RESUMEN
A series of compounds was designed and prepared as inhibitors of interleukin-1beta converting enzyme (ICE), also known as caspase-1. These inhibitors, which employ a diphenyl ether sulfonamide, were designed to improve potency by forming favorable interactions between the diphenyl ether rings and the prime side hydrophobic region. An X-ray crystal structure of a representative member of the diphenyl ether sulfonamide series bound to the active site of caspase-1 was obtained.
Asunto(s)
Inhibidores de Caspasas , Inhibidores Enzimáticos/síntesis química , Éteres/síntesis química , Sulfonamidas/síntesis química , Caspasa 1/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Éteres/química , Éteres/farmacología , Modelos Moleculares , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaAsunto(s)
Antiinflamatorios/química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Inhibidores de Cisteína Proteinasa/química , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Caspasa 1/química , Caspasa 1/genética , Caspasa 1/metabolismo , Caspasas/química , Caspasas/deficiencia , Caspasas/genética , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/farmacología , Citocinas/metabolismo , Diseño de Fármacos , Humanos , Transducción de Señal , Especificidad por SustratoRESUMEN
We have evaluated 619 aspartic ketones with 9 different types of prime-side groups (acyloxymethyl, aryloxymethyl, arylthiomethyl, alkylthiomethyl, acylamino-oxymethyl, sulfonylaminomethyl, alpha-ketoamide, alpha-(1-phenyl-3-trifluoromethyl-pyrazol-5-yl)oxymethyl (PTP), and aliphatic ketones) as inhibitors of caspase-1. The inhibitory behaviors could be classified as reversible, inactivating, or bimodal (i.e. reversible inhibition followed by slow inactivation) based on the kinetically observed formation of reversible thiohemiketal complexes and conversion to an irreversible thioether adduct, and the mechanism of any given ketone was only poorly predictable on the basis of leaving group structure and chemistry. Among 201 bimodal inhibitors, the rate of conversion of the reversible thiohemiketal complex to the inactive thioether (k(i)) was strictly first-order, consistent with direct conversion of the thiohemiketal to the thioether with no intermediate collapse to free ketone and thiolate. We have examined 22 crystallographic structures of caspase-1 complexed as a thiohemiketal with the inhibitors from 8 different ketone classes, and found the Cys285S-C-C(alpha)-leaving group dihedral angle to be near either to 60 degrees or to 180 degrees. Only the 180 degrees conformation was permissive for SN2 displacement of the leaving group and, furthermore, positioned His237Ndelta to stabilize developing charge on the leaving group. Among these structures and 19 additional complexes, all showed a strong interaction between His237Ndelta and the ketone or thiohemiketal oxygen. We therefore propose a proteolytic mechanism for caspase-1 involving polarization of the scissile carbonyl by the His237 imidazolium group. During thiohemiketal/thioether conversion (but probably not during peptide hydrolysis), the leaving group is stabilized by the His237 imidazolium.
