Search

Objectives: To evaluate the effect of L-carnitine and piracetam on the muscle injury induced by simvastatin in healthy male subjects during the therapy with oral doses of 10 mL of a solution containing L-carnitine 100 mg/mL + piracetam 80 mg/mL (test group) or placebo (control group) and 40 mg simvastatin once a day during 35 consecutive days. The effect of L-carnitine and piracetam in the reduction of myopathic symptomatology caused by exercise, as well as safety and tolerability were also evaluated., Materials and Methods: This study was performed on two different occasions, of which 42 subjects were investigated on occasion 1 and 19 on occasion 2. Discomfort or pain was evaluated according to modified Borg scale. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transferase (γ-GT), creatine kinase (CK), and lactic dehydrogenase (LDH) were evaluated on the 4 th , 11 th , 18 th , 25 th , and 32 nd day after therapy, and before and until 4 hours after an exercise test performed on a treadmill on day 36., Results: A higher incidence of pain or discomfort was observed in the control group than in the test group, mainly in occasion 1 (29% vs. 62% experienced pain or discomfort in any period, p = 0.0295). The serum levels of AST, ALT, and LDH were statistically different, with lower values in the test group compared to the control group., Conclusion: Concomitant use of L-carnitine and piracetam might have a muscle-protective effect and protection against simvastatin-induced myalgia. Furthermore, the formulation was safe and well tolerated by the subjects investigated in this trial.

Objective: To perform a comparative bioavailability study between a test (re-formulation) and a reference acetylsalicylic acid formulation (Ecasil-81, 81 mg coated tablet) in healthy subjects under fed condition., Materials and Methods: Healthy subjects (n = 48) were included in this monocentric, open-label, randomized, two-way crossover pharmacokinetic study. They received a single 81-mg oral dose of a test or a reference formulation of acetylsalicylic acid under fed condition, with a 7-day washout period between the treatments. Blood samples were collected over a period of 36 hours. The salicylic acid plasma concentration was measured by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Pharmacokinetic analysis was performed using WinNonlin software., Results: The geometric mean and 90% confidence interval of test/reference formulation ratios were 109.32% (102.54 - 116.54%) and 106.94% (102.97 - 111.07%) for salicylic acid C max and AUC 0-last , respectively. Food decreased the AUC and C max (p < 0.001) and delayed the t max (p = 0.0077). The investigated women presented higher AUC 0-∞ and C max values (p < 0.001) than men. The clinical and laboratory exams did not show significant alterations., Conclusion: The re-formulation is bioequivalent to the reference formulation regarding the absorption extent and rate in fed healthy subjects. The administration of acetylsalicylic acid with food decreased its bioavailability. Moreover, differences in salicylic acid disposition related to sex were observed. The treatments were well tolerated by the investigated subjects.

Cardiovascular magnetic resonance imaging (CMRI) is one of the most accurate non-invasive modalities for evaluation of cardiac function, especially the left ventricle (LV). In this modality, the manual or semi-automatic delineation of LV by experts is currently the standard clinical practice for chambers segmentation. Despite these efforts, global quantification of LV remains a challenge. In this work, a combination of two convolutional neural network (CNN) architectures for quantitative evaluation of the LV is described, which estimates the cavity and the myocardium areas, endocardial cavity dimensions in three directions, and the myocardium regional wall thickness in six radial directions. The method was validated in CMRI exams of 56 patients (LVQuan19 dataset) and evaluated by metrics Dice Index, Mean Absolute Error, and Correlation with superior performance compared to the state-of-the-art methods. The combination of the CNN architectures provided a simpler yet fully automated approach, requiring no specialist interaction.Clinical Relevance- With the proposed method, it is possible to perform automatically the full quantification of regional clinically relevant parameters of the left ventricle in short-axis CMRI images with superior performance compared to state-of-the-art methods.

Pneumonia is one of the leading causes of childhood mortality worldwide. Chest x-ray (CXR) can aid the diagnosis of pneumonia, but in the case of low contrast images, it is important to include computational tools to aid specialists. Deep learning is an alternative because it can identify patterns automatically, even in low-resolution images. We propose herein a convolutional neural network (CNN) architecture with different training strategies towards detecting pneumonia on CXRs and distinguishing its subforms of bacteria and virus. We also evaluated different image pre-processing methods to improve the classification. This study used CXRs from pediatric patients from a public pneumonia CXR dataset. The pre-processing methods evaluated were image cropping and histogram equalization. To classify the images, we adopted the VGG16 CNN and replaced its fully-connected layers with a customized multilayer perceptron. With this architecture, we proposed and evaluated four different training strategies: original CXR image (baseline), chest-cavity-cropped image (A), and histogram-equalized segmented image (B). The last strategy method (C) implemented is based on ensemble between strategies A and B. The performance was assessed by the area under the ROC curve (AUC) with 95% confidence interval (CI), accuracy, sensitivity, specificity, and F1-score. The ensemble model C yielded the highest performances: AUC of 0.97 (CI: 0.96-0.99) to classify pneumonia vs. normal, and AUC of 0.91 (CI: 0.88-0.94) to classify bacterial vs. viral cases. All models that used pre-processed images showed higher AUC than baseline, which used the original CXR image. Image cropping and histogram equalization reduced irrelevant information from the exam, enhanced contrast, and was able to identify fine CXR texture details. The proposed ensemble model increased the representation of inflammatory patterns from bacteria and viruses with few epochs to train the deep CNNs.Clinical relevance- Deep learning can identify complex radiographic patterns in low contrast images due to pneumonia and distinguish its subforms of bacteria and virus. The correlation of imaging with lab results could accelerate the adoption of complementary exams to confirm the disease's cause.

The role of endothelium in the electrical-field stimulation (EFS)-induced contractions of Chelonoidis carbonaria aorta was investigated. Contractions were evaluated in the presence and absence of L-NAME (100 μM), tetrodotoxin (1 μM), phentolamine (10 and 100 μM), phenoxybenzamine (1 and 10 μM), prazosin (100 μM), idazoxan (100 μM), atropine (10 μM), D-tubocurarine (10 μM) or indomethacin (10 μM). EFS-induced contraction was also carried out in endothelium-denuded rings. EFS-induced contraction was investigated by the sandwich assay. Concentration curves to endothelin-1 (0.1-100 nM) and U46619 (0.001-100 μM) were also constructed to calculate both Emax and EC 50 . EFS at 16 Hz contracted Chelonoidis aorta, which was almost abolished by the endothelium removal. The addition of L-NAME increased the EFS response (2.0 ± 0.4 and 8.3 ± 1.9 mN). In L-NAME treated aortic rings, tetrodotoxin did not change the EFS-response (5.1 ± 1.8 and 4.9 ± 1.7 mN). Indomethacin, atropine and d-tubucurarine also did not affect the EFS-response. Phentolamine at 10 μM did not change the EFS-induced contraction; however, at 100 μM, reduced it (3.9 ± 1 and 1.9 ± 0.3 mN). Prazosin and idazoxan did not change EFS-induced contractions. Phenoxybenzamine at 1 μM reduced by 76% (9.6 ± 3.4 and 2.3 ± 0.8 mN) and at 10 μM by 90% the EFS response. Immunohistochemistry identified tyrosine hydroxylase in the endothelium and brain, whereas S100 protein was found only in brain. In conclusion, endothelium modulates EFS-induced contractions in Chelonoidis aortic rings and this modulation may be due to endothelium-derived catecholamines, possibly dopamine., Competing Interests: Declaration of competing interest We declare that the content of this manuscript has not been published or submitted for publication elsewhere. We also declare that this manuscript has no conflicts of interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cardiovascular disease is one of the major health problems worldwide. In clinical practice, cardiac magnetic resonance imaging (CMR) is considered the gold-standard imaging modality for the evaluation of the function and structure of the left ventricle (LV). More recently, deep learning methods have been used to segment LV with impressive results. On the other hand, this kind of approach is prone to overfit the training data, and it does not generalize well between different data acquisition centers, thus creating constraints to the use in daily routines. In this paper, we explore methods to improve the generalization in the segmentation performed by a convolutional neural network. We applied a U-net based architecture and compared two different pre-processing methods to improve uniformity in the image contrast between five cross-dataset training and testing. Overall, we were able to perform the segmentation of the left ventricle using multiple cross-dataset combinations of train and test, with a mean endocardium dice score of 0.82.Clinical Relevance- This work improves the result between the cross-dataset evaluation of the left ventricle segmentation, reducing the constraints for daily clinical adoption of a fully-automatic segmentation method.

