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Background: Down Syndrome (DS) is a genetic condition presenting delay in acquisition of main motor milestones, such as walking. Although studies have been investigating the biomechanical parameters during land walking performed by individual with DS, the literature is scarce regarding kinetic parameters analysis in this population, specially during water walking., Research Question: This study sought to assess the vertical ground reaction force (Fz) of walking performed in water and on land at different speeds by individuals with DS., Methods: Fourteen adults with DS (age: 27.9 ± 7.9 years; body mass: 58.4 ± 12.9 kg; height: 1.4 ± 0.1 m, body mass index: 29.2 ± 5.4 kg.m -2 ) completed two sessions of data collection, one on land and another in aquatic environment. The protocol consisted of walking performed at three self-selected speeds (slow, comfortable and fast) in randomized order. The Fz was assessed with a waterproof force plate in each condition. Two-way repeated-measures ANOVA (environment and speed), with Bonferroni's post hoc tests, were used for analysis. A significance level was set as α = 0.05., Results: Significant differences were observed between environments (p < 0.001), with reduced first peak of Fz (68-73%), second peak of Fz (66-70%), loading rate (75-78%) and impulse (40-41%) in the water walking for all speeds analyzed. In the aquatic environment, no significant difference was observed for the first and second Fz peaks with the increasing speed of walking. Moreover, the loading rate significantly increased (p = 0.019) as the impulse significantly reduced (p < 0.001) in the higher speeds., Significance: Individuals with DS present reduced Fz outcomes during water walking in comparison to land. Therefore, water walking may be performed by individuals with DS with safe vertical loads on lower limbs regardless the self-selected speed for rehabilitation, correction of gait and training purposes., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Elder abuse is a complex public health problem. It is of fundamental importance to ascertain which factors are associated with each specific type of abuse, as a way of enabling the creation of evidence-based public policies. The aim of the present study was to systematically review the literature regarding analytical epidemiological studies of factors associated with elder abuse. Four databases were used for the bibliographic search: Pubmed, Scopus, Web of Science and Lilacs, with no limitations regarding year of publication. Articles were selected by pairs of researchers in two stages: reading of abstracts (3.121) and reading of complete articles (64). The total number of articles selected was 27. The risk of bias was evaluated. The factors associated with general violence were age, sex, marital status, educational level, income, family arrangement, social support, solitude, mental disorder, depression, suicide attempt, dependence on others in daily activities, cognitive function, chronic diseases, alcohol or drug abuse, among others. Elder abuse was found to be a multifactorial and complex phenomenon that should not therefore be viewed in a partial one-dimensional manner, but in such a way as to take into account all dimensions and the interdependence of these.

The CCR5 molecule was reported in 1996 as the main HIV-1 co-receptor. In that same year, the CCR5Δ32 genetic variant was described as a strong protective factor against HIV-1 infection. These findings led to extensive research regarding the CCR5, culminating in critical scientific advances, such as the development of CCR5 inhibitors for the treatment of HIV infection. Recently, the research landscape surrounding CCR5 has begun to change. Different research groups have realized that, since CCR5 has such important effects in the chemokine system, it could also affect other different physiological systems. Therefore, the effect of reduced CCR5 expression due to the presence of the CCR5Δ32 variant began to be further studied. Several studies have investigated the role of CCR5 and the impacts of CCR5Δ32 on autoimmune and inflammatory diseases, various types of cancer, and viral diseases. However, the role of CCR5 in diseases caused by bacteria and parasites is still poorly understood. Therefore, the aim of this article is to review the role of CCR5 and the effects of CCR5Δ32 on bacterial (brucellosis, osteomyelitis, pneumonia, tuberculosis and infection by Chlamydia trachomatis) and parasitic infections (toxoplasmosis, leishmaniasis, Chagas disease and schistosomiasis). Basic information about each of these infections was also addressed. The neglected role of CCR5 in fungal disease and emerging studies regarding the action of CCR5 on regulatory T cells are briefly covered in this review. Considering the "renaissance of CCR5 research," this article is useful for updating researchers who develop studies involving CCR5 and CCR5Δ32 in different infectious diseases., (© 2020 John Wiley & Sons Ltd.)

Objective: In breast cancer patients, treatment at the end of life accounts for a major share of medical spending. However, little is known about the variability of cost trajectories between patients. This study aims to identify underlying latent groups of advanced breast cancer patients with similar cost trajectories over the last year before death., Methods: Data from deceased advanced breast cancer patients, diagnosed between 2010 and 2017, were retrieved from the Southeast Netherlands Advanced Breast Cancer (SONABRE) Registry. Costs of hospital care over the last twelve months before death were analyzed, and the variability of longitudinal patterns between patients were explored using group-based trajectory modeling. Descriptive statistics and multinomial logistic regression were applied to investigate differences between the identified latent groups., Results: We included 558 patients. Over the last twelve months before death, mean hospital costs were €2,255 (SD = €492) per month. Costs increased over the last five months and reached a maximum of €3,614 in the last month of life, driven by hospital admissions, while spending for medication declined over the last three months of life. Based on patients' individual cost trajectories, we identified six latent groups with distinct longitudinal patterns, of which only two showed a marked increase in costs over the last twelve months before death. Latent groups were constituted of heterogeneous patients, and clinical characteristics explained membership only to a limited extent., Conclusions: The average costs of advanced breast cancer patients increased towards the end of life. However, we uncovered several latent groups of patients with divergent cost trajectories, which did not reflect the overall increasing trend. The mechanisms underlying the variability in cost trajectories warrants further research., Competing Interests: The data collection of the Southeast Netherlands Advanced Breast Cancer Registry was funded by the Netherlands Organization for Health Research and Development (ZonMw), Novartis, Pfizer, Roche Nederland B.V., Eisai B.V., and Eli Lilly NL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, and this does also not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: To describe the attendance and ocular profile of competitors and members of delegations who attended the Polyclinic Ophthalmology Division during the Olympic and Paralympic Games Rio 2016., Methods: The eye clinic was allocated in the purpose-built polyclinic opened for competitors and members of delegations from 24 July to 18 September 2016. All individuals who attended the service received a comprehensive ocular examination including biomicroscopy, subjective refraction and fundus evaluation. A main clinical finding was assigned for each eye by the ophthalmologist., Results: 5.6% of Olympic Games competitors and 8.9% of Paralympic Games competitors attended the Polyclinic Ophthalmology Division during the Rio Olympic and Paralympic Games. These rates compare with 2.6% and 6.5% at the London Olympic and Paralympic Games (2012). The main clinical finding was refractive error with 79.0% of the individuals receiving a glass prescription during the Olympic Games and 81.3% during the Paralympic Games., Conclusion: Our outcomes highlight the importance of the eye service at the polyclinic as it may represent the only opportunity for many individuals involved with the Olympic and Paralympic Games to receive ocular evaluation. Our description of clinic structure, delivery of service and clinical results will be useful in the organisation not only for the Olympic and Paralympic Games Tokyo 2020 but also for any other large sporting events that involves medical attention in a polyclinic format., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction. In some species, the population structure of pathogenic bacteria is clonal. However, the mechanisms that determine the predominance and persistence of specific bacterial lineages of group C Streptococcus remain poorly understood. In Brazil, a previous study revealed the predominance of two main lineages of Streptococcus dysgalactiae subsp. equisimilis (SDSE). Aim. The aim of this study was to assess the virulence and fitness advantages that might explain the predominance of these SDSE lineages for a long period of time. Methodology. emm typing was determined by DNA sequencing. Adhesion and invasion tests were performed using human bronchial epithelial cells (16HBE14o-). Biofilm formation was tested on glass surfaces and the presence of virulence genes was assessed by PCR. Additionally, virulence was studied using Caenorhabditis elegans models and competitive fitness was analysed in murine models. Results. The predominant lineages A and B were mostly typed as emm stC 839 and stC 6979, respectively. Notably, these lineages exhibited a superior ability to adhere and invade airway cells. Furthermore, the dominant lineages were more prone to induce aversive olfactory learning and more likely to kill C. elegans . In the competitive fitness assays, they also showed increased adaptability. Consistent with the increased virulence observed in the ex vivo and in vivo models, the predominant lineages A and B showed a higher number of virulence-associated genes and a superior ability to accumulate biofilm. Conclusion. These results suggest strongly that this predominance did not occur randomly but rather was due to adaptive mechanisms that culminated in increased colonization and other bacterial properties that might confer increased bacteria-host adaptability to cause disease.

