RESUMEN
Clinical studies and animal experiments have demonstrated that oxidized low-density lipoprotein (oxLDL) and oxysterols play important roles in atherogenesis. OxLDL is immunogenic, and autoantibodies (Ab) against oxLDL are detectable in serum. We investigated the relevance of oxysterols and Ab against-oxLDL to coronary artery disease (CAD) in 183 patients undergoing coronary angiography. Patient groups included angiographically normal subjects (< 75% stenosis), others with spasm (> 75% narrowing in response to acetylcholine), and some others with fixed stenosis (> 75%). The group with stenosis was subdivided into patients with stable and unstable angina. Serum concentrations of autoantibodies and 25-, 27-, and 7-beta-hydroxycholesterols were significantly higher in the stenotic group than in the normal group (P < 0.01, P < 0.05, P < 0.05, and P < 0.05, respectively). Antibodies, but not oxysterol concentrations, were significantly greater in subjects with unstable than with stable angina (P < 0.01). We conclude that anti-oxLDL antibody and oxysterol concentrations are associated with coronary artery stenosis, and that oxidative stress may be greatly increased in unstable angina.
Asunto(s)
Autoanticuerpos/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedad de la Arteria Coronaria/inmunología , Hidroxicolesteroles/inmunología , Lipoproteínas LDL/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Angina de Pecho/sangre , Angina de Pecho/inmunología , Angina Inestable/sangre , Angina Inestable/inmunología , Autoanticuerpos/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/epidemiología , Vasoespasmo Coronario/sangre , Vasoespasmo Coronario/inmunología , Femenino , Humanos , Hidroxicolesteroles/sangre , Masculino , Persona de Mediana Edad , Estrés Oxidativo , Factores de RiesgoRESUMEN
The cellular localization of the AT(2) receptor and the regulation of its expression in hypertrophied left ventricle are not well known. We compared the expression of the cardiac AT(1) and AT(2) receptor in spontaneously hypertensive rats/Izumo strain (SHR/Izm) and Wistar Kyoto rats/Izumo strain (WKY/Izm), ages 4, 12, and 20 wk, by means of immunohistochemistry and Western blot analysis. In SHR/Izm, compared with WKY/Izm, blood pressure (161 +/- 2 vs. 120 +/- 2 mmHg at 12 wk, P = 0.01, and 199 +/- 3 vs. 123 +/- 3 mmHg at 20 wk, P = 0.01) and heart-to-body weight ratio (3.76 +/- 0.07 vs. 3.06 +/- 0.06 mg/g at 12 wk, P = 0.01, and 3.90 +/- 0.08 vs. 3.01 +/- 0.12 mg/g at 20 wk, P = 0.01) were significantly elevated. There was no difference in these values between the two strains at 4 wk of age. Histologically, 20-wk-old SHR/Izm demonstrated myocardial hypertrophy, a thickening of the smooth muscle layer of the intracardiac arteries, and perivascular fibrosis. By immunohistochemistry, the AT(2) receptor was localized to cardiomyocytes and vascular endothelial cells, but not in the vascular smooth muscle cells. No major AT(2) receptor signal was observed in perivascular fibrosis at any age in either strain of rats. No difference was detected in this localization between the two strains. By Western blotting, a single 44-kDa band for the AT(2) receptor and a single 60-kDa band for the AT(1) receptor were detected in ventricles from both strains of rats at all ages. Densitometric analysis demonstrated that the AT(2) receptor 44-kDa band was decreased by 20% at 12 wk and 32% at 20 wk (P < 0.01) in SHR/Izm compared with WKY/Izm. The intensity of the AT(1) receptor 60-kDa band was increased by 57% in 20-wk-old SHR/Izm compared with WKY/Izm (P < 0.05). There was no significant difference in the intensity of the 44- or 60-kDa bands in 4-wk-old animals of either strain. We demonstrated a decrease in the AT(2) receptor and an increase in the AT(1) receptor protein with no change in their localizations in hypertrophied left ventricular myocytes of SHR/Izm.
