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Drug combinations have been evaluated for Chagas disease in an attempt to improve efficacy and safety. In this line, the objective of this work is to assess the effects of treatment with nitro drugs combinations using benznidazole (BZ) or nifurtimox (NFX) plus the sulfone metabolite of fexinidazole (fex-SFN) in vitro and in vivo on Trypanosoma cruzi infection. The in vitro interaction of fex-SFN and BZ or NFX against infected H9c2 cells by the Y strain was classified as an additive (0.5⩾ΣFIC

Two compounds from citrus peel, tangeretin (TAN) and 3′,4′,3,5,6,7,8‐heptamethoxyflavone (HMF), were investigated for their abilities to repair metabolic damages caused by an high‐fat diet (HFD) in C57BL/6J mice. In the first 4 weeks, mice were fed either a standard diet (11% kcal from fat) for the control group, or a HFD (45% kcal from fat) to establish obesity in three experimental groups. In the following 4 weeks, two groups receiving the HFD were supplemented with either TAN or HMF at daily doses of 100 mg/kg body weight, while the two remaining groups continued to receive the standard healthy diet or the nonsupplemented HFD. Four weeks of supplementation with TAN and HMF resulted in intermediate levels of blood serum glucose, leptin, resistin, and insulin resistance compared with the healthy control and the nonsupplemented HFD groups. Blood serum peroxidation (TBARS) levels were significantly lower in the TAN and HMF groups compared with the nonsupplemented HFD group. Several differences occurred in the physiological effects of HMF versus TAN. TAN, but not HMF, reduced adipocyte size in the mice with pre‐existent obesity, while HMF, but not TAN, decreased fat accumulation in the liver and also significantly increased the levels of an anti‐inflammatory cytokine, IL‐10. In an analysis of the metabolites of TAN and HMF, several main classes occurred, including a new set of methylglucuronide conjugates. It is suggested that contrasts between the observed physiological effects of TAN and HMF may be attributable to the differences in numbers and chemical structures of TAN and HMF metabolites., Tangeretin (TAN) and heptamethoxyflavone (HMF), and their metabolites, influence metabolic parameters in mice with pre‐existing obesity. Differences in the effects of HMF and TAN may be attributed to the very different profiles of metabolites of these two compounds. Unlike TAN, HMF had dramatic influence in alleviating liver steatosis in obese mice.

To investigate pharmacists’ interventions and impact at institutional Long-Term Care (LTC) settings, particularly the therapeutic outcomes in elderly populations. LTC pharmacists deliver a comprehensive set of activities, especially in clinical pharmacy (e.g. medication review, deprescribing) and education, addressing elderly populations under LTC and their therapeutic needs. Pharmacists’ expertise in medicines optimisation is a useful resource in improving healthcare towards institutionalised LTC patients, often a geriatric population. Long-Term Care (LTC) systems have experienced recent developments driven by changes in healthcare and demography (e.g. population ageing). As well, pharmacists are changing from traditional roles to more patient-oriented services. The present study aimed to identify and assess pharmacists’ and/or pharmacy-based interventions in institutional LTC settings, also mapping relevant medications. The review was undertaken in general accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), using three main literature databases (PubMed, Scopus, and Web of Knowledge). A set of 16 keywords, divided into three domains (professional, type of care and type of setting), were combined into search equations. Selected studies were assessed through the Quality Assessment Tool for Quantitative Studies. Twenty-six studies met the inclusion criteria, out of 794 initial hits. Most studies (12) described pharmacist/pharmacy-driven interventions assessing Medication Management Reviews' impact in different endpoints or outcomes. Other studies (3) assessed pharmacists’ interventions on specific medication groups. Good Administration Practices, new pharmaceutical care models, antibiotic stewardship programs, and studies assessing other pharmacists’ interventions, such as pharmacy-managed informatics and education, were addressed by 11 other papers. Six studies were classified as Strong after quality assessment. LTC is a clinically complex type of care benefiting from interdisciplinary work. Despite the overall lower quality of the identified studies, pharmacists perform in a wide array of LTC areas. The broad implementation of pharmaceutical activities in institutional LTC settings opens opportunities to optimise medicines’ use.

As the imaging technology and the understanding of neurological disease improve, a solid understanding of neu-roanatomy has become increasingly relevant. Neuroanatomy teaching includes the practice of cadaveric dissectionand neuroanatomy atlases consisting of images of a brain with its labeled structures. However, the natural inter-individual neuroanatomical variability cannot be taken into account. This work addresses the individual grossneuroanatomy atlas that could enrich medical students’ experiences with various individual variations in anatomi-cal landmarks and their spatial relationships. We propose to deform the CerebrA cortical atlas into the individualanatomical magnetic resonance imaging data to increase students’ opportunity to contact normal neuroanatomicalvariations in the early stages of studies. Besides, we include interactive queries on the labels/names of neu-roanatomical structures from an individual neuroanatomical atlas in a 3D space. An implementation on top ofSimpleITK library and VMTK-Neuro software is presented. We generated a series of surface and internal neu-roanatomy maps from 16 test volumes to attest to the potential of the proposed technique in brain labeling. Forthe age group between 10 to 75, there is evidence that the superficial cortical labeling is accurate with the visualassessment of the degree of concordance between the neuroanatomical and label boundaries.

Polymeric nanoparticles (NPs) are produced using bio-compatible and bio-degradable materials such as PLGA (Poly(lactic-co-glycolic acid)). This technology provides a valuable tool to deliver molecules to the subcellular level with a relatively low risk of cytotoxicity. However their use in the field of reproductive biotechnology is not yet scientifically substantiated. The aim of the present study was to test if PLGA NPs can be taken-up by cumulus-enclosed oocytes as a first step towards potential oocyte-targeted applications to enhance oocyte quality and fertility. We conducted a series of experiments using bovine in vitro oocyte maturation as a model to study FITC-conjugated PLGA internalization (using laser-scanning confocal microscopy) and the effect of some important physical (particle size) and chemical (conjugation with PEG) modifications. We show evidence that PLGA NPs can be taken-up by cumulus cells and to a less extent by the enclosed oocytes regardless of the NP size. The NP transfer to the oocyte appear to be transcellular (via cumulus cells and transzonal projections) and paracellular (via zona pellucida). The PLGA NPs were detected in the vicinity of the oocyte as quick as 2 h post-exposure in a protein-free medium and did not compromise cumulus cell viability nor subsequent early embryo development or embryo quality. These results suggest that PLGA NPs may have promising applications as carriers for drug or molecule delivery targeting cumulus cells and oocytes.

Le document qui suit est la traduction intégrale du compte rendu établi à l’occasion du 252eatelier international ENMC consacré, du 6 ou 8 mars 2020, au « Développement de recommandations pour l’utilisation de la ventilation par embout buccal dans les maladies neuromusculaires », et publié très récemment dans la revueNeuromuscular Disorders(M. Chatwin, M. Gonçalves, J. Gonzalez-Bermejo, M. Toussaint, et al. 252ndENMC international workshop: Developing best practice guidelines for management of mouthpiece ventilation in neuromuscular disorders. March 6thto 8th2020, Amsterdam, the Netherlands.Neuromuscular Disorders2020 ; 30 : 772–81.https://doi.org/10.1016/j.nmd.2020.07.008).

Background: Quinoxaline, a fused heterocycle of benzene and pyrazine rings are becoming recognized as a potent class of anti-cancer compounds, such as, in a wide array of pharmacological activities. Methods: We evaluate the three gallate quinoxalines (G-A1, G-A2, and G-A3) as c-Met kinase inhibitors using a docking study, in vitro anticancer potential measurements, antioxidant and bactericidal activities. Results: The docking study showed hydrogen bond linkage of quinoxalines with amino acids at active site of c-Met kinase structures, indicating a possible cancer inhibition cell proliferation. Therefore, the three quinoxalines were analyzed against four in vitro cancer cell lines, and G-A1 demonstrated cytotoxicity against HL-60 and HCT116 cell lines (IC50= 9.55 and IC50= 16.67 μmol L-1, respectively). In HepG2 and MCF-7 cells, the IC50 were 22.48 and 33.42 μmol L-1, respectively. For G-A2 and G-A3, cytotoxic activity ranged from 61.22 to >101.21 μmol L-1. Potent antioxidant activities were also obtained for G-A2>G-A1>G-A3 (IC50= 4.5-8.4 μmol L-1 and AAI= 8.8-17.8). Six different Bacillius strains showed growth inhibition (11.33 to 13.33 mm) in the presence of quinoxaline G-A1 (500 μg). Conclusion: The present work showed the biological potential of quinoxalines G-A1, G-A2 and G-A3 in inhibiting four cancer cells proliferation, in addition to a very strong antioxidant activity.

Correlations between the photocatalytic activity and the chemical composition of carbon-supported P-Fe-based nanocomposites were found. Nanoporous carbon was prepared by chemical activation with H3PO4 of the endocarp of babassu coconut. The synthesis of the nanocomposites was conducted by aqueous impregnation of the support with Fe(NO3)3⋅9H2O and NH4OH, followed by heat treatments under N2 flow at temperatures from 700 to 1000 °C. The uptake of the composites to remove methylene blue by adsorption was studied previous to photodegradation tests under solar irradiation. The formation of iron phosphates and phosphides phases was accompanied by an enhancement of the adsorption capacities of the nanocomposites. The formation of iron phosphates (FePO4) enhanced the methylene blue degradation, with a remarkable increase in the photocatalytic activity up to 10 times higher than the commercial activated carbon. The increase of the temperature up to 900 °C led to a reduction of Fe(III) to Fe(II) pyrophosphates, with a concomitant decrease in the photoactivity. The formation of iron phosphides at 1000 °C was detrimental to the photocatalytic activity. It can be concluded that the P-Fe-based nanocomposites exhibited an important photocatalytic activity for the methylene blue degradation under solar irradiation, pointing to a promising application of these materials.

To assess visual acuity in 5-year-old children with LEA chart and to estimate the frequency of reduced visual acuity in this age. Study aimed at children attending the last year of preschool education in Public Kindergartens and Private Social Solidarity Institutions (IPSS) under the influence Regional Health Administration of the Medio Tejo, in Portugal. The 15-line LEA charts at 3 m were used and the presentation visual acuity was measured monocularly starting with the right eye. The ETDRS-fast methodology was used. A total of 3072 children participated, being 51% male and 54% from rural area. A rate of 13.7% children with a reduced level of visual acuity was found, that is, visual acuity worse or equal to 0.2 logMAR in at least one eye, or an interocular difference greater than two lines. This research shows that reduced VA frequency rate in children between 5 and 6 years old is high. The literature presents amblyopia (refractive and/or strabismic) and uncorrected refractive errors without amblyopia as the main cause of reduced VA in childhood, and these anomalies negatively affect child development, especially at the educational level. Reduced VA interferes with performance on a number of key tasks in the learning process. Thus, it is important to preserve the running program to identify these deficits and lead to their correction before the beginning of the school stage.

Purpose of Review: Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects approximately 1 in 2,500 individuals globally [Ashizawa et al.: Neurol Clin Pract 2018;8(6):507–20]. In patients with DM1, respiratory muscle weakness frequently evolves, leading to respiratory failure as the main cause of death in this patient population, followed by cardiac complications [de Die-Smulders et al.: Brain 1998;121(Pt 8):1557–63], [Mathieu et al.: Neurology 1999;52(8):1658–62], [Groh et al.: Muscle Nerve 2011;43(5):648–51]. This paper provides a more detailed outline on the diagnostic and management protocols, which can guide pulmonologists who may not have experience with DM1 or who are not part of a neuromuscular multidisciplinary clinic. A group of neuromuscular experts in DM1 including pulmonologists, respiratory physiotherapists and sleep specialists discussed respiratory testing and management at baseline and during follow-up visits, based on their clinical experience with patients with DM1. The details are presented in this report. Recent Findings: Myotonic recruited 66 international clinicians experienced in the treatment of people living with DM1 to develop and publish consensus-based care recommendations targeting all body systems affected by this disease [Ashizawa et al.: Neurol Clin Pract. 2018;8(6):507–20]. Myotonic then worked with 12 international respiratory therapists, pulmonologists and neurologists with long-standing experience in DM respiratory care to develop consensus-based care recommendations for pulmonologists using a methodology called the Single Text Procedure. This process generated a 7-page document that provides detailed respiratory care recommendations for the management of patients living with DM1. This consensus is completely based on expert opinion and not backed up by empirical evidence due to limited clinical care data available for respiratory care management in DM patients. Nevertheless, we believe it is of relevance for professionals treating adults with myotonic dystrophy because it addresses practical issues related to respiratory management and care, which have been adapted to meet the specific issues in patients with DM1. Summary: The resulting recommendations are intended to improve respiratory care for the most vulnerable of DM1 patients and lower the risk of untoward respiratory complications and mortality by providing pulmonologist who are less experienced with DM1 with practical indications on which tests and when to perform them, adapting the general respiratory knowledge to specific issues related to this multiorgan disease.

Complex regional pain syndrome type-I (CRPS-I) is a chronic painful condition resulting from trauma. Bradykinin (BK) is an important inflammatory mediator required in acute and chronic pain response. The objective of this study was to evaluate the association between BK receptors (B1 and B2) and chronic post-ischaemia pain (CPIP) development in mice, a widely accepted CRPS-I model. We assessed mechanical and cold allodynia, and paw oedema in male and female Swiss mice exposed to the CPIP model. Upon induction, the animals were treated with BKR antagonists (HOE-140 and DALBK); BKR agonists (Tyr-BK and DABK); antisense oligonucleotides targeting B1 and B2 and captopril by different routes in the model (7, 14 and 21 days post-induction). Here, we demonstrated that treatment with BKR antagonists, by intraperitoneal (i.p.), intraplantar (i.pl.), and intrathecal (i.t.) routes, mitigated CPIP-induced mechanical allodynia and oedematogenic response, but not cold allodynia. On the other hand, i.pl. administration of BKR agonists exacerbated pain response. Moreover, a single treatment with captopril significantly reversed the anti-allodynic effect of BKR antagonists. In turn, the inhibition of BKRs gene expression in the spinal cord inhibited the nociceptive behaviour in the 14th post-induction. The results of the present study suggest the participation of BKRs in the development and maintenance of chronic pain associated with the CPIP model, possibly linking them to CRPS-I pathogenesis.

The underlying pathogenic mechanisms of cardiomyopathy in Chagas disease are still unsolved. In order to better clarify the role of fat on the evolution of cardiomyopathy, the present study employed three murine models of chronic Trypanosoma cruzi infection: (1) aP2-RIDα/β transgenic mice (RID mice; an adipose tissue model which express a gain-of-function potent anti-inflammatory activity), (2) allograft inflammatory factor-1 knockout mice (Aif1−/−), and (3) a Swiss outbred mice. RID mice and non-transgenic mice (wild type, WT) were infected with blood trypomastigotes of Brazil strain. During the acute stage of infection, RID mice had lower parasitemia, lower heart inflammation, and a decrease in the relative distribution of parasite load from cardiac muscle tissue toward epididymal fat. Nevertheless, comparable profiles of myocardial inflammatory infiltrates and relative distribution of parasite load were observed among RID and WT at the chronic stage of infection. Aif1−/− and Aif1+/+ mice were infected with bloodstream trypomastigotes of Tulahuen strain and fed with high-fat diet (HFD) or regular diet (RD). Interestingly, Aif1+/+ HFD infected mice showed the highest mortality. Swiss mice infected with blood trypomastigotes of Berenice-78 strain on a HFD had higher levels of TNFα and more inflammation in their heart tissue than infected mice fed a RD. These various murine models implicate adipocytes in the pathogenesis of chronic Chagas disease and suggest that HFD can lead to a significant increase in the severity of parasite-induced chronic cardiac damage. Furthermore, these data implicate adipocyte TLR4-, TNFα-, and IL-1β-mediated signaling in pro-inflammatory pathways and Aif-1 gene expression in the development of chronic Chagas disease.

Despite the many studies in the last decades, the low-ionisation structures (LISs) of planetary nebulae (PNe) still hold several mysteries. Recent imaging surveys have demonstrated that LISs are composed of molecular gas. Here we report H$_2$ emission in the LISs of NGC 7009 and NGC 6543 by means of very deep narrow-band H$_2$ images taken with NIRI@Gemini. The surface brightness of the H2 1-0 S(1) line is estimated to be (0.46-2.9)$\times$10$^{-4}$ erg s$^{-1}$ cm$^{-2}$ sr$^{-1}$ in NGC 7009 and (0.29-0.48)$\times$10$^{-4}$ erg s$^{-1}$ cm$^{-2}$ sr$^{-1}$ in NGC 6543, with signal-to-noise ratios of 10-42 and 3-4, respectively. These findings provide further confirmation of hidden H$_2$ gas in LISs. The emission is discussed in terms of the recent proposed diagnostic diagram R(H$_2$)=H$_2$ 1-0 S(1)/H$_2$ 2-1 S(1) versus R(Br$\gamma$)=H$_2$ 1-0 S(1)/Br$\gamma$, which was suggested to trace the mechanism responsible for the H$_2$ excitation. Comparing our observations to shock and ultraviolet (UV) molecular excitation models, as well as a number of observations compiled from the literature showed that we cannot conclude for either UV or shocks as the mechanism behind the molecular emission., Comment: 11 pages, 6 figures, 2 tables, accepted for Publication in MNRAS

Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with an inexorably progressive course which leads to a progressive neuromuscular weakness. Weight loss is one of the major bad prognostic factors in ALS. The placement of percutaneous endoscopic gastrostomy (PEG) is of paramount importance in patients with dysphagia to improve the disease outcomes, although some fear exists regarding the possible ventilatory complications during the procedure. The aim of this study was to evaluate the safety and effectiveness of PEG tube insertion under non-invasive ventilation (NIV) in patients with ALS and severe ventilatory impairment. Methods: A retrospective study of all consecutive PEGs placed in our department from May 2011 to January 2018 in patients with ALS was performed. The procedure was performed under non-invasive positive-pressure ventilation for ventilatory support. Results: We included 59 patients with ALS with severe ventilatory impairment, 58% were female, with a mean age of 67.2 ± 10.1 years and a median follow-up of 6 [2–15] months. The main indication for PEG placement was dysphagia (98%). The median time for PEG tube insertion since the established diagnosis of ALS was 12 [6–25] months and 4 [2–18] months since the beginning of bulbar symptoms. The majority of the patients had placed a 20-Fr PEG (63%) and under mild sedation with midazolam (80%), all under NIV. There were no immediate complications during and after the procedure (no episodes of aspiration or orotracheal intubation) and mortality. Conclusion: The placement of PEG is a very important procedure in patients with ALS and severe ventilatory impairment. The interdisciplinary department collaboration permitted the placement of PEG under NIV, in a safe and effective procedure in this special population.

O PEAK é um instrumento de avaliação e intervenção comportamental com proposta inovadora. O objetivo do presente artigo foi investigar as possibilidades do instrumento para intervenção em equivalência e transformação (RFT). A coleta de dados compreendeu o período de 2014 até 2019 e foi realizada inicialmente no site oficial do instrumento e depois ampliada para periódicos da área. As palavras utilizadas na pesquisa foram “PEAK”, “equivalência” e “transformação”. Os resultados mostraram que o currículo foi eficaz para o ensino de diferentes populações como pessoas com autismo, síndrome de Down e deficiência intelectual. Foram ensinados diferentes conteúdos, como habilidades acadêmicas, relações de sistemas sensoriais e habilidades mais complexas em linguagem e tomada de perspectiva. Como limitações, foram observadas a idade dos participantes e o fato de a maioria dos estudos ter sido realizada pelo grupo de pesquisa do autor do instrumento. Sugerem-se novas investigações.

Background and Aims Regional anesthesia, which includes peripheral nerve blocks, contributes to a multimodal analgesic approach. Iliac fascia block is an alternative or complementary analgesic technique for knee, thigh and hip surgery. Methods 93-year-old man, ASA IV, with history of hypocoagulated atrial fibrillation, NYHA Class III heart failure, benign prostatic hypertrophy, hypertension, diabetes, dementia and dyslipidemia scheduled for femoral intramedullary nailing. Given the patient‘s comorbidities and general condition, with his possible intolerance to the hemodynamic rebound produced by general or spinal anesthesia, the team decided to resort to iliac fascia block as an anesthetic technique. Caregiver’s consent to anesthesia was obtained. To perform the block, a suprainguinal ecoguided approach was used. A linear probe was placed immediately below the antero-superior iliac spine (ASIS). The ASIS was identified and the probe placed transversely and rotated towards the umbilicus. An out of plane technique and a 50 mm needle were used and 20 mL of 1.5% mepivacaine and 20 mL of 0.375% ropivacaine were injected into the fascial illiaca. The block was tested after 40’, with loss of sensitivity and muscle strength in the area of the LCFN and FN. The surgery began 50’ after the block. 15’ and 25’ into surgery, 30 mg and 70 mg of propofol were administered, respectively, due to patient agitation. Results The surgery lasted 60’ and there were no complications or episodes of hemodynamic instability. Conclusions The anesthetic approach used may be another option in hemodynamically unstable patients in which the most common anesthetic techniques incur an important hemodynamic rebound.

Background and Aims Clavicle surgery can be performed under general or regional anesthesia; the latter is preferred when there´s interest in avoiding complications associated with general anesthesia. Multiple rib fractures are associated with significant morbidity such as ventilatory compromise, increased rate of atelectasis, lung contusion and pneumonia. If invasive mechanical ventilation can be avoided, intensive care unit stay and complications from mechanical lung ventilation can be prevented. Methods A 78-year-old male patient weighing 80 Kg and with severe OSA presented to our emergency department with a left clavicle fracture and left costal arc fractures from T1 to T10 after an accidental fall. After stabilization the patient was scheduled for surgical correction of the clavicle fracture. After obtaining consent to perform surgery under regional anesthesia and conscious sedation, we administered 50 mcg of fentanyl and initiated a dexmedetomidine infusion. We performed different ultrasound guided nerve blocks with Ropivacaine 0.5%: 5 mL were administered at the interscalene groove to block the brachial plexus, 5 mL targeted at the supraclavicular nerves and 10 mL at the clavipectoral fascial plane. Results The patient reported no pain throughout the procedure and there was no ventilatory compromise or need for intubation. In the first 24 postoperative hours, the patient did not report pain, either at rest or movement, without need of rescue analgesia. Conclusions The use of peripheral nerve blocks allowed for surgical correction of clavicle fracture in our patient, while avoiding pulmonary complications associated to invasive mechanical ventilation, difficult ventilatory weaning, and prolonged stay at the intensive care unit.

Background and Aims Continuous spinal (CSA) comparing to spinal anesthesia offers advantages in patients with multiple comorbilities. Fractionation of doses allows to obtain a satisfactory sensory and motor block with lower total doses of local anesthetic and less hemodynamic collapse. Methods 89-year-old female, ASA IV admitted for emergency hernioplasty due to strangulated umbilical hernia. She had Hypertension, Diabetes Mellitus, obesity, OSAS, stage IV CKD and heart failure. She was polypneic, tachycardic and hypotensive. The airway assessment was poorly done due to the patient‘s lack of collaboration. Given the severity of the patient‘s clinical situation, the surgical proposal, as well as the absence of criteria for admission to the ICU, we opted for CSA. Caregiver’s consent to anesthesia was obtained. A Tuhoy 18G needle was used in the L3-L4 space and the catheter was inserted 4cm into the subarachnoid space. 2.5 mg of 0.5% hyperbaric bupivacaine were administered through catheter, followed by 1 mL of saline. 5’ and 10’ after the first administration, 1.25 mg + 1.25 mg bupivacaine were administered, respectively. A satisfactory block at T7-T8 level was obtained. The surgery lasted 2.5 hours. At the end of the first and second hour after surgical incision, reinforcement was needed with 2.5 mg of 0.5% bupivacaine. Results The patient remained hemodynamically stable and conscious. She was discharged from the hospital with no record of complications. Conclusions The number of high-risk frail patients is increasing. CSA allows the anesthetist to better manage these patients due to the fractionation of doses and greater control over the hemodynamic repercussions.

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved.

OBJECTIVE The aim of the study was to evaluate the efficacy of noninvasive ventilatory assistance/support via mouthpiece to improve performance in 6-min walk tests for individuals with severe restrictive ventilatory disorders. DESIGN Each subject performed the 6-min walk test breathing spontaneously and again while using mouthpiece noninvasive ventilatory assistance/support at full ventilatory support. Oxyhemoglobin saturation (O2 sat), heart rate, Borg scale, distance walked, and ambulation duration were recorded. RESULTS Eighteen patients using nocturnal nasal noninvasive ventilatory assistance/support, median (interquartile range) age of 58.5 (20) yrs, were studied. Their median baseline forced vital capacity and PaCO2 were 940 (385) ml and 54.1 (6) mm Hg, respectively. All used noninvasive ventilatory assistance/support for at least overnight hours for 36 (111) mos. Because of the progression of ventilatory impairment and hypercapnia, daytime mouthpiece noninvasive ventilatory assistance/support was initiated. All the 6-min walk test parameters improved significantly by using noninvasive ventilatory assistance/support. Both initial and final values of O2 saturation significantly increased (92% [6] vs 96% [2], P < 0.001) and (80% [19] vs 85.50% [13], P = 0.001), respectively. The median distance walked increased by 43% with noninvasive ventilatory assistance/support (175 [218] m vs 250 [113] m, P = 0.017), and the total ambulation time also increased with noninvasive ventilatory assistance/support (5.45 [3] mins vs. 6 [0] mins, P = 0.008). CONCLUSIONS The exercise tolerance of patients with severe ventilatory impairment can improve by using noninvasive ventilatory support.

Toxoplasma gondii is an opportunistic protozoan pathogen with a wide geographic distribution. The chronic phase of toxoplasmosis is often asymptomatic in humans and is characterized by tissue cysts throughout the central nervous system and muscle cells. T. gondii and other pathogens with tropism for the central nervous system are considered risk factors in the etiology of several neuropsychiatric disorders, such as schizophrenia and bipolar disorder, besides neurological diseases. Currently, it is known that cerebral toxoplasmosis increases dopamine levels in the brain and it is related to behavioral changes in animals and humans. Here we evaluate whether chronic T. gondii infection, using the cystogenic ME-49 strain, could induce behavioral alterations associated with neuropsychiatric disorders and glutamatergic neurotransmission dysfunction. We observed that the startle amplitude is reduced in the infected animals as well as glutamate and D-serine levels in prefrontal cortical and hippocampal tissue homogenates. Moreover, we did not detect alterations in social preference and spontaneous alternation despite severe motor impairment. Thus, we conclude that behavioral and cognitive aspects are maintained even though severe neural damage is observed by chronic infection of C57Bl/6 mice with the ME-49 strain.

Melanoma is a type of skin cancer with low survival rates after it has metastasized. In order to find molecular differences that could represent targets of quercetin in anti-melanoma activity, we have chosen SKMEL-103 and SKMEL-28 melanoma cells and human melanocytes as models. Firstly, we observed that quercetin was able in reducing SKMEL-103 cell viability, but not in SKMEL-28. Besides that, quercetin treatment caused inhibition of AXL in both cell lines, but upregulation of PIM-1 in SKMEL-28 and downregulation in SKMEL-103. Moreover, HIF-1 alpha expression decreased in both cell lines. Interestingly, quercetin was more effective against SKMEL-103 than kinases inhibitors, such as Imatinib, Temsirolimus, U0126, and Erlotinib. Interestingly, we observed that while the levels of succinate dehydrogenase and voltage-dependent anion channel increased in SKMEL-103, both proteins were downregulated in SKMEL-28 after quercetin’s treatment. Furthermore, AKT, AXL, PIM-1, ABL kinases were much more active and chaperones HSP90, HSP70 and GAPDH were highly expressed in SKMEL-103 cells in comparison with melanocytes. Our findings indicate, for the first time, that the efficacy of quercetin to kill melanoma cells depends on its ability in inhibiting tyrosine kinase and upregulating mitochondrial proteins, at least when SKMEL-103 and SKMEL-28 cells response were compared.

This work shows an alternative methodology based on a portable near-infrared (NIR) spectroscopy coupled to independent components analysis (ICA) in a pseudo-univariate calibration way to determine total anthocyanins (TA) concentration and antioxidant activity (AA) in whole grape juice. To this, the scores proportions more related to TA and AA were plotted against TA and AA obtained by its respective references methodology to build pseudo-univariate calibration models with correlation coefficients of 0.9699 and 0.9814, respectively. From the results, it is possible the suggestion that NIR spectra coupled to ICA enable to overcome interferences using first-order data and work properly when there is enough selectivity for the analyte profile in the sample data.

