The Effectiveness of Topical Dimethicone Together with a One Health Approach for the Control of Tungiasis in the Sanumás Communities, Yanomami Territory, Amazon Rainforest: A Real-World Study.

BACKGROUND: The success of tungiasis treatment is highly dependent on adequate environmental control. METHODS: This is a real-world observational cohort study designed to monitor the effectiveness of topical dimethicone together with a One Health approach for the control of tungiasis in the Sanumás communities, Amazon rainforest, Brazil. We followed up on 562 indigenous people and 81 domestic dogs for 1.5 years in a 3-month interval. A new molecular method for large-scale soil evaluation was also tested. The control of tungiasis was independently conducted by the Brazilian Ministry of Health and comprised topical dimethicone application (NYDA®) for humans, single-dose oral afoxolaner for dogs, and in-house soil fumigation with fipronil. The main outcome was the occurrence of tungiasis after the use of topical dimethicone together with the One Health approach. RESULTS: A total of 49 of the 562 indigenous people had active tungiasis at enrollment (8.72%). Only three cases of tungiasis resulted in active lesions after the use of topical dimethicone together with the One Health approach, with two cases of recurrence. From the 6-month follow-up and after, soil infestation was not detected. CONCLUSIONS: We conclude that the use of NYDA® together with animal and environmental interventions are effective measures for the control of tungiasis.

Tungiasis in the Sanumás Amerindians in the Amazon Rainforest, Brazil: Prevalence, Intensity and Morbidity.

BACKGROUND: Tungiasis is a disease associated with extreme poverty. We aimed to evaluate the prevalence of tungiasis in six different settlements of the Sanumás indigenous community in a remote area in the Auaris region, Yanomami territory, Brazil. METHODS: We conducted an observational study to detect clinical and epidemiological factors associated with tungiasis using a cross-sectional strategy and multivariate logistic regression. Soil analysis was performed by visual and microscopic methods. RESULTS: We examined 555 persons, 45 of whom had active tungiasis; 18 cases were classified as mild, 16 as moderate and 11 as severe. The disease was significantly more prevalent in children than in adults (odds ratio (OR) 15.77; 95% confidence interval (CI) = 5.34-67.91; p < 0.001). Soil infestation was significantly related to the occurrence of human tungiasis (OR = 12.29; 95% CI = 3.75-45.88). The sex and GPS location of the houses were not related to the occurrence of tungiasis. CONCLUSIONS: We conclude that tungiasis is an important problem in the Sanumás community, especially for children. We suggest that interruption of the off-host transmission cycle, together with regular treatment [human and animal interventions], must be prioritized to achieve control of tungiasis in indigenous populations.

Organoids as a novel tool in modelling infectious diseases.

Infectious diseases worldwide affect human health and have important societal impacts. A better understanding of infectious diseases is urgently needed. In vitro and in vivo infection models have brought notable contributions to the current knowledge of these diseases. Organoids are multicellular culture systems resembling tissue architecture and function, recapitulating many characteristics of human disease and elucidating mechanisms of host-infectious agent interactions in the respiratory and gastrointestinal systems, the central nervous system and the skin. Here, we discuss the applicability of the organoid technology for modeling pathogenesis, host response and features, which can be explored for the development of preventive and therapeutic treatments.

Organoides de cérebro como modelos de doenças de Alzheimer e Parkinson: uma revisão narrativa sobre as perspectivas para medicina regenerativa e personalizada / Brain organoids as models of Alzheimer's and Parkinson's diseases: a narrative review on perspectives for regenerative and personalized medicine

