LPD-3 as a megaprotein brake for aging and insulin-mTOR signaling in C. elegans.

Insulin-mechanistic target of rapamycin (mTOR) signaling drives anabolic growth during organismal development; its late-life dysregulation contributes to aging and limits lifespans. Age-related regulatory mechanisms and functional consequences of insulin-mTOR remain incompletely understood. Here, we identify LPD-3 as a megaprotein that orchestrates the tempo of insulin-mTOR signaling during C. elegans aging. We find that an agonist insulin, INS-7, is drastically overproduced from early life and shortens lifespan in lpd-3 mutants. LPD-3 forms a bridge-like tunnel megaprotein to facilitate non-vesicular cellular lipid trafficking. Lipidomic profiling reveals increased hexaceramide species in lpd-3 mutants, accompanied by up-regulation of hexaceramide biosynthetic enzymes, including HYL-1. Reducing the abundance of HYL-1, insulin receptor/DAF-2 or mTOR/LET-363, normalizes INS-7 levels and rescues the lifespan of lpd-3 mutants. LPD-3 antagonizes SINH-1, a key mTORC2 component, and decreases expression with age. We propose that LPD-3 acts as a megaprotein brake for organismal aging and that its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways.

Visual Information in Basketball Jump-Shots: Differences between Youth and Adult Athletes.

Basketball shooting is a complex skill that requires visual routines and trained players typically evidence a specific oculomotor pattern. This study aimed to examine visual patterns in male novice youth and professional adult players while performing a jump shot. The sample included 20 basketball players grouped as under-16 youth (n = 10) and professional adult (n = 10) players. Each participant completed 50 shots at two distances (long range: 6.80 m; middle range: 4.23 m). Eye tracking glasses were used to obtain quiet eye (QE), the number of fixations, total fixation duration, duration of first and last fixation. An independent t-test was used to assess differences between groups. Shooting accuracy given by % of efficacy indicated that under-16 players attained poorer scores at both distances: long (t = -4.75, p < 0.01) and middle (t = -2.80, p < 0.012) distance. The groups also differed in QE time (long: 600 ms vs. 551 ms; middle: 572 ms vs. 504 ms) and total duration of the fixations (long: 663 ms vs. 606 ms; middle: 663 ms vs. 564 ms) in both long and middle distance shots. Significant differences also occurred in the last fixation (long distance: t = -4.301, p < 0.01; middle distance: t = -3.656, p < 0.01) with professional adult players presenting the value of, on average, 454-458 ms, while youth shooters 363-372 ms. In summary, visual strategy differed between under-16 youth and professional adult basketball players. To support their long-term sport development, it is recommended that youth basketball players focus their attention with longer final fixation before releasing the ball to improve their shot.

An enteroendocrine-microbial axis in the large intestine controls host metabolism.

Nutrient handling is an essential function of the gastrointestinal tract. Most nutrient absorption occurs in the small intestine and is coordinated by hormone-producing intestinal epithelial cells known as enteroendocrine cells (EECs)1. In contrast, the colon mostly reclaims water and electrolytes, and handles the influx of microbially-derived metabolites, including short chain fatty acids (SCFA)2-4. Hormonal responses of small intestinal EECs have been extensively studied but much less in known about the role of colonic EECs in metabolic regulation. To address this core question, we investigated a mouse model deficient in colonic EECs. We found that colonic EEC deficiency leads to hyperphagia and obesity. Surprisingly, colonic EEC deficiency results in altered microbiota composition and metabolism, which we found through antibiotic treatment and transfer to germ free recipients, to be both necessary and sufficient for the development of obesity. Moreover, studying stool and blood metabolomes, we found that differential glutamate production by intestinal microbiota corresponds to increase appetite due to EEC loss. Finally, we show that colonic glutamate administration can directly increase food intake and activate appetite centers in the central nervous system. These observations shed light on an unanticipated host-microbiota axis in the colon, part of a larger gut-brain axis, that regulates host metabolism and body weight.

LPD-3 as a megaprotein brake for aging and insulin-mTOR signaling in C. elegans.

