Polymorphisms at GLUT1 Gene Are Not Associated With the Development of TSP/HAM in Brazilian HTLV-1 Infected Individuals and the Discovery of a New Polymorphism at GLUT1 Gene

The development of HTLV-1 associated clinical manifestations, such as TSP/HAM and ATLL, occur in 2-4% of the infected population and it is still unclear why this infection remains asymptomatic in most infected carriers. Recently, it has been demonstrated that HTLV uses the Glucose transporter type 1 (GLUT1) to infect T-CD4(+) lymphocytes and that single nucleotide polymorphisms (SNP) in the GLUT1 gene are associated with diabetic nephropathy in patients with diabetes mellitus in different populations. These polymorphisms could contribute to a higher GLUT1 protein expression on cellular membrane, facilitating the entry of HTLV and its transmission cell by cell. This could result in a higher provirus load and consequently in the development of TSP/HAM. To evaluate the role of GLUT1 gene polymorphisms in the development of TSP/HAM in HTLV-1 infected individuals, the g.22999G > T, g.15339T > C and c.-2841A > T sites were analyzed by PCR/RFLP or sequencing in 244 infected individuals and 102 normal controls. The proviral load of the HTLV-1 infected patients was also analyzed using Real Time Quantitative PCR. Genotypic and allelic frequencies of the three sites did not differ significantly between controls and HTLV-1 infected individuals. There was no difference in genotypic and allelic distributions among patients as to the presence or absence of HTLV-1 associated clinic manifestations. As regards the quantification of the provirus load, we observed a significant reduction in the asymptomatic individuals compared with the oligosymptomatic and TSP/HAM individuals. These results suggest that g.22999G > T, g.15339T > C, and c.-2841A > T SNP do not contribute to HTLV-1 infection nor to the genetic susceptibility of TSP/HAM in Brazilian HTLV-1 infected individuals. J. Med. Virol. 81:552557, 2009. (C) 2009 Wiley-Liss, Inc.

Intraluminal Esophageal Pressures in Speaking Laryngectomees

Objectives: The objective of the present study was to evaluate intraluminal esophageal pressure during voice and speech emission in speaking laryngectomees with a tracheoesophageal prosthesis. Methods: In our prospective analysis in a tertiary-care academic hospital, 25 laryngectomees were divided into 2 groups: 11 speaking individuals with a tracheoesophageal prosthesis and a control group of 14 nonspeaking laryngectomees. All patients were subjected to manometry during voice and speech emission tests. We determined the pressures achieved in the distal, middle, and proximal parts of the esophagus. Results: Statistical analysis revealed that the amplitude of pressure in the distal esophagus during sound emission was higher in speaking laryngectomees; in the middle esophagus, intraluminal pressure during emission of the sentence was higher in speaking subjects, and in the proximal esophagus there was no difference between the groups. Conclusions: During the manometric evaluation of the distal and middle esophagus in the presence of voice and speech emission, the intraluminal pressure revealed a significant difference for the speaking laryngectomees with a tracheoesophageal prosthesis. The proximal esophagus behaved similarly in the groups of speakers and nonspeakers. Speaking laryngectomees with a tracheoesophageal prosthesis depend on a differentiated performance of the middle and distal parts of the esophagus.

Epidemiologic aspects and clinical outcome of fungal keratitis in southeastern Brazil

PURPOSE. Fungal keratitis (FK) is a sight-threatening disease, more prevalent in developing regions. The present retrospective study was conducted in order to evaluate the epidemiologic and clinical aspects and the progression of FK in patients treated at two ophthalmologic reference centers in Southeast Brazil. METHODS. The charts of patients with infectious keratitis treated between 2000 and 2004 were reviewed. For the 66 cases of FK confirmed by microbiological analysis, data related to patient, disease, and therapeutic approaches were obtained. RESULTS. Mean patient age was 40.7 +/- 16 years. Fifty-three were men and 13 were women. Ocular trauma occurred in 40% of cases (27). Previous medications taken by the patients were quinolone in 72.5% and antimycotics in 30%. Visual acuity (VA) at presentation was >0.3 in 16% and <0.1 in 74.5%. Penetrant keratoplasty was performed in 38% and evisceration in 15%. The causing agents were Fusarium sp in 67%, Aspergillus sp in 10.5%, and Candida sp in 10%. Medication alone resolved 39% of cases within a mean period of 24.5 +/- 12 days. Final VA was >0.3 in 28%, and <0.1 in 63%. CONCLUSIONS. Fungal keratitis presented as a disease with severe complications, predominantly among young males, and was mostly caused by filamentous fungi. The present information permits the establishment of preventive strategies. Reducing the time between onset and treatment and using more accessible specific medication would reverse the negative prognosis. (Eur J Ophthalmol 2009; 19: 355-61)

