Hdac6 deletion delays disease progression in the SOD1G93A mouse model of ALS

Defects in axonal transport are thought to contribute to the pathogenesis of neurodegenerative disease. Because α-tubulin acetylation facilitates axonal transport, inhibition of the α-tubulin deacetylating enzymes, histone deacetylase 6 (Hdac6) and silent information regulator 2 (Sirt2), is thought to be an interesting therapeutic strategy for these conditions. Amyotrophic lateral sclerosis (ALS) is a one such rapidly progressive and fatal neurodegenerative disorder, in which axonal transport defects have been found in vitro and in vivo. To establish whether the inhibition of Hdac6 or Sirt2 may be of interest for ALS treatment, we investigated whether deleting Hdac6 or Sirt2 from the superoxide dismutase 1, SOD1G93A mouse affects the motor neuron degeneration in this ALS model. Deletion of Hdac6 significantly extended the survival of SOD1G93A mice without affecting disease onset, and maintained motor axon integrity. This protective effect was associated with increased α-tubulin acetylation. Deletion of Sirt2 failed to affect the disease course, but also did not modify α-tubulin acetylation. These findings show that Hdac6, rather than Sirt2, is a therapeutic target for the treatment of ALS. Moreover, Sirt2 appears not to be a major α-tubulin deacetylase in the nervous syste

New heterogeneous metal-oxides based catalyst for vegetable oil trans-esterification

Neste trabalho são apresentados a preparação de novos materiais obtidos da co-precipitação de alumina e óxidos de estanho e zinco e seu uso como sistemas catalíticos ativos para alcoólise de óleos vegetais. Foi observado que estes óxidos metálicos do tipo (Al2O3)X(SnO)Y(ZnO) Z são ativos para a alcoólise do óleo de soja usando diversos álcoois, incluindo ramificados. Os melhores resultados foram observados utilizando metanol, sendo atingidas conversões acima de 80% em 4 horas. Foi também possível reciclar estes materiais sem perda aparente de sua atividade catalítica.The preparation of new materials obtained from the co-precipitation of aluminum, tin and zinc oxides and their use as catalytic system activities for vegetable oils alcoholysis are reported herein. It was observed that these metal-oxides of the type (Al2O3)X(SnO)Y(ZnO) Z are active for soybean oil alcoholysis, uzing several alcohols, including branched ones. Best result was achieved using methanol, with conversion yields up to 80% in 4 h. It was also possible to recycle the catalysts without apparent loss of activity

Public health impact and return on investment of Belgium’s pediatric immunization program

ObjectiveWe evaluated the public health impact and return on investment of Belgium’s pediatric immunization program (PIP) from both healthcare-sector and societal perspectives.MethodsWe developed a decision analytic model for 6 vaccines routinely administered in Belgium for children aged 0–10 years: DTaP-IPV-HepB-Hib, DTaP-IPV, MMR, PCV, rotavirus, and meningococcal type C. We used separate decision trees to model each of the 11 vaccine-preventable pathogens: diphtheria, tetanus, pertussis, poliomyelitis, Haemophilus influenzae type b, measles, mumps, rubella, Streptococcus pneumoniae, rotavirus, and meningococcal type C; hepatitis B was excluded because of surveillance limitations. The 2018 birth cohort was followed over its lifetime. The model projected and compared health outcomes and costs with and without immunization (based on vaccine-era and pre–vaccine era disease incidence estimates, respectively), assuming that observed reductions in disease incidence were fully attributable to vaccination. For the societal perspective, the model included productivity loss costs associated with immunization and disease in addition to direct medical costs. The model estimated discounted cases averted, disease-related deaths averted, life-years gained, quality-adjusted life-years gained, costs (2020 euros), and an overall benefit–cost ratio. Scenario analyses considered alternate assumptions for key model inputs.ResultsAcross all 11 pathogens, we estimated that the PIP prevented 226,000 cases of infections and 200 deaths, as well as the loss of 7,000 life-years and 8,000 quality-adjusted life-years over the lifetime of a birth cohort of 118,000 children. The PIP was associated with discounted vaccination costs of €91 million from the healthcare-sector perspective and €122 million from the societal perspective. However, vaccination costs were more than fully offset by disease-related costs averted, with the latter amounting to a discounted €126 million and €390 million from the healthcare-sector and societal perspectives, respectively. As a result, pediatric immunization was associated with overall discounted savings of €35 million and €268 million from the healthcare-sector and societal perspectives, respectively; every €1 invested in childhood immunization resulted in approximately €1.4 in disease-related cost savings to the health system and €3.2 in cost savings from a societal perspective for Belgium’s PIP. Estimates of the value of the PIP were most sensitive to changes in input assumptions for disease incidence, productivity losses due to disease-related mortality, and direct medical disease costs.ConclusionBelgium’s PIP, which previously had not been systematically assessed, provides large-scale prevention of disease-related morbidity and premature mortality, and is associated with net savings to health system and society. Continued investment in the PIP is warranted to sustain its positive public health and financial impact

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Receptores implicados en el efecto neurotrófico del ácido oleico durante el desarrollo del SNC