Insulin-mTOR signaling drives anabolic growth during organismal development, while its late-life dysregulation may detrimentally contribute to aging and limit lifespans. Age-related regulatory mechanisms and functional consequences of insulin-mTOR remain incompletely understood. Here we identify LPD-3 as a megaprotein that orchestrates the tempo of insulin-mTOR signaling during C. elegans aging. We find that an agonist insulin INS-7 is drastically over-produced in early life and shortens lifespan in lpd-3 mutants, a C. elegans model of human Alkuraya-Kucinskas syndrome. LPD-3 forms a bridge-like tunnel megaprotein to facilitate phospholipid trafficking to plasma membranes. Lipidomic profiling reveals increased abundance of hexaceramide species in lpd-3 mutants, accompanied by up-regulation of hexaceramide biosynthetic enzymes, including HYL-1 (Homolog of Yeast Longevity). Reducing HYL-1 activity decreases INS-7 levels and rescues the lifespan of lpd-3 mutants through insulin receptor/DAF-2 and mTOR/LET-363. LPD3 antagonizes SINH-1, a key mTORC2 component, and decreases expression with age in wild type animals. We propose that LPD-3 acts as a megaprotein brake for aging and its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways.

Repeated trans-arterial treatments of LDL-DHA nanoparticles induce multiple pathways of tumor cell death in hepatocellular carcinoma bearing rats.

Introduction: Repeated hepatic arterial delivery of therapeutic agents to the liver by percutaneously implanted port-catheter systems has been widely used to treat unresectable liver cancer. This approach is applied to assess the therapeutic efficacy of repeated low-density lipoprotein-docosahexaenoic acid (LDL-DHA) nanoparticle treatments in a rat model of hepatocellular carcinoma. Methods: N1S1 hepatoma bearing rats underwent placement of a percutaneously implanted hepatic artery port-catheter system and were allocated to untreated, control LDL-triolein (LDL-TO) or LDL-DHA nanoparticle infusions groups. Treatments were performed every three days over a nine day study period. MRI was performed at baseline and throughout the study. At the end of the study tissue samples were collected for analyses. Results and Discussion: Implantation of the port catheters was successful in all rats. MRI showed that repeated infusions of LDL-DHA nanoparticles significantly impaired the growth of the rat hepatomas eventually leading to tumor regression. The tumors in the LDL-TO treated group showed delayed growth, while the untreated tumors grew steadily throughout the study. Histopathology and MRI support these findings demonstrating extensive tumor necrosis in LDL-DHA treated groups while the control groups displayed minor necrosis. Molecular and biochemical analyses also revealed that LDL-DHA treated tumors had increased levels of nuclear factor-kappa B and lipid peroxidation and depletion of glutathione peroxidase 4 relative to the control groups. Evidence of both ferroptosis and apoptosis tumor cell death was observed following LDL-DHA treatments. In conclusion repeated transarterial infusions of LDL-DHA nanoparticles provides sustained repression of tumor growth in a rat hepatoma model.

Proteção jurídica dos profissionais de saúde envolvidos no atendimento em contexto da pandemia da COVID-19 / Legal protection of health professionals involved in care in the context of the COVID-19 pandemic / Protección jurídica de los profesionales sanitarios involucrados en la atención en el contexto de la pandemia COVID-19

A COVID-19 é a primeira crise contemporânea de saúde pública com potencial para sobrecarregar o sistema público de saúde mundial. A assistência à saúde é um recurso da sociedade compartilhada e, portanto, os princípios éticos que orientam seu racionamento exigem que serviços, medicamentos e equipamentos sejam aplicados onde forem mais eficazes, o que prioriza os pacientes com maior probabilidade de se beneficiar do tratamento. Os prestadores de serviços de saúde tomam decisões racionais com recursos escassos e merecem uma liberdade considerável para as suas deliberações de boa-fé, guiadas por estruturas éticas estabelecidas. O padrão de atendimento adequadamente aplicado sofre modulação em sua aplicação, o que requer uma mitigação da responsabilidade civil médica dentro de certos parâmetros objetivos. A lógica normativa é fundamentada no princípio da reciprocidade. Quando a sociedade pede que alguns de seus membros corram grandes riscos pessoais ao servir os interesses do público, é razoável esperar que a sociedade assuma algumas responsabilidades por eles em troca dos riscos assumidos. É apropriado que os formuladores de políticas públicas articulem padrões de atendimento especiais para desastres em massa, como a COVID-19. O objetivo do artigo é identificar como, no Brasil, Portugal e Espanha, a objetiva alteração das circunstâncias impôs a adequação da análise judicial de padrões de conduta profissionais a um panorama de calamidade.