Asunto(s)
Hipertensión/metabolismo , Miocardio/metabolismo , Receptores de Angiotensina/biosíntesis , Angiotensinas/metabolismo , Animales , Corazón/fisiopatología , Hipertensión/fisiopatología , Inmunohistoquímica , Ratas , Ratas Endogámicas SHRRESUMEN
We report two patients with lingual dyskinesia and complaints of food regurgitation following long-term antipsychotic therapy. Esophageal contrast radiography revealed dyskinetic movements extending from the pharynx to the upper portion of the esophagus. The elevation of intraesophageal pressure was confirmed by esophageal manometry. The dyskinetic movements almost disappeared along with improvement of lingual dyskinesia following the administration of sulpiride in one patient. Another patient suddenly died due to asphyxiation of foods before the beginning of treatment. We termed this life-threatening movement, 'esophageal dyskinesia'. It should be emphasized that 'esophageal dyskinesia' associated with lingual dyskinesia is a potentially fatal adverse reaction to antipsychotic therapy.
Asunto(s)
Antipsicóticos/efectos adversos , Discinesia Inducida por Medicamentos/etiología , Esófago/fisiopatología , Anciano , Discinesia Inducida por Medicamentos/fisiopatología , Humanos , Masculino , PresiónRESUMEN
Roots of Prunus armeniaca yielded a new A-type proanthocyanidin whose structure was assigned as ent-epiafzelechin-3-O-p-hydroxybenzoate-(4alpha-->8, 2alpha-->O-->7)-epiafzelechin (1). The structure of 1 was determined through extensive 1D and 2D NMR studies.
Asunto(s)
Antocianinas/aislamiento & purificación , Raíces de Plantas/química , Plantas Medicinales/química , Antocianinas/química , India , Espectroscopía de Resonancia MagnéticaRESUMEN
In preparation for biosynthetic studies on the 3,4-dihydroxy-2, 6-dimethyl-5-phenylvaleric acid portion of neoantimycin (1), the 1H and 13C NMR signals of 1 were assigned unambiguously by means of 2D correlation spectroscopy and NOE experiments. The previously undetermined absolute stereochemistry at C-15 and C-16 was deduced as (S) and (S). The structure of isoneoantimycin (2) was also elucidated. The methyl groups of methionine and propionate were incorporated stereospecifically into C-13 and C-12 of 1, respectively, and the configuration of the methyl group of methionine is inverted in the process. The results also suggest the intervention of phenylpyruvate as an actual precursor.
Asunto(s)
Antibacterianos/química , Antibacterianos/biosíntesis , Biotransformación , Medios de Cultivo , Isomerismo , Espectroscopía de Resonancia Magnética , Compuestos Orgánicos , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Streptomyces/metabolismoRESUMEN
The effect of bezafibrate on plasma lipoproteins was investigated in Japanese familial combined hyperlipidemic patients with or without an impaired glucose tolerance accompanied by a low-density lipoprotein subclass, with the major gradient gel peak at a particle diameter of less than 25.5 nm. Bezafibrate treatment at a dose of 400 mg/d for 12 weeks produced an antiatherogenic effect on lipoprotein profiles, as reflected by a decrease in plasma triglyceride levels, an increase in plasma high-density lipoprotein-cholesterol levels, induction of the large-size subclass of low-density lipoprotein, and disappearance of intermediate-density lipoproteins. The plasma total and low-density lipoprotein-cholesterol-lowering effect of bezafibrate was significant in patients without impaired glucose tolerance but was not significant in patients with impaired glucose tolerance. Bezafibrate increased lipoprotein lipase activity and decreased the activity of cholesteryl ester transfer protein, both in patients with or without impaired glucose tolerance. There was no difference in the distribution of signal peptide insertion/deletion or Xbal polymorphisms of the apolipoprotein B gene in patients with or without impaired glucose tolerance. Mechanisms other than lipoprotein lipase, cholesteryl ester transfer protein activities, and an apolipoprotein B gene polymorphism may be responsible for the resistance to lowering of plasma total and low-density lipoprotein cholesterol levels with bezafibrate treatment in familial combined hyperlipidemic patients with impaired glucose tolerance.
