. The possible reasons for the observed differences in SR Ca2+ release between the horse and rabbit are discussed.
Assuntos
Cálcio/metabolismo , Cavalos/metabolismo , Miócitos Cardíacos/metabolismo , Coelhos/metabolismo , Retículo Sarcoplasmático/metabolismo , Animais , Permeabilidade da Membrana Celular , Tamanho Celular , Coração/anatomia & histologia , Ventrículos do Coração , Hemodinâmica , Cavalos/anatomia & histologia , Cavalos/fisiologia , Técnicas In Vitro , Miócitos Cardíacos/citologia , Coelhos/anatomia & histologia , Coelhos/fisiologiaRESUMO
Two-photon excitation (TPE) spectra of Fura-2, -4F, -6F, -FF, and Furaptra were characterized using a tunable (750-850 nM) ultra-short pulse laser. Two-photon fluorescence of these dyes was studied in free solution and in the cytosol of isolated rabbit ventricular cardiomyocytes. The TPE spectra of the Ca(2+)-free and Ca(2+)-bound forms of the dyes were measured in free solution and expressed in terms of the two-photon fluorescence cross section (Goppert-Meyer units). The Fura dyes displayed the same Ca(2+)-free TPE spectrum in the intracellular volume of permeabilized and intact cardiomyocytes. Fluorescence measurements over a range of laser powers confirmed the TPE of both Ca(2+)-free and Ca(2+)-bound forms of the dyes. Single-wavelength excitation at 810 nM was used to determine the effective dissociation constants (K(eff)) and dynamic ranges (R(f)) of Fura-2, -4F, -6F, -FF, and Furaptra dyes (K(eff) = 181 +/- 52 nM, 1.16 +/- 0.016 micro M, 5.18 +/- 0.3 micro M, 19.2 +/- 1 micro M, and 58.5 +/- 2 micro M; and R(f) = 22.4 +/- 3.8, 12.2 +/- 0.34, 6.3 +/- 0.17, 16.1 +/- 2.8, and 25.4 +/- 4, respectively). Single-wavelength excitation of intracellular Fura-4F resolved diastolic and peak [Ca(2+)] in isolated stimulated cardiomyocytes after calibration of the intracellular signal using reversible exposure to low (100 micro M) extracellular [Ca(2+)]. Furthermore, TPE of Fura-4F allowed continuous, long-term (5-10 min) Ca(2+) imaging in ventricular cardiomyocytes using laser-scanning microscopy without significant cellular photodamage or photobleaching of the dye.
Assuntos
Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Corantes Fluorescentes , Microscopia Confocal/métodos , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Miócitos Cardíacos/metabolismo , Animais , Células Cultivadas , Ventrículos do Coração/citologia , Teste de Materiais , Miócitos Cardíacos/citologia , Coelhos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Função VentricularRESUMO
This study investigated the function of FK506-binding protein (FKBP12.6) using adenoviral-mediated gene transfer to over-express FKBP12.6 (Ad-FKBP12.6) in adult rabbit ventricular cardiomyocytes. Infection with a beta-galactosidase-expressing adenovirus (Ad-LacZ) was used as a control. Peak-systolic intracellular [Ca(2+)] (measured with Fura-2) was higher in the Ad-FKBP12.6 group compared to Ad-LacZ (1 Hz field stimulation at 37 degrees C). The amplitude of caffeine-induced Ca(2+) release was also greater, indicating a higher SR Ca(2+) content in the Ad-FKBP12.6 group. Voltage clamp experiments indicated that FKBP12.6 over-expression did not change L-type Ca(2+) current amplitude or Ca(2+) efflux rates via the Na(+)-Ca(2+) exchanger. Ca(2+) transients comparable to those after Ad-FKBP12.6 transfection could be obtained by enhancing SR Ca(2+) content of Ad-LacZ infected cells with periods of high frequency stimulation. Line-scan confocal microscopy (Fluo-3 fluorescence) of intact cardiomyocytes stimulated at 0.5 Hz (20-21 degrees C) revealed a higher degree of synchronicity of SR Ca(2+) release and fewer non-responsive Ca(2+) release sites in the Ad-FKBP12.6 group compared to control. Ca(2+) spark morphology was measured in beta-escin-permeabilized cardiomyocytes at a free [Ca(2+)](i) of 150 nm. The average values of the spark parameters (amplitude, duration, width and frequency) were reduced in the Ad-FKBP12.6 group. Increasing [Ca(2+)](i) to 400 nm caused coherent propagating Ca(2+) waves in the Ad-FKBP12.6 group but only limited Ca(2+) release events were recorded in the control group. These data indicate that FKBP12.6 over-expression enhances Ca(2+) transient amplitude predominately by increasing SR Ca(2+) content. Moreover, there is also evidence that FKBP12.6 can enhance the coupling between SR Ca(2+) release sites independently of SR content.