Há muitos anos a cultura celular bidimensional (2D) é utilizada como modelo de estudo de doenças, possuindo grande importância na medicina regenerativa, apesar de ainda conter limitações significativas. A fim de contornar essas limitações, a cultura celular tridimensional (3D) propõe uma organização mais complexa e sustentável que pode ser produzida a partir de células-tronco adultas (ASCs), células-tronco embrionárias (ESCs) ou células-tronco pluripotentes induzidas (iPSCs). A cultura 3D possibilitou o cultivo de células em um ambiente mais próximo do fisiológico, levando à formação de distintos tecidos órgãos-específicos. Em outras palavras, a cultura de células 3D possibilita a criação de estruturas orgânicas muito semelhantes aos órgãos de um ser humano, tanto estruturalmente, quanto funcionalmente. Desse modo, tem-se o que é chamado de organoides. O uso dos organoides tem crescido exponencialmente em ambientes in vitro, permitindo a análise e observação dos diversos fenômenos fisiológicos existentes. Como exemplo, pode-se citar os organoides cerebrais ("mini-brains") reproduzidos in vitro buscando delinear as peculiaridades e complexidades do cérebro humano, com o objetivo de compreender algumas disfunções neurológicas que acometem esse sistema, como as duas principais doenças neurodegenerativas: Doenças de Alzheimer e Parkinson. Portanto, os organoides cerebrais podem permitir notável avanço da medicina regenerativa aplicada a doenças neurodegenerativas, já que esses "mini-brains" podem ser produzidos a partir de células do próprio paciente. Isso permitirá intervenções personalizadas, como testagens farmacológicas, a fim de definir qual seria o melhor tratamento medicamentoso. Consequentemente, essa tecnologia pode permitir terapias mais eficientes e individualizadas - o que é fundamental para a Medicina Personalizada (AU).

For many years, two-dimensional (2D) cell culture has been used as a model to study diseases, having great importance in regenerative medicine, despite still having significant limitations. In order to circumvent these limitations, three-dimensional (3D) cell culture proposes a more complex and sustainable organization that can be produced from adult stem cells (ASCs), embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs). The 3D culture enabled the cultivation of cells in an environment closer to the physiological one, leading to the formation of different organ-specific tissues. In other words, 3D cell culture makes it possible to create organic structures very similar to the organs of a human being, both structurally and functionally. In this way, we have what are called organoids. The use of organoids has grown exponentially in in vitro environments, allowing the analysis and observation of the various existing physiological phenomena. As an example, we can mention the brain organoids ("mini-brains") reproduced in vitro, seeking to delineate the peculiarities and complexities of the human brain, in order to understand some neurological dysfunctions that affect this system, such as the two main neurodegenerative diseases: Alzheimer's and Parkinson's Diseases. Therefore, brain organoids may allow a remarkable advance in regenerative medicine applied to neurodegenerative diseases, as these "mini-brains" can be produced from the patient's own cells. This will allow for personalized interventions, such as drug testing, in order to define what would be the best drug treatment. Consequently, this technology can enable more efficient and individualized therapies - which is fundamental for Personalized Medicine (AU).

Growth performance and rumen morphometrics of Nellore and ½ Angus/Nellore feedlot cattle adapted over 9 and 14 days to high-concentrate diets.

The objective of this study was to evaluate the effects of adapting Nellore and ½ Angus/Nellore (AN) feedlot cattle over periods of 9 and 14 days to high-concentrate diets on performance, feeding behaviour, carcass traits and rumen morphometrics. Seventy-two yearling bulls (313.5 kg ± 24.5), 36 Nellore and 36 AN, were randomly allocated in 24 pens (3 animals/pen; 24 m2 and 2.0 m of bunk space/animal) according to a randomized complete block design with a 2 × 2 factorial arrangement of treatments as follows: Nellore adapted for 9 days, Nellore adapted for 14 days, AN adapted for 9 days, and AN adapted for 14 days. Each treatment was composed by 6 pens (considered the experimental unit in this study). The adaptation lasted either 9 or 14 days and consisted of 3 step-up diets. Therefore, yearling bulls received the finishing diet containing 86% concentrate either on day 10 or 15 of the study, which lasted 89 days taking into account adaptation and finishing periods. Cattle were slaughtered in a commercial abattoir, and two 1-cm2 -rumen fragments, one from cranial and another from ventral sac, were collected. The AN cattle outperformed Nellore in terms of average daily gain (1.71 kg/day vs. 1.27 kg/day, p < 0.01), gain:feed ratio (0.137 kg/kg vs. 0.127 kg/kg, p = 0.02) and hot carcass weight (243.64 kg vs. 228.98 kg, p < 0.01). No main effect of the adaptation period was observed for any of the feedlot performance and carcass traits variables evaluated. Compared to feedlot cattle adapted for 9 days, feedlot cattle adapted for 14 days sorted against long (0.68 vs. 0.91, p < 0.01) and for fine particles (1.04 vs. 1.00, p = 0.01). An interaction (p < 0.01) of genotype and adaptation period was observed for rumenitis, where Nellore bulls adapted for 14 days presented the highest scores. In conclusion, there was no evidence that either Nellore or AN cattle benefit from an adaptation period shorter than 14 days.