Asunto(s)
Bezafibrato/uso terapéutico , Glicoproteínas , Hiperlipidemia Familiar Combinada/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Lipoproteínas/sangre , Adulto , Anciano , Apolipoproteínas B/genética , Proteínas Portadoras/sangre , Proteínas de Transferencia de Ésteres de Colesterol , Ésteres del Colesterol/sangre , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Hiperlipidemia Familiar Combinada/sangre , Hiperlipidemia Familiar Combinada/genética , Lipoproteína Lipasa/sangre , Lipoproteínas LDL/sangre , Masculino , Persona de Mediana EdadRESUMEN
The proliferation of vascular smooth muscle cells (VSMCs) plays an important role in the formation of atherosclerotic lesions and restenosis after angioplasty. It has been suggested that probucol inhibits VSMCs proliferation, but this effect has not been directly demonstrated. In this study we investigated the effect of probucol on neointimal formation after balloon injury in normocholesterolemic rabbits and examined whether probucol could inhibit the proliferation of rabbit cultured VSMC stimulated by fetal bovine serum (FBS). Probucol inhibited the formation of neointima by about 63% 2 weeks after balloon injury. Probucol inhibited the increase in the number of cultured VSMCs and bromodeoxyuridine (BrdU) incorporation stimulated by 10% FBS in a dose-dependent manner. Also, 10% FBS stimulated the activities of mitogen-activated protein kinase (MAP kinase) and protein kinase C (PKC) in cultured VSMCs. Probucol inhibited these activities in a dose-dependent fashion. These results suggest that probucol may inhibit neointimal formation after balloon injury in normocholesterolemic rabbits by preventing the proliferation of VSMCs via inactivation of MAP kinase and PKC.
Asunto(s)
Anticolesterolemiantes/farmacología , Arterias Carótidas/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Probucol/farmacología , Túnica Íntima/efectos de los fármacos , Animales , Arterias Carótidas/patología , División Celular/efectos de los fármacos , Células Cultivadas , Colesterol/sangre , Lipoproteínas HDL/sangre , Músculo Liso Vascular/metabolismo , Inhibidores de Proteínas Quinasas , Conejos , Triglicéridos/sangreRESUMEN
The effects of cerivastatin sodium (BAY w 6228), a new type of inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on plasma cholesterol concentrations and the induction of hepatic LDL receptors were investigated with beagle dogs and Hep G2 cells. Oral administration of cerivastatin (0.01, 0.03, and 0.1 mg/kg per day) for 3 weeks reduced plasma total and very low-density lipoprotein plus low-density lipoprotein (VLDL + LDL) cholesterol concentrations and increased hepatic LDL receptor binding activity in dogs. Scatchard plot analysis revealed a 1.9-fold increase in the maximum binding capacity of hepatic LDL receptors in cerivastatin-treated animals. Similar results were obtained by administration of pravastatin (1.0 and 5.0 mg/kg/day) for 3 weeks. Binding activity of the LDL receptor, as well as receptor mRNA and protein concentrations, were increased in a dose-dependent manner (0.01-1.0 microM) by exposure of Hep G2 cells to cerivastatin. The results suggest that cerivastatin reduces plasma cholesterol concentrations by increasing hepatic LDL receptor expression. The mechanism of lowering cholesterol concentration by cerivastatin was the same as with the other previously examined HMG-CoA reductase inhibitors, but the effects with cerivastatin were apparent at doses much lower than the effective doses of the other drugs. Cerivastatin, therefore, shows potential for clinical use as a potent and efficacious plasma cholesterol-lowering drug.
Asunto(s)
Colesterol/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hígado/efectos de los fármacos , Piridinas/farmacología , Receptores de LDL/metabolismo , Animales , Northern Blotting , Línea Celular , Perros , Humanos , Lipoproteínas LDL/metabolismo , Hígado/metabolismo , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , ARN Mensajero/análisis , Receptores de LDL/genéticaRESUMEN
A sister and brother with neonatal alloimmune thrombocytopenic purpura (NAITP) caused by maternal anti-human platelet antigen (HPA)-3a are reported. The children had transient severe thrombocytopenia in the newborn period, and were treated with intravenous gamma-globulin and platelet concentrates from random donors. Although the sister had intracranial hemorrhage on day 2 postnatally, the development of the child has been normal and no neurological sequelae have been observed. The brother only had bloody stool when the platelet count was low, and did not have severe hemorrhagic manifestations. The diagnosis of NAITP was made by the sera from the mother, which contained anti-HPA-3a antibody directed against platelets of the children. The rate of recurrence might be high in this family, because the father of the patients was found to be homozygous for the HPA-3a gene.
