The effect of stromal cell-derived factor 1 (SDF1/CXCL12) genetic polymorphism on HIV-1 disease progression.

The human immunodeficiency virus type 1 (HIV-1) epidemic is increasing in Brazil, and little information has been reported about the genetic host factors related to HIV-1 infection in the Brazilian population. A polymorphism in the conserved 3' untranslated region of the stromal cell-derived factor 1 (SDF1/CXCL12) gene has been related either to resistance to HIV-1 infection and delayed progression to AIDS or to rapid disease progression and death. A longitudinal study was conducted to evaluate the association of the SDF1 polymorphism and the progression of HIV-1 infection in 161 asymptomatic patients infected with HIV-1 (ASYMPT) and 617 patients with AIDS (SYMPT) from Londrina and the surrounding region, southern Brazil. The endpoints used were the development of AIDS, death, and the slopes of the CD4+ T cell counts and HIV-1 RNA plasma levels. Among the 161 ASYMPT patients, all of the 7 patients (4.3%) homozygous for the mutation remained asymptomatic (p=0.1906); 6 of them had not initiated antiretroviral therapy. Among the 617 patients with AIDS, 40 (6.5%) progressed to death. Of these, 33/388 (8.5%) did not have the SDF1-3'A allele, 6/196 (3.1%) were heterozygous and 1/33 (3.0%) was homozygous for the SDF1-3'A allele (p=0.029). The SDF1 genotypes were not associated with the surrogate markers of HIV-1 disease progression such as the CD4+ T cell decline and plasma HIV-1 RNA levels. The results observed in this study support the hypothesis that the mutation of SDF1-3'A could have a possible late-stage protective effect on HIV-1 disease progression in the Brazilian population.

Genetic polymorphisms in glutathione-S-transferases are associated with anxiety and mood disorders in nicotine dependence.

BACKGROUND: Nicotine dependence is associated with an increased risk of mood and anxiety disorders and suicide. The primary hypothesis of this study was to identify whether the polymorphisms of two glutathione-S-transferase enzymes (GSTM1 and GSTT1 genes) predict an increased risk of mood and anxiety disorders in smokers with nicotine dependence. MATERIALS AND METHODS: Smokers were recruited at the Centre of Treatment for Smokers. The instruments were a sociodemographic questionnaire, Fagerström Test for Nicotine Dependence, diagnoses of mood disorder and nicotine dependence according to DSM-IV (SCID-IV), and the Alcohol, Smoking and Substance Involvement Screening Test. Anxiety disorder was assessed based on the treatment report. Laboratory assessment included glutathione-S-transferases M1 (GSTM1) and T1 (GSTT1), which were detected by a multiplex-PCR protocol. RESULTS: Compared with individuals who had both GSTM1 and GSTT1 genes, a higher frequency of at least one deletion of the GSTM1 and GSTT1 genes was identified in anxious smokers [odds ratio (OR)=2.21, 95% confidence interval (CI)=1.05-4.65, P=0.034], but there was no association with bipolar and unipolar depression (P=0.943). Compared with nonanxious smokers, anxious smokers had a greater risk for mood disorders (OR=4.67; 95% CI=2.24-9.92, P<0.001), lung disease (OR=6.78, 95% CI=1.95-23.58, P<0.003), and suicide attempts (OR=17.01, 95% CI=2.23-129.91, P<0.006). CONCLUSION: This study suggests that at least one deletion of the GSTM1 and GSTT1 genes represents a risk factor for anxious smokers. These two genes may modify the capacity for the detoxification potential against oxidative stress.

Oxidative stress and lowered total antioxidant status are associated with a history of suicide attempts.

BACKGROUND: There is evidence that depression is accompanied by inflammation, oxidative and nitrosative stress (O&NS) and metabolic disorders. However links between oxidative stress and suicide attempts in depressed patients are poorly understood. This study examines whether a history of suicide attempts is associated with inflammation, O&NS and metabolic disorders. METHODS: Blood specimens were collected from study participants aged 18-60 (N=342) recruited at the State University of Londrina, Brazil, and measured for oxidative stress biomarkers: nitric oxide metabolites (NOx), lipid hydroperoxides, malondialdehyde, advanced oxidation protein products and plasma total antioxidant potential (TRAP); inflammatory biomarkers: fibrinogen, high-sensitivity C-reactive protein, erythrocyte sedimentation rate, interleukin-6 and tumor necrosis factor-α; and metabolic variables. Subjects were divided into those with (n=141) and without (n=201) a history of suicidal attempts. RESULTS: Individuals with a history of suicide attempts had significantly higher levels of NOx and lipid hydroperoxides and lowered TRAP as compared to individuals without suicide attempts. There were no significant associations between a history of suicide attempts and inflammatory and metabolic biomarkers and metabolic syndrome. Logistic regression showed that both unipolar and bipolar disorder, female gender, smoking behavior and lipid hydroperoxides were significantly associated with a history of suicide attempts. The combined effects of oxidative stress, smoking, depression, female gender were independent from classical risk factors, including marital status, years of education and anxiety. CONCLUSIONS: O&NS as well as lowered antioxidant levels may play a role in the pathophysiology of suicidal behavior independently from the effects of depression and smoking, both of which are associated with increased O&NS, and classical suicide predictors, such as years of education and marital status.

Cytokine profile in relapsing­remitting multiple sclerosis patients and the association between progression and activity of the disease.

Multiple sclerosis (MS) is a progressive immune­ mediated disease caused by demyelination of the central nervous system. Cytokines and their receptors have an important role in the evolution of MS lesions, and pro­ and anti­inflammatory cytokine levels have been found to correlate with changes in MS disease activity. The aims of the present study were to evaluate the pro­inflammatory [tumor necrosis factor (TNF)­α and interleukin (IL) ­1ß, ­6 and ­12], T helper (Th) 1 [interferon (IFN)­Î³], Th17 (IL­17) and Th2 (IL­4 and ­10) cytokine serum levels in relapsing­remitting (RR)­MS patients and to evaluate the association between the cytokine profile and the progression and activity of the disease. Serum cytokine levels were assessed using enzyme linked­immunosorbent assays in 169 RR­MS patients in the remission clinical phase and 132 healthy individuals who were age­, gender­, ethnicity­ and body mass index­matched. Disability and activity of the disease were evaluated using the Expanded Disability Status Scale and magnetic resonance imaging with gadolinium, respectively. IFN­Î³ and IL­6, ­12 and ­4 levels were higher in RR­MS patients compared to controls (P=0.0009, 0.0114, 0.0297 and 0.0004, respectively). IL­1 levels were higher in controls compared with RR­MS patients. IL­4 levels were higher in RR­MS patients with mild disability compared to those with moderate and severe disability (P=0.0375). TNF­α and IL­10 levels were higher in RR­MS patients with inactive disease compared with those with active disease. IL­17 levels showed a trend towards being higher in RR­MS patients with inactive disease compared to those with active disease (P=0.0631). Low TNF­α and high IFN­Î³ levels were independently associated with RR­MS (P=0.0078 and 0.0056, respectively) and also with the activity of the disease (P=0.0348 and 0.0133, respectively). Results indicated that RR­MS patients, even in the remission clinical phase, exhibit a complex system of inflammatory and anti­inflammatory cytokines that may interact to modulate the progression and activity of the disease.

Frequency and diversity of human immunodeficiency virus type 1 mutations associated with antiretroviral resistance among patients from Southern Brazil failing highly active antiretroviral therapy (HAART).

The human immunodeficiency virus type 1 (HIV-1) epidemic in Brazil is spreading to small municipalities as well as the innermost parts of the country and scarce information has been reported on the frequency of HIV-1 resistance-associated mutations in these areas. To determine the frequency and diversity of the HIV-1 antiretroviral resistance-associated mutations among patients failing highly active antiretroviral therapy from Londrina in Southern Brazil, 127 HIV-1 genotyping tests that were assayed during January 2000 to July 2008 from 108 patients were evaluated. Sixty-nine patients (63.9%) were male and 39 (36.1%) were female and the age ranged from 10 to 68 years (mean, 40.8+/-9.2). All of them showed at least one HIV-1 antiretroviral resistance-associated mutation and in 72 (56.7%) genotyping tests, mutations for the three antiretroviral classes were detected simultaneously. Mutations associated with resistance to protease inhibitor (PI) were detected in 124 tests (97.6%), the main ones were L90M in 28 (22.0%), V82A in 27 (21.2%), M46I in 26 (20.5%), and I54V in 23 (18.1%). The main mutations associated with nucleoside reverse transcriptase inhibitor (NRTI) resistance were M184V in 82 (64.6%), and the thymidine analog mutations were D67N in 51 (40.1%) tests, K70R in 45 (35.4%), T215Y in 40 (31.5%), and M41L in 38 (30.0%). The most frequent major mutations associated with resistance to non-nucleoside RT inhibitors (NNRTI) were K103N in 47 (37.0%), G190A in 11 (8.7%), and G190S in 2 (2.6%) tests. Mutations associated with reduced susceptibility to NRTI and IP simultaneously were observed in 46 (36.2%) tests. The results obtained may contribute to the improvement of the treatment strategies and the management of the antiretroviral drug therapy of HIV-1-infected patients from this Brazilian region, reducing public costs for antiretroviral drugs which have not been efficient in therapy.

Analysis of the CC chemokine receptor 5 delta32 polymorphism in a Brazilian population with cutaneous leishmaniasis.

Patients with mucocutaneous leishmaniasis (MCL) show a vigorous T-cell immune response against Leishmania braziliensis. Because the Th response is associated with inflammation, the non-functional CC chemokine receptor 5 (CCR5) may rely in a less severe inflammatory state. The aim of this study was to investigate the CCR5 gene in a Brazilian population with leishmaniasis compared with healthy control subjects and to determine the progression from cutaneous to MCL in the Delta32 allele carriers. Among 100 patients with Montenegro skin test and indirect immunofluorescence assay (IIF) values positive for leishmaniasis, there were 32% women and 68% men. The patients were 89% CCR5/CCR5, 10% CCR5/Delta32, and 1% Delta32/Delta32, while healthy subjects showed a 91% incidence of CCR5/CCR5, 8% of CCR5/Delta32, and 1% of Delta32/Delta32. The CCR5/CCR5 patients (89%) showed a large spectrum of clinical manifestations, where 22.47% had active mucous lesions and 77.53% had cutaneous lesions. In this work, the Delta32 allele carriers (10%) showed only cutaneous manifestations when compared with wild-type individuals. Finally, with regard to the Delta32 allele carriers, a less severe spectrum of clinical manifestations was observed in comparison with wild-type individuals. Although a lack of mucocutaneous lesions was evident among Delta32 allele carriers, the number of individuals studied was small. Therefore, further investigations are needed to elucidate the role of CCR5 in the clinical aspects of leishmaniasis.