COVID-19 is the first contemporary public health crisis with the potential to overwhelm the public health system worldwide. Health care is a resource of the shared society and, therefore, the ethical principles that guide its rationing require that services, medicines and equipment be applied where they are most effective, which prioritizes patients most likely to benefit from treatment. Health service providers make rational decisions with scarce resources, and deserve considerable freedom for their deliberations in good faith guided by established ethical structures. The standard of care properly applied is modulated in its application, which requires a mitigation of medical liability within certain objective parameters. The normative logic is based on the principle of reciprocity. When society asks some of its members to take great personal risks in serving the interests of the public, it is reasonable to expect society to take some responsibility for themin exchange for the risks taken. It is appropriate for public policy makers to articulate special care standards for mass disasters, such as COVID-19. The objective of the article is to identify how in Brazil, Portugal and Spain, the change in circumstances imposed the adequacy of the judicial analysis of professional standards of conduct to a panorama of calamity.

COVID-19 es la primera crisis de salud pública contemporánea con el potencial de abrumar al sistema de salud pública en todo el mundo. La atención de la salud es un recurso de la sociedad compartida y, por tanto, los principios éticos que orientan su racionamiento exigen que los servicios, medicamentos y equipos se apliquen donde sean más efectivos, lo que prioriza a los pacientes con mayor probabilidad de beneficiarse del tratamiento. Los proveedores de servicios de salud toman decisiones racionales con recursos escasos y merecen una libertad considerable para sus deliberaciones de buena fe guiadas por estructuras éticas establecidas. El estándar de atención aplicado correctamente se modula en su aplicación, lo que requiere una mitigación de la responsabilidad médica dentro de ciertos parámetros objetivos. La lógica normativa se basa en el principio de reciprocidad. Cuando la sociedad pide a algunos de sus miembros que asuman grandes riesgos personales para servir a los intereses del público, es razonable esperar que la sociedad asuma alguna responsabilidad por ellos a cambio de los riesgos asumidos. Es apropiado que los formuladores de políticas públicas articulen estándares de atención especial para desastres masivos, como la COVID-19. El objetivo del artículo es identificar cómo en Brasil, Portugal y España, el cambio objetivo de circunstancias impuso la adecuación del análisis judicial de los estándares de conducta profesional a un panorama de calamidad.

An implanted port-catheter system for repeated hepatic arterial infusion of low-density lipoprotein-docosahexaenoic acid nanoparticles in normal rats: A safety study.

BACKGROUND: In recent years, small animal arterial port-catheter systems have been implemented in rodents with reasonable success. The aim of the current study is to employ the small animal port-catheter system to evaluate the safety of multiple hepatic-artery infusions (HAI) of low-density lipoprotein-docosahexaenoic acid (LDL-DHA) nanoparticles to the rat liver. METHODS: Wistar rats underwent surgical placement of indwelling HAI ports. Repeated administrations of PBS or LDL-DHA nanoparticles were performed through the port at baseline and days 3 and 6. Rats were sacrificed on day 9 at which point blood and various organs were collected for histopathology and biochemical analyses. RESULTS: The port-catheter systems were implanted successfully and repeated infusions of PBS or LDL-DHA nanoparticles were tolerated well by all animals over the duration of the study. Measurements of serum liver/renal function tests, glucose and lipid levels did not differ between control and LDL-DHA treated rats. The liver histology was unremarkable in the LDL-DHA treated rats and the expression of hepatic inflammatory regulators (NF-κß, IL-6 and CRP) were similar to control rats. Repeated infusions of LDL-DHA nanoparticles did not alter liver glutathione content or the lipid profile in the treated rats. The DHA extracted by the liver was preferentially metabolized to the anti-inflammatory DHA-derived mediator, protectin DX. CONCLUSION: Our findings indicate that repeated HAI of LDL-DHA nanoparticles is not only well tolerated and safe in the rat, but may also be protective to the liver.

Segurança do paciente: aspectos comparativos entre Brasil e Portugal / Patient safety: comparative aspects between Brazil and Portugal

O artigo buscou refletir sobre as abordagens utilizadas pelos países lusófonos para a gestão do tema segurança do paciente, a partir de um estudo comparado, de bases normativas, entre Brasil e Portugal. Foram identificadas previamente as normas por meio de pesquisa legislativa, leitura de livros e artigos, e conversas com informantes-chaves. O marco temporal inicial da pesquisa normativa foi o ano de 2004, por ocasião da criação da Aliança Mundial para a Segurança do Paciente. Muitas semelhanças foram encontradas na forma de normatizar as questões, e implementa-las dentro das organizações de saúde: criação de protocolos e manuais clínicos; uso de comitês/núcleo como ator responsável pela internalização e execução dos objetivos previstos nos Planos Nacionais, etc. O aumento da qualidade dos cuidados na saúde e a consequente redução dos erros não se dará de forma individual, visto que os eventos adversos são frutos de um processo sistêmico e complexo, próprio das organizações de saúde onde se desenvolvem as atividades. Portugal e Brasil avançam nesse processo por meio da estruturação de sistemas voltados à educação, monitoramento e prevenção de erros evitáveis

Desafios jurídicos da Medicina personalizada / Legal challenges of personalized medicine

A Medicina personalizada - atualmente em notável ascensão graças aos consideráveis progressos científicos no domínio da genética - tem potencial para se afirmar, neste Terceiro Milênio, como uma das mais promissoras abordagens no domínio da saúde. A implementação de um modelo de apoio medico personalizado e adaptado a constituição genética de cada individuo acarreta evidentes vantagens para a prevenção e tratamento de patologias. No entanto, são pertinentes e complexos os desafios que a mesma colocará, sendo necessária uma profunda reflexão sobre eles, de modo a encontrarem-se respostas satisfatórias. É esse o contributo que esperamos dar com esse breve artigo, alertando para problemas e abrindo a porta a certas soluções, embora seja claro que ainda são mais as perguntas que respostas disponíveis.

A emergência do direito da saúde / The emergence of health law / La emergencia del derecho a la salud

Este texto analisa as dificuldades de um léxico uniformizado em torno da área, da prática e da investigação jurídica em torno do Direito e da Saúde, gerando múltiplas designações (Direito Médico, da Medicina, Sanitário, Biodireito, etc.). Seguidamente, defende que o Direito da Saúde se desenvolveu como um ramo do saber jurídico autónomo, com um conjunto de princípios, métodos hermenêuticos, um objeto de análise específico e problemas próprios de organização judiciária. Salientando a importância das ciências vizinhas, como a Bioética, a Medicina Legal, a Economia da Saúde, o Autor defende que só um pensamento jurídico estruturado, com formação dogmática e histórica, com capacidade de diálogo interdisciplinar, permitirá o desenvolvimento do Direito da Saúde, o que assume especial relevância no Século XXI, com a carência de água, com a hiperpopulação e a urbanização crescente da vida em sociedade.

This text analyzes the difficulties of a lexicon standardized around the area of practice and legal research concerning the interface between Law and Healthcare, generating multiple designations (Medical Law, Health Law, Biolaw, etc.). Next, it argues that Healthcare Law developed as a separate branch of knowledge with a set of legal principles, hermeneutical methods, a specific object of analysis and problems of judicial organization. Stressing the importance of neighboring sciences such as bioethics, the Legal Medicine, Health Economics, the author argues that only a structured legal thought, with a dogmatic and historical education, with capacity of interdisciplinary dialogue, will enable the development of Health Law, which is particularly relevant in the twenty-first century, with the lack of water, the global over-population challenge and the increasing urbanization of life in society.

este texto analiza las dificultades de un léxico estandarizado alrededor del área de práctica y la investigación legal en torno a la Ley y la Salud, lo que ha generado múltiples denominaciones (derecho médico, derecho sanitario, Bioderecho, etc.). A continuación, se argumenta que el Derecho de la Salud ha desarrollado como una rama del conocimiento legal separada con un conjunto de principios, métodos hermenéuticos, un objeto específico de análisis y problemas de organización judicial. Destacando la importancia de las ciencias vecinas tales como la bioética, la Medicina Legal, la Economía de la Salud, el autor sostiene que sólo un pensamiento jurídico estructurado, con una formación dogmática e histórica, con capacidad de diálogo interdisciplinario, permitirá el desarrollo del derecho sanitario, que es particularmente relevante en el siglo XXI, con la falta de agua, el reto de la sobre-populación planetaria y el aumento de la urbanización de la vida en la sociedad.