RESUMEN
OBJECTIVE: Diagnosing chronic heart failure (CHF) is important, since subsequent treatments by medication and cardiac intervention improve quality of life. However, accurate CHF diagnosis in the elderly residing in care homes (residents) is hampered by suboptimal diagnostic tools, co-morbidity and physician's unawareness of CHF. We sought to estimate the CHF prevalence among Aruban residents. METHODS: All eligible residents were clinically assessed and screened for CHF signs and symptoms. The diagnosis of CHF was made by final judgment of a cardiologist. Plasma B-type-natriuretic peptide (BNP) levels were determined. RESULTS: Of the 235 residents, 184 (78%) were excluded, mostly because of decreased cognition. The remaining 51 included residents with a mean age of 78 ± 8 years; 57% was female, 59% had diabetes mellitus Type 2 and 71% had renal dysfunction (< 60 mL/min/1.73 m2). Sixteen (31%) had CHF, of which five (31%) were aware of their diagnosis and 11 (69%) were being diagnosed for the first time. Two (29%) residents were previously incorrectly diagnosed with CHF. Most residents with CHF (94%) also had renal dysfunction and 75% had diabetes mellitus Type 2. At a BNP cut-off value of 100 pg/mL, the sensitivity, specificity and predictive values of positive and negative tests were 0.75, 0.69, 0.52 and 0.86, respectively. CONCLUSION: The CHF prevalence in Aruba residents is high (31%) and underestimated. The high CHF prevalence may be related to the high occurrence of diabetes mellitus Type 2 in Arubans. The use of BNP at a cut-off value of 100 pg/mL adds value to the diagnostic work-up of CHF in the elderly residing in care homes.
RESUMEN
The nucleotide excision repair machinery can be targeted preferentially to lesions in transcribed sequences. This mode of DNA repair is referred to as transcription-coupled repair (TCR). In yeast, the Rad26 protein, which is the counterpart of the human Cockayne syndrome B protein, is implicated specifically in TCR. In a yeast strain genetically deprived of global genome repair, a deletion of RAD26 renders cells UV sensitive and displays a defect in TCR. Using a genome-wide mutagenesis approach, we found that deletion of the SPT4 gene suppresses the rad26 defect. We show that suppression by the absence of Spt4 is specific for a rad26 defect and is caused by reactivation of TCR in a Rad26-independent manner. Spt4 is involved in the regulation of transcription elongation. The absence of this regulation leads to transcription that is intrinsically competent for TCR. Our findings suggest that Rad26 acts as an elongation factor rendering transcription TCR competent and that its requirement can be modulated by Spt4.
Asunto(s)
Proteínas de Ciclo Celular , Reparación del ADN , Proteínas Fúngicas/fisiología , Proteínas Nucleares , Proteínas de Saccharomyces cerevisiae , Proteínas de Schizosaccharomyces pombe , Transcripción Genética , Factores de Elongación Transcripcional , Antineoplásicos Alquilantes/farmacología , Relación Dosis-Respuesta en la Radiación , Proteínas Fúngicas/genética , Eliminación de Gen , Biblioteca de Genes , Genotipo , Metilmetanosulfonato/farmacología , Modelos Biológicos , Mutagénesis , Sistemas de Lectura Abierta , Plásmidos/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/fisiología , Temperatura , Factores de Tiempo , Rayos UltravioletaRESUMEN
An HPLC method for the determination of S-phenyl-N-acetylcysteine in urine is described. The sensitivity is 6 mumol/L (CV = 9%) urine. Exposure of rats to six different concentrations of benzene, ranging from 0-30 ppm, was highly associated with urinary excretion of S-phenyl-N-acetylcysteine (r = 0.86) and with total phenol (r = 0.81). A background level of phenol was found in urine of both non-exposed rats and of non-exposed referents. However, no background excretion of S-phenyl-N-acetylcysteine was found, either in rats or in humans. In urine of exposed rats, the level of S-phenyl-N-acetylcysteine was approximately five times lower than the phenol level. Workers occupationally exposed to benzene, showing high levels of urinary phenol, revealed low concentrations of urinary S-phenyl-N-acetylcysteine. The biological monitoring of industrial exposure to benzene by determination of S-phenyl-N-acetylcysteine in urine is not better than the determination of phenol in urine.
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Acetilcisteína/análogos & derivados , Benceno/metabolismo , Monitoreo del Ambiente , Glutatión/metabolismo , Acetilcisteína/orina , Animales , Cromatografía Líquida de Alta Presión , Exposición a Riesgos Ambientales , Humanos , Masculino , Fenol , Fenoles/orina , Ratas , Especificidad de la EspecieRESUMEN
Isolated rat liver cells were shown to metabolize the aromatic amine benzidine to reactive products which are mutagenic to Salmonella typhimurium TA 1538 and which give rise to DNA excision repair within the liver cells. Intact rat liver cells are shown to be more active in the formation of mutagenic metabolites than the 9000-g supernatant from these cells. Data are presented which are in favour of the role of N-acetylation in this respect. Furthermore, indications are presented that a sulfation reaction is involved in the generation of DNA modifying metabolites, whereas formation of mutagenic products is likely to proceed via deacetylation and/or N,O-acyltransfer. Finally, data are given about the extrahepatocellular appearance of premutagenic metabolites which are more prone to metabolic activation by additional metabolic factors in the Salmonella assay than benzidine itself. The impact of these observations on the estimation of the genotoxic potential of benzidine will be discussed.
