Better CD4+T Cell Recovery in Brazilian HIV-Infected Individuals Under HAART Due to Cumulative Carriage of SDF-1-3`A, CCR2-V64I, CCR5-D32 and CCR5-Promoter 59029A/G Polymorphisms

Polymorphisms of chemokines and chemokine-receptors genes have been shown to influence the rate of progression to AIDS; however, their influence on response to HAART remains unclear. We investigated the frequency of the SDF-1-3`A, CCR2-64I, CCR5-D32 and CCR5-Promoter-59029-A/G polymorphisms in Brazilian HIV-1-infected and uninfected individuals and their influence on CD4+ T-cell evolution HIV-1 infected individuals before and during HAART. Polymorphism detection was done in a transversal study of 200 HIV-1-infected and 82 uninfected individuals. The rate of CD4+ T cell increase or decrease was studied in a cohort of 155 HIV-1 infected individuals on pre and post-HAART. Polymorphisms were determined by PCR associated with RFLP. The rate of CD4+ T-cell decline or increase was also determined. HIV-1 infected and uninfected subjects showed, respectively, frequencies of 0.193 and 0.220 for SDF-1-3`A, of 0.140 and 0.110 for CCR2-V64I, of 0.038 and 0.055 for CCR5-D32, and of 0.442 and 0.390 for CCR5-P-59029-A/G. HIV-1-infected subjects carrying one, two or three of these four polymorphisms showed better CD4+ T-cell recovery than HIV-1-infected subjects carrying the four wild-type alleles (+2.7, +1.6, +3.5, and -0.9 lymphocytes/mu l/month, respectively). Regression logistic analysis showed that the CCR5-D32/CCR2-V64I association was predictor of positive CD4+ T cell slope after HAART. The distribution of polymorphisms did not differ between HIV-1-infected and uninfected individuals, but differed from more homogenous ethnic groups probably reflecting the miscegenation of the Brazilian population. We add further evidence of the role of these polymorphisms by showing that the CD4 gain was influenced by carriage of one or more of the polymorphisms studied here. These results highlight the possibility that these genetic traits can be useful to identify patients at risk for faster progression to AIDS or therapeutic failure.

Risk Estimates of Dengue in Travelers to Dengue Endemic Areas Using Mathematical Models

Dengue has emerged as a frequent problem in international travelers. The risk depends on destination, duration, and season of travel. However, data to quantify the true risk for travelers to acquire dengue are lacking. We used mathematical models to estimate the risk of nonimmune persons to acquire dengue when traveling to Singapore. From the force of infection, we calculated the risk of dengue dependent on duration of stay and season of arrival. Our data highlight that the risk for nonimmune travelers to acquire dengue in Singapore is substantial but varies greatly with seasons and epidemic cycles. For instance, for a traveler who stays in Singapore for 1 week during the high dengue season in 2005, the risk of acquiring dengue was 0.17%, but it was only 0.00423% during the low season in a nonepidemic year such as 2002. Risk estimates based on mathematical modeling will help the travel medicine provider give better evidence-based advice for travelers to dengue endemic countries.

Adrenalectomy counteracts the local modulation of astroglial fibroblast growth factor system without interfering with the pattern of 6-OHDA-induced dopamine degeneration in regions of the ventral midbrain

The present study investigated the effects of bilateral adrenalectomy (ADX) on the synthesis of basic fibroblast growth factor (bFGF, FGF-2) mRNA and on the expression of its FGF receptor subtype-2 (FGFR2) mRNA after a 6-hydroxydopamine (6-OHDA)-induced lesion of nigrostriatal dopamine system. In previous papers we have demonstrated that corticosterone increases FGF-2 immunoreactivity mainly in the astrocytes of the substantia nigra [Chadi, G., Rosen, L., Cintra, A., Tinner, B., Zoli, M., Pettersson, R.F., Fuxe, K., 1993b. Corticosterone increases FGF-2 (bFGF) immunoreactivity in the substantia nigra of the rat. Neuroreport 4, 783-786.] and that 6-OHDA injected in the ventral midbrain upregulates FGF-2 synthesis in reactive astrocytes in the ascending dopamine pathways [Chadi, G., Cao, Y., Pettersson, R.F., Fuxe, K., 1994. Temporal and spatial increase of astroglial basic fibroblast growth factor synthesis after 6-hydroxydopamine-induced degeneration of the nigrostriatal dopamine neurons. Neuroscience 61, 891-910.]. Rats were adrenalectomized and received a 6-OHDA stereotaxical injection in the ventral midbrain 2 days later. Seven days after the dopamine lesion, Western blot analysis showed a decreased level of tyrosine hydroxylase in the lesioned side of the midbrain, an event that was not altered by ADX or corticosterone replacement. Moreover, the degeneration of nigral dopamine neurons, which was confirmed by the disappearance of acidic FGF (FGF-1) mRNA and the decrement of tyrosine hydroxylase mRNA labeled nigral neurons, was not altered by ADX. The FGF-2 protein (23 kDa isoform but not 21 kDa fraction) levels increased in the lesioned side of the ventral midbrain. This elevation was counteracted by ADX, an effect that was fully reversed by corticosterone replacement. In situ hybridization revealed that ADX counteracted the elevated FGF-2 mRNA levels in putative glial cells of the ipsilateral pars compacta of the substantia nigra and in the ventral tegmental area. The ADX also counteracted the increased density and intensity of the astroglial FGF-2 immunoreactive profiles within the lesioned pars compacta of the substantia nigra and the ventral tegmental area as determined by stereology. The stereotaxical mechanical needle insertion triggered the expression of FGFR2 mRNA in putative glial cells, spreading to the entire ipsilateral ventral midbrain from the region of needle track, an occurrence that was partially reversed by ADX. In conclusion, bilateral ADX counteracted the increased astroglial FGF-2 synthesis in the dopamine regions of the ventral midbrain following a 6-OHDA-induced local lesion and interfered with FGF receptor regulation around injury. These findings give further evidence that adrenocortical hormones may regulate the astroglial FGF-2-mediated trophic mechanisms and wound repair events in the lesioned central nervous system. (c) 2007 Elsevier B.V. All rights reserved.

Prevalence of cannabis use in Brazil: Data from the I Brazilian National Alcohol Survey (BNAS)

Aims: To estimate the prevalence of cannabis use in the last 12 months in the Brazilian population and to examine its association with individual and geographic characteristics. Design: Cross-sectional survey with a national probabilistic sample. Participants: 3006 individuals aged 14 to 65 years. Measurements: Questionnaire based on well established instruments, adapted to the Brazilian population. Findings: The 12-month prevalence of cannabis use was 2.1% (95%Cl 1.3-2.9). Male gender, better educational level, unemployment and living in the regions South and Southeast were independently associated with higher 12-month prevalence of cannabis use. Conclusion: While the prevalence of cannabis use in Brazil is lower than in many countries, the profile of those who are more likely to have used it is similar. Educational and prevention policies should be focused on specific population groups. (C) 2009 Elsevier Ltd. All rights reserved.

White-matter hyperintensities in first-episode psychosis

Background White-matter hyperintensities have been associated with both schizophrenia and mood disorders, particularly bipolar disorder, but results are inconsistent across studies. Aims To examine whether white-matter hyperintensities are a vulnerability marker for psychosis or are specifically associated with bipolar disorder. Method T-2-weighted magnetic resonance imaging data were acquired in 129 individuals with first-episode psychosis (either affective or non-affective psychoses) and 102 controls who were randomly selected from the same geographical areas. visual white-matter hyperintensity ratings were used for group and subgroup comparisons. Results There were no statistically significant between-group differences in white-matter hyperintensity frequency or severity scores. No significant correlations were found between white-matter hyperintensity scores and duration of illness, duration of untreated psychosis, or severity of psychotic, manic or depressive symptoms. Conclusions White-matter hyperintensities are not associated with vulnerability to psychosis in general, or specifically with affective psychoses. Further, first-episode psychosis investigations using more quantitative methods are warranted to confirm these findings. Declaration of interest None. Funding detailed in Acknowledgements.

Effect of Disease Severity and Optic Disc Size on Diagnostic Accuracy of RTVue Spectral Domain Optical Coherence Tomograph in Glaucoma

PURPOSE. To evaluate the effect of disease severity and optic disc size on the diagnostic accuracies of optic nerve head (ONH), retinal nerve fiber layer (RNFL), and macular parameters with RTVue (Optovue, Fremont, CA) spectral domain optical coherence tomography (SDOCT) in glaucoma. METHODS. 110 eyes of 62 normal subjects and 193 eyes of 136 glaucoma patients from the Diagnostic Innovations in Glaucoma Study underwent ONH, RNFL, and macular imaging with RTVue. Severity of glaucoma was based on visual field index (VFI) values from standard automated perimetry. Optic disc size was based on disc area measurement using the Heidelberg Retina Tomograph II (Heidelberg Engineering, Dossenheim, Germany). Influence of disease severity and disc size on the diagnostic accuracy of RTVue was evaluated by receiver operating characteristic (ROC) and logistic regression models. RESULTS. Areas under ROC curve (AUC) of all scanning areas increased (P < 0.05) as disease severity increased. For a VFI value of 99%, indicating early damage, AUCs for rim area, average RNLI thickness, and ganglion cell complex-root mean square were 0.693, 0.799, and 0.779, respectively. For a VFI of 70%, indicating severe damage, corresponding AUCs were 0.828, 0.985, and 0.992, respectively. Optic disc size did not influence the AUCs of any of the SDOCT scanning protocols of RTVue (P > 0.05). Sensitivity of the rim area increased and specificity decreased in large optic discs. CONCLUSIONS. Diagnostic accuracies of RTVue scanning protocols for glaucoma were significantly influenced by disease severity. Sensitivity of the rim area increased in large optic discs at the expense of specificity. (Invest Ophthalmol Vis Sci. 2011;92:1290-1296) DOI:10.1167/iovs.10-5516

Simplified criteria for the diagnosis of autoimmune hepatitis

Diagnosis of autoimmune hepatitis (AIH) may be challenging. However, early diagnosis is important because immunosuppression is life-saving. Diagnostic criteria of the International Autoimmune Hepatitis Group (IAIHG) were complex and purely meant for scientific purposes. This study of the IAIHG aims to define simplified diagnostic criteria for routine clinical practice. Candidate criteria included sex, age, autoantibodies, immunoglobutins, absence of viral hepatitis, and histology. The training set included 250 AIH patients and 193 controls from 11 centers worldwide. Scores were built from variables showing predictive ability in univariate analysis. Diagnostic value of each score was assessed by the area under the receiver operating characteristic (ROC) curve. The best score was validated using data of an additional 109 AIH patients and 284 controls. This score included autoantibodies, immunoglobulin G, histology, and exclusion of viral hepatitis. The area under the curve for prediction of AIH was 0.946 in the training set and 0.91 in the validation set. Based on the ROC curves, two cutoff points were chosen. The score was found to have 88% sensitivity and 97% specificity (cutoff >= 6) and 81% sensitivity and 99% specificity (cutoff 2:7) in the validation set. Conclusion: A reliable diagnosis of AIH can be made using a very simple diagnostic score. We propose the diagnosis of probable AIH at a cutoff point greater than 6 points and definite AIH 7 points or higher.

Association of EGFR c.2073A > T polymorphism with decreased risk of diffusely infiltrating astrocytoma in a Brazilian case-control study

Epidermal growth factor receptor (EGFR) gene overexpression has been implicated in the development of many types of tumors, including glioblastomas, the most frequent diffusely infiltrating astrocytomas. However, little is known about the influence of the polymorphisms of EGFR on EGFR production and/or activity, possibly modulating the susceptibility to astrocytomas. This study aimed to examine the association of two EGFR promoter polymorphisms (c.-191C > A and c.-216G > T) and the c.2073A > T polymorphism located in exon 16 with susceptibility to astrocytomas, EGFR gene expression and survival in a case-control study of 193 astrocytoma patients and 200 cancer-free controls. We found that the variant TT genotype of the EGFR c.2073A > T polymorphism was associated with a significantly decreased risk of astrocytoma when compared with the AA genotype [sex- and age-adjusted odds ratio 0.51, 95% confidence interval 0.26-0.98]. No association of the two promoter EGFR polymorphisms (or combinations of these polymorphisms) and risk of astrocytomas, EGFR expression or survival was found. Our findings suggest that modulation of the EGFR c.2073A > T polymorphism could play a role in future therapeutic approaches to astrocytoma. (Int J Biol Markers 2008; 23: 140-6)

Nomograms of fetal thyroid measurements estimated by 2-dimensional sonography

Purpose. To build nomograms of fetal thyroid circumference (FTC), fetal thyroid area (FTA), and fetal thyroid transverse diameter (FTTD) throughout gestational age (GA). Method. Between January 2006 and July 2006, FTC, FTA, and FTTD were measured once in 196 normal fetuses examined at a GA of 22-35 weeks. Inclusion criteria were a healthy mother with normal maternal thyrotropin level during pregnancy, a singleton pregnancy with normal fetal morphology on sonography, and GA confirmed via first-trimester sonographic examination. Results. Mean FTC, FTA, and FTTD ranged from 3.21 cm, 0.58 cm(2), and 1.19 cm at 22 weeks to 5.11 cm, 1.69 cm(2), and 1.89 cm at 35 weeks, respectively. Linear regression analysis yielded the following formulas for FTC, FTA, and FTTD according to GA: FTC (cm) = 0.146 X GA (weeks); FTA (cm(2)) = -1.289 + 0.085 X GA (weeks); FTTD (cm) = 0.054 X GA (weeks). The following logarithmic formulas were obtained for the expected fetal thyroid measurements according to estimated fetal weight (FW): FTC (cm) = -4.791 + 1.265 X logN FW; FTA (cm(2)) = -1.676 + 0.455 X logN FW; and FTTD (cm) = 0.399 + 0.001 X logN FW. Conclusion. We describe new nomograms of fetal thyroid measurements throughout gestation that may be useful in case of thyroid dysfunction. (C) 2008 Wiley Periodicals, Inc.

Quality of life before surgery is a predictive factor for satisfaction among patients undergoing sympathectomy to treat hyperhidrosis

Purpose: The objective of this study was to evaluate the postoperative quality of life (QOL) experienced among a group of 1167 patients who underwent video-assisted thoracoscopic sympathectomy (VATS) to treat primary hyperhidrosis, as compared with the presurgical QOL. Methods: Between February 2002 and June 2007, 1167 patients who had undergone VATS were surveyed. The majority had presented with palmar hyperhidrosis (794 patients; 68%), while 340 (29%) had presented with axillary hyperhidrosis. Based on data obtained from the QOL protocol applied to all of the patients preoperatively, the patients were divided into two groups according to the level of their QOL: group 1 consisted of 312 patients (27%) with poor QOL and group 2 of 855 patients (73%) with very poor QOL. The same protocol was applied postoperatively, and five different levels of satisfaction were obtained. The same parameters were evaluated for both the palmar and the axillary hyperhidrosis subgroups. Results: The patients with very poor QOL had much better results in terms of improvement in QOL than did those with poor QOL ( P < .05). The same result was observed for both the palmar and. axillary hyperhidrosis subgroups (P < .05). Conclusion: The worse the preoperative QOL among patients undergoing sympathectomy to treat primary hyperhidrosis is, the better the postoperative improvement in QOL will be. (J Vase Surg 2010;51:1190-4.)

Application of recombinant antibody library for screening specific antigens in a bovine sperm cell subpopulation

Antibody phage display libraries are a useful tool in proteomic analyses. This study evaluated an antibody recombinant library for identification of sex-specific proteins on the sperm cell surface. The Griffin.1 library was used to produce phage antibodies capable of recognizing membrane proteins from Nelore sperm cells. After producing soluble monoclonal scFv, clones were screened on Simental sperm cells by flow cytometry and those that bound to 40-60% of cells were selected. These clones were re-analyzed using Nelore sperm cells and all clones bound to 40-60% of cells. Positive clones were submitted to a binding assay against male and female bovine leukocytes by flow cytometry and one clone preferentially bound to male cells. The results indicate that phage display antibodies are an alternative method for identification of molecules markers on sperm cells. (C) 2007 Elsevier B.V. All rights reserved.

Diagonal band of Broca modulates the cardiac component of the baroreflex in unanesthetized rats

The diagonal band of Broca (DBB) is involved in cardiovascular control in rats, In the present Study, we report the effect of acute and reversible neurotransmission inhibition in the DBB by bilateral microinjection of the nonselective neurotransmission blocker CoCl(2) (1 mM, 100 nL) on the cardiac baroreflex response in unanesthetized rats. Local DBB neurotransmission inhibition did not affect baseline values of either blood pressure or heart rate, Suggesting no tonic DBB influence oil cardiovascular system activity. However, CoCl(2) microinjections enhanced both the reflex bradycardia associated with blood pressure increases caused by i.v. infusion of phenylephrine and tachycardiac response evoked by blood pressure decreases caused by i.v. infusion of sodium nitroprusside. An increase in baroreflex gain was also observed. Baroreflex returned to control values 60 min after CoCl(2) microinjections, confirming its reversible effect. In conclusion, our data suggest that synapses within DBB have a tonic inhibitory influence on both the cardiac parasympathetic and sympathetic components of the baroreflex. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Upregulation of intermediate calcium-activated potassium channels counterbalance the impaired endothelium-dependent vasodilation in stroke-prone spontaneously hypertensive rats

Endothelial dysfunction has been linked to a decrease in nitric oxide (NO) bioavailability and attenuated endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation. The small (SK(Ca)) and intermediate (IK(Ca)) calcium-activated potassium channels play a key role in endothelium-dependent relaxation. Because the repressor element 1-silencing transcription factor (REST) negatively regulates IK(Ca) expression, we hypothesized that augmented REST and decreased IK(Ca) expression contributes to impaired endothelium-dependent vasodilation associated with hypertension. Acetylcholine (ACh) responses were slightly decreased in small mesenteric arteries from male stroke-prone spontaneously hypertensive rats (SHRSPs) versus arteries from Wistar Kyoto (WKY) rats. Incubation with N-nitro-L-arginine methyl ester (L-NAME; 100 mu mol/L) and indomethacin (100 mu mol/L) greatly impaired ACh responses in vessels from SHRSP. lberiotoxin (0.1 mu mol/L), which is a selective inhibitor of large-conductance K(Ca) (BK(Ca)) channels, did not modify EDHF-mediated vasodilation in SHRSP or WKY. UCL-1684 (0.1 mu mol/L.), which is a selective inhibitor of SKCa channels, almost abolished EDHF-mediated vasodilation in WKY and decreased relaxation in SHRSP. 1-((2-chlorophenyl)diphenylmethyl)-1H-pyrazole (TRAM-34; 10 mu mol/L) and charybdotoxin (0.1 mu mol/L), which are both IKCa inhibitors, produced a small decrease of EDHF relaxation in WKY but completely abrogated EDHF vasodilation in SHRSP. EDHF-mediated relaxant responses were completely abolished in both groups by simultaneous treatment with UCL-1684 and TRAM-34 or charybdotoxin. Relaxation to SK(Ca)/IK(Ca) channels agonist NS-309 was decreased in SHRSP arteries. The expression of SK(Ca) was decreased, whereas IK(Ca) was increased in SHRSP mesenteric arteries. REST expression was reduced in arteries from SHRSP. Vessels incubated with TRAM-34 (10 mu mol/L) for 24h displayed reduced REST expression and demonstrated no differences in IK(Ca). In conclusion, IK(Ca) channel upregulation, via decreased REST, seems to compensate deficient activity of SK(Ca) channels in the vasculature of spontaneously hypertensive rats. (Translational Research 2009; 154:183-193)

Antimicrobial Activities of Indole Alkaloids from Tabernaemontana catharinensis

Tabernaemontana catharinensis root bark ethanol extract, EB2 fraction and the MMV alkaloid (12-methoxy-4-methylvoachalotine) were evaluated for their antimicrobial activities. T. catharinensis ethanol extract was effective against both strains of the dermatophyte Trichophyton rubrum at concentrations of 2.5 mg/mL (wild strain) and 1.25 mg/mL (mutant strain), while the EB2 fraction and MMV alkaloid showed a strong antifungal activity against wild and mutant strains with MIC values of <0.02 and 0.16 mg/mL, respectively. The EB2 fraction showed a strong antibacterial activity against ATCC strains of S. aureus, S. epidermidis, E. coli and P. aeruginosa with MICs from <0.02 to 0.04 mg/mL, as well as against resistant clinical isolates species of Enterococcus sp, Klebsiella oxytoca, Citrobacter, K. pneumoniae, P. mirabilis, S. aureus, S. epidermidis, E. coli and P. aeruginosa with MIC values ranging from 0.04 to 0.08 mg/mL. The MMV alkaloid presented a MIC of 0.16 mg/mL against the strains of S. aureus and E. coli ATCC. For the resistant clinical isolates Enterococcus sp, Citrobacter, S. aureus, S. epidermidis, E. coil and P. aeruginosa the MIC of MMV ranged from 0.08 to 0.31 mg/mL. The chromatography analysis of the EB2 fraction revealed the presence of indole alkaloids, including MMV, possibly responsible for the observed antimicrobial activity.

Pharmacokinetics of lidocaine and its metabolite in peridural anesthesia administered to pregnant women with gestational diabetes mellitus

Background Peridural blockade with lidocaine, bupivacaine, and fentanyl is an anesthetic procedure extensively used in obstetrics, justifying the pharmacokinetic study of these drugs during labor. Objective To investigate the influence of the physiopathological changes of gestational diabetes mellitus (GDM) on the pharmacokinetics of lidocaine and its metabolite monoethylglycinexylidide (MEGX) in pregnant women subjected to peridural anesthesia. Patients and methods Ten normal pregnant women (group 1) and six pregnant women with GDM (group 2) were studied, all of them at term. The patients received 200 mg 2% lidocaine hydrochloride without a vasoconstrictor by the peridural locoregional route. Maternal blood samples were collected at predetermined times for the analysis of lidocaine and MEGX by chromatography and pharmacokinetic analysis. Results The median pharmacokinetic parameters of lidocaine for groups 1 and 2 (P <= 0.05), respectively, were as follows: for Cmax 879.11 and 1,145.58 ng/ml, AUC(0-infinity) 256.01 and 455.95 wg min(-1) ml(-1), Cl/f/kg 10.61 and 5.64 ml min(-1) kg(-1), and Vd/f/kg 3.26 and 2.19 L/kg. The median pharmacokinetic parameters of MEGX for groups 1 and 2 (P <= 0.05), respectively, were as follows: for Cmax 82.71 and 141.38 ng/ml, Tmax 44.71 and 193.14 min, t(1/2)alpha 7.64 and 59.77 min, alpha 0.097 and 0.012/min, and AUC(0-infinity) 29.91 and 108.23 mu g min(-1) ml(-1). Conclusion The present data permit us to conclude that the apparent clearance of lidocaine and MEGX was reduced in diabetic patients compared to normal women, suggesting that GDM inhibits the CYP1A2/CYP3A4 isoforms responsible for the metabolism of this drug and its metabolite.