Inflammation, but not skeletal muscle index, is associated with coronavirus disease 2019 mortality in patients with cancer.

BACKGROUND & AIMS: Patients with cancer and coronavirus disease 2019 (COVID-19) have characteristics that can cause the most severe forms of the disease and higher mortality. We aimed to assess the association between computed tomography (CT)-derived muscle abnormalities, anthropometric parameters, inflammation, and mortality in patients with cancer and COVID-19. METHODS: This retrospective study included patients with cancer and COVID-19 admitted between March 1st and December 31st, 2020. All information was collected from medical records (clinical and nutritional parameters, serum albumin, and C-reactive protein [CRP]). Weight loss and body mass index (BMI) were assessed using Global Leadership Initiative on Malnutrition phenotypic criteria. Skeletal muscle index (SMI) and skeletal muscle radiodensity (SMD) at the fourth thoracic vertebra level were assessed using computed tomography scans. RESULTS: This study included 80 patients (61% men, mean age: 58 ± 17 years). Of the patients analyzed, 49% had weight loss >5%, and 14% had low BMI. The median length of hospital stay was 7 (interquartile range: 4-14 days), 27% needed mechanical ventilation, 34% died as a direct consequence of COVID-19 infection and 15% to complications associated with cancer condition. In multivariate logistic regression analysis, low SMI was associated with increased in-hospital mortality [odds ratio (OR): 4.81; 95% confidence interval (95% CI): 1.63; 14.2; p = 0.005), while CRP was associated with COVID-19-related mortality (OR: 1.08; 95% CI: 1.01; 1.15, p = 0.018). CONCLUSION: SMI independently predicts in-hospital mortality in patients with cancer and COVID-19. Additionally, an independent association was observed between CRP and mortality specifically related to COVID-19.

CD4+ Th1 and Th17 responses and multifunctional CD8 T lymphocytes associated with cure or disease worsening in human visceral leishmaniasis.

Introduction: In VL, a proinflammatory phenotype is typically associated with enhanced phagocytosis and a Th1 mediated immune response resulting in infection control. In contrast, an anti-inflammatory phenotype, associated with a predominant regulatory response, typically enables intracellular multiplication of Leishmania parasites and disease progression. Methods: To investigate the impact of chemotherapy on Th2 and Th17 immune responses in patients with visceral leishmaniasis (VL), we assessed all combinations of intracellular expression of IFN-γ, IL-10, IL-4 and IL-17 in the CD4+ and CD8+ T cell populations of peripheral blood mononuclear cell (PBMC) samples from patients, after antigenic stimulation with Leishmania lysate, throughout treatment and follow-up. As increases in spleen and liver sizes and decreases in hematocrit, hemogloblin, erythrocytes, monocytes, leukocytes and platelets levels are strongly related to the disease, we studied the correlations between the frequencies of T cells producing the afore mentioned cytokines, individually and in combination, and these variables, as markers of disease or cure. Results: We found that the frequency of IFN-γ-producingCD4+ T cells increased until the end of chemotherapy with Glucantime® or AmBisome ®, while IL-10, IL-4 and IL-17-producing CD4+ T cells peaked on day 7 following the start of treatment. Although the frequency of CD4+IL-17+ cells decreased during treatment an increase was observed after clinical cure. The frequency of CD4+ T cells producing only IFN-γ or IL-17 correlated with blood monocytes levels. Frequencies of double-producers of IFN-γ and IL-10 or IL-4 correlated positively with eosinophils and platelets levels. Together, this suggest that IFN-γ drives the immune response towards Th1 at cure. In contrast, and associated with disease or Th2 response, the frequency of CD4+ IL-10+ cells correlated positively with spleen sizes and negatively with circulating monocyte levels, while the frequency of CD4+ producing both IL-4 and IL-10 correlated negatively with platelets levels. The frequency of CD8+ single-producers of IFN-γ increased from day 21 to 90 while that of single-producers of IL-10 peaked on day 7, of IL-4 on day 30 and of IL-17, on day 180. IFN-γ expression in CD8+ single- and double-producers of cytokines was indicative of an immune response associated with cure. In contrast, frequencies of CD8+ double-producers of IL-4 and IL-10, IL-4 and IL-17 and IL-10 and IL-17 and producers of three and four cytokines, were associated with disease and were low after the cure. Frequencies of CD8+ T cells producing IFN-γ alone or with IL-17 were positively correlated with platelets levels. In contrast, as markers of disease: 1) frequencies of single producers of IL-10 correlated negatively with leukocytes levels, 2) frequencies of double producers of IL-4 and IL-10 correlated negatively with platelet, leukocyte, lymphocyte and circulating monocyte levels, 3) frequencies of triple-producers of IFN-γ, IL-4 and IL-10 correlated negatively with platelet, leukocyte and neutrophil levels and 4) frequencies of producers of IFN-γ, IL-4, IL-10 and IL-17 simultaneously correlated positively with spleen size, and negatively with leukocyte and neutrophil levels. Discussion: Our results confirmed that the clinical improvement of VL patients correlates with the decrease of an IL-4 and IL-10 CD4+Th2 response, the recovery of CD4+ Th1 and Th17 responses and the frequency of CD8+ single-producers of IFN-γ and double producers of IFN-γ and IL-17.

sTREM-1 and TNF-α levels are associated with the clinical outcome of leprosy patients.

Leprosy reaction (LR) and physical disability (PD) are the most significant clinical complications of leprosy. Herein, we assessed the circulating serum-sTREM-1 and TNF-α levels and their genetic polymorphisms in leprosy. Serum-sTREM-1 and TNF-α levels were measured in leprosy patients (LP) before treatment (n = 51) and from their household contacts (HHCs; n = 25). DNA samples were genotyped using TREM-1 rs2234246 and TNF-α rs1800629-SNP in 210 LPs and 168 endemic controls. The circulating sTREM-1 and TNF-α levels are higher in the multibacillary form. The ROC curve of the serum-sTREM-1 levels was able to differentiate LR from non-LR and PD from non-PD. Similarly, LPs with serum-sTREM-1 levels >210 pg/ml have 3-fold and 6-fold higher chances of presenting with LR and PD, respectively. Genotypes CC+CT of the TREM-1 were associated with leprosy. Taken together, our analyses indicated that sTREM-1 and TNF-α play an important role in the pathogenesis of leprosy and provide promising biomarkers to assist in the diagnosis of leprosy complications.

Novel Strategy for Surface Modification of Titanium Implants towards the Improvement of Osseointegration Property and Antibiotic Local Delivery.

The topography and chemical composition modification of titanium (Ti) implants play a decisive role in improving biocompatibility and bioactivity, accelerating osseointegration, and, thus, determining clinical success. In spite of the development of surface modification strategies, bacterial contamination is a common cause of failure. The use of systemic antibiotic therapy does not guarantee action at the contaminated site. In this work, we proposed a surface treatment for Ti implants that aim to improve their osseointegration and reduce bacterial colonization in surgery sites due to the local release of antibiotic. The Ti discs were hydrothermally treated with 3M NaOH solution to form a nanostructured layer of titanate on the Ti surface. Metronidazole was impregnated on these nanostructured surfaces to enable its local release. The samples were coated with poly(vinyl alcohol)-PVA films with different thickness to evaluate a possible control of drug release. Gamma irradiation was used to crosslink the polymer chains to achieve hydrogel layer formation and to sterilize the samples. The samples were characterized by XRD, SEM, FTIR, contact angle measurements, "in vitro" bioactivity, and drug release analysis. The alkaline hydrothermal treatment successfully produced intertwined, web-like nanostructures on the Ti surface, providing wettability and bioactivity to the Ti samples (Ti + TTNT samples). Metronidazole was successfully loaded and released from the Ti + TTNT samples coated or not with PVA. Although the polymeric film acted as a physical barrier to drug delivery, all groups reached the minimum inhibitory concentration for anaerobic bacteria. Thus, the surface modification method presented is a potential approach to improve the osseointegration of Ti implants and to associate local drug delivery with dental implants, preventing early infections and bone failure.

TREM-1 Expression on the Surface of Neutrophils in Patients With Visceral Leishmaniasis Is Associated With Immunopathogenesis.

Visceral leishmaniasis (VL) is a systemic chronic and potentially fatal disease for humans. Mechanisms related to the dysregulation of the inflammatory response may be involved in both the pathogenesis and prognosis of VL. Triggering Receptor Expressed on Myeloid Cells-1 (TREM-1) is a receptor constitutively expressed on neutrophils and monocyte subsets. The protein serves to regulate and amplify inflammatory responses. This study aimed to evaluate the expression profile of TREM-1 on the surface of neutrophils from patients with VL at varying time points during leishmanicidal treatment. For this purpose, neutrophils were isolated from the peripheral blood of patients with VL at different stages of treatment, which include 0, 7, and 30 days after treatment. Surface TREM-1 expression was assessed by immunophenotyping neutrophil populations. In addition, the association of TREM-1 expression on the surface of neutrophils with clinical and laboratory parameters and serum levels of inflammatory mediators was also evaluated. Results demonstrate a lower surface expression of TREM-1 in VL patients in the absence of treatment. However, increased levels of TREM-1 expression were observed 7 and 30 days after the start of treatment, with levels similar to those of healthy controls. TREM-1 expression was directly correlated with lymphocyte and erythrocyte count and indirectly correlated with spleen and liver size. Furthermore, elevated levels of TREM-1 expression were also correlated with lower serum levels of interleukin (IL)-22. Taken together, these results suggest that infection by Leishmania infantum leads to depressed TREM-1 expression on the neutrophil surface and may contribute to the inflammatory imbalance that characterizes active VL disease.

Ingestão Alimentar de Mulheres com Tumores Ginecológicos em Tratamento Oncológico: Revisão Integrativa da Literatura / Food Intake of Women with Gynecological Tumors Undergoing Cancer Treatment: Integrative Literature Review / Ingestión de Alimentos de Mujeres con Tumores Ginecológicos en Tratamiento Oncológico: Revisión Integradora de la Literatura

Introdução: Pacientes com câncer apresentam uma tendência à perda ponderal e à desnutrição energético-proteica. Isso ocorre em razão das modificações que o organismo sofre pelo desenvolvimento da doença e pelos efeitos adversos do tratamento oncológico que contribuem para a redução da ingestão alimentar. Objetivo: Identificar evidências disponíveis na literatura científica sobre a ingestão alimentar de mulheres com tumores ginecológicos em tratamento oncológico. Método: Revisão integrativa da literatura cujas buscas foram realizadas nas bases de dados Embase, MEDLINE e LILACS por meio da associação de termos descritores e palavras livres. Foram incluídos nas análises estudos observacionais que avaliaram a ingestão alimentar de mulheres adultas com tumores ginecológicos durante o tratamento oncológico, redigidos em português, inglês e espanhol. Resultados: Esta revisão analisou seis estudos que investigaram a mudança na ingestão alimentar dessa população. Identificou-se uma redução da ingestão em até 31% de energia, 39,9% de proteínas, 33,7% de lipídeos, 28,7% de carboidratos e uma inadequação da ingestão de determinados micronutrientes. Conclusão: Mulheres com tumores ginecológicos durante o tratamento oncológico apresentam redução significativa da ingestão de energia, proteínas, lipídeos, carboidratos e micronutrientes. Considerando que a perda de peso e a desnutrição em pacientes com câncer está associada a desfechos clínicos negativos, a avaliação e a análise da ingestão alimentar desses indivíduos são fundamentais para possibilitar uma intervenção nutricional precoce, boa resposta ao tratamento e consequente melhoria da qualidade de vida

Introduction: Cancer patients tend to lose weight and energy-protein malnutrition because of the changes the organism undergoes caused by the progression of the disease and treatment-related adverse effects that contribute for the reduction of food intake. Objective: To identify scientific literature-based evidences on food intake of women with gynecological tumors undergoing cancer treatment. Method: Integrative literature review through searches at the Embase, MEDLINE and LILACS databases with the association of descriptive terms and free words. Observational studies in Portuguese, English and Spanish that evaluated the food intake of this population were included in the analyzes. Results: This review identified 6 studies that investigated the change in food intake of women with gynecological cancer undergoing cancer treatment. A reduction in intake was identified in until 31% of energy, 39.9% of proteins, 33.7% of lipids, 28.7% of carbohydrates and inadequate intake of certain micronutrients. Conclusion: Women with gynecological tumors during cancer treatment present significant reduction of energy, proteins, lipids, carbohydrates and micronutrients intake. Considering that weight loss and malnutrition in cancer patients are associated with negative clinical outcomes, the evaluation and analysis of the food intake of this population individuals is essential for early nutritional intervention, good response to treatment and improvement of the quality of life

Introducción: Los pacientes con cáncer tienen tendencia a la pérdida de peso y a la desnutrición calórico-proteica. Esto ocurre debido a los cambios que sufre el organismo debido al desarrollo de la enfermedad y los efectos adversos del tratamiento del cáncer que contribuyen a la reducción de la ingesta alimentaria. Objetivo: Identificar la evidencia disponible en la literatura científica sobre la ingesta alimentaria de mujeres con tumores ginecológicos en tratamiento oncológico. Método: Revisión integrativa de la literatura cuyas búsquedas se realizaron en las bases de datos Embase, MEDLINE y LILACS mediante la asociación de términos descriptivos y palabras libres. Se incluyeron en los análisis estudios observacionales que evaluaron la ingesta de alimentos de mujeres adultas con tumores ginecológicos durante el tratamiento del cáncer, escritos en portugués, inglés y español. Resultados: Esta revisión analizó seis estudios que investigaron el cambio en la ingesta de alimentos en esta población. Cuantificamos una reducción de la ingesta de hasta un 31% en energía, 39,9% en proteínas, 33,7% en lípidos, 28,7% en carbohidratos y una ingesta inadecuada de determinados micronutrientes. Conclusión: Las mujeres con tumores ginecológicos durante el tratamiento del cáncer tienen una reducción significativa en la ingesta de energía, proteínas, lípidos, carbohidratos y micronutrientes. Teniendo en cuenta que la pérdida de peso en pacientes con cáncer se asocia con resultados clínicos negativos, la evaluación de la ingesta alimentaria de estos individuos es fundamental para permitir una intervención nutricional precoz, una buena respuesta al tratamiento y la consecuente mejora de la calidad de vida

Multifunctional, TNF-α and IFN-γ-Secreting CD4 and CD8 T Cells and CD8High T Cells Are Associated With the Cure of Human Visceral Leishmaniasis.

Visceral leishmaniasis (VL) is a chronic and often fatal disease caused by protozoans of the genus Leishmania that affects millions of people worldwide. Patients with symptomatic VL have an impaired anti-Leishmania-specific CD4+ T-cell response, which is reversed after clinical cure. In contrast, the quality of the CD4+ and CD8+ T-cell responses involved in resistance and/or cure of VL relies on the capability of these cells to activate polyfunctional and memory responses, which are associated with the simultaneous production of three cytokines: IFN-γ, IL-2, and TNF-α. Models for the development of CD4 and CD8 T-cell quality in memory and protection to leishmaniasis have been described previously. We aimed to assess the functionality of the T cells involved in the recovery of the immune suppression throughout the VL treatment. Therefore, we cultured peripheral blood mononuclear cells (PBMCs) from VL patients and healthy controls in vitro with soluble Leishmania antigen (SLA). Cell surface markers and intracellular cytokine production were determined on days 7, 14, 21, 30, 60, 90, and 180 after the beginning of chemotherapy. We observed that the frequencies of CD4+TNF-α+IFN-γ+ and the multifunctional CD4+IL-2+TNF-α+IFN-γ+, together with CD4+TNF-α+ and CD4+IFN-γ+ T cells, increased throughout and at the end of the treatment, respectively. In addition, enhanced frequencies of CD8+IL-2+TNF-α+IFN-γ+ and CD8+TNF-α+IFN-γ T cells were also relevant in the healing process. Noteworthy, the frequencies of the CD4+ and CD8 central-memory T cells, which produce IL-2, TNF-α, and IFN-γ and ensure the memory response against parasite reinfection, are significantly enhanced in cured patients. In addition, the subset of the non-functional CD8Low population is predominant in VL untreated patients and decreases along the chemotherapy treatment. In contrast, a CD8High subset increased towards the cure. Furthermore, the cure due to treatment with meglumine antimoniate or with liposomal amphotericin B was associated with the recovery of the T-cell immune responses. We described the evolution and participation of functional T cells during the treatment of patients with VL. Our results disclosed that the clinical improvement of patients is significantly associated with the participation of the CD4+ and CD8+ cytokine-secreting T cells.

Neuroinflammation and Brain Development: Possible Risk Factors in COVID-19-Infected Children.

COVID-19, a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) betacoronavirus, affects children in a different way than it does in adults, with milder symptoms. However, several cases of neurological symptoms with neuroinflammatory syndromes, such as the multisystem inflammatory syndrome (MIS-C), following mild cases, have been reported. As with other viral infections, such as rubella, influenza, and cytomegalovirus, SARS-CoV-2 induces a surge of proinflammatory cytokines that affect microglial function, which can be harmful to brain development. Along with the viral induction of neuroinflammation, other noninfectious conditions may interact to produce additional inflammation, such as the nutritional imbalance of fatty acids and polyunsaturated fatty acids and alcohol consumption during pregnancy. Additionally, transient thyrotoxicosis induced by SARS-CoV-2 with secondary autoimmune hypothyroidism has been reported, which could go undetected during pregnancy. Together, those factors may pose additional risk factors for SARS-CoV-2 infection impacting mechanisms of neural development such as synaptic pruning and neural circuitry formation. The present review discusses those conditions in the perspective of the understanding of risk factors that should be considered and the possible emergence of neurodevelopmental disorders in COVID-19-infected children.

Vestibular function in severe GH deficiency due to an inactivating mutation in the GH-releasing hormone receptor gene.

PURPOSE: Body balance involves the vestibular, visual, and proprioceptive systems. IGF-I is a GH-dependent key factor in the development and postnatal differentiation of the inner ear in mice and men, but its role in the vestibular function in adult humans is unknown. We have previously described a cohort of individuals with severe isolated GH deficiency (IGHD) caused by a mutation in the GHRH receptor (GHRHR) gene. These individuals complain of dizziness, exhibit mild sensorineural loss, but have normal postural balance, without increase in falls risk. The aim of this study was to evaluate their vestibular function. METHODS: We performed physical examination (clinical head impulse and Fukuda dynamic stepping test), oculomotor (saccadic eye movements, spontaneous, semi-spontaneous and opotokinetic nystagmus, and pendular tracking) and caloric stimulation (postcaloric reflex and ocular fixation index) tests, in 15 GH-naïve IGHD (seven males) and 15 controls (five males). RESULTS: IGHD subjects showed lower height and weight, with similar BMI to controls, and higher number of individuals with abnormal clinical head impulse test and abnormal oculomotor tests, namely the saccadic movements and the spontaneous nystagmus. There was a nonsignificant trend in abnormalities in the Fukuda stepping test and postcaloric reflex test. CONCLUSIONS: Adult untreated IGHD individuals have higher prevalence of moderate peripheral vestibular impairment, and of abnormal vestibular-ocular reflex.

Non-Leishmania Parasite in Fatal Visceral Leishmaniasis-Like Disease, Brazil.

Through whole-genome sequencing analysis, we identified non-Leishmania parasites isolated from a man with a fatal visceral leishmaniasis-like illness in Brazil. The parasites infected mice and reproduced the patient's clinical manifestations. Molecular epidemiologic studies are needed to ascertain whether a new infectious disease is emerging that can be confused with leishmaniasis.

Macrophages From Subjects With Isolated GH/IGF-I Deficiency Due to a GHRH Receptor Gene Mutation Are Less Prone to Infection by Leishmania amazonensis.

Isolated growth hormone (GH) deficiency (IGHD) affects approximately 1 in 4,000 to 1 in 10,000 individuals worldwide. We have previously described a large cohort of subjects with IGHD due to a homozygous mutation in the GH releasing hormone (GHRH) receptor gene. These subjects exhibit throughout the life very low levels of GH and its principal mediator, the Insulin Growth Factor-I (IGF-I). The facilitating role of IGF-I in the infection of mouse macrophages by different Leishmania strains is well-known. Nevertheless, the role of IGF-I in Leishmania infection of human macrophages has not been studied. This study aimed to evaluate the behavior of Leishmania infection in vitro in macrophages from untreated IGHD subjects. To this end, blood samples were collected from 14 IGHD individuals and 14 age and sex-matched healthy controls. Monocytes were isolated and derived into macrophages and infected with a strain of Leishmania amazonensis. In addition, IGF-I was added to culture medium to evaluate its effect on the infection. Cytokines were measured in the culture supernatants. We found that macrophages from IGHD subjects were less prone to Leishmania infection compared to GH sufficient controls. Both inflammatory and anti-inflammatory cytokines increase only in the supernatants of the control macrophages. Addition of IGF-I to the culture medium increased infection rates. In conclusion, we demonstrated that IGF-I is crucial for Leishmania infection of human macrophages.

Clinical and epidemiological indicators and spatial analysis of leprosy cases in patients under 15 years old in an endemic area of Northeast Brazil: an ecological and time series study.

OBJECTIVE: This study aimed to analyse the clinical and epidemiological indicators, temporal trends and the spatial distribution of leprosy in patients under 15 years old in an endemic area of Northeast Brazil. DESIGN: Regional surveillance study of all reported cases. SETTING: State of Sergipe, endemic area of Northeast Brazil. METHODS: An ecological and time series study was conducted, based on secondary data reported by the Brazilian Information System on Notifiable Diseases for leprosy cases diagnosed in Sergipe state (2002-2015). The analysis of temporal trends was performed using the Joinpoint Regression Programme through Poisson regression. We performed spatial analysis by Kernel estimator and Moran index. RESULTS: The incidence rate was reduced from 6.29 to 3.78 cases per 100 000 inhabitants in 2002 and 2015, respectively. However, Sergipe was still classified as highly endemicity in 2015. The mean number of household contacts (HHC) examined was significantly lower than those registered. Clinical data indicated that 21.4% of the patients developed leprosy reactions, and 31.3% presented with some physical disability in the multibacillary groups. Patients diagnosed by examination within the HHC presented better indicators, such as lower percentage of leprosy reaction and physical disability. Spatial analysis showed the most risk areas distributed on the northeast and cities around the capital, Aracaju. CONCLUSION: The data indicate that there is a persistence of active Myobacterium leprae transmission and a delay in disease detection, following a pattern of high endemicity in many municipalities. The early detection by HHC examination is important to stop transmission and also to detect the cases in a less severe state.

Relation between the production of the phoneme /s/ in complex onset and the stomatognathic system in preschool children / Relação entre a produção do fonema /s/ em onset complexo e o sistema estomatognático em pré-escolares

This workverified the relation between the production of the phoneme /s/ in complex onset with the structure, the tone and the mobility of the stomatognathic system in preschool children. The study consisted of 73 preschool children of both sexes, aged between 5 years and 1 month and 5 years and 11 months divided into two groups, GC consisting of 36 children with a complete phonetic and phonological inventory and GCI by 37 Children who had not only acquired the phoneme /s/ in complex onset. Data collection was performed using the Orofacial Myofunctional Evaluation - MBGR protocol. The data were tabulated and submitted to the Chi-Square exact test and Fisher's exact test, considering p≤0.05. About the stomatognathic system, we observed a difference between the groups only in the task oftongue vibration. No significant difference for tonicity of the lips, tongue and cheeks and mobility of phonoarticulatory organs. We're not identified difference comparing the results with the sex of the participants. Children who did not produce the phoneme /s/ in complex onset presented greater difficulty in performing tongue vibration.