Asunto(s)
Antígenos de Plaqueta Humana/inmunología , Isoanticuerpos/inmunología , Púrpura Trombocitopénica/inmunología , Hemorragia Cerebral/etiología , Genotipo , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Recién Nacido , Masculino , Recuento de Plaquetas , Transfusión de Plaquetas , Púrpura Trombocitopénica/complicaciones , Púrpura Trombocitopénica/genética , Púrpura Trombocitopénica/terapiaRESUMEN
We determined the most effective dosage of pentaerythritol tetranicotinate (niceritrol) to reduce plasma lipoprotein(a) [Lp(a)] levels in 44 Japanese patients (16 men and 28 women; mean age, 59.2 +/- 10.8 years) with hyperlipidemia types IIa, IIb, and IV. Patients received oral niceritrol at a dosage of 750 mg (3 tablets)/d for 8 weeks, followed by 1,500 mg (6 tablets)/d for 8 weeks. Administration of niceritrol 750 mg/d for 8 weeks decreased total and low-density lipoprotein (LDL) cholesterol in patients with type IIa hyperlipidemia and decreased triglycerides in patients with type IV hyperlipidemia, but did not affect Lp(a). However, niceritrol 1,500 mg/d for 8 weeks decreased Lp(a) in patients with initial Lp(a) levels greater than 30 mg/dL in addition to decreasing total and LDL cholesterol and triglycerides. These results suggest that the effective dosage of niceritrol to reduce the serum Lp(a) concentration in Japanese hyperlipidemic patients with a high Lp(a) level (> or = 30 mg/dL) is greater than 1,500 mg/d.
Asunto(s)
Hipolipemiantes/farmacología , Lipoproteína(a)/sangre , Niceritrol/farmacología , Anciano , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Triglicéridos/sangreRESUMEN
A case is reported of a pituitary apoplexy which shows remarkable improvement of visual acuity and field by transsphenoidal surgery performed 33 days after hemorrhage. Possible factors contributing to this excellent surgical outcome are speculated about as follows; atrophic brain (wide suprasellar cistern), destruction of the sella floor by the tumor (infrasellar/extracranial decompression), no vasospasm (pure intracapsular hemorrhage), no hypopituitarism, less invasive operation (transsphenoidal surgery), and so on. Transsphenoidal surgery is thought to be worth performing for pituitary apoplexy, even if timing for the operation is later than the acute stage and even if initial visual impairment is severe.