Asunto(s)
Caspasa 1/química , Inhibidores de Caspasas , Cetonas/farmacología , Cristalografía por Rayos X , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Modelos Moleculares , Piridinas/farmacología , Factores de TiempoRESUMEN
OBJECTIVE: To determine premorbid prevalence of attention-deficit hyperactivity disorder (ADHD) in children with moderate and severe closed head injury (CHI), to determine incidence of ADHD 1 year after injury, and to characterize children who develop ADHD by demographic, neuropsychiatric, and outcome variables. METHOD: Ninety-nine children who had severe and moderate CHI were followed up for 1 year. Premorbid and 1-year postinjury psychiatric status were ascertained by parent and child structured interviews and questionnaires measuring affective lability, aggression, apathy, and social judgment. RESULTS: Premorbid prevalence of ADHD was 0.20, significantly higher than in a reference population (0.045). Fifteen of the remaining 80 children (0.19) developed full ADHD criteria (except for age of onset) by the end of the first year. Children who developed secondary ADHD (S-ADHD) had significantly greater premorbid psychosocial adversity, posttraumatic affective lability and aggression, posttraumatic psychiatric comorbidity, and overall disability than children who did not develop S-ADHD. CONCLUSIONS: There is an excess prevalence of premorbid ADHD among children who present with moderate and severe CHI. Children with high psychosocial adversity are more likely to develop S-ADHD after CHI. S-ADHD has criteria in common with personality change due to CHI, a deficit in behavioral inhibition being the major overlapping feature.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Traumatismos Craneocerebrales/epidemiología , Heridas no Penetrantes/epidemiología , Adolescente , Análisis de Varianza , Baltimore/epidemiología , Niño , Preescolar , Femenino , Humanos , Masculino , Prevalencia , Factores de Riesgo , Índices de Gravedad del TraumaRESUMEN
The caspase-1 (interleukin 1beta-converting enzyme; ICE) titrant 3-[2-(2-benzyloxycarbonylamino-3-methylbutyrylamino) propionylamino]-4 -oxo-5-(2-oxo-2H-chromen-7-yloxy)pentanoic acid (1 (Dang, L. C., et al. (1996) Biochemistry 35, 14910-14916)) inhibits caspase-1 activity rapidly, while release of the 7-hydroxycoumarin fluorophore is much slower. Progress curve analysis of 1 and of the related acyloxymethyl ketone 3-[2-(2-benzyloxycarbonylamino-3-methylbutyrylamino) propionylamino]-4 -oxo-5-(1-oxo-3-phenylpropoxy)pentanoic acid (2) identifies distinctive residual patterns which are caused by the superimposition of potent slow-binding reversible inhibition with slower, irreversible inactivation. Standard kinetic models are not entirely adequate for analysis of these bimodal inhibitors, but by measuring the kinetic properties of these inhibitors by several independent techniques and comparing these to simulations which closely mimic the inhibitor actions, careful application of the standard models can provide reasonably accurate kinetic constants.
Asunto(s)
Cromonas/farmacología , Cisteína Endopeptidasas/metabolismo , Inhibidores de Cisteína Proteinasa/farmacología , Ácidos Pentanoicos/farmacología , Caspasa 1 , Cromonas/metabolismo , Cumarinas/metabolismo , Cisteína Endopeptidasas/efectos de los fármacos , Inhibidores de Cisteína Proteinasa/metabolismo , Colorantes Fluorescentes , Cetonas/metabolismo , Cetonas/farmacología , Cinética , Modelos Químicos , Oligopéptidos/metabolismo , Ácidos Pentanoicos/metabolismo , Especificidad por SustratoRESUMEN
Optimization of a 2-step reaction sequence was accomplished in 3-4 days, with over 200 different reaction conditions evaluated. Combinatorial arrays were performed using the optimized conditions to synthesize 590 new compounds which were tested for inhibition against N-His (D381E) ICE. Thirty-five compounds showed at least a tenfold improvement in activity compared to an initial standard.
Asunto(s)
Ácido Aspártico/análogos & derivados , Ácido Aspártico/síntesis química , Inhibidores de Caspasas , Inhibidores de Cisteína Proteinasa/síntesis química , Cetonas/síntesis química , Sustitución de Aminoácidos , Ácido Aspártico/química , Ácido Aspártico/farmacología , Automatización , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacología , Diseño de Fármacos , Indicadores y Reactivos , Cetonas/química , Cetonas/farmacología , Cinética , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The caspase family represents a new class of intracellular cysteine proteases with known or suspected roles in cytokine maturation and apoptosis. These enzymes display a preference for Asp in the P1 position of substrates. To clarify differences in the biological roles of the interleukin-1beta converting enzyme (ICE) family proteases, we have examined in detail the specificities beyond the P1 position of caspase-1, -2, -3, -4, -6, and -7 toward minimal length peptide substrates in vitro. We find differences and similarities between the enzymes that suggest a functional subgrouping of the family different from that based on overall sequence alignment. The primary specificities of ICE homologs explain many observed enzyme preferences for macromolecular substrates and can be used to support predictions of their natural function(s). The results also suggest the design of optimal peptidic substrates and inhibitors.