Objectives: Percutaneous mitral balloon commissurotomy (PMBC) remains the preferred treatment for patients with severe symptomatic rheumatic mitral stenosis (MS) and suitable anatomy. The objective of this study was to propose a new score for the prediction of immediate and late success., Methods: This is a single-center, retrospective analysis of all 1582 patients with severe mitral stenosis who underwent PMBC from August 1987 to July 2010. The composite outcome was cardiovascular death, new PMBC, or mitral valve repair surgery up to 24 years of follow-up., Results: Mean patient age was 36.8 ± 12.9 years, most (86.4%) were female, and Wilkins score was between 9-11 in 49.1% of patients. In the multivariate analysis, the predictors of immediate success were age (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.96-0.99; P=.01), left atrium size (OR, 0.96; 95% CI, 0.93-0.99; P=.01), mean preprocedure mitral gradient (OR, 0.93; 95% CI, 0.89-0.96; P<.001), intermediate Wilkins score 9-11 (OR, 0.62; 95% CI, 0.40-0.94; P=.02), and high Wilkins score ≥12 (OR, 0.35; 95% CI, 0.16-0.76; P<.01). For prediction of late events, age (hazard ratio [HR], 0.98; 95% CI, 0.97-0.98; P<.001), New York Heart Association class III-IV (HR, 1.50; 95% CI, 1.18-1.92; P<.001), left atrium size (HR, 1.02; 95% CI, 1.02-0.04; P<.01), and high Wilkins score ≥12 (HR, 2.02; 95% CI, 1.30-3.15; P<.01) were significant. Two nomograms were developed using significant predictors from the model., Conclusions: In this large population, not only the Wilkins score, but also clinical and hemodynamic features, seem to be relevant in predicting immediate and late success for patients with rheumatic MS who underwent PMBC.

Introduction: Mixed-specifier mood disorders are probably a different subgroup in terms of response to treatment, socio-demographic parameters, course, and family history. Here we describe the rationale and design of a clinical trial aimed to test the efficacy, safety, and tolerability of a non-pharmacological treatment known as theta-burst stimulation (TBS) for treating the mixed depressive episodes of both bipolar (I or II), and unipolar depression., Methods: The study is designed as a randomized, sham-controlled, double-blinded clinical trial evaluating TBS for the treatment of moderate or severe major depressive episodes with mixed features of patients receiving at least one first or second-line pharmacological treatment for depressive episodes without adequate response. Ninety adult (18 to 65 years old) patients will be enrolled and submitted to 6-week (comprising 5 consecutive days a week sessions for the first 3 weeks and then 2 days a week for a further 3 week) of inhibitory followed by excitatory TBS in dorsolateral prefrontal cortex. Participants will be assessed using clinical and neuropsychological tests before and after the intervention. The primary outcome is change in Montgomery-Åsberg Depression Scale (MADRS) score over time and across groups. Cognitive parameters will also be assessed with neuropsychological tests., Results: The clinical results will provide evidence about TBS as an adjunctive treatment for mixed depression treatment and neuropsychological parameters will contribute toward an improved understanding the effects of TBS in cognition., Conclusion: Our results could introduce a novel therapeutic technique for mixed depressive episodes of both bipolar and unipolar disorders., Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT04123301; date of registration: 10/10/2019; URL: https://clinicaltrials.gov/ct2/show/NCT04123301?term=NCT04123301&rank=1., (Copyright © 2020 Tavares, dos Santos, Valiengo, Klein, Borrione, Forte, Brunoni and Moreno.)

To assess the bioequivalence of two zolpidem hemitartrate formulations in 30 healthy volunteers. Plasma samples were obtained over a 24 h period. Plasma concentrations of zolpidem were analyzed by liquid chromatography coupled to tandem mass spectrometry with positive ion electrospray ionization using multiple reaction monitoring. Values of peak concentration (C max ), area under curve (AUC), half-life, elimination constant, volume of distribution and clearance showed statistically significant differences when comparing women (604.34 ng h/ml, 127.36 ng/ml, 4.4 h, 0.18 1/h, 50.56 L and 8.55 L/h, respectively) and men (276.1 ng h/ml, 70.9 ng/ml, 3.3 h, 0.26 1/h, 91.42 L and 24.34 L/h, respectively), receiving the same dose (5 mg), respectively. The geometric means with corresponding 90% confidence interval for Test/Reference percentage ratios were 99.73% (CI 93.69-106.16) for C max, 97.44% (90% CI = 91.85-103.37%) for area under curve of plasma concentration until the last concentration observed (AUC last ) and 98.30% (90% CI = 92.48-104.49) for the area under curve between the first sample (pre-dosage) and infinity (AUC 0-inf ). Since the 90% CI for AUC last , AUC 0-inf and C max ratios were within the 80-125% interval proposed by the US Food and Drug Administration, it was concluded that zolpidem hemitartrate formulation (5 mg orodispersible tablet) is bioequivalent to the zolpidem hemitartrate formulation (Patz SL 5 mg sublingual tablet) with regard to both the rate and the extent of absorption. A new formulation of zolpidem 2.5 mg may be useful in women for the same clinical benefits as the 5 mg formulation in men., (© 2019 John Wiley & Sons, Ltd.)

Electrical field stimulation (EFS) has been used for decades in classical pharmacological preparations in order to characterize the mediators released by neural endings involved in smooth muscle contraction or relaxation. Since most of the human umbilical cord has no innervation, EFS has never been used in this preparation. This study aimed to investigate the effect of EFS on vascular responsiveness from human umbilical cord. Segments of the human umbilical cord were obtained from normotensive parturients and the human umbilical artery (HUA) and the human umbilical vein (HUV) were isolated and mounted in organ bath chambers. Electrical field stimulation-induced contractions in both HUA (2.35 ± 1.31 mN and 3.77 ± 2.31 mN for 8 Hz and 16 Hz respectively, n = 24) and HUV (3.81 ± 2.54 mN and 6.26 ± 4.51 mN for 8 Hz and 16 Hz respectively, n = 25). The addition of tetrodotoxin (1 μM) did not alter the EFS-induced contractions in both tissues (n = 5). Pre-incubation with atropine (10 and 100 μM), glibenclamide (10 μM) and indomethacin (10 μM) did not affect the EFS-induced contractions in both tissues. The contractions of both vessels were significantly reduced by pre-incubation of the tissues with phentolamine (10 and 100 μM). The endothelium removal almost abolished the EFS- induced contractions in both vessels (n = 5). In sandwich preparation, donor tissue (with endothelium) released a factor (s) that promoted contraction of the recipient tissue (endothelium removal) in both HUA and HUV (n = 5, respectively). Our findings indicate a potential role of endothelium-derived catecholamines in modulating HUA and HUV reactivities., (Copyright © 2020. Published by Elsevier Inc.)

Background: More than 30% of major depressive disorder patients fail to respond to adequate trials of medications and psychotherapy. While modern neuromodulation approaches (ie, vagal nerve stimulation, deep brain stimulation) are yet to prove their efficacy for such cases in large randomized controlled trials, trigeminal nerve stimulation (TNS) has emerged as an alternative with promising effects on mood disorders., Objective: To assess efficacy, safety, tolerability, and placebo effect duration of continuous subcutaneous TNS (sTNS) in treatment-resistant depression (TRD)., Methods: The TREND study is a single-center, double-blind, randomized, controlled, phase II clinical trial. Twenty unipolar TRD patients will receive V1 sTNS as adjuvant to medical therapy and randomized to active vs sham stimulation throughout a 24-wk period. An additional 24-wk open-label phase will follow. Data concerning efficacy, placebo response, relapse, and side effects related to surgery or electrical stimulation will be recorded. We will use the HDRS-17, BDI-SR, IDS&#95;SR30, and UKU scales., Expected Outcomes: The main outcome measure is improvement in depression scores using HAM-17 under continuous sTNS as adjuvant to antidepressants. Active stimulation is expected to significantly impact response and remission rates. Minor side effects are expected due to the surgical procedure and electrical stimulation. The open-label phase should further confirm efficacy and tolerability., Discussion: This study protocol is designed to define efficacy of a novel adjuvant therapy for TRD. We must strive to develop safe, reproducible, predictable, and well-tolerated neuromodulation approaches for TRD patients impaired to manage their lives and contribute with society., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Background: Treatment of bipolar disorder (BD) usually requires drug combinations. Combinations of lithium plus valproic acid (Li/VPA) and lithium plus carbamazepine (Li/CBZ) are used in clinical practice but were not previously compared in a head-to-head trial., Objective: The objective of this trial was to compare the efficacy and tolerability of Li/VPA versus Li/CBZ in treating type 1 BD in any phase of illness in young individuals., Methods: LICAVAL was a randomized, unicenter, open-label, parallel-group trial that was conducted from January 2009 to December 2012 in a tertiary hospital in São Paulo, Brazil. Participants were between 18 and 35 years old and were followed up for 2 years. Our primary outcome was the number of participants achieving/maintaining response and remission during the acute and maintenance phases of BD treatment, respectively. Other outcomes assessed were symptom severity and adverse events throughout the study. In the analysis of the primary outcome, we compared groups by using a two-way repeated measures analysis of variance and estimated effect sizes by using Cohen's d., Results: Of our 64 participants, 36 were allocated to Li/VPA and 28 to Li/CBZ. Our sample was composed predominantly of females (66.6%) and the average age was 27.8 years. A total of 27 (45.0%) participants had depression, 17 (28.3%) had mania/hypomania, and 16 (26.7%) had a mixed state. We found no between-group differences in CGI-BP (Clinical Global Impression Scale modified for use in bipolar disorder) scores (P = 0.326) or in any other outcome. Side effects differed significantly between groups only in the first week of treatment (P = 0.021), and there were more side effects in the Li/VPA group. Also, the Li/VPA group gained weight (+2.1 kg) whereas the Li/CBZ group presented slight weight loss (-0.2 kg)., Conclusion: Our study suggests that Li/VPA and Li/CBZ have similar efficacy and tolerability in BD but that Li/CBZ might have metabolic advantages in the long term., Trial Registration: ClinicalTrials.gov identifier: NCT00976794 . Registered on September 9, 2009.