Asunto(s)
Hipofisectomía/métodos , Apoplejia Hipofisaria/cirugía , Agudeza Visual , Campos Visuales , Enfermedad Crónica , Femenino , Humanos , Persona de Mediana Edad , Apoplejia Hipofisaria/fisiopatologíaRESUMEN
The antioxidative effect of monatepil maleate (CAS 103379-03-9, AJ-2615), a new antihypertensive agent, was investigated by measuring its ability to inhibit copper-induced lipid hydroperoxidation of low density lipoprotein (LDL) and was compared with those of diltiazem (Ca(2+)-channel antagonist), prazosin (alpha 1-adrenoceptor antagonist), and probucol. The concentration of AJ-2615 required to inhibit copper-induced lipid hydroperoxidation of LDL by 50% (IC50) was 28 mumol/l. The IC50 values for diltiazem, prazosin, and probucol were > 1 mmol/l, > 1 mmol/l, and 17 mumol/l, respectively. These results indicate that AJ-2615 has the same potent antioxidative effect as probucol and suggest that a previously reported ability of AJ-2615 to inhibit the progression of atherosclerosis may be due to this antioxidative property. In addition, the dihydrodibenzothiepine ring of AJ-2615 may have an antioxidative functions.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Dibenzotiepinas/farmacología , Peroxidación de Lípido/efectos de los fármacos , Lipoproteínas LDL/sangre , Anticolesterolemiantes/farmacología , Cobre/química , Sulfato de Cobre , Depresión Química , Dibenzotiepinas/química , Diltiazem/farmacología , Humanos , Técnicas In Vitro , Lipoproteínas LDL/química , Piperazinas/química , Piperazinas/farmacología , Prazosina/farmacología , Probucol/farmacologíaRESUMEN
We undertook the present study in 66 Japanese patients with essential hypertension to identify genetic factors associated with salt sensitivity. Patients were classified into salt-sensitive or salt-resistant groups on the basis of changes in their mean blood pressures from a week of a low salt diet (50 mmol/d) to a week of a high salt diet (340 mmol/d). Salt sensitivity and resistance were studied in relation to a 287-bp insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme gene detected by a polymerase chain reaction method and the haptoglobin phenotype determined by polyacrylamide gel electrophoresis. Patients with the angiotensin I-converting enzyme gene genotype II were more apt to be salt sensitive than patients with the ID and DD genotypes, although plasma renin activity was similar in each group. The frequency of the I allele in the salt-sensitive group was significantly higher than that in the salt-resistant group (chi2 = 7.4, odds ratio = 2.78). However, there was no significant relationship between haptoglobin phenotype and salt sensitivity. These data suggest that an I/D polymorphism of the angiotensin I-converting enzyme gene is a genetic factor associated with salt sensitivity of blood pressure independently of plasma renin activity in Japanese patients with essential hypertension.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Hipertensión/genética , Peptidil-Dipeptidasa A/genética , Sodio en la Dieta/administración & dosificación , Adulto , Anciano , Secuencia de Bases , Femenino , Humanos , Hipertensión/metabolismo , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Polimorfismo GenéticoRESUMEN
We developed a simple, sensitive and accurate method for assaying cellular free and total cholesterol by monitoring 4-cholesten-3-one, a conversion product of the cholesterol oxidase-catalyzed oxidation of the free cholesterol that has a strong chromophoric alpha, beta-unsaturated ketone at 240 nm, using a high-pressure liquid chromatographic system. This method measured picomole quantities of free and total cholesterol and precisely determined their concentrations in cells (10(4) range) in culture using 7 beta-hydroxycholesterol as an internal standard.
Asunto(s)
Colestenonas/metabolismo , Colesterol/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Biomarcadores , Células Cultivadas , Humanos , Valores de Referencia , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
A new acetophenone glycoside, affinoside, was isolated from the aerial parts of Exacum affine and its structure was determined as 2-O-primeverosylpaenol. The known glucosides, gentiopicroside, 2'-O-E/Z-p-coumaroylloganin and glucopaeonol, were also identified.
Asunto(s)
Acetofenonas/química , Disacáridos/química , Glicósidos/química , Extractos Vegetales , Acetofenonas/aislamiento & purificación , Conformación de Carbohidratos , Secuencia de Carbohidratos , Disacáridos/aislamiento & purificación , Glicósidos/aislamiento & purificación , Japón , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Estructura Molecular , Rotación Óptica , PlantasRESUMEN
The effects of dietary oleic acid on cholesterol metabolism were investigated and compared with those of palmitic acid in hamsters. Addition of 5% oleic acid to a 0.1% cholesterol-supplemented diet decreased plasma total cholesterol, very low density lipoprotein (VLDL) cholesterol, and low density lipoprotein (LDL) cholesterol, increased hepatic LDL receptor activity, and decreased plasma cholesteryl ester transfer protein (CETP) activity in comparison with 0.1% cholesterol alone. In contrast, addition of 5% palmitic acid to a 0.1% cholesterol-supplemented diet increased total cholesterol and LDL-cholesterol, increased plasma CETP activity, and suppressed hepatic LDL receptor activity to a greater extent than 0.1% cholesterol alone. Neither oleic acid nor palmitic acid altered hepatic microsomal 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity, but oleic acid increased hepatic microsomal cholesterol 7 alpha-hydroxylase activity. These results suggest that dietary oleic acid inhibits the increases in total, VLDL-, and LDL-cholesterol induced by dietary cholesterol by preventing both LDL receptor suppression and increased CETP activity, whereas dietary palmitic acid augments the cholesterol-induced increases in total and LDL-cholesterol by both further suppression of LDL receptor activity and further stimulation of CETP activity.
