La detención operativa en la frontera entre el Derecho Internacional Humanitario y el Derecho Internacional de los Derechos Humanos

La tesis analiza, desde una perspectiva de Derecho internacional, la detención de personas y algunostemas relacionados, en particular los asesinatos selectivos como alternativa legítima a la detención, en operaciones internacionales básica, pero no exclusivamente militares. El primer capítulo analiza aspectos generales: el concepto mismo de detención, la aplicación extraterritorial del Derecho de los Derechos Humanos, la aplicación del Derecho Internacional Humanitario, la interacción entre estas dos ramas del Derecho internacional, y el concepto de los "funcionarios encargados de hacer cumplir la ley", esto último para aproximarse al modelo o paradigma policial-judicial en materia de uso de la fuerza. El segundo capítulo analiza la detención operativa en sus posibles contextos: el conflicto armado internacional, el conflicto no internacional y las operaciones de paz, estas últimas en sus aspectos militar y policial. Hay una especial referencia a la detención de terroristas, que incluye los distintos enfoques del Derecho Internacional Humanitario y del modelo policial-judicial, con un apartado relativo a la práctica de los EEUU. Por último, se explora la detención operativa como posible figura autónoma en conflictos armados no internacionales y otras situaciones de violencia que no alcanzan el umbral del conflicto armado, ámbitos en los que se desenvuelven frecuentement las fuerzas militares internacionales en el marco del sistema de seguridad colectiva de la Carta de las Naciones Unidas. Al hilo de la exposición se examinan aspectos relacionados con la detención distinguiendo su tratamiento en el contexto del Derecho Internacional Humanitario y del Derecho Internacional de los Derechos Humanos, en particular los llamados "targeted killings" o asesinatos selectivos, o la tortura, como práctica ilegal o criminal normalmente asociada a las situaciones de privación de libertad. Hay también, en paralelo al análisis propio del Derecho militar operativo, y como se expone anteriormente, un análisis de instituciones, organizaciones y marco jurídico de actuación propio de los institutos policiales, con referencias comparativas a distintos modelos policiales, organismos de cooperación y posibilidades reales de actuación efectiva, en particular en lo que se refiere a la lucha contra el terrorismo y otras formas de criminalidad como la piratería o el tráfico internacional de estupefacientes a gran escala, o en apoyo del terrorismo, que está implicando a las fuerzas armadas de diversos Estados

Enzyme-responsive intracellular controlled release using nanometric silica mesoporous supports capped with "saccharides"

This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Nano, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/nn101499d.The synthesis of new capped silica mesoporous nanoparticles for on-command delivery applications is described. The gate-like functional hybrid systems consisted of nanoscopic MCM-41-based materials functionalized on the pore outlets with different “saccharide” derivatives and a dye contained in the mesopores. A series of hydrolyzed starch products as saccharides were selected. The mesoporous silica nanoparticles S1, S2, and S3 containing the grafted starch derivatives Glucidex 47, Gludicex 39, and Glucidex 29 were synthesized. Additionally, for comparative purposes solid S4 containing lactose was prepared. Delivery studies in pure water in the presence of pancreatin or -D-galactosidase were carried out for S1S3 and S4, respectively. S1, S2, and especially S3 showed very low release in the absence of enzyme, but displayed cargo delivery in the presence of the corresponding enzyme. Moreover, nanoparticles of S1 were used to study the controlled release of the dye in intracellular media. Cell viability assays using HeLa and LLC-PK1 cells indicated that S1 nanoparticles were devoid of unspecific cell toxicity. The endocytosis process for S1 nanoparticle internalization in HeLa cells was confirmed, and the anchored starch was degraded by the lysosomal enzymes. Furthermore, a new mesoporous silica nanoparticle functionalized with Glucidex 47 and loaded with a cytotoxic, S1-DOX, was developed. The cell viability with S1-DOX decreased due to the internalization of the nanoparticle, enzyme-dependent opening of the saccharide molecular gate and the consequent release of the cytotoxic agent. As far as the authors know, this is the first example of enzyme-induced in-cell delivery using capped silica mesoporous nanoparticles.The authors wish to express their gratitude to the Spanish Government (Projects MAT2009 14564 C04 01 MAT2009 14564 C04 04 and BIO2007 60066) and the Generalitat Valencia (Projects PROMETEO/2009/016 and PROMETEO/2010/005) for support A B is grateful to the Universidad Politecnica de Valencia for an FPI grant E A thanks the MICINN for a FPU contract We thank Roquette for the Glucidex samples We would like to thank the CIPF confocal microscopy service for technical supportBernardos Bau, A.; Mondragón Martínez, L.; Aznar, E.; Marcos Martínez, MD.; Martínez-Máñez, R.; Sancenón Galarza, F.; Soto Camino, J.... (2010). Enzyme-responsive intracellular controlled release using nanometric silica mesoporous supports capped with "saccharides". ACS Nano. 4(11):6353-6368. https://doi.org/10.1021/nn101499dS6353636841

Silica-based powders and monoliths with bimodal pore systems

Porous pure and doped silicas with pore sizes at two length scales (meso/macroporous) have been prepared and shaped both as powders and monoliths through a one-pot surfactant assisted procedure by using a simple template agent and starting from atrane complexes as inorganic precursors.El Haskouri, Jamal, [email protected] ; Latorre Saborit, Julio, [email protected] ; Beltran Porter, Aurelio, [email protected] ; Beltran Porter, Daniel, [email protected] ; Amoros del Toro, Pedro Jose, [email protected]

Stability of different mesoporous silica particles during an in vitro digestion

Mesoporous silica materials have the ability to entrap drugs, nutrients and functional biomolecules and can be able to act as smart delivery systems capable to control and target the release of their cargo in a particular part of the gastrointestinal tract when administrated orally. However, the aptness of these encapsulation supports in in vivo oral controlled release relies on their chemical stability through the digestive tube. In this context, we have evaluated the stability of four different mesoporous silica particles, frequently used as encapsulating supports, during an in vitro digestion process comprising buccal, stomach and intestinal phases. Results showed that after 4 h of digestion, the textural properties of silica supports in the form of nanoparticles (MCM-41 and UVM-7 nanoparticles) were lost in varying degrees, whereas silica microparticles supports (MCM-41 and SBA-15 microparticles) endures better the digestion process. Moreover, the functionalization of the surface with N-1-(3-trimethoxysilylpropyl)diethylenetriamine, an organic moiety commonly used in the preparation of pH-responsive mesoporous silica particles, resulted in an improvement of the stability of the supports. (C) 2016 Elsevier Inc. All rights reserved.Authors gratefully acknowledge the financial support from the Ministerio de Economia y Competitividad (Projects AGL2012-39597-C02-01, AGL2012-39597-C02-02 and MAT2012-38429-C04-01 and MAT2012-38429-C04-03), Generalitat Valenciana (project PROMETEO/2009/016) and FEDER founding. E.P. and M.R are grateful to the Ministerio de Ciencia e Innovacion for their grants (AP2008-00620, AP2010-4369). Electron Microscopy Service of the UPV is also acknowledged.Pérez-Esteve, É.; Ruiz Rico, M.; Torre, CDL.; Llorca Martínez, ME.; Sancenón Galarza, F.; Marcos Martínez, MD.; Amoros Del Toro, PJ.... (2016). Stability of different mesoporous silica particles during an in vitro digestion. Microporous and Mesoporous Materials. 230:196-207. https://doi.org/10.1016/j.micromeso.2016.05.004S19620723

Amidase-responsive controlled release of antitumoral drug into intracellular media using gluconamide-capped mesoporous silica nanoparticles