Assuntos
Sinalização do Cálcio/fisiologia , Miócitos Cardíacos/fisiologia , Proteína 1A de Ligação a Tacrolimo/fisiologia , Adenoviridae/genética , Animais , Cafeína/farmacologia , Cálcio/metabolismo , Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Células Cultivadas , Estimulação Elétrica , Escina/farmacologia , Fura-2/química , Expressão Gênica , Vetores Genéticos/genética , Humanos , Potenciais da Membrana/fisiologia , Microscopia Confocal , Microscopia de Fluorescência , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Técnicas de Patch-Clamp , Coelhos , Retículo Sarcoplasmático/química , Retículo Sarcoplasmático/metabolismo , Espectrometria de Fluorescência , Proteína 1A de Ligação a Tacrolimo/genética , Tetrodotoxina/farmacologia , Tapsigargina/farmacologia , TransfecçãoRESUMO
A case of fatal overdose of tramadol is described, occurring in a 67-year-old man with painful rib fractures who accidentally ingested more than the recommended daily dose. The mode of death was acute liver failure due to fulminant hepatic necrosis. Post-mortem toxicology was negative apart from revealing a blood tramadol concentration well above the normal therapeutic range. This is the first report of fatal tramadol ingestion occurring in a therapeutic setting and also the first tramadol-related death where the mechanism was liver failure.
Assuntos
Analgésicos Opioides/intoxicação , Falência Hepática Aguda/induzido quimicamente , Tramadol/intoxicação , Acidentes , Idoso , Overdose de Drogas , Evolução Fatal , Humanos , MasculinoRESUMO
The Ca(2+) dissociation constant (K(d)) of Fluo-3 was determined using confocal fluorescence microscopy in two different situations: (i) within the cytosol of a permeabilised cardiomyocyte; and (ii) in an intact cardiomyocyte after incubation with the acetoxymethyl ester form of Fluo-3 (AM). Measurements were made on isolated rabbit ventricular cardiomyocytes after permeabilisation by a brief treatment with beta-escin (0.1mg/ml) and equilibration with 10 microM Fluo-3. The K(d) of Fluo-3 within the cytosol was not significantly different from that in free solution (558 +/- 15 nM, n=6). Over a range of cytoplasmic [Ca(2+)], the minimum [Ca(2+)] values between Ca(2+) waves was relatively constant despite changes in wave frequency. After loading intact cardiomyocytes with Fluo-3 by incubation with the -AM, spontaneous Ca(2+) waves were produced by incubation with strophanthidin (10 microM). By assuming a common minimum [Ca(2+)] in permeabilised and intact cells, the intracellular K(d) of Fluo-3 in intact myocytes was estimated to be 898 +/-64 nM (n=6). Application of this K(d) to fluorescence records shows that Ca(2+) waves in intact cells have similar amplitudes to those in permeabilised cells. Stimulation of cardiac myocytes at 0.5 Hz in the absence of strophanthidin (room temperature) resulted in a Ca(2+) transient with a maximum and minimum [Ca(2+)] of 1190 +/- 200 and 158 +/- 30 nM (n=11), respectively.
