RESUMO
Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. Recent literature has proposed two subgroups of PD. The "body-first subtype" is associated with a prodrome of isolated REM-sleep Behavior Disorder (iRBD) and a relatively symmetric brain degeneration. The "brain-first subtype" is suggested to have a more asymmetric degeneration and a prodromal stage without RBD. This study aims to investigate the proposed difference in symmetry of the degeneration pattern in the presumed body and brain-first PD subtypes. We analyzed 123I-FP-CIT (DAT SPECT) and 18F-FDG PET brain imaging in three groups of patients (iRBD, n = 20, de novo PD with prodromal RBD, n = 22, and de novo PD without RBD, n = 16) and evaluated dopaminergic and glucose metabolic symmetry. The RBD status of all patients was confirmed with video-polysomnography. The PD groups did not differ from each other with regard to the relative or absolute asymmetry of DAT uptake in the putamen (p = 1.0 and p = 0.4, respectively). The patient groups also did not differ from each other with regard to the symmetry of expression of the PD-related metabolic pattern (PDRP) in each hemisphere. The PD groups had no difference in symmetry considering mean FDG uptake in left and right regions of interest and generally had the same degree of symmetry as controls, while the iRBD patients had nine regions with abnormal left-right differences (p < 0.001). Our findings do not support the asymmetry aspect of the "body-first" versus "brain-first" hypothesis.
RESUMO
Idiopathic Rem sleep Behavior Disorder (iRBD) is a significant biomarker for the development of alpha-synucleinopathies, such as Parkinson's disease (PD) or Dementia with Lewy bodies (DLB). Methods to identify patterns in iRBD patients can help in the prediction of the future conversion to these diseases during the long prodromal phase when symptoms are non-specific. These methods are essential for disease management and clinical trial recruitment. Brain PET scans with 18F-FDG PET radiotracers have recently shown promise, however, the scarcity of longitudinal data and PD/DLB conversion information makes the use of representation learning approaches such as deep convolutional networks not feasible if trained in a supervised manner. In this work, we propose a self-supervised learning strategy to learn features by comparing the brain hemispheres of iRBD non-convertor subjects, which allows for pre-training a convolutional network on a small data regimen. We introduce a loss function called hemisphere dissimilarity loss (HDL), which extends the Barlow Twins loss, that promotes the creation of invariant and non-redundant features for brain hemispheres of the same subject, and the opposite for hemispheres of different subjects. This loss enables the pre-training of a network without any information about the disease, which is then used to generate full brain feature vectors that are fine-tuned to two downstream tasks: follow-up conversion, and the type of conversion (PD or DLB) using baseline 18F-FDG PET. In our results, we find that the HDL outperforms the variational autoencoder with different forms of inputs.
RESUMO
We have studied at the ultrastructural level the presence of manganese (Mn) in rat basal ganglia, which are target regions of the brain for Mn toxicity. The rats underwent a moderate level of Mn exposure induced per os for 13 weeks. Mn was detected by means of electron spectroscopy imaging (ESI) and electron energy-loss spectroscopy (EELS) analyses on perfusion fixed samples embedded in resin. While no significant contamination by exogenous Mn occurred during the processing procedures, less than 50% of endogenous Mn was lost during fixation and dehydration of the brain samples. The residual Mn ions in the samples appeared as discrete particles, localized in selected sub-cellular organelles in a cell, suggesting that no significant translocation had occurred in the surrounding area. In control rats, the Mn sub-cellular localization and relative content were the same in neurons and astrocytes of rat striatum and globus pallidus: the Mn level was highest in the heterochromatin and in the nucleolus, intermediate in the cytoplasm, and lowest in the mitochondria (p<0.001). After chronic Mn treatment, while no ultrastructural damage was detected in the neurons and glial cells, the largest rate of Mn increase was noted in the mitochondria of astrocytes (+700%), an intermediate rate in the mitochondria of neurons (+200%), and the lowest rate in the nuclei (+100%) of neurons and astrocytes; the Mn level in the cytoplasm appeared unchanged. EELS analysis detected the specific spectra of Mn L(2,3) (peak at DeltaE = 665 eV) in such organelles, confirming the findings of ESI. Although a consistent loss of Mn occurred during the processing of tissue samples, ESI and EELS can be useful methods for localization of endogenous Mn in embedded tissues. The high rate of Mn sequestration in the mitochondria of astrocytes in vivo may partly explain the outstanding capacity of astrocytes to accumulate Mn, and their early dysfunction in Mn neurotoxicity. The high level of Mn in the heterochromatin and nucleoli of neurons and astrocytes in basal conditions and its further increase after Mn overload should provide insight into new avenues of investigating the role of Mn in the normal brain and a baseline for future Mn toxicity studies.
