Assuntos
Nevo Azul/diagnóstico , Neoplasias Cutâneas/diagnóstico , Pele/patologia , Biópsia , Criança , Diagnóstico Diferencial , Pé , Humanos , MasculinoRESUMO
WHAT IS KNOWN AND OBJECTIVE: Niemann-Pick C1-Like 1 (NPC1L1) plays a pivotal role in intestinal cholesterol absorption. Ezetimibe is known as an inhibitor for NPC1L1 and decreases concentration of low-density lipoprotein cholesterol (LDL-C) in blood. Responses of the decrease of serum LDL-C levels to ezetimibe have been reported to be different among NPC1L1 variants. However, there are still limited data concerning the genetic variation in the NPC1L1 gene, specifically, in Japanese patients with dyslipidemia. The purpose of this study is to elucidate genotype and allele frequencies of the NPC1L1 gene in Japanese patients with dyslipidemia. METHODS: Written informed consent was obtained from all participants. All patients were administered ezetimibe at the dose of 10 mg for once a day either alone or coadministered with statins. Patient's data were retrospectively obtained from their medical records. Genomic DNA was extracted from whole blood samples and analysed three NPC1L1 SNPs (rs2072183, rs217428 and rs217434) by the direct sequencing method. RESULTS AND DISCUSSION: We found that there is a significant difference of genotype frequencies between healthy Japanese and dyslipidemic subjects in rs2072183. No significant differences were observed in rs217428 and rs217434; however, comparison of our data with literature reports suggests that there are significant differences in the frequencies of rs217428 and rs217434 between Canadian and Japanese dyslipidemic patients. WHAT IS NEW AND CONCLUSION: Our study is the first report concerning the genotype and allele frequencies of the gene coding for NPC1L1 in Japanese patients with dyslipidemia. The most notable result was to demonstrate that there exists a significant difference in rs2072183 variant between healthy Japanese and dyslipidemic subjects and also found that there exists genetic variation of rs2072183 between Japanese and Canadian patients with dyslipidemia. Our results are expected to facilitate research in the proper use of ezetimibe-based mono- or combination therapies. Further studies will be required to evaluate the effects of rs2072183 on the efficacy of LDL cholesterol reduction by ezetimibe.
Assuntos
Anticolesterolemiantes/uso terapêutico , Azetidinas/uso terapêutico , Dislipidemias/genética , Proteínas de Membrana/genética , Idoso , Povo Asiático/genética , Estudos de Casos e Controles , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Primers do DNA , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Ezetimiba , Feminino , Frequência do Gene , Genótipo , Humanos , Japão , Masculino , Proteínas de Membrana Transportadoras , Pessoa de Meia-Idade , Estudos Retrospectivos , Triglicerídeos/sangueRESUMO
Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer with a higher propensity for recurrence and metastasis than melanoma or squamous cell carcinoma. Despite aggressive behavior and the tripling of its reported incidence in the past 20 years, there is extensive confusion about how MCC should be managed. Here we address two issues that have impeded optimal MCC management: lack of a consensus staging system and lack of unique diagnostic codes for MCC. Five conflicting systems currently used to stage MCC will be replaced by one system in 2010 that will diminish confusion about prognosis and management among physicians and patients. The diagnostic bundling of MCC with numerous less aggressive skin cancers leads to care refusals by insurance and an inability to track MCC care costs. Worldwide adoption in 2009 of specific diagnostic codes for MCC will also improve understanding and management of this often-lethal skin cancer (AU)
El carcinoma de células de Merkel (CCM) es una neoplasia cutánea neuroendocrina con una mayor propensión para desarrollar recurrencias y metástasis que el melanoma o el carcinoma epidermoide. A pesar de su comportamiento agresivo, y el hecho de que su incidencia se haya triplicado en los últimos 20 años, aún existe una gran confusión respecto al tratamiento del CCM. En esta revisión abordaremos dos cuestiones que han dificultado el tratamiento óptimo del CCM: la carencia de un sistema de estadificación consensuado y la falta de códigos diagnósticos exclusivos para el CCM. Los 5 sistemas contradictorios que actualmente se utilizan para estadificar el CCM serán reemplazados solamente por uno en 2010, lo que disminuirá la confusión sobre el pronóstico y el tratamiento entre los médicos y pacientes. La codificación diagnóstica del CCM, junto con numerosas neoplasias cutáneas menos agresivas, ha condicionado la denegación de atención por parte de las compañías aseguradoras y la incapacidad para evaluar los costes de la atención sanitaria por CCM. La adopción, que se ha efectuado en 2009, de códigos diagnósticos específicos para el CCM también mejorará la comprensión y el tratamiento de esta neoplasia cutánea frecuentemente letal( AU)
Assuntos
Humanos , Carcinoma de Célula de Merkel/diagnóstico , Neoplasias Cutâneas/diagnóstico , Carcinoma de Célula de Merkel/terapia , Neoplasias Cutâneas/terapia , Prognóstico , Estadiamento de Neoplasias , Polyomavirus/patogenicidadeRESUMO
Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer with a higher propensity for recurrence and metastasis than melanoma or squamous cell carcinoma. Despite aggressive behavior and the tripling of its reported incidence in the past 20 years, there is extensive confusion about how MCC should be managed. Here we address two issues that have impeded optimal MCC management: lack of a consensus staging system and lack of unique diagnostic codes for MCC. Five conflicting systems currently used to stage MCC will be replaced by one system in 2010 that will diminish confusion about prognosis and management among physicians and patients. The diagnostic bundling of MCC with numerous less aggressive skin cancers leads to care refusals by insurance and an inability to track MCC care costs. Worldwide adoption in 2009 of specific diagnostic codes for MCC will also improve understanding and management of this often-lethal skin cancer.
Assuntos
Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/virologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/virologia , Consenso , Humanos , Estadiamento de Neoplasias , PrognósticoRESUMO
BACKGROUND: Interleukin-6 (IL-6) and metalloproteinases (MMPs) are involved in the instability of vulnerable plaque associated with the induction of acute myocardial infarction (AMI). We examined the regional changes of cytokines, MMPs and adhesion molecules in patients with AMI to elucidate how these factors are involved in the onset of AMI. MATERIALS AND METHODS: One hundred and twenty-two patients with AMI were included. Blood was aspirated from the culprit coronary artery with a thrombectomy catheter, and was also sampled from peripheral veins during the coronary intervention. Control samples were obtained from the peripheral blood of age-matched patients. RESULTS: The serum levels of IL-6 (P < 0.05), tumour necrosis factor-alpha (P < 0.005), MMP-1 (P < 0.001), MMP-13 (P < 0.001), soluble intercellular adhesion molecule-1 (P < 0.005), and soluble vascular cellular adhesion molecule-1 (P < 0.05) in peripheral blood were significantly higher in the AMI group than in the controls. Aspirated serum contained significantly higher levels of IL-6 (P < 0.001), MMP-1 (P < 0.001), and MMP-13 (P < 0.05) compared to the peripheral blood of AMI. Serum IL-6 levels were significantly higher in the aspirated than in the peripheral blood in the patients hospitalized within 6 h and 6-12 h, but were similar in the aspirated and peripheral blood of the patients hospitalized 12-24 h after the onset of AMI. There were no differences between the aspirated serum and peripheral blood in the levels of interleukin-1beta and MMP-2. CONCLUSIONS: The levels of MMP-1, MMP-13 and IL-6 were higher in the culprit coronary artery than in the peripheral blood. These factors appear to be involved in the early stage of AMI.
Assuntos
Biomarcadores/sangue , Vasos Coronários/metabolismo , Infarto do Miocárdio/sangue , Doença Aguda , Circulação Coronária , Feminino , Humanos , Molécula 1 de Adesão Intercelular/sangue , Interleucina-6/sangue , Masculino , Metaloproteinases da Matriz/sangue , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Low-density lipoprotein (LDL) particle size is strongly affected by both fasting and postprandial triglyceride levels. We report here that the LDL phenotype shifts toward the smaller phenotype during oral fat tolerance tests (OFTTs) in some patients with myocardial infarction (MI); a condition closely associated with postprandial increases of triglyceride and remnant-like particles (RLPs). METHODS: Oral fat tolerance tests were performed on 63 MI patients with fasting serum triglyceride levels of less than 2.25 mmol L-1 (= 200 mg dL-1). Remnant-like particles and other serum lipids were compared among patients characterized by three LDL phenotypes based on nondenaturing gradient gel electrophoresis: pattern A (large LDLs, peak LDL particle size > or = 260 A), pattern I (intermediate-sized LDLs, LDL size > 255 A, < 260 A), and pattern B (small, dense LDLs, LDL size < or = 255 A). RESULTS: The LDL size decreased significantly in patients with the highest tertile of areas under the incremental curves (AUICs) of triglycerides above the fasting levels. The LDL phenotype shifted toward the smaller phenotype after a fat load in three of eight patients with pattern A and in seven of 35 patients with pattern I. The AUICs of triglyceride-rich lipoproteins were significantly higher in these patients than in the patients exhibiting little change in LDL size, whereas the fasting metabolic parameters were similar among the patients of the same LDL phenotype in the fasting state. CONCLUSION: These results suggest that alimentary lipaemia plays an important role in the remodeling of LDL particles into the more atherogenic small, dense LDLs in patients with MI.
Assuntos
Lipoproteínas LDL/sangue , Infarto do Miocárdio/sangue , Período Pós-Prandial , Adulto , Idoso , Idoso de 80 Anos ou mais , Eletroforese em Gel de Ágar , Jejum/sangue , Feminino , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/complicações , Lipoproteínas LDL/química , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Tamanho da Partícula , Triglicerídeos/sangueRESUMO
OBJECTIVES: Differences in the mechanism of restenosis after stenting between coil and tubular stents were examined in porcine coronary arteries using histological and immunohistochemical methods. METHODS: Twenty-four pigs underwent balloon-induced injury in the left anterior descending coronary artery. Two weeks later, seven different stents clinically available in Japan (Coil stents: GR I, GR II, Wiktor, Cordis; Tubular stents: gfx, Multilink, Palmaz-Schatz) were implanted in the injured site. Four weeks after the stent implantation, the pigs were sacrificed for histological examination and for morphometrical analysis of the lumen, neointima, media and adventitia. Immunohistochemical studies using anti-proliferating cell nuclear antigen (PCNA), anti-alpha-smooth muscle actin and anti-macrophage antibody were also performed. RESULTS: The coil stents formed eccentric, and the tubular stents formed concentric neointimal proliferation. Although there was no difference in the area of neointima between the stents, the area of lumen in the tubular stents was bigger than that in the coil stents (p < 0.01), because the vascular area was bigger in the tubular stents (p < 0.05). Immunohistochemical examination found many PCNA-positive cells in the proliferated neointima, especially in the area around the stent strut. Many of these cells around the stent strut were positively stained by anti-macrophage antibody. Other cells positively stained for PCNA were confirmed as smooth muscle cells. CONCLUSIONS: Tubular stents maintained a wider lumen than coil stents, because negative remodeling after stenting was less in the tubular stents. Implantation of stents with less negative remodeling is very important to prevent restenosis after stenting.