Este estudo objetivou verificar a relação entre a produção do fonema /s/ em onset complexo com a estrutura, o tônus e a mobilidade do sistema estomatognático em pré-escolares. Participaram do estudo 73 pré-escolares, de ambos os sexos, com idades entre 5 anos e 1 mês e 5 anos e 11 meses divididos em dois grupos, sendo grupo controle constituído por 36 crianças com inventário fonético e fonológico completo e o estudo por 37 crianças que não haviam adquirido apenas o fonema /s/ em onset complexo. Para a avaliação miofuncional orofacial foi utilizado o protocolo MBGR. Os dados foram tabulados e submetidos ao teste exato de Fisher e Mann Whitney, considerando-se p≤0,05. Com relação ao sistema estomatognático, observou-se diferença entre os grupos apenas na tarefa de vibração de língua. Não foram identificadas associações significativas ao se comparar os resultados com a tonicidade dos lábios, língua e bochechas e demais movimentos solicitados dos órgãos fonoarticulatórios. Não foram identificadas diferenças entre o sexo e os resultados encontrados. Assim, as crianças que não produziram o fonema /s/ em onset complexo apresentaram maior dificuldade em realizar vibração de língua.

Mycobacterium leprae Recombinant Antigen Induces High Expression of Multifunction T Lymphocytes and Is Promising as a Specific Vaccine for Leprosy.

Leprosy is a chronic disease caused by M. leprae infection that can cause severe neurological complications and physical disabilities. A leprosy-specific vaccine would be an important component within control programs but is still lacking. Given that multifunctional CD4 T cells [i.e., those capable of simultaneously secreting combinations of interferon (IFN)-γ, interleukin (IL)-2, and tumor necrosis factor (TNF)] have now been implicated in the protective response to several infections, we tested the hypothesis if a recombinant M. leprae antigen-specific multifunctional T cells differed between leprosy patients and their healthy contacts. We used whole blood assays and peripheral blood mononuclear cells to characterize the antigen-specific T cell responses of 39 paucibacillary (PB) and 17 multibacillary (MB) leprosy patients and 31 healthy household contacts (HHC). Cells were incubated with either crude mycobacterial extracts (M. leprae cell sonicate-MLCS) and purified protein derivative (PPD) or recombinant ML2028 protein, the homolog of M. tuberculosis Ag85B. Multiplex assay revealed antigen-specific production of IFN-γ and IL-2 from cells of HHC and PB, confirming a Th1 bias within these individuals. Multiparameter flow cytometry then revealed that the population of multifunctional ML2028-specific T cells observed in HHC was larger than that observed in PB patients. Taken together, our data suggest that these multifunctional antigen-specific T cells provide a more effective response against M. leprae infection that prevents the development of leprosy. These data further our understanding of M. leprae infection/leprosy and are instructive for vaccine development.

Desenvolvimento neuropsicomotor e das habilidades auditivas em pré-escolares / Neuropsychomotor development and auditory skills in preschool children

INTRODUCTION: Neuropsychomotor development and auditory abilities, influenced by biological and environmental factors, are directly related to school performance. In this way, a screening test in school environment allows the prior identification of change in development, reducing the losses in child life. OBJECTIVE: To characterize the relationship between neuropsychomotor development and auditory processing skills in preschool children. METHODS: 108 preschool children from three public institutions with ages between four years and one month to five years and eleven months, of both sexes were screened. It was performed the screening of Central Auditory Processing (CAP) through the simplified evaluation of auditory processing and the neurodevelopment using the Developmental Screening Test II Denver. The data were analyzed by chi-square tests and bivariate correlation with Pearson coefficient, adopting a significance level of 5% and alpha of 0.1. RESULTS: The screening of the CAP, 100% of the subjects showed normal responses in the test detection, 81.5% in sound localization, 49% in the test of non-verbal sequential memory and 58.3% in the test of verbal sequential memory. In the neuropsychomotor development screening, the frequency of appropriate responses to the chronological age was significant in all areas, being 86.1% (93) in personal social area, 92.5% (100) in the adaptive fine motor, 87 % (94) in language and 92.5% (100) in gross motor. It was found a significant relationship only between the language alterations and proofs of sequential memory (p <0.05). CONCLUSION: It was found that the group studied was relationship between the language alterations and alterations in the temporal ordering skills of the central auditory processing.

INTRODUÇÃO: O desenvolvimento neuropsicomotor e das habilidades auditivas, influenciados tanto por fatores biológicos como ambientais, tem relação direta com o desempenho escolar. Dessa forma, a realização de triagens em ambiente escolar possibilita a identificação precoce de alterações nesse desenvolvimento reduzindo assim, os prejuízos na vida dessas crianças. OBJETIVO: Caracterizar a relação entre o desenvolvimento neuropsicomotor e as habilidades do processamento auditivo em pré-escolares. MÉTODO: Foram realizados em 108 pré-escolares de três instituições públicas, com idades entre quatro anos e um mês e cinco anos e 11 meses, de ambos os sexos. Foram realizadas teste de reatreio do processamento auditivo central (PAC) por meio da avaliação simplificada do processamento auditivo (ASPA) e do desenvolvimento neuropsicomotor utilizando o Teste de Triagem de Desenvolvimento Denver II. Os dados foram analisados pelos Testes Qui-quadrado e Correlação Bivariada com coeficiente Pearson, adotando-se significância de 5% e alfa de 0,1. RESULTADOS: No rastreamento do PAC, 100% dos sujeitos apresentaram respostas normais na prova de detecção, 81,5% na de localização sonora, 49% na prova de memória sequencial não verbal e 58,3% na prova de memória sequencial verbal. Na triagem do desenvolvimento neuropsicomotor, a frequência de respostas adequadas à idade cronológica foi significativa em todas as áreas, sendo de 86,1% (93) na área pessoal social, 92,5% (100) no motor fino adaptativo, 87% (94) na linguagem e 92,5% (100) no motor grosseiro. Constatou-se relação significativa apenas entre as alterações de linguagem e as provas de memória sequencial (p<0,05). CONCLUSÃO: Houve relação entre as alterações de linguagem e as alterações nas habilidades de ordenação temporal do processamento auditivo central.

Anti-obesogenic effects of WY14643 (PPAR-alpha agonist): Hepatic mitochondrial enhancement and suppressed lipogenic pathway in diet-induced obese mice.

Non-alcoholic fatty liver disease (NAFLD) presents with growing prevalence worldwide, though its pharmacological treatment remains to be established. This study aimed to evaluate the effects of a PPAR-alpha agonist on liver tissue structure, ultrastructure, and metabolism, focusing on gene and protein expression of de novo lipogenesis and gluconeogenesis pathways, in diet-induced obese mice. Male C57BL/6 mice (three months old) received a control diet (C, 10% of lipids, n = 10) or a high-fat diet (HFD, 50% of lipids, n = 10) for ten weeks. These groups were subdivided to receive the treatment (n = 5 per group): C, C-alpha (PPAR-alpha agonist, 2.5 mg/kg/day mixed in the control diet), HFD and HFD-alpha group (PPAR-alpha agonist, 2.5 mg/kg/day mixed in the HFD). The effects were compared with biometrical, biochemical, molecular biology and transmission electron microscopy (TEM) analyses. HFD showed greater body mass (BM) and insulinemia than C, both of which were tackled by the treatment in the HFD-alpha group. Increased hepatic protein expression of glucose-6-phosphatase, CHREBP and gene expression of PEPCK in HFD points to increased gluconeogenesis. Treatment rescued these parameters in the HFD-alpha group, eliciting a reduced hepatic glucose output, confirmed by the smaller GLUT2 expression in HFD-alpha than in HFD. Conversely, favored de novo lipogenesis was found in the HFD group by the increased expression of PPAR-gamma, and its target gene SREBP-1, FAS and GK when compared to C. The treatment yielded a marked reduction in the expression of all lipogenic factors. TEM analyses showed a greater numerical density of mitochondria per area of tissue in treated than in untreated groups, suggesting an increase in beta-oxidation and the consequent NAFLD control. PPAR-alpha activation reduced BM and treated insulin resistance (IR) and NAFLD by increasing the number of mitochondria and reducing hepatic gluconeogenesis and de novo lipogenesis protein and gene expressions in a murine obesity model.

Spatial analysis of viral hepatitis and schistosomiasis coinfection in an endemic area in Northeastern Brazil.

INTRODUCTION:: This cross-sectional study analyzed the spatial distribution of hepatitis B or C virus (HBV/HBC) and schistosomiasis coinfection. METHODS:: Serum samples were collected from patients with Schistosoma mansoni infection. These were tested for serological markers of HBV/HCV infection. The spatial distribution of coinfection was analyzed using intensity kernel estimation. RESULTS:: Overall, 9.4% of individuals had contact with HBV and 1.7% of samples tested positive for anti-HCV antibodies. We identified clusters of risk located in the central region. CONCLUSIONS:: Spatial analysis allowed visualization of high-risk areas, leading to a definition of priority areas to be targeted for intensification of control interventions.

Spatial analysis of viral hepatitis and schistosomiasis coinfection in an endemic area in Northeastern Brazil

Abstract INTRODUCTION: This cross-sectional study analyzed the spatial distribution of hepatitis B or C virus (HBV/HBC) and schistosomiasis coinfection. METHODS: Serum samples were collected from patients with Schistosoma mansoni infection. These were tested for serological markers of HBV/HCV infection. The spatial distribution of coinfection was analyzed using intensity kernel estimation. RESULTS: Overall, 9.4% of individuals had contact with HBV and 1.7% of samples tested positive for anti-HCV antibodies. We identified clusters of risk located in the central region. CONCLUSIONS: Spatial analysis allowed visualization of high-risk areas, leading to a definition of priority areas to be targeted for intensification of control interventions.

Leishmania donovani Nucleoside Hydrolase (NH36) Domains Induce T-Cell Cytokine Responses in Human Visceral Leishmaniasis.

Development of immunoprotection against visceral leishmaniasis (VL) focused on the identification of antigens capable of inducing a Th1 immune response. Alternatively, antigens targeting the CD8 and T-regulatory responses are also relevant in VL pathogenesis and worthy of being included in a preventive human vaccine. We assessed in active and cured patients and VL asymptomatic subjects the clinical signs and cytokine responses to the Leishmania donovani nucleoside hydrolase NH36 antigen and its N-(F1), central (F2) and C-terminal (F3) domains. As markers of VL resistance, the F2 induced the highest levels of IFN-γ, IL-1ß, and TNF-α and, together with F1, the strongest secretion of IL-17, IL-6, and IL-10 in DTH+ and cured subjects. F2 also promoted the highest frequencies of CD3+CD4+IL-2+TNF-α-IFN-γ-, CD3+CD4+IL-2+TNF-α+IFN-γ-, CD3+CD4+IL-2+TNF-α-IFN-γ+, and CD3+CD4+IL-2+TNF-α+IFN-γ+ T cells in cured and asymptomatic subjects. Consistent with this, the IFN-γ increase was correlated with decreased spleen (R = -0.428, P = 0.05) and liver sizes (R = -0.428, P = 0.05) and with increased hematocrit counts (R = 0.532, P = 0.015) in response to F1 domain, and with increased hematocrit (R = 0.512, P 0.02) and hemoglobin counts (R = 0.434, P = 0.05) in response to F2. Additionally, IL-17 increases were associated with decreased spleen and liver sizes in response to F1 (R = -0.595, P = 0.005) and F2 (R = -0.462, P = 0.04). Conversely, F1 and F3 increased the CD3+CD8+IL-2+TNF-α-IFN-γ-, CD3+CD8+IL-2+TNF-α+IFN-γ-, and CD3+CD8+IL-2+TNF-α+IFN-γ+ T cell frequencies of VL patients correlated with increased spleen and liver sizes and decreased hemoglobin and hematocrit values. Therefore, cure and acquired resistance to VL correlate with the CD4+-Th1 and Th-17 T-cell responses to F2 and F1 domains. Clinical VL outcomes, by contrast, correlate with CD8+ T-cell responses against F3 and F1, potentially involved in control of the early infection. The in silico-predicted NH36 epitopes are conserved and bind to many HL-DR and HLA and B allotypes. No human vaccine against Leishmania is available thus far. In this investigation, we identified the NH36 domains and epitopes that induce CD4+ and CD8+ T cell responses, which could be used to potentiate a human universal T-epitope vaccine against leishmaniasis.

RIPK1 and PGAM5 Control Leishmania Replication through Distinct Mechanisms.

Leishmaniasis is an important parasitic disease found in the tropics and subtropics. Cutaneous and visceral leishmaniasis affect an estimated 1.5 million people worldwide. Despite its human health relevance, relatively little is known about the cell death pathways that control Leishmania replication in the host. Necroptosis is a recently identified form of cell death with potent antiviral effects. Receptor interacting protein kinase 1 (RIPK1) is a critical kinase that mediates necroptosis downstream of death receptors and TLRs. Heme, a product of hemoglobin catabolism during certain intracellular pathogen infections, is also a potent inducer of macrophage necroptosis. We found that human visceral leishmaniasis patients exhibit elevated serum levels of heme. Therefore, we examined the impact of heme and necroptosis on Leishmania replication. Indeed, heme potently inhibited Leishmania replication in bone marrow-derived macrophages. Moreover, we found that inhibition of RIPK1 kinase activity also enhanced parasite replication in the absence of heme. We further found that the mitochondrial phosphatase phosphoglycerate mutase family member 5 (PGAM5), a putative downstream effector of RIPK1, was also required for inhibition of Leishmania replication. In mouse infection, both PGAM5 and RIPK1 kinase activity are required for IL-1ß expression in response to Leishmania However, PGAM5, but not RIPK1 kinase activity, was directly responsible for Leishmania-induced IL-1ß secretion and NO production in bone marrow-derived macrophages. Collectively, these results revealed that RIPK1 and PGAM5 function independently to exert optimal control of Leishmania replication in the host.