Differentiating Induced Pluripotent Stem Cells into Renal Cells: A New Approach to Treat Kidney Diseases.

Renal disease is a major issue for global public health. Despite some progress in supportive care, the mortality rates among patients with this condition remain alarmingly high. Studies in pursuit of innovative strategies to treat renal diseases, especially stimulating kidney regeneration, have been developed. In this field, stem cell-based therapy has been a promising area. Induced pluripotent stem cell-derived renal cells (iPSC-RCs) represent an interesting source of cells for treating kidney diseases. Advances in regenerative medicine using iPSC-RCs and their application to the kidney are discussed in this review. Furthermore, the way differentiation protocols of induced pluripotent stem cells into renal cells may also be applied for the generation of kidney organoids is also described, contributing to studies in renal development, kidney diseases, and drug toxicity tests. The translation of the differentiation methodologies into animal model studies and the safety and feasibility of renal differentiated cells as a treatment for kidney injury are also highlighted. Although only few studies were published in this field, the results seem promising and support the use of iPSC-RCs as a potential therapy in the future.

Enhancing the Therapeutic Potential of Mesenchymal Stem Cells with the CRISPR-Cas System.

Mesenchymal stem cells (MSCs), also known as multipotent mesenchymal stromal stem cells, are found in the perivascular space of several tissues. These cells have been subject of intense research in the last decade due to their low teratogenicity, as well as their ability to differentiate into mature cells and to secrete immunomodulatory and trophic factors. However, they usually promote only a modest benefit when transplanted in experimental disease models, one of the limitations for their clinical application. The CRISPR-Cas system, in turn, is highlighted as a simple and effective tool for genetic engineering. This system was tested in clinical trials over a relatively short period of time after establishing its applicability to the edition of the mammalian cell genome. Similar to the research evolution in MSCs, the CRISPR-Cas system demonstrated inconsistencies that limited its clinical application. In this review, we outline the evolution of MSC research and its applicability, and the progress of the CRISPR-Cas system from its discovery to the most recent clinical trials. We also propose perspectives on how the CRISPR-Cas system may improve the therapeutic potential of MSCs, making it more beneficial and long lasting.

Long-term anabolic steroids in male bodybuilders induce cardiovascular structural and autonomic abnormalities.

OBJECTIVE: The aims of this study were to examine the hypothesis that users of anabolic androgenic steroids (AAS) would have cardiac autonomic disorders and that there is a correlation between sympathetic modulation, high blood pressure (BP) and alterations to cardiac dimensions. METHODS: Forty-five male subjects were enrolled in the study. They were categorized into three groups comprising bodybuilders actively using AAS (AAS users; n = 15), bodybuilders who had never used AAS (nonusers; n = 15) and age-paired healthy sedentary controls (n = 15). Hemodynamic parameters, linear and nonlinear analyses of heart rate variability and electrocardiography and echocardiography analyses were performed at rest. RESULTS: Bodybuilders in the AAS group had a higher mean BP than those in the ASS nonuser group (p < 0.05) and the sedentary controls (p < 0.001). Cardiac sympathetic modulation was higher in AAS users than in AAS nonusers (p < 0.05) and the sedentary controls (p < 0.001), and parasympathetic modulation was lower in AAS users than in nonusers and the sedentary controls (p < 0.05). Shannon entropy was lower in AAS users than in the sedentary (p < 0.05) controls, and the corrected QT interval and QT dispersion were higher in AAS users than in the sedentary controls (p < 0.05). The interventricular septal thickness, left ventricle posterior wall thickness and relative diastolic wall thickness were higher in AAS users than in AAS nonusers and the sedentary controls (p < 0.001). AAS users showed a positive correlation between increased sympathetic modulation and high BP (r = 0.48, p < 0.005), as well as sympathetic modulation and cardiac hypertrophy (r = 0.66, p < 0.001). CONCLUSION: There was a marked cardiac autonomic alteration in AAS users, with a shift toward sympathetic modulation predominance and vagal attenuation. The high BP observed in our group of bodybuilders using AAS was associated with increased sympathetic modulation, and this increased sympathetic modulation was associated with structural alterations in the heart. This association may constitute an important mechanism linking AAS abuse to increased cardiovascular risk.

Patentes, inovação e direito à saúde: análise sobre as discussões de propriedade intelectual em saúde publica na Organização Mundial da Saúde entre 2006 e 2016 / Patents, innovation and the right to health: analysis of the discussions on intellectual property in public health at the World Health Organization between 2006 and 2016

O acordo TRIPS enrijeceu as normas de garantias de propriedade intelectual n os países signatários da Organização Mundial do Comercio (OMC) e, atualmente, caracteriza-se como um grande desafio aos países em desenvolvimento, bem como à promoção da inovação em saúde. A Organização Mundial da Saúde (OMS) iniciou trabalhos para discutir os impactos dos direitos de propriedade intelectual e a saúde pública. Tem por objetivo analisar as discussões realizadas na OMS sobre propriedade intelectual e a saúde publica, no período entre 2006 e 2016. A inovação e a promoção da inovação são fundamentais para o desenvolvimento de novas tecnologias e produtos para a saúde, e devem enquadrar-se em uma estrutura m ais ampla de esforços intersetoriais para melhorar a saúde e desenvolvimento dos países. É evidente o papel da inovação em relação à consolidação e sustentabilidade do Sistema Único e Saúde, assim como possui função fundamental no desenvolvimento de tecnologias portadoras de futuro, e que no caso dos países em desenvolvimento e menos desenvolvidos, deve estar focada na resolutividade das doenças mais prevalentes nestes países

Patentes e o direito à saúde: análise sobre as discussões de propriedade intelectual na Organização Mundial da Saúde, entre 2006 e 2016 / Patents and the right to health: an analysis of intellectual property discussions in the World Health Organization, between 2006 and 2016 / Patentes y el derecho a la salud: análisis sobre las discusiones de propiedad intelectual em la Organización Mundial de la Salud, entre 2006 y 2016

Objetivo ­ Analisar as discussões realizadas na OMS sobre propriedade intelectual e saúde pública, no período entre 2006 e 2016. Resultados ­ Houve destaque às funções sociais da propriedade intelectual, contudo, observado que países em desenvolvimento e menos desenvolvidos não são capazes de se beneficiar de uma maior proteção à propriedade intelectual, pelo que devem utilizar-se das flexibilidades presentes nas normas regulatórias, como o Acordo TRIPS e reafirmadas na Declaração de Doha. Considerações Finais ­ Observa-se que os debates sobre a propriedade intelectual, em especial acerca produtos farmacêuticos, vem cercada de controvérsias relacionadas ao acesso das populações aos medicamentos essenciais, à promoção da inovação e transferência de tecnologias dos países desenvolvidos aos países em desenvolvimento , Importa assinalar que no contexto brasileiro o reconhecimento de propriedade intelectual promoveu um aumento de custo dos produtos farmacêuticos, em virtude do monopólio, e torna-se um dos elementos de barreira ao acesso e à universalização do direito à saúde

Objective ­ To analyze the discussions held at WHO on intellectual property and public health, between 2006 and 2016. Results ­ The social functions of intellectual property were highlighted, however, observing that developing and less developed countries are not able to benefit from protection of intellectual property, so that the flexibilities in regulatory standards, such as the TRIPS Agreement and reaffirmed in the Doha Declaration, should be used. Final Considerations ­ Discussions on intellectual property, in particular on pharmaceuticals, are surrounded by controversies regarding the access of populations to essential medicines, the promotion of innovation and the transfer of technologies from developed to developing countries, It matters to point out that in the Brazilian context the recognition of intellectual property promoted an increase in the cost of pharmaceutical products, due to the monopoly, and becomes one of the barrier elements to the access and universalization of the right to health.

Objetivo ­ Analizar las discusiones realizadas en la OMS sobre propiedad intelectual y salud pública, en el período entre 2006 y 2016. Resultados ­ Hubo destaque a las funciones sociales de la propiedad intelectual, sin embargo, observó que los países en desarrollo y menos desarrollados no son capaces de beneficiarse una mayor protección a la propiedad intelectual, por lo que deben utilizarse las flexibilidades presentes en las normas regulatorias, como el Acuerdo ADPIC y reafirmadas en la Declaración de Doha. Consideraciones finales ­ Se observa que los debates sobre la propiedad intelectual, en particular sobre productos farmacéuticos, están rodeados de controversias relacionadas con el acceso de las poblaciones a los medicamentos esenciales, la promoción de la innovación y la transferencia de tecnologías de los países desarrollados a los países en desarrollo, señalar que en el contexto brasileño el reconocimiento de propiedad intelectual promovió un aumento de costo de los productos farmacéuticos, en virtud del monopolio, y se convierte en uno de los elementos de barrera al acceso ya la universalización del derecho a la salud.

Biological properties of cardiac mesenchymal stem cells in rats with diabetic cardiomyopathy.

Cardiomyopathy is a major outcome in patients with diabetes mellitus (DM) and contributes to the high morbidity/mortality observed in this disease. AIMS: To evaluate several biological properties of cardiac mesenchymal stem cells (cMSCs) in a rat model of streptozotocin-induced DM with concomitant diabetic cardiomyopathy. MAIN METHODS: After 10weeks of DM induction, diabetic and control rats were assessed using ECG and ventricular hemodynamics monitoring. Then, the hearts were excised and processed for histology and for extracting non-cardiomyocytic cells. A pool of these cells was plated for a colony forming units-fibroblasts (CFU-F) assay in order to estimate the number of cMSCs. The remaining cells were expanded to assess their proliferation rate as well as their osteogenic and adipogenic differentiation ability. KEY FINDINGS: DM rats presented intense hyperglycemia and changes in ECG, LV hemodynamic, cardiac mass index and fibrosis, indicating presence of DCM. The CFU-F assay revealed a higher number of cardiac CFU-Fs in DM rats (10.4±1.1CFU-F/105 total cells versus 7.6±0.7CFU-F/105 total cells in control rats, p<0.05), which was associated with a significantly higher proliferative rate of cMSCs in DM rats. In contrast, cMSCs from DM rats presented a lower capacity to differentiate into both osteogenic (20.8±4.2% versus 10.1±1.0% in control rats, p<0.05) and adipogenic lineages (4.6±1.0% versus 1.3±0.5% in control rats, p<0.05). SIGNIFICANCE: The findings suggest, for the first time, that in chronic DM rats with overt DCM, cMSCs increase in number and exhibit changes in several functional properties, which could be implicated in the pathogenesis of diabetic cardiomyopathy.

Priming Mesenchymal Stem Cells with Endothelial Growth Medium Boosts Stem Cell Therapy for Systemic Arterial Hypertension.

Systemic arterial hypertension (SAH), a clinical syndrome characterized by persistent elevation of arterial pressure, is often associated with abnormalities such as microvascular rarefaction, defective angiogenesis, and endothelial dysfunction. Mesenchymal stem cells (MSCs), which normally induce angiogenesis and improve endothelial function, are defective in SAH. The central aim of this study was to evaluate whether priming of MSCs with endothelial growth medium (EGM-2) increases their therapeutic effects in spontaneously hypertensive rats (SHRs). Adult female SHRs were administered an intraperitoneal injection of vehicle solution (n = 10), MSCs cultured in conventional medium (DMEM plus 10% FBS, n = 11), or MSCs cultured in conventional medium followed by 72 hours in EGM-2 (pMSC, n = 10). Priming of the MSCs reduced the basal cell death rate in vitro. The administration of pMSCs significantly induced a prolonged reduction (10 days) in arterial pressure, a decrease in cardiac hypertrophy, an improvement in endothelium-dependent vasodilation response to acetylcholine, and an increase in skeletal muscle microvascular density compared to the vehicle and MSC groups. The transplanted cells were rarely found in the hearts and kidneys. Taken together, our findings indicate that priming of MSCs boosts stem cell therapy for the treatment of SAH.

Endogenous resident c-Kit cardiac stem cells increase in mice with an exercise-induced, physiologically hypertrophied heart.

Physical activity evokes well-known adaptations in the cardiovascular system. Although exercise training induces cardiac remodeling, whether multipotent stem cells play a functional role in the hypertrophic process remains unknown. To evaluate this possibility, C57BL/6 mice were subjected to swimming training aimed at achieving cardiac hypertrophy, which was morphologically and electrocardiographically characterized. Subsequently, c-Kit(+)Lin(-) and Sca-1(+)Lin(-) cardiac stem cells (CSCs) were quantified using flow cytometry while cardiac muscle-derived stromal cells (CMSCs, also known as cardiac-derived mesenchymal stem cells) were assessed using in vitro colony-forming unit fibroblast assay (CFU-F). Only the number of c-Kit(+)Lin(-) cells increased in the hypertrophied heart. To investigate a possible extracardiac origin of these cells, a parabiotic eGFP transgenic/wild-type mouse model was used. The parabiotic pairs were subjected to swimming, and the wild-type heart in particular was tested for eGFP(+) stem cells. The results revealed a negligible number of extracardiac stem cells in the heart, allowing us to infer a cardiac origin for the increased amount of detected c-Kit(+) cells. In conclusion, the number of resident Sca-1(+)Lin(-) cells and CMSCs was not changed, whereas the number of c-Kit(+)Lin(-) cells was increased during physiological cardiac hypertrophy. These c-Kit(+)Lin(-) CSCs may contribute to the physiological cardiac remodeling that result from exercise training.

Effects of cholinergic stimulation with pyridostigmine bromide on chronic chagasic cardiomyopathic mice.

The aim of the present study was to assess the effects of an anticholinesterase agent, pyridostigmine bromide (Pyrido), on experimental chronic Chagas heart disease in mice. To this end, male C57BL/6J mice noninfected (control:Con) or chronically infected (5 months) with Trypanosoma cruzi (chagasic:Chg) were treated or not (NT) with Pyrido for one month. At the end of this period, electrocardiogram (ECG); cardiac autonomic function; heart histopathology; serum cytokines; and the presence of blood and tissue parasites by means of immunohistochemistry and PCR were assessed. In NT-Chg mice, significant changes in the electrocardiographic, autonomic, and cardiac histopathological profiles were observed confirming a chronic inflammatory response. Treatment with Pyrido in Chagasic mice caused a significant reduction of myocardial inflammatory infiltration, fibrosis, and hypertrophy, which was accompanied by a decrease in serum levels of IFNγ with no change in IL-10 levels, suggesting a shift of immune response toward an anti-inflammatory profile. Lower nondifferent numbers of parasite DNA copies were observed in both treated and nontreated chagasic mice. In conclusion, our findings confirm the marked neuroimmunomodulatory role played by the parasympathetic autonomic nervous system in the evolution of the inflammatory-immune response to T. cruzi during experimental chronic Chagas heart disease in mice.

Autonomic nervous system modulation affects the inflammatory immune response in mice with acute Chagas disease.

The aim of the present study was to evaluate the effects of changes to the autonomic nervous system in mice during the acute phase of Chagas disease, which is an infection caused by the parasite Trypanosoma cruzi. The following types of mice were inoculated with T. cruzi (CHG): wild-type (WT) and vesicular acetylcholine transporter knockdown (KDVAChT) C57BL/6j mice; wild-type non-treated (NT) FVB mice; FVB mice treated with pyridostigmine bromide (PYR) or salbutamol (SALB); and ß(2)-adrenergic receptor knockout (KOß2) FVB mice. During infection and at 18-21 days after infection (acute phase), the survival curves, parasitaemia, electrocardiograms, heart rate variability, autonomic tonus and histopathology of the animals were evaluated. Negative control groups were matched for age, genetic background and treatment. The KDVAChT-CHG mice exhibited a significant shift in the electrocardiographic, autonomic and histopathological profiles towards a greater inflammatory immune response that was associated with a reduction in blood and tissue parasitism. In contrast, the CHG-PYR mice manifested reduced myocardial inflammation and lower blood and tissue parasitism. Similar results were observed in CHG-SALB animals. Unexpectedly, the KOß2-CHG mice exhibited less myocardial inflammation and higher blood and tissue parasitism, which were associated with reduced mortality. These findings could have been due to the increase in vagal tone observed in the KOß2 mice, which rendered them more similar to the CHG-PYR animals. In conclusion, our results indicate a marked immunomodulatory role for the parasympathetic and sympathetic autonomic nervous systems, which inhibit both the inflammatory immune response and parasite clearance during the acute phase of experimental Chagas heart disease in mice.