The gluteus maximus (GMax) is one of the primary hip extensors. Several exercises have been performed by strength and conditioning practitioners aiming to increase GMax strength and size. This systematic review aimed to describe the GMax activation levels during strength exercises that incorporate hip extension and use of external load. A search of the current literature was performed using PubMed/Medline, SportDiscuss, Scopus, Google Scholar, and Science Direct electronic databases. Sixteen articles met the inclusion criteria and reported muscle activation levels as a percentage of a maximal voluntary isometric contraction (MVIC). The exercises classified as very high level of GMax activation (>60% MVIC) were step-up, lateral step-up, diagonal step-up, cross over step-up, hex bar deadlift, rotational barbell hip thrust, traditional barbell hip thrust, American barbell hip thrust, belt squat, split squat, in-line lunge, traditional lunge, pull barbell hip thrust, modified single-leg squat, conventional deadlift, and band hip thrust. We concluded that several exercises could induce very high levels of GMax activation. The step-up exercise and its variations present the highest levels of GMax activation followed by several loaded exercises and its variations, such as deadlifts, hip thrusts, lunges, and squats. The results of this systematic review may assist practitioners in selecting exercised for strengthening GMax., (© Journal of Sports Science and Medicine.)

A series of novel thiourea and amide liquid crystals containing 5-membered isoxazoline and isoxazole rings were synthetized and the liquid crystal properties studied. Thioureas were obtained using a condensation reaction of benzoyl chlorides, arylamines and ammonium thiocyanate. The amides, on the other hand, were the byproduct of a quantitative reaction which used potassium cyanate as the starting material. Thiourea and amide derivatives were predominantly SmA mesophase inductors. A nematic mesophase was observed only for thioureas and amides containing an isoxazole ring. Additionaly, the liquid crystal behavior was also dependent on the relative position of nitrogen and oxygen atoms on the 5-membered heterocycle., (Copyright © 2020, Gonçalves et al.; licensee Beilstein-Institut.)

Chagas disease, also known as American trypanosomiasis, is a potentially life-threatening illness caused by the protozoan parasite, Trypanosoma cruzi, and is transmitted by triatomine insects during its blood meal. Proliferative epimastigotes forms thrive inside the insects in the presence of heme (iron protoporphyrin IX), an abundant product of blood digestion, however little is known about the metabolic outcome of this signaling molecule in the parasite. Trypanosomatids exhibit unusual gene transcription employing a polycistronic transcription mechanism through trans-splicing that regulates its life cycle. Using the Deep Seq transcriptome sequencing we characterized the heme induced transcriptome of epimastigotes and determined that most of the upregulated genes were related to glucose metabolism inside the glycosomes. These results were supported by the upregulation of glycosomal isoforms of PEPCK and fumarate reductase of heme-treated parasites, implying that the fermentation process was favored. Moreover, the downregulation of mitochondrial gene enzymes in the presence of heme also supported the hypothesis that heme shifts the parasite glycosomal glucose metabolism towards aerobic fermentation. These results are examples of the environmental metabolic plasticity inside the vector supporting ATP production, promoting epimastigotes proliferation and survival., Competing Interests: The authors have declared that no competing interests exist.

Background: Chagas disease (CD) is a tropical parasitic disease. Although the number of people infected is very high, the only drugs available to treat CD, nifurtimox (Nfx) and benznidazole, are highly toxic, particularly in the chronic stage of the disease. Coumarins are a large class of compounds that display a wide range of interesting biological properties, such as antiparasitic. Hence, the aim of this work is to find a good antitrypanosomal drug with less toxicity. The use of simple organism models has become increasingly attractive for planning and simplifying efficient drug discovery. Within these models, Caenorhabditis elegans has emerged as a convenient and versatile tool with significant advantages for the toxicological potential identification for new compounds., Methods: Trypanocidal activity: Forty-two 4-methylamino-coumarins were assayed against the epimastigote form of Trypanosoma cruzi (Tulahuen 2 strain) by inhibitory concentration 50% (IC 50 ). Toxicity assays: Lethal dose 50% (LD 50 ) and Body Area were determined by Caenorhabditis elegans N2 strain (wild type) after acute exposure. Structure-activity relationship: A classificatory model was built using 3D descriptors., Results: Two of these coumarins demonstrated near equipotency to Nifurtimox (IC 50  = 5.0 ± 1 μM), with values of: 11 h (LaSOM 266), (IC 50  = 6.4 ± 1 μM) and 11 g (LaSOM 231), (IC 50  = 8.2 ± 2.3 μM). In C. elegans it was possible to observe that Nfx showed greater toxicity in both the LD 50 assay and the evaluation of the development of worms. It is possible to observe that the efficacy between Nfx and the synthesized compounds (11 h and 11 g) are similar. On the other hand, the toxicity of Nfx is approximately three times higher than that of the compounds. Results from the QSAR-3D study indicate that the volume and hydrophobicity of the substituents have a significant impact on the trypanocidal activities for derivatives that cause more than 50% of inhibition. These results show that the C. elegans model is efficient for screening potentially toxic compounds., Conclusion: Two coumarins (11 h and 11 g) showed activity against T. cruzi epimastigote similar to Nifurtimox, however with lower toxicity in both LD 50 and development of C. elegans assays. These two compounds may be a feasible starting point for the development of new trypanocidal drugs.

Background: Melatonin has been described in the literature as a potent antioxidant. However, melatonin presents variable, low bioavailability and a short half-life. The use of polymeric nanoparticulated systems has been proposed for controlled release. Thus, the purpose of this study was to investigate the action of melatonin-loaded lipid-core nanocapsules (Mel-LNC) in the antioxidant system of Caenorhabditis elegans, and the possible protective effect of this formulation against lipid peroxidation caused by paraquat (PQ)., Methods: The suspensions were prepared by interfacial deposition of the polymer and were physiochemically characterized. C. elegans N2 wild type and transgenic worm CF1553, muls84 [sod-3p::gfp; rol6(su1006)] were obtained from the Caenorhabditis Genetics Center (CGC). The worms were divided into 5 groups: Control, PQ 0.5 mM, PQ 0.5 mM + Mel-LNC 10 μg/mL, PQ + unloaded lipid-core nanocapsules (LNC), and PQ + free melatonin (Mel) 10 μg/mL. The lipid peroxidation was assessed through thiobarbituric acid (TBARS) levels and the fluorescence levels of the transgenic worms expressing GFP were measured., Results: The LNC and Mel-LNC presented a bluish-white liquid, with pH values of 5.56 and 5.69, respectively. The zeta potential was - 6.4 ± 0.6 and - 5.2 ± 0.2, respectively. The mean particle diameter was 205 ± 4 nm and 203 ± 3 nm, respectively. The total melatonin content was 0.967 mg/ml. The TBARS levels were significantly higher in the PQ group when compared to the control group (p < 0.001). Mel-LNC reduced TBARS levels to similar levels found in the control group. Moreover, only Mel-LNC significantly enhanced the SOD-3 expression (p < 0.05). Mel-LNC was capable of protecting C. elegans from lipid peroxidation caused by PQ and this was not observed when free melatonin was used. Moreover, Mel-LNC increased the fluorescence intensity of the transgenic strain that encodes the antioxidant enzyme SOD-3, demonstrating a possible mechanism of protection from PQ-induced damage., Conclusion: These findings demonstrated that melatonin, when associated with nanocapsules, had improved antioxidant properties and the protective activity against PQ-induced lipid peroxidation could be associated with the activation of antioxidant enzymes by Mel-LNC in C. elegans.

Purpose: To verify the access to speech-language pathology (SLP) therapy and continuity of assistance in Primary Health Care (PHC) for victims of motorcycle accidents., Methods: A quantitative and qualitative study was conducted at a large hospital in the city of Recife, Pernanbuco state, Brazil. Among the 99 victims recruited between June and July 2014, 30 had SLP complaints as a result of the accidents. After hospital discharge, all victims were contacted for investigation of the SLP rehabilitation process. Absolute and relative frequencies were used for the analysis in PHC, and data were displayed in tables for the therapy cases., Results: Among the 30 individuals who reported having alterations of the stomatognathic system, eight were undergoing rehabilitation and 18 reported residing in an area covered by the Family Health Strategy (primary care modality). Seeking and obtaining continuity of treatment (medication and bandaging) in primary care were frequent; in contrast, home visits were less frequent. The main obstacles to access SLP therapy were distance to the service and waiting time to begin treatment., Conclusion: This study identified obstacles that hamper access to SLP therapy in PHC, such as the low frequency of home visits, contributing to the fragmentation of continuous and complete care for victims.

The Guama virus (GMAV) is a member of Peribunyaviridae family, Orthobunyavirus genus. Several strains of the virus were isolated in South and Central Americas from several hosts, such as humans, wild animals, including nonhuman primates, wild rodents and mosquitoes as well as mice used as sentinels. The virus is able to cause febrile disease in humans. Here we describe for the first time pathologic and biochemical findings in golden hamsters (Mesocricetus auratus) infected with the prototype GMAV. Blood and organs of infected and control animals were collected every 24 h after infection from the 1st to the 7th day post infection (dpi) and at 21 dpi when experiment was ended. The tissues were processed for histopathology and immunohistochemistry. The blood and serum were used to determine viremia and biochemical markers plus to detect anti-GMAV antibodies. The viremia was early detected already on the 1st dpi and it was no longer detected on the 3rd dpi. Total anti-GMAV antibodies were detected from the 6th dpi. Hepatic markers as ALT of infected animals were increased and showed statistically significant difference in comparison with control animals, indicating damage of the liver; indeed the liver was the most affected organ, but other organs presented lesions and positive GMAV immunostaining as brain, lung, liver, spleen, and kidney. Our findings indicate that golden hamsters are a good animal model for experimental infection of the GMAV., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Melanin is produced by melanocytes and protects against DNA damage by ultraviolet light. Unfortunately, the melanin protein present in melanoma tumor cells is often co-purified during DNA extraction, and this contamination may inhibit subsequent PCR methods, which directly impacts research applications and the molecular diagnostic tests needed for targeted therapeutics. There are presently no described purification protocols that efficiently remove melanin from genomic DNA. In this study, we compare six different methods for melanin removal from genomic DNA: Agarose Gel Electrophoresis, 1mg Chelex®-100, Chelex®-100 5%, centrifugation, OneStep™ PCR Inhibitor Removal Kit and centrifugation plus OneStep™ PCR Inhibitor Removal Kit. Each comparison was made using 16 formalin-fixed paraffin-embedded (FFPE) and 11 fresh cell line samples. All samples were initially tested using the multiplex PCR reaction for GAPDH gene that generates different sized amplified products: 100, 200, 300 and 400 base pairs, which could be inhibited by the addition of exogenous melanin. Six purification protocols were then applied, and all samples that amplified at least one GAPDH fragment were sequenced to analyze the presence of the BRAF V600E mutation. The efficiencies of amplification decreased for larger sized fragments in all methods. Our comparisons showed that centrifugation combined with the OneStep™ PCR Inhibitor Removal Kit was superior to all other methods for successful BRAF sequencing with 100% (100bp), 75% (200bp), 50% (300bp), and 31.3% (400bp) amplification efficiencies for the different amplicon sizes. In conclusion, this genomic DNA extraction method is highly efficient for successful PCR when tumor samples are contaminated with melanin.

This review correlates and summarizes the role of the maternal-fetal interface in the immune tolerance of the fetus and the processes that lead to infection avoidance, emphasizing the participation of exosomes and other extracellular vesicles in both situations. Exosomes are released into the extracellular medium by several cell types and are excellent carriers of biomolecules. Host-derived exosomes and the transport of pathogen-derived molecules by exosomes impact infections in different ways. The interactions of exosomes with the maternal immune system are pivotal to a favorable gestational outcome. In this review, we highlight the potential role of exosomes in the establishment of an adequate milieu that enables embryo implantation and discuss the participation of exosomes released at the maternal-fetal interface during the establishment of an immune-privileged compartment for fetal development. The placenta is a component where important strategies are used to minimize the risk of infection. To present a contrast, we also discuss possible mechanisms used by pathogens to cross the maternal-fetal interface. We review the processes, mechanisms, and potential consequences of dysregulation in all of the abovementioned phenomena. Basic information about exosomes and their roles in viral immune evasion is also presented. The interactions between extracellular vesicles and bacteria, fungi, parasites and proteinaceous infectious agents are addressed. The discovery of the placental microbiota and the implications of this new microbiota are also discussed, and current proposals that explain fetal/placental colonization by both pathogenic and commensal microbes are addressed. The comprehension of such interactions will help us to understand the immune dynamics of human pregnancy and the mechanisms of immune evasion used by different pathogens., (© 2019 Published by Elsevier Ltd.)

Leishmaniasis is one of the major neglected tropical diseases in the world and it is considered endemic in 88 countries. This disease is transmitted by a Leishmania spp. infected sandfly and it may lead to cutaneous or systemic manifestations. The preconized treatment has low efficacy and there are cases of resistance to some drugs. Therefore, the search for new efficient molecular targets that can lead to the preparation of new drugs must be pursued. This review aims to evaluate both Leishmania enzymes PTR1 and DHFR-TS as potential drug targets, highlight their inhibitors and to discuss critically the use of chemoinformatics to elucidate interactions and propose new molecules against these enzymes.

A systematic review of the literature on analytical epidemiologic studies about factors associated with the use of health services by elderly men was conducted. Four databases were researched, namely PubMed, Scopus, Web of Science and Lilacs and the following key words "health services," "health services for the aged," "aged," "aged 80 and over," "men" and "men's health" and their corresponding expressions in Portuguese were used. After independent reading and selection of the abstracts and full texts of the 1782 articles located, only eight were included in this review. The Health Services Utilization model assisted in the presentation of the results. Predisposing factors associated with regard to the use of the healthcare services were identified: place of residence; lifestyle habits; age bracket; family history; education and marital status; training factors: private health services use and affiliation to a health insurance plan; effective factors of need; perception of health status; perceived susceptibility to stress; medical history; comorbidities; and functional status. The issue of aging among the male population is still poorly studied and deserves special attention to establish how elderly men express their needs and how they are being assisted by healthcare systems.

Objective: This study is a characterization of the treatment patterns and outcomes of a Brazilian melanoma cohort collected of 1848 patients enrolled between 1996 and 2015., Results: The superficial spreading subtype (35.1%) was the most prevalent, and the favoured anatomical location was the trunk (32.8%). The most common clinical stage was I (27.6%). The most frequent initial treatment was surgery (84.7%). Sentinel node biopsy was positive in 23.3% of cases. Chemotherapy was used to treat 298 patients (16.1%), immunotherapy for 67 (3.6%) and targeted therapy for 19 (1.0%). Distant recurrence was commonly observed (22.5%) and the mutation status of the BRAF gene was verified in 132 cases, with 42.4% positivity in this subset of patients. The melanoma specific actuarial 5-year survival for the cohort was 68.8%. There was a higher 5-year survival observed in metastatic melanoma patients who received immunotherapy and/or targeted therapy (34.2%) compared patients treated with just chemotherapy (20.0%). The survival analysis showed that sex, age, Breslow, clinical stage and distant recurrence were significant prognostic factors. This study provides a real-world description of how the introduction of new therapies such as immunotherapy and BRAF inhibitors is changing treatment strategies for melanoma in developing countries.

To obtain usnic acid potassium salt (PS-UA), the usnic acid (UA) was extracted and purified from the lichen Cladonia substellata , and modified to produce PS-UA. The structure was determined by 1 H-NMR, IR and elemental analysis, ratified through computational models, as well as identification the site of K + insertion in the molecule. Antinociceptive activity was detected through contortions in mice induced by acetic acid and formalin (phases I and II) after treatments with 10 and 20 mg/kg of PS-UA, indicating interference in both non-inflammatory and inflammatory pain. After oral administration at doses of 500, 1000 and 2000 mg/kg, no deaths of mice with treatments below 2000 mg/kg were observed. Except for body weight gain, food and water consumption decreased with treatments of 1000 and 2000 mg/kg, and the number of segmented leukocytes was higher for both treatments. Regarding serum levels, cholesterol and triglycerides decreased, however, there was an increase in hepatic transaminases with both treatments. Liver and kidney histological changes were detected in treatments of 2000 mg/kg, while the spleen was preserved. The PS-UA demonstrated antinociceptive activity while the acute toxicity at the concentration of 2000 mg/kg was the only dose that presented morphological changes in the liver and kidney.

An efficient and new electrochemical biosensor for detection of DNA damage, induced by the interaction of the hybrid anti-cancer compound (7ESTAC01) with DNA, was studied by differential pulse voltammetry (DPV). The biosensor consists of a Stem-Loop DNA (SL-DNA) probe covalently attached to the gold electrode (GE) surface that hybridizes to a complementary DNA strand (cDNA) to form a double-stranded DNA (dsDNA). The interaction and DNA damage induced by 7ESTAC01 was electrochemically studied based on the oxidation signals of the electroactive nucleic acids on the surface of the GE by DPV. As a result, the SL-DNA/GE and dsDNA/GE were tested with the reduced 7ESTAC01, showing the voltammetric signal of guanine and adenine, increase in the presence of 7ESTAC01. Under optimum conditions, the dsDNA/GE biosensor exhibited excellent DPV response in the presence of 7ESTAC01. The bonding interaction between 7ESTAC01 and calf thymus DNA (ctDNA) was confirmed by UV-Vis absorption spectroscopy, dynamic simulations (performed to investigate the DNA structure under physiological conditions), and molecular docking. Theoretical results showed the presence of hydrogen bonding and intercalation in the minor groove of DNA, involving hydrophobic interactions., (Copyright © 2019. Published by Elsevier B.V.)

Strategies focused on the prevention of emerging infectious disease outbreaks are currently in the spotlight of discussions among researchers committed to infectious disease control. In this mini-review, we provided a brief update on this discussion and characterized the three main targets for investments in emerging infectious disease prevention: animals, human sentinels for spillover events, and the general human population. Furthermore, the pros and cons of each target are highlighted. Despite the particularities of the proposed targets, each of them can fill different gaps in the surveillance of infectious diseases. When all three targets are focused on together, they create a powerful strategy of emerging infectious disease prevention., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pre-eclampsia (PE) is a hypertensive disorder that affects an important number of pregnant women worldwide. The exact causes of PE remain poorly understood. However, inflammation and deregulation of innate immune cells, such as natural killer (NK) cells, contribute to PE pathogenesis. Besides, the mother's genetic background also impacts on PE susceptibility. Thus, genetic variants that potentially modify the behaviour of inflammatory cells may help us to understand the causes of PE. Variants of genes encoding NKG2C (expressed in NK cells) and C-C chemokine receptor type 5 (CCR5) (expressed mainly in leucocytes) are important targets in the study of gestational disorders. In this context, we evaluated the impact of both NKGC2 gene deletion and CCR5Δ32 gene variant on PE susceptibility in a population sample from central-southeast Brazil composed by 369 women (156 with PE and 213 healthy pregnant women). No statistically significant association between the NKG2C gene deletion and susceptibility to PE was observed. However, taking into consideration the important role of NK cells in pregnancy, the influence of NKG2C gene deletion on PE pathogenesis should not be ruled out and deserves further studies in populations with different genetic/ethnic backgrounds. In addition, our results regarding CCR5Δ32 corroborate previous data from our group approaching a distinct cohort and reinforce CCR5Δ32 as a protective factor against PE development (p < 0.05)., (© 2019 John Wiley & Sons Ltd.)

Background: Serological evidence of West Nile virus (WNV) infection has been reported in different regions of Brazil from equine and human hosts but the virus had never been isolated in the country., Objectives: We sought to identify the viral etiology of equine encephalitis in Espírito Santo state., Methods: We performed viral culture in C6/36 cells, molecular detection of WNV genome, histopathology and immunohistochemistry from horse cerebral tissue. We also carried out sequencing, phylogenetic analysis and molecular clock., Findings: Histopathologic analysis from horse cerebral tissue showed injury related to encephalitis and WNV infection was confirmed by immunohistochemistry. The virus was detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) from brain tissue and subsequently isolated in C6/36 cells. WNV full-length genome was sequenced showing the isolated strain belongs to lineage 1a. The molecular clock indicated that Brazilian WNV strain share the same common ancestor that were circulating in US during 2002-2005., Main Conclusions: Here we report the first isolation of WNV in Brazil from a horse with neurologic disease, which was clustered into lineage 1a with others US WNV strains isolated in beginning of 2000's decade.

Background: Leishmaniasis reaches millions of people around the world. The control of the disease is difficult due to the restricted access to the diagnosis and medication, and low adherence to the treatment. Thus, more efficient drugs are needed and natural products are good alternatives. Iridoids, natural products with reported leishmanicidal activity, can be exploited for the development of anti- Leishmania drugs. The aim of this study was to isolate and to investigate the in vitro activity of iridoids against Leishmania amazonensis and to compare the activity in silico of these compounds with those reported as active against this parasite., Methods: Iridoids were isolated by chromatographic methods. The in vitro activity of asperuloside (1) and geniposide (2) from Escalonia bifida, galiridoside (3) from Angelonia integerrima and theveridoside (4) and ipolamiide (5) from Amphilophium crucigerum was investigated against promastigote forms of Leishmania amazonensis. Molecular modeling studies of 1-5 and iridoids cited as active against Leishmania spp. were performed., Results: Compounds 1-5 (5-100 µM) did not inhibit the parasite survival. Physicochemical parameters predicted for 1-5 did not show differences compared to those described in literature. The SAR and the pharmacophoric model confirmed the importance of maintaining the cyclopentane[C]pyran ring of the iridoid, of oxygen-linked substituents at the C1 and C6 positions and of bulky substituents attached to the iridoid ring to present leishmanicidal activity., Conclusion: The results obtained in this study indicate that iridoids are a promising group of secondary metabolites and should be further investigated in the search for new anti-Leishmania drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Placental vascularization is a tightly regulated physiological process in which the maternal immune system plays a fundamental role. Vascularization of the maternal-placental interface involves a wide range of mechanisms primarily orchestrated by the fetal extravillous trophoblast and maternal immune cells. In a healthy pregnancy, an immune cross-talk between the mother and fetal cells results in the secretion of immunomodulatory mediators, apoptosis of specific cells, cellular differentiation/proliferation, angiogenesis, and vasculogenesis, altogether favoring a suitable microenvironment for the developing embryo. In the context of vasculopathy underlying common pregnancy disorders, it is believed that inefficient invasion of extravillous trophoblast cells in the endometrium leads to a poor placental blood supply, which, in turn, leads to decreased secretion of angiogenic factors, hypoxia, and inflammation commonly associated with preterm delivery, intrauterine growth restriction, and preeclampsia. In this review, we will focus on studies published by Latin American research groups, providing an extensive review of the role of genetic variants from candidate genes involved in a broad spectrum of biological processes underlying the pathophysiology of preeclampsia. In addition, we will discuss how these studies contribute to fill gaps in the current understanding of preeclampsia. Finally, we discuss some trending topics from important fields associated with pregnancy vascular disorders (e.g., epigenetics, transplantation biology, and non-coding RNAs) and underscore their possible implications in the pathophysiology of preeclampsia. As a result, these efforts are expected to give an overview of the extent of scientific research produced in Latin America and encourage multicentric collaborations by highlighted regional research groups involved in preeclampsia investigation.

What are the factors that influence human hepatitis C virus (HCV) infection, hepatitis status establishment, and disease progression? Firstly, one has to consider the genetic background of the host and HCV genotypes. The immunogenetic host profile will reflect how each infected individual deals with infection. Secondly, there are environmental factors that drive susceptibility or resistance to certain viral strains. These will dictate (I) the susceptibility to infection; (II) whether or not an infected person will promote viral clearance; (III) the immune response and the response profile to therapy; and (IV) whether and how long it would take to the development of HCV-associated diseases, as well as their severity. Looking at this scenario, this review addresses clinical aspects of HCV infection, following by an update of molecular and cellular features of the immune response against the virus. The evasion mechanisms used by HCV are presented, considering the potential role of exosomes in infection. Genetic factors influencing HCV infection and pathogenesis are the main topics of the article. Shortly, HLAs, MBLs, TLRs, ILs, and IFNLs genes have relevant roles in the susceptibility to HCV infection. In addition, ILs, IFNLs, as well as TLRs genes are important modulators of HCV-associated diseases. The viral aspects that influence HCV infection are presented, followed by a discussion about evolutionary aspects of host and HCV interaction. HCV and HIV infections are close related. Thus, we also present a discussion about HIV/HCV co-infection, focusing on cellular and molecular aspects of this interaction. Pharmacogenetics and treatment of HCV infection are the last topics of this review. The understanding of how the host genetics interacts with viral and environmental factors is crucial for the development of new strategies to prevent HCV infection, even in an era of potential development of pan-genotypic antivirals., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Leishmaniasis, affecting more than 12 million people worldwide has become a severe public-health problem. The therapeutic arsenal against leishmaniasis is mainly administered by parenteral route; it is toxic, expensive, and associated with recurrence risk. The need for further therapeutic compounds research is pressing. In previous studies, we demonstrated the antileishmanial activities of ten 2-amino-thiophene derivatives, which evidenced the action of a compound, called SB-83, having expressive antileishmania activity in an in vitro infection model. In the present work, we describe preclinical studies of the thiophenic derivative SB-83, such as acute toxicity, genotoxicity, in vivo oral efficacy in a murine model, and in vitro antileishmanial activity against an L. amazonensis Sb III -resistant strain. Determining acute preclinical toxicity, the LD 50 of SB-83 was estimated at 2500 mg/kg orally, with few behavioral changes in Swiss mice. Further, treatment with 2000 mg/kg of SB-83 did not induce in vivo genotoxic activity in the peripheral blood micronucleus assay. In 7 weeks of oral treatment, SB-83 reduced paw lesion size in L. amazonensis infected mice by 52.47 ± 5.32%, and decreased the parasite load of the popliteal lymph node and spleen at the highest dose tested (200 mg/kg) respectively by 42.57 ± 3.14%, and 100%, without presenting weight change or other changes of clinical importance in the biochemical and hematological profiles. The treatment of promastigotes and intracellular amastigotes of Sb III sensitive and resistant strains with SB-83 did not produce differences in antileishmania activity, which suggests no cross-resistance. Thus, this work demonstrated that SB-83 has potential as a new active drug candidate even when orally administered, which may become a new therapeutic alternative for the treatment of leishmaniasis., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Cytokines are essential to maintain and coordinate the correct activity of immune cells during human pregnancy. IL-17 is a pro-inflammatory cytokine that induces the expression of many inflammatory mediators. The aim of this study was to compare the levels of Th1, Th2 and Th17 cytokines of women ongoing normal pregnancy with those found in women who suffered spontaneous abortion. IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, and IFN-γ peripheral blood levels were measured in women who suffered spontaneous abortion (n = 13, blood collected up to 24 h after abortion), and were compared with healthy successful pregnancies (n = 16). Cytokine levels were measured using a cytometric bead array (CBA analysis). Similar cytokine levels were observed between spontaneous abortion and healthy pregnant women excepted to IL-17, which levels were increased in the healthy pregnant women (p = 0.0232). Our results show high IL-17 levels in the peripheral blood of women at late stages of healthy pregnancy, although low IL-17 levels were detected in the peripheral blood of women just after spontaneous abortion. In line with recent studies, this finding highlights IL-17 as a regulatory cytokine essential to the maintenance of a successful pregnancy.

Identifying and monitoring multiple disease biomarkers and other clinically important factors affecting the course of a disease, behavior or health status is of great clinical relevance. Yet conventional statistical practice generally falls far short of taking full advantage of the information available in multivariate longitudinal data for tracking the course of the outcome of interest. We demonstrate a method called multi-trajectory modeling that is designed to overcome this limitation. The method is a generalization of group-based trajectory modeling. Group-based trajectory modeling is designed to identify clusters of individuals who are following similar trajectories of a single indicator of interest such as post-operative fever or body mass index. Multi-trajectory modeling identifies latent clusters of individuals following similar trajectories across multiple indicators of an outcome of interest (e.g., the health status of chronic kidney disease patients as measured by their eGFR, hemoglobin, blood CO 2 levels). Multi-trajectory modeling is an application of finite mixture modeling. We lay out the underlying likelihood function of the multi-trajectory model and demonstrate its use with two examples.

Tacaiuma virus (TCMV) is antigenically characterized as a member of the Anopheles A complex in the Orthobunyavirus genus, Peribunyaviridae family (Bunyavirales order). Clinically, the TCMV infection is characterized by acute febrile illness with myalgia and arthralgia lasting three to five days. However, the genomic and evolutionary aspect of this virus has not been elucidated. In this study, we described the complete coding sequences of three segments of two TCMV strains isolated in Brazil and three complete coding sequences of the small segment of three TCMV strains. All the strains sequenced in this study showed the typical genomic organization of orthobunyaviruses that infect vertebrates, except for the absence of the open reading frame that encodes the well-described non-structural small protein. This study presents the genomic and evolutionary characterization of TCMV strains and would be helpful for diagnostic purposes and epidemiology., (Copyright © 2018 Elsevier B.V. All rights reserved.)

An original and focused library of two sets of dihydropyrimidin-2-thiones (DHPMs) substituted with N-1 aryl groups derived from monastrol was designed and synthesized in order to discover a more effective Eg5 ligand than the template. Based on molecular docking studies, four ligands were selected to perform pharmacological investigations against two glioma cell lines. The results led to the discovery of two original compounds, called 20h and 20e , with an anti-proliferative effects, achieving IC 50 values of about half that of the IC 50 of monastrol in both cell lines. As with monastrol, flow cytometry analyses showed that the 20e and 20h compounds induced cell cycle arrest in the G 2 /M phase, and immunocytochemistry essays revealed the formation of monopolar spindles due to Eg5 inhibition without any toxicity to Caenorhabditis elegans .

Aims: The aim of this study was to evaluate the association between vitamin D deficiency and risk of heart failure in elderly patients of cardiology outpatient clinics., Methods and Results: A cross-sectional study with an analytical approach was employed. Clinical data were collected from the elderly from August 2015 to February 2016. The dependent variable was the risk of heart failure; the independent variable was vitamin D deficiency; and intervening factors were age, gender, education, ethnicity, hypertension, diabetes mellitus, hypothyroidism, renal failure, dementia, stroke, dyslipidaemia, depression, smoking, alcoholism, obesity, andropause, and cardiac arrhythmia. To analyse the association between vitamin D deficiency and risk of heart failure, we used the bivariate logistic analysis, followed by analysis through the multivariate logistic regression model. Of the 137 elderly, the study found the following: women (75.9%); overweight (48.2%); obese (30.6%); increase in the index waist/hip (88.3%); dyslipidaemia (94.2%) and hypertension (91.2%); coronary artery disease (35.0%); and 27.7% with cardiac arrhythmia or left ventricular hypertrophy. Sixty-five per cent of the elderly were deficient in vitamin D. The risk of heart failure was significantly associated with vitamin D deficiency [odds ratio (OR): 12.19; 95% confidence interval (CI) = 4.23-35.16; P = 0.000], male gender (OR: 15.32; 95% CI = 3.39-69.20, P = 0.000), obesity (OR: 4.17; 95% CI = 1.36-12.81; P = 0.012), and cardiac arrhythmia (OR: 3.69; 95% CI = 1.23-11.11; P = 0.020)., Conclusions: There was a high prevalence of vitamin D deficiency in the elderly, and the evidence shows a strong association between vitamin D deficiency and increased risk of heart failure in this population., (© 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

This text presents complementary data corresponding to schistosomiasis mansoni's vector control and enviromental toxicity using usnic acid. These informations support our research article "Toxicity of Usnic Acid from Cladonia substellata (Lichen) to embryos and adults of Biomphalaria glabrata " by Araújo et al. [1], and focuses on the analysis of the detailed data regarding the different concentrations of Usnic Acid and their efficiency to B. glabrata mortality and non-viability, as also to environmental toxicity, evaluated by A. salina mortality.