Assuntos
Reestenose Coronária/patologia , Vasos Coronários/patologia , Stents , Actinas/análise , Angioplastia Coronária com Balão , Animais , Imuno-Histoquímica , Macrófagos/imunologia , Masculino , Antígeno Nuclear de Célula em Proliferação/análise , SuínosRESUMO
An implantable cardioverter defibrillator (ICD) was used in a 62-year-old man with dilated cardiomyopathy (DCM) because of hemodynamically intolerable ventricular tachycardia (VT). Amiodarone was administered after a second episode of ICD discharge. Three weeks later, incessant VT appeared, and DC discharge failed to terminate it. Microvolt T wave alternans (TWA), measured by a spectral method, was observed in this patient with and without amiodarone administration. The onset heart rate with TWA was lower and the alternans voltage was higher with amiodarone than without it. The effects of amiodarone appeared to be related to the exacerbation of VT and an increased defibrillation threshold. TWA might be useful in predicting the proarrhythmic effects of amiodarone in similar cases.
Assuntos
Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Cardiomiopatia Dilatada/tratamento farmacológico , Amiodarona/uso terapêutico , Antiarrítmicos/uso terapêutico , Cardiomiopatia Dilatada/fisiopatologia , Desfibriladores Implantáveis , Eletrocardiografia , Humanos , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/efeitos dos fármacos , Valor Preditivo dos TestesRESUMO
BACKGROUND: Mild oxidation of LDL enhances its atherogenic potential and induces a synergistic interaction with serotonin (5HT) on vascular smooth muscle cell (VSMC) proliferation. Because of its complex chemical nature, the mitogenic components of mildly oxidized LDL (moxLDL) remain unclear. METHODS AND RESULTS: We examined both the effects of lysophosphatidylcholine (LPC) and hydrogen peroxide (H(2)O(2)), a donor of reactive oxygen species, as major components of moxLDL and their interactions with 5HT on VSMC proliferation. Growth-arrested VSMCs were incubated with different concentrations of moxLDL, LPC, H(2)O(2), or LPC with H(2)O(2) in the absence or presence of 5HT. DNA synthesis in VSMCs was examined by [(3)H]thymidine incorporation. MoxLDL, LPC, H(2)O(2), and 5HT stimulated DNA synthesis in a dose-dependent manner. MoxLDL had a maximal stimulatory effect at a concentration of 5 microg/mL (211%), LPC at 15 micromol/L (156%), H(2)O(2) at 5 micromol/L (179%), and 5HT at 50 micromol/L (205%). Added together, moxLDL (50 ng/mL) and 5HT (50 micromol/L) synergistically increased DNA synthesis (443%). Coincubation of LPC (1 micromol/L) with H(2)O(2) (0.5 micromol/L) and 5HT (5 micromol/L) resulted in a synergistic increase in DNA synthesis (439%), which was nearly equal to that of moxLDL with 5HT (443%). The combined effects of LPC, H(2)O(2), and 5HT on DNA synthesis were completely reversed by the combined use of an antioxidant, N:-acetylcysteine (400 micromol/L) or butylated hydroxytoluene (20 micromol/L), with a 5HT(2) receptor antagonist, LY281067 (10 microg/mL). CONCLUSIONS: Our results suggest that both LPC and reactive oxygen species may contribute to the mitogenic effect of moxLDL on VSMCs and its synergistic effect with 5HT.
Assuntos
Peróxido de Hidrogênio/farmacologia , Lipoproteínas LDL/farmacologia , Ácido Lisérgico/análogos & derivados , Lisofosfatidilcolinas/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Serotonina/farmacologia , Animais , Antioxidantes/farmacologia , Contagem de Células , Divisão Celular/efeitos dos fármacos , DNA/biossíntese , DNA/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Técnicas In Vitro , Ácido Lisérgico/farmacologia , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/fisiologia , Coelhos , Espécies Reativas de Oxigênio/metabolismo , Antagonistas da Serotonina/farmacologiaRESUMO
To clarify the role of vascular endothelial growth factor (VEGF) in the process of restenosis, a Palmaz-Schatz stent was implanted in the left anterior descending coronary artery of male pigs at 2 weeks after balloon injury (balloon/artery ratio 1.2:1). The animals were euthanized at 1, 2, and 4 weeks after stenting, and western blot and immunohistochemical analysis were performed using VEGF, fms-like tyrosine kinase (flt)-1, and platelet-derived growth factor (PDGF) antibodies. The expressions of VEGF and flt-1 protein in the neointima were observed as early as 1 week after stenting and remained for up to 4 weeks, while re-endothelialization was complete at 2 weeks. These protein expressions were demonstrated in proliferated smooth muscle cells throughout the entire period after stenting and, in addition, they were observed in the macrophages and endothelial cells of microvessels around stent struts at 4 weeks. The expression pattern of VEGF corresponded with that of PDGF, a growth factor well-known to induce neointimal proliferation. The cell proliferative activity, measured by the proliferating cell nuclear antigen index, around the struts remained high until 4 weeks after stenting, while that in the other areas declined at 4 weeks. These results suggest that VEGF is involved in the process of restenosis not only through its angiogenic properties and induction of monocyte chemotaxis, but also by a synergistic effect with PDGF.
Assuntos
Reestenose Coronária/metabolismo , Vasos Coronários/metabolismo , Fatores de Crescimento Endotelial/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Linfocinas/metabolismo , Neovascularização Patológica/metabolismo , Stents , Túnica Íntima/metabolismo , Animais , Western Blotting , Contagem de Células , Divisão Celular , Reestenose Coronária/patologia , Vasos Coronários/patologia , Vasos Coronários/cirurgia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Técnica Indireta de Fluorescência para Anticorpo , Técnicas Imunoenzimáticas , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Monócitos/metabolismo , Monócitos/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Neovascularização Patológica/patologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Suínos , Túnica Íntima/patologia , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular , Fator de von Willebrand/metabolismoRESUMO
BACKGROUND: Previous studies have shown that very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) from hyperlipidemic plasma are more atherogenic than those from normal plasma. Since platelet aggregation at sites of atherosclerotic injury exposes the cells to high concentrations of serotonin (5HT), a known mitogen for vascular smooth muscle cells (VSMCs), it was examined whether VLDL, IDL or LDL from plasma of 1% cholesterol-fed rabbits can potentiate the mitogenic effect of 5HT on VSMC. METHODS: Growth arrested primary aortic VSMC in 1st or 2nd passage were incubated with different concentrations of VLDL, IDL or LDL in the presence or absence of pertusis toxin (PTX) for 24 h followed by incubation with 5HT for 24 h. The amount of [3H]thymidine incorporated into the DNA as well as the increase in cell number was measured. RESULTS: Either VLDL, IDL or LDL at a concentration of 60 microg/ml induced proliferation of VSMC by themselves (196, 137 or 122% increase in [3H]thymidine incorporation, or 122, 119 or 122% increase in cell number, respectively when compared to the control, P<0.05). This effect on DNA synthesis was markedly potentiated by 50 microM 5HT to 465, 714 and 1369%, respectively. PTX reversed the mitogenic effect of 5HT, but not that of VLDL, IDL or LDL. CONCLUSION: These results suggest that even low concentration of VLDL, IDL or LDL from hypercholesterolemic plasma may significantly potentiate the mitogenic effect of 5HT, that is released by aggregating platelets at sites of vascular damage.
Assuntos
Hipercolesterolemia/fisiopatologia , Lipoproteínas LDL/farmacologia , Lipoproteínas VLDL/farmacologia , Lipoproteínas/farmacologia , Mitose/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Serotonina/farmacologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Sequestradores de Radicais Livres/farmacologia , Técnicas In Vitro , Lipoproteínas IDL , Mitose/fisiologia , Músculo Liso Vascular/citologia , Músculo Liso Vascular/fisiopatologia , Coelhos , Valores de Referência , Sensibilidade e EspecificidadeRESUMO
OBJECTIVES: The relationship between plasma low-density lipoprotein (LDL) cholesterol and the risk of coronary artery disease (CAD) is known, but the other characteristics of LDL, particularly particle size and density, are unclear. The relationship between small dense LDL phenotype and non-diabetic, normocholesterolemic CAD was investigated in 70 patients with angiographically documented CAD, and 38 age-matched control subjects. METHODS: Peak LDL particle diameter was determined by using 2-16% polyacrylamide gradient gel electrophoresis. Small dense LDL phenotype was defined as particle diameter equal to or less than 255 A. RESULTS: LDL particle diameters in patients with CAD were significantly smaller than those in controls (252.4 +/- 6.9 vs 259.3 +/- 8.8 A, mean +/- SD, p < 0.0001). Prevalence of small dense LDL was markedly higher in patients with CAD (72%) than in subjects without CAD (24%). CAD patients had significantly lower high-density lipoprotein (HDL)-cholesterol and apolipoprotein A-I levels (39.3 +/- 8.8 vs 49.8 +/- 12.0, 108.1 +/- 20.6 vs 122.9 +/- 20.1 mg/dl), and higher lipoprotein (a) and apolipoprotein B levels (28.8 +/- 30.4 vs 16.8 +/- 18.8, 96.5 +/- 21.8 vs 80.2 +/- 14.9 mg/dl) than non-CAD subjects, whereas total cholesterol, LDL-cholesterol, triglyceride, remnant-like particle cholesterol and insulin levels were not increased in CAD patients compared with non-CAD subjects. Stepwise regression analysis revealed that LDL particle size was the most powerful independent determinant of CAD (F value = 20.04, p < 0.0001). Logistic regression analysis revealed that small dense LDL phenotype [relative risk (RR) of 7.0, 95% confidence interval (95% CI) 2.4-20.1], low HDL-cholesterol (RR of 5.6, 95% CI 2.1-15.2), and increased apolipoprotein B (RR of 5.8, 95% CI 1.8-18.5) were independently associated with incidence of CAD. CONCLUSIONS: High prevalence of small dense LDL is a leading cause of CAD with even normal cholesterol levels.
Assuntos
Colesterol/sangue , Doença das Coronárias/sangue , Lipoproteínas LDL/sangue , Idoso , Feminino , Humanos , Masculino , Análise por Pareamento , Valores de Referência , Análise de Regressão , Fatores de RiscoRESUMO
Low density lipoprotein (LDL) and mildly oxidized low density lipoprotein (mox-LDL) are known mitogens for vascular smooth muscle cell (VSMC). Since aggregating platelets at sites of atherosclerotic injury release thromboxane A2(TXA2), a known mitogen for VSMC, we examined whether TXA2 can act synergistically with mox-LDL or its oxidative components in inducing VSMC proliferation. Growth arrested primary aortic rabbit VSMCs in 1st or 2nd passage were incubated with different concentrations of LDL or mox-LDL or lysophosphatidylcholine (LPC) or H2O2 or 4-hydroxy-2-nonenel (HNE) for 24 h followed by incubation with TXA2 mimetic U46619 for another 24 h. The amount of 3[H]-thymidine incorporated into the DNA was measured. Both LDL and mox-LDL at a concentration of 120 microg/ml induced proliferation of VSMC (168% or 184% respectively) when compared to the control. U46619 induced VSMC proliferation was observed at a concentration of 5 microm/L. As compared to native LDL, the mitogenic effect of mox-LDL on VSMC proliferation was markedly potentiated by U46619 to 301% or 316% at 0.5 or 5 microm/L U46619 respectively. LPC, H2O2 and HNE induced DNA synthesis was also marked by enhanced by U46619. These results suggest that even low concentration of TXA2 released from aggregating platelets may potentiate the mitogenic effect of mox-LDL at sites of vascular damage. The mitogenic effect of mox-LDL may be mediated via its oxidation products LPC, H2O2 (reactive oxygen species donor), and HNE.
