Cannabinoid type-1 receptor blockade restores neurological phenotypes in two models for Down syndrome.

Intellectual disability is the most limiting hallmark of Down syndrome, for which there is no gold-standard clinical treatment yet. The endocannabinoid system is a widespread neuromodulatory system involved in multiple functions including learning and memory processes. Alterations of this system contribute to the pathogenesis of several neurological and neurodevelopmental disorders. However, the involvement of the endocannabinoid system in the pathogenesis of Down syndrome has not been explored before. We used the best-characterized preclinical model of Down syndrome, the segmentally trisomic Ts65Dn model. In male Ts65Dn mice, cannabinoid type-1 receptor (CB1R) expression was enhanced and its function increased in hippocampal excitatory terminals. Knockdown of CB1R in the hippocampus of male Ts65Dn mice restored hippocampal-dependent memory. Concomitant with this result, pharmacological inhibition of CB1R restored memory deficits, hippocampal synaptic plasticity and adult neurogenesis in the subgranular zone of the dentate gyrus. Notably, the blockade of CB1R also normalized hippocampal-dependent memory in female Ts65Dn mice. To further investigate the mechanisms involved, we used a second transgenic mouse model overexpressing a single gene candidate for Down syndrome cognitive phenotypes, the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). CB1R pharmacological blockade similarly improved cognitive performance, synaptic plasticity and neurogenesis in transgenic male Dyrk1A mice. Our results identify CB1R as a novel druggable target potentially relevant for the improvement of cognitive deficits associated with Down syndrome.

Space Radiation Protection Countermeasures in Microgravity and Planetary Exploration.

BACKGROUND: Space radiation is one of the principal environmental factors limiting the human tolerance for space travel, and therefore a primary risk in need of mitigation strategies to enable crewed exploration of the solar system. METHODS: We summarize the current state of knowledge regarding potential means to reduce the biological effects of space radiation. New countermeasure strategies for exploration-class missions are proposed, based on recent advances in nutrition, pharmacologic, and immune science. RESULTS: Radiation protection can be categorized into (1) exposure-limiting: shielding and mission duration; (2) countermeasures: radioprotectors, radiomodulators, radiomitigators, and immune-modulation, and; (3) treatment and supportive care for the effects of radiation. Vehicle and mission design can augment the overall exposure. Testing in terrestrial laboratories and earth-based exposure facilities, as well as on the International Space Station (ISS), has demonstrated that dietary and pharmacologic countermeasures can be safe and effective. Immune system modulators are less robustly tested but show promise. Therapies for radiation prodromal syndrome may include pharmacologic agents; and autologous marrow for acute radiation syndrome (ARS). CONCLUSIONS: Current radiation protection technology is not yet optimized, but nevertheless offers substantial protection to crews based on Lunar or Mars design reference missions. With additional research and human testing, the space radiation risk can be further mitigated to allow for long-duration exploration of the solar system.

Clinical and genomic insights into circulating tumor DNA-based alterations across the spectrum of metastatic hormone-sensitive and castrate-resistant prostate cancer.

BACKGROUND: Metastatic prostate cancer is a clonally heterogeneous disease state characterized by progressive somatic perturbations. The aim of this study was to identify cell free DNA- (cfDNA-) based alterations and their associations with outcomes in progressive metastatic prostate cancer. METHODS: In this longitudinal prospective cohort study plasma cfDNA/circulating tumor DNA (ctDNA) was analyzed before, during, and after androgen deprivation therapy (ADT) in 4 independent patient groups ranging from untreated metastatic hormone sensitive prostate cancer (mHSPC) to metastatic castrate resistant prostate cancer (mCRPC). Next generation sequencing was performed on ctDNA and germline DNA to characterize alterations and associations with clinical outcomes were determined for each group. FINDINGS: cfDNA yields were different in progressive mHSPC and mCRPC states (P < .001). In mHSPC, a higher than median ctDNA fraction was predictive of shorter time to ADT failure (HR, 2.29 [95% CI, 1.13-4.65]; Log-Rank P = .02). cfDNA, ctDNA taken with volume of metastatic disease in mHSPC and with alkaline phosphatase levels prognosticated survival better than clinical factors alone in mHSPC and mCRPC states (Log Rank P = 0.03). ctDNA-based AR, APC mutations were increased in mCRPC compared to mHSPC (P < ·05).TP53 mutations, RB1 loss, and AR gene amplifications correlated with poorer survival in mCRPC. Mutations in multiple DNA repair genes (ATM, BRCA1, BRCA2, CHEK2) were associated with time to ADT treatment failure and survival in mHSPC. INTERPRETATION: ctDNA fraction can further refine clinical prognostic factors in metastatic prostate cancer. Somatic ctDNA alterations have potential prognostic, predictive, and therapeutic implications in metastatic prostate cancer management. FUNDING: Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.

