Presente y futuro de la tributación del capital en el marco de una economía globalizada.

Uno de los principales fenómenos que han caracterizado a la economía mundial durante las dos últimas décadas es su creciente apertura y globalización, favorecida por un proceso progresivo de desregulación y liberalización de distintos sectores económicos. Sin duda, el sector en el que ha cobrado una mayor importancia este fenómeno de la globalización es el financiero, apoyado por la cada vez mayor libertad de movimientos de capitales y por la aparición de nuevos productos, especialmente los “productos financieros derivados”, que facilitan crecientemente la cobertura de riesgos en la inversión a la vez que favorecen la realización de operaciones especulativas. Todas estas circunstancias plantean retos crecientes a los sistemas tributarios de los países desarrollados, que se han traducido en los últimos años en reformas de la tributación de los rendimientos de capital (con nuevos planteamientos impositivos como los denominados “impuestos duales”), intentando evitar en lo posible la huida de los capitales nacionales al extranjero. Los países que forman parte de la Unión Europea se han visto especialmente afectados por éste fenómeno, favorecido por la entrada en vigor de la Unión Económica y Monetaria, y que plantea especiales problemas ante la ausencia de medidas de armonización de la tributación directa dentro de la UE. El objetivo de este trabajo consiste en analizar los desafíos que se plantean para los sistemas tributarios nacionales, haciendo especial énfasis en los objetivos de equidad y eficiencia que deben definir la tributación del capital a nivel internacional, la evolución que han seguido dichos sistemas tributarios en los últimos años, y los planteamientos de futuro existentes a partir de las propuestas de armonización planteadas por la Comisión Europea

Hypoinsulinaemic, hypoketotic hypoglycaemia due to mosaic genetic activation of PI3-kinase.

OBJECTIVE: Genetic activation of the insulin signal-transducing kinase AKT2 causes syndromic hypoketotic hypoglycaemia without elevated insulin. Mosaic activating mutations in class 1A phospatidylinositol-3-kinase (PI3K), upstream from AKT2 in insulin signalling, are known to cause segmental overgrowth, but the metabolic consequences have not been systematically reported. We assess the metabolic phenotype of 22 patients with mosaic activating mutations affecting PI3K, thereby providing new insight into the metabolic function of this complex node in insulin signal transduction. METHODS: Three patients with megalencephaly, diffuse asymmetric overgrowth, hypoketotic, hypoinsulinaemic hypoglycaemia and no AKT2 mutation underwent further genetic, clinical and metabolic investigation. Signalling in dermal fibroblasts from one patient and efficacy of the mTOR inhibitor Sirolimus on pathway activation were examined. Finally, the metabolic profile of a cohort of 19 further patients with mosaic activating mutations in PI3K was assessed. RESULTS: In the first three patients, mosaic mutations in PIK3CA (p.Gly118Asp or p.Glu726Lys) or PIK3R2 (p.Gly373Arg) were found. In different tissue samples available from one patient, the PIK3CA p.Glu726Lys mutation was present at burdens from 24% to 42%, with the highest level in the liver. Dermal fibroblasts showed increased basal AKT phosphorylation which was potently suppressed by Sirolimus. Nineteen further patients with mosaic mutations in PIK3CA had neither clinical nor biochemical evidence of hypoglycaemia. CONCLUSIONS: Mosaic mutations activating class 1A PI3K cause severe non-ketotic hypoglycaemia in a subset of patients, with the metabolic phenotype presumably related to the extent of mosaicism within the liver. mTOR or PI3K inhibitors offer the prospect for future therapy

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Efficacy of clozapine versus standard treatment in adult individuals with intellectual disability and treatment-resistant psychosis (CLOZAID): study protocol of a multicenter randomized clinical trial

BackgroundIntellectual disability (ID) affects approximately 1% of the worldwide population and individuals with ID have a higher comorbidity with mental illness, and specifically psychotic disorders. Unfortunately, among individuals with ID, limited research has been conducted since ID individuals are usually excluded from mental illness epidemiological studies and clinical trials. Here we perform a clinical trial to investigate the effectiveness of clozapine in the treatment of resistant psychosis in individuals with ID. The article highlights the complexity of diagnosing and treating psychopathological alterations associated with ID and advocates for more rigorous research in this field.MethodsA Phase IIB, open-label, randomized, multicenter clinical trial (NCT04529226) is currently ongoing to assess the efficacy of oral clozapine in individuals diagnosed with ID and suffering from treatment-resistant psychosis. We aim to recruit one-hundred and fourteen individuals (N=114) with ID and resistant psychosis, who will be randomized to TAU (treatment as usual) and treatment-with-clozapine conditions. As secondary outcomes, changes in other clinical scales (PANSS and SANS) and the improvement in functionality, assessed through changes in the Euro-QoL-5D-5L were assessed. The main outcome variables will be analyzed using generalized linear mixed models (GLMM), assessing the effects of status variable (TAU vs. Clozapine), time, and the interaction between them.DiscussionThe treatment of resistant psychosis among ID individuals must be directed by empirically supported research. CLOZAID clinical trial may provide relevant information about clinical guidelines to optimally treat adults with ID and treatment-resistant psychosis and the benefits and risks of an early use of clozapine in this underrepresented population in clinical trials.Trial registrationClinicaltrials.gov: NCT04529226. EudraCT: 2020-000091-37