Asunto(s)
Caspasas , Cisteína Endopeptidasas/metabolismo , Caspasa 1 , Caspasa 3 , Caspasa 6 , Caspasa 7 , Cromatografía Líquida de Alta Presión , Cisteína Endopeptidasas/química , Colorantes Fluorescentes/metabolismo , Cinética , Oligopéptidos/metabolismo , Transducción de Señal , Especificidad por SustratoRESUMEN
Crx is a novel paired-like homeodomain protein that is expressed predominantly in retinal photoreceptors and pinealocytes. Its gene has been mapped to chromosome 19q13.3, the site of a disease locus for autosomal dominant cone-rod dystrophy (CORDII). Analysis of the proband from a family with autosomal dominant CORD revealed an Arg41Trp substitution in the third residue of the CRX homeodomain. The sequence change cosegregated with the disease phenotype and was not detected in 247 normal controls. Recombinant CRX homeodomain containing the Arg41Trp substitution showed decreased DNA binding activity. Analysis of another 169 CORD probands identified three additional CRX sequence variations (Arg41Gln, Val242Met, and a 4 bp deletion in codons 196/7) that were not found among the controls. This data suggests that mutations in the CRX gene are associated with photoreceptor degeneration and that the Crx protein is necessary for the maintenance of normal cone and rod function.
Asunto(s)
Proteínas de Homeodominio/genética , Mutación Puntual , Retinitis Pigmentosa/genética , Eliminación de Secuencia , Transactivadores/genética , Adulto , Secuencia de Bases , Mapeo Cromosómico , Cromosomas Humanos Par 19 , Codón , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Exones , Femenino , Genes Dominantes , Proteínas de Homeodominio/biosíntesis , Proteínas de Homeodominio/metabolismo , Humanos , Intrones , Escala de Lod , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Reacción en Cadena de la Polimerasa , Proteínas Recombinantes de Fusión/biosíntesis , Retina/patología , Retinitis Pigmentosa/patología , Retinitis Pigmentosa/fisiopatología , Transactivadores/biosíntesis , Transactivadores/metabolismo , Agudeza VisualRESUMEN
We describe the expression, purification, and characterization of human interleukin-1 beta converting enzyme (ICE) containing an affinity tag and modified to resist autoproteolysis. The point mutation Asp381 to Glu was added to eliminate the major site of autolytic degradation while maintaining catalytic activity, and an N-terminal polyhistidine tag was added in place of the ICE pro-region to facilitate purification. N-His (D381E) ICE was expressed in Escherichia coli and purified by nickel-chelating Sepharose and size-exclusion chromatography (SEC). The enzyme was stabilized greater than 80-fold against autolytic degradation relative to wild-type N-His ICE. SDS-PAGE analysis with silver-staining revealed no impurities, and 85% of the protein was catalytically active as determined by titration with a novel titrant, PD 163594 (3-[2-(2-benzyloxycarbonylamino-3-methylbutyrylamino)prop ionylamino]-4- oxo-5-(2-oxo-2H-chromen-7-yloxypentanoic acid). An oxidized adduct of ICE with glutathione, formed by disulfide rearrangement with oxidized glutathione to inhibit and stabilize the enzyme during purification, was rapidly reduced upon exposure to 5 mM DTT. One mole of glutathione was released per mole of active enzyme. Of the nine cysteines in ICE, eight were present in their reduced form in the glutathione adduct. N-His (D381E) ICE cleaved Ac-YVAD-Amc with the Michaelis-Menten parameters K(M) = 14 microM and Kcat = 0.7 s-1, values essentially identical to those reported for enzyme from natural sources.