MCM-41 silica nanoparticles were used as inorganic scaffolding to prepare a nanoscopic-capped hybrid material S1, which was able to release an entrapped cargo in the presence of certain enzymes, whereas in the absence of enzymes, a zero release system was obtained. S1 was prepared by loading nanoparticles with Safranine O dye and was then capped with a gluconamide derivative. In the absence of enzymes, the release of the dye from the aqueous suspensions of S1 was inhibited as a result of the steric hindrance imposed by the bulky gluconamide derivative, the polymerized gluconamide layer and the formation of a dense hydrogen-bonded network around the pore outlets. Upon the addition of amidase and pronase enzymes, delivery of Safranine O dye was observed due to the enzymatic hydrolysis of the amide bond in the anchored gluconamide derivative. S1 nanoparticles were not toxic for cells, as demonstrated by cell viability assays using HeLa and MCF-7 cell lines, and were associated with lysosomes, as shown by confocal microscopy. Finally, the S1¿CPT material loaded with the cytotoxic drug camptothecin and capped with the gluconamide derivative was prepared. The HeLa cells treated with S1¿CPT underwent cell death as a result of material internalization, and of the subsequent cellular enzyme-mediated hydrolysis and aperture of the molecular gate, which induced the release of the camptothecin cargo.We thank the Spanish Government (Project MAT2009-14564-C04 and SAF2010-15512) and the Generalitat Valenciana (Project PROMETEO/2009/016and/2010/005) for support. I. C. thanks the Universitat Politecnica de Valencia for her fellowship. L. M. thanks the Generalitat Valenciana for her post-doctoral VALi+d contract. E. A. and C. T. also thank the CIBER-BBN for contracts. We thank Eva Maria Lafuente Villarreal and Alberto Hernandez Cano from the Confocal Microscopy service of CIPF and the Electronic Microscopy service of UPV for their technical support.Candel Busquets, I.; Aznar Gimeno, E.; Mondragón Martínez, L.; De La Torre Paredes, C.; Martínez Mañez, R.; Sancenón Galarza, F.; Marcos Martínez, MD.... (2012). Amidase-responsive controlled release of antitumoral drug into intracellular media using gluconamide-capped mesoporous silica nanoparticles. Nanoscale. 4(22):7237-7245. https://doi.org/10.1039/c2nr32062bS7237724542

High prevalence of liver fibrosis among european adults with unknown liver disease: a population-based study

[Background & Aims] Liver fibrosis is the main determinant of long-term outcome in chronic liver diseases. Little is known about the prevalence of liver fibrosis in the general population. The aim of the study was to investigate the prevalence of liver fibrosis in the general adult population with unknown liver disease.[Methods] This was a population-based, cross-sectional study performed in the Barcelona metropolitan area. Subjects aged 18 to 75 years old were identified randomly from citizens included in the primary health care registry. Of 4866 subjects invited, 3076 participated (63.2%). Liver fibrosis was estimated by measuring liver stiffness (LS) with transient elastography (TE). Liver histology was assessed in 92 subjects with increased LS.[Results] Prevalence estimates of increased LS (≥6.8, ≥8.0, and ≥9.0 kPa) were 9.0%, 5.8%, and 3.6%, respectively. The etiology of liver disease was mainly nonalcoholic fatty liver disease (NAFLD), followed by alcohol risk consumption (consumption of ≥21 standard drinking units/wk in men and ≥14 standard drinking units/wk in women). Factors independently associated with increased LS were male sex, abdominal obesity, type 2 diabetes, serum glucose, high-density lipoprotein, and triglyceride levels. Subjects without risk factors for NAFLD or without alcohol risk consumption had a very low prevalence of increased LS. The best cut-off value of LS for significant liver fibrosis (F2–F4) was 9.2 kPa, with high sensitivity and specificity. TE was more accurate than alanine aminotransferase, NAFLD fibrosis score, or Fibrosis 4. An algorithm for screening for liver fibrosis using TE in the community setting is proposed.[Conclusions] These findings show a high prevalence of silent liver disease with advanced fibrosis mainly related to NAFLD in adult European subjects without known liver disease. An LS value less than 9.2 kPa predicts the absence of significant liver fibrosis with high accuracy and could be used for screening purposes.The project received a research grant from the Carlos III Institute of Health, Ministry of Economy and Competitiveness (Spain), awarded on the 2011 call under the Health Strategy Action 2013–2016, within the National Research Program oriented to Societal Challenges, within the Technical, Scientific and Innovation Research National Plan 2013–2016, with reference PI11/0267, co-funded by European Union European Regional Development Fund funds. Also supported by grants from Fondo de Investigación Sanitaria Instituto de Salud Carlos III-Subdirección General de Evaluación and the European Regional Development Fund Fondo Europeo de Desarrollo Regional (PI16/ 00043), the Agencia de Gestió d’Ajuts Universitarisi de Recerca, and the European Horizon 20/20 program, H20/20-SC1-2016-RTD, and an Institució Catalana de Recerca I Estudis Avançats Academy Award (P.G.).Peer reviewe

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio