Hereditary coagulation factor XI deficiency: a rare or neglected disease? Results from a retrospective, single-centre cohort in northern Italy.

To examine real-life clinical data regarding hereditary factor XI (FXI) deficiency from a secondary care centre. Retrospective review of clinical records for every FXI:C 0.7 IU/ml or less reported from 2012 to 2020. Seventy-nine patients were included. Six (7.6%) had a severe deficiency (FXI:C <0.2 IU/ml). Only 55 (69.6%) patients were referred to the Haemostasis Centre. Among them, six (15%) were subsequently not identified at increased haemorrhagic risk before a surgical/obstetrical procedure. Thirty-three (41.8%) experienced at least one bleeding event, minor (25 patients) and/or major (16 patients). Minor bleedings were predominantly spontaneous and more frequent in women, major events were mainly provoked. No correlation was found between FXI:C and risk of bleeding ( P  = 0.9153). Lower FXI:C, but not a positive bleeding history, was related with higher likelihood of being referred to the Haemostasis Centre ( P  = 0.0333). Hereditary FXI deficiency prevalence is likely underestimated, real-life clinical practices outside reference centres could be suboptimal.

Comprometimento da saúde no pós-alta de pacientes tratados por hanseníase e fatores relacionados: revisão de escopo / Post-discharge health impairment of patients treated for leprosy and related factors: scope review / Deterioro de la salud tras el alta en pacientes tratados por lepra y factores re-lacionados: una revisión general

Objetivo: mapear evidências na literatura científica sobre o comprometimento de saúde no pós-alta de pacientes tratados por Hanseníase e fatores relacionados. Materiais e Método: revisão de escopo realizada a partir das bases de dados CINAHL, LILACS, MEDLINE, PUBMED, SCOPUS e Web of Science em março de 2021, norteados pela estratégia mnemônica que auxilia na identificação do Problema, Conceito e Contexto propostos pelo Instituto Joanna Briggs, sistematizados por meio do fluxograma PRISMA-ScR e registrados na Open Science Framework (osf.io/vmdc6). Foram incluídos estudos sobre a temática publicados até fevereiro de 2021 no cenário nacional e internacional. Resultados: dos dez artigos incluídos na amostra final, nove evidenciaram algum grau de comprometimento funcional, demonstrando fragilidades no acompanhamento desde o diagnóstico até o período pós-alta. Conclusões: evidencia-se acometimentos com maior frequência sobretudo de ordem física, que impactam diretamente a funcionalidade nas atividades de vida diária e social dessas pessoas. As fragilidades no monitoramento pós-alta foram relacionadas ao déficit de profissionais capacitados, ao desconhecimento de técnicas de avaliação e classificação do grau de incapacidade, à carência na oferta de educação em saúde, à dificuldade de acesso aos serviços de saúde, ao atraso no tratamento dos episódios reacionais e reabilitação biopsicossocial e à ausência da sistematização do cuidado.(AU)

Objective: to map evidence in the scientific literature on the post-discharge health impairment of patients treated for leprosy and related factors. Materials and Method: scope review carried out from the CINAHL, LILACS, MEDLINE, PUBMED, SCOPUS and Web of Science databases in March 2021, guided by the mnemonic strategy that helps to identify the Problem, Concept and Context proposed by the Joanna Institute Briggs, systematized through the PRISMA-ScR flowchart, and registered in the Open Science Framework (osf.io/vmdc6). Studies on the subject published until February 2021 in the national and international scenario were included. Results: of the ten articles included in the final sample, nine showed some degree of functional impairment, demonstrating weaknesses in follow-up from diagnosis to the post-discharge period. Conclusions: there is evidence of more frequent involvement, especially of a physical nature, which directly impact the functionality of these people's daily and social activities. Weaknesses in post-discharge monitoring were related to the lack of trained professionals, lack of knowledge of assessment techniques and classification of the degree of disability, lack of health education provision, difficulty in accessing health services, delay in treatment of reactional episodes and biopsychosocial rehabilitation and the absence of systematization of care.(AU)

Objetivo: mapear en la literatura científica las evidencias sobre el deterioro de la salud post-alta en pacientes tratados por lepra y factores relacionados. Materiales y Métodos: revisión de alcance realizada a partir de las bases de datos CINAHL, LILACS, MEDLINE, PUBMED, SCOPUS y Web of Science en marzo de 2021, guiada por la estrategia mnemotécnica que ayu-da a identificar el Problema, Concepto y Contexto propuesta por el Instituto Joanna Briggs, sistematizada a través del flujograma PRISMA-ScR y registrada en el Open Science Framework (osf.io/vmdc6). Fueron incluidos estudios sobre el tema, publicados hasta febrero de 2021, en el escenario nacional e internacional. Resultados: de los diez artículos incluidos en la muestra final, nueve mostraron algún grado de deterioro funcional, demostrando debilidades en el seguimiento desde el diagnóstico hasta el período posterior al alta. Conclusiones: se evidencia con mayor frecuencia ataques sobre todo de orden físico que impactan directamente en la funcionalidad en las actividades de la vida diaria y social de las personas. Fragilidades en el seguimiento postoperatorio relacionadas con el déficit de profesionales capacitados, el desco-nocimiento de las técnicas de evaluación y clasificación del grado de incapacidad, la carencia en la oferta de educación en salud, la dificultad de acceso a los servicios de salud, el retraso en el tratamiento de los episodios reaccionarios y la rehabilitación biopsicosocial y la ausencia de...(AU)

Perceived water-related risk factors of Buruli ulcer in two villages of south-central Côte d'Ivoire.

BACKGROUND: Buruli ulcer, caused by Mycobacterium ulcerans, is a neglected tropical skin disease that is primarily endemic in West and Central Africa, including Côte d'Ivoire. Studies indicate that M. ulcerans infections are caused by contact with an environmental reservoir of the bacteria, governed by specific human biological conditions. Yet, the nature of this reservoir and the exact mode of transmission remain unknown. METHODOLOGY: To identify ecologic risk factors of Buruli ulcer in south-central Côte d'Ivoire, we pursued a qualitative study matched with geo-referencing inquiry. Embedded in a broader integrated wound management research project, we (i) mapped households and water sources of laboratory confirmed Buruli ulcer cases and (ii) interviewed 12 patients and four health care workers to assess exposure to surface water and to deepen the understanding of perceived transmission pathways. PRINCIPAL FINDINGS: Water availability, accessibility, and affordability were reported as key determinants for choosing water resources. Furthermore, perceived risks were related to environmental, structural, and individual factors. Despite the presence of improved water sources (e.g., drilled wells), communities heavily relied on unprotected surface water for a multitude of activities. The nearby Bandama River and seasonal waterbodies were frequently used for washing, bathing, and collection of water for drinking and cooking. Many residents also reported to cross the river on a daily basis for agricultural chores, and hence, are exposed to stagnant water during farming activities. CONCLUSIONS/SIGNIFICANCE: Our study in two Buruli ulcer endemic villages in south-central Côte d'Ivoire revealed a wide range of water-related domestic activities that might expose people to an increased risk of contracting the disease. Environmental, biological, social, and cultural risk factors are closely interlinked and should be considered in future investigations of Buruli ulcer transmission. Active participation of the communities is key to better understand their circumstances to advance research and fight against Buruli ulcer and other neglected tropical diseases.

Scurvy in children - A neglected disease?

BACKGROUND: The incidences of pediatric scurvy has decreased substantially, particularly in developed countries, but there are still reports of it from developing countries. Unusual manifestations have led to delays in diagnosis and treatment. Nevertheless, there are few publications regarding misdiagnosis of scurvy. The objective is to determine dietary factors, clinical manifestations, laboratory and radiologic findings, treatment, and outcomes of scurvy cases. The occurrence of misdiagnosis and its associated factors are also explored. METHOD: The medical records of 0-18 year-old children from 2003 to 2016, diagnosed with scurvy, were included and reviewed. Clinical data, and data regarding feeding history, nutritional status, laboratory and radiologic findings, and misdiagnosis were collected. Univariate and logistic regression analysis were used for identification of the independent associated factors. RESULTS: The study consisted of 106 children. The boys-to-girls ratio was 2.2:1, and their mean age was 44.65 months ± 30.50 months. The common manifestations were refusal to walk, tenderness, and swelling at the lower extremities. Four participants had unusual manifestations including proptosis and scalp hematoma. Low serum vitamin C level and abnormal radiologic findings were detected in most patients. All of them fully recovered after receiving vitamin C supplementation. Misdiagnosis was identified in 74 cases (69%). Logistic regression analysis revealed that temperature higher than or equal to 38 °C, participants aged 3 years or below, and swelling at lower extremities were independently associated with misdiagnosis (adjusted OR 5.91, 3.78, and 3.56 respectively). CONCLUSIONS: Scurvy still exists, and misdiagnosis often occurs. Taking a careful medical history and conducting a physical examination are still the best way to diagnose scurvy.

Noma, a neglected disease: prevention is better than cure.

PURPOSE OF REVIEW: There is a need for concerted effort to increase Global awareness about noma (cancrum oris). This paper aims to summarize the recent literature on noma and provide suggestions that could be implemented to raise awareness about this neglected disease. RECENT FINDINGS: Noma has been recognized, diagnosed and reported for centuries. Despite significant progress in scientific methods over time, the published literature on noma has predominantly been of low level clinical and scientific evidence. Recent studies have reported on noma's global distribution and its predisposing risk factors, its treatment, its knowledge and beliefs and has included a number of literature reviews. Noma cases are being reported from an increasingly diverse set of geographical locations. SUMMARY: Noma has largely been neglected in the research sphere. Noma is a preventable disease and its progression can be halted if patients are recognized and treated in the early stages of disease. Treatment for late stage noma survivors remains complex and time consuming, requiring substantial human and financial resources most commonly not achieving functional and cosmetic anatomy. The ultimate aim is therefore prevention, initiatives should be integrated into existing health programs.

