Isnard Elman Litvin

Exercise training contributes to H2O2/VEGF signaling in the lung of rats with monocrotaline-induced pulmonary hypertension.

Abstract Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling and right ventricle overload. Given that angiogenesis is a key factor involved in the reduction of vascular resistance to blood flow, we tested the hypothesis that aerobic exercise exerts a positive impact on hydrogen peroxide (H 2 O 2 ) and protein kinase B (Akt) levels in the lung parenchyma. To study the effects of aerobic exercise on lung angiogenesis signaling, Wistar rats were administered monocrotaline (MCT) (60xa0mg/kg i.p.) or the same volume of saline (0.9% NaCl i.p.). There was an increase in H 2 O 2 (43%) in PAH-trained animals (TM) compared to control animals (SM). H 2 O 2 showed a positive correlation (rxa0=xa00.77) with vascular endothelial growth factor (VEGF). VEGF was higher (4.7 fold) in TM animals compared to SM. VEGF and angiopoietin-1 (Ang-1) showed positive staining in the lung parenchyma of TM and SM. Glutathione peroxidase showed higher activity in the TM group (49%) compared to trained control (TC). Aerobic exercise increased the activity of peroxiredoxin (Pxa0 2 O 2 /VEGF/p-Akt signaling for pulmonary physiological angiogenesis. It is associated with an improvement in RV function, as evaluated by echocardiography.

Effects of aerobic exercise training on metabolism of nitric oxide and endothelin-1 in lung parenchyma of rats with pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and proliferative obstruction of pulmonary vessels, which promotes a progressive increase in pulmonary vascular resistance (PVR). The effect of exercise training on oxidative stress, metabolism, and markers of nitric oxide (NO) and endothelin-1 (ET-1) was analyzed in the lung tissue of rats with PAH induced by monocrotaline (MCT).Twenty-four Wistar rats were divided into four groups (5–7 animals): sedentary control (SC), sedentary MCT (SM), trained control (TC), and trained MCT (TM). The TC and TM groups participated in a treadmill training protocol (60% VO2 max) for 5xa0weeks, 3xa0weeks of which were performed after the injection of MCT (60xa0mg/kg i.p.) or saline. MCT administration promoted an increase in PVR and right ventricle hypertrophy, and reduction of right ventricle systolic function assessed by echocardiography. These changes were not improved by exercise training. The activity of NO synthase was reduced in the animals of the TC, TM, and SM groups. No significant differences were found in total nitrite concentration and expression of endothelial NO synthase. Moreover, the TM group showed strong staining for iNOS and nitrotyrosine, suggesting an increase in oxidative stress in these animals. In parallel, reduced expression of type B ET-1 receptors was noticed in the SM and TM groups in comparison to controls. In conclusion, the aerobic training protocol was unable to mitigate changes in the metabolism of NO and ET-1, probably because of the disease severity in these animals, especially in the TM group.

Accuracy of p57 KIP2 compared with genotyping for the diagnosis of complete hydatidiform mole: protocol for a systematic review and meta-analysis

BackgroundDistinguishing hydatidiform moles (HMs) from non-molar specimens and the subclassification of HM are important because complete hydatidiform mole (CHM) is associated with an increased risk of gestational trophoblastic neoplasia. However, diagnosis based solely on morphology has poor interobserver reproducibility. Recent studies have demonstrated that the use of p57KIP2 immunostaining improves diagnostic accuracy for CHM.MethodsWe will conduct a systematic review of prospective and retrospective studies to evaluate the accuracy of p57KIP2 immunostaining compared with molecular genotyping for the diagnosis of CHM. A high-sensitivity search strategy will be employed in MEDLINE, EMBASE, LILACS, The Grey Literature Report, OpenGrey, OAIster, and Cochrane CENTRAL. Two reviewers will independently screen all identified references for eligibility and extract data. The methodological quality and bias of the included studies will be assessed according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool, and the overall quality of evidence will be assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. If a meta-analysis is possible, pooled estimates of sensitivity, specificity, and positive and negative likelihood ratios will be calculated using bivariate random-effects models. Statistical heterogeneity will be evaluated with I2 statistics and explored through sensitivity analysis.DiscussionThere is considerable overlap between the histological features of molar and non-molar pregnancies and between complete and partial HMs, which results in significant interobserver variability in the diagnosis of CHM and its mimics. Therefore, molecular techniques are used to correctly diagnosis and treat CHM. However, these molecular diagnostic methods are technically difficult to perform, relatively costly, and unavailable in most pathology laboratories. According to our results, p57KIP2 immunostaining appears to be a practical and accurate adjunct for the diagnosis of CHM and its mimics because this technique is relatively simple, reliable, cost-efficient, and rapid. This systematic review will help to determine whether p57KIP2 immunostaining is an adequate alternative diagnostic test for CHM.Systematic review registrationPROSPERO CRD42015024181