Asunto(s)
Cisteína Endopeptidasas/genética , Sitios de Unión , Caspasa 1 , Clonación Molecular , Cumarinas/metabolismo , Cisteína Endopeptidasas/aislamiento & purificación , Cisteína Endopeptidasas/metabolismo , Estabilidad de Enzimas , Escherichia coli , Glutatión/metabolismo , Humanos , Mutagénesis , Oligopéptidos/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/metabolismo , VolumetríaRESUMEN
We report the preparation and characterization of interleukin-1beta converting enzyme (ICE) refolded from its p20 and p10 protein fragments. Refolded ICE heterodimer (p20p10) was catalytically active but unstable, and in size exclusion chromatography eluted at an apparent molecular mass of 30 kDa. The mechanisms of the observed instability were pH-dependent dissociation at low enzyme concentrations, and autolytic degradation of the p10 subunit at high concentrations. Binding and subsequent removal of a high affinity peptidic inhibitor increased the apparent molecular mass to 43 kDa (by size exclusion chromatography), and significantly increased its stability and specific activity. Chemical cross-linking and SDS-polyacrylamide gel electrophoresis analysis of the 43-kDa size exclusion chromatography conformer revealed a 60-kDa species, which was absent in the 30-kDa conformer, suggesting that inhibitor binding caused formation of a (p20p10)2 homodimer. The observation of a reversible equilibrium between ICE (p20p10) and (p20p10)2 suggests that analogous associations, possibly between ICE and ICE homologs, can occur in vivo, resulting in novel oligomeric protease species.
Asunto(s)
Cisteína Endopeptidasas/química , Secuencia de Bases , Caspasa 1 , Cromatografía en Gel , Cromatografía Líquida de Alta Presión , Electroforesis en Gel de Poliacrilamida , Estabilidad de Enzimas , Concentración de Iones de Hidrógeno , Datos de Secuencia Molecular , Peso Molecular , Reacción en Cadena de la Polimerasa , Conformación Proteica , Estructura Terciaria de ProteínaRESUMEN
We have examined statistically the actions of thyrotropin-releasing hormone (TRH) and Bay K 8644, an L-type Ca(2+)-channel agonist, on the frequency and shape of cytosolic Ca2+ spikes in individual GH4C1 rat pituitary cells. TRH induced a brief (0-40 s) suppression of Ca2+ spikes followed by a period (40-200 s) of increased spike frequency. TRH treatment reduced the rate of rise and amplitude of Ca2+ spikes, and increased the rate of fall, relative to spontaneous spikes before treatment. TRH had no significant effect on the correlation between spike amplitude and the spike decay time constant tau, suggesting that the increased rate of fall was due to enhanced Ca2+ extrusion and not to decreased Ca(2+)-induced Ca2+ release. Bay K rapidly (t1/2 = 9-13 s) induced a 2-fold increase in the rate of rise of spikes with no change in the total rise time, leading to an increase in spike amplitude. It increased by 2-fold the fall time of spikes, as predicted solely by the previously observed relationship between spike amplitude and fall time. Bay K therefore appeared to increase the number of Ca2+ channels participating in each spike event without altering the kinetics of channel activation or deactivation, and without influencing Ca2+ extrusion. After addition of Bay K, the interval between spikes gradually (t1/2 approximately 100 s) increased, whereas the rate of rise remained constant and maximal. To explain these actions of TRH and Bay K, we postulate that a fraction of L-type Ca2+ channels are inactivated during each spike and must be re-activated in order to participate in a subsequent spike. We conclude further that the changes in spike frequency and profiles induced by these secretagogues are most consistent with a model in which TRH induces increases in both Ca2+ influx and efflux while Bay K induces a large increase in Ca2+ influx but has little effect on efflux.
Asunto(s)
Ácido 3-piridinacarboxílico, 1,4-dihidro-2,6-dimetil-5-nitro-4-(2-(trifluorometil)fenil)-, Éster Metílico/farmacología , Calcio/metabolismo , Hipófisis/fisiología , Hormona Liberadora de Tirotropina/farmacología , Potenciales de Acción/efectos de los fármacos , Compuestos de Anilina , Animales , Línea Celular , Fluorescencia , Colorantes Fluorescentes , Cinética , Hipófisis/efectos de los fármacos , Ratas , XantenosRESUMEN
The Goldhelox Project is the construction and use of a near-normal incidence soft x-ray robotic solar telescope by undergraduate students at Brigham Young University. Once it is completed and tested, it will be deployed from a Get-Away-Special (GAS) canister in the bay of a space shuttle. It will image the sun at a wavelength of 171-181Å with a time resolution of 1 sec and a spatial resolution of 2.5 arcsec. The observational bandpass was chosen to image x-rays from highly ionized coronal Fe lines. The data will be an aid in better understanding the beginning phases of solar flares and how flaring relates to the physics of the corona-chromosphere transition region. Goldhelox is tentatively scheduled to fly on a space shuttle sometime in 1995 or 1996. This paper outlines the project goals, basic instrument design, and the unique aspects of making this an undergraduate endeavor.
RESUMEN
To evaluate the role of thyrotropin-releasing hormone (TRH)-stimulated guanine nucleotide exchange in the biphasic cellular responses to TRH, we have examined the kinetics, reversibility, and inhibition by QC120 (an antiserum recognizing the carboxyl terminus of alpha q/11) of TRH-stimulated guanosine-5'-(alpha-[35S] thio)triphosphate ([35S]GTP alpha S) binding in membranes from GH4C1 cells. Enhanced binding of [35S]GTP alpha S stimulated by TRH was dose dependent and readily detectable within 8 sec of TRH treatment. Binding measured within the first 20 sec was largely inhibited by QC120, whereas additional binding that accumulated during incubations of 3-6 min was not inhibited by even high concentrations of the antiserum. TRH-stimulated binding was reversible, in that, after membranes were incubated with TRH and [35S]GTP alpha S, subsequent addition of excess GTP caused exchange of 70-100% of the prebound radioligand. Exchange of TRH-stimulated [35S]GTP alpha S binding occurred in fast and slow phases, with half-times of < 5 sec and 187 sec, respectively. Addition of QC120 before the GTP chase inhibited the fast phase of exchange, whereas reduction of the TRH concentration in the preincubation selectively reduced the magnitude of the slow phase. Neither phase of exchange was affected by prior treatment of cells with pertussis toxin. Our observations indicate that Gq/11 is rapidly activated by the TRH receptor and that a second, unidentified, G protein is slowly activated by the TRH receptor.
Asunto(s)
Membrana Celular/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Hormona Liberadora de Tirotropina/fisiología , Secuencia de Aminoácidos , Sitios de Unión , Línea Celular , Membrana Celular/efectos de los fármacos , Proteínas de Unión al GTP/inmunología , Proteínas de Unión al GTP/metabolismo , Sueros Inmunes , Cinética , Datos de Secuencia Molecular , Toxina del Pertussis , Factores de Virulencia de Bordetella/farmacologíaRESUMEN
Interleukin-1 beta-converting enzyme (ICE) proteolytically cleaves pro-IL-1 beta to its mature, active form. The crystal structure at 2.5 A resolution of a recombinant human ICE-tetrapeptide chloromethylketone complex reveals that the holoenzyme is a homodimer of catalytic domains, each of which contains a p20 and a p10 subunit. The spatial separation of the C-terminus of p20 and the N-terminus of p10 in each domain suggests two alternative pathways of assembly and activation in vivo. ICE is homologous to the C. elegans cell death gene product, CED-3, and these may represent a novel class of cytoplasmic cysteine proteases that are important in programmed cell death (apoptosis). Conservation among members of the ICE/CED-3 family of the amino acids that form the active site region of ICE supports the hypothesis that they share functional similarities.