La existencia de un receptor específico para la albúmina en el cerebro, responsable de la elevada concentración de la albúmina en el cerebro durante los primeros días de vida posnatal y cuya expresión se encuentre regulada durante el desarrollo, se ha postulado durante décadas. Sin embargo, se desconocía todavía la naturaleza del receptor, así como el tipo de endocitosis empleada para la internalización de la albúmina en los astrocitos. En este trabajo, hemos observado que la megalina, la caveolina-1 y la caveolina-2, pero no la clatrina, colocalizan con la albúmina en la membrana plasmática. Además, dado que el silenciamiento de la megalina, de la caveolina-1 y de la caveolina-2, pero no el de la clatrina, reducen la capacidad de la albúmina para unirse a la membrana e internalizarse, se puede concluir que la megalina es el receptor de la albúmina en los astrocitos y que la endocitosis de la albúmina en los astrocitos está mediada por caveolas y no por vesículas recubiertas de clatrina. La internalización de la albúmina en los astrocitos promueve la sintesis del factor neurotrófico ácido oleico, que induce la diferenciación neuronal (aumento de las neuritas y aumento de las proteínas marcadoras de diferenciación axonal, GAP-43, y dendrítico, MAP-2). Dado que el ácido oleico es un ligando y activador de los PPARs, hemos investigado el papel de estos como receptores para el ácido oleico en neuronas. Nuestros resultados muestran que, pese a que las neuronas en cultivo primario expresen las tres isoformas de los PPARs (?,? and ?), solo la activación por ligandos específicos del PPAR?, y no del PPAR? y del PPAR?, induce la diferenciación neuronal. Además, el ácido oleico activa el PPAR? en las neuronas en cultivo. Finalmente, el silenciamiento del PPAR? previene la diferenciación neuronal inducida por el ácido oleico, lo que sugiere que el PPAR? es el receptor del ácido oleico para su efecto neurotrófico en la diferenciación neuronal.The existence of a specific receptor for albumin in the newborn brain, responsible for the high concentrations of albumin in the brain during development and whose expression would be regulated during that period, has been suggested for more than two decades. Nonetheless, the nature of this receptor as well as the mechanism of endocytosis used for albumin uptake in astrocytes was still unknown. In this work, we found that megalin, caveolin-1 and caveolin-2, but nor clathrin, colocalize with albumin in the plasma membrane. In addition, when the expression of megalin, caveolin-1 and caveolin-2 was silenced by siRNA, albumin binding and internalization was strongly reduced. Clathrin silencing had no effect on albumin binding and uptake. These results indicate that megalin is a receptor for albumin in astrocytes and that albumin uptake in astrocytes is mediated by caveolae and not by clathrin-coated vesicles. The uptake of albumin in astrocytes promotes the synthesis oleic acid, a neurotrophic factor for neurons that induce neuronal differentiation (promoting neurite outgrowth and increasing the expression of molecular markers of axonal and dendritic differentiation, GAP-43 and MAP-2, respectively). Since oleic acid is a ligand and activator of PPARs, we investigated PPARs as receptors for oleic acid in neurons. Our results show that, although all PPAR isoforms (?,? and ?) are expressed in neurons from primary culture, only PPAR? activation by specific agonists induced neuronal differentiation, while PPAR? and ? agonists did not modify neuronal differentiation. Besides, our results indicate that oleic acid activates PPAR? in neurons. Finally, the neurotrophic effect of oleic acid is prevented in neurons after PPAR? has been silenced by siRNA, suggesting that PPAR? is the receptor for oleic acid in neurons, mediating its neurotrophic effect

Estudio del receptor de la albúmina en astrocitos y su importancia en la respuesta al daño cerebral

Premios: Ayudas a la Investidación Ignacio Larramendi, 200

Fiscal analysis of the pediatric immunization program in Belgium applying a lifetime government perspective framework

A public economic framework was used to explore lifetime government costs and benefits in relation to the Pediatric Immunization Program (PIP) in Belgium based on cases and deaths averted. To estimate changes in net government revenue, we developed a decision-analytic model that quantifies lifetime tax revenues and transfers based on changes in morbidity and mortality arising from Belgium’s Pediatric Immunization Program (PIP). The model considered differences in incidence rates with vaccines included in Belgium’s PIP: compared with the pre-vaccine era. Changes in deaths and comorbid conditions attributed to PIP on the Belgium 2020 birth cohort were used to estimate gross lifetime earnings changes, tax revenue gains attributed to averted morbidity and mortality avoidance, disability transfer cost savings, and averted special education costs associated with each vaccine. Vaccinating a single birth cohort according to the PIP gives rise to fiscal gains of €56 million in averted tax revenue loss, €8 million disability savings, and €6 million special education cost-savings. Based on the costs of implementing the PIP, we estimate the fiscal benefit–cost ratio (fBCR) of €2.2 investment return for the government from every €1 invested excluding longevity costs. Reducing vaccine-preventable conditions generates tax revenue for the government, providing fiscal justification for sustained immunization investments.</p