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The aim of this study was to determine accumulation of heavy metals and metalloids which are widely distributed in the environment and in food chain using wild edible mushrooms belonging to the Boletaceae family mushrooms. In addition, methanol extracts of mushrooms were tested for in vitro protective effect by the cytochalasin-B blocked micronucleus (CBMN) assay using chromosome aberrations in human peripheral lymphocytes as a model. The genotoxic activity of methanol extracts prepared at 4 different concentrations (1, 2, 3 or 6 µg/ml) was examined using amifostine and mitomycin C as positive controls. Extracts of species B. regius and B. edulis exhibited the greatest reduction in the frequency of micronuclei (MN). Extract of B. regius at concentrations of 2 µg/ml showed the highest decrease in number of MN. In comparison, extract of mushroom B. edulis at a concentration of 3 µg/ml displayed less reduction. However, as heavy metals and metalloids are found in mushrooms, another aim was to examine whether these agents affected genotoxicity. Principal component analysis (PCA) identified clustering differences between control and heavy metals and metalloids groups and might explain the influence of heavy element content and genotoxic activity in mushrooms.
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Agaricales , Arsênio , Basidiomycota , Mercúrio , Metaloides , Metais Pesados , Humanos , Cádmio/toxicidade , Mercúrio/análise , Sérvia , Metanol , Chumbo/toxicidade , Chumbo/análise , Metais Pesados/toxicidade , Metais Pesados/análise , Metaloides/análise , Dano ao DNARESUMO
In October 2017, most European countries reported unique atmospheric detections of aerosol-bound radioruthenium (106Ru). The range of concentrations varied from some tenths of µBq·m-3 to more than 150 mBq·m-3 The widespread detection at such considerable (yet innocuous) levels suggested a considerable release. To compare activity reports of airborne 106Ru with different sampling periods, concentrations were reconstructed based on the most probable plume presence duration at each location. Based on airborne concentration spreading and chemical considerations, it is possible to assume that the release occurred in the Southern Urals region (Russian Federation). The 106Ru age was estimated to be about 2 years. It exhibited highly soluble and less soluble fractions in aqueous media, high radiopurity (lack of concomitant radionuclides), and volatility between 700 and 1,000 °C, thus suggesting a release at an advanced stage in the reprocessing of nuclear fuel. The amount and isotopic characteristics of the radioruthenium release may indicate a context with the production of a large 144Ce source for a neutrino experiment.
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Traces of particulate radioactive iodine (131I) were detected in the European atmosphere in January/February 2017. Concentrations of this nuclear fission product were very low, ranging 0.1 to 10 µBq m-3 except at one location in western Russia where they reached up to several mBq m-3. Detections have been reported continuously over an 8-week period by about 30 monitoring stations. We examine possible emission source apportionments and rank them considering their expected contribution in terms of orders of magnitude from typical routine releases: radiopharmaceutical production units > sewage sludge incinerators > nuclear power plants > spontaneous fission of uranium in soil. Inverse modeling simulations indicate that the widespread detections of 131I resulted from the combination of multiple source releases. Among them, those from radiopharmaceutical production units remain the most likely. One of them is located in Western Russia and its estimated source term complies with authorized limits. Other existing sources related to 131I use (medical purposes or sewage sludge incineration) can explain detections on a rather local scale. As an enhancing factor, the prevailing wintertime meteorological situations marked by strong temperature inversions led to poor dispersion conditions that resulted in higher concentrations exceeding usual detection limits in use within the informal Ring of Five (Ro5) monitoring network.
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Poluentes Radioativos do Ar , Neoplasias da Glândula Tireoide , Europa (Continente) , Humanos , Radioisótopos do Iodo , Federação RussaRESUMO
Rabies virus replicates in the cytoplasm of host cells, but rabies virus phosphoprotein (P-protein) undergoes active nucleocytoplasmic trafficking. Here we show that the largely nuclear P-protein isoform P3 can localize to nucleoli and forms specific interactions with nucleolin. Importantly, depletion of nucleolin expression inhibits viral protein expression and infectious virus production by infected cells. This provides the first evidence that lyssaviruses interact with nucleolin and that nucleolin is important to lyssavirus infection.
