RESUMEN
BACKGROUND: Close supervision of intraocular pressure (IOP) means monitoring an important risk factor for glaucoma. METHOD: After instruction in its use, patients measure their own IOP several times a day with the Drager self-tonometer. The measurements are subsequently transmitted to a server via the telephone keypad and recorded separately for each patient. The software enables statistical evaluation of the pressure levels collected. RESULTS: Up to now 30 of 35 patients transmit measurements or had done so for at least 6 months. Registration of measurement levels covering months and years provides the opportunity for optimizing treatment and hence can be considered a start toward quality assurance in the treatment of glaucoma patients. CONCLUSION: TAS is a cost-efficient method for obtaining long-term profiles of eye pressure. Thus, the possibility exists for early therapeutic intervention in patients at risk. The compliance gained by the close relationship between the physician and the patient represents a positive prognostic factor.
Asunto(s)
Glaucoma/diagnóstico , Medición de Riesgo/métodos , Autocuidado/instrumentación , Telemedicina/instrumentación , Tonometría Ocular/instrumentación , Diseño de Equipo , Análisis de Falla de Equipo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Garantía de la Calidad de Atención de Salud/métodos , Reproducibilidad de los Resultados , Autocuidado/métodos , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Telemedicina/métodos , Tonometría Ocular/métodosRESUMEN
The sarcoglycan complex is found normally at the plasma membrane of muscle. Disruption of the sarcoglycan complex, through primary gene mutations in dystrophin or sarcoglycan subunits, produces membrane instability and muscular dystrophy. Restoration of the sarcoglycan complex at the plasma membrane requires reintroduction of the mutant sarcoglycan subunit in a manner that will permit normal assembly of the entire sarcoglycan complex. To study sarcoglycan gene replacement, we introduced transgenes expressing murine gamma-sarcoglycan into muscle of normal mice. Mice expressing high levels of gamma-sarcoglycan, under the control of the muscle-specific creatine kinase promoter, developed a severe muscular dystrophy with greatly reduced muscle mass and early lethality. Marked gamma-sarcoglycan overexpression produced cytoplasmic aggregates that interfered with normal membrane targeting of gamma-sarcoglycan. Overexpression of gamma-sarcoglycan lead to the up-regulation of alpha- and beta-sarcoglycan. These data suggest that increased gamma-sarcoglycan and/or mislocalization of gamma-sarcoglycan to the cytoplasm is sufficient to induce muscle damage and provides a new model of muscular dystrophy that highlights the importance of this protein in the assembly, function, and downstream signaling of the sarcoglycan complex. Most importantly, gene dosage and promoter strength should be given serious consideration in replacement gene therapy to ensure safety in human clinical trials.
Asunto(s)
Proteínas del Citoesqueleto/genética , Glicoproteínas de Membrana/genética , Músculo Esquelético/metabolismo , Distrofia Muscular Animal/genética , Animales , Bovinos , Distroglicanos , Distrofina/genética , Regulación de la Expresión Génica , Ratones , Ratones Transgénicos , Fibras Musculares de Contracción Rápida/metabolismo , Fibras Musculares de Contracción Rápida/patología , Músculo Esquelético/patología , Distrofia Muscular Animal/patología , Mutación , Miocardio/metabolismo , Miocardio/patología , SarcoglicanosRESUMEN
Muscular dystrophy is a heterogeneous genetic disease that affects skeletal and cardiac muscle. The genetic defects associated with muscular dystrophy include mutations in dystrophin and its associated glycoproteins, the sarcoglycans. Furthermore, defects in dystrophin have been shown to cause a disruption of the normal expression and localization of the sarcoglycan complex. Thus, abnormalities of sarcoglycan are a common molecular feature in a number of dystrophies. By combining biochemistry, molecular cell biology, and human and mouse genetics, a growing understanding of the sarcoglycan complex is emerging. Sarcoglycan appears to be an important, independent mediator of dystrophic pathology in both skeletal muscle and heart. The absence of sarcoglycan leads to alterations of membrane permeability and apoptosis, two shared features of a number of dystrophies. beta-sarcoglycan and delta-sarcoglycan may form the core of the sarcoglycan subcomplex with alpha- and gamma-sarcoglycan less tightly associated to this core. The relationship of epsilon-sarcoglycan to the dystrophin-glycoprotein complex remains unclear. Animals lacking alpha-, gamma- and delta-sarcoglycan have been described and provide excellent opportunities for further investigation of the function of sarcoglycan. Dystrophin with dystroglycan and laminin may be a mechanical link between the actin cytoskeleton and the extracellular matrix. By positioning itself in close proximity to dystrophin and dystroglycan, sarcoglycan may function to couple mechanical and chemical signals in striated muscle. Sarcoglycan may be an independent signaling or regulatory module whose position in the membrane is determined by dystrophin but whose function is carried out independent of the dystrophin-dystroglycan-laminin axis.
Asunto(s)
Proteínas del Citoesqueleto/genética , Glicoproteínas de Membrana/genética , Distrofias Musculares/genética , Secuencia de Aminoácidos , Animales , Cardiomiopatías/genética , Cardiomiopatías/patología , Proteínas del Citoesqueleto/química , Proteínas del Citoesqueleto/deficiencia , Proteínas del Citoesqueleto/metabolismo , Modelos Animales de Enfermedad , Distrofina/genética , Distrofina/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Humanos , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Datos de Secuencia Molecular , Distrofias Musculares/metabolismo , Distrofias Musculares/patología , Mutación , Miocardio/metabolismo , Sarcoglicanos , Homología de Secuencia de AminoácidoRESUMEN
Recent data indicate that sterol carrier protein-2 (SCP-2) functions in the rapid movement of newly synthesized cholesterol to the plasma membrane (Puglielli, L., Rigotti, A., Greco, A. V., Santos, M. J., and Nervi, F. (1995) J. Biol. Chem. 270, 18723-18726). In order to further characterize the cellular function of SCP-2, we transfected McA-RH7777 rat hepatoma cells with a pre-SCP-2 cDNA expression construct. In stable transfectants, pre-SCP-2 processing resulted in an 8-fold increase in peroxisomal levels of SCP-2. SCP-2 overexpression increased the rates of newly synthesized cholesterol transfer to the plasma membrane and plasma membrane cholesterol internalization by 4-fold. There was no effect of SCP-2 overexpression on the microsomal levels of acyl-CoA:cholesterol acyltransferase and neutral cholesterol ester (CE) hydrolase; however, in the intact cell, CE synthesis and mass were reduced by 50%. SCP-2 overexpression also reduced high density lipoprotein-cholesterol secretion and apoA-I gene expression by 70% and doubled the rate of plasma membrane desmosterol conversion to cholesterol. We conclude that SCP-2 overexpression enhances the rate of cholesterol cycling, which reduces the availability of cholesterol for CE synthesis and alters the activity of a cellular cholesterol pool involved in regulating apoA-I-mediated high density lipoprotein cholesterol secretion. The net result of these changes in cholesterol metabolism is a 46% increase in plasma membrane cholesterol content, the implications of which are discussed.
Asunto(s)
Proteínas Portadoras/fisiología , Ésteres del Colesterol/biosíntesis , HDL-Colesterol/metabolismo , Proteínas de Plantas , Esteroles/metabolismo , Animales , Apolipoproteína A-I/metabolismo , Apolipoproteínas E/metabolismo , Membrana Celular/metabolismo , Hidroxicolesteroles/metabolismo , Hígado/metabolismo , Neoplasias Hepáticas Experimentales/metabolismo , Ratas , Escualeno/metabolismo , Transfección , Células Tumorales CultivadasRESUMEN
Recent findings indicate that low-tension glaucoma is associated with impaired ocular blood flow. In the present study we evaluated the blood-flow in the ophthalmic artery in regulated open-angle glaucoma. Using pulsed Doppler sonography (4 MHz), the blood-flow velocity in the ophthalmic artery of 183 eyes of 95 persons with open-angle glaucoma was examined (mean age, 66.6 +/- 14.5 years). The patients showed advanced glaucomatous optic-nerve atrophy (cup-to-disk ratio, 0.74 +/- 0.27) and regulated intraocular pressure (IOP: range, 8-25 mm Hg; mean, 16.4 +/- 3.9 mm Hg). The blood pressure (BP) was 140 +/- 22 (systolic) and 79 +/- 14 mm Hg (diastolic). The control group (84 eyes of 44 persons: mean age, 69.7 +/- 7.7 years; IOP range, 10-22 mm Hg; mean IOP, 15.2-2.6 mm Hg; BP, 143 +/- 20/81 +/- 9 mmHg was matched for age and circulatory risk factors. The vascular resistance index (RIO) was calculated by the equation RIO = (systolic blood velocity-diastolic blood velocity)/systolic blood velocity. We found that the blood velocity in the ophthalmic artery was significantly decreased in glaucomatous eyes in contrast to normal eyes: systolic peak velocity, 36.9 +/- 16.2 cm/s (normal, 40.2 +/- 10.9 cm/s; P < 0.001); diastolic peak velocity 9.9 +/- 4.4 cm/s (normal, 11.7 +/- 4.0 cm/s, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Velocidad del Flujo Sanguíneo/fisiología , Glaucoma de Ángulo Abierto/fisiopatología , Arteria Oftálmica/fisiología , Anciano , Presión Sanguínea , Humanos , Presión Intraocular , Arteria Oftálmica/diagnóstico por imagen , Ultrasonografía Doppler de Pulso , Resistencia Vascular/fisiologíaRESUMEN
We investigated the effect of clonidine (Isoglaucon, an alpha-agonist) and metipranolol (Betamann, a beta-antagonist) on the blood flow in the ophthalmic artery and the anterior uvea of 40 young, healthy volunteers (mean age, 23.5 +/- 2 years) in a prospective, randomized simple blind study. The blood flow in the iris and ciliary body was detected by laser-Doppler flowmetry (bpm, 403a; TSI; wavelength, 780 nm; power, < 1.6 mW). The blood flow in the ophthalmic artery was measured by pulsed Doppler sonography (4 MHz, EME). The blood pressure, pulse respiration, and intraocular pressure (IOP) were recorded. Vascular resistance (RF) was calculated by the equation RF = (RRmean--IOP)/blood flow. Group 1 was treated with a single drop of Betamann (3 mg/ml) applied topically, and group 2 was treated with Isoglaucon (2.5 mg/ml). Measurements were made before and 30 min after application. Both drugs significantly lowered the IOP by about 7% (P = 0.01). Clonidine did not affect the blood velocity in the ophthalmic artery. In group 2 (metipranolol) we found a significant increase in the blood velocity in the ophthalmic artery during the diastolic period (from 11.0 +/- 3.7 to 11.9 +/- 2.2 cm/s, P = 0.05). Both clonidine and metipranolol decreased the iridal blood flow [clonidine, from 9.3 +/- 3.9 to 7.6 +/- 3.1 (flux), P = 0.05; metipranolol, from 7.5 +/- 2.9 to 6.5 +/- 2.6 (flux), P = 0.05]. Vascular resistance in the iris increased under the effect of clonidine (P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)