Asunto(s)
Conformación Proteica , Serpinas/química , Proteínas Virales , Clorometilcetonas de Aminoácidos/metabolismo , Secuencia de Aminoácidos , Apoptosis , Cristalización , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Unión Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Serpinas/genética , Serpinas/metabolismoRESUMEN
We have examined statistical relationships between the amplitudes and the kinetics (rise times, fall times, and decay constants) of cytosolic free calcium fluctuations (spikes) in a population of 353 individual GH4C1 rat pituitary cells. The fast falling phase was approximated by a single exponential decay, and the decay time constant, tau, increased linearly with spike amplitude in 80% of the cells studied. The slope of the tau versus amplitude plot for each cell was inversely related to the cell's mean spike amplitude. Thus, some process responsible for prolonging the decay phase of spikes appeared to operate strongly in cells with spikes of low amplitude, but to become less prominent in cells with high amplitude spikes. Mean tau correlated more strongly with mean rise and fall times than with mean spike amplitude, indicating that the kinetic properties of spikes were not tightly coupled to spike amplitude. These findings are consistent with a model wherein the rise phase corresponds to entry of extracellular calcium via L-type calcium channels into localized sub-plasmalemmal domains, followed by diffusion of subplasmalemmal calcium into the cell interior; and the falling phase corresponds to further calcium diffusion combined with activation of cytoplasmic calcium-induced calcium release, which prolongs the falling phase.
Asunto(s)
Calcio/metabolismo , Hipófisis/metabolismo , Compuestos de Anilina , Animales , Fenómenos Biofísicos , Biofisica , Línea Celular , Citosol/metabolismo , Difusión , Colorantes Fluorescentes , Transporte Iónico/fisiología , Cinética , Modelos Biológicos , Ratas , XantenosRESUMEN
An analogue of thyrotropin-releasing hormone (TRH, pGlu-His-ProNH2), i.e. pGlu-His-ProNH-(CH2)6-(4-azidosalicylamide) (TRH-ASA), has been synthesized and, in a radioiodinated form (TRH-IASA), characterized and used as a photoaffinity reagent to label the TRH receptor on rat pituitary GH4C1 cells. TRH-IASA bound to GH4C1 cells with high affinity (Kd = 8 nM), comparable with that of TRH binding. The binding of TRH-IASA was competitive with binding of TRH, two TRH analogues and a TRH receptor antagonist, chlordiazepoxide. TRH-IASA did not bind to or label GH12C1 cells, which lack functional TRH receptors. Labelling of GH4C1 cells with TRH-IASA followed by SDS/PAGE and autoradiography of membrane proteins demonstrated labelling of a single polypeptide which ran as a diffuse band between 71 and 91 kDa, centred at 76 kDa. No change in this labelling pattern was observed as a function of the length of time (between 5 min and 2 h) that GH4C1 cells were incubated with 3 nM-TRH-IASA. Using either a very short (5 s) photolysis interval or low TRH-IASA concentrations, only the 76 kDa band was labelled. Minor bands appeared only after extended photolysis and use of high TRH-IASA concentrations. We conclude that the TRH receptor from rat pituitary GH4C1 cells is a single peptide with an apparent molecular mass of 76 kDa. Details of the chemical synthesis of TRH-ASA are given in Supplementary Publication SUP 50167 (5 pages), which has been deposited at the British Library Document Supply Centre, Boston Spa, Wetherby, West Yorkshire LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1992) 281, 5.
Asunto(s)
Marcadores de Afinidad/síntesis química , Azidas/síntesis química , Receptores de Neurotransmisores/metabolismo , Hormona Liberadora de Tirotropina/análogos & derivados , Animales , Azidas/metabolismo , Unión Competitiva , Línea Celular , Indicadores y Reactivos , Radioisótopos de Yodo/metabolismo , Cinética , Peso Molecular , Fotólisis , Receptores de Neurotransmisores/efectos de los fármacos , Receptores de Neurotransmisores/aislamiento & purificación , Receptores de Hormona Liberadora de Tirotropina , Hormona Liberadora de Tirotropina/síntesis química , Hormona Liberadora de Tirotropina/metabolismoRESUMEN
We describe five eyes of five patients that developed an exudative retinal detachment following a central retinal vein occlusion (including one eye with a hemicentral [hemispheric] retinal vein occlusion). The time interval between the occurrence of the vein occlusion and the appearance of the retinal detachment ranged from 7 to 36 weeks in the four cases seen in the acute period. Each detachment involved the posterior retina and was associated with the development of marked retinal ischemia. Neovascular glaucoma occurred in two cases. The subretinal fluid completely or partially resorbed in the four eyes that were treated with retinal photocoagulation, but the final visual acuity was poor in all cases. Exudative retinal detachment is a potential complication of central retinal vein occlusion and in this series was associated with a poor visual prognosis.
