Attenuation of the levels of pro-inflammatory cytokines prevents depressive-like behavior during ethanol withdrawal in mice.

Clinical studies indicate that alcohol-dependent patients may develop depressive symptoms during abstinence, which may increase the likelihood of relapse. It is known that both in alcohol exposure and depression, there is an increase in the levels of pro-inflammatory cytokines in the brain. However, the putative contribution of increased levels of pro-inflammatory cytokines in the development of depressive-like behavior during ethanol withdrawal has not been evaluated. In the present study, we aimed to investigate if ethanol withdrawal-induced depressive-like behavior is related to increased levels of pro-inflammatory cytokines in the brain. Male mice were treated with vehicle (saline 0.9%, v.o.) or ethanol (2 g/kg, v.o.) for 14 days. After 5 days of cessation of the ethanol treatment, mice were subjected to the forced swim test (FST), tail suspension test (TST), and open field test (OFT) and then sacrificed. Their brains were analyzed for the levels of pro-inflammatory cytokines. Ethanol withdrawal mice showed increased immobility time in the FST and TST than by the control group, indicating increased depressive-like behavior. No alterations in OFT were observed. Ethanol withdrawal increased the levels of tumor necrosis factor-alpha (TNF-α) in the hippocampus and striatum, interleukin-1 beta (IL-1ß) in the hippocampus, and IL-6 in the prefrontal cortex and hippocampus. Treatment of mice with nimesulide (5 or 10 mg/kg/day), a cyclooxygenase-2 inhibitor, during ethanol withdrawal prevented the increase in immobility time in the TST. Similar results were observed in the FST upon nimesulide treatment, although with a higher dose. Nimesulide treatment (10 mg/kg) prevented the ethanol withdrawal-induced alterations in the levels of TNF-α, IL-1ß, and IL-6 in the hippocampus, prefrontal cortex, and striatum. Treatment of mice with an atypical antidepressant drug, vilazodone (0.3 or 1 mg/kg) prevented the increase in depressive-like behavior induced by ethanol withdrawal in the TST. In the FST, the increase in immobility time was prevented only by 1 mg/kg vilazodone treatment. Vilazodone prevented the increase in the levels of TNF-α, IL-1ß, and IL-6 in the hippocampus, IL-6 in the prefrontal cortex, and TNF-α in the striatum. In conclusion, these data indicate that increased levels of pro-inflammatory cytokines may play a role in the development of depressive-like behavior during ethanol withdrawal in mice.

Polymorphism in the pvcrt-o and pvmdr-1 genes of Plasmodium vivax associated with a better prognosis for malaria.

The early molecular identification of strains of Plasmodium vivax that have a worse prognosis is important to stratify the risk of complications and choice of conduct made by medical teams. Thus, the aim of the present study was to associate the presence of polymorphisms in the pvmdr-1 and pvcrt-o resistance genes of P. vivax in patients with better or worse prognosis. This cross-sectional epidemiological study was conducted based on data obtained from the records of 120 patients diagnosed with malaria in the Brazilian Amazon. The T958M and F1076L mutations of the pvmdr-1 gene had a frequency of 3.3 and 4.2%, respectively, and primo-infected patients had a 17 times greater chance of being infected with protozoa with the T958M mutation compared to patients with previous episodes. Regarding pvcrt-o, the C393T and T786C polymorphisms had a frequency of 14.2 and 3.3%, respectively, and self-declared white patients had a 3.1 times greater chance of being infected with protozoa with the C393T polymorphism. In addition, patients with this pvcrt-o polymorphism had lower concentrations of C-reactive protein, indicating a better prognosis. These data present clues of genetic indicators useful for assessing the virulence of the parasite and the prognosis of patients with vivax malaria.

Polymorphism in the pvcrt-o and pvmdr-1 genes of Plasmodium vivax associated with a better prognosis for malaria

@#The early molecular identification of strains of Plasmodium vivax that have a worse prognosis is important to stratify the risk of complications and choice of conduct made by medical teams. Thus, the aim of the present study was to associate the presence of polymorphisms in the pvmdr-1 and pvcrt-o resistance genes of P. vivax in patients with better or worse prognosis. This cross-sectional epidemiological study was conducted based on data obtained from the records of 120 patients diagnosed with malaria in the Brazilian Amazon. The T958M and F1076L mutations of the pvmdr-1 gene had a frequency of 3.3 and 4.2%, respectively, and primo-infected patients had a 17 times greater chance of being infected with protozoa with the T958M mutation compared to patients with previous episodes. Regarding pvcrt-o, the C393T and T786C polymorphisms had a frequency of 14.2 and 3.3%, respectively, and self-declared white patients had a 3.1 times greater chance of being infected with protozoa with the C393T polymorphism. In addition, patients with this pvcrt-o polymorphism had lower concentrations of C-reactive protein, indicating a better prognosis. These data present clues of genetic indicators useful for assessing the virulence of the parasite and the prognosis of patients with vivax malaria.

Atorvastatin prevents lipopolysaccharide-induced depressive-like behaviour in mice.

Clinical and pre-clinical evidences indicate an association between inflammation and depression since increased levels of pro-inflammatory cytokines are associated with depression-related symptoms. Atorvastatin is a cholesterol-lowering statin that possesses pleiotropic effects including neuroprotective and antidepressant actions. However, the putative neuroprotective effect of atorvastatin treatment in the acute inflammation mice model of depressive-like behaviour has not been investigated. In the present study, we aimed to investigate the effect of atorvastatin treatment on lipopolysaccharide (LPS) induced depressive-like behaviour in mice. Mice were treated with atorvastatin (1 or 10 mg/kg, v.o.) or fluoxetine (30 mg/kg, positive control, v.o.) for 7 days before LPS (0.5 mg/kg, i.p.) injection. Twenty four hours after LPS infusion, mice were submitted to the forced swim test, tail suspension test or open field test. After the behavioural tests, mice were sacrificed and the levels of tumour necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), glutathione and malondialdehyde were measured. Atorvastatin (1 or 10 mg/kg/day) or fluoxetine treatment prevented LPS-induced increase in the immobility time in the forced swim and tail suspension tests with no alterations in the locomotor activity evaluated in the open field test. Atorvastatin (1 or 10 mg/kg/day) or fluoxetine treatment also prevented LPS-induced increase in TNF-α and reduction of BDNF levels in the hippocampus and prefrontal cortex. Treatment with atorvastatin (1 or 10 mg/kg/day) or fluoxetine prevented LPS-induced increase in lipid peroxidation and the reduction of glutathione levels in the hippocampus and prefrontal cortex. The present study suggests that atorvastatin treatment exerted neuroprotective effects against LPS-induced depressive-like behaviour which may be related to reduction of TNF-α release, oxidative stress and modulation of BDNF expression.

Association of the GSTT1 polymorphism in upper aerodigestive tract cancer with tobacco smoking.

Polymorphisms in genes encoding xenobiotic-metabolizing enzymes might explain differences in the susceptibility to upper aerodigestive tract (UADT) cancers in individuals exposed to tobacco or other carcinogens. The present study aimed to evaluate the association of polymorphisms in the glutathione S-transferase (GST) candidate genes GSTM1, GSTT1, and GSTP1 with the risk of UADT cancers. GST gene polymorphisms were determined in 116 individuals with UADT cancer and 224 healthy controls using polymerase chain reaction-based methods. The GSTT1-null polymorphism was found to be a protective factor for UADT cancer [(odds ratio (OR) = 0.5, 95% confidence interval (CI) = 0.27-0.93)], although this association was not confirmed when adjusted for gender, age, smoking, alcoholism, and self-reported skin color in the multivariate logistic regression model (OR = 0.61, 95%CI = 0.29-1.28). The combined effect of GSTT1-positive genotypes with either the GSTP1 wild-type genotype (Ile/Ile) or the GSTP1 variant genotypes (Ile/Val or Val/Val) increased the risk for UADT cancer (OR = 4.34, 95%CI = 1.06-17.78 and OR = 4.55, 95%CI = 1.12-18.42, respectively). A significant interaction was observed among moderate smokers carrying the GSTT1-positive genotype. In this population, the significant gene-gene and gene-environment interactions of GST polymorphisms may confer a substantial risk to UADT cancers.

Endothelial nitric oxide synthase gene haplotypes affect nitrite levels in black subjects.

Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene have been associated with variations in nitric oxide (NO) formation and response to drugs in white subjects. We examined whether genetic polymorphisms (T-786C, b/a intron 4 and Glu298Asp) and haplotypes of the eNOS gene affect NO formation in 179 healthy black subjects. To assess NO formation, we measured the concentrations of nitrite in the plasma, red blood cells and whole blood. Although we found no effects of individual eNOS polymorphisms on NO formation, we found that the 'C-4b-Glu' haplotype is significantly more common in subjects with low circulating plasma and whole blood nitrite concentrations compared with subjects with high circulating nitrite concentrations (both P<0.0007). These findings reproduce previous findings in white subjects and are consistent with the idea that defining genetic markers is more important than ethnic classification, at least in terms of NO formation.

Efeito da sibutramina na redução do peso e no perfil metabólico em indivíduos obesos de uma população brasileira / Effects of sibutramine on weight reduction and metabolic profile in obese individuals in a brazilian population

O objetivo deste trabalho é avaliar a eficácia e a segurança da dose de 20 mg/dia de sibutramina em voluntários obesos, com IMC superior a 35, e compará-las com a dose de 10 mg/dia e à mudança de estilo de vida de pacientes com IMC inferior a 35 (a avaliação e a comparação foram realizadas em um período de 24 semanas). Foram submetidos a um estudo transversal 54 voluntários, distribuídos em três grupos de observação: grupo sem tratamento farmacológico (GMEV), grupo com IMC inferior a 35 e uma dose de 10 mg/ dia de sibutramina (G1) e grupo com IMC superior a 35 e dose de 20 mg/ dia de sibutramina (G2). Os parâmetros avaliados foram peso, circunferência abdominal e perfil metabólico. Os grupos submetidos ao tratamento farmacológico demonstraram maior redução do peso (G1: redução média de 9,4% ; G2: redução média de 20,6%) quando comparados a indivíduos sem tratamento farmacológico (GMEV: redução de 3,9%), assim como da circunferência abdominal (redução de 7,1%, 12,8% e 3,1% em G1, G2 e GMEV, respectivamente). Em relação aos achados laboratoriais, foram observados redução da glicemia de jejum (14,8%, 22,9% e 5% em G1, G2 e GMEV, respectivamente), aumento do HDL colesterol (31,2%, 40% e 14,2% em G1, G2 e GMEV, respectivamente) e redução do colesterol total (29,0%, 32,8% e 13,7% em G1, G2 e GMEV, respectivamente). Os resultados deste estudo demonstram que a dose de 20 mg de sibutramina é uma indicação segura e eficaz em pacientes obesos com IMC superior a 35

The aim of this study is to assess the efficacy and safety of an oral daily dose of 20 mg sibutramine in obese volunteers (BMI > 35), in comparison with a dose of 10 mg/day and changed lifestyle in patients whose BMI is less than 35. The testing and comparison were performed over 24 weeks. The 54 volunteers were subjected to a cross-sectional study in three observation groups: a reference group without pharmacological treatment (GMEV), a group with BMI < 35, treated with 10 mg ?day sibutramine (G1), and another with BMI ? 35, on a dose of 20 mg? day (G2). The variables assessed were weight, abdominal circumference and metabolic profile. The groups subjected to the drug treatments exhibited greater weight losses (G1: -9.4% and G2: -20.6%) than the group that took no drugs (GMEV: -3.9%). The abdominal circumference was reduced by 7.1%, 12.8% and 3.1% in G1, G2 and GMEV, respectively. Regarding the biochemical variables, there was a reduction in fasting glucose levels (-14.8%, -22.9% and -5% in G1, G2 and GMEV, respectively); an increase in HDL cholesterol (+31.2%, +40% and +14.2% in G1, G2 and GMEV, respectively) and a reduction in total cholesterol (-29.0%, -32.8% and ?13.7% in G1, G2 and GMEV, respectively). The results of this study show that sibutramine, in doses of 20 mg/ day, is a safe and efficient drug for obesity treatment in patients whose BMI exceeds 35.