Since the AAS abuse is so widespread, a better comprehension of the pathological effects induced by these drugs may be helpful for the development of new forms of therapy of AAS-induced lesions.

This is the first report that, taking advantage of three bioassays performed on the same subject, demonstrated a considerable interindividual variability and tissue-specific GC sensitivity in a young healthy population.

Glucocorticoids (GC) represent the main treatment for pemphigus; however, some patients show GC resistance. GC sensitivity was evaluated in 19 pemphigus patients and 41 controls by the number of binding sites [B max (fmol/mg protein)] and the affinity of GC receptor [Kd (nM)] to dexamethasone (DEX) as well as by the pattern of cytokine by DEXmediated inhibition of concanavalin-A (Con-A)-stimulated PBMC proliferation. The Kd (15.7±2.8 vs.8.1±1.3) and Bmax (6.5±0.9 vs. 3.9±0.3) were higher in pemphigus than controls (p00.002). Considering the values above the 95th percentile of normal group as a cut-off (K d >24.9 nM and B max >8.1 fmol/mg protein), elevated K d and B max were observed in 9.8% and 2.4% of controls and 15.8% and 36.8% of patients (p00.02). PBMC proliferation was stimulated by Con-A and inhibited by DEX (p<0.001) in both pemphigus and control groups. IL-6 and TNFα (pg/mL) basal production were higher in patients than controls. There was an increment of these cytokines after Con-A stimulation, and they were inhibited by DEX (p00.002) in controls and remained elevated in pemphigus (p<0.02). Patients and controls showed no difference in basal and stimulated production of IL-8 and IL-10. There is an alteration on GC sensitivity in pemphigus patients and a higher production of proinflammatory cytokines. Therefore, in pemphigus patients, proinflammatory cytokines might be involved in the mechanism of GC resistance and/or in its maintenance.

Objective: The Brazilian population has heterogeneous ethnicity. No previous study evaluated NR3C1 polymorphisms in a Brazilian healthy population. Materials and methods: We assessed NR3C1 polymorphisms in Brazilians of Caucasian, African and Asian ancestry (n = 380). In a subgroup (n = 40), we compared the genotypes to glucocorticoid (GC) sensitivity, which was previously evaluated by plasma (PF) and salivary (SF) cortisol after dexamethasone (DEX) suppression tests, GC receptor binding affinity (K d ), and DEX-50% inhibition (IC 50 ) of concanavalin-A-stimulated mononuclear cell proliferation. p.N363S (rs6195), p.ER22/23EK (rs6189-6190), and BclI (rs41423247) allelic discrimination was performed by Real-Time PCR (Polymerase Chain Reaction). Exons 3 to 9 and exon/intron boundaries were amplified by PCR and sequenced. Results: Genotypic frequencies (%) were: rs6195 (n = 380; AA:96.6/AG:3.14/GG:0.26), rs6189-6190 (n = 264; GG:99.6/ GA:0.4), rs41423247 (n = 264; CC:57.9/CG:34.1/GG:8.0), rs6188 (n = 155; GG:69.6/GT:25.7/TT:4.7), rs258751 (n = 150; CC:88.0/CT:10.7/TT:1.3), rs6196 (n = 176; TT:77.2/TC:20.4/CC:2.4), rs67300719 (n = 137; CC:99.3/CT:0.7), and rs72542757 (n = 137; CC:99.3/CG:0.7). The rs67300719 and rs72542757 were found only in Asian descendants, in whom p.N363S and p.ER22/23EK were absent. The p.ER22/23EK was observed exclusively in Caucasian descendants. Hardy-Weinberg equilibrium was observed, except in the Asian for rs6188 and rs258751, and in the African for p.N363S. The K d , IC 50 , baseline and after DEX PF or SF did not differ between genotype groups. However, the mean DEX dose that suppressed PF or SF differed among the BclI genotypes (P = 0.03). DEX dose was higher in GG-(0.7 ± 0.2 mg) compared to GC-(0.47 ± 0.2 mg) and CC-carriers (0.47 ± 0.1 mg). Conclusion: The genotypic frequencies of NR3C1 polymorphisms in Brazilians are similar to worldwide populations. Additionally, the BclI polymorphism was associated with altered pituitary-adrenal axis GC sensitivity. Arq Bras Endocrinol Metab. 2014;58(1):53-61 Keywords NR3C1 genotypes; allelic frequencies; glucocorticoid sensitivity RESUMO Objetivo: Este estudo avalia polimorfismos (SNPs) do NR3C1 na população brasileira, que possui origem étnica heterogênea. Materiais e métodos: SNPs do NR3C1 foram avaliados em brasileiros de ancestralidade caucasiana, africana ou japonesa (n = 380). Em um subgrupo (n = 40), os genótipos foram comparados à sensibilidade aos glicocorticoides (GC), previamente avaliada por cortisol plasmático (PF) e salivar (SF) após supressão com dexametasona (DEX), ensaio de afinidade do receptor ao GC (K d ) e inibição por DEX de 50% da proliferação de mononucleares estimulada por concanavalina-A (IC 50 ). Discriminação alélica de p.N363S (rs6195), p.ER22/23EK (rs6189-6190) e BclI (rs41423247) foi realizada por PCR em tempo real. Éxons 3 a 9 e transições éxon/íntron foram amplificados e sequenciados. Resultados: Frequências genotípicas (%) foram: rs6195 (n = 380; AA:96,6/AG:3,14/GG:0,26), rs6189-6190 (n = 264; GG:99,6/GA:0...

BackgroundAlterations in the structure of resistance vessels contribute to elevated systemic vascular resistance in hypertension and are linked to sympathetic hyperactivity and related lesions in target organs.ObjectiveTo assess the effects of exercise training on hemodynamic and autonomic parameters, as well as splenic arteriolar damages in male Wistar Kyoto (WKY) and Spontaneously Hypertensive Rats (SHR).MethodsNormotensive sedentary (WKYS) and trained (WKYT) rats, and hypertensive sedentary (SHRS) and trained (SHRT) rats were included in this study. After 9 weeks of experimental protocol (swimming training or sedentary control), arterial pressure (AP) and heart rate (HR) were recorded in freely moving rats. We assessed the autonomic control of the heart by sympathetic and vagal autonomic blockade. Morphometric analyses of arterioles were performed in spleen tissues. The statistical significance level was set at p < 0.05.ResultsResting bradycardia was observed in both trained groups (WKYT: 328.0 ± 7.3 bpm; SHRT: 337.0 ± 5.2 bpm) compared with their respective sedentary groups (WKYS: 353.2 ± 8.5 bpm; SHRS: 412.1 ± 10.4 bpm; p < 0.001). Exercise training attenuated mean AP only in SHRT (125.9 ± 6.2 mmHg) vs. SHRS (182.5 ± 4.2 mmHg, p < 0.001). The WKYT showed a higher vagal effect (∆HR: 79.0 ± 2.3 bpm) compared with WKYS (∆HR: 67.4 ± 1.7 bpm; p < 0.05). Chronic exercise decreased sympathetic effects on SHRT (∆HR: -62.8 ± 2.8 bpm) in comparison with SHRS (∆HR: -99.8 ± 9.2 bpm; p = 0.005). The wall thickness of splenic arterioles in SHR was reduced by training (332.1 ± 16.0 µm2 in SHRT vs. 502.7 ± 36.3 µm2 in SHRS; p < 0.05).ConclusionsExercise training attenuates sympathetic activity and AP in SHR, which may be contributing to the morphological improvement of the splenic arterioles.

This study examines in vitro steroid sensitivity in chronic renal failure (CRF) patients and its influence on the allograft outcome. We determined the inhibitory effect of dexamethasone (DEX) on concanavalin A (Con-A)-stimulated peripheral blood mononuclear cell (PBMC) proliferation, and glucocorticoid receptor' (GR) number of binding sites (B(max)) and affinity (K(d)) in 28 CRF patients and 40 normal healthy controls. Based on K(d) values >95th percentile from controls, patients were divided into two groups: glucocorticoid resistant (n = 11) and glucocorticoid sensitive (n = 17). Patients were followed during 18 months post-transplantation observing acute rejection episodes (ARE), chronic allograft nephropathy (CAN), allograft failure and death. The DEX concentration that caused 50% inhibition of Con-A-stimulated PBMC proliferation (IC(50)) was higher in CRF than in healthy controls (2.2 x 10(-5) +/- 1.0 x 10(-5) versus 8.3 x 10(-6) +/- 4.2 x 10(-6) mol/L, P = 0.02). Values of K(d) (12.4 +/- 1.8 versus 7.2 +/- 0.9 nM) and B(max) (7.7 +/- 1.1 versus 4.1 +/- 0.3 fmol/mg protein) were higher in CRF patients (P = 0.02 and P = 0.001, respectively). There were higher incidences of ARE (P = 0.02) and CAN (P = 0.002) in the glucocorticoid-resistant group. Univariate and multivariate logistic regression showed that K(d) was an independent predictor of ARE (OR 8.8, P = 0.03) as well as of CAN (OR 16.5, P = 0.01). In conclusion, we observed glucocorticoid resistance in a subgroup of CRF patients undergoing dialysis, which led to a higher morbidity due to ARE and CAN in an 18-month follow-up period.

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