Comparación: acetaminofén vs ibuprofeno para el tratamiento de los síntomas en pacientes con infección por SARS-CoV-2 / Comparação: paracetamol vs ibuprofeno para o tratamento de sintomas em pacientes com infecção por SARS-CoV-2 / Comparison: acetaminophen vs ibuprofen for the treatment of symptoms in patients with SARS-CoV-2 infection

La propagación del COVID-19 fue expedita y tras varios informes la eficacia de algunos medicamentos antiinflamatorios no esteroideos, como el ibuprofeno, estuvo bajo sospecha. Mientas que el paracetamol (acetaminofén) se sugirió como una alternativa segura y recomendable para el manejo temprano y domiciliario del dolor y fiebre en pacientes. Objetivo. Comparar el uso del acetaminofén vs ibuprofeno para tratamiento de los síntomas en pacientes con infección por SARS-COV-2". Metodología. La investigación es una revisión sistemática, donde, se analizaron artículos científicos publicados en revistas vinculadas a áreas de salud, disponibles en buscadores y plataformas digitales tales, como Scienedirect, Pubmed, Elsevier y Springer Link. Las búsquedas se realizaron utilizando las palabras claves previamente definidas. Conclusión. El uso del ibuprofeno ha estado en duda desde sus inicios, en pacientes con COVID-19. Sin embargo, ningún estudio afirma asociar el uso del mismo con aumentos importantes en estadía hospitalaria, ingresos en UCI, necesidad de ventilación mecánica, ni mortalidad. Sin embargo, el acetaminofén ha sido utilizado desde un principio, su uso no estuvo en duda, pero los hallazgos recientes parecen indicar que no es tan eficaz como se pensaba en un principio. Siendo bastante inferior en la comparación directa con el ibuprofeno.

The spread of COVID-19 was expeditious and after several reports the efficacy of some non-steroidal anti-inflammatory drugs, such as ibuprofen, was under suspicion. While paracetamol (acetaminophen) was suggested as a safe and recommended alternative for early and home management of pain and fever in patients. Objective. To compare the use of acetaminophen vs ibuprofen for symptom management in patients with SARS-COV-2 infection". Methodology. The research is a systematic review, where scientific articles published in journals related to health areas, available in search engines and digital platforms such as Scienedirect, Pubmed, Elsevier and Springer Link, were analyzed. Searches were performed using previously defined keywords. Conclusion. The use of ibuprofen has been in question since its inception in patients with COVID-19. However, no study claims to associate its use with significant increases in hospital stay, ICU admissions, need for mechanical ventilation, or mortality. However, acetaminophen has been used from the beginning, its use was not in doubt, but recent findings seem to indicate that it is not as effective as originally thought. It is quite inferior in direct comparison with ibuprofen.

A disseminação da COVID-19 foi rápida e, após vários relatos, a eficácia de alguns anti-inflamatórios não esteroides, como o ibuprofeno, ficou sob suspeita. Já o paracetamol (acetaminofeno) foi sugerido como uma alternativa segura e recomendada para o tratamento precoce e domiciliar da dor e da febre nos pacientes. Objetivo. Comparar o uso de acetaminofeno versus ibuprofeno para o controle dos sintomas em pacientes com infecção por SARS-COV-2". Metodologia. A pesquisa é uma revisão sistemática, onde foram analisados artigos científicos publicados em periódicos relacionados às áreas de saúde, disponíveis em sites de busca e plataformas digitais como Scienedirect, Pubmed, Elsevier, e Springer Link. As buscas foram realizadas por meio de palavras-chave previamente definidas. Conclusões. O uso do ibuprofeno tem sido questionado desde sua criação em pacientes com COVID-19. No entanto, nenhum estudo afirma associar seu uso a aumentos significativos na permanência hospitalar, internações em UTI, necessidade de ventilação mecânica ou mortalidade. No entanto, o acetaminofeno tem sido usado desde o início, seu uso não foi questionado, mas descobertas recentes parecem indicar que ele não é tão eficaz quanto se pensava originalmente. Ele é muito inferior em comparação direta com o ibuprofeno.

Afectación cardiaca por Síndrome Inflamatorio Multisistémico asociado A SARS-CoV-2 en pacientes pediátricos / Cardiac involvement due to SARS-CoV-2 Associated Multisystem Inflammatory Syndrome in pediatric patients / Envolvimento cardíaco pela Síndrome Inflamatória Multissistêmica Associada a SARS-CoV-2 em pacientes pediátricos

Estudios recientes han planteado que el curso clínico puede ser crítico en niños debido a la naturaleza multifacética de la enfermedad. El Síndrome inflamatorio multisistémico asociado a SARS-CoV-2 (MIS-C), cursa con daño multisistémico, con predominio de afectación cardíaca que compromete la vida del paciente pediátrico. Objetivo. Identificar las principales alteraciones cardíacas por Síndrome inflamatorio multisistémico asociado a SARS-CoV-2 en pacientes pediátricos. Metodología. Se realizó una revisión sistemática mediante una búsqueda informativa en bases de datos. Se incluyeron estudios recientes publicados desde el año 2019 hasta el año 2022 que informaron acerca de las manifestaciones por afectación cardíaca, tratamiento en pacientes con alteración cardíaca por MIS-C y factores de riesgo asociados a MIS-C grave. Conclusiones. Las principales alteraciones cardiacas por síndrome inflamatorio multisistémico asociado a SARS-CoV-2 en pacientes pediátricos mostraron que las patologías más comunes fueron shock, arritmias cardíacas, derrame pericárdico, dilatación de las arterias coronarias y miocarditis aguda, por ende, las comorbilidades cardíacas son muy frecuentes en niños con MIS-C, donde, la afectación cardíaca y sistémica juega un papel muy importantes en el desarrollo de disfunción ventricular, miocarditis, anomalías de las arterias coronarias, arritmias y alteraciones del ritmo consideradas entres las más comunes.

Recent studies have suggested that the clinical course may be critical in children due to the multifaceted nature of the disease. The Multisystem Inflammatory Syndrome associated with SARS-CoV-2 (MIS-C) presents with multisystem damage, with a predominance of cardiac involvement that compromises the life of the pediatric patient. Objetive. To identify the main cardiac alterations due to Multisystem Inflammatory Syndrome associated with SARS-CoV-2 in pediatric patients. Methodology. A systematic review was carried out through an informative search in databases. Recent studies published from 2019 to 2022 that reported on manifestations due to cardiac involvement, treatment in patients with cardiac impairment due to MIS-C, and risk factors associated with severe MIS-C were included. Conclusions. The main cardiac alterations due to multisystem inflammatory syndrome associated with SARS-CoV-2 in pediatric patients showed that the most common pathologies were shock, cardiac arrhythmias, pericardial effusion, dilation of the coronary arteries and acute myocarditis, therefore, cardiac comorbidities are very high. Frequent in children with MIS-C, where cardiac and systemic involvement play a very important role in the development of ventricular dysfunction, myocarditis, coronary artery anomalies, arrhythmias, and rhythm disturbances considered among the most common.

Estudos recentes sugerem que o curso clínico pode ser crítico em crianças devido à natureza multifacetada da doença. A Síndrome Inflamatória multissistêmica associada ao SARS-CoV-2 (MIS-C) apresenta danos multissistêmicos, com predominância de acometimento cardíaco que compromete a vida do paciente pediátrico. Objetivo. Identificar as principais alterações cardíacas decorrentes da Síndrome Inflamatória multissistêmica associada ao SARS-CoV-2 em pacientes pediátricos. Metodologia. Uma revisão sistemática foi realizada por meio de uma pesquisa informativa em bancos de dados. Foram incluídos estudos recentes publicados de 2019 a 2022 que relataram manifestações devido ao envolvimento cardíaco, tratamento em pacientes com comprometimento cardíaco devido a MIS-C e fatores de risco associados a MIS-C grave. Conclusões. As principais alterações cardíacas devido à síndrome inflamatória multissistêmica associada ao SARS-CoV-2 em pacientes pediátricos mostraram que as patologias mais comuns foram choque, arritmias cardíacas, derrame pericárdico, dilatação das artérias coronárias e miocardite aguda, portanto, as comorbidades cardíacas são muito altas Frequente em crianças com MIS-C, onde o envolvimento cardíaco e sistêmico desempenha um papel muito importante no desenvolvimento de disfunção ventricular, miocardite, anomalias das artérias coronárias, arritmias e distúrbios do ritmo considerados entre os mais comuns.

Hiperprocalcitonemia como pronóstico clínico en pacientes sépticos de los centros hospitalarios privados de la ciudad de Cuenca ­ Ecuador / Hyperprocalcitonemia as a clinical prognosis in septic patients of private hospitals in the city of Cuenca­Ecuador

La procalcitonina, reactante de fase aguda, permite establecer el estado de los pacientes con diagnóstico de sepsis, brindando la posibilidad de asociarlo con su pronóstico. El objetivo de este estudio fue el determinar el pronóstico clínico de la hiperprocalcitonemia en pacientes sépticos de los centros hospitalarios privados de Cuenca­Ecuador. El estudio fue analítico de corte transversal, la muestra fueron 207 pacientes. Los datos se analizaron con el programa estadístico SPSS (25,0); el análisis se realizó mediante estadística descriptiva; la asociación mediante Odds Ratio (OR), intervalo de confianza (95%), considerando valores estadísticamente significativos con p <0,05. La prevalencia de hiperprocalcitonemia severa fue 63,29%, la media de edad 67,25±19,07 años; predominó el sexo masculino 57% y la etnia mestiza. Se evidenció asociación estadística entre hiperprocalcitonemia severa y mayor estancia hospitalaria (>15 días) OR: 2,41 (IC 95% 1,11-5,19 p: 0,015); de igual manera con la mortalidad intrahospitalaria OR: 9,37 (IC 95% 4,31-20,37 p: <0,000). Se determinó asociación, mas no significancia estadística con la presencia de comorbilidades OR: 1,35 (IC 95% 0,69-2,64 p: 0,243). Se evidenció hiperprocalcitonemia severa en casi 2/3 de los pacientes, y existió asociación con aumento de mortalidad y estancia hospitalaria.

Procalcitonin, an acute phase's reactant, enables to establish sepsis-diagnosis'-patients status, bringing the possibility of associate it with its prognosis. The aim of this study was to determine the clinical prognosis of hyperprocalcitonemia in septical patients of private hospital centers in Cuenca­Ecuador. The study was cross-sectional, the sample were 207 patients. Data was analyzed with SPSS statistical program (25.0); analysis was done through descriptive statistic; association through Odds Ratio (OR), confidence interval (95%), considering statiscally significant values with p <0.05. Severe hyperprocalcitonemia prevalence was 63.29%, average age 67.25±19.07 years old; male sex prevailed 57% and half-blood ethnic group. A statistical association between severe hyperprocalcitonemia and longer hospital stay (≥15 days) was shown OR: 2.41 (CI 95% 1.11­5.19 p: 0.015); likewise, with in-hospital mortality OR: 9.37 (CI 95% 4.31­20.37 p: <0.000). Association was determined, but statistical significance with presence of comorbidities was not OR: 1.35 (CI 95% 0.69­2.64 p:0.243). Severe hyperprocalcitonemia was shown in almost 2/3 of patients, and there was an association with mortality increase and hospital stay.

Antioxidant-chemoprevention diet ameliorates late effects of total-body irradiation and supplements radioprotection by MnSOD-plasmid liposome administration.

Abstract Many acute and chronic effects of ionizing radiation are mediated by reactive oxygen species and reactive nitrogen species, which deplete antioxidant stores, leading to cellular apoptosis, stem cell depletion and accelerated aging. C57BL/6NHsd mice receiving intravenous MnSOD-PL prior to 9.5 Gy total-body irradiation (TBI) show increased survival from the acute hematopoietic syndrome, and males demonstrated improved long-term survival (Epperly et al., Radiat. Res. 170, 437-444, 2008). We evaluated the effect of an antioxidant-chemopreventive diet compared to a regular diet on long-term survival in female mice. Twenty-four hours before the LD(50/30) dose of 9.5 Gy TBI, subgroups of mice were injected intravenously with MnSOD-PL (100 µg plasmid DNA in 100 µl of liposomes). Mice on either diet treated with MnSOD-PL showed decreased death after irradiation compared to irradiated mice on the house diet alone (P = 0.031 for the house diet plus MnSOD-PL or 0.015 for antioxidant diet plus MnSOD-PL). The mice on the antioxidant-chemoprevention diet alone or with MnSOD-PL that survived 30 days after irradiation had a significant increase in survival compared to mice on the regular diet (P = 0.04 or 0.01, respectively). In addition, mice treated with MnSOD-PL only and surviving 30 days after radiation also had increased survival compared to those on the regular diet alone (P = 0.02). Survivors of acute ionizing radiation damage have ameliorated life shortening if they are fed an antioxidant-chemopreventive diet.