For more than 40 years, the fluid mosaic model of cellular membranes has supported our vision of an inert lipid bilayer containing membrane protein receptors that are randomly hit by extracellular molecules to trigger intracellular signaling events. However, the notion that compartmentalized cholesterol- and sphingomyelin-rich membrane microdomains (known as lipid rafts) spatially arrange receptors and effectors to promote kinetically favorable interactions necessary for the signal transduction sounds much more realistic. Despite their assumed importance for the dynamics of ligand-receptor interactions, lipid rafts and biomembranes as a whole remain less explored than the other classes of biomolecules because of the higher variability and complexity of their membrane phases, which rarely provide the detailed atomic-level structural data in X-ray crystallography assays necessary for molecular modeling studies. The fact that some alkylphospholipids (e.g. edelfosine: 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) selectively induce the apoptotic death of cancer cells by recruiting Fas death receptors and the downstream signaling molecules into clusters of lipid rafts suggests these potential drug targets deserve a more in-depth investigation. Herein, we review the structure of lipid rafts, their role in apoptotic signaling pathways and their potential role as drug targets for the treatment of cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Purpose: The current data suggest that the presence of lower third molars predisposes the patient to a greater risk of mandibular angle fracture. Thus, the present review sought to determine whether an association exists between the presence of a lower third molar and the occurrence of a mandibular angle fracture in adults and to assess the influence of third molar position according to the Pell and Gregory classification., Materials and Methods: The present study was a systematic review and meta-analysis of analytical observational studies. The present review included all reports of the relationship between mandibular angle fractures and lower third molars. No restriction regarding year, language, or publication status was used. The review protocol was registered at the PROSPERO database (registration no. CRD42016047057). Electronic searches unrestricted for publication period and language were performed in the PubMed, Scopus, SciELO, and Latin American and Caribbean Health Sciences databases. Google Scholar and OpenGrey databases were used to search the "gray literature," avoiding selection and publication biases. The entire search was performed by 2 eligibility reviewers. Association and proportion meta-analyses were planned for the studies with sufficient data. The primary predictor variable was the relationship between the presence of a lower third molar and the development of mandibular angle fractures. The secondary outcome variables were the vertical and horizontal positions of the lower third molar, according to the Pell and Gregory classification and their relationship to the susceptibility to developing a mandibular angle fracture., Results: The search strategies resulted in 411 studies, from which 16 were selected for qualitative and quantitative review. The association meta-analysis included all the selected studies and showed that patients with lower third molars are 3.16 times more likely to develop mandibular angle fractures. The proportion meta-analysis included 5 studies and showed that the overall rate of mandibular angle fractures was 51.58% and that positions III and C are more likely to result in fracture, with a rate of 59.84 and 63.67%, respectively., Conclusions: The results of the present study have shown that the presence of impacted third molars increases by 3.16 times the risk of mandibular angle fractures in adults, with the greatest risk present when third molars are classified as IIIC according to Pell and Gregory. The available evidence is not sufficiently robust to determine whether third molar presence or the level of impaction is the main causative factor for the occurrence of mandibular angle fractures., (Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Regional lymph nodes are affected frequently by melanoma metastasis. Its microenvironment may be associated with tumor progression. We investigated sentinel nodes with and without tumor and negative nodes surrounding positive nodes, looking for patterns related to tumor immune interaction and lymphovascular progression. We quantified programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1, vascular endothelial growth factor (VEGF)-A/VEGF-C expressions in lymph nodes of 103 patients who underwent sentinel lymph node biopsy. Two groups were studied: negative sentinel lymph nodes and positive ones. Negative lymph nodes of sequential lymphadenectomy from positive cases were also studied. Markers were assessed by immunohistochemistry. Results were related to clinical/histological outcomes. VEGF-A/VEGF-C analysis showed higher positivity in metastatic nodes and higher positivity in the surrounding negative nodes from positive cases in comparison with nonmetastatic patients. Programmed cell death-ligand 1, studied only in metastasis, presented high positivity, not associated with prognosis. PD-1 expressions were similar in the groups with a 1% cutoff and higher in the metastasis with a 5% cutoff. Higher VEGF-A expression was related to higher pathological stages. PD-1 expression in the lymph node was associated with higher survival. Other clinical and histopatological variables were not associated with marker expression patterns. VEGF-A and VEGF-C expressions in lymph nodes were associated with the presence of lymph node metastasis. PD-1 expression in the lymph node was related to higher survival rates and this should be explored in the context of adjuvant immunotherapy.

Inhibition of mushroom tyrosinase was observed with synthetic dihydropyrano[3,2-b]chromenediones. Among them, DHPC04 displayed the most potent tyrosinase inhibitory activity with a K i value of 4 μm, comparable to the reference standard inhibitor kojic acid. A kinetic study suggested that these synthetic heterocyclic compounds behave as competitive inhibitors for the L-DOPA binding site of the enzyme. Furthermore, molecular modeling provided important insight into the mechanism of binding interactions with the tyrosinase copper active site., (© 2017 John Wiley & Sons A/S.)

To speed up the drug-discovery process, molecular dynamics (MD) calculations performed in GROMACS can be coupled to docking simulations for the post-screening analyses of large compound libraries. This requires generating the topology of the ligands in different software, some basic knowledge of Linux command lines, and a certain familiarity in handling the output files. LiGRO-the python-based graphical interface introduced here-was designed to overcome these protein-ligand parameterization challenges by allowing the graphical (non command line-based) control of GROMACS (MD and analysis), ACPYPE (ligand topology builder) and PLIP (protein-binder interactions monitor)-programs that can be used together to fully perform and analyze the outputs of complex MD simulations (including energy minimization and NVT/NPT equilibration). By allowing the calculation of linear interaction energies in a simple and quick fashion, LiGRO can be used in the drug-discovery pipeline to select compounds with a better protein-binding interaction profile. The design of LiGRO allows researchers to freely download and modify the software, with the source code being available under the terms of a GPLv3 license from http://www.ufrgs.br/lasomfarmacia/ligro/ .

Malaria, a tropical parasitic disease caused by Plasmodium spp., continues to place a heavy social burden, with almost 200 million cases and more than 580,000 deaths per year. Plasmodium falciparum purine nucleoside phosphorylase (PfPNP) can be targeted for antimalarial drug design since its inhibition kills malaria parasites both in vitro and in vivo. Although the currently known inhibitors of PfPNP, immucillins, are orally available and of low toxicity to animals and humans, to the best of our knowledge, none of these compounds has entered clinical trials for the treatment of malaria. Using a pharmacophore-based virtual screening coupled to a consensual molecular docking approach, we identified 59 potential PfPNP inhibitors that are predicted to be orally absorbed in a Caco-2 cell model. Although most of these compounds are predicted to have high plasma protein binding levels, poor water solubility (except for compound 25) and CYP3A4 metabolic stability (except for 4, 7 and 8), four structures (4, 7, 8 and 25) remain as potential leads because of their plausible interaction with a specific hydrophobic pocket of PfPNP, which would confer them higher selectivity for PfPNP over human PNP. Additionally, both predicted Gibbs free energies for binding and molecular dynamics suggest that compound 4 may form a more stable complex with PfPNP than 5[Formula: see text]-methylthio-immucillin-H, a potent and selective inhibitor of PfPNP.

Background: Acridine derivatives, including amsacrine, have antitumor activity. However, side effects, development of resistance and their low bioavailability, have limited their use. Herein, we described the synthesis, and evaluated the toxicity and antitumor activity of a new amsacrine analogous, the N'-(2-chloro-6-methoxy-acridin-9-yl)-2-cyano-3-(4-dimethylaminophenyl)-acrilohidrazida (ACS-AZ10)., Methods: The compound was obtained in a linear pathway where the ASC-Az intermediate was obtained by coupling of 6,9-dichloro-3-methoxy-acridine and 2-ciany-acethohidrazide followed by condensation with the corresponding aldehyde. The toxicity of ACS-AZ10 was evaluated in mice using acute toxicity and micronucleus assays. Ehrlich ascites carcinoma model was used to investigate the antitumor activity and toxicity of ACS-AZ10 (7.5, 15 or 30mg/kg, i.p.), after nine days of treatment. Cell cycle and angiogenesis were also evaluated., Results: The ASC-AZ10 was obtained with satisfactory yields and its structure was confirmed by spectroscopic and spectrometric techniques. On acute toxicity study, ACS-AZ10 (2000mg/kg, i.p.) induced transient depressant effects on central nervous system. The LD 50 was approximately 2500mg/kg. ACS-AZ10 (15 or 30mg/kg) displayed significant antitumor activity considering the tumor weight and volume, cell viability, and total Ehrlich cell count. ACS-AZ10 (7.5mg/kg) induced an increase in sub-G1 peak, suggesting apoptosis. At 15mg/kg ACS-AZ10 induced cell cycle arrest in G2/M phase and a reduction in the percentage of cells in G0/G1 and S phases, suggesting a pre-mitotic blockade. ACS-AZ10 reduced the microvessel density, indicating an antiangiogenic effect. Weak hematological, biochemical and histopathological toxicity were observed. The compound doesn't show genotoxicity in micronucleus assay., Conclusions: ACS-AZ10 has potent antitumor activity in vivo along with low toxicity., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

In Saccharomyces cerevisiae mitochondrial dysfunction induces retrograde signaling, a pathway of communication from mitochondria to the nucleus that promotes a metabolic remodeling to ensure sufficient biosynthetic precursors for replication. Rtg2p is a positive modulator of this pathway that is also required for cellular longevity. This protein belongs to the ASKHA superfamily, and contains a putative N-terminal ATP-binding domain, but there is no detailed structural and functional map of the residues in this domain that accounts for their contribution to retrograde signaling and aging. Here we use Decomposition of Residue Correlation Networks and site-directed mutagenesis to identify Rtg2p structural determinants of retrograde signaling and longevity. We found that most of the residues involved in retrograde signaling surround the ATP-binding loops, and that Rtg2p N-terminus is divided in three regions whose mutants have different aging phenotypes. We also identified E137, D158 and S163 as possible residues involved in stabilization of ATP at the active site. The mutants shown here may be used to map other Rtg2p activities that crosstalk to other pathways of the cell related to genomic stability and aging.