Assuntos
Compostos de Anilina/farmacocinética , Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Xantenos/farmacocinética , Compostos de Anilina/metabolismo , Animais , Sinalização do Cálcio/fisiologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/fisiologia , Células Cultivadas , Difusão/efeitos dos fármacos , Escina/farmacologia , Ventrículos do Coração/metabolismo , Líquido Intracelular/efeitos dos fármacos , Líquido Intracelular/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Contração Muscular/fisiologia , Coelhos , Estrofantidina/farmacologia , Xantenos/metabolismoRESUMO
Spontaneous sarcoplasmic reticulum (SR) Ca(2+) release and propagated intracellular Ca(2+) waves are a consequence of cellular Ca(2+) overload in cardiomyocytes. We examined the relationship between average intracellular [Ca(2+)] and Ca(2+) wave characteristics. The amplitude, time course and propagation velocity of Ca(2+) waves were measured using line-scan confocal imaging of beta-escin-permeabilised cardiomyocytes perfused with 10 microM Fluo-3 or Fluo-5F. Spontaneous Ca(2+) waves were evident at cellular [Ca(2+)] > 200 nM. Peak [Ca(2+)] during a wave was 2.0-2.2 microM; the minimum [Ca(2+)] between waves was 120-160 nM; wave frequency was approximately 0.1 Hz. Raising mean cellular [Ca(2+)] caused increases in all three parameters, particularly Ca(2+) wave frequency. Increases in the rate of SR Ca(2+) release and Ca(2+) uptake were observed at higher cellular [Ca(2+)], indicating calcium-sensitive regulation of these processes. At extracellular [Ca(2+)] > 2 microM, the mean [Ca(2+)] inside the permeabilised cell did not increase above 2 microM. This extracellular-intracellular Ca(2+) gradient could be maintained for periods of up to 5 min before the cardiomyocyte developed a sustained and irreversible hypercontraction. Inclusion of mitochondrial inhibitors (2 microM carbonyl cyanide m-chlorophenylhydrazone and 2 microM oligomycin) while perfusing with > 2 microM Ca(2+) abolished the extracellular-intracellular Ca(2+) gradient through the generation of Ca(2+) waves with a higher peak [Ca(2+)] compared to control conditions. Under these conditions, cardiomyocytes rapidly (< 2 min) developed a sustained and irreversible contraction. These results suggest that mitochondrial Ca(2+) uptake acts to delay an increase in [Ca(2+)] by blunting the peak of the Ca(2+) wave.
Assuntos
Sinalização do Cálcio/fisiologia , Cálcio/farmacocinética , Miócitos Cardíacos/metabolismo , Animais , Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia , Permeabilidade da Membrana Celular , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Oligomicinas/farmacologia , Coelhos , Fatores de Tempo , Desacopladores/farmacologiaRESUMO
Race and gender differences in lipoproteins and apolipoproteins have repeatedly been demonstrated in adults. The same disparities have been observed in children of different race and gender, implying that these differences may be influenced by genetic factors. To further explore this hypothesis, cord blood concentrations of both lipoproteins and apolipoproteins were examined in black and white neonates of both sexes. Results were controlled for the observed effects of gestational age and growth parameters. Similar patterns of lipoprotein differences to those observed in adults and children were also detected between black and white, and between male and female neonates. These findings support the concept that the aetiology of the difference in lipoprotein concentration observed between race and gender groups includes a significant genetic component.
Assuntos
População Negra , Sangue Fetal/metabolismo , Lipoproteínas/sangue , Caracteres Sexuais , População Branca , Apolipoproteínas/sangue , Feminino , Idade Gestacional , Humanos , Recém-Nascido , MasculinoRESUMO
BACKGROUND: Paraoxonase (PON1) gene variants have been identified as risk factors for cardiovascular disease (CVD). There are two common PON1 polymorphisms at position 55 (Leu-Met change) and 192 (Gln-Arg change) of the amino acid chain. Leucine at position 55 and arginine at position 192 have been associated with increased cardiovascular risk. The increased prevalence of CVD in renal transplant recipients can be only partly explained by the increased prevalence of conventional risk factors. METHODS: We therefore investigated PON1 polymorphisms in renal transplant recipients (N = 491) with (N = 103) and without CVD (N = 388) using polymerase chain reaction-restriction fragment length analysis. PON1 polymorphisms and their associated PON1/arylesterase activities were also assessed in a subgroup of patients (N = 165). RESULTS: The genotype distribution and allele frequencies for both polymorphisms were similar in both groups. The frequencies for LL, LM, and MM genotypes for the 55 position in patients with CVD were 0.39, 0.51, and 0.10, respectively, compared with 0.43, 0.43, and 0.14 in patients without CVD (P = 0.31). The distribution for the QQ, QR, and RR genotypes at the 192 position were 0.48, 0.43, and 0.09, respectively, in patients with CVD compared with 0.46, 0.46, and 0.08 in patients without CVD (P = 0.8). There were highly significant differences in serum activities of PON1/arylesterase between genotypes defined by 55 and 192 polymorphisms. Leucine at position 55 and arginine at position 192 were associated with higher activities. CONCLUSION: These data indicate that there is no association between the PON1 gene variants, conferring higher enzyme activity, and the increased cardiovascular risk in renal transplant recipients.
Assuntos
Doenças Cardiovasculares/genética , Esterases/genética , Transplante de Rim , Polimorfismo Genético/fisiologia , Adulto , Alelos , Sequência de Aminoácidos/genética , Arildialquilfosfatase , Hidrolases de Éster Carboxílico/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Esterases/sangue , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Complicações Pós-Operatórias , Fatores de RiscoRESUMO
Increased plasma homocysteine is an independent risk factor for cardiovascular disease. We have investigated homocysteine and B-group vitamin levels in renal transplant patients. Fasting blood was collected from 55 renal transplant recipients with good renal function and 32 age/sex matched control subjects. Total homocysteine was increased in transplant recipients in comparison to controls (10.9+/-1.5 vs. 6.7+/-1.3 micromol/l, P < 0.001). There was no difference in homocysteine between patients receiving cyclosporin (n = 39, homocysteine 11.0+/-1.5 micromol/l) and patients receiving prednisolone + azathioprine (n = 16, 10.8+/-1.6 micromol/l, mean+/-S.D.), although there was a significant correlation between homocysteine and serum cyclosporin concentration in the sub-group of patients receiving that immunosuppressive regimen (r = 0.42, P < 0.05). Levels of B-group vitamins were similar in patients and controls. Plasma homocysteine is increased in renal transplant recipients even in the presence of minor degrees of renal impairment and normal levels of B-group vitamins.
Assuntos
Homocisteína/sangue , Transplante de Rim , Complexo Vitamínico B/sangue , Adolescente , Adulto , Idoso , Azatioprina/uso terapêutico , Ciclosporina/uso terapêutico , Feminino , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Modelos Químicos , Prednisolona/uso terapêuticoRESUMO
Oxidation of VLDL in vitro increases macrophage uptake and promotes foam cell formation, and the dyslipidaemia of chronic renal failure is characterised by an increase in VLDL. However, little information is available with regard to the susceptibility of VLDL to oxidation in patients at increased risk of atherosclerosis. We have therefore assessed the composition and susceptibility to oxidation of VLDL from haemodialysis patients and control subjects. VLDL from haemodialysis patients contained increased lipid hydroperoxides (81.6 +/- 12.6 versus 16.1 +/- 3.4 nmol/mg protein, P < 0.001) and malondialdehyde (35.9 +/- 7.3 versus 16.0 +/- 4.1 nmol/mg protein, P < 0.05). Susceptibility to oxidation was increased as shown by an increased rate of propagation of the copper induced lipid peroxidation chain-reaction (11.6 +/- 1.5 x 10(-5) versus 7.6 +/- 1.1 x 10(-5)abs. U/min, P < 0.05) and a greater increase in conjugated diene formation during peroxidation (0.47 +/- 0.04 versus 0.25 +/- 0.03 abs. U, P < 0.001). Increased VLDL peroxidation in dialysis patients may contribute to the increased risk of cardiovascular disease observed in this group of patients.
Assuntos
Doenças Cardiovasculares/etiologia , Falência Renal Crônica/sangue , Peroxidação de Lipídeos , Lipoproteínas VLDL/sangue , Diálise Renal , Adulto , Feminino , Humanos , Falência Renal Crônica/complicações , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Oxirredução , Vitamina E/sangueRESUMO
Tuberculosis can be transmitted from patients to health care workers. However, where the incidence of tuberculosis is low, and good infection control practices exist, the risk of health care workers acquiring the disease is likely to be small. The objective of this study was to determine the rate of notification of tuberculosis in health care workers in Northern Ireland compared with the general population. Information from the statutory tuberculosis notification forms for the period 1982-1991 was entered on to a computer database. Those patients involved in health care occupations were identified and age and sex standardized incidence rates were calculated. The overall notification rate for tuberculosis was 7.4 cases per 100,000 of general population. There was no significant increase in notification of tuberculosis among health care workers [standardized incidence ratio: 126% (95% CI 91-170)]. No cases were diagnosed as a result of screening methods performed during employment. It was concluded that health care workers in Northern Ireland did not have a significantly increased incidence of tuberculosis compared with the general population over the 10-year period studied. This suggests that the risk of transmission from patients to health care workers is negligible in the setting of a low general incidence of tuberculosis and good infection control practice. Under these circumstances, the present findings support the cessation of routine screening of health care workers.