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Interações Hospedeiro-Patógeno , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Vírus da Raiva/fisiologia , Proteínas Estruturais Virais/metabolismo , Linhagem Celular , Humanos , Chaperonas Moleculares , Mapeamento de Interação de Proteínas , NucleolinaRESUMO
The determination of radionuclide activity concentration requires a prior knowledge of the full-energy peak (FEP) efficiency at all photon energies for a given measuring geometry. This problem has been partially solved by using procedures based on Monte Carlo simulations, developed in order to complement the experimental calibration procedures used in gamma-ray measurements of environmental samples. The aim of this article is to apply GEANT4 simulation for calibration of two HPGe detectors, for measurement of liquid and soil-like samples in cylindrical geometry. The efficiencies obtained using a simulation were compared with experimental results, and applied to a realistic measurement. Measurement uncertainties for both simulation and experimental values were estimated in order to see whether the results of the realistic measurement fall within acceptable limits. The trueness of the result was checked using the known activity of the measured samples provided by IAEA.
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Calibragem/normas , Modelos Estatísticos , Monitoramento de Radiação/instrumentação , Monitoramento de Radiação/normas , Manejo de Espécimes/normas , Espectrometria gama/instrumentação , Espectrometria gama/normas , Algoritmos , Simulação por Computador , Desenho de Equipamento , Análise de Falha de Equipamento , Raios gama , Internacionalidade , Método de Monte Carlo , Doses de Radiação , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sérvia , SoftwareRESUMO
L-arginine is conditionally essetcial amino acid, required for normal cell growth, protein synthesis, ammonia detoxification, tissue growth and general performance, proposed in the treatment of men sterility and prevention of male impotence. The aim of the present paper was to estimate the activity of the enzymes of adenine nucleotide metabolism: 5'-nucleotidase (5'-NU), adenosine deaminase (ADA), AMP deaminase, and xanthine oxidase (XO), during dietary intake of L-arginine for a period of four weeks of male Wistar rats. Adenosine concentration in tissues is maintained by the relative activities of the adenosine-producing enzyme, 5'-NU and the adenosine-degrading enzyme-ADA adenosine deaminase. Dietary L-arginine intake directed adenine nucleotide metabolism in liver, kidney, and testis tissue toward the activation of adenosine production, by increased 5'-NU activity and decreased ADA activity. Stimulation of adenosine accumulation could be of importance in mediating arginine antiatherosclerotic, vasoactive, immunomodulatory, and antioxidant effects. Assuming that the XO activity reflects the rate of purine catabolism in the cell, while the activity of AMP deaminase is of importance in ATP regeneration, reduced activity of XO, together with the increased AMP-deaminase activity, may suggest that adenine nucleotides are presumably directed to the ATP regenerating process during dietary L-arginine intake.
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Nucleotídeos de Adenina/metabolismo , Arginina/metabolismo , 5'-Nucleotidase/metabolismo , AMP Desaminase/metabolismo , Adenosina Desaminase/metabolismo , Animais , Rim/metabolismo , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar , Testículo/metabolismo , Xantina Oxidase/metabolismoRESUMO
Radioactive emissions into the atmosphere from the damaged reactors of the Fukushima Dai-ichi nuclear power plant (NPP) started on March 12th, 2011. Among the various radionuclides released, iodine-131 ((131)I) and cesium isotopes ((137)Cs and (134)Cs) were transported across the Pacific toward the North American continent and reached Europe despite dispersion and washout along the route of the contaminated air masses. In Europe, the first signs of the releases were detected 7 days later while the first peak of activity level was observed between March 28th and March 30th. Time variations over a 20-day period and spatial variations across more than 150 sampling locations in Europe made it possible to characterize the contaminated air masses. After the Chernobyl accident, only a few measurements of the gaseous (131)I fraction were conducted compared to the number of measurements for the particulate fraction. Several studies had already pointed out the importance of the gaseous (131)I and the large underestimation of the total (131)I airborne activity level, and subsequent calculations of inhalation dose, if neglected. The measurements made across Europe following the releases from the Fukushima NPP reactors have provided a significant amount of new data on the ratio of the gaseous (131)I fraction to total (131)I, both on a spatial scale and its temporal variation. It can be pointed out that during the Fukushima event, the (134)Cs to (137)Cs ratio proved to be different from that observed after the Chernobyl accident. The data set provided in this paper is the most comprehensive survey of the main relevant airborne radionuclides from the Fukushima reactors, measured across Europe. A rough estimate of the total (131)I inventory that has passed over Europe during this period was <1% of the released amount. According to the measurements, airborne activity levels remain of no concern for public health in Europe.
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Poluentes Radioativos do Ar/análise , Radioisótopos de Césio/análise , Radioisótopos do Iodo/análise , Liberação Nociva de Radioativos , Europa (Continente) , Japão , Centrais Nucleares , Monitoramento de RadiaçãoAssuntos
Anafilaxia/imunologia , Imunoglobulina E/imunologia , Musa/imunologia , Adulto , Feminino , HumanosRESUMO
Glucocorticoid hormones (GC) are essential in all aspects of human health and disease. Their anti-inflammatory and immunosuppressive properties are reasons for therapeutic application in several diseases. GC suppress immune activation and uncontrolled overproduction and release of cytokines. GC inhibit the release of pro-inflammatory cytokines and stimulate the production of anti-inflammatory cytokines. Investigation of GC's mechanism of action, suggested that polyamines (PA) may act as mediators or messengers of their effects. Beside glucocorticoids, spermine (Spm) is one of endogenous inhibitors of cytokine production. There are many similarities in the metabolic actions of GC and PA. The major mechanism of GC effects involves the regulation of gene expression. PA are essential for maintaining higher order organization of chromatin in vivo. Spermidine and Spm stabilize chromatin and nuclear enzymes, due to their ability to form complexes with negatively charged groups on DNA, RNA and proteins. Also, there is an increasing body of evidence that GC and PA change the chromatin structure especially through acetylation and deacetylation of histones. GC display potent immunomodulatory activities, including the ability to induce T and B lymphocyte apoptosis, mediated via production of reactive oxygen species (ROS) in the mitochondrial pathway. The by-products of PA catabolic pathways (hydrogen peroxide, amino aldehydes, acrolein) produce ROS, well-known cytotoxic agents involved in programmed cell death (PCD) or apoptosis. This review is an attempt in the better understanding of relation between GC and PA, naturally occurring compounds of all eukaryotic cells, anti-inflammatory and apoptotic agents in physiological and pathological conditions connected to oxidative stress or PCD.
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Apoptose , Glucocorticoides/metabolismo , Inflamação/metabolismo , Poliaminas/metabolismo , Animais , Glucocorticoides/imunologia , Humanos , Estresse Oxidativo , Poliaminas/imunologiaRESUMO
The extent of hantavirus seroprevalence in the healthy population from Bosnia and Herzegovina has not yet been investigated; therefore, the aim of this study was to assess the hantavirus seroprevalence in the population from different regions of Bosnia and Herzegovina and in different risk groups. The serosurvey included 1331 subjects from endemic and non-endemic regions in Bosnia and Herzegovina. All sera samples were examined using IgG ELISA, and Western blot (Bunyavirus IgG) tests. Hantavirus seroprevalence was 7.4% in the endemic region and 2.4% in the non-endemic region (P<0.05). Former soldiers from the endemic region had significantly the highest seroprevalence (16.1%) compared to the general population from the endemic region (6.2%), the occupational risk group from the non-endemic region (5.6%) and the general population from the non-endemic region (0.8%) (P<0.01). No difference in hantavirus seroprevalence between gender or age groups was observed. Hantavirus seroprevalence in different populations in Bosnia and Herzegovina was found to be highest compared to other central European countries.
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Doenças Endêmicas , Infecções por Hantavirus/epidemiologia , Orthohantavírus/isolamento & purificação , Adolescente , Adulto , Fatores Etários , Idoso , Anticorpos Antivirais/análise , Bósnia e Herzegóvina/epidemiologia , Distribuição de Qui-Quadrado , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Militares , Exposição Ocupacional , Fatores de Risco , Estudos SoroepidemiológicosAssuntos
Antraz/diagnóstico , Bacillus anthracis/isolamento & purificação , Dermatopatias Bacterianas/diagnóstico , Adulto , Animais , Antraz/microbiologia , Antraz/transmissão , Bósnia e Herzegóvina , Bovinos/microbiologia , Doenças Transmitidas por Alimentos/microbiologia , Humanos , Masculino , População Rural , Dermatopatias Bacterianas/microbiologia , Dermatopatias Bacterianas/transmissão , Resultado do TratamentoRESUMO
An internal consistency test of the calculation of coincidence-summing correction factors FC for volume sources is presented. The test is based on exact equations relating the values of FC calculated for three ideal measurement configurations. The test is applied to a number of 33 sets of FC values sent by 21 teams. Most sets passed the test, but not the results obtained using the quasi-point source approximation; in the latter case the test qualitatively indicated the magnitude of the bias of FC.
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The probabilities of locating peaks with a high relative peak-area uncertainty were determined empirically with nine types of peak-location software used in laboratories engaged in gamma-ray spectrometry measurements. It was found that it is not possible to locate peaks with a probability of 0.95, when they have a relative peak-area uncertainty in excess of 50%. Locating peaks at these relatively high peak-area uncertainties with a probability greater than 0.95 is only possible in the library-driven mode, where the peak positions are supposed a-priori. The deficiencies of the library-driven mode and the possibilities to improve the probabilities of locating peaks are briefly discussed.
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Under physiological conditions insulin controls the metabolism of carbohydrates, lipids and proteins. Diabetes mellitus is a metabolic disease characterized by a disturbance in the intermediary metabolism of glucose and glucose-induced insulin release. Arginase (L-arginine amidinohydrolase, EC 3.5.3.1) modulates nitric oxide synthase activity by regulating intracellular L-arginine availability. In diabetes mellitus, a decrease in nitric oxide bioavailability is a central mechanism for endothelial dysfunction. The aim of our study was to assess arginase activity in the blood of children with diabetes mellitus. Blood arginase activity, serum glucose (14.155 +/- 4.197 mmol/L; p < .001) and blood HbA1c (11.222 +/- 3.186 %; p < .001), were significantly higher in diabetic children than in healthy controls, whereas the magnesium (Mg2+) level, a cofactor of many enzymes, was significantly lower (0.681 +/- 0.104 micromol; p < .001). In diabetic children, arginase activity, hyperglycemia (r = 0.143), and the HbA1, level (r = 0.381) showed a positive correlation between but a negative correlation between Mg2+ and arginase activity (r= -0.206). The higher arginase activity and the lower Mg2+' levels in diabetic children could be a consequence of reduced insulin action and increased protein catabolic processes in these pathophysiological conditions. The inverse directions of arginase activity and serum Mg2+ levels are in agreement with this concept.
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Arginase/sangue , Diabetes Mellitus/metabolismo , Magnésio/sangue , Adolescente , Criança , Pré-Escolar , Células Endoteliais/fisiologia , Feminino , Hemoglobinas Glicadas/análise , Humanos , Masculino , Óxido Nítrico/fisiologiaRESUMO
Our study was undertaken to elucidate the effects of selenomethionine (SeMet) on polyamine metabolism in regenerating rat liver tissue, as useful model of rapidly growing normal tissue. We have examined the levels of spermine, spermidine and putrescine in liver tissue. At the same time we have evaluated the activities of polyamine oxidase (PAO) and diamine oxidase (DAO), the catabolic enzymes of polyamine metabolism. The obtained results suggest that polyamine levels in regenerating liver tissue, at 7(th) day after two-thirds partial hepatectomy, were higher in comparison with control group. The administration of selenomethionine to hepatectomized animals during seven days, in a single daily dose of 2.5 microg/100 g body weight, increases the amount of spermine and spermidine; the level of putrescine does not change under the influence of SeMet in regenerating rat liver tissue.PAO activity is lower in regenerating hepatic tissue than in control group. Supplementation of hepatectomized animals with SeMet significantly decreases the activity of this enzyme. DAO activity was significantly higher in hepatectomized and in operated animals treated with SeMet compared to the sham-operated and control ones. The differential sensitivity observed in our model of highly proliferating normal tissue to SeMet, compared with the reported anticancer activity of this molecule is discussed.
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Fígado , Poliaminas/metabolismo , Regeneração , Selenometionina/metabolismo , Amina Oxidase (contendo Cobre)/metabolismo , Animais , Hepatectomia , Humanos , Fígado/enzimologia , Fígado/patologia , Fígado/fisiologia , Masculino , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Ratos , Ratos Wistar , Poliamina OxidaseRESUMO
Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). Using site-specific cross-linking, RNA gel shift, and DCS RNA affinity chromatography assays, we characterized the binding of several proteins to specific sites along the DCS RNA. Heterogeneous nuclear ribonucleoprotein (hnRNP) H, polypyrimidine tract binding protein (PTB), and KH-type splicing-regulatory protein (KSRP) each bind to distinct elements within this sequence. We also identified a new 60-kDa tissue-specific protein that binds to the CUCUCU splicing repressor element of the DCS RNA. This protein was purified, partially sequenced, and cloned. The new protein (neurally enriched homolog of PTB [nPTB]) is highly homologous to PTB. Unlike PTB, nPTB is enriched in the brain and in some neural cell lines. Although similar in sequence, nPTB and PTB show significant differences in their properties. nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA. These experiments identify specific cooperative interactions between the proteins that assemble onto an intricate splicing-regulatory sequence and show how this hnRNP assembly is altered in different cell types by incorporating different but highly related proteins.
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Proteínas do Tecido Nervoso/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ribonucleoproteínas/metabolismo , Transativadores , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular , Cromatografia de Afinidade , Clonagem Molecular , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H , Ribonucleoproteínas Nucleares Heterogêneas , Humanos , Modelos Genéticos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/isolamento & purificação , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteínas Nucleares/isolamento & purificação , Proteínas Nucleares/metabolismo , Especificidade de Órgãos , Filogenia , Proteína de Ligação a Regiões Ricas em Polipirimidinas , Ligação Proteica , Splicing de RNA/genética , RNA Nuclear Heterogêneo/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/isolamento & purificação , Sequências Reguladoras de Ácido Nucleico , Ribonucleoproteínas/química , Ribonucleoproteínas/genética , Ribonucleoproteínas/isolamento & purificação , Homologia de Sequência de AminoácidosRESUMO
In this paper the impact of the Solar magnetic field on 7Be activity concentration in aerosols was investigated. The changes in the 7Be activity in aerosols in the period from the second part of 22nd to the second part of 24th Solar cycle were mathematically processed using the Fourier analysis and the 22 years period was pointed out. It corresponds to the most intense period of the Solar polar field strength for the same observed period. The Pearson's linear coefficient between the average annual value of 7Be activity in aerosols and the Solar polar field strength was 0.58.
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Glucocorticoids are potent anti-inflammatory and immunosuppressive agents. As endogenous inhibitors of cytokine synthesis, glucocorticoids suppress immune activation and uncontrolled overproduction of cytokines, preventing tissue injury. Also, polyamine spermine is endogenous inhibitor of cytokine production (inhibiting IL-1, IL-6 and TNF synthesis). The idea of our work was to examine dexamethasone effects on the metabolism of polyamines, spermine, spermidine and putrescine and polyamine oxidase activity in liver and spleen during sensitization of guinea pigs. Sensitization was done by application of bovine serum albumin with addition of complete Freund's adjuvant. Our results indicate that polyamine amounts and polyamine oxidase activity increase during immunogenesis in liver and spleen. Dexamethasone application to sensitized and unsensitized guinea pigs causes depletion of polyamines in liver and spleen. Dexamethasone decreases polyamine oxidase activity in liver and spleen of sensitized guinea pigs, increasing at the same time PAO activity in tissues of unsensitized animals.
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Dexametasona/farmacologia , Glucocorticoides/farmacologia , Imunização , Fígado/metabolismo , Poliaminas/metabolismo , Baço/metabolismo , Animais , Citocinas/imunologia , Citocinas/metabolismo , Dexametasona/metabolismo , Adjuvante de Freund , Glucocorticoides/metabolismo , Cobaias , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/imunologia , Masculino , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/imunologia , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Poliaminas/antagonistas & inibidores , Putrescina/metabolismo , Soroalbumina Bovina/imunologia , Espermidina/metabolismo , Espermina/metabolismo , Baço/efeitos dos fármacos , Baço/enzimologia , Baço/imunologia , Poliamina OxidaseRESUMO
Air sample monitoring in Serbia, Belgrade started in the 1960s, while (7)Be activity in air and total (dry and wet) deposition has been monitored for the last 22 years by the Environment and Radiation Protection Department of the Institute for Nuclear Sciences, Vinca. Using this data collection, the changes of the (7)Be activity in the air and the total (wet and dry) deposition samples, as well as their correlation with meteorological parameters (temperature, pressure, cloudiness, sunshine duration, precipitation and humidity) that affect (7)Be concentration in the atmosphere, were mathematically described using the Fourier analysis. Fourier analysis confirmed the expected; the frequency with the largest intensity in the harmonic spectra of the (7)Be activity corresponds to a period of 1 year, the same as the largest intensity frequency in Fourier series of meteorological parameters. To analyze the quality of the results produced by the Fourier analysis, we compared the measured values of the parameters with the values calculated according to the Fourier series. Absolute deviations between measured and predicted mean monthly values are in range from 0.02 mBq/m(3) to 0.7 mBq/m(3) for (7)Be activity in air, and 0.01 Bq/m(2) and 0.6 Bq/m(2) for (7)Be activity in deposition samples. Relatively good agreement of measured and predicted results offers the possibility of prediction of the (7)Be activity.
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Poluentes Radioativos do Ar/análise , Atmosfera/química , Berílio/análise , Análise de Fourier , Meteorologia , Monitoramento de Radiação/métodos , Umidade , SérviaRESUMO
Epidemiological studies support the hypothesis that genetic factors modulate the risk for diabetic nephropathy (DN). Aldose reductase (ALDR1), the rate-limiting enzyme in the polyol pathway, is a potential candidate gene. The present study explores the hypothesis that polymorphisms of the (A-C)n dinucleotide repeat sequence, located 2.1 kb upstream of the transcription start site, modulate ALDR1 gene expression and the risk for DN. We conducted studies at two different institutions, the University of New Mexico Health Sciences Center (UNMHSC), and the Istituto Scientifico H San Raffaele (HSR). There were four groups of volunteers at UNMHSC: group I, normal subjects; group II, patients with insulin-dependent diabetes mellitus (IDDM) without DN; group III, IDDM with DN; and group IV, nondiabetics with kidney disease. At HSR we studied volunteers in groups I, II, and III. ALDR1 genotype was assessed by PCR and fluorescent sequencing of the (A-C)n repeat locus, and ALDR1 messenger ribonucleic acid (mRNA) was measured by ribonuclease protection assay in peripheral blood mononuclear cells. At UNMHSC we identified 10 alleles ranging from Z-10 to Z+8. The prevalence of the Z-2 allele among IDDM patients was increased in those with DN. Sixty percent of group III and 22% of group II were homozygous for Z-2. Moreover, 90% and 67% of groups III and II, respectively, had 1 or more copy of Z-2. In contrast, among nondiabetics, 19% of group IV and 3% of group I were homozygous for Z-2, and 69% and 32%, respectively, had 1 copy or more of Z-2. Among diabetics, homozygosity for the Z-2 allele was associated with renal disease [odds ratio (OR), 5.25; 95% confidence interval, 1.71-17.98; P = 0.005]. ALDR1 mRNA levels were higher in patients with DN (group III; 0.113 +/- 0.050) than in group I (0.068 +/- 0.025), group II (0.042 +/- 0.020), or group IV (0.015 +/- 0.011; P < 0.01). Among diabetics, ALDR1 mRNA levels were higher in Z-2 homozygotes (0.098 +/- 0.06) and Z-2 heterozygotes (0.080 +/- 0.04) than in patients with no Z-2 allele (0.043 +/- 0.02; P < 0.05). In contrast, among nondiabetics, ALDR1 mRNA levels in Z-2 homozygotes (0.034 +/- 0.04) and Z-2 heterozygotes (0.038 +/- 0.03) were similar to levels in patients without a Z-2 allele (0.047 +/- 0.03; P = NS). At HSR we identified eight alleles ranging from Z- 12 to Z+2. The prevalence of the Z-2 allele was higher in group III than in group II. In group III, 43% of the patients were homozygous for Z-2, and 81% had one copy or more of the Z-2 allele. In contrast, in group II, 4% were homozygous for Z-2, and 36% had one copy or more of the Z-2 allele. IDDM patients homozygous for Z-2 had an increased risk for DN compared with those lacking the Z-2 allele (OR, 18; 95% confidence interval, 2-159). IDDM patients who had one copy or more of Z-2 had increased risk (OR, 7.5; 95% confidence interval, 1.9-29.4) for DN compared with those without the Z-2 allele. These results support our hypothesis that environmental-genetic interactions modulate the risk for DN. Specifically, the Z 2 allele, in the presence of diabetes and/or hyperglycemia, is associated with increased ALDR1 expression. This interaction may explain the observed association between the Z-2 allele and DN.