Assuntos
Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Lipoproteínas LDL/farmacologia , Mitógenos/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Tromboxano A2/farmacologia , Animais , Aorta/citologia , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Replicação do DNA/efeitos dos fármacos , Sinergismo Farmacológico , Peróxido de Hidrogênio/farmacologia , Peroxidação de Lipídeos , Lisofosfatidilcolinas/farmacologia , Músculo Liso Vascular/citologia , Oxirredução , Agregação Plaquetária , Coelhos , Espécies Reativas de OxigênioRESUMO
OBJECTIVES: The purpose of this study was to examine whether low density lipoproteins (LDLs) or mildly oxidized LDL (mox-LDL) are mitogens for vascular smooth muscle cells (VSMCs) and whether they can act synergistically with serotonin (5HT), a known mitogen for VSMC, in potentiating the proliferative effect of 5HT on VSMC. BACKGROUND: Whether LDL or mox-LDL has a mitogenic effect on VSMC has been controversial. It is possible that LDL may not be mitogenic to VSMC but modification of LDL may confer mitogenic properties on LDL. A known mitogen for VSMC is 5HT that is released by aggregating platelets at sites of atherosclerotic changes or endothelial dysfunction. It is possible that LDL may interact with 5HT to enhance VSMC proliferation induced by 5HT. METHODS: Growth arrested primary VSMCs were incubated with different concentrations of LDL or mox-LDL for 24 h followed by incubation with 5HT for another 24 h (mild oxidation of LDL was achieved by incubating LDL with Cu++ which increased the thiobarbituric acid product formation without a change in electrophoretic mobility). The increase in cell number or the amount of 3H-thymidine incorporated into the DNA was then measured. RESULTS: Low density lipoprotein and mox-LDL induced significant VSMC proliferation by themselves and this effect was potentiated by 5HT. The 5HT2 receptor antagonist (LY281067) and pertussis toxin reversed only the proliferative effect of 5HT. Polyinosinic acid (poly-I), an inhibitor of scavenger receptors, did not inhibit the proliferative effect of LDL or mox-LDL or their synergistic interaction with 5HT. CONCLUSIONS: These results suggest that LDL and mox-LDL act synergistically with 5HT in inducing VSMC proliferation. The synergistic interaction could be blocked by LY281067 and pertussis toxin but not by poly-I acid.
Assuntos
Lipoproteínas LDL/fisiologia , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Serotonina/fisiologia , Animais , Divisão Celular/efeitos dos fármacos , Ácido Lisérgico/análogos & derivados , Ácido Lisérgico/farmacologia , Mitógenos , Toxina Pertussis , Coelhos , Antagonistas da Serotonina/farmacologia , Fatores de Virulência de Bordetella/farmacologiaRESUMO
Free radical generation was studied by the electron spin resonance (ESR) technique using alpha-phenyl N tert butyl nitrone (PBN) in a brief ischemia-reperfusion model of the canine heart, and correlated with biochemical changes of the sarcoplasmic reticulum (SR). ESR spectra (aH=0.3-0.4mT, aN=1.43-1.58mT) were observed as PBN spin adducts, which peaked at levels 5-fold above the control levels at 5 min after reperfusion. The simulated coupling constants of PBN spin adducts suggested that the sample should contain at least 2 carbon-centered radicals at 5 min after reperfusion (radical A: aH=0.350mT, aN=1.485mT; radical B: aH=0.370mT, aN=1.615 mT). At this time point, a significant reduction in Ca-ATPase activity of the SR was found without degradation of the major ATPase protein. Superoxide dismutase (SOD) significantly reduced the intensity of the PBN spin adduct signals and preserved the Ca-ATPase activity of the SR to 80% of the control level. Reperfusion injury after brief ischemia may be the result of inactivation of intracellular Ca-ATPase by free radicals generated during reperfusion, and SOD contributes to the protective effect by scavenging the radicals.