Assuntos
Busca de Comunicante , Pessoal de Saúde , Transmissão de Doença Infecciosa do Paciente para o Profissional , Tuberculose/epidemiologia , Tuberculose/transmissão , Bases de Dados Factuais , Notificação de Doenças , Humanos , Incidência , Programas de Rastreamento/estatística & dados numéricos , Irlanda do Norte/epidemiologia , Vigilância da População , Tuberculose/prevenção & controleRESUMO
Cardiovascular disease is the major cause of mortality in patients receiving hemodialysis for chronic renal failure. Increased lipid peroxidation and depletion of chain-breaking antioxidants may contribute to increased risk of atherosclerosis. We have therefore assessed the effect of a single episode of hemodialysis on antioxidant status in 22 patients and control subjects. Overall, total antioxidant capacity of serum was increased in dialysis patients, but there was a marked reduction after hemodialysis [571 +/- 31 vs 342 +/- 22 mumol/L Trolox (water-soluble vitamin E analog) equivalents, P < 0.001]. The increase in total antioxidant capacity before hemodialysis was almost entirely due to relatively high serum urate. Among individual chain-breaking antioxidants, dialysis led to a decrease in urate (398 +/- 15 vs 136 +/- 12 mumol/L, P < 0.001), ascorbate (10.5 +/- 1.7 vs 5.9 +/- 1.0 mumol/L, P < 0.01), and lipid-corrected tocopherol (4.70 +/- 0.56 vs 4.26 +/- 0.39 mumol/mmol cholesterol, P < 0.05). Protein thiol groups increased after dialysis (328 +/- 16 vs 422 +/- 22 mumol/L, P < 0.001), whereas albumin remained unchanged (40.1 +/- 1.1 vs 41.0 +/- 1.6 g/L, not significant). Although total antioxidant capacity of serum is increased in hemodialysis patients, depletion of key chain-breaking antioxidants may lead to accelerated atherogenesis.
Assuntos
Antioxidantes/metabolismo , Proteínas Sanguíneas/metabolismo , Diálise Renal , Compostos de Sulfidrila/sangue , Adulto , Idoso , Ácido Ascórbico/sangue , Colesterol/sangue , Feminino , Humanos , Falência Renal Crônica , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Albumina Sérica/metabolismo , Ácido Úrico/sangue , Vitamina E/sangueRESUMO
Patients with chronic renal failure, including those receiving regular long-term haemodialysis, have a high incidence of premature cardiovascular disease. Oxidative stress, which occurs when there is excessive free-radical production or low antioxidant levels, has recently been implicated as a causative factor in atherogenesis. The aim of this study was to determine if chronic renal failure and haemodialysis were associated with increased oxidative stress. Serum malondialdehyde was measured as a marker of lipid peroxidation in 15 patients with conservatively managed chronic renal failure (CRF), 15 patients with CRF undergoing regular haemodialysis and 15 healthy controls. Selenium, glutathione peroxidase and antioxidant vitamins were also measured. Malondialdehyde was elevated in dialysis patients in comparison to CRF and control groups (dialysis 1.16 +/- 0.08 mumol/l, CRF 0.94 +/- 0.07, controls 0.66 +/- 0.10). Antioxidants, including vitamin C, selenium and glutathione peroxidase, were decreased in dialysis patients and to a lesser extent in the CRF group (vitamin C-dialysis 16.43 +/- 3.76 mumol/l, CRF 34.5 +/- 8.6, controls 56.11 +/- 7.41; selenium-dialysis 0.77 +/- 0.07 mumol/l, CRF 0.69 +/- 0.06, controls 1.09 +/- 0.06: glutathione peroxidase-dialysis 101 +/- 5 U/l, CRF 160 +/- 11, controls 290 +/- 10). These findings indicate oxidative stress in patients with CRF which is further exacerbated by haemodialysis, as evidenced by increased lipid peroxidation and low antioxidant levels. This stress may play a role in the development of atherosclerosis in these groups.
Assuntos
Falência Renal Crônica/metabolismo , Estresse Oxidativo , Diálise Renal , Adulto , Idoso , Ácido Ascórbico/sangue , Feminino , Glutationa Peroxidase/sangue , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Selênio/sangueRESUMO
Patients undergoing chronic haemodialysis are known to have a high incidence of premature atherosclerosis for reasons which have not been fully elucidated. The susceptibility of low density lipoprotein (LDL) to oxidation by copper ions in vitro is widely used as a measure of its atherogenicity in vivo. We measured the susceptibility of LDL to oxidation using copper ions in haemodialysis patients and found, surprisingly, a markedly increased resistance to oxidation. The experiment was therefore repeated using an alternative free radical generator, AAPH [2,2'-azobis-(2-amidinopropane hydrochloride)], to promote LDL oxidation; using AAPH, the susceptibility to oxidation was similar in the dialysis group compared to controls. Abnormal LDL composition in the dialysis patients was also demonstrated. We suggest that, in such situations, susceptibility of LDL to oxidation in vitro may be highly dependent on the biochemical method employed and therefore may not accurately reflect atherogenic risk.