Background and Objectives: Nanotechnology may increase the speed of penetration into the skin. This study evaluated the efficacy, safety, and pharmacokinetics of a novel topical anesthetic nanocapsule formulation (2 g) containing 2.5% lidocaine and 2.5% prilocaine (nanorap-test formulation) compared to placebo (control formulation) in skin types I-III patients of both sexes submitted to the ablative fractional CO 2 laser treatment., Methods: The patients (n = 120) included in this double-blind, single-center, randomized trial, received topical application of 2 g of the test formulation (50 mg lidocaine + 50 mg prilocaine) and placebo on the forehead region. Efficacy was assessed as pain sensation in four quadrants of each side of the forehead using a visual analogue scale immediately (0 min) and at 30, 60, and 90 minutes after laser application compared to placebo. The safety and tolerability of the test product were evaluated based on the occurrence of systemic adverse events as well as the occurrence of immediate and late skin reactions. Pharmacokinetic evaluation was performed in plasma of eight patients using a validated LC-MS/MS method for drugs quantification., Results: Nanorap induced a clinically significant reduction in the pain assessment at all evaluated times (57.2%, 41.6%, 38.6%, and 37.3% at 0, 30, 60, and 90 minutes after drug application, respectively. Mean values of C max were 14.20 and 5.36 ng/ml and t max were 3.5 and 1.8 hour for lidocaine and prilocaine, respectively. No systemic adverse events were observed., Conclusion: The nanorap formulation demonstrated a clinically and statistically significant efficacy providing analgesia after the ablative fractional CO 2 laser therapy in the investigated patients, when compared to placebo. The product also presented good safety and tolerability. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc., (© 2019 Wiley Periodicals, Inc.)

In this study the nitric oxide (NO)-soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) pathway was characterized in tortoise Chelonoidis carbonaria aorta. Concentration response curves (CCR) to ATP, ADP, AMP, adenosine and histamine were performed in the presence and absence of L-NAME in aorta pre-contracted with ACh (3 μM). CCR to SNP, BAY 41-2272 (sGC stimulator), BAY 60-2770 (sGC activator) and tadalafil (PDE-5 inhibitor) were constructed in the presence and absence of ODQ (10 μM). ATP (pEC 50 6.1 ± 0.1), ADP (pEC 50 6.0 ± 0.2), AMP (pEC 50 6.8 ± 0.1) and histamine (pEC 50 6.8 ± 0.12) relaxed Chelonoidis aorta and the addition of L-NAME reduced their efficacy (p < .05). Adenosine effects (pEC 50 6.6 ± 0.1) were not changed in the presence of L-NAME. SNP (pEC 50 7.5 ± 0.7; Emax 102.2 ± 2.5%), BAY 41-2272 (pEC 50 7.3 ± 0.2; Emax 130.3 ± 10.2%), BAY 60-2770 (pEC 50 11.4 ± 0.1; Emax 130.3 ± 6.5%) and tadalafil (pEC 50 6.7 ± 0.3; Emax 121.3 ± 15.3%) relaxed Chelonoidis aorta. The addition of ODQ reduced the SNP and tadalafil maximum response (p < .05) and promoted 63 fold right shift on BAY 41-2272 curve. In contrast, no alteration was observed on BAY 60-2770 response. Transcriptomic analysis for eNOS and sGC were found in aorta and brain libraries with high homology when compared with human transcripts. The NO-sGC-PDE-5 is functionally present in Chelonoidis aorta with a functional and genomic similarity to mammalian vessels. Unlike most of mammalian vessels, ACh did not cause endothelium-dependent relaxation in Chelonoidis carbonaria aortic rings., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: The Montgomery-Åsberg Depression Rating Scale (MADRS) is widely used to assess depression severity. The Structured Interview Guide for the MADRS (SIGMA) was created to standardize MADRS assessment. The objective of this study was to translate and validate the original SIGMA into a Brazilian Portuguese version (SIGMA-VB)., Methods: We translated and cross-culturally validated the original SIGMA into the SIGMA-VB, and assessed its psychometric properties using data from 93 adult outpatients enrolled in the Integral Assessment in Unipolar Depression (AIUNI) trial. Participants were assessed by two raters on five visits over 8 weeks. We calculated multiple interrater reliability indexes for the SIGMA-VB and used the Hamilton Depression Hating Scale (HAM-D) for validation purposes., Results: According to the SIGMA-VB, participants had moderate depression at baseline followed by mild depression at 8 weeks. We found over 90% of correlation between scores attributed by different raters using the SIGMA-VB. Correlations between the SIGMA-VB and the HAM-D were above 66%., Conclusion: Our findings confirm that the SIGMA-VB is a valid and reliable instrument to assess depression severity in clinical research and practice. Its interrater reliability was similar to that of a previously published Japanese version of the SIGMA.

