La movilidad internacional de las empresas en la Unión Europea: respuestas del Tribunal de Justicia de la Unión Europea

El mercado único es uno de los pilares de la estrategia de la UE, y para su completo éxito es indispensable el buen funcionamiento de las libertades fundamentales. Más en concreto, dado que los operadores económicos más relevantes en el proceso de internacionalización son las sociedades, tiene especial relevancia el funcionamiento del derecho de circulación de persona, dentro del que se encuentra la libertad de establecimiento. En este trabajo en primer lugar introduciremos la situación actual del Derecho de sociedades en la Unión Europea, su relevancia en el marco comunitario, su pilar: la libertad de establecimiento, su contenido, modalidades y escasa regulación. En segundo lugar analizaremos con detalle el caso concreto de desplazamiento de sociedades en la Unión Europea a través del traslado de su sede social entre Estados miembros utilizando para ello las dos últimas sentencias del TJUE en la materia: Cartesio y VALE. Por último haremos una breve reflexión sobre el estado actual de la normativa española referente al traslado de domicilio y su adecuación a la más reciente jurisprudencia del TJUE en esta materia

Developing a model to predict the early risk of hypertriglyceridemia based on inhibiting lipoprotein lipase (LPL): a translational study

Hypertriglyceridemia; Inhibiting lipoprotein lipaseHipertrigliceridèmia; Inhibició de la lipoproteïna lipasaHipertrigliceridemia; Inhibición de la lipoproteína lipasaHypertriglyceridemia (HTG) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). One of the multiple origins of HTG alteration is impaired lipoprotein lipase (LPL) activity, which is an emerging target for HTG treatment. We hypothesised that early, even mild, alterations in LPL activity might result in an identifiable metabolomic signature. The aim of the present study was to assess whether a metabolic signature of altered LPL activity in a preclinical model can be identified in humans. A preclinical LPL-dependent model of HTG was developed using a single intraperitoneal injection of poloxamer 407 (P407) in male Wistar rats. A rat metabolomics signature was identified, which led to a predictive model developed using machine learning techniques. The predictive model was applied to 140 humans classified according to clinical guidelines as (1) normal, less than 1.7 mmol/L; (2) risk of HTG, above 1.7 mmol/L. Injection of P407 in rats induced HTG by effectively inhibiting plasma LPL activity. Significantly responsive metabolites (i.e. specific triacylglycerols, diacylglycerols, phosphatidylcholines, cholesterol esters and lysophospholipids) were used to generate a predictive model. Healthy human volunteers with the impaired predictive LPL signature had statistically higher levels of TG, TC, LDL and APOB than those without the impaired LPL signature. The application of predictive metabolomic models based on mechanistic preclinical research may be considered as a strategy to stratify subjects with HTG of different origins. This approach may be of interest for precision medicine and nutritional approaches.This research was financially supported by the Catalan Government through the funding grant ACCIÓ-Eurecat (PRIV2019-PREVENTOMICS) and by the Centre for the Development of Industrial Technology (CDTI) of the Spanish Ministry of Science and Innovation under grant agreement: TECNOMIFOOD project. CER-20191010

A Pilot Study for Metabolic Profiling of Obesity-Associated Microbial Gut Dysbiosis in Male Wistar Rats

Obesity is one of the most incident and concerning disease worldwide. Definite strategies to prevent obesity and related complications remain elusive. Among the risk factors of the onset of obesity, gut microbiota might play an important role in the pathogenesis of the disease, and it has received extensive attention because it affects the host metabolism. In this study, we aimed to define a metabolic profile of the segregated obesity-associated gut dysbiosis risk factor. The study of the metabolome, in an obesity-associated gut dysbiosis model, provides a relevant way for the discrimination on the different biomarkers in the obesity onset. Thus, we developed a model of this obesity risk factors through the transference of gut microbiota from obese to non-obese male Wistar rats and performed a subsequent metabolic analysis in the receptor rats. Our results showed alterations in the lipid metabolism in plasma and in the phenylalanine metabolism in urine. In consequence, we have identified metabolic changes characterized by: (1) an increase in DG:34:2 in plasma, a decrease in hippurate, (2) an increase in 3-HPPA, and (3) an increase in o-coumaric acid. Hereby, we propose these metabolites as a metabolic profile associated to a segregated dysbiosis state related to obesity disease

Alterations in Metabolome and Microbiome Associated with an Early Stress Stage in Male Wistar Rats: A Multi-Omics Approach

Stress disorders have dramatically increased in recent decades becoming the most prevalent psychiatric disorder in the United States and Europe. However, the diagnosis of stress disorders is currently based on symptom checklist and psychological questionnaires, thus making the identification of candidate biomarkers necessary to gain better insights into this pathology and its related metabolic alterations. Regarding the identification of potential biomarkers, omic profiling and metabolic footprint arise as promising approaches to recognize early biochemical changes in such disease and provide opportunities for the development of integrative candidate biomarkers. Here, we studied plasma and urine metabolites together with metagenomics in a 3 days Chronic Unpredictable Mild Stress (3d CUMS) animal approach that aims to focus on the early stress period of a well-established depression model. The multi-omics integration showed a profile composed by a signature of eight plasma metabolites, six urine metabolites and five microbes. Specifically, threonic acid, malic acid, alpha-ketoglutarate, succinic acid and cholesterol were proposed as key metabolites that could serve as key potential biomarkers in plasma metabolome of early stages of stress. Such findings targeted the threonic acid metabolism and the tricarboxylic acid (TCA) cycle as important pathways in early stress. Additionally, an increase in opportunistic microbes as virus of the Herpesvirales was observed in the microbiota as an effect of the primary stress stages. Our results provide an experimental biochemical characterization of the early stage of CUMS accompanied by a subsequent omic profiling and a metabolic footprinting that provide potential candidate biomarkers

Modulation of mir-33 and mir-122 by dietary polyphenols

mi(cro)RNAs are becoming relevant for the epigenetic control of metabolism. miRNAs are small non-conding RNAs of approximately 19-24 nucleotides in length that regulate the expression of target genes at post-transcriptional level. Specifically, miR-33 is a critical regulator of cholesterol and fatty acid homeostasis by repressesing fatty acid oxidation, hepatic HDL biogenesis and cholesterol efflux to HDL. Furthermore, miR-122, which is liver-specific, regulates several genes that control fatty acid and triglyceride biosynthesis. On the other hand, dietary components, such polyphenols, are reported to have benefitial effects againts cardiovascular diseases, reducing triglycerides and/or cholesterol plasma levels. Hence, the main objective of this thesis was to evaluate the capacity of polyphenols, mainly proanthocyanidins, to modulate miR-33 and miR-122 in different physiological situations. Result showed that polyphenols modulate these miRNAs and their target genes in liver, suggesting that miRNAs regulation are a new molecular mechanims used by some polyphenols to modulate lipid metabolism and to improve the atherogenic profile. Moreover, NMR studies showed that polyphenols directly bind to miR-33 and miR-122, suggesting that polyphenols can modulate cell miRNAs levels by a direct interaction.Las proantocianidinas, que son agentes hipolipidémicos, son los polifenoles mayoritarios en la dieta humana que ayudan a combatir factores de riesgo contra la obesidad y la enfermedad cardiovascular. Por otro lado, los mi(cro)RNAs participan en la regulación de genes del metabolismo lipídico y, el efecto de las proantocianidinas sobre dichos miRNAs es desconocido. Por ello, el principal objetivo de la tesis ha sido evaluar si los polifenoles, principalmente proantocianidinas, modulan miR-33 i miR-122, dos miRNAs involucrados en el metabolismo lipídico. Para ello se usaron modelos animales y celulares. Los resultados muestran que los compuestos de la dieta modulan estos miRNAs, mejorando el metabolismo lipídico, y que los polifenoles se unen directamente a miR-33 i miR-122. En conclusión, las proantocianidinas al modular los níveles de miR-33 i miR-122 pueden ser útiles para tratar enfermedades metabólicas. Además, estos resultados también sugieren que la modulación los miRNAs puede ser un mecanismo molecular usado por los componentes de la dieta por el que mejoran un perfil aterogénic

Treatment of Osteoarthritis of the Knee with a Combination of Autologous Conditioned Serum and Physiotherapy: A Two-Year Observational Study.

BACKGROUND:Autologous conditioned serum (ACS) is an autologous blood product that has shown efficacy against knee osteoarthritis (OA) in randomized controlled trials. However, there are few reports of its effectiveness in everyday practice. Here, we report clinical efficacy results from a two-year prospective observational study of patients with highly symptomatic knee OA who received ACS in conjunction with physiotherapy. METHODS:118 patients with unilateral knee OA (Kellgren-Lawrence grades I-IV), who were candidates for surgery but instead chose conservative treatment, were treated with a combination of four intra-articular injections of ACS (2 mL each) once weekly over four weeks and subsequent physiotherapy applied 4 weeks after ACS injection. Main endpoints of the study were pain (Numeric Rating Scale [NRS]) assessed at 0, 3, 6, 12 and 24 months, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) global score, assessed at 0 and 24 months. The effect size (Cohen's d) was calculated for pain and WOMAC outcomes, with effect sizes >0.8 considered large. RESULTS:By 3 months, there were significant improvements in pain (NRS) from baseline (-63.0%, p5) and WOMAC improvement (8.0-13.6) were very large. Only one patient received total knee joint replacement during the study. Clinical improvement did not correlate with gender, age, Kellgren-Lawrence grade, or body mass index. CONCLUSIONS:Treatment with ACS and physiotherapy produced a rapid decline in pain, which was sustained for the entire two years of the study. This was accompanied by a large improvement in WOMAC scores at two years. These results confirm that ACS combined with physiotherapy is an effective treatment for OA of the knee

Pain (NRS) scores for baseline, 3, 6, 12 and 24 months after treatment with ACS and physiotherapy.

<p>Error bars denote standard deviation. ACS: Autologous conditioned serum; NRS: Numeric Rating Scale.</p

WOMAC global and WOMAC subscores pain, stiffness and function at baseline and 24 months after treatment with ACS and physiotherapy.

<p>Error bars denote standard deviation. ACS: Autologous conditioned serum; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index.</p

Microcystic Lymphatic Malformation Successfully Treated With Topical Rapamycin

Microcystic lymphatic malformations (MLM) are low-flow vascular malformations composed of multiple small cysts. MLM usually affect deep lying structures, which makes their treatment even more difficult and complex. A novel and interesting treatment is rapamycin, a mammalian target of rapamycin inhibitor that when orally administrated has offered favorable results. However, until recently, topical rapamycin had not been used in the treatment of MLM. Case 1 is a girl aged 13 years with extensive MLM affecting the muscles in the right buttock. The patient had received frequent cycles of cryotherapy, but they had failed to control the associated symptoms. In the previous 12 months, the patient had reported greater discomfort, swelling, exudate, and superinfection of the affected region. Because no specific treatment has yet been approved for MLM, and as a step before the use of aggressive systemic or intralesional treatments, it was decided to initiate treatment with 1% rapamycin ointment. After 4 months of treatment, the patient presented a marked improvement, with a significant reduction of associated complications and no major side effects. Case 2 is a boy aged 5 years who underwent surgery for an intergluteal lipoblastoma at 3 weeks of life and developed a MLM on the scar 6 months afterward. The lesion showed slow growth and continuous exudation with frequent episodes of superinfection. Treatments with laser multiplex and intralesionalbleomycin were performed unsuccessfully. In the previous 4 months, the patient had been treated with 1% rapamycin ointment with significant improvement and no side effects

Beneficial effects of the Mediterranean spices and aromas on non-alcoholic fatty liver disease

Background Non-alcoholic fatty liver disease (NAFLD) can be regarded as the hepatic manifestation of metabolic syndrome (MS), which has a high prevalence in Western-lifestyle countries. NAFLD can progress to more severe pathologies such as cirrhosis and fibrosis, thus worsening individuals\u2019 life quality and increasing health costs. In the last decades, many efforts have been made in order to understand the molecular mechanisms of NAFLD and how to cure it. It has become clear that alimentary regimen is of primary importance for preventing/treating MS and NAFLD. Scope and approach Beneficial effects of the Mediterranean diet (MedDiet) on MS and NAFLD are now recognized and can be ascribed to low calories intake but also to abundance of anti-oxidant and anti-inflammatory compounds which are present in fruit and vegetables as well as in herbs and spices widely used to flavor traditional Mediterranean dishes. The aim of this review is to summarize briefly NAFLD molecular pathways and therapies, while focusing on the beneficial effects and mechanisms of action of the most used Mediterranean aromatic plants and spices (MAPS). Key findings and conclusions All MAPS reviewed here have been documented to exert hepatoprotective actions and almost the totality has a direct or indirect lipid-lowering effect on the liver, accompanied by amelioration of other MS parameters. We suggest that culinary MAPS use can contribute to the health benefits of MedDiet without the danger of adverse effects that can occur when the active compounds are used in pharmacological doses