Leishmaniose visceral e susceptibilidade genética

Visceral leishmaniasis is a serious infectious disease caused by an obligate intracellular protozoan of the genus Leishmania. The disease encompasses a wide spectrum of clinical manifestations, which can range from asymptomatic cases, to the classical form of the disease characterized by hepatosplenomegaly, fever and wasting, and even the more severe bleeding that can progress to death. Some factors can alter the severity of clinical manifestations, among them the genetic predisposition. Through research of genetic polymorphism it is possible to evaluate which genes may be related to susceptibility to infection and predisposition to the most severe forms of the diseaseA leishmaniose visceral é uma grave doença infecciosa causada por um protozoário intracelular obrigatório do gênero Leishmania. A doença abrange um grande espectro de manifestações clínicas que podem variar desde infecções assintomáticas, passando pela forma clássica da doença caracterizada por hepatoesplenomegalia, febre e caquexia, chegando até formas mais graves com sangramentos que podem evoluir para a morte. Alguns fatores podem alterar a gravidade das manifestações clínicas, sendo um deles a predisposição genética. Por meio da pesquisa de polimorfismos genéticos é possível avaliar quais os genes que podem estar relacionados com a susceptibilidade à infecção e com a predisposição às formas mais graves da doenç

Similarities and differences in RANTES and (AOP)-RANTES-triggered signals : implications for chemotaxis

11 páginas, 8 figuras.Chemokines are a family of proinflammatory cytokines that attract and activate specific types of leukocytes. Chemokines mediate their effects via interaction with seven transmembrane G proteinÐcoupled receptors (GPCR). Using CCR5-transfected HEK-293 cells, we show that both the CCR5 ligand, RANTES, as well as its derivative, aminooxypentane (AOP)-RANTES, trigger immediate responses such as Ca2+ influx, receptor dimerization, tyrosine phosphorylation,and Gai as well as JAK/STAT association to the receptor. In contrast to RANTES, (AOP)-RANTES is unable to trigger late responses, as measured by the association of focal adhesion kinase (FAK) to the chemokine receptor complex, impaired cell polarization required for migration, or chemotaxis. The results are discussed in the context of the dissociation of the late signals, provoked by the chemokines required for cell migration, from early signals.Peer reviewe

Disease Tolerance and Pathogen Resistance Genes May Underlie Trypanosoma cruzi Persistence and Differential Progression to Chagas Disease Cardiomyopathy

Chagas disease is caused by infection with the protozoan Trypanosoma cruzi and affects over 8 million people worldwide. In spite of a powerful innate and adaptive immune response in acute infection, the parasite evades eradication, leading to a chronic persistent infection with low parasitism. Chronically infected subjects display differential patterns of disease progression. While 30% develop chronic Chagas disease cardiomyopathy (CCC)—a severe inflammatory dilated cardiomyopathy—decades after infection, 60% of the patients remain disease-free, in the asymptomatic/indeterminate (ASY) form, and 10% develop gastrointestinal disease. Infection of genetically deficient mice provided a map of genes relevant for resistance to T. cruzi infection, leading to the identification of multiple genes linked to survival to infection. These include pathogen resistance genes (PRG) needed for intracellular parasite destruction, and genes involved in disease tolerance (protection against tissue damage and acute phase death—DTG). All identified DTGs were found to directly or indirectly inhibit IFN-γ production or Th1 differentiation. We hypothesize that the absolute need for DTG to control potentially lethal IFN-γ PRG activity leads to T. cruzi persistence and establishment of chronic infection. IFN-γ production is higher in CCC than ASY patients, and is the most highly expressed cytokine in CCC hearts. Key DTGs that downmodulate IFN-γ, like IL-10, and Ebi3/IL27p28, are higher in ASY patients. Polymorphisms in PRG and DTG are associated with differential disease progression. We thus hypothesize that ASY patients are disease tolerant, while an imbalance of DTG and IFN-γ PRG activity leads to the inflammatory heart damage of CCC

Reflexões sobre o crescente número de cesáreas no Brasil: um chamado à consciência