Postnatal growth and cardiometabolic profile in young adults born large for gestational age

Context The association between large for gestational age (LGA) phenotype, postnatal growth and cardiometabolic risk (CMR) in adult life remains unclear. The role of IGF1 genotype on LGA-related outcomes in adult life is unknown. Aim To assess the postnatal growth, IGF-I levels, CMR and the influence of the 737.738 IGF1 in adults born LGA. Subjects Case-control study (n = 515) nested in a population-based prospective cohort (n = 2063); 117 LGA and 398 gender-matched controls appropriate for gestational age (AGA) subjects. Methods Anthropometry was evaluated at birth, at 9-10 and at 23-25 years old. At the age of 23-25 years, blood pressure (BP), glycaemia, insulinaemia, homeostasis model assessment - insulin resistance, lipids, fibrinogen, and plasma IGF-I and 737.738 IGF1 polymorphism were assessed. Results Large for gestational age subjects remained heavier and taller than AGA at 9-10 and 23-25 years (P < 0.05); at 23-25 years, LGA had greater waist circumference (WC; P < 0.05) and higher BP (P < 0.05) than controls. Body proportionality at birth did not predict metabolic outcome. LGA subjects presenting catch-down of weight in childhood had lower body mass index (BMI; P = 0.001), lower WC (P < 0.05) and lower BP (P < 0.05) at 2325 years. 737.738 IGF-I genotype differed between groups (P < 0.001). Homozygosis for polymorphic alleles was associated with increased odds of LGA (OR: 3.2; 95% CI: 1.5-6.9), higher IGF-I (56.9 +/- 16.4 vs 37.7 +/- 16.0 nm; P < 0.01) and lower BP (114/68 vs 121/73 mmHg; P < 0.05). Conclusions Young adults born LGA presented higher BMI, WC and BP and appear to be at higher CMR risk than AGA subjects. The 737.738 IGF1 polymorphism appears to play a role on birth size and LGA-related metabolic outcomes.

Birth weight and bone mass in young adults from Brazil

Background: Birth weight is positively associated with adult bone mass. However, it is not clear if its effect is already evident in early adulthood. Objective: To investigate the association between birth weight, adult body size, the interaction between them and bone mass in young adults. Methods: Bone densitometry by DXA was performed on 496 individuals (240 men) aged 23-24 years from the 1978/79 Ribeirao Preto (southern Brazil) birth cohort, who were born and still residing in the city in 2002. Birth weight and length as well as adult weight and height were directly measured and converted to z-scores. The influence of birth weight and length, and adult weight and height on bone area (BA), bone mineral content (BMC) and bone mineral density (BMD) at the lumbar spine, proximal femur and femoral neck were investigated through simple and multiple linear regression models. Adjustments were made for sex, skin color, gestational age, physical activity level, smoking status and dietary consumption of protein, calcium and alcohol. Interaction terms between birth weight and adult weight, and birth length and adult height were tested. Results: Men in the highest fertile of birth weight distribution had greater BA and BMC at all three bone sites when compared with their counterparts in the lowest tertiles (p<0.008). For BMD, this trend was observed only in the lumbar spine. Adult weight and height were positively associated with BA and BMC at all three bone sites (p<0.05). For BMD, these associations were seen for adult weight, but for adult height an association was observed only in the lumbar spine. Birth weight retained positive associations with proximal femur BA and BMC after adjustments for current weight and height. No interaction was observed between variables measuring prenatal growth and adult body size. Conclusion: Birth weight and postnatal growth are independent determinants of adult bone mass in a sample of Brazilian adults. This effect is already evident in early adulthood. (C) 2010 Elsevier Inc. All rights reserved.

Adiponectin: serum levels, promoter polymorphism, and associations with birth size and cardiometabolic outcome in young adults born large for gestational age

Objective: To assess whether the -11391G > A polymorphism in the regulatory region of the adiponectin gene (ADIPOQ) is associated with birth size, postnatal growth, adiponectinemia, and cardiometabolic risk in adult life. Design: Case-control study nested within a prospective cohort of 2063 community subjects born in 1978/1979 and followed since birth to date. Methods: ADIPOQ -11391G > A genotype-phenotype associations were evaluated in 116 subjects born large for gestational age (LGA) and 392 gender-matched controls at birth (birth size), at 8-10 years (catch-down growth), and at 23-25 years of age (cardiometabolic profile). Results: The -11391A variant allele frequency was higher in LGA subjects (P=0.04). AA genotype was associated with augmented probability of being born LGA (odds ratio=4.14; 95% confidence interval: 1.16-16.7; P=0.03). This polymorphism was associated neither with body composition nor with postnatal growth pattern. At the age of 23-25 years, the -11391A variant allele was associated with higher serum adiponectin levels (GG: 10.7 +/- 6.2 versus GA: 12.2 +/- 6.5 versus AA: 14.2 +/- 6.8 mu g/ml; P < 0.01). Subjects born LGA presented higher body mass index (BMI; P=0.01), abdominal circumference (P=0.04), blood pressure (P=0.04), and homeostasis assessment model for insulin resistance (P=0.01) than adequate for gestational age. Symmetry at birth did not influence these variables. The occurrence of catch-down of weight was associated with lower BMI and abdominal circumference (P < 0.001) at 23-25 years. Conclusions: The -11391A ADIPOQ gene variant was associated with increased chance of being born LGA and with higher adiponectin levels in early adult life.

Long-term treatment of familial male-limited precocious puberty (testotoxicosis) with cyproterone acetate or ketoconazole

Background Familial male-limited precocious puberty (FMPP) or testotoxicosis is a rare gonadotrophin-independent form of sexual precocity caused by constitutively activating mutations of the LH receptor. Several clinical therapeutic approaches have been reported for this disorder, but with a paucity of long-term outcome data. Objective To evaluate the long-term treatment of testotoxicosis with cyproterone acetate or ketoconazole. Design A multicentric retrospective clinical study. Patients Ten boys from eight unrelated Brazilian families who carried known LH-receptor activating mutations were treated with 70 mg/m(2) cyproterone acetate (n = 5) or 10 mg/kg ketoconazole (n = 5) for a mean period of 5 and 8 years, respectively. Measurements Chronological and bone ages, bone age/chronological age ratio, target height (TH) range, adult height, basal and GnRH-stimulated gonadotrophin levels and basal testosterone levels were assessed. Results Growth velocity decreased significantly during treatment with cyproterone acetate or ketoconazole when compared to pretreatment value in each group (P < 0.05). Bone age/chronological age ratio decreased significantly after cyproterone acetate or ketoconazole therapy. Basal testosterone levels were significantly lower in patients undergoing ketoconazole compared to cyproterone acetate treatment [0.6 +/- 0.3 nmol/l (42 +/- 21 ng/dl) vs. 5.6 +/- 4.0 nmol/l (392 +/- 280 ng/dl); P < 0.05], as expected. Secondary gonadotrophin-dependent precocious puberty occurred at a similar frequency (40%) in both groups. Five patients have attained adult height and two patients have already reached 90% of their adult height. Two of them achieved their TH range and one patient, for whom TH was not available, had an adult height of 0.3 SDS. Four boys (two in each group) did not attain their TH range. Conclusion Long-term treatment with cyproterone acetate or ketoconazole resulted in similar outcomes without important side-effects in boys with testotoxicosis. However, both therapies showed limited efficacy in attaining normal adult height.

Risk stratification in neonates and infants submitted to cardiac surgery with cardiopulmonary bypass: A multimarker approach combining inflammatory mediators, N-terminal pro-B-type natriuretic peptide and troponin I

Low cardiac output syndrome (LCOS) is a common problem following cardiac surgery with cardiopulmonary bypass (CPB) in neonates and infants, and its early recognition remains a challenging task. We aimed to test whether a multimarker approach combining inflammatory and cardiac markers provides complementary information for prediction of LCOS and death in children submitted to cardiac surgery with CPB. Forty-six children younger than 18 months with congenital heart defects were prospectively enrolled. No intervention was made. Blood samples were collected pre-operatively, during CPB and post-operatively (PO) for measurement of interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, cardiac troponin I (cTnI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Clinical data and outcome variables were recorded. Logistic regression was used to identify predictors of LCOS and death. Multivariate logistic regression identified pre-operative NT-proBNP and IL-8 4 h PO as independent predictors of LCOS, while cTnI 4 h PO and CPB length were independent predictors of death. The use of inflammatory and cardiac markers in combination improved sensitivity, negative predictive value and accuracy of the models. In conclusion, the combined assessment of inflammatory and cardiac biochemical markers can be useful for identifying young children at increased risk for LCOS and death after heart surgery with CPB. (C) 2008 Elsevier Ltd. All rights reserved.

Treatment of Hepatocellular Carcinoma With Liver Transplantation: A Single-Center Experience From Brazil

Introduction. Orthotopic liver transplantation (OLT) is the treatment of choice of hepatocellular carcinoma (HCC) for patients with cirrhosis, mainly those with early HCC. Herein we have present the clinical characteristics and outcomes of cirrhotic patients with HCC who underwent OLT from cadaveric donors in our institution. Methods. From May 2001 to May 2009, we performed 121 OLT including 24 patients (19.8%) with cirrhosis and HCC within the Milan criteria. In 4 cases, HCC was an incidental finding in the explants. Results. The patients` average age was 55 +/- 10 years, including 82% men. Fifty percent of patients were Child class B or C. The average Model for End Stage Liver Disease for Child A, B, and C categories were 11, 15, and 18, respectively. The HCC diagnosis was made by 2 dynamic images in 16 cases; 1 dynamic image plus alphafetoprotein >400 ng/mL in 4; and 4 by histologic confirmation. Twenty patients received a locoregional treatment before OLT: 6 percutaneous ethanol injection, 9 transarterial chemoembolization, 1 transarterial embolization, and 4 a combination of these modalities. The median follow-up after OLT was 19.7 months (range, 1-51). A vascular invasion was observed in the explant of 1 patient, who developed an HCC recurrence and succumbed at 8 months after OLT. Two further patients, without vascular invasion or satellite tumor displayed tumor recurrences at 7 and 3 months after OLT, and death at 2 and 1 month after the diagnosis. The remaining 25 patients have not shown a tumor recurrence. Conclusion. In the present evaluation, OLT patients with early HCC and no vascular invasion showed satisfactory results and good disease-free survival. Strictly following the Milan criteria for liver transplantation in patients with HCC greatly reduces but does not completely avoid, the chances of tumor recurrence.

Imipramine enhances cell proliferation and decreases neurodegeneration in the hippocampus after transient global cerebral ischemia in rats

This study was aimed to determine whether imipramine chronic treatment promotes neurogenesis in the dentate gyrus (DG) and interferes with neuronal death in the CA1 subfield of the hippocampus after transient global cerebral ischemia (TGCI) in rats. After TGCI, animals were treated with imipramine (20 mg/kg, i.p.) or saline during 14 days. 5-Bromo-2`-deoxyuridine-5`-monophosphate (BrdU) was injected 24 h after the last imipramine or saline injection to label proliferating cells. In order to confirm the effect of TGCI on neuronal death and cell proliferation, a group of animals was sacrificed 7 days after TGCI. Neurogenesis and neurodegeneration were evaluated by doublecortin (DCX)-immunohistochemistry and Fluoro-Jade C (FJC)- staining, respectively. The rate of cell proliferation increases 7 days but returns to basal levels 14 days after TGCI. There was a significant increase in the number of FJC-positive neurons in the CA1 of animals 7 and 14 days after TGCI. Chronic imipramine treatment increased cell proliferation in the SGZ of DG and reduced the neurodegeneration in the CA] of the hippocampus 14 days after TGCI. Immunohistochemistry for DCX detected an increased number of newly generated neurons in the hippocampal DG 14 days after TGCI, which was not affected by imipramine treatment. Further studies are needed to evaluate whether imipramine treatment for longer time would be able to promote survival of newly generated neurons as well as to improve functional recovery after TGCI. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Pitfalls in the Differential Diagnosis of Renal Tumor in an Adolescent

The differential diagnosis of renal tumors, particularly in adolescents, may be challenging. We describe an 11-year-old female with a primary intra-renal mass. Initial differential diagnoses included primitive neuroectodermal tumor (PNET), desmoplastic small round cell tumor (DSRCT), and Wilms Turner (WT). Extensive pathologic and molecular analysis on initial and relapsed tumor samples confirmed WT. The EWS-WTI and EWS-FL11 rearrange-merits, distinctive of DSRCT and PNET were negative. The differential diagnosis on monophasic blastemal WT may be complex. Primary renal DSRCT and MET have been rarely described. Nevertheless, molecular confirmation for these rare conditions may be necessary in selected cases. Pediatr Blood Cancer 2010;54:3 19-321. (C) 2009 Wiley-Liss, Inc.