Dear Editor, Practising evidence-based medicine in an ageing population is challenging. Nevertheless, using age as a diagnostic or therapeutic procedure contraindication is less and less common. Domiciliary non-invasive ventilation (NIV) in chronic respiratory failure patients has been largely used; however, data from older people is scarce...

The current study was undertaken to test the hypothesis that the high physical capacity of rowing athletes may not reverse the influence of age on cardiac autonomic control decline estimated by heart rate variability (HRV). Forty-four male subjects divided in four groups: 11 young athletes (YA; 18 ±1 year), 11 young non-athletes (YNA; 20 ±1 year), 11 middle age athletes (MAA; 43 ±6 years) and 11 middle age non-athletes (MNA; 44 ±8 years) participated in the study. Heart rate (HR) was recorded beat-by-beat for 10 minutes in supine (SUP) and 10 min in orthostatic (ORT) positions. HRV was analyzed in the frequency domain to obtain the spectral power in the high (HF) and low frequency (LF) bands, and the changes to ORT (%∆HRV) were calculated (ORT – SUP / SUP). During SUP, HF was lower in MNA and MA compared to YA and YNA, while LF was lower in MNA than YA. For %ΔHRV, %ΔHF was higher in YA than YNA, MA and MNA. The %ΔLF was not different among groups. In conclusion, aging seems to overcome the influence of physical fitness on neural regulation of the heart, as highlighted by the HRV response to active standing.

Background: Typically, patients with progressive neuromuscular disorders (NMDs) develop acute respiratory failure (ARF), are intubated, and when failing spontaneous breathing trials (SBTs) undergo a tracheotomy and receive tracheostomy mechanical ventilation (TMV). However, increasing numbers of patients use nasal noninvasive ventilation (NIV), initially for sleep and this is extended to continuous dependence (CNVS). This can be used as a strategy to assist in successful extubation . We retrospectively reviewed 19 centers offering CNVS and mechanical insufflation-exsufflation (MI-E) as an alternative to TMV. Methods: Centers with publications or presentations concerning CNVS outcomes data were pooled for amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), and spinal muscular atrophy type 1 (SMA1). Progression to CNVS dependence without hospitalization, duration of dependence, and extubations and decannulations to CNVS were recorded. Prolongation of life was defined by duration of CNVS dependence without ventilator free breathing ability (VFBA). Results: There were 1623 part time (

The use of chemometric tools is progressing to scientific areas where analytical chemistry is present, such as food science. In analytical food evaluation, oils represent an important field, allowing the exploration of the antioxidant effects of herbs and seeds. However, traditional methodologies have some drawbacks which must be overcome, such as being time-consuming, requiring sample preparation, the use of solvents/reagents, and the generation of toxic waste. The objective of this study is to evaluate the protective effect provided by plant-based substances (directly, or as extracts), including pumpkin seeds, poppy seeds, dehydrated goji berry, and Proven&ccedil, al herbs, against the oxidation of antioxidant-free soybean oil. Synthetic antioxidants tert-butylhydroquinone and butylated hydroxytoluene were also considered. The evaluation was made through thermal degradation of soybean oil at different temperatures, and near-infrared spectroscopy was employed in an n-way mode, coupled with Parallel Factor Analysis (PARAFAC) to extract nontrivial information. The results for PARAFAC indicated that factor 1 shows oxidation product information, while factor 2 presents results regarding the antioxidant effect. The plant-based extract was more effective in improving the frying stability of soybean oil. It was also possible to observe that while the oxidation product concentration increased, the antioxidant concentration decreased as the temperature increased. The proposed method is shown to be a simple and fast way to obtain information on the protective effects of antioxidant additives in edible oils, and has an encouraging potential for use in other applications.

Respiratory physiotherapy techniques for augmenting the normal mucociliary clearance, lung expansion and cough efficacy have been used for many years to treat patients with respiratory disorders. In recent years, new technologies and more advanced techniques have been developed to be more comfortable and effective for airway clearance and lung expansion. Airway clearance refers to two separate but connected mechanisms: mucociliary clearance and cough efficacy. The purpose of this chapter is to describe an updated review of devices and techniques for airway clearance that include the main clinical criteria to justify the application of each one as well as the evidence of efficacy in patients with respiratory dysfunction.

A di-urethane cross-linked poly(oxyethylene)/silica hybrid matrix [di-urethanesil, d-Ut(600)], synthesized by the sol-gel process, was doped with lithium triflate (LiCF3SO3) and the 1-butyl-3-methylimidazolium chloride ([Bmim]Cl) ionic liquid. The as-produced xerogel film is amorphous, transparent, flexible, homogeneous, hydrophilic, and has low nanoscale surface roughness. It exhibits an ionic conductivity of 3.64 x 10(-6) and 5.00 x 10(-4) S cm(-1) at 21 and 100 degrees C, respectively. This material was successfully tested as electrolyte in an electrochromic device (ECD) with the glass/ITO/a-WO3/d-Ut(600)(10)LiCF3SO3[Bmim]Cl/c-NiO/ITO/glass configuration, where a-WO3 and c-NiO stand for amorphous tungsten oxide and crystalline nickel oxide, respectively. The device demonstrated attractive electro-optical performance: fast response times (1-2 s for coloring and 50 s for bleaching), good optical memory [loss of transmittance (T) of only 41% after 3 months, at 555 nm], four mode modulation [bright mode (+3.0 V, T = 77% at 555 nm), semi-bright mode (-1.0 V, T = 60% at 555 nm), dark mode (-1.5 V, T = 38 % at 555 nm), and very dark mode (-2.0 V, T = 11% and -2.5 V, T = 7% at 555 nm)], excellent cycling stability denoting improvement with time, and high coloration efficiency [CEin = -6727 cm(2) C-1 (32th cycle) and CEout = +2794 cm(2) C-1 (480th cycle), at 555 nm]., The authors are grateful to Fundacao para a Ciencia e a Tecnologia (FCT) and when applicable by FEDER under the PT2020 Partnership Agreement for financial support under contracts PEst-OE/SAU/UI0709/2014, UID/Multi/00709/2013, UID/QUI/00686/2016, UID/QUI/00686/2018, UID/QUI/00686/2019, PEst-OE/QUI/UI0616/2016, FCOMP-01-0124-FEDER037271, UID/CTM/50011/2013, LUMECD project (POCI01-0145-FEDER-016884 and PTDC/CTM-NAN/0956/2014), UniRCell project (SAICTPAC/0032/2015 and POCI-01-0145FEDER-016422). RP and SN acknowledge FCT-MCTES for grants (SFRH/BPD/87759/2012 and LUMECD, respectively). RP thanks FCT-UM for the contracts in the scope of Decreto-Lei 57/2016 and 57/2017. MF acknowledges FCTUTAD for the contract in the scope of Decreto-Lei 57/2016 -Lei 57/2017. HG acknowledges projects POCI-010145-FEDER-030858 and PTDC/BTM-MAT/30858/2017 for financial support.

The underlying pathogenic mechanisms of cardiomyopathy in Chagas Disease are still unsolved. In order to better clarify the role of fat on the evolution of cardiomyopathy, the present study employed three murine models of chronic Trypanosoma cruzi infection: (1) aP2-RIDα/β transgenic mice (RID mice; an adipose tissue model which express a gain-of function potent anti-inflammatory activity), (2) allograft inflammatory factor-1 knockout mice (Aif1(−/−)) and (3) a Swiss outbred mice. RID mice and non-transgenic mice (wild type – WT) were infected with blood trypomastigotes of Brazil strain. During acute stage RID showed lower parasitemia, lower heart inflammation and a decrease in the relative distribution of parasite load from cardiac muscle tissue towards epididymal fat. Nevertheless, comparable profiles of myocardial inflammatory infiltrates and relative distribution of parasite load were observed amongst RID and WT at chronic stage. Aif1(−/−) and Aif1(+/+) mice were infected with bloodstream trypomastigotes of Tulahuen strain and fed with high fat diet (HFD) or regular diet (RD). Interestingly, Aif1(+/+) HFD infected mice showed the highest mortality. Swiss mice infected with blood trypomastigotes of Berenice-78 strain on a HFD had higher levels of TNFα and more inflammation in their heart tissue than infected mice fed a RD. These various murine models implicate adipocytes in the pathogenesis of chronic Chagas Disease and suggest that HFD can lead to a significant increase in the severity of parasite-induced chronic cardiac damage. Furthermore, these data implicate adipocyte TLR4-, TNFα- and IL-1β- mediated signaling in pro-inflammatory pathways and Aif-1 gene expression in the development of chronic Chagas disease.

The vermiform appendix is a potential site of initiation of Parkinson’s disease (PD) pathology. We hypothesized that the appendectomy earlier in life may alter the clinical expression of PD. To explore the effects of appendectomy prior to onset of PD motor symptoms on patients’ symptoms, in particular on cognitive dysfunction. Two hundred and sixty-two consecutive PD patients were asked about past history of appendectomy and underwent an evaluation, which included the Unified Parkinson’s Disease Rating Scale (UPDRS), Hoehn & Yahr scale (H&Y), Schwab & England Independence Scale (S&E), Dementia Rating Scale-2 (DRS-2), Apathy Evaluation Scale, Hospital Anxiety and Depression Scale, and Brief Smell Identification Test. Motor symptoms were evaluated in OFF and ON states. Non-parametric group comparisons and logistic regressions were used for data analyses. Thirty-one patients (11.8%) had history of appendectomy prior to PD onset. These patients had more severe motor symptoms (UPDRS-III and H&Y) and lower functional independence (S&E) in ON and had higher frequency of cognitive dysfunction (DRS-2 Initiation/Perseveration, Conceptualization, and Memory subscales) (p

Samples of chia seeds (Salvia hispanica L.) were degreased by cold pressing and the residue obtained named degreased chia seeds (DCS) had the antioxidants extract obtained. A 22 experimental design was employed in order to evaluate the factors ethanol concentration and extraction time. The optimized conditions were extraction time 15 min with ethanol 70% where the activity (RSA), evaluated by the DPPH (2,2-diphenyl-1-picryl-hydrazyl) method was 94.76%. For this extract, the total phenolics content was 359.64 mg EGA/100 g. A pseudo-univariate calibration model is proposed as an alternative methodology to determine the %RSA by using the relative concentration from multivariate curve resolution with alternating least squares (MCR-ALS) from near-infrared (NIR) spectra of the antioxidant extract from DCS. The results suggest the possibility of %RSA determination directly from NIR spectra from extracts from DCS by using the multivariate resolution method MCR-ALS.

Alzheimer’s disease (AD), the most common type of dementia, not only imposes a huge financial burden on the health care system, but also a psychological and emotional burden on patients and their families. There is thus an urgent need to infer trajectories of cognitive performance over time and identify biomarkers predictive of the progression. In this article, we propose the multi-task learning with fused Laplacian sparse group lasso model, which can identify biomarkers closely related to cognitive measures due to its sparsity-inducing property, and model the disease progression with a general weighted (undirected) dependency graphs among the tasks. An efficient alternative directions method of multipliers based optimization algorithm is derived to solve the proposed non-smooth objective formulation. The effectiveness of the proposed model is demonstrated by its superior prediction performance over multiple state-of-the-art methods and accurate identification of compact sets of cognition-relevant imaging biomarkers that are consistent with prior medical studies.

This paper describes the degradation of the antibiotic chloramphenicol by a photo-Fenton process under artificial and solar irradiation. Using artificial radiation, the role of different sources and concentrations of iron (salts of Fe2+ and Fe3+ and the iron complexes citrate (FeCit) and oxalate (FeOx)), initial pH, concentration of H2O2 and addition of oxalate at initial pH 6.0 were evaluated. The concentration of chloramphenicol was reduced to below the quantification limit of the equipment (

Several distinct fluid flow phenomena occur in solid tumors, including intravascular blood flow and interstitial convection. Interstitial fluid pressure is often raised in solid tumors, which can limit drug delivery. To probe low-velocity flow in tumors resulting from raised interstitial fluid pressure, we developed a novel MRI technique named convection-MRI, which uses a phase-contrast acquisition with a dual-inversion vascular nulling preparation to separate intra- and extravascular flow. Here, we report the results of experiments in flow phantoms, numerical simulations, and tumor xenograft models to investigate the technical feasibility of convection-MRI. We observed a significant correlation between estimates of effective fluid pressure from convection-MRI with gold-standard, invasive measurements of interstitial fluid pressure in mouse models of human colorectal carcinoma. Our results show how convection-MRI can provide insights into the growth and responsiveness to vascular-targeting therapy in colorectal cancers. Significance: A noninvasive method for measuring low-velocity fluid flow caused by raised fluid pressure can be used to assess changes caused by therapy. Cancer Res; 78(7); 1859–72. ©2018 AACR.

Pharmaceutical compounds are known to be persistent. Their presence after conventional treatments in sewage treatment plants may harm aquatic environments. The simultaneous degradation of the pharmaceuticals gemfibrozil, hydrochlorothiazide and naproxen involving photo-Fenton processes was evaluated using different sources and concentrations of iron (Fe2+, Fe3+ and the iron complexes of oxalate – FeOx), initial pH (2.6, 5.0 and 7.0) and concentrations of H2O2. The classic photo-Fenton reaction (at initial pH 2.6, using Fe2+and Fe3+) showed a limited efficiency in promoting gemfibrozil degradation, which, based on evidence provided by LC–MS measurements, is related to the formation of associations between this compound and iron ions. The simultaneous degradation of gemfibrozil and the other compounds was improved using FeOx (1.0 mg L−1 in iron) at an initial pH of 2.6 and 2.0 mg L−1H2O2. In addition, using this catalyst it was possible to efficiently degrade the pharmaceuticals at an initial pH of 5.0, reaching complete degradation of these compounds with a treatment time varying between 20 and 60 min and generating a low toxicity effluent. These results highlight the potential applicability of ferrioxalate as a photocatalyst in the photo-Fenton process as an alternative method to degrade this kind of pollutant at a pH near neutrality.

Benznidazole and nifurtimox-treatments regimens currently used in human are supported by very limited experimental data. This study was designed to evaluate the time and dose dependence for efficacy of the most important nitroheterocyclic drugs in use for Chagas disease. In order to evaluate time dependence, Y strain-infected mice received benznidazole for a total of 1, 3, 7, 10, 20, and 40 days. Treatment courses of 3–10-day were effective in clearing parasitaemia and suppressing mortality, but parasitological cure was not achieved. Extending the treatments to 20 or 40 days clearly improved benznidazole efficacy. The 20-day treatment induced cure in 57.1% of Y strain infections (partially drug resistant) but failed to cure Colombian strain infections (full drug resistant), while the 40-day treatment resulted in cure of 100% of Y and 50% of Colombian strain infected mice. The increased cure rates in T. cruzi infected animals that received nifurtimox for 40 days confirm the relationship between the length of treatment and efficacy. An improvement in efficacy was observed with increasing benznidazole doses; cure was verified in 28.6% (75 mg/kg), 57.1% (100 mg/kg) and 80% (300 mg/kg). Overall, these nonclinical study data provide evidence that the efficacy of benznidazole is dose and time dependent. These findings may be relevant for optimizing treatment of human Chagas disease.

Chagas disease, caused by Trypanosoma cruzi, is a major neglected tropical disease that occurs mainly as chronic infection and systemic infection. Currently, there is no suitable and effective drug to treat this parasitic disease. Administration of nutrients with immunomodulatory properties, such as arginine and nitric oxide radicals, may be helpful as antiparasitic therapy. In this study, we evaluated the effects of arginine supplementation during the acute phase of infection under the development of chronic Chagas' heart disease in Swiss mice inoculated with the Berenice-78 strain of T. cruzi. The effectiveness of arginine was determined by daily detection of the parasite in the blood and long-term serum levels of nitric oxide and tumor necrosis factor-alpha, in addition to evaluation of heart tissue damage. Arginine could flatten parasitemia and prevent elevation of tumor necrosis factor-alpha in T. cruzi-infected mice. Regarding chronic inflammatory myocardial derangements, similar findings were verified among T. cruzi-infected groups. Arginine promoted collagenogenesis in the heart muscle tissue of T. cruzi-infected arginine-supplemented group. These data show the paradoxical benefits of arginine in improving the outcome of Chagas chronic cardiomyopathy.

The so-called works of special arts, are constructions of high complexities that allow the advancement of widening gaps and overcoming obstacles previously unthinkable. With the increase in magnitude of these structures, in addition to greater investments, the maintenance of these structures becomes an increasingly important factor for engineering. Among the elements of bridge structures, the support devices are components with important structural functions, being essential for their proper functioning and especially the durability of the entire structure. This paper aims to evaluate the pathological manifestations in support devices so, according to inspections performed and the diagnosis of causes, define their best practices and treatments for the maintenance and mitigation of the pathologies found. In the practical study the following steps were performed: survey and selection of the structures currently under maintenance of MetrôRio; selection of criteria for the evaluation of pathologies; carrying out inspections; comparative analysis between the viaducts to determine the priority order for negotiations; and definition of conduct. The results obtained were the result of evaluation of the field analysis, diagnosis and comparison with tests performed in support devices. Having as input the tests in the support devices, the best treatments and suggestions to avoid new pathologies were proposed.