CYP3A5*3 and CYP2C8*3 variants influence exposure and clinical outcomes of tacrolimus-based therapy.

Aim: The influence of variants in pharmacokinetics-related genes on long-term exposure to tacrolimus (TAC)-based therapy and clinical outcomes was investigated. Patients & methods: Brazilian kidney recipients were treated with TAC combined with everolimus (n = 178) or mycophenolate sodium (n = 97). The variants in CYP2C8, CYP2J2, CYP3A4, CYP3A5, POR, ABCB1, ABCC2, ABCG2, SLCO1B1 and SLCO2B1 were analyzed. Main results:CYP3A5*3/*3 genotype influenced increase in TAC concentration from week 1 to month 6 post-transplantation (p < 0.05). The living donor and CYP2C8*3 variant were associated with reduced risk for delayed graft function (OR = 0.07; 95% CI = 0.03-0.18 and OR = 0.45; 95% CI = 0.20-0.99, respectively, p < 0.05). Conclusion: The CYP3A5*3 variant is associated with increased early exposure to TAC. Living donor and CYP2C8*3 variant seem to be protective factors for delayed graft function in kidney recipients.

Increased TLR2 expression in patients with type 1 diabetes: evidenced risk of microalbuminuria.

OBJECTIVE: To study the activation of an inflammatory cascade through leukocyte mRNA expression of TLR2, TLR4, MyD88, and pro-inflammatory cytokines in individuals with childhood onset type 1 diabetes. DESIGN AND METHODS: Seventy-six type 1 diabetic patients and 100 normoglycemic subjects (NG) 6 to 20 years old were recruited. Type 1 diabetic patients (DM1) were considered to have good (DM1G) or poor (DM1P) glycemic control according to the values of glycated hemoglobin. TLR2, TLR4, MyD88, interleukin -1ß (IL-1ß), IL-6, and tumor necrosis factor alpha (TNF-α) mRNA expressions were measured in peripheral blood leukocytes (PBL) by real-time polymerase chain reaction (PCR). Urea, creatinine, albumin, and total protein serum levels were determined. Urinary albumin-to-creatinine ratio (ACR) was calculated. RESULTS: DM1 and DM1P patients showed higher glycated hemoglobin (10 and 11%, respectively) and serum glucose concentrations (208 and 226 mg/dL, respectively) compared to NG (Glycated hemoglobin: 7% and glucose: 76 mg/dL) (p < 0.05). PBL mRNA expressions of TLR2, MyD88, IL-1ß, IL-6, and TNF-α were higher in DM1 and TLR2, IL-1ß, and IL-6 expressions were higher in DMP1 compared to NG (p < 0.05). In DM1, serum albumin and total protein were lower, while serum urea and ACR were higher in comparison to NG (p < 0.05). However, these differences compared to NG were more pronounced in DM1P, which included nine individuals with microalbuminuria. CONCLUSIONS: Increased mRNA expression of TLR2, MyD88, and pro-inflammatory cytokines in leukocytes of patients with childhood onset type 1 diabetes indicates the development of a TLR2-mediated pro-inflammatory process, which may also be associated with an early inflammatory process in the kidney and the occurrence of microalbuminuria.

AMI is associated with polymorphisms in the NOS3 and FGB but not in PAI-1 genes in young adults

Background: We investigated the relationship between NOS3, FGB and PAI-1 polymorphisms and endothelial dysfunction and risk factors for acute myocardial infarction (AMI) in young adults.Methods: Endothelial function was measured by response to flow mediated vasodilation (FMV) and induced by nitrate (FMN). Biochemical parameters were measured by standard enzymatic methods and plasma total nitrate was analyzed by the NOA™system. NOS3 (T-786C, G894T and intron 4A/B STR), FGB (C-148T and G-455A) and PAI-1 (4G/5G) polymorphisms were determined by PCR-RFLP.Results: Concentrations of total and LDL cholesterol, apo B, triglycerides, nitrate, PAI-1 and fibrinogen were higher and apo AI, HDL cholesterol and FMVwere lower in AMI patients than in controls ( pb0.001). PAI-1 ( pb0.001) but not nitrate was higher in AMI patients with low response toFMV. NOS3 T-786C and FGB C-148T polymorphisms were associated with AMI ( pb0.050). NOS3 T-786C was also related to hypertension ( p=0.049).NOS3 intron 4A/B STR was associated with increased concentrations of total cholesterol and apo B. NOS3-786TT/894GT haplotype was associated with increased FMV ( p=0.018) than the other haplotypes. Conclusions: Our data suggest NOS3 and FGB polymorphisms are associated with AMI. NOS3 is also related to hypertension, endothelialdysfunction and variation on serum cholesterol in young adults with AMI.

Regulaçäo da expressão da óxido nítrico sintase induzível (iNOS) pelo hormônio de crescimento (GH): Estudo in vitro e em modelo animal de glumerulosclerose (camundongo trangênico para GH) / Regulation of the inducible nitric oxide synthases (INOS) expression by growth hormone (GH): In vitro study and in transgenic mouse model of glomerulosclerosis

Estudamos a regulação de enzimas da via de metabolização da L-arginina (óxido nítrico sintase induzível, iNOS, ornitina descarboxilase, ODC, e ornitina aminotransferase, OAT) pelo hormônio de crescimento (GH) em células mesangiais e em córtex renal de camundongos bGH. Estes animais apresentam concentração sérica elevada de GH e desenvolvem glomerulosclerose (GS) progressiva. Há várias evidências da participação do GH no desenvolvimento de GS. Demonstrou-se também uma associação entre o acúmulo de matrix extracelular (MEC) nos glomérulos e a expressão aumentada de iNOS, OAT e ODC. Nós demonstramos, pela primeira vez, uma ligação entre o GH e a iNOS em células mesangiais, além de uma expressão aumentada desta enzima em córtex renal de camundongo bGH com GS severa...

Correlações entre anormalidades de mão e risco de retinopatia diabética / Correlations between Hand Abnormalities and Diabetic Retinopathy Risk - Description of a new syndrom

Uma correlação entre retinopatia diabética e certo tipo de anormalidades de mão, em contratura é analisada sobre uma população de 81 pacientes diabéticos. A gravidade da retinopatia proliferativa e outras alterações microvasculares na presença das contraturas é ressaltada em seis casos com severa anomalia de mão, e 14 com alterações moderadas, onde a frequencia e gravidade da retinopatia foi superior à da população sem anormalidades (50 por cento e 30 por cento respectivamente); alto nível de correlação foi encontrado entre retinpatia diabética proliferativa e presença de alterações de mão. O autor conclui com base na casuístia apresentada e recentes dados da literatura, ser esta população de diabéticos de alto risco ao desenvolvimento de complicações microvasculares, principalmente retinopatia grave, sendo o exame das mãos, de fácil execução, importante subsídio à detecção e triagem dessa população de risco.