Analysis of placenta vascularization in patients with uterine altered artery Doppler flow velocity exams

Background: One of the frequent questions in obstetric practice is to determine placental vascular changes that may account for abnormal Doppler flow velocity alterations in maternal uterine vessels from women and fetuses without pregnancy pathology. Methods: A retrospective morphometric study was realized using 27 placentas from patients submitted for Doppler flow velocity exam during pregnancy. The placentas were morphologically examined using hematoxylin-eosin staining. Measurements of villi were made with the use of a video camera coupled to a common light microscope and a computer with automatic image analyzing software. Results: Of the 27 placentas, 13 (48%) were of patients showing unaltered Doppler and 14 (52%) showing altered Doppler. The number of stem villi vessels was significantly larger in the placentas of patients with Doppler exam alterations (P = 0.003). This group also presented greater stem villi vessel thickness, although without significant difference. The number of intermediary and terminal villi vessels was greater in the placentas of patients with altered Doppler exams (P < 0.001), and a greater terminal villi area was observed in these cases (P < 0.001). Conclusion: The morphological proof that uterine artery Doppler flow velocity exam alterations are associated with placental vascular alterations demonstrates the importance of this exam during prenatal care, even in the absence of maternal-fetal alterations.

Nitrite or sildenafil, but not BAY 41-2272, blunt acute pulmonary embolism-induced increases in circulating matrix metalloproteinase-9 and oxidative stress

Introduction: Inhibition of matrix metalloproteinases (MMPs) improves the hemodynamics during acute pulmonary embolism (APE) and oxidative stress upregulates MMPs. We compared the effects of different NO-cGMP pathway activators on APE-induced increases in MMPs. Materials and Methods: Hemodynamic and biochemical evaluations were performed in non-embolized dogs treated with saline (N = 5), and in microspheres embolized dogs receiving saline (n = 9), or nitrite (6.75 mu mol/kg i.v. over 15 min followed by 0.28 mu mol/kg/min; n = 5), or sildenafil (0.25 mg/kg; n = 5), or BAY 41-2272 (0.03, 0.1, 0.3, and 1 mg/kg/h; n = 5). Plasma thiobarbituric acid reactive substances (TBARS) concentrations were determined. Zymograms of plasma samples were performed, and in vitro antioxidant effects or inhibition of MMPs by these drugs were examined. Results: APE increased mean pulmonary artery pressure by similar to 25 mmHg. Nitrite, BAY 41-2272, or sildenafil reversed this increase by similar to 40% (P < 0.05). Similar effects were seen on the pulmonary vascular resistance. While both nitrite and sildenafil produced no systemic effects, the highest dose of BAY 41-2272 produced systemic hypotension (P<0.05). While nitrite and sildenafil blunted the increases in plasma pro-MMP-9 levels and TBARS (all P < 0.05), BAY 41-2272 produced no such effects. Nitrite and sildenafll produced in vitro antioxidant effects and inhibited MMPs only at high concentrations. BAY 41-2272 produced no such effects. Conclusions: Activation of the NO-cGMP pathway with nitrite or sildenafil, but not with BAY 41-2272, attenuates APE-induced oxidative stress and increased MMP-9 levels. These findings are consistent with the idea that NO-cGMP pathway activators with antioxidant effects prevent the release of MMP-9 during APE. (c) 2008 Elsevier Ltd. All rights reserved.

Evidence of early involvement of matrix metalloproteinase-2 in lead-induced hypertension

Lead exposure increases blood pressure (BP) by unknown mechanisms. Many recent studies have shown the involvement of matrix metalloproteinases (MMPs) in hypertension, particularly MMP-2. In this work, we have examined whether MMP-2 levels increase with lead-induced increase in BP. We have also investigated whether doxycycline (an MMP inhibitor) affects these alterations. To this end, rats were exposed to lead (90 ppm) and treated with doxycycline or vehicle for 8 weeks. Similar aortic and whole blood lead levels were found in lead-exposed rats treated with either doxycycline or vehicle. Lead-induced increases in BP and aortic MMP-2 levels (activity, protein, and mRNA) were blunted by doxycycline. Doxycycline also prevented lead-induced increases in the MMP-2/TIMP-2 mRNA ratio. No significant changes in vascular reactivity or morphometric parameters were found. In conclusion, lead exposure increases BP and vascular MMP-2, which is blunted by doxycycline. This observation suggests that MMP-2 may play a role in lead-induced increases in BP.

Glucocorticoid resistance in dialysis patients may impair the kidney allograft outcome

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 ( IC50) 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 Kd ( 12.4 +/- 1.8 versus 7.2 +/- 0.9 nM) and Bmax ( 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 Kd was an independent predictor of ARE ( OR 8.8, P= 0.03) aswell 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.