Asunto(s)
Colesterol en la Dieta/farmacología , Colesterol/metabolismo , Grasas de la Dieta/farmacología , Glicoproteínas , Ácidos Oléicos/administración & dosificación , Ácidos Palmíticos/administración & dosificación , Animales , Proteínas Portadoras/sangre , Colesterol/sangre , Colesterol 7-alfa-Hidroxilasa/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol , Colesterol en la Dieta/administración & dosificación , LDL-Colesterol/sangre , VLDL-Colesterol/sangre , Cricetinae , Grasas de la Dieta/administración & dosificación , Hidroximetilglutaril-CoA Reductasas/metabolismo , Hígado/metabolismo , Masculino , Mesocricetus , Microsomas Hepáticos/enzimología , Ácido Oléico , Ácidos Oléicos/farmacología , Ácido Palmítico , Ácidos Palmíticos/farmacología , Receptores de LDL/metabolismoRESUMEN
The effects of fluvastatin sodium (XU62-320), a new type of inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on plasma cholesterol and triacylglycerol levels were investigated using homozygous Watanabe-heritable hyperlipidemic (WHHL) rabbit, an LDL-receptor-deficient animal which expresses a hepatic LDL receptor activity less than 5% that of control rabbits. Plasma levels of total, VLDL- and LDL-cholesterol were decreased profoundly after oral administration of fluvastatin at a dose of 50 mg/kg per day for 4 weeks. Plasma triacylglycerol levels were not affected by fluvastatin. Hepatic HMG-CoA reductase activity increased by 3-fold and hepatic LDL receptor activity increased by only 3.7-fold, as calculated by Scatchard plot analysis, with fluvastatin administration for 4 weeks, and the hepatic mRNA level for the rabbit LDL receptor was increased by 3-fold. Combined administration of fluvastatin (50 mg/kg per day) and cholestyramine, a bile acid sequestrant resin, at a level of 2% of the diet for 4 weeks more profoundly decreased plasma total, VLDL- and LDL-cholesterol levels with induction of hepatic cholesterol 7 alpha-hydroxylase and no further induction of the hepatic LDL receptor. Plasma triacylglycerol levels were increased by the combination treatment. These results suggest that high dose of fluvastatin sodium is effective in lowering plasma cholesterol levels in homozygous WHHL rabbits through the shared mechanisms involving decrease in production and secretion of cholesterol from the liver and the induction of hepatic LDL receptor. Additional effect of cholestyramine on decrease in plasma cholesterol levels seems to be due to the further decrease in hepatic cholesterol secretion by up-regulation of hepatic cholesterol 7 alpha-hydroxylase.