Assuntos
Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Superóxido Dismutase/metabolismo , Animais , Cães , Espectroscopia de Ressonância de Spin Eletrônica , Eletrofisiologia , Radicais Livres , Retículo Sarcoplasmático/metabolismo , Fatores de TempoRESUMO
SUMMARY: The population structure of the Japanese Brown in Kumamoto Prefecture was investigated with pedigree analysis. Two hundred heifers were randomly sampled, in 1960, 1970, 1980, and 1990. Population genetic parameters, i.e. F-statistics, index of subdivision, generation interval, effective population size, and effective number of sires, were estimated. The effective number of sires decreased, most dramatically, from 1970 to 1980. The average inbreeding coefficient (F(IT) ) increased, from 0.64% in 1960 to 5.43% in 1990. F(ST) increased in parallel with F(IT) , while F(IS) remained low. From 1960 to 1980, the index of diversity showed a decreasing trend, but this improved a little, with the index at 1.1 in 1990. The generation interval tended to be longer year by year, and was 5.52 during 1980-90. On the other hand, N(e) decreased, from 724.6 before 1960 to 40.1 at the present. The population structure of the Japanese Brown is not problematical at present, when considering F(IT) , but the irreversible inbreeding coefficient (F(ST) ) increases constantly. ZUSAMMENFASSUNG: Untersuchungen der Populationsstruktur der japanischen braunen Rasse Die Populationsstruktur in der Kumamotopräfektur wurde an Hand einer Pedigreeanalyse untersucht. Zweihundert Kalbinnen wurden in den Jahren 1960, 1970, 1980 und 1990 zufällig ausgewählt und populationsgenetische Parameter F-Werte, Index der Unter-teilung und genetisch wirksame Zahl von Stieren geschätzt. Die wirksame Zahl von Vatertieren hat abgenommen, wobei das am stärksten zwischen 1970 und 1980 vor sich gegangen ist. Der durchschnittliche Inzuchtkoeffizient (F(IT) ) zeigte Zunahme von 0, 64% im Jahr 1960 auf 5, 43% im Jahr 1990. F(ST) nahm parallel mit F(IT) zu, während F(IS) nieder geblieben ist. Von 1960 bis 1980 zeigte der Diversitätsindex eine abnehmende Tendenz, hat aber später etwas zugenommen, wobei der Index im Jahr 1990 1, 1 erreicht hat. Die Populationsstruktur des japanischen Braunviehs ist derzeit keinen alarmierenden Status, aber F(ST) steigt kontinuierlich an.
RESUMO
Myocellular injury induced by acute ischemia and subsequent reperfusion was studied in 38 dogs, with special reference to sarcolemmal permeability as determined by the vital ionic lanthanum (La3+) probe technique and electron microscopy. The left anterior descending coronary artery (LAD) was occluded in 14 dogs for 10 to 60 min, and the ischemic zone was perfused slowly for 7 min with a La(3+)-containing solution. In 21 dogs, the LAD was released for 10 min after occlusion and was then reperfused for 7 min with arterial blood plus the La(3+)-containing solution. Subsequently, in both groups of animals, the ischemic myocardium was subjected to perfusion fixation in preparation for electron microscopy. In normal cardiac myocytes, La3+ was localized exclusively in the extracellular space. After 10 to 20 min of ischemia, more than 80% of myocytes appeared normal or were damaged only slightly, and the majority continued to exclude La3+. After 10 min of ischemia, deposits of lanthanum were detected in 1 and 6% of myocytes in the absence or presence of reperfusion, respectively. The number of cells with such deposits was markedly increased after 30 min of ischemia (19%), as well as after 20 min of ischemia followed by reperfusion (17%), prior to the development of irreversible myocardial damage. After 60 min of ischemia with or without reperfusion, about 30% of myocytes showed severe injury with particulate deposits of lanthanum throughout the entire cell. These results indicate that sarcolemmal permeability increases during the early stage of myocardial injury due to ischemia or ischemia-reperfusion and contributes to the development of myocardial damage.