INTRODUÇÃO: A incidência de cesarianas tem aumentado ao longo das décadas em escala global, e no Brasil, esse índice atingiu uma marca significativa de 56% -  colocando-o substancialmente acima da média observada em nações em desenvolvimento. METODOLOGIA: Revisão narrativa da literatura realizada a partir da busca bibliográfica na base de dados PubMed, com os descritores “Cesarean”, “Prenatal care”, “Childbirth”. RESULTADOS: Os estudos pesquisados foram publicados em periódicos internacionais, sendo selecionados artigos de revisão, revisão sistemática e metanálise. DISCUSSÃO: No contexto obstétrico nacional, a tendência de aumento nas taxas de cesáreas começou a se manifestar em 2017 e foi exacerbada pela pandemia. Apesar dos esforços para reorganizar a rede de assistência pré-natal durante o período pandêmico, especialmente para pacientes com risco obstétrico, na prática, esses esforços foram limitados. Consequentemente, observou-se um influxo de gestantes em estágios avançados de complicações obstétricas nas unidades de maternidade, muitas das quais necessitando de cesariana para mitigar desfechos materno-perinatais desfavoráveis. CONCLUSÃO: Em conclusão, o aumento nas taxas de cesáreas no Brasil, que já vinha sendo observado há quase uma década e foi intensificado durante a pandemia, destaca a necessidade urgente de políticas e práticas que promovam uma abordagem mais equilibrada e baseada em evidências na assistência obstétrica

Preoperative psychological profile of women with increased risk of breast cancer

Aim: analyze depressive and anxiety symptomatology, body image and quality of life in a group of women with genetic vulnerability to breast cancer who were going to undergo a riskreducing mastectomy. Method:184 women participated in this study, all of whom had an increased risk of breast cancer, either because they were BRCA1/2 mutation carriers or because they had several affected relatives. The psychological instruments used were: Hospital Anxiety and Depression Scale, Body Image Scale, European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 and BR23. Results: The results of this study showed that the participants presented clinical anxiety symptomatology and subclinical depressive symptomatology. However, all the sample were at normative levels in body image and quality of life. Participants with previous diagnosis of cancer showed, higher dissatisfaction with their body image, lower levels on the scales of physical, and cognitive and global functioning on quality of life, as well as higher fatigue, more general pain also in the breast and in the arm compared to women without diagnosis. Conclusions: BRCA1/2 non-mutation carriers showed more symptomatology in the breast and in the arm fatigue than BRCA1/2 mutation carriers. BRCA1/2 mutation carriers had more economic difficulties than non-carriers. It is highly recommended a psychological intervention before a risk-reducing surgery.Objetivo: analizar los niveles de sintomatología ansiosa y depresiva, imagen corporal y calidad de vida en un grupo de mujeres con vulnerabilidad genética de cáncer de mama que se iban a someter a una mastectomía reductora de riesgo. Método: 184 mujeres participaron en este estudio, todas ellas tenían riesgo aumentado de cáncer de mama, bien por ser portadoras de una mutación BRCA1/2 o por agregación familiar. Los instrumentos utilizados fueron: Escala de Ansiedad y Depresión Hospitalaria, Escala de Imagen Corporal, European Organisation for Research and Treatment of Cancer calidad de vida oncológica C30 y BR23. Resultados: Los resultados de este estudio mostraron que las participantes presentaban niveles clínicos en sintomatología ansiosa y subclínicos en sintomatología depresiva. Sin embargo, se encontraban en niveles normativos en imagen corporal y calidad de vida. Las participantes con antecedentes oncológicos manifestaban, mayor insatisfacción con la imagen corporal, niveles inferiores en las escalas de funcionamiento físico, cognitivo y global de la calidad de vida, así como mayor fatiga, dolor general, en el brazo y en la mama en comparación con las mujeres sin diagnósticos previos. Conclusiones: Las mujeres sin mutación poseían mayor sintomatología en la mama y en el brazo que las mujeres con mutación, las cuales presentaban más dificultades económicas que las mujeres no portadoras. Evidenciando la necesidad de realizar una intervención psicológica antes de la cirugía especialmente en este colectivo

Efeito da acupuntura na variabilidade da frequência cardíaca em indivíduos com esclerose múltipla: um protocolo para ensaio randomizado controlado duplo cego

Backgroung: the growing of patients with multiple sclerosis seeking acupuncture treatment is based on clinical reports of improvements in symptoms. Considering that autonomic impairment, including cardiovascular autonomic dysfunction, is not uncommon in patients with MS, neuromodulation with acupuncture could be an interesting tool to change heart rate variability in this population. Objective: to evaluate heart rate variability in patients with multiple sclerosis, during the application of acupuncture, in order to analyze the behavior of the autonomic nervous system before, during and after therapy and changes in condition after a longitudinal intervention. Methods: a double-blinded randomized sham-controlled crossover trial with a 1:1 allocation ratio will be conducted, with 40 individuals without a previous illness, who will constitute the control group, and 40 individuals with Multiple Sclerosis, who will constitute the experimental group, paired by age and sex. All participants will undertake active or sham acupuncture sessions. Discussion: according to the studies found, cardiovascular autonomic dysfunction is expected, with alterations in heart rate variability. Although neuromodulation with acupuncture can control pain and inflammation, there are still difficulties in affirming whether the balance between the sympathetic and parasympathetic systems can be changed by acupuncture. Trial registration: We registered this trial on ClinicalTrials.gov, ID: NCT05523466Introdução: o crescimento de pacientes com esclerose múltipla que procuram tratamento com acupuntura é baseado em relatos clínicos de melhora dos sintomas. Considerando que o comprometimento autonômico, incluindo a disfunção autonômica cardiovascular, não é incomum em pacientes com EM a neuromodulação com acupuntura pode ser uma ferramenta interessante para alterar a variabilidade da frequência cardíaca nessa população. Objetivo: avaliar a variabilidade da frequência cardíaca em pacientes com esclerose múltipla, durante a aplicação da Acupuntura, a fim de analisar o comportamento do sistema nervoso autônomo antes, durante e após a terapia e as mudanças na condição após uma intervenção longitudinal. Métodos: será realizado um ensaio clínico cruzado, randomizado, placebo-controlado, duplo-cego, com proporção de alocação de 1:1, com 40 indivíduos sem doença prévia, que constituirão o grupo controle, e 40 indivíduos com Esclerose Múltipla, que constituirão o grupo experimental. grupo, pareado por idade e sexo. Todos os participantes realizarão sessões de acupuntura ativas ou simuladas. Discussão: de acordo com os estudos encontrados, é esperada disfunção autonômica cardiovascular, com alterações na variabilidade da frequência cardíaca. Embora a neuromodulação com acupuntura possa controlar a dor e a inflamação, ainda há dificuldades em afirmar se o equilíbrio entre os sistemas simpático e parassimpático pode ser alterado pela acupuntura. Registro do estudo: registramos este estudo em ClinicalTrials.gov, ID: NCT0552346

Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways

Abstract\ud \ud Background\ud Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. The others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Migration of Th1-type T cells play a major role in myocardial damage.\ud \ud \ud Methods\ud Our genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects.\ud \ud \ud Results\ud The CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%.\ud \ud \ud Conclusions\ud Our data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets.FAPES

Elimination of Isoxazolyl-Penicillins antibiotics in waters by the ligninolytic native Colombian strain Leptosphaerulina sp. considerations on biodegradation process and antimicrobial activity removal

In this work, Leptosphaerulina sp. (a Colombian native fungus) significantly removed three Isoxazolyl-Penicillin antibiotics (IP): oxacillin (OXA, 16000 µg L-1), cloxacillin (CLX, 17500 µg L-1) and dicloxacillin (DCX, 19000 µg L-1) from water. The biological treatment was performed at pH 5.6, 28 °C, and 160 rpm for 15 days. The biotransformation proccess and lack of toxicity of the final solutions (antibacterial activity (AA) and cytotoxicity) were tested. The role of enzymes in IP removal was analysed through in vitro studies with enzymatic extracts (crude and pre-purified) from Leptosphaerulina sp., commercial enzymes and enzymatic inhibitors. Futhermore, the applicabililty of mycoremediation process to a complex matrix (simulated hospital wastewater) was evaluated. IP were considerably abated by the fungus, OXA was the fastest degraded (day 6), followed by CLX (day 7) and DCX (day 8). Antibiotics biodegradation was associated to laccase and versatile peroxidase action. Assays using commercial enzymes (i.e. laccase from Trametes versicolor and horseradish peroxidase) and inhibitors (EDTA, NaCl, sodium acetate, manganese (II) ions) confirmed the significant role of enzymatic transformation. Whereas, biomass sorption was not an important process in the antibiotics elimination. Evaluation of AA against Staphylococcus aureus ATCC 6538 revealed that Leptosphaerulina sp. also eliminated the AA. In addition, the cytotoxicity assay (MTT) on the HepG2 cell line demonstrated that the IP final solutions were non-toxic. Finally, Leptosphaerulina sp. eliminated OXA and its AA from synthetic hospital wastewater at 6 days. All these results evidenced the potential of Leptosphaerulina sp. mycoremediation as a novel environmentally friendly process for the removal of IP from aqueous systems

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery