Nutrition supplementation plus standard of care versus standard of care alone or standard of care plus unconditional cash transfer in the prevention of chronic malnutrition in Southern Angola: study protocol for the MuCCUA study, a cluster randomized controlled trial.

BACKGROUND: Chronic malnutrition is a condition associated with negative impacts on physical and cognitive development. It is multi-causal and can start very early in life, already in utero, thus it is especially challenging to find appropriate interventions to tackle it. The government of Angola is implementing a standard of care program with potential to prevent it, and the provision of cash transfers and the supplementation with small quantity lipid-based nutrients (SQ-LNS) are also promising interventions. We aimed to evaluate the impact of the standard of care program alone and of the standard of care plus a cash transfer intervention in the lineal growth of children less than 2 years old and compare it to the effectiveness of a nutrition supplementation plus standard of care program in Southern Angola. METHODS/DESIGN: The three-arm parallel cluster randomised controlled trial is set in four communes of Huila and Cunene provinces. Clusters are villages or neighbourhoods with a population around 1075 people. A total of twelve clusters were selected per arm and forty pregnant women are expected to be recruited in each cluster. Pregnant women receive the standard of care alone, or the standard of care plus unconditional cash transfer or plus nutritional supplementation during the first 1000 days, from pregnancy to the child reaching 24 months. The primary outcome is the prevalence of stunting measured as height-for-age Z-score (HAZ) < -2 in children below 2 years. Impact will be assessed at 3, 6, 12, 18 and 24 months of children's age. Secondary outcomes include mortality, morbidity, caring, hygiene and nutrition behaviours and practices, and women and children's dietary diversity. Quantitative data are also collected on women's empowerment, household food security, expenditure and relevant clinical and social events at baseline, endline and intermediate time points. DISCUSSION: The results will provide valuable information on the impact of the standard of care intervention alone as well as combined with an unconditional cash transfer intervention compared to a nutrition supplementation plus standard of care intervention, carried out during the first 1000 days, in the children´s growth up to 2 years and related outcomes in Southern Angola. TRIAL REGISTRATION: Clinical Trials NCT05571280. Registered 7 October 2022.

Therapy-induced APOBEC3A drives evolution of persistent cancer cells.

Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1-4, the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined. Here we report that lung cancer targeted therapies commonly used in the clinic can induce cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Therapy-induced A3A promotes the formation of double-strand DNA breaks, increasing genomic instability in drug-tolerant persisters. Deletion of A3A reduces APOBEC mutations and structural variations in persister cells and delays the development of drug resistance. APOBEC mutational signatures are enriched in tumours from patients with lung cancer who progressed after extended responses to targeted therapies. This study shows that induction of A3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that suppression of A3A expression or activity may represent a potential therapeutic strategy in the prevention or delay of acquired resistance to lung cancer targeted therapy.

Diagnosis and treatment of interstitial lung disease related to systemic autoimmune myopathies: a narrative review.

Systemic autoimmune myopathies (SAMs) are rare diseases that lead to muscle inflammation and may be associated with a variety of systemic manifestations. Although there is great heterogeneity in the spectrum of extra-muscular involvement in SAMs, interstitial lung disease (ILD) is the most frequent lung manifestation. SAM-related ILD (SAM-ILD) presents significant variations according to geographic location and temporal trends and is associated with increased morbidity and mortality. Several myositis autoantibodies have been discovered over the last decades, including antibodies targeting aminoacyl-tRNA synthetase enzymes, which are associated with a variable risk of developing ILD and a myriad of other clinical features. In this review, the most relevant topics regarding clinical manifestations, risk factors, diagnostic tests, autoantibodies, treatment, and prognosis of SAM-ILD are highlighted. We searched PubMed for relevant articles published in English, Portuguese, or Spanish from January 2002 to September 2022. The most common SAM-ILD patterns are nonspecific interstitial pneumonia and organizing pneumonia. The combination of clinical, functional, laboratory, and tomographic features is usually sufficient for diagnostic confirmation, without the need for additional invasive methods. Glucocorticoids remain the first-line treatment for SAM-ILD, although other traditional immunosuppressants, such as azathioprine, mycophenolate, and cyclophosphamide have demonstrated some efficacy and, therefore, have an important role as steroid-sparing agents.

Barrier proteins and eosinophilic esophagitis in children: the role of E-cadherin and filaggrin

This study aimed to assess the protein expression of E-cadherin and filaggrin (FLG) in the oesophagus of paediatric and adolescent patients diagnosed with eosinophilic esophagi-tis (EoE). It is a cross-sectional study conducted with 24 patients with EoE and 17 control patients, from June 2015 to June 2018. The histological analyses were performed by a trained pathologist. The protein expression of E-cadherin and FLG in oesophageal biopsy fragments was determined using an immunohistochemical technique. The epidemiological data were retrieved from medical records. There were no statistical differences in age and sex between case-patients and control patients. Food allergy was significantly higher in patients with EoE, as was the number of eosinophils present in the oesophageal biopsy materials. The immu-nohistochemical studies did not indicate FLG expression in any patient from the two groups. E-cadherin showed significantly reduced expression in patients with EoE. We concluded that FLG did not seem to play an important role in the mucosal alteration in EoE and that E-cadherin under expression could be a promising marker of epithelial damage in these patients.© 2022 Codon Publications. Published by Codon Publications (AU)

COVID-19 as potential aggravating factor for the natural course of new onset-dermatomyositis.

Borges et al. have recently reported the first case of a dermatomyositis onset in close association with established coronavirus disease 2019 (COVID-19). Similarly, we report a patient who, on the contrary, had COVID-19 following early established dermatomyositis. We report prospectively the outcome of her disease.

Anatomical and morphometric study of goat middle ear ossicles (Capra aegagrus hircus) / [Estudo anatômico e morfométrico dos ossículos da orelha média de caprinos (Capra aegagrus hircus)]

The social and economic roles of goat farming in Northeastern Brazil, allied to the fact that the use of goat middle ear ossicles for research and human ear surgery training has not yet been proposed, justify the study of their applicability as an experimental model. The middle ears of 19 goats (Capra aegagrus hircus) from the bone collection of the Laboratory and Didactic Anatomy Museum of Domestic and Wild Animals of the Federal University of Vale do São Francisco (UNIVASF) were dissected. The malleus, incus, and stapes were evaluated regarding their macroscopic morphology and biometry (length, width, and height). Ossicle morphology was similar to sheep, human, and bovine morphology. The malleus was 1.3 times heavier and 2.2 times longer than the incus, and 9.0 times heavier and 3.7 times longer than the stapes. The size relationship was positive between the stapes and the malleus and negative between the stapes and the incus. It is concluded that the middle ear size and the anatomical similarities with human ossicles make goats a useful model for experimental scientific studies, reconstructive surgery practice of the ossicular chain, and human ear surgery training.(AU)

Tanto o papel social quanto o econômico da caprinocultura na região Nordeste do Brasil, somados ao fato de que o uso de ossículos da orelha média de caprinos para estudos e treinamento cirúrgico otológico humano ainda não foi proposto, justificam o estudo de sua aplicabilidade como modelo experimental. Foram dissecadas as orelhas médias de 19 caprinos (Capra aegagrus hircus), provenientes do ossuário do Laboratório e Museu Didático de Anatomia dos Animais Domésticos e Silvestres - Universidade Federal do Vale do São Francisco. Martelos, bigornas e estribos tiveram a morfologia macroscópica e a biometria (comprimento, largura e altura) avaliadas. A morfologia dos ossículos assemelhou-se a de ovinos, humanos e bovinos. O martelo foi 1,3 vez mais pesado e 2,2 vezes mais comprido que a bigorna e 9,0 vezes mais pesado e 3,7 vezes mais comprido que o estribo. A relação de tamanho entre o estribo e o martelo foi positiva, e entre o estribo e a bigorna negativa. Conclui-se que o tamanho da orelha média e as semelhanças anatômicas com os ossículos humanos tornam os caprinos um modelo útil para estudos científicos experimentais, prática cirúrgica reconstrutiva da cadeia ossicular e treinamento cirúrgico otológico humano.(AU)

Morphological alterations of Thymus during the early murine leishmaniasis.

Leishmaniasis is a neglected and endemic disease that affects poorest population mainly in developing countries. Thymus provides an essential complex environment for T cell maturation and differentiation during leishmania infection. The aim of this study was to investigate the pathological alterations of the Thymus during early Leishmania amazonensis murine infection. BALB/c mice were infected with 105 amastigotes for 24 h, 3 days, 7 days, 15 days or 30 days. At different times of infection, the relative weight of the Thymus was obtained, and the Thymus cellularity was determined by counting total cells of one thymic lobe. The thymic lobe was, alternatively, processed for standard Haematoxylin and Eosin protocol. Our results suggest thymic alteration during the early days of BALB/c mice infection with L. amazonensis. The thymic hypertrophy was accompanied by histological alterations in Thymus architecture with thickening cortex at 3 days p.i. and loss of an evident delimitation between the cortex and medulla at 7 days p.i. when compared to the control mice. That is the first time that Thymus hypertrophy was observed during the early leishmaniasis. However, how it may contribute to infection susceptibility requires further investigation.

The effect of thoracic manipulation on pulmonary function in swimmers / Efecto de la manipulación torácica en la función pulmonar de nadadores / Efeito da manipulação torácica na função pulmonar em nadadores

Objective: Spinal manipulation has been used to improve respiratory function in healthy individuals. However, it has been observed that there are no studies in the context of sports activities. The objective of this study was to analyse the effect of thoracic spinal manipulation on forced vital capacity, forced expiratory volume in one second and maximal voluntary ventilation in swimmers.Method: A randomized controlled crossover study consisting of 21 swimmers, divided into two groups (Intervention vs Control), aged 16 – 24y, where forced vital capacity, forced expiratory volume in one second and maximal voluntary ventilation were measured in five evaluation moments: at baseline and, 1 minute, 10 minutes, 20 minutes and 30 minutes following the thoracic spinal manipulation procedures.Results: ANOVA tests showed no statistically significant differences for forced vital capacity (p = 0.35) and forced expiratory volume in one second (p = 0.25) among the five evaluation moments. With the maximal voluntary ventilation there was a statistically significant (p = 0.02) reduction, observed between baseline (86.00 litres) and at 10 minutes (79.29 litres) and 30 minutes (76.24 litres). No significant differences were observed between the results of intervention and control groups.Conclusions: In the current study no significant differences were observed in pulmonary function after thoracic spinal manipulation. Future research efforts should examine the effects of different manual therapy techniques and treatment protocols. (AU)

Objetivo: La manipulación espinal se ha utilizado para mejorar la función respiratoria en individuos sanos. Sin embargo, se ha observado que no hay estudios en el contexto de las actividades deportivas. El objetivo de este estudio fue analizar el efecto de la manipulación de la columna torácica en la capacidad vital forzada, el volumen espiratorio forzado en el primer segundo y la ventilación voluntaria máxima en nadadores.Método: Un estudio cruzado controlado aleatorio que consta de 21 nadadores, divididos en dos grupos (Intervención vs Control), de 16 a 24 años, donde se midieron la capacidad vital forzada, el volumen espiratorio forzado en el primer segundo y la ventilación voluntaria máxima en cinco momentos de evaluación: al inicio y, 1 minuto, 10 minutos, 20 minutos y 30 minutos después de los procedimientos de la manipulación de la columna torácica.Resultados: Las pruebas ANOVA no mostraron diferencias estadísticamente significativas para la capacidad vital forzada (p = 0.35) y el volumen espiratorio forzado en el primer segundo (p = 0.25) entre los cinco momentos de evaluación. Con la ventilación voluntaria máxima hubo una reducción estadísticamente significativa (p = 0.02), observada entre lo inicio (86.00 litros) y a los 10 minutos (79.29 litros) y 30 minutos (76.24 litros). No se observaron diferencias significativas entre los resultados de los grupos de intervención y control.Conclusiones: En el presente estudio, no se observaron diferencias significativas en la función pulmonar después de la manipulación de la columna torácica. Futuros estudios de investigación deberían examinar los efectos de diferentes técnicas de terapia manual y protocolos de tratamiento. (AU)

Objetivo: A manipulação da coluna vertebral tem sido utilizada para melhorar a função respiratória em indivíduos saudáveis. No entanto, observou-se que não existem estudos no contexto de atividades desportivas. O objetivo deste estudo foi analisar o efeito da manipulação da coluna torácica na capacidade vital forçada, volume expiratório forçado no primeiro segundo e ventilação voluntária máxima em nadadores.Método: Estudo aleatorizado controlado cruzado composto por 21 nadadores, divididos em dois grupos (Intervenção vs Controlo), com idades entre 16 e 24 anos, onde a capacidade vital forçada, volume expiratório forçado no primeiro segundo e ventilação voluntária máxima foram medidos em cinco momentos de avaliação: no início e, 1 minuto, 10 minutos, 20 minutos e 30 minutos após os procedimentos da manipulação da coluna torácica.Resultados: Os testes ANOVA não mostraram diferenças estatisticamente significativas para a capacidade vital forçada (p = 0.35) e volume expiratório forçado no primeiro segundo (p = 0.25) entre os cinco momentos da avaliação. Com a ventilação voluntária máxima houve uma redução estatisticamente significante (p = 0.02), observada entre o início (86.00 litros) e as medições aos 10 minutos (79.29 litros) e 30 minutos (76.24 litros). Não foram observadas diferenças significativas entre os resultados dos grupos intervenção e controlo.Conclusões: No presente estudo, não foram observadas diferenças significativas na função pulmonar após a manipulação da coluna torácica. Futuras pesquisas devem examinar os efeitos de diferentes técnicas de terapia manual e protocolos de tratamento. (AU)

Cardiomiopatia hipertrófica apical x infarto apical: strain longitudinal ou ressonância magnética? / Apical hypertrophic cardiomyopathy vs. apical infarction: longitudinal strain or MRI?

INTRODUÇÃO: A cardiomiopatia hipertrófica apical (CMHA) ou síndrome de Yamaguchi é uma condição relativamente rara, que apresenta acometimento predominante da região apical do ventrículo esquerdo (VE). O Ecocardiograma com strain nesta condição apresenta uma redução no ápice bem semelhante à imagem obtida no Infarto Apical. Descrevemos um caso onde as duas condições estavam presentes. (Figuras 1 -4) RELATO DE CASO: Masculino, de 78 anos, previamente hipertenso, procurou o pronto socorro por dor precordial teve o diagnóstico de infarto sem supra do segmento ST. Seu eletrocardiograma evidenciava ondas T profundas na parede anterior e lateral. Submetido à estratificação invasiva, sendo evidenciada coronária direita (CD) ocluída no terço proximal (CD), com circulação colateral presente e lesão grave em terço proximal de artéria circunflexa (Cx). Foi submetido à angioplastia com stent farmacológico na CX. Um mês após o evento coronariano agudo, o paciente retorna ao serviço referindo persistência de dor precordial, semelhante ao quadro anterior. Mantinha-se em uso de dupla antiagregação plaquetária, de modo que foi optado por nova estratificação invasiva, que revelou as mesmas lesões previamente citadas, com stent farmacológico em Cx apresentando fluxo TIMI 3. Ao ECO com strain, evidenciou-se aumento isolado da espessura da região apical do VE, medindo 15mm, com contratilidade miocárdica preservada nesta região, redução do strain global de 11.2% e área de redução muito acentuada sugerindo fibrose nessa mesma região poupando as demais paredes. Neste momento, não foi possível a determinação da causa da redução do strain apical, se IAM, Takotsubo ou CMH. A ressonância magnética cardíaca (RMC) com estresse com dipiridamol observou hipertrofia miocárdica assimétrica apical com carga fibrótica de 16% e presença de isquemia miocárdica em segmentos inferosseptal e inferior medioapical, além de realce tardio de padrão não coronariano acometendo a porção apical do VE, com fração de ejeção de 66%. CONCLUSÃO: A identificação da etiologia da fibrose apical só foi possível com a ressonância magnética, que deixou claro ser decorrente da CMHA, já que o padrão de realce era não coronariano. Ao estresse com Dipiridamol, evidenciou isquemia na parede inferior e inferosseptal medioapical determinando que a dor precordial tinha como causa a circulação colateral insuficiente da CD. Concluímos pela necessidade do diagnóstico ser multimodalidades de imagem, com resultados mais conclusivos com RMC.

Miocardio não compactado em esportista ­ um desafio diagnóstico / Uncompressed myocardium in sportsman - a diagnostic challenge

INTRODUÇÃO: Miocárdio não compactado (MNC) é uma cardiopatia congênita rara que teve seu primeiro caso publicado há menos de 40 anos caracterizado pela falta de compactação miocárdica com a formação de trabéculas no ventrículo esquerdo (VE), afetando principalmente a região apical, podendo estar associado à hipertrofia e dilatação do VE. CASO: Masculino, 69 anos, praticante de atividade física (corrida de rua, 10km, 3x/semana). Durante avaliação inicial apresentava-se assintomático e exame físico normal, trazendo resultado de exames de cinco anos atrás, quando ainda era sedentário, apresentando eletrocardiograma (ECG) e ECO normais. Na admissão, apresenta ECG com bloqueio atrioventricular grau I, Teste ergométrico (TE) com boa capacidade funcional, não compatível com resposta isquêmica. O ECO evidenciou hipertrabeculação dominante no ápice do VE com disfunção global do VE (FE 40%). Na RMC mostrou uma relação entre miocárdio não compactado/compactado de 3,0 e confirmou disfunção do VE. Assim, foi realizada a hipótese diagnóstica de MNC, orientada limitação das atividades físicas a leves a moderadas e contraindicado atividades de alta intensidade além de ser iniciado tratamento para disfunção O paciente foi acompanhado com ECOs evidenciando persistência das trabeculações do VE, TE e Holter que não revelaram presença de arritmias ventriculares significativas. Na última avaliação, após um ano de sedentarismo do paciente o ECO evidenciou diminuição da trabeculação no VE e a nova RMC mostrou disfunção do VE (FE 42%) associado a um aumento discreto das trabeculações na porção apical, porém sem fechar critérios para o diagnóstico de MNC com uma relação miocárdio não compactado/compactado <2,3e com ausência de comprometimento septal. Após afastado o diagnóstico inicial, foi levantada a hipótese de miocardiopatia dilatada idiopática, orientando limitação de atividades físicas para leves a moderadas. DISCUSSÃO: Já está bem estabelecido que o treinamento físico pode estar associado a adaptações cardíacas, elétricas e estruturais, e, em casos raros, essas adaptações, tidas como fisiológicas, podem se sobrepor a expressões morfologicamente leves das cardiomiopatias primárias e resolver este dilema diagnóstico pode ser desafiador. O MNC é um distúrbio miocárdico relativamente novo, podendo levar a disfunção sistólica do VE, arritmias ventriculares e até a morte súbita. Eventualmente atletas podem exibir critérios convencionais para MNC destacando a natureza não específica dos critérios diagnósticos atuais se aplicados a populações de atletas.

Pituitary neuroendocrine tumors and differentiated thyroid cancer: do metabolic and inflammatory risk factors play roles?

PURPOSE: It is postulated that patients with different types of pituitary neuroendocrine tumors (PitNETs) may present a higher incidence of cancer. Factors underlying individuals becoming overweight, such as insulin resistance, hyperleptinemia, and low-grade inflammation, may play a role in the risk of differentiated thyroid carcinoma (DTC) in such patients. This study aimed to investigate the frequency of and obesity-related risk factors associated with DTC in patients with PitNETs. METHODS: This cross-sectional study involved 149 patients with nonacromegalic PitNETs (AG group), 71 patients with acromegaly (ACRO group), and 156 controls (CG group). All participants underwent insulin and blood glucose measurements with the determination of the homeostatic model assessment-insulin resistance (HOMA-IR) index, leptin, and high-sensitivity C-reactive protein (hsCRP), and they also underwent thyroid ultrasound. Clinically significant nodules were biopsied for subsequent cytopathological evaluation, and participants were operated on when indicated. RESULTS: Patients in the AG group had high levels of insulin resistance and significantly higher levels of leptin and hsCRP compared with those of patients in the ACRO group. There were no cases of DTC in the AG group; two findings, one incidental, of DTC occurred in the CG group, and three cases of DTC were present in the ACRO group. Acromegaly was associated with DTC after adjusted analysis. CONCLUSIONS: Our findings in patients with nonacromegalic PitNETs do not indicate a high risk for DTC despite the presence of metabolic and inflammatory risk factors for neoplastic events. In contrast, acromegaly promotes a greater risk of DTC.

Switching from originator recombinant growth hormone (Genotropin™) to biosimilar (CRISCY™): Results from a 6-month, multicentric, non-inferiority, extension trial.

OBJECTIVE: A previous 12-month comparative trial with Criscy™ (r-hGH Cristália), a biosimilar recombinant growth hormone, demonstrated equivalent efficacy and safety to Genotropin™. This extension trial evaluated the effects of switching patients treated with Genotropin™ to the biosimilar Criscy™ over an additional 6-month treatment period, comparing efficacy, safety, and immunogenicity parameters with patients remaining in the Criscy™ arm. DESIGN: This extension study included 11 research centers and 81 patients who participated in the CERES study (Czepielewski et al., 2019 [1]). Participants from the Genotropin™ arm (n = 39) had the drug replaced by Criscy™ and the remaining participants were kept in the Criscy™ arm (n = 42) for an additional 6-month period to evaluate immunogenicity, efficacy (growth rate, height SDS), and safety (laboratory tests, and adverse events). RESULTS: Before the switch, both Criscy™ and Genotropin groups were similar concerning demographics, and auxological measures: age, sex, height, height SDS, weight, and BMI. Height velocity (HV) after 18 months of treatment was 8.7 ± 1.56 cm/year for Criscy™ group and 8.9 ± 1.36 cm/year for Genotropin™ group in the ITT population (p = 0.43). The auxological parameters and IGF-1 and IGFBP-3 SDS were comparable between both groups of patients. No participants were excluded from the study due to adverse events. There were no clinical or statistical relevant differences between the treatment groups concerning frequency, distribution, intensity, and AEs outcome. Similarly, no new anti-r-hGH (ADA) cases among patients that switched from Genotropin™ to Criscy™ were reported. No neutralizing antibody (nAb) was detected in either group. CONCLUSIONS: This trial showed that switching from originator recombinant human growth hormone to Criscy™ had no impact on efficacy, safety, nor immunogenicity as compared to continued treatment with Criscy™. Growth rates and ADA incidence remained the same as seen before the switch.

Morphological alterations of Thymus during the early murine leishmaniasis

@#Leishmaniasis is a neglected and endemic disease that affects poorest population mainly in developing countries. Thymus provides an essential complex environment for T cell maturation and differentiation during leishmania infection. The aim of this study was to investigate the pathological alterations of the Thymus during early Leishmania amazonensis murine infection. BALB/c mice were infected with 105 amastigotes for 24 h, 3 days, 7 days, 15 days or 30 days. At different times of infection, the relative weight of the Thymus was obtained, and the Thymus cellularity was determined by counting total cells of one thymic lobe. The thymic lobe was, alternatively, processed for standard Haematoxylin and Eosin protocol. Our results suggest thymic alteration during the early days of BALB/c mice infection with L. amazonensis. The thymic hypertrophy was accompanied by histological alterations in Thymus architecture with thickening cortex at 3 days p.i. and loss of an evident delimitation between the cortex and medulla at 7 days p.i. when compared to the control mice. That is the first time that Thymus hypertrophy was observed during the early leishmaniasis. However, how it may contribute to infection susceptibility requires further investigation.

Influence of dietary patterns on contaminants bioaccessibility and intestinal transport by in vitro assays.

Food contaminants are usually studied as isolated molecules, not considering the overall meal components. Notwithstanding, contaminants are not ingested individually, therefore their risks should be assessed in the context of the overall diet. In the present study the influence of three well known dietary patterns, Western (W), Mediterranean (M) and vegetarian (V), on the bioaccessibility and intestinal transport of polycyclic aromatic hydrocarbons (PAHs) (benzo[a]pyrene (BaP) and benzo[b]fluoranthene (BbF)), heterocyclic aromatic amines (HAAs) (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-Amino-9H-pyrido[2,3-b]indole (AAC)) and mycotoxins (MY) (aflatoxin B2 (AB2) and ochratoxin A (OTA)) was evaluated. Whole meals representative of W, M and V patterns were spiked with 100 µg kg-1 of each contaminant and subjected to the Infogest in vitro digestion method. Intestinal transport was performed using Caco-2 cells in apical/basolateral inserts. Contaminants were quantified by QuEChERS/HPLC/Fluorescence analysis. The dietary pattern itself influenced significantly the bioaccessibility of some contaminants, since higher bioaccessibility of HAAs (PhIP and AAC) was observed for V diet, while higher bioaccessibility of PAHs (BBF and BAP) and the MY (OTA) was observed for W diet. Concerning intestinal transport, the effect of the diet matrices was less noticed. Notwithstanding, AAC transport increased with W diet, while AB2s transport increased with the V diet. Regarding PAHs the three patterns either blocked (BbF) or reduced (BaP) the transport. Besides the well known nutritional, protective or deleterious effects of the different dietary patterns, the increased bioaccessibility or intestinal transport of some food contaminants, can have an additional influence on the global health impact.

Microbial Control of Leptopharsa heveae Drake & Poor (Hemiptera: Tingidae) in Brazilian Rubber Tree Plantations: a Brief Historical Account and Identification of Entomopathogenic Fungi by Means of Multigene Phylogeny.

Over the last decades, a few fungal species have been mentioned in the literature associated with the rubber tree lace bug, Leptopharsa heveae Drake & Poor (Hemiptera: Tingidae). The rubber plantation area treated with these biocontrol agents has been steady since the 1990s, estimated in 10,000-15,000 ha per year. A few large-scale rubber operations, one biocontrol company, and three government-owned laboratories were, and currently one still is, involved in their commercialization. One species, currently referred to as Sporothrix insectorum, has been historically deployed in biocontrol applications in Brazilian rubber farms. However, L. heveae-infecting isolates have only been identified through morphological examinations; therefore, proper molecular assessments are needed for accurate identifications. Hence, DNA of six L. heveae-infecting isolates (five of which have been deployed in field applications) were extracted and sequenced. Multigene phylogeny found that both Simplicillium lanosoniveum and Cordyceps (formerly Isaria) sp. have been sprayed on rubber plantations to manage L. heveae populations, although the former is the only one currently applied. Simplicillium lanosoniveum and Cordyceps sp. have no relation whatsoever to true Sporothrix species associated with human and animal diseases. Therefore, our molecular data may encourage biocontrol companies to register mycoinsecticides targeting L. heveae. We also added unpublished historical accounts after contacting key contributors to the launching of this not so well-known biocontrol program in the 1980s.

