RESUMO
A high proviral load (PVL) is recognized as a risk factor for human T cell leukemia virus-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), but there is a lack of prospective studies evaluating whether or not HTLV-1 carriers with high PVL are at risk of developing HAM/TSP or other HTLV-1-related diseases. Here, we compare the incidence of clinical manifestations and the cytokine levels in 30 HTLV-1 carriers with high (> 50,000 copies/106 PBMC) and an equal number of subjects with low proviral load. Participants were followed for 3 to 16 years (median of 11 years). The PVL, IFN-γ, TNF, and IL-10 levels were quantified at entry and at the end of the follow-up. Among the self-reported symptoms in the initial evaluation, only the presence of paresthesia on the hands was more frequent in the group with high PVL (p < 0.04). The production of IFN-γ was higher in the group with high PVL group (median of 1308 versus 686 pg/ml, p < 0.011) when compared with the control group in the first assessment. There was no difference in the occurrence of urinary symptoms or erectile dysfunction, periodontal disease, Sicca syndrome, and neurologic signs between the two groups during the follow-up. The observation that none of the HTLV-1 carriers with high PVL and with exaggerated inflammatory response progressed to HAM/TSP indicates that other factors in addition to the PVL and an exaggerated immune response are involved in the pathogenesis of HAM/TSP.
Assuntos
Portador Sadio/imunologia , Infecções por HTLV-I/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Leucócitos Mononucleares/imunologia , Provírus/imunologia , Adulto , Idoso , Portador Sadio/diagnóstico , Portador Sadio/virologia , Disfunção Erétil/diagnóstico , Disfunção Erétil/genética , Disfunção Erétil/imunologia , Disfunção Erétil/virologia , Feminino , Expressão Gênica , Infecções por HTLV-I/diagnóstico , Infecções por HTLV-I/genética , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/crescimento & desenvolvimento , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Leucócitos Mononucleares/virologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Noctúria/diagnóstico , Noctúria/genética , Noctúria/imunologia , Noctúria/virologia , Provírus/crescimento & desenvolvimento , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/virologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Carga Viral/imunologiaRESUMO
Arginase 1 (ARG1) and arginase 2 (ARG2) compete with nitric oxide synthases for the substrate l-arginine. Here we aim to assess whether arginase 1 and 2 plasma levels, plasma arginase activity or genetic factors are associated with altered responsiveness to sildenafil. We studied 71 post-prostatectomy erectile dysfunction (ED) patients (PED group) and 72 clinical ED patients (CED). Patients responded to the International Index of Erectile Function questionnaire before and after the treatment. We found positive and negative correlations between plasma levels of arginase 1 and sildenafil responsiveness in the PED and CED groups, respectively. PED group also presented negative correlation between plasma arginase activity and sildenafil responsiveness. Sildenafil poor responders have shown higher plasma arginase activity in PED and higher arginase 1 levels on CED groups. In addition, variant genotypes for the rs2781659, rs2781667 and rs17599586 polymorphisms were associated with reduced arginase activity, as well as the GTTT ARG1 haplotype in CED group.
Assuntos
Arginase/sangue , Arginase/genética , Disfunção Erétil/sangue , Disfunção Erétil/genética , Citrato de Sildenafila/sangue , Vasodilatadores/sangue , Adulto , Idoso , Arginase/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Disfunção Erétil/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico , Resultado do Tratamento , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêuticoRESUMO
Arginase 1 and Arginase 2 are homologous enzymes that convert l-Arginine to Urea and l-ornithine and compete with nitric oxide synthases for l-Arginine. Increased Arginase 1 and 2 activity may reduce nitric oxide production by the endothelium in disease states, including erectile dysfunction (ED). Here we aimed at assessing whether Arginase 1 and 2 plasma levels, plasma arginase activity, or genetic factors are associated with ED risk and severity. Blood samples were collected from healthy controls (n = 106) and from patients with ED (n = 110) after completion of the IIEF questionnaire (international index of erectile function). Plasma Arginase 1 and 2 concentrations were assessed by ELISA, while plasma arginase activity was measured by spectrophotometry. Genotypes of ARG1 (rs2781659, rs2781667, rs2246012 and rs17599586) and ARG2 (rs3742879 and rs10483801) were determined by Taqman genotyping assays by real-time polymerase chain reaction. Increased Arginase 2 concentrations were found in clinical ED and are associated with increased risk for ED. ARG1 rs2781659 AA and rs2781667 TT genotypes are associated with lower IIEF scores (higher severity) only in clinical ED. Similarly, the ARG1 GTCC haplotype is associated with higher IIEF scores in clinical ED. This study shows that plasma Arginase 2 concentrations may serve as risk factor for ED. Besides, Arginase 1 genetic variations affect ED severity.
Assuntos
Arginase/sangue , Arginase/genética , Disfunção Erétil/enzimologia , Disfunção Erétil/genética , Polimorfismo Genético , Adulto , Idoso , Idoso de 80 Anos ou mais , Disfunção Erétil/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
We examined the relationship between chronic hypoxia and erectile dysfunction in rat and its possible pathogenic mechanism. Forty-eight white male adult Sprague-Dawley rats were randomly divided into a test group and a control group. In accordance with the experimental time (2, 6, and 10 weeks), each group was divided into 3 subgroups, with 8 rats in each subgroup. Rats in the test group were fed in an airtight hypoxia cabin, while rats in the control group were maintained in a normal environment, with other conditions kept the same. At 2, 6, and 10 weeks, the rats in each group were observed for erectile function. Affinity purification was used to detect neural nitric oxide synthase (nNOS)-positive nerve fibers and endothelial nitric oxide synthase (eNOS) expression. After hypoxia, erectile frequency decreased significantly compared to before hypoxia (P < 0.001). Comparison of the test group and control group revealed a significant difference in the quantity of nNOS-positive nerve fiber and eNOS protein expression (P < 0.01). Hypoxia may influence erectile function and nNOS and eNOS expression in rats. The decrease in the quantity of nNOS nerve fibers and expression of eNOS may contribute to erectile dysfunction under hypoxic conditions in rats.
Assuntos
Disfunção Erétil/genética , Hipóxia/genética , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo I/genética , Oxigênio/farmacologia , Ereção Peniana/efeitos dos fármacos , Animais , Disfunção Erétil/metabolismo , Disfunção Erétil/fisiopatologia , Regulação da Expressão Gênica , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Masculino , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/metabolismo , Fibras Nervosas/patologia , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ereção Peniana/genética , Pênis/irrigação sanguínea , Pênis/efeitos dos fármacos , Pênis/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
Sildenafil and other PDE-5 inhibitors have revolutionized erectile dysfunction (ED) treatment. However, a significant number of patients do not respond or present adverse reactions to these drugs. While genetic polymorphisms may underlie this phenomenon, very little research has been undertaken in this research field. Most of the current knowledge is based on sildenafil, thus almost completely ignoring other important pharmacological therapies. Currently, the most promising genes with pharmacogenetic implications in ED are related to the nitric oxide and cGMP pathway, although other genes are likely to affect the responsiveness to treatment of ED. Nevertheless, the small number of studies available opens the possibility of further exploring other genes and phenotypes related to ED. This article provides a comprehensive overview of the genes being tested for their pharmacogenetic relevance in the therapy of ED.
Assuntos
Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/genética , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Animais , GMP Cíclico/genética , Humanos , Masculino , Óxido Nítrico/genética , Farmacogenética/métodos , Inibidores da Fosfodiesterase 5/efeitos adversos , Piperazinas/efeitos adversos , Polimorfismo Genético/genética , Purinas/efeitos adversos , Purinas/farmacologia , Purinas/uso terapêutico , Citrato de Sildenafila , Sulfonamidas/efeitos adversosRESUMO
AIM: Sildenafil potentiates the nitric oxide (NO) signaling pathway. Since neuronal NOS is very important in the penis, we assessed whether NOS1 polymorphisms are associated with altered responsiveness to sildenafil in erectile dysfunction (ED). MATERIALS & METHODS: Patients (n = 137) were divided as clinical ED or postoperative ED. They were subdivided as good responders or poor responders to sildenafil, and genotypes for rs41279104 and rs2682826 NOS1 polymorphisms were determined. RESULTS: We found that the rs41279104 CT genotype was associated with good responders in postoperative ED patients, while rs2682826 CT genotype was associated with good responders in postoperative ED, and the TT genotype associated with good responders in both groups. Finally, the CT haplotype was associated with good responders in postoperative ED. CONCLUSION: NOS1 polymorphisms are associated with responsiveness to sildenafil in ED. Original submitted 20 November 2013; Revision submitted 31 January 2014.
Assuntos
Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/genética , Óxido Nítrico Sintase Tipo I/genética , Piperazinas/uso terapêutico , Polimorfismo Genético/genética , Sulfonas/uso terapêutico , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Purinas/uso terapêutico , Citrato de SildenafilaRESUMO
Erectile dysfunction (ED) is usually treated with sildenafil. Although genetic polymorphisms in the endothelial nitric oxide synthase (eNOS) gene may impair endogenous NO formation, there is little information about how eNOS polymorphisms and haplotypes affect the responses to sildenafil. We studied 118 patients; 63 patients had ED secondary to radical prostatectomy (PED) and 55 had organic, clinical ED. eNOS genotypes for three eNOS polymorphisms (T(-786)C, rs2070744; a variable number of tandem repeats (VNTR) in intron 4; and Glu298Asp, rs1799983) were determined, and eNOS haplotypes were estimated using PHASE 2.1. The clinical responses to sildenafil were evaluated and the patients were classified as good responders (GR) or poor responders (PR) when their changes in five-item version of International Index for Erectile Function questionnaire were above or below the median value. The TC/CC genotypes and the C allele for the T(-786)C polymorphism were more common in GR, compared with PR patients with PED. However, the 4b4a/4a4a genotypes and the 4a allele for the VNTR polymorphism in intron 4 were more common in GR, compared with PR patients with clinical ED. The C-4a-Glu haplotype was more common in GR than in PR patients with PED. Conversely, the T-4b-Asp haplotype was less common in GR than in PR patients with PED. No other significant differences were found. Our findings show evidence that eNOS polymorphisms affect the responses of PED and clinical ED patients to sildenafil.
Assuntos
Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/genética , Óxido Nítrico Sintase Tipo III/genética , Piperazinas/administração & dosagem , Sulfonas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Farmacológicos , Disfunção Erétil/patologia , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites , Piperazinas/efeitos adversos , Polimorfismo de Nucleotídeo Único , Prostatectomia , Purinas/administração & dosagem , Purinas/efeitos adversos , Citrato de Sildenafila , Sulfonas/efeitos adversos , Inquéritos e QuestionáriosRESUMO
Vascular endothelial growth factor (VEGF) is a cytokine involved in angiogenesis and is closely related to the nitric oxide-cyclic guanosine monophosphate pathway, a target for sildenafil. We investigated for the first time whether three clinically relevant polymorphisms in the VEGF gene are associated with altered responsiveness to sildenafil treatment in postoperative erectile dysfunction (PED) and clinical erectile dysfunction (CED). We determined VEGF genotypes for three polymorphisms in VEGF promoter: -2578C>A (rs699947), -1154G>A (rs1570360) and -634G>C (rs2010963) in 126 patients with erectile dysfunction (ED; 66 patients with PED and 60 patients with CED). The patients were classified as good or poor responders to sildenafil (GR and PR groups, respectively) according to their responses with basis on the changes in five-item version of the International Index for Erectile Function (5-IIEF). We found an association of the -1154AA genotype with PR in both PED and CED patients (P<0.05), whereas the -2578AA and the -2578CA genotypes were associated with PR only in the CED group (P<0.05). The AAG haplotype was more common in PR than in GR patients (38% versus 20%, respectively; P=0.032) in the CED group, thus increasing the risk for a worse response to sildenafil (odds ratio, OR=2.33, 95% confidence interval, CI=1.07-5.09). However, this finding does not resist to Bonferroni's correction (P>0.0125). Our results indicate that VEGF polymorphisms affect the responsiveness of PED and CED patients to sildenafil. These findings may help to improve the therapy of patients with ED.
Assuntos
Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/genética , Piperazinas/uso terapêutico , Sulfonas/uso terapêutico , Agentes Urológicos/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Regiões Promotoras Genéticas , Purinas/uso terapêutico , Citrato de SildenafilaRESUMO
INTRODUCTION: In recent years, new tools for the study of molecular biology and genetics have resulted in significant contributions to the scientific community. The potential use of genetic variations as biomarkers in the management of current and future conditions is generating considerable excitement in health care for disorders such as erectile dysfunction (ED). AIM: This review briefly describes the molecular and genetic mechanisms involved in ED and provides an overall view of the literature relevant to possible relationships between genetic factors and ED. METHODS: This is a narrative review of studies on the potential influence of polymorphisms on the risk of developing ED. MAIN OUTCOME MEASURE: We reviewed genetic association studies involving polymorphisms and the ED phenotype. RESULTS: There is growing evidence for the influence of genetic polymorphisms on the risk of ED and on the interindividual variability in sildenafil treatment. CONCLUSIONS: Although this field is still in its infancy, genetic association studies aimed at defining a molecular basis for ED have provided some important evidence that a patient's genotype may be used in the future to assess risk, as well as to plan treatment and prevention programs in the clinic.
Assuntos
Disfunção Erétil/genética , Polimorfismo Genético/fisiologia , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/fisiopatologia , Marcadores Genéticos/efeitos dos fármacos , Marcadores Genéticos/genética , Marcadores Genéticos/fisiologia , Humanos , Masculino , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/fisiologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/fisiologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Piperazinas/uso terapêutico , Polimorfismo Genético/efeitos dos fármacos , Polimorfismo Genético/genética , Purinas/uso terapêutico , Citrato de Sildenafila , Sulfonas/uso terapêuticoRESUMO
Erectile dysfunction (ED) can be affected by androgen levels, which exert their action through the androgen receptor (AR). Androgenic action has been demonstrated to inversely correlate with a polymorphic trinucleotide CAG repeat region in the AR gene. We conducted an epidemiologic study to determine the potential association between the CAG repeat polymorphism of the AR gene and ED complaints, gonadal steroids, and sleep parameters in a large population-based sample in São Paulo, Brazil. AR CAG repeat was genotyped in 79 men with ED complaints and in 340 controls. Sleep and hormonal profiles were measured in all men. There was no association between the AR CAG repeat polymorphism and ED complaints. Moreover, there was no significant correlation among free and total testosterone, estradiol, follicle-stimulating hormone, and luteinizing hormone levels, as well as sleep parameters with the CAG repeat length, when evaluating the population as a whole, as well as subdivided into ED and control groups independently. The results were not affected when the data were analyzed in quartiles, divided by the median of the sample, or after correction for population stratification. AR CAG repeat polymorphism is not associated with ED complaints, gonadal steroids, and sleep parameters in men from a population-based sample in Brazil.