RESUMEN
The CXC chemokine gamma interferon (IFN-gamma)-inducible protein CXCL10/IP-10 is markedly elevated in cerebrospinal fluid and brain of individuals infected with human immunodeficiency virus type 1 (HIV-1) and is implicated in the pathogenesis of HIV-associated dementia (HAD). To explore the possible role of CXCL10/IP-10 in HAD, we examined the expression of this and other chemokines in the central nervous system (CNS) of transgenic mice with astrocyte-targeted expression of HIV gp120 under the control of the glial fibrillary acidic protein (GFAP) promoter, a murine model for HIV-1 encephalopathy. Compared with wild-type controls, CNS expression of the CC chemokine gene CCL2/MCP-1 and the CXC chemokine genes CXCL10/IP-10 and CXCL9/Mig was induced in the GFAP-HIV gp120 mice. CXCL10/IP-10 RNA expression was increased most and overlapped the expression of the transgene-encoded HIV gp120 gene. Astrocytes and to a lesser extent microglia were identified as the major cellular sites for CXCL10/IP-10 gene expression. There was no detectable expression of any class of IFN or their responsive genes. In astrocyte cultures, soluble recombinant HIV gp120 protein was capable of directly inducing CXCL10/IP-10 gene expression a process that was independent of STAT1. These findings highlight a novel IFN- and STAT1-independent mechanism for the regulation of CXCL10/IP-10 expression and directly link expression of HIV gp120 to the induction of CXCL10/IP-10 that is found in HIV infection of the CNS. Finally, one function of IP-10 expression may be the recruitment of leukocytes to the CNS, since the brain of GFAP-HIV gp120 mice had increased numbers of CD3(+) T cells that were found in close proximity to sites of CXCL10/IP-10 RNA expression.
Asunto(s)
Astrocitos/metabolismo , Quimiocinas CXC/genética , Proteína gp120 de Envoltorio del VIH/metabolismo , VIH-1/metabolismo , Animales , Astrocitos/citología , Encéfalo/metabolismo , Encéfalo/patología , Células Cultivadas , Quimiocina CXCL10 , Quimiocinas CXC/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/fisiología , Expresión Génica , Proteína Ácida Fibrilar de la Glía/genética , Proteína gp120 de Envoltorio del VIH/genética , VIH-1/genética , Humanos , Interferón-alfa/metabolismo , Interferón-alfa/farmacología , Interferón gamma/metabolismo , Interferón gamma/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores CXCR3 , Receptores de Quimiocina/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Factor de Transcripción STAT1 , Solubilidad , Linfocitos T/citología , Transactivadores/genética , Transactivadores/fisiologíaRESUMEN
This review examines the contribution of sociological perspectives to the study of relationships in later life. Three main areas are analysed: first, the family life of older people, second, marital relationships; third, friendship in later life. The article concludes with an assessment of the changes affecting the social lives of different groups of older people.
Asunto(s)
Envejecimiento/psicología , Familia , Relaciones Interpersonales , Matrimonio , Apoyo Social , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Fenómenos Fisiológicos de la Nutrición , Paleontología , Apetito/fisiología , Conducta/efectos de los fármacos , Conducta/fisiología , Evolución Biológica , Dieta/tendencias , Carbohidratos de la Dieta/farmacología , Grasas de la Dieta/farmacología , Conducta Alimentaria , Humanos , Longevidad , Aptitud Física , Cambio Social , Vanadio/efectos adversosRESUMEN
Elder abuse is now being recognised as a serious social problem. This article discusses the difficulties in defining elder abuse and describes the characteristics of the abused and the abuser. It then suggests how nurses may recognise abuse and outlines the interventions that may be employed.
Asunto(s)
Abuso de Ancianos/prevención & control , Anciano , Abuso de Ancianos/estadística & datos numéricos , Humanos , Evaluación en Enfermería , Factores de RiesgoRESUMEN
A procedure that uses the PCR to make rapid successive steps through a random-primed cDNA library has been developed to provide a method for sequencing very long genes that are difficult to obtain as a single clone. In each successive step, the portions of partial clones that extend out from the region of known DNA sequence are amplified by two stages of PCR with nested, outward-directed primers designed approximately 50 bases in from the end of the known sequence, together with a general primer based on the sequence of the vector. This procedure has been used to determine the coding sequence of the cDNA for the beta heavy chain of axonemal dynein from embryos of the sea urchin Tripneustes gratilla. By starting from a single parent clone, whose translated amino acid sequence overlapped the microsequence of a tryptic peptide of the beta heavy chain, and making 3 such walk steps downstream and 14 walk steps upstream, we obtained a sequence of 13,799 base pairs that had an open reading frame of 13,398 base pairs. This sequence encodes a polypeptide with 4466 residues of Mr 511,804 that is believed to correspond to the complete beta heavy chain of ciliary outer arm dynein.
Asunto(s)
ADN/genética , Dineínas/genética , Reacción en Cadena de la Polimerasa/métodos , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Northern Blotting , Biblioteca de Genes , Datos de Secuencia Molecular , Oligonucleótidos/química , ARN Mensajero/genética , Erizos de MarRESUMEN
6 polycyclic aromatic hydrocarbons were assayed for mutagenicity in the Ames test, in the presence of hepatic post-mitochondrial preparations isolated from the mouse, rat, hamster, pig and man. Benzo[a]pyrene, dibenzo[a,i]pyrene and benz[a]anthracene gave a positive mutagenic response only in the presence of activation systems derived from the hamster. With the exception of the pig, activation systems derived from all animal species could convert 3-methylcholanthrene to mutagens, the hamster being the most efficient. With the exception of the rat and pig, all animal species activated 7,12-dimethylbenz[a]-anthracene to mutagens, the human preparation being the most effective followed by the hamster and mouse. Dibenz[a,h]anthracene was not activated by any of the hepatic preparations. It is concluded that, among the animal species studied the hamster is generally the most efficient in activating polycyclic aromatic hydrocarbons to mutagens in the Ames test.
Asunto(s)
Pruebas de Mutagenicidad , Compuestos Policíclicos/metabolismo , 9,10-Dimetil-1,2-benzantraceno/metabolismo , Animales , Benzo(a)pireno/metabolismo , Biotransformación , Cricetinae , Humanos , Masculino , Mesocricetus , Metilcolantreno/metabolismo , Ratones , Ratones Endogámicos , Mitocondrias Hepáticas/efectos de los fármacos , Ratas , Ratas Endogámicas , Salmonella typhimurium/efectos de los fármacos , PorcinosRESUMEN
Rat hepatic microsomal mixed-function oxidase activities were not significantly affected by vitamin A deficiency. Similarly cytosolic glutathione S-transferase and glutathione reductase activities as well as total glutathione levels were unaffected by the vitamin A status. Induction of the mixed-function oxidases by 3-methylcholanthrene or phenobarbitone was independent of the vitamin A status. No significant differences in microsomal chemiluminescence, before and following challenge with tertiary butyl hydroperoxide, were evident between the vitamin-A-deficient animals and those maintained on vitamin-A-supplemented diets. The present findings indicate that the protective action of vitamin A against chemical carcinogens is unlikely to involve modulation of the enzyme systems responsible for their metabolism.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Glutatión Transferasa/metabolismo , Microsomas Hepáticos/enzimología , Oxigenasas de Función Mixta/metabolismo , Oxígeno/metabolismo , Deficiencia de Vitamina A/enzimología , Animales , Radicales Libres , Masculino , Ratas , Ratas EndogámicasRESUMEN
Irradiation of soluble dynein 1 from sea urchin sperm flagella at 365 nm in the presence of MgATP and 0.05-50 microM vanadate (Vi) cleaves the alpha and beta heavy chains (Mr 428,000) at their V1 sites to give peptides of Mr 228,000 and 200,000, without the nonspecific side effects produced by irradiation at 254 nm as described earlier (Lee-Eiford, A., Ow, R. A., and Gibbons, I. R. (1986) J. Biol. Chem. 261, 2337-2342). The decrease in intact heavy chain material is biphasic; in 10 microM Vi, approximately 80% occurs with a half-time of 7 min and the remainder with a half-time of about 90 min, and the yield of cleavage peptides is better than 90%. Loss of dynein ATPase activity appears to be a direct result of the cleavage process and is not significantly affected by the presence of up to 0.1 M cysteamine (CA, 60-23-1) or 2-aminoethyl carbamimidothioic acid dihydrobromide (CA, 56-10-0) as free radical trapping agents. The concentration of Vi required for 50% maximal initial cleavage rate is 4.5 microM, while that for 50% ATPase inhibition is 0.8 microM, both in a 0.6 M NaCl medium. In the presence of 20 microM Vi, CTP and UTP support cleavage at about half the rate of ATP, whereas GTP and ITP support cleavage only if the Vi concentration is raised to about 200 microM. Substitution of any of the transition metal cations Cr2+, Mn2+, Fe2+, or Co2+ for the usual Mg2+ suppresses the photocleavage, presumably by quenching the excited chromophore prior to scission of the heavy chain. The photocleaved dynein 1 binds to dynein-depleted flagella similarly to intact dynein 1, but upon reactivation of the flagella with 1 mM ATP their motility is partially inhibited, rather than being augmented as with intact dynein. These results indicate that Vi acts as a photosensitizing catalyst and suggest that the cleavage proceeds through excitation of Vi bound to dynein at the hydrolytic ATP binding site on each heavy chain, probably in a dynein X MgADP X Vi complex. The exquisite specificity of Vi-sensitized photocleavage will aid the peptide mapping of dynein heavy chains and may be of broader use in studies of protein structure.
Asunto(s)
Adenosina Trifosfatasas/metabolismo , Adenosina Trifosfato/metabolismo , Dineínas/metabolismo , Vanadio/metabolismo , Animales , Cisteamina/farmacología , Electroforesis en Gel de Poliacrilamida , Flagelos/fisiología , Cinética , Movimiento , Nucleótidos/metabolismo , Fotoquímica , Erizos de Mar , Rayos Ultravioleta , VanadatosRESUMEN
The O-deethylation of ethoxyresorufin and the metabolic activation of benzo[a]pyrene to mutagens were determined in hepatic microsomal preparations from control and induced animals. An excellent direct correlation (r = 0.95) has been observed between ethoxyresorufin O-deethylase and the metabolic activation of benzo[a]pyrene to mutagens when the fraction of cytochromes P-450 present as cytochrome P-448 was altered by the administration of phenobarbitone and 3-methylcholanthrene alone or in combination with 9-hydroxyellipticine. The correlation between these activities was maintained following treatment of animals with Arochlor 1254, benzo[a]pyrene, benzo[e]pyrene, 7,12-dimethylbenzo[a]anthracene,2-anthramine and 2-naphthylamine.
Asunto(s)
Benzo(a)pireno/metabolismo , Citocromos/metabolismo , Microsomas Hepáticos/metabolismo , Animales , Biotransformación , Citocromo P-450 CYP1A2 , Inducción Enzimática , Masculino , Microsomas Hepáticos/enzimología , Oxigenasas de Función Mixta/metabolismo , Pruebas de Mutagenicidad , Ratas , Ratas EndogámicasRESUMEN
The topic of health education and older people is being given greater emphasis in primary care settings. A survey was mounted to investigate the contribution of vocational training in preparing GPs for this area of work. The balance of education was found to be towards the sick and frail elderly; developing 'healthy lifestyles' for old age was given very limited attention. The article concludes with some suggestions for change in the context of training programmes.
Asunto(s)
Educación Médica Continua , Educación en Salud/métodos , Servicios de Salud para Ancianos , Médicos de Familia/educación , Anciano , Inglaterra , Estudios de Evaluación como Asunto , HumanosRESUMEN
Dimethylnitrosamine, dipropylnitrosamine, methylethylnitrosamine, nitrosopiperidine and nitrosopyrrolidine were assayed for mutagenicity in the Ames test in the presence of hepatic postmitochondrial preparations isolated from the mouse, rat, hamster, pig and man. Prior to each mutagenicity assay all activation systems were fully characterised with respect to monoamine oxidase, mixed-function amine oxidase and mixed-function oxidase activities. The hamster was the most efficient activator for all nitrosamines followed by the mouse. The latter species, however, activated nitrosopyrrolidine only weakly which was the only carcinogen readily activated by the human preparation. None of the aliphatic nitrosamines was activated by the rat or pig. No correlation was observed between efficiency of activation and any of the enzyme activities studied.
Asunto(s)
Nitrosaminas/metabolismo , Animales , Biotransformación , Cricetinae , Humanos , Técnicas In Vitro , Masculino , Mesocricetus , Ratones , Microsomas Hepáticos/enzimología , Pruebas de Mutagenicidad , Ratas , Ratas Endogámicas , Especificidad de la Especie , PorcinosRESUMEN
Three enzymes used for the determination of cytochrome P-448 activity, namely aryl hydrocarbon hydroxylase, biphenyl 2-hydroxylase and ethoxyresorufin O-de-ethylase, were evaluated with respect to their specificity, sensitivity and inducibility. Purified cytochrome P-448 (LM4), but not cytochrome P-450 (LM2), catalysed the O-de-ethylation of ethoxyresorufin in a reaction that was markedly inhibited by 9-hydroxyellipticine. After the administration of 3-methylcholanthrene to rats all three activities were induced, the extent of induction being highest for ethoxyresorufin O-de-ethylase. Administration of very small doses of benzo[a]pyrene (50 micrograms/kg) to rats to induce cytochrome P-448 specifically increased only the O-de-ethylation of ethoxyresorufin. 3-Hydroxybenzo[a]pyrene, the major metabolite determined by the aryl hydrocarbon hydroxylase assay, undergoes further NADPH-dependent oxygenation leading to loss of fluorescence. On the basis of these observations and those by other workers, we conclude that ethoxyresorufin O-de-ethylase provides the most specific, sensitive and reproducible means of determining cytochrome P-448 activity.
Asunto(s)
Citocromos/metabolismo , Animales , Benzo(a)pireno , Benzopirenos/farmacología , Citocromo P-450 CYP1A2 , Sistema Enzimático del Citocromo P-450/metabolismo , Citocromos/antagonistas & inhibidores , Elipticinas/farmacología , Técnicas In Vitro , Masculino , Métodos , Metilcolantreno/farmacología , Microsomas Hepáticos/metabolismo , Oxigenasas de Función Mixta/metabolismo , Oxazinas/metabolismo , Ratas , Ratas Endogámicas , Especificidad por SustratoRESUMEN
2-Acetylaminofluorene, 2-aminofluorene, 4-aminobiphenyl, 2-naphthylamine, 2-aminoanthracene and benzidine were assayed for mutagenicity in the Ames test in the presence of hepatic microsomal preparations derived from mouse, hamster, rat, pig and man. Prior to each mutagenicity assay all activation systems were fully characterized with respect to mono-oxygenase and mixed-function amine oxidase activities. All compounds were metabolically activated to mutagens by all activation systems, but with markedly different efficiencies, hamster being the only species which readily activated all amines. The hamster also exhibited the highest ethoxyresorufin O-deethylase and dimethylaniline N-oxidase activities.
Asunto(s)
Aminas/toxicidad , Microsomas Hepáticos/metabolismo , Mutágenos , Mutación , 2-Acetilaminofluoreno/metabolismo , 2-Acetilaminofluoreno/toxicidad , Aminas/metabolismo , Compuestos de Aminobifenilo/metabolismo , Compuestos de Aminobifenilo/toxicidad , Animales , Antracenos/metabolismo , Antracenos/toxicidad , Bencidinas/metabolismo , Bencidinas/toxicidad , Biotransformación , Cricetinae , Fluorenos/metabolismo , Fluorenos/toxicidad , Humanos , Masculino , Ratones , Pruebas de Mutagenicidad , Ratas , Ratas Endogámicas , Salmonella typhimurium/efectos de los fármacos , Especificidad de la Especie , Relación Estructura-Actividad , PorcinosRESUMEN
The interaction of substrates of the microsomal mixed-function oxidases with cytochromes P-450 and P-448 was investigated by using liver microsomes from rats pretreated with phenobarbital or 3-methylcholanthrene, and with purified forms of the cytochromes isolated from rabbit liver. The two forms of the cytochrome have different substrate specificities; cytochrome P-450 has one type 1 substrate-binding site that can accommodate a large variety of substrates, but in contrast cytochrome P-448 may possess two type 1 substrate-binding sites, one of which is different to that of cytochrome P-450 in that it shows a specificity for substrates such as safrole and 9-hydroxy-ellipticine. These findings explain why the two forms of the cytochrome have different substrate specificities and play contrasting roles in the activation and deactivation of xenobiotics.
Asunto(s)
Citocromos/metabolismo , Microsomas Hepáticos/enzimología , Animales , Benzfetamina/metabolismo , Sitios de Unión , Citocromo P-450 CYP1A2 , Sistema Enzimático del Citocromo P-450/metabolismo , Elipticinas/metabolismo , Fluorenos/metabolismo , Técnicas In Vitro , Masculino , Metilcolantreno/farmacología , Microsomas Hepáticos/efectos de los fármacos , Fenobarbital/farmacología , Ratas , Ratas Endogámicas , Safrol/metabolismo , Espectrofotometría , Especificidad por SustratoRESUMEN
Pretreatment of hamsters with phenobarbitone, 3-methylcholanthrene and Arochlor 1254 induced the hepatic microsomal mixed function oxidases, yet decrease the efficiency of activation of dimethylnitrosamine (DMN) to intermediates mutagenic to the Salmonella typhimurium strain TA-100. Furthermore, no correlation was obtained between cytochrome P-450 content, microsomal demethylation of DMN and its activation to mutagens. These results indicate that the demethylation of DMN by the mixed-function oxidases is not the rate-limiting step in the metabolic activation of the carcinogen to mutagen(s), and that other microsomal or soluble enzymes may be involved.