Asunto(s)
Anticolesterolemiantes/farmacología , Colesterol/sangre , Ácidos Grasos Monoinsaturados/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hiperlipidemias/sangre , Indoles/farmacología , Animales , HDL-Colesterol/sangre , LDL-Colesterol/sangre , VLDL-Colesterol/sangre , Resina de Colestiramina/farmacología , Fluvastatina , Homocigoto , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Hígado/metabolismo , Microsomas Hepáticos/enzimología , ARN Mensajero/análisis , ARN Mensajero/biosíntesis , Conejos , Receptores de LDL/biosíntesis , Receptores de LDL/genética , Triglicéridos/sangreRESUMEN
The hypothesis that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3, also known as calcitriol] modulates myosin expression in vascular smooth muscle was tested. Wistar-Kyoto or spontaneously hypertensive rats given intraperitoneal injections of 25 ng 1,25(OH)2D3/100 g body weight for varying periods of time showed a greater than twofold increase in aortic mRNA encoding the myosin regulatory light chain relative to 18S rRNA (P < 0.05). 1,25(OH)2D3 administration to Wistar rats caused a significant increase in the aortic content of total myosin regulatory light chain and total myosin heavy chain. The increase in myosin light chain was the result of a specific increase in expression of its smooth muscle isoform [control = 65.2 +/- 3.4% vs. 1,25(OH)2D3 = 78.7 +/- 3.6%, P = 0.020]. 1,25(OH)2D3 had no effect on total myosin light chain or heavy chain in the superior mesenteric artery. The hormone did, however, increase the proportion of the smooth muscle isoform of the light chain in this vessel [control = 81.4 +/- 2.6% vs. 1,25(OH)2D3 = 88.8 +/- 2.1%, P = 0.048]. In branch II and III mesenteric resistance arteries, 1,25(OH)2D3 significantly increased the active stress response to 10 mumol/l norepinephrine but was without effect on total myosin light chain or heavy chain content or on the relative expression of the myosin light chain isoforms [control = 94.0 +/- 1.4% vs. 1,25(OH)2D3 = 95.8 +/- 1.1%, P = 0.33].(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Arterias/efectos de los fármacos , Arterias/metabolismo , Calcitriol/metabolismo , Calcitriol/farmacología , Miosinas/metabolismo , Animales , Aorta/metabolismo , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/metabolismo , Arterias Mesentéricas/fisiología , Miosinas/genética , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Resistencia Vascular/efectos de los fármacos , Vasoconstricción/efectos de los fármacosRESUMEN
Ten cases of primary oculomotor nerve palsy due to head injury are presented. All ten patients had a dilated, non reactive pupil. Seven had complete oculomotor palsy. Two had partial extraocular palsy or blepharoptosis and one had neither extraocular palsy nor blepharoptosis. The initial ophthalmoplegia was recognized immediately after trauma. Nine patients had severely impaired consciousness on admission, but eight patients recovered fully within two months after the traumatic event, while one patient remained disoriented. Emergency CT scan on admission showed mass lesions in no patients except one who had a hematoma measuring 3 cm in the frontal lobe, but had no herniation sign. Patients with complete oculomotor palsy had a high incidence of traumatic SAH (71%) or skull fracture (57%). Recovery from third nerve palsy was not so good. The follow-up period extended from 3 months to 18 months. Of the 10 patients, none recovered completely from third nerve palsy. The prognoses of blepharoptosis, external ophthalmoplegia and internal ophthalmoplegia were analyzed separately. The recovery rates were 78%, 44% and 20%, respectively, the internal ophthalmoplegia showing poorest recovery. We discuss the mechanism of direct injury to the oculomotor nerve.
Asunto(s)
Traumatismos Craneocerebrales/complicaciones , Enfermedades del Nervio Oculomotor/etiología , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Enfermedades del Nervio Oculomotor/fisiopatología , PronósticoRESUMEN
We have identified a murine gene, metaxin, that spans the 6-kb interval separating the glucocerebrosidase gene (GC) from the thrombospondin 3 gene on chromosome 3E3-F1. Metaxin and GC are transcribed convergently; their major polyadenylylation sites are only 431 bp apart. On the other hand, metaxin and the thrombospondin 3 gene are transcribed divergently and share a common promoter sequence. The cDNA for metaxin encodes a 317-aa protein, without either a signal sequence or consensus for N-linked glycosylation. Metaxin protein is expressed ubiquitously in tissues of the young adult mouse, but no close homologues have been found in the DNA or protein data bases. A targeted mutation (A-->G in exon 9) was introduced into GC by homologous recombination in embryonic stem cells to establish a mouse model for a mild form of Gaucher disease. A phosphoglycerate kinase-neomycin gene cassette was also inserted into the 3'-flanking region of GC as a selectable marker, at a site later identified as the terminal exon of metaxin. Mice homozygous for the combined mutations die early in gestation. Since the same amino acid mutation in humans is associated with mild type 1 Gaucher disease, we suggest that metaxin protein is likely to be essential for embryonic development in mice. Clearly, the contiguous gene organization at this locus limits targeting strategies for the production of murine models of Gaucher disease.