Assuntos
Gânglios da Base/efeitos dos fármacos , Manganês/metabolismo , Manganês/toxicidade , Oligoelementos/metabolismo , Oligoelementos/toxicidade , Análise de Variância , Animais , Gânglios da Base/metabolismo , Gânglios da Base/ultraestrutura , Citoplasma/efeitos dos fármacos , Citoplasma/ultraestrutura , Masculino , Microscopia Eletrônica de Transmissão/métodos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Ratos , Ratos Wistar , Espectroscopia de Perda de Energia de Elétrons/métodos , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismoRESUMO
To elucidate the bleeding tendency that follows the administration of ticlopidine, we investigated the skin bleeding time and some ex vivo functions of platelets obtained from eight healthy volunteers before and 1 wk after daily administration of 500 mg of ticlopidine. We found the following: ticlopidine significantly (P less than 0.001) prolonged the skin bleeding time and impaired the binding of radiolabeled fibrinogen and von Willebrand Factor, the clot retraction and the aggregation of platelets in response to ADP, epinephrine, thrombin, ionophore A23187, collagen, or arachidonic acid. In contrast, the administration of this drug did not affect intraplatelet levels of cAMP, agglutination and binding of von Willebrand Factor in response to ristocetin, shape change in response to ADP, collagen, thrombin, or arachidonic acid, or binding of prostaglandin E1 to resting platelets. Secretion of ATP in response to ADP or epinephrine was completely inhibited, whereas secretion as well as thromboxane synthesis in response to high concentrations of collagen, arachidonic acid, calcium ionophore A23187, or thrombin was unaffected. Studies with monoclonal antibodies showed that the glycoprotein IIb-IIIa complex (the putative receptor for fibrinogen and von Willebrand Factor on the surface of platelets exposed to naturally occurring aggregating agents) was quantitatively unaffected by ticlopidine. This observation was further confirmed by densitometric scannings of Periodic Acid-Schiff-stained gels of platelet suspensions. The onset, as well as the cessation of the inhibitory effect of ticlopidine on platelets was very slow, and reached a maximum after a 3-5-d administration. In addition, ticlopidine appeared to be a much more potent inhibitor when administered to subjects than when added in vitro to platelets. Finally, abnormalities comparable to those found in volunteers taking ticlopidine were observed when platelets from untreated subjects were incubated in the plasma of ticlopidine-treated subjects. We conclude that ticlopidine induces a thrombasthenic state in normal platelets without affecting the glycoprotein IIb-IIIa complex quantitatively. Furthermore, our data suggest that one or more active metabolites rather than the native drug mediate the abnormalities of platelet function observed in ticlopidine-treated subjects.
Assuntos
Transtornos Plaquetários/induzido quimicamente , Plaquetas/efeitos dos fármacos , Tiofenos/farmacologia , Trifosfato de Adenosina/metabolismo , Adulto , Animais , Tempo de Sangramento , Plaquetas/fisiologia , Retração do Coágulo , Feminino , Fibrinogênio/metabolismo , Glicoproteínas/sangue , Humanos , Técnicas In Vitro , Masculino , Proteínas de Membrana/sangue , Agregação Plaquetária/efeitos dos fármacos , Glicoproteínas da Membrana de Plaquetas , Ratos , Ticlopidina , Fator de von Willebrand/fisiologiaRESUMO
Impaired platelet aggregation, normal shape change, and agglutination and normal ATP secretion and thromboxane synthesis in response to high concentrations of thrombin or arachidonic acid were found in a patient with multiple myeloma and hemorrhagic tendency. The purified IgG1 kappa or its F(ab1)2 fragments induced similar changes when added in vitro to platelet-rich plasma from normal subjects. In addition, the paraprotein inhibited adhesion to glass microbeads, fibrin clot retraction, and binding of radiolabeled fibrinogen or von Willebrand factor to platelets exposed to thrombin or arachidonic acid without affecting intraplatelet levels of cAMP. The radiolabeled para-protein bound to an average of 35,000 sites on normal platelets but it bound to less than 2,000 sites on the platelets from a patient with Glanzmann's thrombasthenia. Immunoprecipitation studies showed that the platelet antigen identified by the paraprotein was the glycoprotein IIIa. Furthermore, binding of radiolabeled prostaglandin E1 (PGE1) to resting platelets as well as binding of von Willebrand factor to platelets stimulated with ristocetin were entirely normal in the presence of patient's inhibitor. These studies indicate that bleeding occurring in dysproteinemia may be the result of a specific interaction of monoclonal paraproteins with platelets. In addition, our data support the concept that the interaction of fibrinogen and/or von Willebrand factor with the platelet glycoprotein IIb-IIIa complex is essential for effective hemostasis.
Assuntos
Especificidade de Anticorpos , Hemorragia Gastrointestinal/imunologia , Glicoproteínas/imunologia , Proteínas de Membrana/imunologia , Proteínas do Mieloma/fisiologia , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Monoclonais/fisiologia , Sítios de Ligação de Anticorpos , Fibrinogênio/metabolismo , Hemorragia Gastrointestinal/sangue , Glicoproteínas/metabolismo , Humanos , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Peso Molecular , Mieloma Múltiplo/sangue , Mieloma Múltiplo/imunologia , Proteínas do Mieloma/isolamento & purificação , Agregação Plaquetária , Glicoproteínas da Membrana de Plaquetas , Fator de von Willebrand/metabolismoRESUMO
BACKGROUND: Hypertensive patients are characterized by development of both left ventricular hypertrophy (LVH) and endothelial dysfunction METHODS AND RESULTS: We enrolled 65 never-treated hypertensive patients (36 men and 29 women aged 45.6+/-6.0 years) to assess the possible relationship between echocardiographic left ventricular mass (LVM) and endothelium-dependent vasodilation. Left ventricular measurements were performed at end diastole and end systole according to the recommendations of the American Society of Echocardiography and the Penn Convention. LVM was calculated with the Devereux formula and indexed by body surface area and height raised to the 2.7th power. The endothelial function was tested as responses of forearm vasculature to acetylcholine (ACh), an endothelium-dependent vasodilator (7.5, 15, and 30 microg. mL-1. min-1, each for 5 minutes), and sodium nitroprusside (SNP), an endothelium-independent vasodilator (0.8, 1.6, and 3.2 microg. mL-1. min-1, each for 5 minutes). Drugs were infused into the brachial artery, and forearm blood flow (FBF) was measured by strain-gauge plethysmography. A negative significant relationship between indexed LVM and peak of increase in FBF was found during ACh infusions (r=-0. 554; P<0.0001). In addition, hypertrophic patients had a significantly lower responsive to ACh than patients without LVH (the peak increase in FBF was 9.9+/-3.7 versus 16.1+/-8.1 mL per 100 mL of tissue per minute; P<0.0001). No significant correlation was observed between LVM and FBF during SNP infusion. CONCLUSIONS: Our data provide the first evidence that echocardiographic LVM in hypertensive patients is inversely related to FBF responses to the endothelium-dependent vasodilating agent ACh, but it is likely that both endothelium and LVM are damaged by hypertension.
Assuntos
Endotélio Vascular/fisiopatologia , Ventrículos do Coração/patologia , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/etiologia , Vasodilatação/efeitos dos fármacos , Acetilcolina/farmacologia , Adaptação Fisiológica , Adulto , Doenças Cardiovasculares/epidemiologia , Diástole , Ecocardiografia , Feminino , Antebraço/irrigação sanguínea , Humanos , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/patologia , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/fisiologia , Nitroprussiato/farmacologia , Tamanho do Órgão , Pletismografia , Fatores de Risco , Sístole , Vasodilatadores/farmacologiaRESUMO
The mechanisms underlying macrovascular complications in NIDDM are partially understood. In addition to increased prevalence and severity of systemic cardiovascular risk factors, local alterations of arterial wall and hemodynamics may play a role. Atherosclerotic lesions usually lie in regions of low wall shear stress. We therefore investigated the wall shear stress--that is, the frictional force acting tangentially to the endothelial surface--in the common carotid artery of diabetic and control subjects. Enrolled were 18 male NIDDM subjects and 18 age-matched control subjects. None of the participants were hypertensive, hyperlipidemic, or a cigarette smoker. Common carotid wall shear stress was calculated according to the following equation: blood viscosity x blood velocity/internal diameter. Blood viscosity was measured by use of a cone/plate viscometer. Blood velocity and internal diameter were measured by high-resolution echo-Doppler. Wall shear stress was significantly lower in NIDDM subjects than in control subjects (mean wall shear stress: 9.7 +/- 2.4 vs. 11.7 +/- 2.6 dynes/cm2, P < or = 0.005). Six diabetic participants had a plaque in one carotid tree and no lesions in the contralateral carotid. Among these subjects, mean wall shear stress was significantly lower in the side with lesion (8.1 +/- 1.6 vs. 10.5 +/- 2.4 dynes/cm2, P < or = 0.02). These findings suggest that diabetes is associated with a more atherosclerosis-prone carotid hemodynamic profile, which might represent an additional factor contributing to the increased prevalence and severity of carotid atherosclerosis in diabetic patients compared with general population.
Assuntos
Artéria Carótida Primitiva/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Arteriosclerose/etiologia , Velocidade do Fluxo Sanguíneo/fisiologia , Viscosidade Sanguínea/fisiologia , Artérias Carótidas/patologia , Artéria Carótida Primitiva/diagnóstico por imagem , Diabetes Mellitus Tipo 2/patologia , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/fisiopatologia , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Estresse Mecânico , UltrassonografiaRESUMO
Endothelial dysfunction has been reported in obese subjects, but its mechanism has not been elucidated. We have therefore investigated 1) the possible relationship among BMI, waist-to-hip ratio (WHR), and endothelium-dependent vasodilation and 2) whether oxidative stress participates in endothelial dysfunction. We recruited 76 healthy subjects (50 men and 26 women aged 21-45 years) and measured their BMI (kg/m2), WHR, and insulin resistance (IR) estimated by the homeostasis model assessment (HOMA). Endothelium-dependent and -independent vasodilation were assessed by increasing doses of acetylcholine (ACh) (7.5, 15, and 30 pg x ml(-1) x min(-1)) and sodium nitroprusside (SNP) (0.8, 1.6, and 3.2 microg x ml(-1) x min(-1)) during saline and vitamin C coinfusion (24 mg/min). The effects of cyclooxygenase activity were evaluated by a dose-response curve to intrabrachial coinfusion of ACh and indomethacin (500 microg/min). Three different groups have been identified according to their BMI: group A (BMI <25), consisting of 10 men and 5 women; group B (BMI between 25 and 29), consisting of 16 men and 8 women; and group C (BMI > or =30), consisting of 24 men and 13 women. Obese subjects had significantly lower forearm blood flow (FBF) during ACh infusions (means +/- SD): 19.8 +/- 2.8, 10.8 +/- 2.7, and 6.5 +/- 1.8 ml x 100 ml(-1) tissue x min(-1) (P < 0.0001) for groups A, B, and C, respectively. SNP caused comparable increments in FBF in all groups. Regression analysis revealed a significant negative correlation between BMI (r = -0.676, P < 0.0001), WHR (r = -0.631, P < 0.0001), fasting insulin (r = -0.695, P < 0.0001), HOMA-IR (r = -0.633, P < 0.0001), and percent peak increase in FBF during ACh infusion. In obese subjects, both vitamin C and indomethacin increased the impaired vasodilating response to ACh, whereas the SNP effect was unchanged. In conclusion, in obese subjects, ACh-stimulated vasodilation is blunted, and the increase in FBF is inversely related to BMI, WHR, fasting insulin, and HOMA-IR. The effects of both vitamin C and indomethacin on impaired ACh-stimulated vasodilation support the hypothesis that oxidative stress contributes to endothelial dysfunction in human obesity.
Assuntos
Tecido Adiposo/patologia , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Obesidade/fisiopatologia , Estresse Oxidativo , Acetilcolina/farmacologia , Adulto , Combinação de Medicamentos , Feminino , Humanos , Indometacina/farmacologia , Injeções Intra-Arteriais , Masculino , Nitroprussiato/farmacologia , Vasodilatação , Vasodilatadores/farmacologiaRESUMO
OBJECTIVES: This study sought to evaluate the possible association of polymorphism of the angiotensin-converting enzyme (ACE) gene with blood pressure and left ventricular mass index (LVMI). BACKGROUND: The renin-angiotensin system seems to be involved in the pathogenesis of essential hypertension. Moreover, recent epidemiologic observations demonstrate that many subjects with left ventricular hypertrophy have normal blood pressure levels, suggesting that factors other than hemodynamic overload may contribute to the hypertrophy. METHODS: The study included 140 untreated hypertensive outpatients who underwent ambulatory blood pressure monitoring, echocardiographic evaluation and analysis for insertion (I)/ deletion (D) polymorphism in intron 16 of the ACE gene by polymerase chain reaction. Blood pressure was measured at 24 h, and LVMI was calculated by the Devereux formula, in each patient. RESULTS: Left ventricular mass index values (mean +/- SD) were 137 +/- 28 g/m2 in patients with the DD genotype, 125 +/- 27 g/m2 in those with the ID genotype and 115 +/- 27 g/m2 in those with II genotype. The frequencies of the DD, ID and II genotypes were 45.71% (n = 64), 46.42% (n = 65) and 7.85% (n = 11), respectively, and were in Hardy-Weinberg equilibrium. The strongest association between left ventricular mass and DD genotype in our cohort appeared to be an independent cardiovascular risk factor (DD vs. ID: odds ratio [OR] 2.497, 95% confidence interval [CI] interval 1.158 to 5.412, p < 0.05; DD vs. II: OR 6.577, 95% CI 1.169 to 28.580, p < 0.02). CONCLUSIONS: Our data show that the LVMI was significantly enhanced in patients with the DD genotype.
Assuntos
Deleção de Genes , Hipertensão/genética , Hipertrofia Ventricular Esquerda/genética , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Adulto , Idoso , Ecocardiografia , Feminino , Genótipo , Humanos , Itália , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To verify whether carotid arterial intimal plus media thickness (IMT) is greater in non-insulin-dependent diabetes mellitus (NIDDM) subjects, known to be at high risk for atherosclerosis. Evidence is growing that IMT is increased in subjects with coronary heart disease (CHD) risk factors like hypercholesterolemia and cigarette smoking. RESEARCH DESIGN AND METHODS: Fifty-four NIDDM subjects and 54 sex- and age-matched control subjects underwent CHD risk factors assessment and echo-Doppler examination of carotid arteries. IMT was measured by computer technique in the common carotid artery (CCA). Presence of plaques and/or stenosis (carotid atherosclerosis [CA]) was also evaluated by a single-blinded reader. RESULTS: NIDDM subjects had larger IMT, higher levels of triglycerides, and lower concentrations of high-density lipoprotein (HDL) cholesterol compared with control subjects. IMT was positively correlated to age and systolic blood pressure and inversely to HDL cholesterol in both groups. The prevalence of CA was 46% in NIDDM subjects and 18% in control subjects. In multiple regression analysis, IMT was the only variable significantly associated to CA. CONCLUSIONS: IMT of CCA is enlarged in NIDDM subjects compared with control subjects. Its association with carotid plaques and/or stenosis might be of importance to detect early atherosclerotic lesions in the carotid arteries.
Assuntos
Artérias Carótidas/diagnóstico por imagem , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Angiopatias Diabéticas/diagnóstico por imagem , Arteriosclerose/sangue , Arteriosclerose/diagnóstico por imagem , Doença das Coronárias/sangue , Doença das Coronárias/diagnóstico por imagem , Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/sangue , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Túnica Íntima/diagnóstico por imagem , Túnica Média/diagnóstico por imagem , Ultrassonografia DopplerRESUMO
OBJECTIVE: To examine whether middle (two months) and long-term (six months) isradipine sustained-release treatment improves endothelium-dependent vasodilation in never treated hypertensive patients. METHODS: The responses of the forearm vasculature to acetylcholine (7.5, 15 and 30 micrograms/min) and sodium nitroprusside (0.8, 1.6, 3.2 micrograms/min) were evaluated in 12 normotensive controls (seven men and five women, aged 25 to 49 years), and in 12 hypertensives (eight men and four women, aged 20 to 47 years) at baseline and after two and six months of isradipine sustained-release treatment. Drugs were infused into the brachial artery, and forearm blood flow was measured by strain-gauge plethysmography. RESULTS: At baseline, the response to acetylcholine was significantly lower in hypertensives vs controls: at the highest dose (30 micrograms/min), forearm blood flow was 28.6 +/- 2.4 ml/100 ml of tissue per min in the controls vs 8.9 +/- 1.0 ml/100 ml of tissue per min in hypertensive (p < 0.0001). Similarly, vascular resistance was significantly (p < 0.0001) higher in hypertensives: 4.8 +/- 0.5 units (controls) vs 15.1 +/- 1.7 units (hypertensives). After isradipine treatment, the forearm blood flow in hypertensive patients changed from 8.9 +/- 1.0 ml/100 ml of tissue per min to 16.0 +/- 1.2 ml/100 ml of tissue per min (two months; p < 0.0001) and 15.2 +/- 1.4 ml/100 ml of tissue per min (six months; p < 0.0001). Isradipine treatment did not modify the vasodilating effect of sodium nitroprusside. CONCLUSIONS: Our data demonstrate for the first time that the calcium antagonist isradipine improves acetylcholine-induced vasodilation in hypertensives.
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Hipertensão/tratamento farmacológico , Isradipino/uso terapêutico , Acetilcolina , Adulto , Análise de Variância , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Feminino , Antebraço/irrigação sanguínea , Humanos , Masculino , Pessoa de Meia-Idade , Nitroprussiato , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fatores de Tempo , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , VasodilatadoresRESUMO
OBJECTIVE: To evaluate the relationship between ACE-gene polymorphism and left ventricular geometry in never treated hypertensives. METHODS: We enrolled 200 hypertensive outpatients that underwent clinical and ambulatory blood pressure measurements, echocardiographic evaluation and analysis for insertion (I)/deletion (D) polymorphism by PCR. Patients with normal or increased (> 125 g/m2 in males and > 110 g/m2 in females) left ventricular mass were considered to have concentric remodeling or concentric left ventricular hypertrophy if their relative wall thickness was > or = 0.45. RESULTS: The left ventricular mass index values (g/m2) were 136 +/- 30 in DD genotype, 124 +/- 26 in ID genotype, and 116 +/- 20 in II genotype (DD vs. ID P < 0.005; DD vs. II P < 0.05), and were unrelated to blood pressure. Ninety-six patients presented left ventricular hypertrophy (48.0%): 51 with concentric and 45 with eccentric hypertrophy. The eccentric left ventricular hypertrophy was detected in 32 (36.8%) DD patients, in ten (10.5%) ID patients (P < 0.05), and in three (16.6%) II patients. The relative septal thickness was 0.43 +/- 0.09 in DD genotype, 0.45 +/- 0.08 in ID genotype, and 0.43 +/- 0.10 in II genotype. In DD and ID genotypes, the relative posterior wall thickness (0.37 +/- 0.07 vs. 0.41 +/- 0.07; P < 0.0001) and the end-diastolic left ventricular internal dimension (52.8 +/- 3.3 mm vs. 48.3 +/- 2.8 mm; P < 0.0001) were statistically different. CONCLUSIONS: The DD genotype of the ACE-gene is associated with an increased left ventricular mass and with a significantly higher prevalence of eccentric left ventricular hypertrophy, when compared to ID genotype.
Assuntos
Hipertensão/patologia , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Remodelação Ventricular , Fatores Etários , Análise de Variância , Estudos de Avaliação como Assunto , Feminino , Genótipo , Humanos , Hipertensão/genética , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores SexuaisRESUMO
The expression of the asialoglycoprotein receptor of hepatocytes and the galactose-specific receptors of non-parenchymal liver cells during the onset of apoptosis in liver of rats treated with lead nitrate was studied. During the involution of lead nitrate-induced hyperplasia in rat liver (occurring at 5 days after the injection) a significant increase of asialoglycoprotein receptor (ASGP-R) expression on hepatocytes coincided with the massive death by apoptosis of the same cells. The increase in the receptor expression was sustained by a large increase in the level of its specific mRNA. As a consequence of lead nitrate injection, we also detected a drastic change of the galactose-specific receptor expression and distribution on the surface of rat liver sinusoidal cells. However, the modulation of the receptor expression on the Kupffer cells did not parallel that observed for the ASGP-R: the peak of surface expression measured on hepatocytes always followed the one observed on Kupffer cells. Our data show a first evidence of a receptor modulation during the process of apoptosis. In fact, the entire carbohydrate recognition system of the liver is modulated during the onset of apoptosis induced by lead nitrate injection, but the pattern of modulation depends on the cellular types. We suggest that a physiological role for the hepatic carbohydrate recognition systems is related to the apoptosis of liver.
Assuntos
Apoptose , Fígado/metabolismo , Receptores de Superfície Celular/biossíntese , Animais , Apoptose/efeitos dos fármacos , Receptor de Asialoglicoproteína , Carboidratos/fisiologia , Invaginações Revestidas da Membrana Celular/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperplasia , Células de Kupffer/efeitos dos fármacos , Células de Kupffer/metabolismo , Chumbo/farmacologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Nitratos/farmacologia , RNA Mensageiro/biossíntese , Ratos , Ratos Wistar , Receptores de Superfície Celular/fisiologiaRESUMO
The response of the forearm vasculature to acetylcholine (7.5, 15, and 30 microg/min, each for 5 minutes) and sodium nitroprusside (0.8, 1.6, and 3.2 microg/min, each for 5 minutes) was evaluated in 32 never-treated hypertensive outpatients (17 men and 15 women, aged 43+/-7 years) and in 24 normotensive control subjects (14 men and 10 women, aged 42+/-6 years). Drugs were infused into the brachial artery, and forearm blood flow was measured by strain-gauge plethysmography. In both hypertensive and normotensive groups, a deletion (D)/insertion (I) polymorphism in intron 16 of the angiotensin-converting enzyme (ACE) gene was determined by polymerase chain reaction. The response to acetylcholine was significantly reduced in hypertensive patients versus control subjects: at the highest dose (30 microg/min), forearm blood flow was 13.9+/-6.3 mL x 100 mL tissue(-1) x min(-1) in hypertensives versus 27.1+/-9.7 mL x 100 mL tissue(-1) x min(-1) in the controls (P<.001); similarly, vascular resistance was 10.6+/-5.6 U in hypertensive patients and 4.9+/-1.9 U in normotensive subjects. In the hypertensive group, the patients with DD genotype showed significantly less endothelium-dependent vasodilation compared with ID+II genotypes (at the highest dose of acetylcholine, forearm blood flow was 12.1+/-4.2 versus 17.0+/-4.1 mL x 100 mL tissue(-1) x min(-1)) (P<.005). The vasodilator effect of sodium nitroprusside infusions was not statistically different in DD and ID+II hypertensive patients. In conclusion, our data suggest that ACE polymorphism affects endothelium-dependent vasodilation in hypertensive patients and confirm that hypertensive patients had a blunted response to the endothelium-dependent agent acetylcholine.
Assuntos
Endotélio Vascular/fisiologia , Hipertensão/genética , Peptidil Dipeptidase A/genética , Vasodilatação/fisiologia , Adulto , Análise de Variância , Pressão Sanguínea , Feminino , Genótipo , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo GenéticoRESUMO
The lipophilic probe 1,6-diphenyl-1,3,5-hexatriene was incorporated into erythrocyte ghosts of either normal or obese humans, and the polarization of fluorescence was measured between 0 and 40 C. The membrane lipid fluidity, evaluated by fluorescence polarization, was consistently higher in the ghosts from obese subjects. A strong correlation was found between increased 1,6-diphenyl-1,3,5-hexatriene fluorescence polarization and excess body weight. Measurements of cholesterol and phospholipids indicated increased cholesterol and decreased phospholipids in erythrocyte ghosts from obese subjects. These data suggest that alterations in lipid composition in erythrocytes of obese subjects are responsible for abnormal physical properties of plasma membranes, which, in turn, may cause altered enzymatic activities.
Assuntos
Membrana Eritrocítica , Fluidez de Membrana , Lipídeos de Membrana/fisiologia , Obesidade/sangue , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espectrometria de Fluorescência , TemperaturaRESUMO
The association between angiotensin-converting enzyme (ACE) gene polymorphism and insulin resistance (IR) in hypertensive subjects remains controversial. Thus, we evaluated the possible association between IR and ACE gene polymorphism in a group of hypertensive, never-treated patients compared with that in a normotensive control group. We enrolled 200 (114 men and 86 women; age, 45.5 +/- 4.7 yr) hypertensive patients and 96 (54 men and 42 women; age, 44.0 +/- 4.7 yr) normotensive subjects. A double PCR assay was used to identify ACE genotypes. We determined fasting glucose and insulin by the glucose oxidase method and using a standard RIA technique. IR was estimated using the homeostasis model assessment (HOMA(IR)). Both fasting glucose (5.0 +/- 0.3 vs. 4.7 +/- 0.3 mmol/L; P < 0.0001), insulin levels (12.3 +/- 4.7 vs. 4.9 +/- 1.5 muU/mL; P < 0.0001), and HOMA(IR) (2.7 +/- 1.1 vs. 1.1 +/- 0.3; P < 0.0001) were significantly higher in hypertensive patients than in the normotensive control group. When we subdivided hypertensive patients according to ACE genotype, we observed that fasting insulin and HOMA(IR) were 16.3 +/- 3.3 and 3.6 +/- 0.8 in the DD genotype, 9.4 +/- 3.1 and 2.1 +/- 0.7 in the ID genotype, and 8.3 +/- 2.8 and 1.9 +/- 0.7 muU/mL in the II group (P < 0.0001, by ANOVA). No significant differences were observed in the normotensive control group. In conclusion, we extended previous data regarding the relationship of hypertension and IR by demonstrating a dependence of this relationship upon the ACE gene polymorphism.
Assuntos
Hipertensão/fisiopatologia , Resistência à Insulina , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Adulto , Alelos , Glicemia/análise , Feminino , Frequência do Gene , Genótipo , Homeostase , Humanos , Hipertensão/genética , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Valores de ReferênciaRESUMO
The localization of atherosclerotic lesions is influenced by hemodynamic factors, namely, shear stress and tensive forces. The present study investigated the relationships between shear stress and circumferential wall tension and between these hemodynamic factors and the intima-media thickness (IMT) of the common carotid artery in healthy men. Fifty-eight subjects were studied. Shear stress was calculated as blood viscosityxblood velocity/internal diameter. Circumferential wall tension was calculated as blood pressurexinternal radius. Blood velocity, internal diameter, and IMT were measured by high-resolution echo-Doppler. Mean shear stress was 12.6+/-3.3 dynes/cm(2) (mean+/-SD; range, 4.8 to 20.4) and was inversely related with age, blood pressure, and body mass index (BMI). Mean circumferential wall tension was 3.4+/-0.6x10(4) dynes/cm (range 2.4 to 5.6) and was directly associated with age and BMI. IMT was inversely associated with shear stress (r=0.55, P<0. 0001) and directly associated with circumferential wall tension (r=0. 43, P<0.0001). Shear stress and circumferential wall tension were inversely correlated (r=0.66, P<0.0001). In multiple regression analysis, shear stress and (marginally) cholesterol were independently associated with IMT, whereas circumferential wall tension, age, and BMI were not. These findings confirm that common carotid shear stress varies among healthy individuals and decreases as age, blood pressure, and BMI increase. Our findings also demonstrate that circumferential wall tension is directly associated with wall thickness, age, and BMI and that shear stress is associated with common carotid IMT independent of other hemodynamic, clinical, or biochemical factors.
Assuntos
Artéria Carótida Primitiva/patologia , Artéria Carótida Primitiva/fisiologia , Hemodinâmica , Adulto , Fatores Etários , Velocidade do Fluxo Sanguíneo , Pressão Sanguínea/fisiologia , Viscosidade Sanguínea , Índice de Massa Corporal , Artéria Carótida Primitiva/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Cardiovasculares , Análise de Regressão , Estresse Mecânico , Túnica Íntima/patologia , Túnica Média/patologia , Ultrassonografia DopplerRESUMO
In order to assess peripheral levels and activities of a broad spectrum of non-enzymatic and enzymatic antioxidants in elderly subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD), plasma levels of water-soluble (Vitamin C and uric acid) and of lipophilic (Vitamin A, Vitamin E and carotenoids including lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha- and beta-carotene) antioxidant micronutrients as well as activities of plasma and red blood cell (RBC) superoxide dismutase (SOD) and of plasma glutathione peroxidase (GPx) were measured in 25 patients with MCI, 63 AD patients and 53 controls. Peripheral levels and activities of antioxidants were similarly lower in MCI and AD patients as compared to controls. As MCI may represent a prodromal stage of AD, and oxidative damage appears to occur as one of the earliest pathophysiological events in AD, an increased intake of antioxidants in patients with MCI could be helpful in lowering the risk of conversion to dementia.
Assuntos
Doença de Alzheimer/fisiopatologia , Antioxidantes/análise , Transtornos Cognitivos/fisiopatologia , Estresse Oxidativo/fisiologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Ácido Ascórbico/sangue , Carotenoides/sangue , Transtornos Cognitivos/sangue , Eritrócitos/enzimologia , Feminino , Glutationa Peroxidase/metabolismo , Humanos , Masculino , Análise por Pareamento , Plasma/química , Valores de Referência , Superóxido Dismutase/metabolismo , Ácido Úrico/sangue , Vitamina A/sangue , Vitamina E/sangueRESUMO
Computerised image analysis, performed on histological sections of (C57BL6/N) mouse lungs that had been intravenously (i.v.) injected with B16-F10 melanoma cells was used to develop a novel method to quantify the efficacy of potential antineoplastic drugs. This procedure allowed the evaluation of the rate of inhibition of growth and the anti-invasive capability of new molecules, thus resulting in more accurate data than that obtained from common macroscopical counting of surface metastatic foci. Several morphological parameters can be measured by this method: the percentage of tissue area occupied by metastases, which accounts for tumour implantation into the organ; the growth index, related to the size of the metastases, and the invasion index, related to the frequency of foci. These morphometric data were found to be correlated to the levels of lung hydroxyproline and transglutaminase activity, well known markers of tumour invasion and cell differentiation, respectively. The main objective of this computerised procedure was to evaluate how the tumour cell is affected in the host by the drug under investigation. The use of the method is exemplified by an analysis of the antitumour activity of some methylxanthines.
Assuntos
Antineoplásicos/uso terapêutico , Interpretação de Imagem Assistida por Computador/métodos , Neoplasias Pulmonares/secundário , Melanoma/secundário , Animais , Divisão Celular , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Células Tumorais CultivadasRESUMO
There is increasing evidence that arterial intima-media thickness (IMT) might represent an early atherosclerotic lesion. The clinical importance of its measurement is, however, still debated. The aim of the present study was to analyze the effect of coronary heart disease (CHD) risk factors on carotid IMT and to verify whether intima-media thickening is associated with overt atherosclerosis of carotid arteries. Two hundred and seventy-six subjects referred to the Angiology Unit for echo-Doppler examination of carotid arteries during the period January-June 1993 were enrolled. Echo-Doppler was performed with a Multigon Angioview 600. IMT was measured in the common carotid artery, 1 cm proximal to the bulb. CHD risk factors were evaluated by routine methods. In males IMT increased significantly with increasing number of CHD risk factors. In females only the presence of three CHD risk factors was associated with a significant IMT increase. In both sexes IMT was higher in subjects with evidence of atherosclerotic lesions in the carotid arteries. In multiple regression analysis IMT was strongly and significantly associated with the presence of plaques and/or stenosis in the carotid arteries. The present findings suggest that IMT measurement can be useful in clinical practice, giving a comprehensive picture of the damage caused by several CHD risk factors over time on arterial wall.