The combination of medroxyprogesterone acetate 25 mg + estradiol cypionate 5 mg is a highly effective, monthly injectable contraceptive. For the first time, this study presents the development and validation of a sensitive method for estradiol cypionate analysis in human plasma by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Aliquots (500 μL) of plasma were extracted with ethyl ether (100%) and derivatized with dansyl chloride. Its separation was performed on a Jones Chromatography Genesis C8 column and the quantification was performed with a mass spectrometer equipped with an electrospray interface operating in negative ion mode. The run time was 6 min and the calibration curve was linear over the range of 0.005-0.15 ng/mL. The method was applied to evaluate the pharmacokinetics of estradiol cypionate in plasma collected up to 1008 h (42 days) after a single intramuscular administration of 25 mg/mL medroxyprogesterone acetate +5 mg/mL estradiol cypionate to healthy female volunteers (n = 12). The estradiol cypionate maximum plasma concentration (C max ) was 0.14 ± 0.08 ng/mL reached at 16.83 ± 21.07 h and the area under the plasma concentration versus time curve (AUC 0-last ) was 14.07 ± 6.32 ng.h/mL. Elimination half-life (t ½ ), apparent volume of distribution (Vd/F), apparent clearance (CL/F) and mean residence time (MRT) were 89.65 ± 76.04 h, 28038 ± 9636 L, 49.02 ± 10.62 L/h and 576.05 ± 238.32 h, respectively, showing that the estradiol cypionate release from the administration site was prolonged and there was no drug accumulation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Riluzole is a benzothiazole anticonvulsant used in the treatment of patients with amyotrophic lateral sclerosis and it is being investigated for clinical use in patients with spinal cord injury. The present study evaluated the pharmacokinetics of riluzole in beagle dogs after oral dose administration., Methods: The oral doses (1.5, 5, 15 and 50 mg/kg) of riluzole were administered to beagle dogs and blood samples were collected from 0 h to 24 h post drug administration. Riluzole was quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS)., Results: The method was sensitive, precise, accurate and selective to riluzole quantification in plasma of beagle dogs. The pharmacokinetics following oral administration was linear from 1.5 to 15 mg/kg and the t 1/2 was 2.16, 1.5, 1.8 and 3.0 h after oral administration of 1.5, 5.0, 15 and 50 mg/kg riluzole., Conclusion: The riluzole pharmacokinetics was linear up to 15 mg/kg and had a significantlyshorter t 1/2 in beagle dogs than in humans., Competing Interests: The authors have no conflict of interests., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: In the treatment of Bipolar disorder (BD), achieving euthymia is highly complex and usually requires a combination of mood stabilizers. The mechanism of action in stabilizing mood has not been fully elucidated, but alterations in N-Acetylaspartate (NAA), Myo-Inositol (mI) and Choline (Cho) have been implicated. Proton magnetic resonance spectroscopy ( 1 H-MRS) is the gold standard technique for measuring brain NAA, Cho and mI in vivo. The objective of this study was to investigate the association of lithium use in BD type I and brain levels of NAA, mI and Cho in the (anterior cingulate cortex) ACC., Methods: 129 BD type I subjects and 79 healthy controls (HC) were submitted to a 3-Tesla brain magnetic resonance imaging scan ( 1 H-MRS) using a PRESS ACC single voxel (8cm 3 ) sequence., Results: BD patients exhibited higher NAA and Cho levels compared to HC. Lithium prescription was associated with lower mI (combination + monotherapy) and higher NAA levels (monotherapy)., Conclusion: The results observed add to the knowledge about the mechanisms of action of mood stabilizers on brain metabolites during euthymia. Additionally, the observed decrease in mI levels associated with lithium monotherapy is an in vivo finding that supports the inositol-depletion hypothesis of lithium pharmacodynamics., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Bipolar disorder is a chronic and recurrent illness characterized by depressive and manic episodes. Proton magnetic resonance spectroscopy ( 1 H-MRS) studies have demonstrated glutamate (Glu) system abnormalities in BD, but it is unclear how Glu varies among mood states and how medications modulate it. The objective of this study was to investigate the influence of mood stabilizers on anterior cingulate cortex Glu levels using 1 H-MRS during euthymia., Methods: One hundred twenty-eight bipolar I disorder (BDI) euthymic subjects and 80 healthy control subjects underwent 3T brain 1 H-MRS imaging examination including acquisition of an anterior cingulate cortex single voxel (8 cm 3 ) 1 H-MRS, based on a point resolved spectroscopy (PRESS) sequence with an echo time of 80 ms and a repetition time of 1500 ms (BIPUSP MRS study). The Glu system was described by measuring Glu and the sum of Glu and glutamine (Glx) using creatine (Cre) as a reference., Results: Euthymic BDI subjects presented with higher ratios of Glu/Cre and Glx/Cre compared to healthy control subjects. Glu/Cre ratios were lower among patients using anticonvulsants, while Glx/Cre did not differ between the two groups. Lithium, antipsychotics, and antidepressants did not influence Glu/Cre or Glx/Cre., Conclusions: We reported Glu/Cre and Glx abnormalities in the largest sample of euthymic BDI patients studied by 1 H-MRS to date. Our data indicate that both Glu/Cre and Glx/Cre are elevated in BDI during euthymia regardless of medication effects, reinforcing the hypothesis of glutamatergic abnormalities in BD. Furthermore, we found an effect of anticonvulsants on Glu/Cre during euthymia, which might indicate a mechanism of mood stabilization in BD., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: Vaginal route is often used in topical antifungal formulations. Vaginal permeability assays are generally performed as in vitro tests., Method: An in vivo vaginal permeability assay was developed using female rabbits. Fenticonazole permeability was evaluated by assessing fenticonazole bioavailability in plasma by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS). Toxicity was monitored histopathologically after 8 consecutive days of antifungal treatment (20 mg/animal)., Results: The method of quantification was linear with a lower limit of quantification (LLOQ) of (0.1 ng/mL). The area-under-the-curves (AUC) of fenticonazole on day 1 and 8 of treatment were 280.3 ± 86.1 ng/mL ∗ h and 805.7 ± 252.4 ng/mL ∗ h, respectively. The calculated systemic bioavailability was 12.73% ± 0.14%. No signs of toxicity were observed both macroscopically and histologically after 8 days fenticonazole treatment., Discussion: The plasma levels of fenticonazole observed in rabbits are similar to that observed in human. Rabbit vagina may be a suitable model to evaluate vaginal antifungal formulations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to assess very long term outcomes after successful percutaneous balloon mitral valvuloplasty (PBMV)., Background: PBMV remains the preferred treatment for patients with severe symptomatic rheumatic mitral stenosis and suitable anatomy., Methods: All consecutive patients who underwent successful PBMV between 1987 and 2010 were included. The primary endpoint was the composite of all-cause mortality, need for mitral surgery, or repeat PBMV up to 23 years., Results: Among all 1,582 consecutive patients undergoing PBMV, acute success was achieved in 90.9% (n = 1,438). Independent predictors of acute success included left atrial size (odds ratio: 0.96; 95% confidence interval [CI]: 0.93 to 0.99; p = 0.045), Wilkins score ≤8 (odds ratio: 1.66; 95% CI: 0.48 to 0.93; p = 0.02) and age (odds ratio: 0.97; 95% CI: 0.96 to 0.99; p = 0.006). Very long term follow-up (median 8.3 years, mean 15.6 years) was obtained in 79.1% of successful cases. The incidence of the primary endpoint was 19.1% (95% CI: 17.0% to 21.1%). The rates of overall mortality, need for mitral valve surgery, or repeat PBMV were 0.6% (95% CI: 0.3% to 1.2%), 8.3% (95% CI: 7.0% to 9.9%), and 10.0% (95% CI: 8.5% to 11.7%), respectively. On multivariate analysis, New York Heart Association functional class III or IV (hazard ratio: 1.62; 95% CI: 1.26 to 2.09; p < 0.001), higher age (hazard ratio: 0.97; 95% CI: 0.96 to 0.98; p = 0.028), and mitral valve area ≤1.75 cm 2 after the procedure (hazard ratio: 1.67; 95% CI: 1.28 to 2.11; p = 0.028) were independent predictors of the primary endpoint., Conclusions: In very long term follow-up, more than 75% of patients exhibited sustained results. Prediction of late favorable results is multifactorial and strongly determined by age, previous symptoms and post-procedural mitral valve area., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: It is unclear if individuals with Major Depressive Disorder (MDD) present different nonverbal behavior (NVB) compared with healthy individuals, and also if depression treatments affect NVB. In this study, we compared the NVB of MDD subjects and healthy controls. We also verified how MDD subjects' NVB is affected by depression severity and acute treatments., Methods: We evaluated 100 MDD outpatients and 83 controls. We used a 21-category ethogram to assess the frequency of positive and negative NVB at baseline. MDD subjects were also assessed after eight weeks of treatment (pharmacotherapy or neuromodulation). We used the Wilcoxon signed-rank test to compare the NVB of MDD subjects and controls; beta regression models to verify associations between MDD severity and NVB; the Shapiro-Wilk test to verify changes in NVB after treatment; and logistic regression models to verify NVB associated with treatment response according to the Hamilton depression rating scale., Results: Compared with controls, MDD subjects presented higher levels of six negative NVB (shrug, head and lips down, adaptive hand gestures, frown and cry) and lower levels of two positive NVB (eye contact and smile). MDD subjects' NVB was not associated with depression severity, and did not significantly change after depression treatment. Treatment responders showed more interpersonal proximity at baseline than non-responders., Limitations: Our ethogram had no measure of behavior duration, and we had a short follow-up period., Conclusions: MDD subjects have more negative and less positive social NVB than controls. Their nonverbal behavior remained stable after clinical response to acute depression treatments., (Copyright © 2018. Published by Elsevier B.V.)

Capecitabine is a prodrug and is selectively activated by tumor cells to its cytotoxic moiety, 5-fluorouracil, by thymidine phosphorylase, which is generally expressed at high levels in tumors. Clinical and pharmacokinetic studies of capecitabine have been performed in patients with cancer. This study aims to evaluate the bioequivalence of two capecitabine formulations (150-mg tablet) using healthy male subjects under nonfasting conditions. The study was conducted as an open, randomized, three-period, semi-replicated design with three sequences (RRT, RTR, TRR) with a 1-week washout interval. The subjects were selected for the study after having their health status previously assessed by a clinical evaluation and laboratory tests (biochemical and hematological parameters, and urinalysis). A single capecitabine tablet (150 mg) was given in each occasion. Plasma capecitabine concentrations were analyzed by liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM). The geometric mean and 90% confidence intervals (CI) of capecitabine/Xeloda® (T/R) percent ratio were 104.34% (98.74 - 110.25%) for AUClast, 103.06% (97.48 - 108.96%) for AUCinf, and 104.07% (88.13 - 122.90%) for Cmax. Since the 90% CI for Cmax, AUClast, and AUCinf ratios were all inside the 80 - 125% interval proposed by the US Food and Drug Administration Agency, it was concluded that the capecitabine formulation elaborated by Eurofarma Laboratórios Ltda. is bioequivalent to Xeloda® formulation for both the rate and the extent of absorption. The drug was well tolerated by the subjects, indicating that it is safe to perform capecitabine bioequivalence studies in healthy male subjects.
.

Endothelium is the main source of catecholamine release in the electrical-field stimulation (EFS)-induced aortic contractions of the non- venomous snake Panterophis guttatus. However, adrenergic vasomotor control in venomous snakes such as Crotalus durissus terrificus and Bothrops jararaca has not yet been investigated. Crotalus and Bothrops aortic rings were mounted in an organ bath system. EFS-induced aortae contractions were performed in the presence and absence of guanethidine (30 μM), phentolamine (10 μM) or tetrodotoxin (1 μM). Frequency-induced contractions were also performed in aortae with endothelium removed. Immunohistochemical localization of both tyrosine hydroxylase (TH) and S-100 protein in snake aortic rings and brains, as well as in human tissue (paraganglioma tumour) were carried out. EFS (4 to 16 Hz) induced frequency-dependent aortic contractions in both Crotalus and Bothrops. The EFS-induced contractions were significantly reduced in the presence of either guanethidine or phentolamine in both snakes (p<0.05), whereas tetrodotoxin had no effect in either. Removal of the endothelium abolished the EFS-induced contractions in both snakes aortae (p<0.05). Immunohistochemistry revealed TH localization in endothelium of both snake aortae and human vessels. Nerve fibers were not observed in either snake aortae. In contrast, both TH and S100 protein were observed in snake brains and human tissue. Vascular endothelium is the main source of catecholamine release in EFS-induced contractions in Crotalus and Bothrops aortae. Human endothelial cells also expressed TH, indicating that endothelium- derived catecholamines possibly occur in mammalian vessels., Competing Interests: The authors have declared that no competing interests exist.

Purpose of Review: The present manuscript reviews the mechanism of action of drug-coated balloons (DCBs), offering a brief summary of the main clinical evidence on these devices., Recent Findings: DCBs are regular semi-compliant balloons coated with antiproliferative agents that are rapidly released on contact with the vessel intima, exerting an anti-restenotic effect. This technology may offer some benefits of drug-eluting stents, in particular for the treatment of restenotic lesions, small vessels, and in patients at high-bleeding risk, when the prolonged dual antiplatelet regimen should be avoided. Most recent data have pointed to a possible benefit of these devices in treating bare metal stents (BMS) or drug-eluting stents in-stent restenosis (DES ISR), effectively reducing the recurrence of restenosis and avoiding additional layers of metal in the same coronary segment. In other clinical scenarios such as bifurcations, small vessels, and de novo lesions, data is more scarce and the benefits are still unclear. There are potential benefits related to the use of DCB in selected populations. However, larger clinical trials with longer follow-up are still needed to confirm the enthusiastic initial results.

Background: Bipolar depression (BD) is a highly prevalent condition associated with marked cognitive deficits that persist even in the euthymic phase of the illness. Pharmacological treatments for BD might further aggravate cognitive impairment, highlighting the need of developing interventions that present cognitive safety. In this study, we evaluated the cognitive effects of H1-coil (deep) transcranial magnetic stimulation (TMS) in patients with treatment-resistant bipolar depression., Methods: Fourty-three patients were randomized to receive 20 sessions of active (55 trains, 18 Hz, 120% resting motor threshold intensity) or sham rTMS within a double-blind, sham-controlled trial. A battery of 20 neuropsychological assessments, grouped in 6 domains (attention and processing speed, working memory and executive function, inhibitory control, language, immediate verbal memory, and long-term verbal memory) was performed at baseline and after 4 and 8 weeks of trial onset. Depressive symptoms were assessed with the 17-item Hamilton Rating Scale for Depression., Results: Cognitive improvement was shown for all cognitive domains. It occurred regardless of intervention group and depression improvement. For the language domain, greater improvement was observed in the sham group over time. No correlations between depression (at baseline or during treatment) and cognitive improvement were found., Limitations: Absence of healthy control group., Conclusion: The results of this exploratory study provide evidence on the cognitive safety of H1-coil TMS for BD patients. Putative pro-cognitive effects of rTMS in BD were not observed and thus should be further investigated., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Viral nonstructural proteins, which are not packaged into virions, are essential for the replication of most viruses. Reovirus, a nonenveloped, double-stranded RNA (dsRNA) virus, encodes three nonstructural proteins that are required for viral replication and dissemination in the host. The reovirus nonstructural protein σNS is a single-stranded RNA (ssRNA)-binding protein that must be expressed in infected cells for production of viral progeny. However, the activities of σNS during individual steps of the reovirus replication cycle are poorly understood. We explored the function of σNS by disrupting its expression during infection using cells expressing a small interfering RNA (siRNA) targeting the σNS-encoding S3 gene and found that σNS is required for viral genome replication. Using complementary biochemical assays, we determined that σNS forms complexes with viral and nonviral RNAs. We also discovered, using in vitro and cell-based RNA degradation experiments, that σNS increases the RNA half-life. Cryo-electron microscopy revealed that σNS and ssRNAs organize into long, filamentous structures. Collectively, our findings indicate that σNS functions as an RNA-binding protein that increases the viral RNA half-life. These results suggest that σNS forms RNA-protein complexes in preparation for genome replication. IMPORTANCE Following infection, viruses synthesize nonstructural proteins that mediate viral replication and promote dissemination. Viruses from the family Reoviridae encode nonstructural proteins that are required for the formation of progeny viruses. Although nonstructural proteins of different viruses in the family Reoviridae diverge in primary sequence, they are functionally homologous and appear to facilitate conserved mechanisms of dsRNA virus replication. Using in vitro and cell culture approaches, we found that the mammalian reovirus nonstructural protein σNS binds and stabilizes viral RNA and is required for genome synthesis. This work contributes new knowledge about basic mechanisms of dsRNA virus replication and provides a foundation for future studies to determine how viruses in the family Reoviridae assort and replicate their genomes., (Copyright © 2018 American Society for Microbiology.)

Propafenone is an antiarrhythmic drug applied to ventricular arrhythmias, initially recognized as a sodium channel blocker. This study aims to evaluate the bioequivalence of two propafenone formulations (300 mg tablet) in healthy subjects under non-fasting conditions. The study was conducted as an open, randomized, 2-period design with a 2-sequence (RT, TR) with a 1-week washout interval. The subjects were selected for the study after having their health status previously assessed by a clinical evaluation and laboratory tests (biochemical and hematological parameters, and urinalysis). Debrisoquine phenotype of healthy subjects was determined by analysis of urinary excretion of debrisoquine and its major metabolite, 4-hydroxydebrisoquine. A single propafenone tablet (300 mg) was given in each occasion. Plasma propafenone concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (HPLC/MS/MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM). The geometric mean and 90% confidence intervals (CI) of propafenone/Ritmonorm ® (T/R) percent ratio were 100.44% (88.39 - 114.13%) for AUC last , 99.84% (90.31 - 110.36%) for AUC inf , and 99.30% (90.08 - 109.47%) for C max . Since the 90% CI for C max , AUC last , and AUC inf ratios were all inside the 80 - 125% interval proposed by the US Food and Drug Administration Agency, it was concluded that the propafenone formulation elaborated by Biolab Sanus Farmacêutica Ltda. is bioequivalent to Ritmonorm ® formulation for both the rate and the extent of absorption. The drug was well tolerated by the subjects, indicating that it is safe to perform propafenone bioequivalence studies in healthy subjects with intermediate/extensive metabolism.
.

In this work, the relationship between surface properties and drug release mechanism from binary composition tablets formed by quetiapine fumarate and biopolymer materials was studied. The biopolymers correspond to xanthan and tragacanth gums, which are projected as modified drug release systems. The surface studies were carried out by the sessile drop method, while the surface free energy (SFE) was determinate through Young-Dupree and OWRK semi-empirical models. On the other hand, the drug release studies were performed by in vitro dissolution tests, where the data were analyzed through kinetic models of zero order, first order, Higuchi, and Korsmeyer-Peppas. The results showed that depending on the type and the proportion of biopolymer, surface properties, and the drug release processes are significantly affected, wherein tragacanth gum present a usual erosion mechanism, while xanthan gum describes a swelling mechanism that controls the release of the drug., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Temporal lobe epilepsy caused by hippocampal sclerosis (TLE-HS) is the most frequent form of drug-resistant epilepsy in adults. Mood disorders are the most frequent psychiatric comorbidities observed in these patients. Common pathophysiological mechanisms of epilepsy and psychiatric comorbidities include abnormalities in the serotonin pathway. The primary goal of this study was to determine the possible association between polymorphisms of genes encoding the serotonin receptors 5HT1A (rs6295), 5HT1B (rs6296), and 5HT2C (rs6318) and the presence of mood disorders in patients with TLE-HS. Our secondary goal was to evaluate the possible association between these variants and susceptibility to develop seizures in TLE-HS., Methods: We assessed 119 patients with TLE-HS, with and without psychiatric comorbidities; 146 patients with major depressive disorder; and 113 healthy volunteers. Individuals were genotyped for the rs6295, rs6296, and rs6318 polymorphisms., Results: No difference was observed between the group with TLE-HS, healthy controls, and the group with major depressive disorder without epilepsy regarding the polymorphisms that were evaluated. There was no correlation between rs6318, rs6295, rs6296, and epilepsy-related factors and history of psychiatric comorbidities., Conclusions: Our work suggests that the studied polymorphisms were not related to the presence of TLE, psychiatric comorbidities in TLE, and epilepsy-related factors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Renal replacement lipomatosis is a condition characterized by varying degrees of renal parenchymal atrophy and perirenal fibrofatty proliferation secondary to chronic inflammation such as xanthogranulomatous pyelonephritis. In severe cases, imaging findings can be misdiagnosed as retroperitoneal liposarcoma., Competing Interests: Conflict of interest: None declared., (Copyright® by the International Brazilian Journal of Urology.)

A tetrodotoxin (TTX)-resistant mechanism is responsible for the electrical field stimulation (EFS)-induced contractions and relaxations of Crotalus durissus terrificus corpora cavernosa. Here it was investigated whether this mechanism also occurs in corpora cavernosa and aortae of the non-venomous snake Pantherophis guttatus corpora cavernosa and aortae. Corpora cavernosa and aortic rings isolated from Pantherophis guttatus snake were mounted in organ bath system for isometric tension recording. EFS-induced contractions in both tissues were performed in the presence and absence of guanethidine (30 μM), phentolamine (10 μM) and tetrodotoxin (1 μM). In another set of experiments, the endothelium was removed from aortic rings and EFS-induced contractions were performed in the denuded rings. Electrical field stimulation-induced contractions were frequency-dependent in Pantherophis guttatus corpora cavernosa and aortic rings. The contractions were significantly reduced in the presence of guanethidine (30 μM) or phentolamine (10 μM). Pre-treatment with tetrodotoxin had no effect on the EFS-induced contractions of either corpora cavernosa or aortic rings. Surprisingly, the EFS-induced contractions of aortic rings denuded of endothelium were almost abolished. These results indicate that the TTX-resistant mechanism is present in EFS-induced contractions of Pantherophis guttatus corpora cavernosa and aortae. The experiments performed in the aorta indicate that the endothelium is the main source for the release of catecholamines induced by EFS.

Introduction: Clinical efficacy and safety of adjunctive thrombus aspiration (TA) in patients with ST-segment elevation myocardial infarction (STEMI) during percutaneous coronary intervention (PCI) remain controversial., Evidence Acquisition: Twenty-five eligible randomized controlled trials were included to compare the use of TA with PCI and PCI-only for STEMI. The primary endpoint was major adverse cardiac events (MACE) according to study definitions. The secondary endpoints were all-cause mortality, recurrent myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis (ST) and stroke., Evidence Synthesis: In comparison with conventional PCI, TA followed by PCI was associated with a lower risk for MACE with statistical significance [relative risk (RR): 0.91; 95% confidence interval (CI): 0.83-0.99; P=0.04). Regarding secondary endpoints, there was a significant increase in the risk for stroke (RR: 1.56; 95% CI: 1.09-2.24; P=0.015); there were no differences in the risk of all-cause mortality (RR: 0.88; 95% CI: 0.78-1.01; P=0.06), myocardial infarction (RR: 0.94; 95% CI: 0.79-1.13; P=0.537), target vessel revascularization (RR: 0.92; 95% CI: 0.82-1.04; P=0.177), and definite or probable stent thrombosis (RR: 0.84; 95% CI: 0.66-1.07; P=0.151)., Conclusions: Updated data about routine TA-assisted PCI in STEMI showed reduced risk of subsequent MACE in comparison with conventional primary PCI, but get limited benefits related to the clinical endpoints, and may be associated with an increase in the risk of stroke. As a routine strategy, TA in patients with STEMI cannot be supported.

Bipolar depression (BD) is a highly prevalent condition with limited therapeutic options. Deep (H1-coil) transcranial magnetic stimulation (dTMS) is a novel TMS modality with established efficacy for unipolar depression. We conducted a randomized sham-controlled trial to evaluate the efficacy and safety of dTMS in treatment-resistant BD patients. Patients received 20 sessions of active or sham dTMS over the left dorsolateral prefrontal cortex (H1-coil, 55 18 Hz 2 s 120% MT trains). The primary outcome was changes in the 17-item Hamilton Depression Rating Scale (HDRS-17) from baseline to endpoint (week 4). Secondary outcomes were changes from baseline to the end of the follow-up phase (week 8), and response and remission rates. Safety was assessed using a dTMS adverse effects questionnaire and the Young Mania Rating Scale to assess treatment-emergent mania switch (TEMS). Out of 50 patients, 43 finished the trial. There were 2 and 5 dropouts in the sham and active groups, respectively. Active dTMS was superior to sham at end point (difference favoring dTMS=4.88; 95% CI 0.43 to 9.32, p=0.03) but not at follow-up. There was also a trend for greater response rates in the active (48%) vs sham (24%) groups (OR=2.92; 95% CI=0.87 to 9.78, p=0.08). Remission rates were not statistically different. No TEMS episodes were observed. Deep TMS is a potentially effective and well-tolerated add-on therapy in resistant bipolar depressed patients receiving adequate pharmacotherapy.

Background: The impact of paravalvular regurgitation (PVR) following transcatheter aortic valve implantation (TAVI) remains uncertain., Objective: To evaluate the impact of PVR on mortality and hospital readmission one year after TAVI., Methods: Between January 2009 and June 2015, a total of 251 patients underwent TAVI with three different prostheses at two cardiology centers. Patients were assessed according to PVR severity after the procedure., Results: PVR was classified as absent/trace or mild in 92.0% (n = 242) and moderate/severe in 7.1% (n = 18). The moderate/severe PVR group showed higher levels of aortic calcification (22% vs. 6%, p = 0.03), higher serum creatinine (1.5 ± 0.7 vs. 1.2 ± 0.4 mg/dL, p = 0.014), lower aortic valve area (0.6 ± 0.1 vs. 0.7 ± 0.2 cm2, p = 0.05), and lower left ventricular ejection fraction (49.2 ± 14.8% vs. 58.8 ± 12.1%, p = 0.009). Patients with moderate/severe PVR had more need for post-dilatation (p = 0.025) and use of larger-diameter balloons (p = 0.043). At one year, all-cause mortality was similar in both groups (16.7% vs. 12%, p = 0.08), as well as rehospitalization (11.1% vs. 7.3%, p = 0.915). PVR grade significantly reduced throughout the first year after the procedure (p < 0.01). The presence of moderate/severe PVR was not associated with higher one-year mortality rates (HR: 0.76, 95% CI: 0.27-2.13, p = 0.864), rehospitalization (HR: 1.08, 95% CI: 0.25-4.69, p=0.915), or composite outcome (HR: 0.77, 95% CI: 0.28-2.13, p = 0.613)., Conclusion: In this sample, moderate/severe PVR was not a predictor of long-term mortality or rehospitalization. (Arq Bras Cardiol. 2017; [online].ahead print, PP.0-0).

Purpose: Medial patellofemoral ligament (MPFL) reconstruction offers good clinical results with a very low rate of instability recurrence. However, its in vivo effect on patellar tracking is not clearly known. The aim of this study is to investigate the effects of MPFL reconstruction on patellar tracking using dynamic 320-detector-row CT., Methods: Ten patients with patellofemoral instability referred to isolated MPFL reconstruction surgery were selected and subjected to dynamic CT before and ≥6 months after surgery. Patellar tilt angles and shift distance were analysed using computer software specifically designed for this purpose. Kujala and Tegner scores were applied, and the radiation of the CTs was recorded. Two protocols for imaging acquisition were compared: a tube potential of 80 kV and 50 mA versus a tube potential of 120 kV and 100 mA, both with a slice thickness of 0.5 mm and an acquisition duration of 10 s., Results: There were no changes in patellar tracking after MPFL reconstruction. There was no instability relapse. Clinical scores improved from a mean of 51.9 (±15.6)-74.2 (±20.9) on the Kujala scale (p = 0.011) and from a median of 2 (range 0-4) to 4 (range 1-6) on the Tegner scale (p = 0.017). The imaging protocols produced a dose-length product (DLP) of 254 versus 1617 mGycm and a radiation effective estimated dose of 0.2 versus 1.3 mSv, respectively. Both protocols allowed the analysis of the studied parameters without loss of precision., Conclusions: Reconstruction of the MPFL produced no improvement in patellar tilt or shift in the population studied. The low-radiation protocol was equally effective in measuring changes in patellar tracking and is recommended. Although the procedure successfully stabilized the patella, knee surgeons should not expect patellar shift and tilt correction when performing isolated patellofemoral ligament reconstruction in patients with recurrent patellar instability., Level of Evidence: IV.

Reptiles are the first amniotes to develop an intromitent penis, however until now the mechanisms involved in the electrical field stimulation-induced contraction on corpora cavernosa isolated from Crotalus durissus terrificus were not investigated. Crotalus and rabbit corpora cavernosa were mounted in 10 mL organ baths for isometric tension recording. Electrical field stimulation (EFS)-induced contractions were performed in presence/absence of phentolamine (10 μM), guanethidine (30 μM), tetrodotoxin (1 μM and 1mM), A-803467 (10 μM), 3-iodo-L-Tyrosine (1 mM), salsolinol (3 μM) and a modified Krebs solution (equimolar substitution of NaCl by N-methyl-D-glucamine). Immuno-histochemistry for tyrosine hydroxylase was also performed. Electrical field stimulation (EFS; 8 Hz and 16 Hz) caused contractions in both Crotalus and rabbit corpora cavernosa. The contractions were abolished by previous incubation with either phentolamine or guanethidine. Tetrodotoxin (1 μM) also abolished the EFS-induced contractions of rabbit CC, but did not affect EFS-induced contractions of Crotalus CC. Addition of A-803467 (10 μM) did not change the EFS-induced contractions of Crotalus CC but abolished rabbit CC contractions. 3-iodo-L-Tyrosine and salsolinol had no effect on EFS-induced contractions of Crotalus CC and Rabbit CC. Replacement of NaCl by N- Methyl-D-glucamine (NMDG) abolished EFS-induced contractions of rabbit CC, but did not affect Crotalus CC. The presence of tyrosine hydroxylase was identified in endothelial cells only of Crotalus CC. Since the EFS-induced contractions of Crotalus CC is dependent on catecholamine release, insensitive to TTX, insensitive to A803467 and to NaCl replacement, it indicates that the source of cathecolamine is unlikely to be from adrenergic terminals. The finding that tyrosine hydroxylase is present in endothelial cells suggests that these cells can modulate Crotalus CC tone.

Objective: We sought to compare the new transcatheter aortic valve replacement (TAVR) device ACURATE neo (ACT) with the already established CoreValve (MCV) and SAPIEN XT (SXT) for the treatment of severe aortic stenosis (AS)., Background: Very few data on TAVR devices are available beyond MCV and SAPIEN and there is no previous study comparing ACT with MCV and SXT., Methods: We prospectively evaluated consecutive patients who underwent transfemoral TAVR for the treatment of severe AS. Clinical outcomes were reported following Valve Academic Research Consortium 2 (VARC-2) criteria., Results: A total of 162 patients (ACT n = 49, MCV n = 56, SXT n = 57), were included. MCV group had higher valve embolization/migration rates (ACT none; MCV 9%; SXT 2%; P = 0.034) causing lower device success rates (ACT 98%; MCV 86%; SXT 95%; P = 0.043). At 30 days, there was no significant difference in all-cause mortality (P = 0.22), cardiovascular mortality (P = 0.20), periprocedural myocardial infarction (P = 0.40), stroke (P = 0.64), major vascular complications (P = 0.48), life-threatening bleeding (P = 0.29), acute kidney injury stage 2/3 (P = 0.69), or VARC-2 composite early safety endpoints (P = 0.21). MCV group had higher rates of new permanent pacemaker implantation (ACT 6%; MCV 25%; SXT 11%; P = 0.013). Follow-up echocardiography showed no significant difference in aortic valve mean pressure gradient (P = 0.73) or moderate/severe aortic regurgitation (P = 0.19) between groups., Conclusions: In a "real world" registry, ACT compared favorably against the well-studied SXT and MCV devices in both safety and efficacy. MCV implantation was associated with lower device success rates and higher rates of new permanent pacemaker implantation. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objectives: The present study examined the association between Multicenter CTO Registry in Japan (J-CTO) score in predicting failure of percutaneous coronary intervention (PCI) correlating with the estimated duration of chronic total occlusion (CTO)., Background: The J-CTO score does not incorporate estimated duration of the occlusion., Methods: This was an observational retrospective study that involved all consecutive procedures performed at a single tertiary-care cardiology center between January 2009 and December 2014., Results: A total of 174 patients, median age 59.5 years (interquartile range [IQR], 53-65 years), undergoing CTO-PCI were included. The median estimated occlusion duration was 7.5 months (IQR, 4.0-12.0 months). The lesions were classified as easy (score = 0), intermediate (score = 1), difficult (score = 2), and very difficult (score ≥3) in 51.1%, 33.9%, 9.2%, and 5.7% of the patients, respectively. Failure rate significantly increased with higher J-CTO score (7.9%, 20.3%, 50.0%, and 70.0% in groups with J-CTO scores of 0, 1, 2, and ≥3, respectively; P<.001). There was no significant difference in success rate according to estimated duration of occlusion (P=.63). Indeed, J-CTO score predicted failure of CTO-PCI independently of the estimated occlusion duration (P=.24). Areas under receiver-operating characteristic curves were computed and it was observed that for each occlusion time period, the discriminatory capacity of the J-CTO score in predicting CTO-PCI failure was good, with a C-statistic >0.70., Conclusion: The estimated duration of occlusion had no influence on the J-CTO score performance in predicting failure of PCI in CTO lesions. The probability of failure was mainly determined by grade of lesion complexity.

Systemic arterial hypertension is a major risk factor for cerebrovascular disease. Therefore, adequate control of blood pressure is of enormous importance. One of the many fixed-dose single-pill antihypertensive formulations available on the market is the combination of nebivolol and hydrochlorothiazide. The objective of this study was to develop two distinct high-performance liquid chromatography coupled to tandem mass spectrometry methods to simultaneously quantify nebivolol and hydrochlorothiazide in human plasma. The methods were employed in a bioequivalence study, the first assay involving a nebivolol fixed-dose single-pill formulation based on healthy Brazilian volunteers. Nebilet HCT™ (nebivolol 5 mg + hydrochlorothiazide 12.5 mg tablet, manufactured by Menarini) was the test formulation. The reference formulations were Nebilet™ (nebivolol 5 mg tablet, manufactured by Menarini) and Clorana™ (hydrochlorothiazide 25 mg tablet, manufactured by Sanofi). For both analytes, liquid-liquid extraction was employed for sample preparation and the chromatographic run time was 3.5 min. The limits of quantification validated were 0.02 ng/mL for nebivolol and 1 ng/mL for hydrochlorothiazide. Since the 90% CI for C max , AUC (0-last) and AUC (0-inf) individual test/reference ratios were within the 80-125% interval indicative of bioequivalence, it was concluded that Nebilet HCT™ is bioequivalent to Nebilet™ and Clorana™., (Copyright © 2016 John Wiley & Sons, Ltd.)

Calcium channels control the inflow of calcium ions into cells and are involved in diverse cellular functions. The CACNA1C gene polymorphism rs1006737 A allele has been strongly associated with increased risk for bipolar disorder (BD) and with modulation of brain morphology. The medial prefrontal cortex (mPFC) has been widely associated with mood regulation in BD, but the role of this CACNA1C polymorphism in mPFC morphology and brain aging has yet to be elucidated. One hundred seventeen euthymic BD type I subjects were genotyped for CACNA1C rs1006737 and underwent 3 T three-dimensional structural magnetic resonance imaging scans to determine cortical thickness of mPFC components (superior frontal cortex (sFC), medial orbitofrontal cortex (mOFC), caudal anterior cingulate cortex (cACC) and rostral anterior cingulate cortex (rACC)). Carriers of the CACNA1C allele A exhibited greater left mOFC thickness compared to non-carriers. Moreover, CACNA1C A carriers showed age-related cortical thinning of the left cACC, whereas among A non-carriers there was not an effect of age on left cACC cortical thinning. In the sFC, mOFC and rACC (left or right), a negative correlation was observed between age and cortical thickness, regardless of CACNA1C rs1006737 A status. Further studies investigating the direct link between cortical thickness, calcium channel function, apoptosis mechanism and their underlying relationship with aging-associated cognitive decline in BD are warranted.