Serum biochemistry of Trachemys scripta elegans and Trachemys dorbignyi (Testudines: Emydidae) bred in captivity in the Northeastern semiarid region of Brazil.

AIM: This study aimed to assess fundamental biochemical values of healthy animals and to provide useful data on comparative physiologies of Testudines, being assessed the serum biochemistry profiles, and body and tail biometry of Trachemys scripta elegans and Trachemys dorbignyi bred in interaction in the semiarid region of the São Francisco river valley. MATERIALS AND METHODS: Serum biochemistry variables (urea, creatinine, glucose, total serum protein, albumin, globulin, and albumin/globulin ratio), and biometry values of the body (mass [body mass (BM)], maximum curvilinear length [carapace length (CL)], and width [carapace width (CW)] of the carapace, maximum curvilinear length [plastron length (PL)], and width [plastron width PW] of the plastron), and the tail (total length of the tail [TLT], pre-cloacal tail length [PrCL], post-cloacal tail length [PoCL]) were measured after 24 h fasting. RESULTS: T. s. elegans displayed higher BM, CL, CW, PL, PW, AST, TP, albumin, and globulin values. T. dorbignyi displayed higher values of glucose, TLT, and PrCL. Variables aspartate aminotransferase (AST) and total protein (TP) in T. s. elegans and glucose in T. dorbignyi explained most of the variance between the species and could serve to distinguish them. CONCLUSION: We conclude that most of the differences between T. s. elegans and T. dorbignyi shall be explained by biometric variables, AST, TP, and glucose, which characterize interspecific differences. Our results point out terms of reference for these species bred in captivity in the semiarid region of Brazilian Northeastern region and serve as a model for the comparative intra- and inter-species physiology and as a base for the health assessment of these species.

Nanofibrils vs nanocrystals bio-nanocomposites based on sodium alginate matrix: An improved-performance study.

To develop bio-nanocomposites using natural biopolymers, nanocomposite films were prepared based on sodium alginate and kapok nanofibrils (CNFs). CNFs when subjected to TEMPO-mediated oxidation gave rise to cellulose nanocrystals (TOCNCs), with carboxyl groups at the surface ( K a / K b = 3.64). The differences between the two types of nanocelluloses (nanofibrils and nanocrystals) and their impact in the preparation of bio-nanocomposites, were studied. When incorporated in the matrix, the CNFs particles have the tendency to form surface aggregation ( K a / K b = 2.37), distorting the alginate network, creating heterogeneous films, with high surface roughness (S a = 29.37 nm), porosity (D p = 0.087 cm2/min) and vulnerability to heat. The TOCNCs present good dispersion creating a 3D network, which forms uniform (D p = 0.122 cm2/min) and homogeneous films, with smooth surface (S a = 16.83 nm). The ultrasonication treatment facilitated the dispersion improving the interfacial interaction between the reinforcing phase and the matrix. The results show the reinforcement potential of kapok nanocellulose in an industrially and medically important biopolymer, sodium alginate, especially when TOCNCs and ultrasonication were used.

Anxiogenesis induced by social defeat in male mice: Role of nitric oxide, NMDA, and CRF1 receptors in the medial prefrontal cortex and BNST.

Nitric oxide (NO) release in the right medial prefrontal cortex (RmPFC) produces anxiogenesis. In the bed nucleus of the stria terminalis (BNST), a region that receives neuronal projections from the mPFC, NO provokes anxiety, an effect that is blocked by local injections of corticotrophin-releasing factor type 1 receptor (CRF1) or n-methyl-d-aspartate receptor (NMDAr) antagonist. Anxiety is also enhanced by social defeat stress, and chronic stress impairs and facilitates, respectively, PFC and BNST roles in modulating behavioral responses to aversive situations. This study investigated whether the (i) chronic social defeat stress (CSDS) increases NO signaling in the mPFC; and/or (ii) anxiogenic effects provoked by the intra-RmPFC injection of NOC-9 (an NO donor) or by CSDS are prevented by intra-BNST injections of AP-7 (0.05 nmol) or CP 376395 (3.0 nmol), respectively, NMDAr and CRF1 antagonists, in male Swiss-Webster mice exposed to the elevated plus-maze (EPM). Results showed that (a) CSDS increased anxiety (i.e., reduced open-arm exploration) and repeatedly activated nNOS-containing neurons, as measured by ΔFosB (a stable nonspecific marker of neural activity) + nNOS double-labeling, in the right (but not left) mPFC, (b) NOC-9 in the RmPFC also increased anxiety, and (c) both CSDS and NOC-9 effects were reversed by injections of AP-7 or CP 376395 into the BNST. These results suggest that NMDA and CRF1 receptors located in BNST play an important role in the modulation of anxiety provoked by NO in the RmPFC, as well as by chronic social defeat in mice.

Activation of Prejunctional P2x2/3 Heterotrimers by ATP Enhances the Cholinergic Tone in Obstructed Human Urinary Bladders.

The objective of this study was to investigate the role of ATP in cholinergic neurotransmission in the urinary bladder of control men and of patients obstructed as a result of benign prostatic hyperplasia (BPH). Human detrusor samples were collected from 41 patients who submitted to transvesical prostatectomy resulting from BPH and 26 male organ donors. The release of [3H]acetylcholine ([3H]ACh) was evoked by electrical field stimulation (10 Hz, 200 pulses) in urothelium-denuded detrusor strips. Myographic recordings were performed to test detrusor strip sensitivity to ACh and ATP. Nerve-evoked [3H]ACh release was 1.5-fold higher in detrusor strips from BPH patients compared with controls. This difference was abolished after desensitization of ionotropic P2X1-3 receptors with an ATP analog, α,ß-methylene ATP (30 µM, applied for 15 minutes). TNP-ATP (10 nM, a preferential P2X2/3 antagonist) and A317491 (100 nM, a selective P2X3 antagonist) were about equipotent in decreasing nerve-evoked [3H]ACh release in control detrusor strips, but the selective P2X1 receptor antagonist NF023 (3 µM) was devoid of effect. The inhibitory effect of TNP-ATP (10 nM) increased from 27% ± 9% to 43% ± 6% in detrusor strips of BPH patients, but the effect of A317491 (100 nM) [3H]ACh release unaltered (20% ± 2% vs. 24% ± 4%). The amplitude of ACh (0.1-100 µM)-induced myographic recordings decreased, whereas sensitivity to ATP (0.01-3 mM) increased in detrusor strips from BPH patients. Besides the well characterized P2X1 receptor-mediated contractile activity of ATP in pathologic human bladders, we show here for the first time that cholinergic hyperactivity in the detrusor of BPH patients is facilitated by activation of ATP-sensitive P2X2/3 heterotrimers. SIGNIFICANCE STATEMENT: Bladder outlet obstruction often leads to detrusor overactivity and reduced bladder compliance in parallel to atropine-resistant increased purinergic tone. Our data show that P2X1 purinoceptors are overexpressed in the detrusor of patients with benign prostatic hyperplasia. Besides the P2X1 receptor-mediated detrusor contractions, ATP favors nerve-evoked acetylcholine release via the activation of prejunctional P2X2/3 excitatory receptors in these patients Thus, our hypothesis is that manipulation of the purinergic tone may be therapeutically useful to counteract cholinergic overstimulation in obstructed patients.

Efficacy and safety of a biosimilar recombinant human growth hormone (r-hGH Cristalia) compared with reference r-hGH in children with growth hormone deficiency (CERES study): A randomized, multicentric, investigator-blind, phase 3 trial.

OBJECTIVE: The CERES study was a randomized, multicenter, investigator-blind trial aimed to evaluate the efficacy and safety of a recombinant human growth hormone (r-hGH) developed by Cristalia, as a biosimilar product, with analytical, functional and pharmacokinetics similarities comparable to Genotropin™, in children with growth hormone deficiency (GHD). DESIGN: A total of 135 naïve prepubertal children with GHD were recruited, of whom 97 were randomized in 14 Brazilian sites to received either r-hGH Cristalia (n = 49) or Genotropin™ (n = 48). Efficacy was evaluated considering the height standard deviation score (SDS) and growth velocity as auxological parameters, IGF-1 and IGFBP-3 were measured as pharmacodynamic parameters during 12 months treatment time. Safety was assessed by monitoring adverse events, immunogenicity, blood count with platelets, biochemical profile and hormonal levels particularly fasting glucose, insulin and HbA1C. RESULTS: The auxological parameters and IGF-1 and IGFBP-3 levels were comparable between both groups of patients. At end of study or the 12th month treatment, the means growth velocity was 9.7 cm/year and 9.5 cm/year, for r-hGH Cristalia and Genotropin™, respectively. The ANCOVA mean difference between the groups was 0.16 cm/year to Cristalia group (CI 95% = -0.72 to 1.03 cm/year). There was no difference in adherence among the treatment groups. The safety profile was comparable between groups. CONCLUSIONS: The clinical similarity between r-hGH and Genotropin™ was demonstrated within 12 month of treatment. On the basis of comparability of quality, safety, and efficacy to the reference product, r-hGH from Cristalia can be considered a cost-effective therapeutic option for patients with growth disorders.