Bucindolol improves right ventricle function in rats with pulmonary arterial hypertension through the reversal of autonomic imbalance

ABSTRACT Pulmonary arterial hypertension (PAH) is characterised by an elevation in afterload imposed on the right ventricle (RV), leading to hypertrophy and failure. The autonomic nervous system (ANS) plays a key role in the progression to heart failure, and the use of beta‐blockers attenuates this process. The aim of this study was to verify the role of bucindolol, a&bgr;1‐, &bgr;2‐ and &agr;1‐blocker, on the ANS, and its association with RV function in rats with PAH. Male Wistar rats were divided into four groups: control, monocrotaline, control+bucindolol, and monocrotaline+bucindolol. PAH was induced by a single intraperitoneal injection of monocrotaline (60 mg/kg). After two weeks, animals were treated for seven days with bucindolol (2 mg/kg/day i.p.) or vehicle. At the end of the treatment, animals underwent echocardiographic assessment, catheterisation of the femoral artery and RV, and tissue collection for morphometric and histological evaluation. In the monocrotaline+bucindolol group, there was a decrease in mean pulmonary artery pressure (33%) and pulmonary congestion (21%), when compared to the monocrotaline. Bucindolol treatment also reduced RV pleomorphism, necrosis, fibrosis and infiltration of inflammatory cells. An improvement in RV systolic function was also observed in the monocrotaline+bucindolol group compared to the monocrotaline. In addition, bucindolol promoted a decrease in the cardiac sympathovagal balance (93%) by reducing sympathetic drive (70%) and increasing parasympathetic drive (142%). Bucindolol also reduced blood pressure variability (75%). Our results show that the beneficial effects from bucindolol treatment appeared to be a consequence of the reversal of monocrotaline‐induced autonomic imbalance.

Designing the Review

Evidence-based medicine (EBM) or practice integrates the best research evidence with clinical experience and client values. A systematic review (SR) uses explicit and transparent methods to identify, select, appraise, and synthesize results from different, but related, studies. Diagnostic tests are used to aid health professionals in the diagnosis or detection of a specific health outcome. They provide information related to the current stage of the condition, considering the clinical context, to help professionals make decisions.

Exercise training versus T3 and T4 hormones treatment: The differential benefits of thyroid hormones on the parasympathetic drive of infarcted rats

Aims: This study aimed to investigate whether beneficial effects of thyroid hormones are comparable to those provided by the aerobic exercise training, to verify its applicability as a therapeutic alternative to reverse the pathological cardiac remodeling post‐infarction. Materials and methods: Male rats were divided into SHAM‐operated (SHAM), myocardial infarction (MI), MI subjected to exercise training (MIE), and MI who received T3 and T4 treatment (MIH) (n = 8/group). MI, MIE and MIH groups underwent an infarction surgery while SHAM was SHAM‐operated. One‐week post‐surgery, MIE and MIH groups started the exercise training protocol (moderate intensity on treadmill), or the T3 (1.2 &mgr;g/100 g/day) and T4 (4.8 &mgr;g/100 g/day) hormones treatment by gavage, respectively, meanwhile SHAM and MI had no intervention for 9 weeks. The groups were accompanied until 74 days after surgery, when all animals were anesthetized, left ventricle echocardiography and femoral catheterization were performed, followed by euthanasia and left ventricle collection for morphological, oxidative stress, and intracellular kinases expression analysis. Key findings: Thyroid hormones treatment was more effective in cardiac dilation and infarction area reduction, while exercise training provided more protection against fibrosis. Thyroid hormones treatment increased the lipoperoxidation and decreased GSHPx activity as compared to MI group, increased the t‐Akt2 expression as compared to SHAM group, and increased the vascular parasympathetic drive. Significance: Thyroid hormones treatment provided differential benefits on the LV function and autonomic modulation as compared to the exercise training. Nevertheless, the redox unbalance induced by thyroid hormones highlights the importance of more studies targeting the ideal duration of this treatment.

Bucindolol attenuates the vascular remodeling of pulmonary arteries by modulating the expression of the endothelin-1 A receptor in rats with pulmonary arterial hypertension

The aim of this study was to investigate the role of the ß-adrenergic blocker bucindolol on endothelial dysfunction and pulmonary vascular remodeling in rats with pulmonary arterial hypertension (PAH). Male Wistar rats were divided into four groups: control, monocrotaline (MCT), control?+?bucindolol and monocrotaline?+?bucindolol (MCT?+?BCD). PAH was induced by an injection of monocrotaline (60?mg/kg i.p.). After two weeks, the animals were treated for seven days with bucindolol (2?mg/kg/day i.p.) or vehicle. Echocardiography was performed upon treatment completion to analyze pulmonary vascular resistance (PVR) and right ventricle (RV) myocardial performance index. Lungs were collected for oxidative stress and western blot analysis, and the pulmonary artery was analyzed for histological and immunohistochemical parameters. The MCT?+?BCD group showed a decrease (32%) in the protein expression of endothelin-1 type A receptor (ETAR) and in the ratio of ETA/endothelin-1 type B receptor (ETBR) (62%) as compared to the MCT group. Bucindolol treatment did not alter oxidative stress, as determined by lipid peroxidation analysis and antioxidant enzyme activities and expression, endothelial nitric oxide synthase immunocontent and decreased nitrotyrosine levels. Moreover, bucindolol improved vascular remodeling of the pulmonary artery in the MCT?+?BCD group by decreasing (21%) PVR and increasing RV workload in relation to MCT.

Expression analysis of transglutaminase 2 in premalignant lesions of the cervix

BackgroundThe medical management of low-grade squamous intraepithelial lesions (LSIL) is variable, thus a biomarker could assist with the clinical conduct. Type 2 transglutaminase (TG2) has been proposed as a cellular-interfering factor in HPV infection and carcinogenesis. Therefore, this study has the objective of evaluating TG2 expression in LSIL and high-grade squamous intraepithelial lesions (HSIL) and of relating it to the different HPV viral types.MethodsThis study included 146 patients with suspected LSIL or HSIL detected in routine conventional Papanicolaou tests. The presence of HPV DNA and viral typing was defined by the polymerase chain reaction method (PCR). TG2 Immunohistochemistry (IHC) was conducted according to the manufacturers instructions; IHC was carried out in an Autosteiner-Link 48 Dako equipment. IHC quantitation was performed by relative expression and by using the software Image J. Qualitative variables, such as frequencies and proportions, were compared by using the χ2 test for independent samples. For comparison of the qualitative to the quantitative data, nonparametric Mann-Whitney test was used.ResultsThe association between histopathological examination and TG2 was statistically significant (p <0.05). Results showed that patients with normal cervical histopathology and LSIL are locally associated with TG2 expression levels >50% (p <0.05), and patients with HSIL are associated with no TG2 expression (p <0.05). The analysis of the samples with the Image J software shows a significant (p <0,001) decrease in TG2 immunostaining in HSIL if compared to normal and to LSIL samples. This demonstrates a correlation between the relative quantification and the results provided by Image J. Analysis of HPV types showed a significant association with HPV11 (pu2009=u20090.031). This indicates that patients with HPV type 11 had higher TG2 values than patients with different types. Image J analysis showed no significant association between TG2 and HPV viral types.ConclusionThe present data suggest that TG 2 has a high expression in LSIL and normal tissues, and decreased in HSIL. We also observed that its expression is associated with HPV11.