The Peptide Antibiotic Corramycin Adopts a ß-Hairpin-like Structure and Is Inactivated by the Kinase ComG.

The rapid development of antibiotic resistance, especially among difficult-to-treat Gram-negative bacteria, is recognized as a serious and urgent threat to public health. The detection and characterization of novel resistance mechanisms are essential to better predict the spread and evolution of antibiotic resistance. Corramycin is a novel and modified peptidic antibiotic with activity against several Gram-negative pathogens. We demonstrate that the kinase ComG, part of the corramycin biosynthetic gene cluster, phosphorylates and thereby inactivates corramycin, leading to the resistance of the host. Remarkably, we found that the closest structural homologues of ComG are aminoglycoside phosphotransferases; however, ComG shows no activity toward this class of antibiotics. The crystal structure of ComG in complex with corramycin reveals that corramycin adopts a ß-hairpin-like structure and allowed us to define the changes leading to a switch in substrate from sugar to peptide. Bioinformatic analyses suggest a limited occurrence of ComG-like proteins, which along with the absence of cross-resistance to clinically used drugs positions corramycin as an attractive antibiotic for further development.

Effects of taurine, cysteine and melatonin as antioxidant supplements to the freezing medium of Prochilodus brevis sperm.

Cryopreservation consist of a set of methods to preserve cells and tissues by drastically reducing the temperature. Among some undesired effects, cryopreservation might generate reactive oxygen species that lead to an increase of oxidative stress, causing damage to cells. This study aimed to test taurine, cysteine, and melatonin on the freezing of Prochilodus brevis sperm and assess its effects on post-thawed sperm quality. Sperm was collected and seven pools were formed (n = 7). They were diluted (1:9) in standard medium (5% glucose, 10% dimethyl sulfoxide and 5% egg yolk) supplemented or not (control) with taurine (0.3, 1.0, 3.16 or 10.0 mM), cysteine (0.3, 1.0, 3.16 or 10.0 mM) or melatonin (0.6, 1.12, 2.0 or 3.56 mM). Post-thawed sperm was evaluated for kinetic (total motility, velocities, and percentage of rapid cells), morphology and membrane and DNA integrity. Differences were found when melatonin was used as an antioxidant. For the variables rapid sperm and sperm velocities, 3.56 mM melatonin presented higher results than the control (melatonin 0 mM). Melatonin 2 mM was similar to 3.56 mM on rapid sperm, average path velocity (VAP) and curvilinear velocity (VCL). No difference was found between concentration 0 mM (control) and taurine treatments. As for cysteine, 0.3 mM presented the best results for rapid sperm than 10 mM, and higher VCL and VAP than 1 mM. Melatonin 3.56 mM presented higher results on kinetic parameters (rapid motility, VCL, VSL and VAP) than other tested antioxidants. Therefore, melatonin 3.56 mM is recommended to be added to the sperm freezing medium of P. brevis.

Essential role of the CCL2-CCR2 axis in Mayaro virus-induced disease.

Mayaro virus (MAYV) is an emerging arbovirus member of the Togaviridae family and Alphavirus genus. MAYV infection causes an acute febrile illness accompanied by persistent polyarthralgia and myalgia. Understanding the mechanisms involved in arthritis caused by alphaviruses is necessary to develop specific therapies. In this work, we investigated the role of the CCL2/CCR2 axis in the pathogenesis of MAYV-induced disease. For this, wild-type (WT) C57BL/6J and CCR2-/- mice were infected with MAYV subcutaneously and evaluated for disease development. MAYV infection induced an acute inflammatory disease in WT mice. The immune response profile was characterized by an increase in the production of inflammatory mediators, such as IL-6, TNF, and CCL2. Higher levels of CCL2 at the local and systemic levels were followed by the significant recruitment of CCR2+ macrophages and a cellular response orchestrated by these cells. CCR2-/- mice showed an increase in CXCL-1 levels, followed by a replacement of the macrophage inflammatory infiltrate by neutrophils. Additionally, the absence of the CCR2 receptor protected mice from bone loss induced by MAYV. Accordingly, the silencing of CCL2 chemokine expression in vivo and the pharmacological blockade of CCR2 promoted a partial improvement in disease. Cell culture data support the mechanism underlying the bone pathology of MAYV, in which MAYV infection promotes a pro-osteoclastogenic microenvironment mediated by CCL2, IL-6, and TNF, which induces the migration and differentiation of osteoclast precursor cells. Overall, these data contribute to the understanding of the pathophysiology of MAYV infection and the identification future of specific therapeutic targets in MAYV-induced disease.IMPORTANCEThis work demonstrates the role of the CCL2/CCR2 axis in MAYV-induced disease. The infection of wild-type (WT) C57BL/6J and CCR2-/- mice was associated with high levels of CCL2, an important chemoattractant involved in the recruitment of macrophages, the main precursor of osteoclasts. In the absence of the CCR2 receptor, there is a mitigation of macrophage migration to the target organs of infection and protection of these mice against bone loss induced by MAYV infection. Much evidence has shown that host immune response factors contribute significantly to the tissue damage associated with alphavirus infections. Thus, this work highlights molecular and cellular targets involved in the pathogenesis of arthritis triggered by MAYV and identifies novel therapeutic possibilities directed to the host inflammatory response unleashed by MAYV.

Surgical Strategies for Tuberculous Spondylodiscitis With Severe Osteoporosis: A Case Illustrating the Challenges of Delayed Intervention.

Tuberculous spondylodiscitis (Pott's spine) is a complex extrapulmonary manifestation of tuberculosis (TB) that poses significant medical challenges, characterized by vertebral destruction affecting approximately 2% of all TB cases. The management of this condition involves a multidisciplinary approach, with surgical intervention indicated for specific cases, including those with neurological complications, spinal instability, and kyphosis. We report a case of a 49-year-old female with a confirmed diagnosis of tuberculous spondylodiscitis who had undergone eight months of tuberculostatic therapy. She was referred for neurosurgical consultation due to uncontrollable axial pain, despite favorable clinical and imaging responses, which had rendered her immobile for six months. Imaging revealed a complete collapse of the L5 vertebral body, and a complementary dual x-ray absorptiometry (DEXA) scan demonstrated severe osteoporosis. A two-stage surgical approach was chosen to address her condition, involving corpectomy through an anterior approach, followed by lumbopelvic stabilization. Postoperative recovery was uneventful, with progressive improvement in pain and mobility. This case highlights the challenges of managing tuberculous spondylodiscitis and underscores the significance of early detection to prevent complications like severe osteoporosis. In this case, delayed referral for surgery following an extended period of immobility added complexity to an already difficult case. The severe osteoporosis, with a t-score of -5.7, had a substantial impact on surgical planning, leading to a more robust approach to arthrodesis with substantial lumbopelvic instrumentation in order to mitigate the risks associated with implant failure. This case shows that timely intervention and a comprehensive multidisciplinary approach are essential for the effective management of tuberculous spondylodiscitis, especially in cases complicated by severe osteoporosis.

Is dyslipidemia a risk factor for trastuzumab-induced cardiotoxicity in breast cancer patients? A systematic review and meta-analysis.

INTRODUCTION: Breast cancer patients undergoing trastuzumab therapy have greater risk of cardiovascular disease. Risk factors for this effect have been proposed. However, the role of dyslipidemia is not completely understood. This systematic review aimed to explore the role of dyslipidemia in trastuzumab-induced cardiotoxicity. METHODS: The investigators searched MEDLINE, Scopus, and Web of Science up to October 25, 2020. A random-effects model was used to determine pooled estimates of the results. The primary endpoint was trastuzumab-induced cardiotoxicity in patients with and without dyslipidemia. RESULTS: A total of 39 studies were selected for inclusion in our systematic review assessing 21079 patients. One study demonstrated a statistically significant association between dyslipidemia and cardiotoxicity (OR=2.28, 95% CI 1.22-4.26, p=0.01). In all other studies, no such association was observed. Twenty-one studies including 6135 patients were eligible for meta-analysis. In this meta-analysis of unadjusted data, dyslipidemia was significantly associated with cardiotoxicity (OR=1.25, 95% CI 1.01-1.53, p=0.04, I2=0%), however, a subgroup analysis of studies reporting adjusted measures did not demonstrate a significant association (OR=0.89, 95% CI 0.73-1.10, p=0.28, I2=0%). CONCLUSION: This systematic review and meta-analysis did not demonstrate a significant association between dyslipidemia alone and the development of cardiotoxicity. In the absence of other relevant cardiovascular risk factors, review of lipid profile may not be obligatory, and management of patients could be performed without referral for cardio-oncology assessment. Further investigation of risk factors for trastuzumab-induced cardiotoxicity is required to confirm these results.

Cardiovascular risk factors during pregnancy impact the postpartum cardiac and vascular reverse remodeling.

Pregnant women with cardiovascular risk (CVR) factors are highly prone to develop cardiovascular disease later in life. Thus, recent guidelines suggest extending the follow-up period to 1 yr after delivery. We aimed to evaluate cardiovascular remodeling during pregnancy and determine which CVR factors and potential biomarkers predict postpartum cardiac and vascular reverse remodeling (RR). Our study included a prospective cohort of 76 healthy and 54 obese and/or hypertensive and/or with gestational diabetes pregnant women who underwent transthoracic echocardiography, pulse-wave velocity (PWV), and blood collection at the 1st trimester (1T) and 3rd trimester (3T) of pregnancy as well as at the 1st/6th/12th mo after delivery. Generalized linear mixed-effects models was used to evaluate the extent of RR and its potential predictors. Pregnant women develop cardiac hypertrophy, as confirmed by a significant increase in left ventricular mass (LVM). Moreover, ventricular filling pressure (E/e') and atrial volume increased significantly during gestation. Significant regression of left ventricular (LV) volume, LVM, and filling pressures was observed as soon as 1 mo postpartum. The LV global longitudinal strain worsened slightly and recovered at 6 mo postpartum. PWV decreased significantly from 1T to 3T and normalized at 1 mo postpartum. We found that arterial hypertension, smoking habits, and obesity were independent predictors of increased LVM during pregnancy and postpartum. High C-reactive protein (CRP) and low ST2/IL33-receptor levels are potential circulatory biomarkers of worse LVM regression. Arterial hypertension, age, and gestational diabetes positively correlated with PWV. Altogether, our findings pinpoint arterial hypertension as a critical risk factor for worse RR and CRP, and ST2/IL33 receptors as potential biomarkers of postpartum hypertrophy reversal.NEW & NOTEWORTHY This study describes the impact of cardiovascular risk factors (CVR) in pregnancy-induced remodeling and postpartum reverse remodeling (up to 1 yr) by applying advanced statistic methods (multivariate generalized linear mixed-effects models) to a prospective cohort of pregnant women. Aiming to extrapolate to pathological conditions, this invaluable "human model" allowed us to demonstrate that arterial hypertension is a critical CVR for worse RR and that ST2/IL33-receptors and CRP are potential biomarkers of postpartum hypertrophy reversal.

Clinical, hematological, biochemical, and histopathological evaluations in domestic cats (Felis catus) infected by Leishmania infantum.

A high frequency of feline leishmaniasis has been reported in several countries. However, much information about disease progression in cats still needs to be clarified. This study aimed to verify the occurrence of clinicopathological changes in cats infected with Leishmania infantum. A total of 60 cats were divided into three groups of 20 animals each: control, suspects, and infected. All 60 cats underwent blood count and biochemical analyses. Serum samples from 20 animals with leishmaniasis were also used to diagnose feline immunodeficiency virus and feline leukemia virus. A total of five of the infected animals underwent necropsy for a histopathological study. The main clinical findings in cats with leishmaniasis were lymphadenomegaly (65%), alopecia (55%), ulcerative skin lesions and weight loss (40%), skin nodules (25%), a significant reduction in red blood cells (p=0.0005) and hematocrit (p=0.0007), hyperplasia in spleen 4/5(80%), presence of Leishmania in the spleen 2/5(40%), hepatitis 3/5(60%), liver degeneration 4/5(80%) and inflammatory nephropathy 3/5(60%). It was concluded that cats with leishmaniasis presented significant clinical, hematological, and histopathological alterations compatible with L. infantum infection. The observation of lymphadenomegaly, weight loss, skin lesions and low concentration of red blood cells, contributes significantly to the diagnosis and analysis of progression of feline leishmaniasis.

Pre-Clinical Assessment of Roflumilast Therapy in a Thoracic Model of Spinal Cord Injury.

The failure of axons to regenerate after a spinal cord injury (SCI) remains one of the greatest challenges in neuroscience. The initial mechanical trauma is followed by a secondary injury cascade, creating a hostile microenvironment, which not only is not permissive to regeneration but also leads to further damage. One of the most promising approaches for promoting axonal regeneration is to maintain the levels of cyclic adenosine monophosphate (cAMP), specifically by a phosphodiesterase-4 (PDE4) inhibitor expressed in neural tissues. Therefore, in our study, we evaluated the therapeutic effect of an FDA-approved PDE4 inhibitor, Roflumilast (Rof), in a thoracic contusion rat model. Results indicate that the treatment was effective in promoting functional recovery. Rof-treated animals showed improvements in both gross and fine motor function. Eight weeks post-injury, the animals significantly recovered by achieving occasional weight-supported plantar steps. Histological assessment revealed a significant decrease in cavity size, less reactive microglia, as well as higher axonal regeneration in treated animals. Molecular analysis revealed that IL-10 and IL-13 levels, as well as VEGF, were increased in the serum of Rof-treated animals. Overall, Roflumilast promotes functional recovery and supports neuroregeneration in a severe thoracic contusion injury model and may be important in SCI treatment.

Cardiovascular toxicity in breast cancer patients - contributors and role of cardioprotective drugs.

Breast cancer (BC) patients treated with anthracyclines and/or anti-HER2-targeted therapies (AHT) are highly associated with cardiovascular toxicity (CVT). Our objective was to evaluate the risk of CVT secondary to cancer treatment and the role of cardioprotective-drugs (CPD) in BC patients. We collected a retrospective cohort of females with BC treated with chemotherapy and/or AHT from 2017 to 2019. CVT was defined as LVEF<50% or decline ≥10% during follow-up. As CPD, we considered renin-angiotensin-aldosterone-system inhibitors and beta-blockers. A subgroup analysis of the AHT patients was also performed. A total of 203 women were enrolled. The majority had high or very-high CVT risk score and normal cardiac function at presentation. As for CPD, 35.5% were medicated pre-chemotherapy. All patients were submitted to chemotherapy; AHT were applied to 41.7%. During a 16 months follow-up, 8.5% developed CVT. There was a significant decrease of GLS and LVEF at 12-months (decrease of 1.1% and 2.2%, p<0.001). AHT and combined therapy were significantly associated with CVT. In the AHT sub-group analysis (n=85), 15.7% developed CVT. Patients previously medicated with CPD had a significative lower incidence of CVT (2.9% vs 25.0%, p=0.006). Patients already on CPD presented a higher LVEF at 6-months follow-up (62.5% vs 59.2%, p=0.017). Patients submitted to AHT and anthracycline therapy had higher risk of developing CVT. In the AHT sub-group, pre-treatment with CPD was significantly associated with a lower prevalence of CVT. These results highlight the importance of cardio-oncology evaluation and strengthen the value of primary prevention.

Concessão dos benefícios assistenciais para pessoas com paralisia cerebral no Brasil: tendência temporal e análise espacial / Continuous cash benefit for people with cerebral palsy in Brazil: temporal trend and spatial analysis

Objetivo: Analisar a tendência temporal e distribuição espacial dos benefícios concedidos para as pessoas com Paralisia Cerebral. Método: Estudo ecológico em que foram incluídos os benefícios concedidos às pessoas com Paralisia Cerebral, nos períodos de 2004 a 2016, no Brasil. Os dados foram coletados do Instituto Nacional de Seguridade Social e Instituto Brasileiro de Geografia Estatística. Utilizou-se o software Join Point Regression, 4.5.0.1, sendo as tendências classificadas em decrescente; crescente e estacionária. Na distribuição espacial foi realizada Análise Exploratória de Dados Espaciais com o software QGIS versão 3.18. Resultados: Observou-se uma tendência decrescente do BPC do ano de 2004 até o ano de 2016, no Brasil. Na região Norte o número de concessões aumentou de 2004-2010, mas, após isso, houve um decréscimo. Já as regiões Sudeste, Sul e Centro Oeste apresentaram tendência decrescente em todo o período analisado. Na análise espacial, as regiões Norte e Nordeste apresentaram maior frequência de BPC proporcionalmente à população com pessoas até 19 anos, aos domicílios e às famílias com até um salário mínimo nas unidades federativas do Brasil. Conclusão: Foi possível observar a diminuição de concessões do BPC em todas as regiões do país no período de 2004 a 2016. As regiões que possuem os índices mais elevados de distribuição do BPC são Nordeste e Norte, reconhecidamente, as que possuem os maiores indicadores de pobreza e extrema pobreza do país

Objective: To analyze the temporal trend and spatial distribution of benefits granted to people with Cerebral Palsy. Method: An ecological study that included the benefits granted to people with Cerebral Palsy, from 2004 to 2016, in Brazil. Data were recorded from the National Institute of Social Security and the Brazilian Institute of Geography. The software Join Point Regression, 4.5.0.1 was used and the trends were classified as increasing; growing and stationary. In the spatial distribution, Exploratory Spatial Data Analysis was performed with the QGIS software version 3.18. Results: There is a downward trend in BPC from 2004 to 2016 in Brazil. In the North region, the number of concessions increased from 2004-2010, but after that, there was a decline. The regions and Center West, on the other hand, show a decreasing trend throughout the Southeast and South period. In the spatial analysis, the most frequent North and Northeast regions of BPC in proportion to the population with people aged 19 years, to families with units up to one minimum wage in the federative units of Brazil. Conclusion: A decrease in BPC extensions was observed in all regions of the country in the period 2016. Poverty and extreme poverty in the country

Assessment of the self-confidence of obstetrics & gynecology fellows to perform a postpartum hemostasis hysterectomy.

INTRODUCTION: Hemostasis Hysterectomy (HH) is a last resort surgical procedure performed in situations of uncontrolled post-partum hemorrhage in maternity wards. The chances of being confronted with this situation are scarce during residency, and the situation is not well suited for teaching. Nevertheless, every obstetrician-gynecologist can be confronted with this stressful situation, and should therefore possess the surgical competence required, regardless of his routine practice. The aim of the present study is to evaluate clinical exposure and self-awareness concerning HH amongst obstetrics and gynecology residents and fellows. MATERIEL AND METHODS: We performed a survey amongst French obstetrics and gynecology fellows. An anonymous survey was sent by email between December 1, 2020 to July 1, 2021. RESULTS: Half of the interrogated fellows had practiced (as operator) an HH during residency with a senior and only 22,6% in post-residency. During the last year of residency 70% of them had performed less than 10 scheduled hysterectomies as primary operator. The laparoscopic approach was the most frequently practiced. Very few hysterectomies were performed as primary operator. Fellows with a surgical or mixed activity (both gynecological surgery and obstetrical activity in current practice) felt significantly more capable of performing HH compared to those with exclusive obstetrical or reproductive medicine activity; respectively 60% vs 36%, p = 0.008; Odds Ratio: 2.629 (95% CI 1.2214; 5.8094). CONCLUSION: The number of scheduled hysterectomies or HH performed as primary operator is very low during residency or fellowship. It remains largely inferior to the number deemed necessary in previous publications about the learning curve for scheduled hysterectomy, which varies from 18 to 80 interventions. Nowadays, the increasing number of residents, added to the decrease of hemostasis hysterectomies through better management of post-partum hemorrhage, pushes towards the development of specific training, such as "damage control simulation".

Tumour necrosis factor plays a deleterious role in the pathogenesis of chikungunya virus infection.

Arthralgia is a hallmark of chikungunya virus (CHIKV) infection and can be very debilitating and associated with a robust local inflammatory response. Many pathophysiological aspects associated with the disease remain to be elucidated. Here, we describe a novel model of CHIKV infection in immunocompetent mice and evaluate the role of tumour necrosis factor in the pathogenesis of the disease. C57BL/6 wild type (WT) or TNF receptor 1 deficient (TNFR1-/- ) mice were inoculated with 1 × 106 PFU of CHIKV in the paw. Alternatively, etanercept was used to inhibit TNF in infected WT mice. Hypernociception, inflammatory and virological analysis were performed. Inoculation of CHIKV into WT mice induced persistent hypernociception. There was significant viral replication in target organs and local production of inflammatory mediators in early time-points after infection. CHIKV infection was associated with specific humoral IgM and IgG responses. In TNFR1-/- mice, there was a decrease in the hypernociception threshold, which was associated with a milder local inflammatory response in the paw but delayed viral clearance. Local or systemic treatment with etanercept reduced CHIKV-induced hypernociception. This is the first study to describe hypernociception, a clinical correlation of arthralgia, in immunocompetent mice infected with CHIKV. It also demonstrates the dual role of TNF in contributing to viral clearance but driving tissue damage and hypernociception. Inhibition of TNF may have therapeutic benefits but its role in viral clearance suggests that viral levels must be monitored in CHIKV-infected patients and that TNF inhibitors should ideally be used in combination with anti-viral drugs.

Alberta infant motor scale in Brazilian research: a bibliometric study / Escala Motora Infantil de Alberta en la investigación brasileña: un estudio bibliométrico / Alberta infant motor scale em pesquisas brasileiras: estudo bibliométrico

ABSTRACT The Alberta infant motor scale (AIMS) is an instrument for assessing the gross motor development of newborns, aged 0-18 months. This study aimed to summarize the Brazilian studies that used the AIMS and identify their objectives to know the main uses of the scale for professionals interested in child motor development. This is a bibliometric study on SciELO, PubMed, Scopus, and Web of Science databases. The searched keywords were "Alberta infant motor scale" and "Brazil," with their equivalents in Portuguese and united by "AND." Inclusion criteria were: use of AIMS with children aged 0-18 months carried out in Brazil. The variables database, journal, year of publication, language, region of the institution linked to the authors, and type of study were analyzed in a descriptive quantitative manner. Content analysis was performed on the objectives described in the articles. In total, 79 articles were included and most of them had a cross-sectional design and were linked to institutions in the South and Southeast regions. Furthermore, most studies were from the last 10 years and in English. The journal Fisioterapia e Pesquisa was the Brazilian journal that most published studies of the sample. The analyzed objectives were distributed into six word classes, with two large groups: psychometric validity (19.1%) and evaluative studies (80.9%). The latter considered the various child populations analyzed. We presented studies that used the AIMS to evaluate the motor development of Brazilian children, reinforcing the importance of this instrument in the national context and also encouraging its use.

RESUMEN La Escala Motora Infantil de Alberta (AIMS) es un instrumento que evalúa el desarrollo motor grueso de los recién nacidos de entre 0 y 18 meses de edad. Este estudio pretendió hacer una síntesis de estudios brasileños que utilizaron la AIMS, así como identificar sus objetivos, con el fin de proporcionar una tabla de los principales usos de la escala a los profesionales interesados en el desarrollo motor infantil. Se trata de un estudio bibliométrico, en el que se realizaron búsquedas en las bases de datos SciELO, PubMed, Scopus y Web of Science. Los descriptores utilizados fueron "escala motora infantil de Alberta" y "Brasil", con sus equivalentes en inglés, unidos por el término booleano "AND". El criterio de inclusión fue la aplicación de la AIMS en Brasil, con niños de entre 0 y 18 meses. Las variables base de datos, revista, año de publicación, idioma, región de la institución vinculada a los autores y tipo de estudio se analizaron de manera cuantitativa y descriptiva. Se realizó un análisis de contenido de los objetivos descritos en los estudios, y se incluyeron 79 estudios, de los cuales la mayoría presentó un diseño transversal y estaba vinculado a instituciones de las regiones Sur y Sudeste de Brasil. La mayoría de las publicaciones son de los últimos 10 años, en inglés, y la revista Fisioterapia e Pesquisa fue la revista nacional que más publicó estudios. Los objetivos analizados se dividieron en seis clases de palabras, que contienen dos grupos principales: validez psicométrica (19,1%) y estudios evaluativos (80,9%). Este último tuvo en cuenta las diversas poblaciones infantiles analizadas. Este estudio presentó las investigaciones que evaluaron la AIMS respecto al desarrollo motor de los niños brasileños. Esto destaca la importancia del citado instrumento en el contexto nacional, además estimula su uso.

RESUMO A Alberta infant motor scale (AIMS) é um instrumento de avaliação do desenvolvimento motor grosso dos recém-nascidos entre 0 e 18 meses de idade. Este estudo buscou sumarizar as pesquisas brasileiras que utilizaram a AIMS e identificar seus objetivos, a fim de fornecer um quadro das principais utilizações da escala aos profissionais interessados no desenvolvimento motor infantil. Trata-se de um estudo bibliométrico realizado por meio de buscas nas bases de dados SciELO, PubMed, Scopus, e Web of Science. Os descritores foram "escala motora infantil de Alberta" e "Brasil", com seus equivalentes em inglês, unidos pelo termo booleano "AND". O critério de inclusão foi a utilização da AIMS no Brasil, com crianças de 0 a 18 meses. As variáveis base de dados, revista, ano de publicação, idioma, região da instituição vinculada aos autores e tipo de estudo foram analisadas de forma quantitativa descritiva. Foi realizada análise de conteúdo dos objetivos descritos nas pesquisas, e foram incluídos 79 estudos, a maioria dos quais apresentou delineamento transversal e estava vinculada a instituições das regiões Sul e Sudeste. Boa parte das publicações era dos últimos 10 anos, em inglês, e a revista Fisioterapia e Pesquisa foi o periódico nacional que mais publicou estudos referentes à amostra. Os objetivos analisados foram distribuídos em seis classes de palavras, contidas em dois grandes grupos: validades psicométricas (19,1%) e estudos avaliativos (80,9%). Este último considerou as várias populações infantis analisadas. O estudo apresentou as pesquisas que utilizaram a AIMS para avaliar o desenvolvimento motor de crianças brasileiras. Isso reforça a importância deste instrumento no contexto nacional, além de estimular sua utilização.

Art and science: impact of semioccluded vocal tract exercises and choral singing on quality of life in subjects with congenital GH deficiency

ABSTRACT Objectives: Currently, not much is known about the interactions between voice and growth hormone (GH). We have described large kindred with isolated GH deficiency (IGHD) due to a GHRH receptor mutation, resulting in severe short stature and high-pitched voice. These IGHD individuals have little interest in GH treatment, as they consider themselves "short long-lived people", rather than patients. Interestingly, they report normal general quality of life, but they rate their Voice-Related Quality of Life (V-RQOL) as low. Here, we assessed the social and auditory-perceptual impacts of artistic-intervention voice therapy with semioccluded vocal tract exercises (SOVTE) and choral singing, on their voices. Material and methods: Seventeen GH-naïve adult IGHD individuals were enrolled in a single-arm interventional pre-post study with 13 weekly sessions of choir singing over 90 days. Outcome measures were V-RQOL scores, self-assessment of voice, and auditory-perceptual analysis (GRBAS scale, G: grade of the severity of dysphonia; R: roughness; B: breathiness; A: asthenia; and S: strain). Results: Marked improvements in total (p = 0.0001), physical (p = 0.0002), and socioemotional (p = 0.0001) V-RQOL scores and in self-assessment of voice (p = 0.004) were found. The general grades of vocal deviation (p = 0.0001), roughness (p = 0.0001), breathiness (p = 0.0001) and strain (p = 0.0001) exhibited accentuated reductions. Conclusions: Voice therapy with semioccluded vocal tract exercises and choral training improved social impact and perceptual voice assessments in IGHD subjects and markedly improved their voice-related quality of life. This is particularly important in a setting where GH replacement therapy is not widely accepted.

SPCS1-Dependent E2-p7 processing determines HCV Assembly efficiency.

Recent studies identified signal peptidase complex subunit 1 (SPCS1) as a proviral host factor for Flaviviridae viruses, including HCV. One of the SPCS1's roles in flavivirus propagation was attributed to its regulation of signal peptidase complex (SPC)-mediated processing of flavivirus polyprotein, especially C-prM junction. However, whether SPCS1 also regulates any SPC-mediated processing sites within HCV polyprotein remains unclear. In this study, we determined that loss of SPCS1 specifically impairs the HCV E2-p7 processing by the SPC. We also determined that efficient separation of E2 and p7, regardless of its dependence on SPC-mediated processing, leads to SPCS1 dispensable for HCV assembly These results suggest that SPCS1 regulates HCV assembly by facilitating the SPC-mediated processing of E2-p7 precursor. Structural modeling suggests that intrinsically delayed processing of the E2-p7 is likely caused by the structural rigidity of p7 N-terminal transmembrane helix-1 (p7/TM1/helix-1), which has mostly maintained membrane-embedded conformations during molecular dynamics (MD) simulations. E2-p7-processing-impairing p7 mutations narrowed the p7/TM1/helix-1 bending angle against the membrane, resulting in closer membrane embedment of the p7/TM1/helix-1 and less access of E2-p7 junction substrate to the catalytic site of the SPC, located well above the membrane in the ER lumen. Based on these results we propose that the key mechanism of action of SPCS1 in HCV assembly is to facilitate the E2-p7 processing by enhancing the E2-p7 junction site presentation to the SPC active site. By providing evidence that SPCS1 facilitates HCV assembly by regulating SPC-mediated cleavage of E2-p7 junction, equivalent to the previously established role of this protein in C-prM junction processing in flavivirus, this study establishes the common role of SPCS1 in Flaviviridae family virus propagation as to exquisitely regulate the SPC-mediated processing of specific, suboptimal target sites.

Bowel cleansing efficacy for colonoscopy: prospective, randomized comparative study of same-day dosing with 1-L and 2-L PEG + ascorbate.

Background and study aims Polyethylene glycol (PEG) bowel preparations are effective but associated with high ingestion volume. In this study, 1-L PEG and 2-L PEG preparations were compared in a randomized, colonoscopist-blinded, single-center trial. Patients and methods Patients were aged > 18 years, required colonoscopy, and provided informed consent. Randomization was 1:1 to 1-L PEG or 2-L PEG, based on hospital identification number (odd or even). Preparations were administered using same-day dosing adjusted for colonoscopy start time. The primary endpoint was successful bowel preparation on the Boston Bowel Preparation Scale (BBPS) (no segment scored < 2). Results A total of 852 patients were randomized. In the intention-to-treat (ITT) population, significantly more patients had diabetes in the 2-L PEG arm, resulting in the creation of the modified-ITT population (mITT) that excluded diabetic patients to correct the imbalance (1-L PEG, n = 239; 2-L PEG, n = 238). In the mITT, there was no significant difference in successful cleansing between 1-L PEG and 2-L PEG (88.3 % vs. 82.4 %; P  = 0.067). Excellent cleansing (BBPS 7-9; no segment < 2) was significantly improved with 1-L PEG (60.7 % vs. 50.4 %; P  < 0.024), as were mean scores in the right and left colon (right: 2.47 vs. 2.30; P  < 0.008; left: 2.55 vs. 2.39; P  = 0.008). Adverse events were mild to moderate in intensity and none resulted in discontinuation. Rates of nausea and vomiting were significantly higher with 1-L PEG, but that did not affect successful cleansing. Conclusions The lower-volume 1-L PEG was associated with higher levels of excellent bowel cleansing and greater mean segmental scores on the BBPS than 2-L PEG.

C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations.

The concept of Pan-Assay Interference Compounds (PAINS) is regarded as a threat to the recognition of the broad bioactivity of natural products. Based on the established relationship between altered membrane dipole potential and transmembrane protein conformation and function, we investigate here polyphenols' ability to induce changes in cell membrane dipole potential. Ultimately, we are interested in finding a tool to prevent polyphenol PAINS-type behavior and produce compounds less prone to untargeted and promiscuous interactions with the cell membrane. Di-8-ANEPPS fluorescence ratiometric measurements suggest that planar lipophilic polyphenols-phloretin, genistein and resveratrol-act by decreasing membrane dipole potential, especially in cholesterol-rich domains such as lipid rafts, which play a role in important cellular processes. These results provide a mechanism for their labelling as PAINS through their ability to disrupt cell membrane homeostasis. Aiming to explore the role of C-glucosylation in PAINS membrane-interfering behavior, we disclose herein the first synthesis of 4-glucosylresveratrol, starting from 5-hydroxymethylbenzene-1,3-diol, via C-glucosylation, oxidation and Horner-Wadsworth-Emmons olefination, and resynthesize phloretin and genistein C-glucosides. We show that C-glucosylation generates compounds which are no longer able to modify membrane dipole potential. Therefore, it can be devised as a strategy to generate bioactive natural product derivatives that no longer act as membrane dipole potential modifiers. Our results offer a new technology towards rescuing bioactive polyphenols from their PAINS danger label through C-C ligation of sugars.