Asunto(s)
Desprendimiento de Retina/etiología , Oclusión de la Vena Retiniana/complicaciones , Adolescente , Adulto , Anciano , Exudados y Transudados , Femenino , Angiografía con Fluoresceína , Estudios de Seguimiento , Fondo de Ojo , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Desprendimiento de Retina/patología , Desprendimiento de Retina/cirugía , Agudeza VisualRESUMEN
We examined six patients with Gardner's syndrome, eight first-degree relatives, and 31 age- and sex-matched controls to document the presence, distribution, and morphologic features of congenital hypertrophy of the retinal pigment epithelium. Patients with Gardner's syndrome had multiple, bilateral lesions, with 288 of 346 foci (83%) located posterior to the equator. Linear-shaped congenital hypertrophy of the retinal pigment epithelium, a distinctive finding in these patients, accounted for 44 of 140 large lesions (31%). Despite multifocal fundus involvement, results of electro-oculography were normal in all eyes tested.
Asunto(s)
Electrooculografía , Síndrome de Gardner/fisiopatología , Adolescente , Adulto , Anciano , Niño , Síndrome de Gardner/patología , Humanos , Hipertrofia , Persona de Mediana Edad , Epitelio Pigmentado Ocular/patología , Epitelio Pigmentado Ocular/fisiopatología , PigmentaciónRESUMEN
5-thio-D-glucose at 40 mg/kg body weight was administered daily by intraperitoneal injections to male C3H mice. The animals were studied via direct counts of the spermatogenic cells in histologic sections of the testes. These revealed the selective loss or injury of early spermatids followed later in treatment by significantly diminished spermatocyte number. Spermatogonia and Sertoli cells were not significantly affected by thiosugar. After 35 daily doses, testicular and epithelium was noted. The results are indicative of an early drug action on spermatids with later effects on spermatocytes. Recovery began within three weeks of drug withdrawal and was characterized by restoration of the severely disturbed architecture and with the progressive resumption of spermatogenesis. Epididymis sperm counts returned to 91 percent that of control animals; however, testis weights remained somewhat below normal.
Asunto(s)
Epidídimo/citología , Glucosa/análogos & derivados , Testículo/citología , Animales , Antiespermatogénicos/farmacología , Relación Dosis-Respuesta a Droga , Glucosa/farmacología , Masculino , Ratones , Ratones Endogámicos C3H/anatomía & histología , Tamaño de los Órganos , Células de Sertoli/citología , Espermátides/citología , Espermatocitos/citología , Espermatogonias/citología , Espermatozoides/citología , Testículo/anatomía & histología , Factores de TiempoRESUMEN
Under the conditions of the present study, 5-thio-D-glucose was found to be an effective and useful reversible male contraceptive. Treatment of male mice with 5-thio, administered intraperitoneally or orally at 40 or 60 mg/kg for 28 to 35 days produced germinal cell degeneration and complete inhibition of spermatogenesis in the seminiferous tubules. These treatment regimens also resulted in complete sterility in males lasting for several weeks. Resumption of sperm development and fertility occurred with 5 to 6 weeks after treatment was discontinued. The Leydig cell population, Sertoli cells, and spermatogonia apparently were not affected and male libido was not impaired. There was no evidence of embryotoxic or teratogenic effect in litters of pregnant females treated orally with 5-thio on days 6--12 of gestation.