Is noma a neglected/overlooked tropical disease?

Noma is a debilitating orofacial necrotizing bacterial disease that disproportionately affects impoverished malnourished persons, particularly young children, the vast majority of whom live in tropical and subtropical areas in sub-Saharan Africa. It has a very high mortality rate; causes significant physical and psychological morbidity, stigmatization and social discrimination; could be prevented, controlled and indeed eliminated by common public health interventions; and is overlooked with regard to public health awareness, in-depth scientific research activities and allocation of funding for prevention, treatment and research. According to the WHO, noma comprises five sequential 'stages': (1) necrotizing gingivitis, (2) edema, (3) gangrene, (4) scarring and (5) sequelae. This WHO staging of noma is contentious, leading to diagnostic confusion with misestimation of the number of noma cases reported in epidemiological studies. We therefore suggest a simpler, more practical and scientifically valid two-stage classification comprising only (1) acute noma and (2) arrested noma. Noma meets all the WHO criteria for classification as a neglected tropical disease (NTD). Most survivors of noma live with gross physical disfigurement and disability, and with impaired psychosocial functioning, so they are very often stigmatized and unjustifiably discriminated against. Owing to the paucity of evidence-based epidemiological data on noma, the relatively low number of people affected worldwide, and its apparently limited geographic distribution, noma does not yet feature on the WHO's list of NTDs, or on any global health agenda, and thus has not become a health priority for global action. We strongly support the inclusion of noma within the WHO list of NTDs. Without doubt this will increase the awareness of noma among healthcare providers and promote the systematic international accumulation and recording of data about noma.

Noma: A Neglected Area for Research.

Noma, a debilitating and destructive orofacial gangrene, remains endemic in the poor countries of sub-Saharan Africa and other noma hotbeds across the globe, mainly in countries characterized as underdeveloped economies with significant impoverished populations. Noma mostly affects children and infants. This is in spite of the universally held notion that noma is a preventable disease. Indeed, the current noma status quo has been cast as a human rights shortfall, since this devasting disease overwhelmingly affects children from poor countries. At the recently held Noma Research Day, a renewed call for the World Health Organization (WHO) to recognize and include noma as one of the neglected tropical diseases was accompanied by a recognition that research into all aspects of noma has waned or remained completely lacking-particularly that which addresses the basic science questions of the etiology, pathophysiology/pathobiology, and underlying mechanisms of the disease. Yet, a lack of incremental knowledge on the various aspects of noma continues to hamper our composite understanding of its biology. Without a fundamental understanding of the biology of noma, current preventive measures and treatment modalities will continue to fall short of the goals of prevention and eradication. This opinion piece draws renewed attention to the urgency of listing noma as a neglected tropical disease by the WHO. It also calls for major international research funding agencies, including the WHO and the National Institutes of Health, to renew their resolve to robustly fund structured, collaborative, and coordinated proposals that address questions on the epidemiology, etiology, pathophysiology/pathobiology, and molecular mechanisms of the disease. This is with a view to achieving more effective public health approaches toward prevention and to designing potential therapeutic regimens for early lesions. These steps are key to the ultimate eradication of noma.

Ocular leptospirosis: a review of current state of art of a neglected disease.

Introduction: Leptospirosis is a neglected and re-emerging zoonotic disease that may cause ocular involvement, uveitis being the main complication of the systemic disease. Aim: The purpose of this review was to raise awareness and update on uveitis caused by leptospirosis, which is a challenging pathology because it can mimic other types of uveitis. Materials and methods: An article review, was conducted by searching PubMed (MEDLINE), Scielo, Cochrane Library databases using the following MeSH and DeCS terms: "leptospirosis", "uveitis", "ocular", "eye" and "human". The inclusion criteria were articles between 2000 and 2021 in English, Spanish, French or Portuguese. Results and Discussion: A total of 49 articles were obtained with the mentioned inclusion criteria, and additionally 5 articles before the year 2000, which were considered due to their relevance and scarcity of articles on the pathology. Afterwards, a description of the disease was made. Conclusion: This literature review was steered to raise awareness and to apprise physicians and ophthalmologists about a pathology that is becoming increasingly relevant, but underdiagnosed, even in developed countries. Abbreviations: REU = recurrent equine uveitis, MAT = microagglutination.

Toxocariasis-associated urinary system diseases: a systematic review of reported cases.

BACKGROUND: Toxocariasis is a neglected tropical disease caused by Toxocara canis and Toxocara cati. Toxocara species can involve many organs, such as the brain, heart and lungs, however, the urinary system involvement of toxocariasis is largely unknown. METHODS: We performed a systematic review to identify cases infected with urinary tract toxocariasis. RESULTS: We identified seven cases that were eligible to be reviewed. Among the included citations, four studies reported bladder involvement and three reported kidney involvement. Fever, urinary, and abdominal presentations were amongst the most important clinical symptoms. Eosinophilic cystitis and nephrotic syndrome were the most common diagnoses.. The treatment regimen included a combination of anthelmintic drugs and steroids. CONCLUSIONS: In cases of urinary tract presentations accompanied by eosinophilia or histopathologic findings suggestive of parasitic infection, toxocariasis should be included in the list of differential diagnoses, especially in endemic areas.

Planejamento, síntese e avaliação biológica de candidatos a fármacos: busca de inibidores epigenéticos da Sirtuína 2 Sir2 / Design, synthesis and biological evaluation of drug candidates: search for Sirtuin 2 (Sir 2) epigenetic inhibitors

As doenças negligenciadas são causadas por agentes infecciosos e parasitários, como vírus, bactérias, protozoários e helmintos. Essas doenças são prevalentes em populações de baixa renda que vivem em países em desenvolvimento e são responsáveis por incapacitar e levar milhares de pessoas à morte. Este nome se dá pois, apesar de sua grande relevância médica, recebem pouca atenção dos governos e indústrias farmacêuticas. Dentre essas doenças podemos destacar a Doença de Chagas, doença infecciosa causada pelo parasita hemoflagelado Trypanosoma cruzi. Endêmica em 21 países, com 6 a 7 milhões de pessoas infectadas resultando em 7500 mortes por ano. A quimioterapia disponível contra essa parasitose é baseada em apenas dois medicamentos, o benznidazol e o nifurtimox, ativos principalmente na fase aguda da doença e com efeitos adversos graves que comprometem a adesão ao tratamento e, além disso, apesar dos enormes esforços na pesquisa de novos agentes antichagásicos em nível nacional e internacional, na maioria realizada academicamente, ainda não foram encontradas alternativas terapêuticas para a doença, persistindo, assim, a necessidade de descoberta e desenvolvimento de novos fármacos. O início de um planejamento de um novo fármaco se dá pela definição de um alvo bioquímico a ser utilizado na busca de moléculas que possam exercer a função de inibidores ou moduladores, conforme a atividade biológica desejada. Neste sentido, as sirtuínas 2 (Sir2) são enzimas que se mostraram essenciais para o crescimento in vitro do T. cruzi em suas formas amastigota e epimastigota. No caso de tripanossomatídeos, em geral, a superexpressão de Sir2 está relacionada à sobrevivência de formas amastigotas. Assim, essas evidências indicam que a Sir2 de tripanosomatídeos tem grande potencial como alvo biológico na busca e desenvolvimento de novos fármacos antichagásicos. O objetivo principal deste projeto foi identificar moléculas que apresentaram atividade inibitória para a sirtuína 2 de T. cruzi por meio da utilização da estratégia de Planejamento de Fármacos Baseada no Ligante - Ligand Based Drug Design (LBDD) e o desenvolvimento de análogos dos inibidores da Sir2. A modificação molecular está entre algumas das técnicas tradicionais usadas no desenvolvimento racional de um fármaco, e é usada principalmente no desenvolvimento de análogos, e busca melhorar as propriedades farmacocinéticas e/ou farmacodinâmicas de um protótipo, obter propriedades de interação semelhantes ao alvo e, em alguns casos, revelar uma atividade biológica. Com este intuito, análogos do sirtinol e da salermida foram sintetizados e uma nova rota sintética utilizando o microrreator em fluxo contínuo foi desenvolvida e apresentou rendimento superior quando comparado à síntese em bancada. A partir desta metodologia foram obtidos 20 compostos. Os ensaios in vitro contra formas amastigotas do T. cruzi indicaram que 8 compostos inibiram a atividade parasitária em mais de 50%, na dose de 10 µM, sendo que alguns destes apresentaram maior inibição parasitária quando comparados ao benznidazol, o fármaco de referência e único disponível no Brasil. Com estes resultados preliminares, novos ensaios estão sendo realizados para identificar potência e mecanismo de ação destes candidatos a agentes tripanomicidas

Neglected diseases are caused by infectious and parasitic agents such as viruses, bacteria, protozoa and helminths. These diseases are prevalent in low-income populations living in developing countries and are responsible for disabling and killing thousands of people. They get this name because, despite their great medical relevance, they end up receiving little attention from governments and pharmaceutical industries. Among these diseases, we can highlight Chagas disease, an infectious endemic disease caused by the hemoflagellate parasite Trypanosoma cruzi. This disease is endemic in 21 countries, with 6 to 7 million people infected resulting in 7,500 deaths per year. Chemotherapy is based on just two drugs, benznidazole and nifurtimox, which are mainly active in the acute phase of the disease. These drugs have adverse effects that compromise adherence, even more, considering that they are not effective from the point of view of the chronic phase of the disease. Despite the enormous efforts in researching new anti-chagasic agents at the national and international level, and mostly carried out academically, therapeutic alternatives for the disease have not yet been found, thus, the need for the discovery and development of new drugs persists. Sirtuins 2 (Sir2) are enzymes that have been shown to be essential for the in vitro growth of T. cruzi in its amastigote and epimastigote forms. In the case of trypanosomatids in general, Sir2 overexpression is related to the survival of amastigote forms. Sir2 inhibitors, such as sirtinol, have shown efficacy in leishmanicides. Thus, these evidences indicate that Sir2 from trypanosomatids can be considered as a biological target in the search and development of new anti-chagasic drugs. The beginning of a new drug planning study is the definition of a biochemical target to be used in the search for molecules that can play the role of inhibitors or modulators, according to the desired biological activity. The main objective of this project was to identify molecules that presented inhibitory activity to sirtuin 2 of T. cruzi using the Ligand Based Drug Design (LBDD) strategy of planning and the development of analogues of Sir2 inhibitors. Molecular modification is a traditional technique used in the rational development of a drug, as well as the use of natural products, combinatorial chemistry, high-throughput screening (HTS), among others. Mainly used in the development of analogues, molecular modification is applied for different purposes, among them, it seeks to improve the pharmacokinetic and/or pharmacodynamic properties of a prototype, obtain target-like interaction properties and, in some cases, reveal an activity biological. For this purpose, analogues of sirtinol and salermide were synthesized and a new synthetic route using the microreactor in continuous flow was developed and presented superior yield when compared to benchtop synthesis. From this methodology, 20 compounds were obtained. in vitro assays against amastigote forms of T. cruzi indicated that 8 compounds inhibited parasitic activity by more than 50% at a dose of 10 µM, and some of these showed greater parasitic inhibition when compared to benznidazole, the reference drug, and only available in Brazil. With these preliminary results, new assays are being carried out to identify the potency and mechanism of action of these candidate trypanocidal agents

Hippocampal Atrophy/Sclerosis Is Associated with Old, Calcified Parenchymal Brain Neurocysticercosis, But Not with More Recent, Viable Infections.

Magnetic resonance images from 197 patients with calcified neurocysticercosis (NCC), 38 with viable NCC and 197 NCC-free healthy rural villagers were evaluated to compare the frequency of hippocampal atrophy/sclerosis (HAS) across these populations. Scheltens' medial temporal atrophy scale was used for hippocampal rating. The median age of the 432 study participants was 46 years (interquartile range, 29-62 years), and 58% were women. Hippocampal atrophy/sclerosis was disclosed in 26.9% patients with calcified NCC, compared with 7.9% in patients with viable NCC and 8.1% in healthy rural villagers. After adjusting for age, gender, and history of epilepsy, hippocampal atrophy/sclerosis was more frequent in patients with calcified NCC than in those with viable cysts (RR, 3.60; 95% CI, 1.18- 0.99; P = 0.025) and healthy rural villagers (RR, 3.43; 95% CI, 1.94-6.06; P < 0.001), suggesting that hippocampal damage develops late in the course of this parasitic disease.

Case Report: Visceral Leishmaniasis and Hemophagocytic Lymphohistiocytosis: Three Clinical Cases, Three Different Patterns.

Visceral leishmaniasis (VL) is a neglected tropical disease with more than 30,000 cases annually reported worldwide. In Brazil, about 3,700 cases are annually reported. The VL clinical presentation is variable, from asymptomatic to severe cases with a high risk of death. We reported three cases of VL with clinical sign similarities but distinct development. All cases had bone marrow hemophagocytosis and hemophagocytic lymphohistiocytosis (HLH) criteria. HLH is a rare condition that may have secondary causes, including infectious and parasitic diseases, like VL. The delayed recognition of the secondary HLH (sHLH) association to VL may cause unfavorable outcomes and death.

Sleep disorders related to nutrition and digestive diseases: a neglected clinical condition.

Sleep disturbances often result from inappropriate lifestyles, incorrect dietary habits, and/or digestive diseases. This clinical condition, however, has not been sufficiently explored in this area. Several studies have linked the circadian timing system to the physiology of metabolism control mechanisms, energy balance regulation, and nutrition. Sleep disturbances supposedly trigger digestive disorders or conversely represent specific clinical manifestation of gastrointestinal (GI) diseases. Poor sleep may worsen the symptoms of GI disorders, affecting the quality of life. Conversely, short sleep may influence dietary choices, as well as meal timing, and the circadian system drives temporal changes in metabolic patterns. Emerging evidence suggests that patients with inappropriate dietary habits and chronic digestive disorders often sleep less and show lower sleep efficiency, compared with healthy individuals. Sleep disturbances may thus represent a primary symptom of digestive diseases. Further controlled trials are needed to fully understand the relationship between sleep disturbances, dietary habits, and GI disorders. It may be also anticipated that the evaluation of sleep quality may prove useful to drive positive interventions and improve the quality of life in a proportion of patients. This review summarizes data linking sleep disorders with diet and a series of disease including gastro-esophageal reflux disease, peptic disease, functional gastrointestinal disorders, inflammatory bowel diseases, gut microbiota alterations, liver and pancreatic diseases, and obesity. The evidence supporting the complex interplay between sleep dysfunction, nutrition, and digestive diseases is discussed.

Pró-Fármacos dendriméricos potencialmente ativos em Malária e Tuberculose: Síntese e avaliação da atividade biológica / Dendrimeric prodrugs potentially active in malaria and tuberculosis: Synthesis and evaluation of biological activity

HIV/AIDS, tuberculose, malária e as doenças tropicais negligenciadas representam uma grande preocupação em Saúde em muitas regiões do mundo. Os fármacos disponíveis para o tratamento apresentam diversos problemas, tais como toxicidade e resistência ao parasita. Mesmo com esse triste panorama, o investimento em pesquisa nessa área é, ainda, pouco significativo. Assim, dentre os métodos de modificação molecular para melhorar propriedades farmacêuticas, farmacocinéticas e/ou farmacodinâmica de compostos bioativos destaca-se a latenciação. Já os dendrímeros vêm despertando interesse em aplicações biológicas, principalmente como transportadores de fármacos, além de atuarem como transportadores de genes, imagem em diagnóstico e compostos com ação per se. Face ao exposto e tendo em vista o caráter promissor dos dendrímeros como sistemas de drug delivery, o objetivo deste trabalho foi a síntese de pró-fármacos dendriméricos potencialmente ativos em malária e tuberculose. Os dendrímeros de Bis-MPA (gerações 0, 1 e 2) foram sintetizados pelo grupo do Professor Scott Grayson, da Tulane University (EUA). No Brasil, foram feitas as funcionalizações destes compostos, através do acoplamento do ácido succínico (que funciona como espaçante) e as moléculas ativas. Selecionaram-se as seguintes substâncias: (1) primaquina, com ação antimalárica e (2) isoniazida, de ação nos primeiros estágios da tuberculose. Foram sintetizados os pró-fármacos dendriméricos de isoniazida nas gerações 0 e 1 (G0-Iso e G1-Iso), e primaquina nas gerações 0, 1 e 2 (G0-Pq, G1-Pq e G2Pq). Importante mencionar que os resultados de Ressonância Magnética e Nuclear de 1H e de 13C demostraram as obtenções dos respectivos produtos, porém contendo impurezas. Já a análise do resultado proveniente da espectrometria de massas do composto G0-Iso revelou a presença de um subproduto ciclizado da isonizaida succinoilada (CIso-Suc), o qual pode ser um potencial pró-fármaco ou apresentar atividade per se. Como não se conhece este composto, o laboratório coordenado pela Profas Elizabeth Igne Ferreira e Jeanine Giarolla manifestou interesse em pesquisa-lo, principalmente quanto suas propriedades físico- químicas, bem como quanto à atividade biológica. Assim, utilizando metodologia analítica previamente estabelecida para o G0-Iso, os estudos de estabilidade química da CIso-Suc, em diferentes valores de pH, demonstraram a capacidade da forma ciclizada em se converter no protótipo Iso-Suc, majoritariamente em pH 7,4 e 8,5. Como perspectivas, destaca-se a avaliação da estabilidade enzimática deste potencial derivado. Ressalta-se, ainda, a a avaliação da respectiva atividade antimicobacteriana. Em relação aos pró-fármacos, as necessidades de aprimoramentos das sínteses são, também, evidenciadas. Uma vez sintetizados e caracterizados, estes últimos derivados serão avaliados quanto à atividade biológica. Ademais, estudos computacionais, sobretudo simulações de docking molecular, foram desenvolvidos com intuito de se entender o modo de interação de alguns compostos com alvos biológicos pré-determinados

HIV/AIDS, tuberculosis, malaria and neglected diseases are a major health concern in many regions of the world. The drugs available present various problems, such as toxicity and parasite resistance. Even with this sad outlook, research investment in this area is still insignificant. Among the molecular modification methods to improve the pharmaceutical, pharmacokinetic and/or pharmacodynamic properties we stands out prodrug design. On the other hand, dendrimers are arousing interest in biological applications, mainly as drug carriers, besides gene delivery, diagnostic imaging, as well as acting as compounds with activity per se. Considering that, added to the promising dendrimer drug delivery features, the aim of this study was to synthesize potentially active dendrimer prodrugs in malaria and tuberculosis. Bis-MPA dendrimers (generations 0, 1 and 2) were synthesized by the group of Professor Scott Grayson of Tulane University (USA). Herein in Brazil, the compounds were functionalized by coupling succinic acid (spacer group), as well as the active molecules. We selected the following substances: (1) primaquine, with antimalarial action and (2) isoniazid, acting in the early stages of tuberculosis. Isoniazid dendrimer prodrugs were synthesized generations 0 and 1 (G0-Iso and G1-Iso), and primaquine in generations 0, 1 and 2 (G0-Pq, G1-Pq and G2-Pq). It is important to mention that the results related to Nuclear and Magnetic Resonance 113C showed chemical structures features, however with impurities. Analysis of the mass spectrometry regarding G0-Iso has revealed the presence of a cyclized by-product of succinylated isonized (CIso-Suc), which may be a potential prodrug or may presentactivity itself. Using the analytical methodology performed for G0-Iso, ICso-Suc demonstrated its ability to convert the Iso-Suc prototype at different pH values, especially at pH 7.4 and 8.5. As perspectives, we highlight the determinations of the chemical stability of ICsoSuc at pH 1.5 and 6.0, as well as the evaluation of the enzymatic stability. We will also investigate the respective antimicobacterial activities. Regarding prodrugs, the needs for synthesis enhancements are also necessary. Once synthesized and characterized, these latter derivatives will be evaluated for biological activity. Moreover, computational studies, especially molecular docking simulations, were developed in order to understand the mode of interaction of some compounds with predetermined biological targets

Novel kidney injury biomarkers in tropical infections: a review of the literature.

Tropical diseases are mainly found in the tropical regions of Asia, Africa and Latin America. They are a major Public Health problem in these regions, most of them are considered neglected diseases and remain as important contributors to the development of AKI (Acute Kidney Injury), which is associated with increased patients' morbidity and mortality. In most countries, kidney disease associated to tropical diseases is attended at health services with poor infrastructure and inadequate preventive measures. The long-term impacts of these infections on kidney tissue may be a main cause of future kidney disease in these patients. Therefore, the investigation of novel kidney injury biomarkers in these tropical diseases is of utmost importance to explain the mechanisms of kidney injury, to improve their diagnosis and prognosis, as well as the assessment to health systems by these patients. Since 2011, our group has been studying renal biomarkers in visceral and cutaneous leishmaniasis, schistosomiasis, leptospirosis and leprosy. This study has increased the knowledge on the pathophysiology of kidney disease in the presence of these infections and has contributed to the early diagnosis of kidney injury, pointing to glomerular, endothelial and inflammatory involvement as the main causes of the mechanisms leading to nephropathy and clinical complications. Future perspectives comprise establishing long-term cohort groups to assess the development of kidney disease and the patients' survival, as well as the use of new biomarkers such as urinary exosomes to detect risk groups and to understand the progression of kidney injuries.

Compostos carbonílicos α, ß-insaturados e hidrazonas sintéticas como antiparasitários / α, ß-Unsaturated carbonyl compounds and Synthetic hydrazones as antiparasitics

Apesar da grande relevância médica e social, e por serem responsáveis por grande parte das mortes em países subdesenvolvidos e em desenvolvimento as doenças negligenciadas (DN), ainda, não apresentam terapêutica eficaz. Dentre as diversas DN, doenças como a doença de Chagas, a Leishmaniose visceral e a malária, se destacam no cenário nacional, por terem alta incidência e prejuízos sociais. Os fármacos disponíveis para o tratamento destas parasitoses, apresentam alta toxicidade e, em alguns casos, resistência por parte dos parasitas. Assim sendo, faz-se necessário o planejamento e desenvolvimento de novos agentes quimioterápicos mais seguros e eficazes. Dentre as diferentes estratégias de planejamento de fármacos, selecionamos o planejamento de fármacos baseado na estrutura do ligante - LBDD (Ligand-Based Drug Design) - como base para desenvolvimento deste trabalho. Nesta estratégia, utiliza-se o conhecimento de moléculas (ligantes) e de suas atividades biológicas conhecidas previamente determinadas experimentalmente, como protótipos para a busca de novas entidades químicas com atividade biológica semelhante ou melhorada. Sendo assim, o presente trabalho teve como objetivo a síntese e avaliação biológica de moléculas bioativas para o tratamento de doenças parasitárias. Baseando-se no conhecimento prévio da atividade antiparasitária de compostos carbonílicos α,ß-insaturados e hidrazonas, foram sintetizados séries de compostos destas classes químicas na busca de novos agentes quimioterápicos. Os compostos obtidos foram avaliados contra a forma epimastigota de Trypanosoma cruzi, promastigota de Leishmania donovani, amastigota de Leishmania infantum e, também, determinou-se o seu grau de citotoxicidade (CC50) frente a células de macrófago humanos diferenciado (THP-1). As 31 moléculas obtidas foram caracterizadas por técnicas de ponto de fusão, RMN 1H e RMN 13C e avaliada sua pureza por HPLC. Os compostos da classe da cinamoil-hidrazonas apresentaram-se como promissores antiparasitários, mostrando atividade frente a forma promastigota (Leishmania donovani), 4 dos 12 compostos foram ativos (IC50= 1,27 - 13,68 µM) e frente a forma amastigota (Leishmania infantum), 10 dos 12 compostos apresentaram atividade (9,09 - 63,5 µM). Mesmo apresentando citotoxicidade moderada (CC50 = 8,83 - 87,47 µM), os compostos obtiveram valores inferiores ao fármaco de referência (doxorubicina: CC50 = 0,26 µM). Diante do exposto, o planejamento de fármacos realizado por LBDD mostrou-se bem-sucedido, pois a classe de cinamoil-hidrazonas mostrou-se promissora como antiparasitários, visto sua atividade na escala de baixo micromolar e moderada citotoxicidade em células humanas. Esses resultados assinalam que a classe de compostos descrita está passível a continuar sendo investigada no intuito de aprimorar os protótipos obtidos na busca de novos agentes quimioterápicos antiparasitários e desvendar os mecanismos de ação leishmanicida

Despite to the great medical and social relevance and the amount of deaths in underdeveloped and developing countries, neglected diseases (ND) still do not have an effective therapy. Among the various ND, illnesses such as Chagas disease, visceral leishmaniasis and malaria holds a great importance in the Brazilian scenario due to high incidence and social damage. The drugs available for the treatment of these parasitosis present high toxicity and, in some cases, resistance by the pathogens. Thus, the planning and development of new, safer and more effective chemotherapeutic substances are urgent needed. Among the different drug planning strategies, we selected ligand-based drug design (LBDD) as the basis for the development of this work. In this strategy, we use the knowledge of molecules (ligands) and their known biological activities previously determined experimentally, as prototypes to search for new chemical entities with similar or improved biological activity. Therefore, the present work aimed the synthesis and biological evaluation of bioactive molecules for the treatment of parasitic diseases. Based on previous knowledge of the antiparasitic activity of α,ß-unsaturated and hydrazone carbonyl compounds, series of compounds of these chemical classes were synthesized in search of new chemotherapeutic agents. The compounds obtained were evaluated against the epimastigote form of Trypanosoma cruzi, Leishmania donovani promastigote, Leishmania infantum amastigote and their cytotoxicity (CC50) against differentiated human macrophages (THP-1). The 31 molecules obtained were characterized by melting point, 1 H NMR and 13C NMR techniques and their purity were characterized by HPLC. The cinnamoyl hydrazone class compounds showed promising antiparasitic activity, showing activity against promastigote form (L. donovani), 4 of 12 compounds were active (IC50 = 1.27 - 13.68 µM) and amastigote form (L. infantum), 10 of the 12 compounds showed activity (9.09 - 63.5 µM). Even presenting moderate cytotoxicity (CC50 = 8.83 - 87.47 µM), the compounds had values below the reference drug (doxorubicin: CC50 = 0.26 µM). Considering the results, LBDD drug planning proved to be successful and the class of cinnamoyl hydrazones were promising as antiparasitics due to its activity in low micromolar scale and moderate cytotoxicity in human cells. These results indicate that the described class of compounds can be further investigated in order to improve the prototypes obtained in the search for new antiparasitic chemotherapeutic agents and to unravel the mechanisms of action of leishmanicidal molecules

A Review of Hearing Loss Associated with Zika, Ebola, and Lassa Fever.

The neglected tropical diseases Zika, Ebola, and Lassa fever (LF) have all been noted to cause some degree of hearing loss (HL). Hearing loss is a chronic disability that can lead to a variety of detrimental effects, including speech and language delays in children, decreased economic productivity in adults, and accelerated cognitive decline in older adults. The objective of this review is to summarize what is known regarding HL secondary to these viruses. Literature for this review was gathered using the PubMed database. Articles were excluded if there were no data of the respective viruses, postinfectious complications, or conditions related to survivorship. A total of 50 articles were included in this review. Fourteen articles discussing Zika virus and subsequent complications were included. Across these studies, 56 (21.2%) of 264 Zika-infected individuals were found to have HL. Twenty-one articles discussing Ebola virus and subsequent complications were included, with 190 (5.7%) of 3,350 Ebola survivors found to have HL. Fifteen additional articles discussing LF and subsequent complications were included. Of 926 individuals with LF, 79 (8.5%) were found to have HL. These results demonstrate a relationship between HL and infection. The true prevalence is likely underestimated, however, because of lack of standardization of reporting and measurement. Future studies of viral sequelae would benefit from including audiometric evaluation. This information is critical to understanding pathophysiology, preventing future cases of this disability, and improving quality of life after survival of infection.