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Bencidinas/metabolismo , Hígado/metabolismo , Acetilación , Animales , Bencidinas/toxicidad , Biotransformación , Reparación del ADN/efectos de los fármacos , Técnicas In Vitro , Masculino , Mutágenos , Ratas , Ratas EndogámicasRESUMEN
The involvement of sequential side-chain oxidation, sulphation and glutathione conjugation in the formation of mercapturic acids from toluene and xylenes was investigated. It was found that not only aralkanes but also aralkyl alcohols were excreted as mercapturic acids in the rat. The extent of mercapturic acid excretion varied over a more than 20-fold range. Inhibition of ADH caused an increase and inhibition of sulphotransferase a decrease in the urinary excretion of thio compounds after administration of toluene, benzyl alcohol, o-xylene and o-methylbenzyl alcohol to rats. The position of the methyl groups attached to the aromatic nucleus affects the metabolism of aromatic hydrocarbons considerably. Factors that are involved in the high yield of mercapturic acids after administration of o-xylene as compared to m- and p-xylene, include the relatively low apparent affinity of o-methylbenzyl alcohol for cytosolic ADH, the relatively high apparent affinity of o-methylbenzyl alcohol for cytosolic sulphotransferase, and the high electrophilic reactivity of the o-methylbenzyl sulphate.
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Acetilcisteína/metabolismo , Alcoholes/metabolismo , Sulfatos/metabolismo , Tolueno/metabolismo , Xilenos/metabolismo , Alcohol Deshidrogenasa , Oxidorreductasas de Alcohol/análisis , Animales , Creatinina/orina , Citosol/metabolismo , Glutatión/metabolismo , Hígado/metabolismo , Masculino , Ratas , Ratas EndogámicasRESUMEN
Thioether concentrations were determined in urine samples obtained from ten workers in the despatch department (n = 69), three chemical waste incinerator operators (n = 67), and an analyst (n = 21), all working in the same chemical plant. Urine samples (n = 196) obtained from non-exposed men, including smokers, served as controls. Enhanced excretion of thioethers was found in urine samples taken from incinerator workers at the end of work. A regular pattern in the time course of the urinary thioether excretion was shown by a non-smoking incinerator worker; end-of-work values were always higher than prework values. This phenomenon was not found in samples obtained from the analyst. These findings suggest that incinerator workers inhale or otherwise absorb electrophilic compounds or their precursors, which are subsequently metabolised to, and excreted as, thioethers in urine.
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Industria Química , Medicina del Trabajo , Sulfuros/orina , Ritmo Circadiano , Creatinina/orina , Exposición a Riesgos Ambientales , Humanos , Eliminación de Residuos , FumarRESUMEN
The aromatic amine 2-aminofluorene (2-AF) is metabolised by isolated rat liver cells to reactive species, thereby causing mutagenic effects in Salmonella typhimurium TA 1538 and evoking DNA-excision repair within the liver cells. The pathway leading to the production of metabolites mutagenic in Salmonella is likely to proceed via direct N-hydroxylation of 2-AF to N-hydroxy-2-aminofluorene (N-OH-2-AF). On the other hand, the formation of intermediates giving rise to hepatocellular DNA-repair is shown to depend upon N-acetylation of 2-AF to 2-acetylaminofluorene(2-AAF), whereas a subsequent conjugation reaction, most likely to be sulfate ester formation, is also essentially involved.
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Reparación del ADN/efectos de los fármacos , Fluorenos/metabolismo , Hígado/metabolismo , Mutágenos , 2-Acetilaminofluoreno/metabolismo , Animales , Biotransformación , Interacciones Farmacológicas , Fluorenos/toxicidad , Hígado/citología , Hígado/efectos de los fármacos , Ratas , Salmonella typhimurium/genéticaRESUMEN
Urinary metabolites of rats treated with benzidine and some other genotoxic aromatic amines became mutagenic in the Ames assay after activation with liver cytosol from rat, mouse and guinea pig. Most of the mutagenic metabolites appeared in urine as glucuronides. Strong evidence was found that N,O-acyltransferase is responsible for the mutagenic activation by rat liver cytosol. The inhibitory effect of paraoxon and sodium fluoride indicates that the activation by mouse liver cytosol is due to the action of deacetylase. Mutagenic activation by guinea pig liver cytosol seemed to be mediated in part by deacetylase. The metabolite activated by these enzymes most likely is a glucuronidated, N-acetylated, N-hydroxylated product.
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Aminas/orina , Bencidinas/orina , Mutágenos , Aminas/farmacología , Animales , Bencidinas/metabolismo , Bencidinas/farmacología , Biotransformación , Citosol/metabolismo , Cobayas , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Pruebas de Mutagenicidad , Mutágenos/metabolismo , Paraoxon/farmacología , Ratas , Ratas Endogámicas , Salmonella typhimurium/efectos de los fármacosAsunto(s)
Reparación del ADN/efectos de los fármacos , Salicilamidas/farmacología , Animales , Benzo(a)Antracenos/metabolismo , Benzo(a)Antracenos/farmacología , Biotransformación , Carcinógenos , ADN/genética , Depresión Química , Evaluación Preclínica de Medicamentos , Técnicas Genéticas , Hígado/metabolismo , Masculino , RatasRESUMEN
Isolated rat liver cells are able to metabolize 2-acetylaminofluorene (2-AAF) to reactive species, capable of producing mutagenic effects in Salmonella typhimurium TA 1518 and evoking unscheduled DNA synthesis within the hepatocytes. Indications are presented, that these genotoxic effects are caused by different reactive metabolites. Mutagenesis could be blocked almost completely by paraoxon, an inhibitor of the de-acetylation reaction, whereas induction of DNA excision repair was prevented by antagonizing the sulfation reaction by means of salicylamide.
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2-Acetilaminofluoreno/metabolismo , Bacterias/genética , Reparación del ADN/efectos de los fármacos , Hígado/metabolismo , 2-Acetilaminofluoreno/toxicidad , Animales , Biotransformación , Masculino , Mutágenos , Paraoxon/farmacología , Ratas , Salicilamidas/metabolismo , Salmonella typhimurium/genética , Timidina/metabolismoRESUMEN
Administration of toluene and xylenes to rats caused a decrease in liver glutathione concentration. The effect was most pronounced after the administration of o-xylene. 26% of the initial glutathione level was found three hours after treatment with o-xylene (4.0 mmoles/kg). No in vitro conjugation of o-xylene with glutathione was observed, neither spontaneously nor in the presence of 105,000 g supernatant from rat liver homogenate, containing glutathione S-transferases. Thus, a metabolite of o-xylene, which is not formed during incubation with 105,000 g supernatant, reacts with glutathione. A thioether was isolated from urine of rats given o-xylene; the compound was identified as o-methylbenzyl mercapturic acid by GC-MS and NMR. Chromatographic evidence was found for the presence of benzyl mercapturic acid in the urine of toluene-treated rats. The amounts of mercapturic acids excreted in the urine after administration of toluene, p-xylene, m-xylene, and o-xylene were 0.4-0.7,0.6,1.3, and 10-21% of the dose, respectively. These results demonstrate the involvement of a thusfar unknown pathway in the biotransformation of toluene and xylenes.
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Acetilcisteína/orina , Glutatión/metabolismo , Hígado/metabolismo , Tolueno/toxicidad , Xilenos/toxicidad , Animales , Biotransformación , Glutatión/orina , Inactivación Metabólica , Masculino , Ratas , Sulfuros/orina , Tolueno/orina , Xilenos/orinaRESUMEN
The mutagenicity of urine from rats treated with benzidine or 5 other arylamines (0.25 mmol/kg; i.p.) was studied using the Ames-assay. It was found that samples of urine collected for 24 h after the administration of the carcinogens, benzidine, 4-aminobiphenyl and 2-aminonaphthalene, showed significantly mutagenic activity, whereas no mutagenicity was observed in urine after treatment with 3,3'-5,5'-tetramethylbenzidine, 2-aminobiphenyl and 1-aminonaphthalene. Mutagenic activities were dependent on the use of either hepatic S-9 Mix or cytosol as the activating enzyme preparation. The addition of beta-glucuronidase enhanced mutagenicity, except for 2-aminonaphthalene. The appearance of mutagens in urine was studied at varying doses of benzidine and at different time-intervals after the administration. The different excretion patterns found after the activation either with S-9 Mix or with cytosolic enzyme(s) suggest the presence in urine of different types of mutagenic products.
Asunto(s)
Aminas/metabolismo , Bencidinas/metabolismo , Mutágenos/orina , Animales , Citosol/metabolismo , Hígado/metabolismo , Masculino , Pruebas de Mutagenicidad , NADP/metabolismo , Ratas , Factores de TiempoRESUMEN
In vitro cultured bovine liver cells were labelled with radioactive thymidine and dissolved in 0.5% sodium dodecyl sulphate. Centrifugation of the lysate through sucrose gradients in a zonal rotor revealed a slowly sedimenting fraction of preferentially pulse labelled DNA. The DNA of this zone was further analysed by chromatography on hydroxy-apatite, banding in CsCl density gradients, and sedimentation in neutral and alkaline sucrose gradients. It contained besides small amounts of fragmented bulk DNA, single-stranded nascent DNA and single-stranded pre-labelled DNA which could be separated from each other by using BrdU as a density label. The density labelling also revealed small amounts of nascent-nascent DNA duplexes. The slowly sedimenting fraction was practically absent from cell lysates which were prepared in 2 M NaCl - 50 microgram/ml pronase. The results suggest that nascent single-strands and nascent-nascent duplexes are released from the forks of replicating DNA by branch migration. Pre-labelled single strands may be released by the same branch migration. Pre-labelled single strands may be released by the same mechanism, but the in vivo structure from which they originate has yet to be elucidated.