Objective: The aim of the present study was to analyze the use of anodal tDCS of the cerebellar region combined with treadmill training to improve balance and functional performance in children with ataxic cerebral palsy., Design: Single-blind, sham-controlled, crossover, pilot study., Setting: Rehabilitation center and research motion analysis laboratory., Participants: Children (N = 6) with ataxic cerebral palsy and balance deficit., Main Outcome Measures: Static balance (oscillations of the center of pressure), functional balance (Pediatric Balance Scale) and functional performance (Pediatric Evaluation of Disability Inventory) were evaluated., Results: Significant reductions occurred in oscillations of the center of pressure with eyes closed after active anodal tDCS only. The effects of treadmill training on functional balance and functional performance in mobility were maintained in the active tDCS group only., Conclusion: These preliminary data support the notion that anodal tDCS of the cerebellar region combined with treadmill training improves balance in children with ataxic cerebral palsy.

Lectins are proteins extensively used in biomedical applications with property to recognize carbohydrates through carbohydrate-binding sites, which identify glycans attached to cell surfaces, glycoconjugates, or free sugars, detecting abnormal cells and biomarkers related to diseases. These lectin abilities promoted interesting results in experimental treatments of immunological diseases, wounds, and cancer. Lectins obtained from virus, microorganisms, algae, animals, and plants were reported as modulators and tool markers in vivo and in vitro; these molecules also play a role in the induction of mitosis and immune responses, contributing for resolution of infections and inflammations. Lectins revealed healing effect through induction of reepithelialization and cicatrization of wounds. Some lectins have been efficient agents against virus, fungi, bacteria, and helminths at low concentrations. Lectin-mediated bioadhesion has been an interesting characteristic for development of drug delivery systems. Lectin histochemistry and lectin-based biosensors are useful to detect transformed tissues and biomarkers related to disease occurrence; antitumor lectins reported are promising for cancer therapy. Here, we address lectins from distinct sources with some biological effect and biotechnological potential in the diagnosis and therapeutic of diseases, highlighting many advances in this growing field., Competing Interests: The authors have declared that no competing interests exist.

Background: Guanine phosphoribosyltransferase (GPRT) is a very attractive target for the development of new drugs against G. lamblia because of its critical role in the synthesis of DNA and RNA. Herein we report the use of in silico approaches to identify potential G. lamblia GPRT inhibitors., Methods: Analyses of the binding site of the enzyme accomplished through the use of several methods allowed the construction of a pharmacophore model, which was screened against a database of commercial substances. The resulting retrieved compounds were then screened against GPRT by consensus docking with two different methods, and the top 10% scored compounds had their poses visually inspected. Root Mean Square Deviation (RMSD) values ≤ 2.0 Å were used to define a consensual pose while RMSD values between 2 and 3 Å defined a partial consensus. Main toxicity endpoints were predicted through substructural analyses., Results: From the 1,230 compounds retrieved in the pharmacophore-based screening, eleven had their binding modes consensually ascribed by the docking methods, suggesting a better selectivity for the parasite enzyme in comparison to the human counterpart by avoiding steric bumps with a flexible loop in the human enzyme binding site. One compound, ZINC38139588, was predicted to be totally devoid of toxicity, being perhaps the most promising of this series., Conclusion: Through rigorously validated docking protocols, we predicted the binding mode of these compounds in the GPRT binding site. The use of a consensus docking strategy yielded more reliable predictions of the binding modes to guide the future biological assays., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Congenital or infantile nephrotic syndromes (CNS/INS) correspond to a heterogeneous group of rare diseases in which glomerular renal dysfunction and proteinuria are prominent. The aim of this study is to present six cases of possible CNS/INS with diagnoses based on clinical findings and especially histological, ultrastructural, and immunohistochemical characteristics of renal biopsies. Four cases are presented with diffuse mesangial sclerosis, one of them possibly part of Denys-Drash syndrome and two cases with CNS probably of the Finnish type in patients between 3 months old and 13 years old. The study focuses on the late evolution of Denys-Drash syndrome to end-stage renal disease in a 13-year-old patient and the diagnosis of diffuse mesangial sclerosis in an 8-year-old patient. Thus, it contributes to a better epidemiological characterization of these syndromes, demonstrating cases of CNS/INS in infrequent age groups.

Purpose: To investigate factors associated with speech-language disorders in victims of motorcycle accidents., Methods: This is a cross-sectional study. Victims of motorcycle accidents studied were treated at Hospital da Restauração between June and July 2014. The data were collected by consulting the records and direct interviews with these, at admission and after discharge. For analysis were raised single frequencies, average and chi-square test or Fisher's exact test. The margin of error used in the statistical tests was 5%, and the intervals were obtained with 95% reliability., Results: 99 individuals were studied, 90.9% male, the mean age of 32.7 years. It found a high percentage of 42.3% of drunk drivers and 51.5% were not enabled. The Head Injuries were present in 30.3% of cases. The most affected body area were the lower limbs (71.7%), followed by the head and face region (56.6%). It was also found that 30.3% had complaints of speech pathology after hospital discharge and a statistically significant association between speech therapy complaint and not enabled (p=0.012) and collisions between bikes (p=0.004)., Conclusion: There was a high percentage of lesions in the head and face resulting from accidents, associated mainly not eligible to drive bike and collisions between motorcycles, suggesting that these factors can aggravate injuries speech therapy.

Objective: to estimate the healing rate of complex surgical wounds and its associated factors., Method: retrospective cohort study from 2003 to 2014 with 160 outpatients of a Brazilian university hospital. Data were obtained through consultation of the medical records. Survival function was estimated using the Kaplan-Meier method and Cox regression model to estimate the likelihood of the occurrence of healing., Results: the complex surgical wound healing rate was 67.8% (95% CI: 60.8-74.9). Factors associated with a higher likelihood of wound healing were segmentectomy/quadrantectomy surgery, consumption of more than 20 grams/day of alcohol, wound extent of less that 17.3 cm2 and the length of existence of the wound prior to outpatient treatment of less than 15 days, while the use of hydrocolloid covering and Marlex mesh were associated with a lower likelihood of healing., Conclusion: the wound healing rate was considered high and was associated with the type of surgical intervention, alcohol consumption, type of covering, extent and length of wound existence. Preventive measures can be implemented during the monitoring of the evolution of the complex surgical wound closure, with possibilities of intervention in the modifiable risk factors.