Nonverbal behaviors exhibited by patients with depression in their interactions with others may reflect social maladjustment and depression maintenance. Investigations of associations between unipolar depression and both patients' and interviewers' behaviors have been scarce and restricted to European samples. This study examined whether nonverbal behavior in patients and their interviewers is associated with depression severity and recovery. Cultural differences were explored. Seventy-eight depressed outpatients (28 Brazilians, 50 Dutch) were evaluated before and after 8-week pharmacological treatment. Patients were videotaped during the Hamilton Depression Scale interview before treatment, and the Brazilians were also videotaped after treatment. Nonverbal behaviors (patients' speaking effort and interviewers' encouragement) were analyzed using a two-factor ethogram. Results revealed that speaking effort was associated with encouragement and both are not influenced by baseline depression severity. However, from before to after treatment, whereas encouragement remained unchanged, speaking effort increased among unrecovered patients. Speaking effort was associated with patients' culture: Brazilians exhibited higher speaking effort than Dutch. These findings highlight that whereas the supportive nonverbal behavior of the interviewer may be stable, the set of nonverbal behaviors composed by head movements, eye contact and gestures displayed by the patients during their speaking in clinical interviews reflects depression persistence after treatment., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The objectives of the present study were to analyze the variation of renal function after transcatheter aortic valve replacement (TAVR) focused on acute kidney injury (AKI) and its impact on short- and mid-term mortality., Background: Changes on renal function after TAVR and their impact on clinical outcomes are incompletely understood until now., Methods: At two tertiary centers 221 consecutive patients were submitted to TAVR. Kidney injury was defined according to VARC-2 criteria. Patients were classified according to the presence (group 1) or absence (group 2) of AKI. Creatinine values were collected daily until seventh day after procedure, 1 month, 6 months, and then 1 year after TAVR., Results: At baseline, groups were similar, except for EuroSCORE II (8.66% vs. 7.34%, P = 0.02) and glomerular filtration rate (GFR) (39.59 vs. 48.49 mL/min.1.73 m 2 , P = 0.002). Overall 30 day-mortality and 1-year mortality were 6.3% and 14.0%, respectively. Both 30-day mortality (23.1% vs. 1.2%, P < 0.001) and 1-year mortality (44.2% vs. 4.7%, P < 0.001) were higher in group 1. After multivariable-adjusted models, the only independent predictor for AKI after TAVR was baseline GFR (HR: 1.37, 95% CI: 1.08-1.77, P = 0.01). The independent risk factors for 1-year mortality were AKI (HR: 15.66, 95% CI: 6.07-44.63, P < 0.001), COPD (HR: 3.14, 95% CI: 1.05-9.40, P = 0.04) and aortic regurgitation grade postprocedure ≥ 2 (P = 0.05) also after multivariate analysis., Conclusions: In this TAVR cohort, baseline GFR was the only independent predictor of AKI, which negatively impacted on 30-day and 1-year mortality. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The aim of this study was to investigate associations between poor spinal posture and the recurrence of major depressive episodes and severity of symptoms in patients with major depressive disorder (MDD). This was a cross-sectional quantitative study of MDD patients. Outpatients were recruited from consecutive admissions at a mood disorders unit of a tertiary psychiatric hospital. Of 136 MDD patients, 72 (53 women, 19 men; mean age, 42.4±9.1years) met all the criteria and completed the study. Forty-one patients were classified with a recurrent episode (RE) of MDD and 31 with a single episode (SE). Quantitative assessments of postural deviations were made using photogrammetry, including kyphosis, shoulder protraction, and head inclination. The severity of depressive episodes was assessed using the Hamilton Depression Rating Scale. The diagnosis and classification of patients were performed according to DSM-IV-TR and SCID criteria. Multivariate analysis of variance indicated that the RE group had greater anterior head inclination (35.39; SD: 1.57), greater scapular abduction (1.69; SD: 0.93), and worse thoracic kyphosis (139.38; SD: 1.19) than the SE group (p<0.001 for all). Multivariate analysis of covariance showed an interaction between the severity of depressive symptoms and the degree of thoracic kyphosis (p=0.002). Recurrence of depressive episodes is associated with measures of postural misalignment., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background:: Bioresorbable vascular scaffolds (BVS) were developed to improve the long-term results of percutaneous coronary intervention, restoring vasomotion., Objectives:: To report very late follow-up of everolimus-eluting Absorb BVS (Abbott Vascular, Santa Clara, USA) in our center., Methods:: Observational retrospective study, in a single Brazilian center, from August 2011 to October 2013, including 49 patients submitted to Absorb BVS implantation. Safety and efficacy outcomes were analyzed in the in-hospital and very late follow-up phases (> 2 years)., Results:: All 49 patients underwent a minimum follow-up of 2.5 years and a maximum of 4.6 years. Mean age was 56.8 ± 7.6 years, 71.4% of the patients were men, and 26.5% were diabetic. Regarding clinical presentation, the majority (94%) had stable angina or silent ischemia. Device success was achieved in 100% of cases with 96% overall procedure success rate. Major adverse cardiovascular events rate was 4% at 30 days, 8.2% at 1 year, and 12.2% at 2 years, and there were no more events until 4.6 years. There were 2 cases of thrombosis (1 subacute and 1 late)., Conclusions:: In this preliminary analysis, Absorb BVS showed to be a safe and effective device in the very late follow-up. Establishing the efficacy and safety profiles of these devices in more complex scenarios is necessary., Fundamento:: Os suportes vasculares bioabsorvíveis (SVB) foram desenvolvidos com o intuito de melhorar os resultados da intervenção coronária percutânea a longo prazo, restabelecendo-se a vasomotricidade., Objetivos:: Reportar o seguimento muito tardio do implante do SVB eluidor de everolimus Absorb® (Abbot Vascular, Santa Clara, EUA) em nosso centro., Métodos:: Estudo observacional, retrospectivo, em um único centro brasileiro, que incluiu 49 pacientes submetidos ao implante do SVB Absorb® entre agosto/2011 e outubro/2013. Foram analisados os desfechos de segurança e eficácia na fase hospitalar e bastante tardia (> 2 anos)., Resultados:: Todos os 49 pacientes completaram um seguimento mínimo de 2,5 anos, sendo o máximo de 4,6 anos. A média de idade foi 56,8 ± 7,6 anos, sendo 71,4% da população estudada do sexo masculino e 26,5% composta por diabéticos. Considerando a apresentação clínica, a grande maioria (94%) tinha angina estável ou isquemia silenciosa. Obteve-se sucesso do dispositivo em 100% dos casos e do procedimento, em 96%. A taxa de eventos cardiovasculares maiores foi de 4% aos 30 dias, de 8,2% em 1 ano, e de 12,2% em 2 anos, sem mais eventos até 4,6 anos. Houve 2 casos de trombose (1 subaguda e 1 tardia) até o último seguimento., Conclusões:: Nesta análise preliminar, o uso do SVB Absorb® mostrou-se seguro e eficaz no seguimento bastante tardio. Faz-se necessário estabelecer o perfil de eficácia e segurança destes dispositivos em cenários de maior complexidade.

Objective: Oxidative stress and mitochondrial dysfunction are 2 closely integrated processes implicated in the physiopathology of bipolar disorder. Advanced proton magnetic resonance spectroscopy techniques enable the measurement of levels of lactate, the main marker of mitochondrial dysfunction, and glutathione, the predominant brain antioxidant. The objective of this study was to measure brain lactate and glutathione levels in bipolar disorder and healthy controls., Methods: Eighty-eight individuals (50 bipolar disorder and 38 healthy controls) underwent 3T proton magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (2x2x4.5cm(3)) using a 2-D JPRESS sequence. Lactate and glutathione were quantified using the ProFit software program., Results: Bipolar disorder patients had higher dorsal anterior cingulate cortex lactate levels compared with controls. Glutathione levels did not differ between euthymic bipolar disorder and controls. There was a positive correlation between lactate and glutathione levels specific to bipolar disorder. No influence of medications on metabolites was observed., Conclusion: This is the most extensive magnetic resonance spectroscopy study of lactate and glutathione in bipolar disorder to date, and results indicated that euthymic bipolar disorder patients had higher levels of lactate, which might be an indication of altered mitochondrial function. Moreover, lactate levels correlated with glutathione levels, indicating a compensatory mechanism regardless of bipolar disorder diagnosis., (© The Author 2016. Published by Oxford University Press on behalf of CINP.)