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The depressive disorder coexists in a high prevalence with a substance-related disorder, which is asso- ciated with a worst prognosis. The therapeutic interventions for this co-morbidity lack of the appropriate scientific sup- port. The existing evidence suggest that the currently avail- able anti-depressive drugs are of minor efficacy in this group of patients. An alternative would be the use of different drugs with distinctive neurobiological mechanism of action. The aim of this study was to describe the clinical develop- ment of a series of patients affected by this comorbidity un- der treatment with tianeptine under usual clinical practices.

Objective: To show the clinical development of Ornibel® (ExeltisHealthcare, Spain) a contraceptive vaginal ring manufactured with a new polymer composition and containing etonogestrel/ethin...

Los autores de este trabajo forman parte de PREDIMED study investigators. Son los siguientes: Principales: Xavier Pintó, Marta Fanlo-Maresma, Emili Corbella, Xavier Corbella, M Teresa Mitjavila, Juan J Moreno, Rosa Casas, Ramon Estruch, Dolores Corella, Mònica Bulló, Miguel Ruiz-Canela, Olga Castañer, J Alfredo Martinez, Emilio Ros, PREDIMED Study Investigators. PREDIMED Study investigators: Estruch R, Martínez-González MA, Corella D, Fitó M, Ros E, Salas-Salvadó J, Arós F, Aldamiz-Echevarría M, Alonso-Gómez AM, Berjón J, Forga L, Gállego J, García-Layana A, Larrauri A, Portu-Zapirain J, Timiraos J, Ros E, Covas MI, Martínez-González MA, Salas-Salvadó J, Pérez-Heras A, Serra-Mir M, Pi-Sunyer X, González CA, Hu FB, Sabaté J, de la Cruz E, Galera A, Gimenez-Garcia M, Lafuente H, Rodríguez-Sanchez MA, Trias F, Sarasa I, Figueras R, Liceran M, Pallarols C, Esteve V, Storniolo C, Serra-Mir M, Pérez-Heras A, Sala-Vila A, Valls-Pedret C, Viñas C, Casas R, Medina-Remón A, Romero S, Baena JM, García M, Oller M, Amat J, Duaso I, García Y, Iglesias C, Simón C, Quinzavos L, Parra L, Liroz M, Benavent J, Clos J, Pla I, Amorós M, Bonet MT, Martín MT, Sánchez MS, Altirriba J, Manzano E, Altés A, Cofán M, Doménech M, Freitas-Simoes TM, Roth I, Amor AJ, Ortega E, Laguna JC, Alegret M, Gilabert R, Bargalló N, Martínez-González MA, Buil-Cosiales P, Toledo E, García-Arellano A, Cenoz-Osinaga JC, Lecea-Juárez O, Razquin C, Sánchez-Tainta A, Sanjulián B, Díez-Espino J, Zazpe I, Basterra-Gortari FJ, Eguaras S, Goñi E, Vazquez Z, Bes-Rastrollo M, Gea A, Martín-Calvo N, Berrade N, Marti A, Alfredo Martínez J, Martínez-Lapiscina EH, García-López M, Cervantes S, Barcena Amigo F, Oreja Arrayago C, Lasanta Saez MJ, Quintana Pedraza L, Cia Lecumberri P, Elcarte Lopez T, Forcen Alonso T, Alvárez-Alvárez I, Salas-Salvadó J, Guasch-Ferré M, González R, Molina C, Márquez F, Babio N, García Roselló J, Diaz-López A, Martin F, Tort R, Isach A, Becerra N, Ferreira C, Cabré JJ, Fernández-Ballart J, Ibarrola-Jurado N, Mestres G, Rosique-Esteban N, Alegret C, Martínez P, Millán S, Piñol JL, Basora T, Salas-Huetos A, Hernández JM, Carrasco P, Ortega-Azorín C, Asensio EM, Osma R, Barragán R, Francés F, Guillén M, González JI, Sáiz C, Portolés O, Giménez FJ, Coltell O, Fernández-Carrión R, Guillem-Sáiz P, González-Monje I, Quiles L, Pascual V, Riera C, Pages MA, Godoy D, Carratalá-Calvo A, Sánchez-Navarro S, Valero-Barceló C, Fitó M, Vila J, Subirana I, Tello S, de la Torre R, Muñoz-Aguayo D, Elosua R, Marrugat J, Schröder H, Molina N, Maestre E, Rovira A, Farré M, Arós F, Timiraos J, Salaverría I, Rekondo J, Belló MC, Del Hierro T, Algorta J, Francisco S, Alonso A, San Vicente J, Sanz E, Felipe I, Alonso Gómez A, Loma-Osorio A, Gómez-Gracia E, Fernández-Crehuet J, Gutiérrez-Bedmar M, Benítez Pont R, Bianchi Alba M, Wärnberg J, Gómez-Huelgas R, Martínez-González J, Velasco García V, de Diego Salas J, Baca Osorio A, Gil Zarzosa J, Sánchez Luque JJ, Vargas López E, Romaguera D, García-Valdueza M, Moñino M, Yáñez A, Proenza A, Prieto R, Munuera S, Vivó M, Bestard F, Munar JA, Coll L, Fiol F, Ginard M, Jover A, García J, Leal M, Martínez E, Santos-Lozano JM, Ortega-Calvo M, Román P, José García F, Iglesias P, Corchado Y, Mellado L, Miró-Moriano L, Lozano-Rodríguez JM, Domínguez-Espinaco C, Vaquero-Díaz S, López-Sabater MC, Castellote-Bargalló AI, Quifer-Rada P, Palmas L, Álvarez-Pérez J, Díaz-Benítez EM, Sánchez-Villegas A, Casañas-Quintana LT, Pérez-Cabrera J, Ruano-Rodríguez C, Bautista-Castaño I, Sarmiento de la Fe F, García Pastor JA, Díaz-González BV, Castillo Anzalas JM, Sosa-Also RE, Medina-Ponce J, Cabezas C, Vinyoles E, Rovira MA, García L, Flores G, Verdú JM, Baby P, Ramos A, Mengual L, Roura P, Yuste MC, Guarner A, Rovira A, Santamaría MI, Mata M, de Juan C, Brau A, Ruiz-Gutiérrez V, Sánchez Perona J, Montero Romero E, García-García M, Jurado-Ruiz E, Portillo MP, Sáez G, Tur J., Background Adherence to a Mediterranean diet (MedDiet) is thought to reduce liver steatosis. Objectives To explore the associations with liver steatosis of 3 different diets: a MedDiet + extra-virgin olive oil (EVOO), MedDiet + nuts, or a control diet. Methods This was a subgroup analysis nested within a multicenter, randomized, parallel-group clinical trial, PREvención con DIeta MEDiterránea (PREDIMED trial: ISRCTN35739639), aimed at assessing the effect of a MedDiet on the primary prevention of cardiovascular disease. One hundred men and women (mean age: 64 ± 6 y), at high cardiovascular risk (62% with type 2 diabetes) from the Bellvitge-PREDIMED center were randomly assigned to a MedDiet supplemented with EVOO, a MedDiet supplemented with mixed nuts, or a control diet (advice to reduce all dietary fat). No recommendations to lose weight or increase physical activity were given. Main measurements were the percentage of liver fat and the diagnosis of steatosis, which were determined by NMR imaging. The association of diet with liver fat content was analyzed by bivariate analysis after a median follow-up of 3 y. Results Baseline adiposity and cardiometabolic risk factors were similar among the 3 treatment arms. At 3 y after the intervention hepatic steatosis was present in 3 (8.8%), 12 (33.3%), and 10 (33.3%) of the participants in the MedDiet + EVOO, MedDiet + nuts, and control diet groups, respectively (P = 0.027). Respective mean values of liver fat content were 1.2%, 2.7%, and 4.1% (P = 0.07). A tendency toward significance was observed for the MedDiet + EVOO group compared with the control group. Median values of urinary 12(S)-hydroxyeicosatetraenoic acid/creatinine concentrations were significantly (P = 0.001) lower in the MedDiet + EVOO (2.3 ng/mg) than in the MedDiet + nuts (5.0 ng/mg) and control (3.9 ng/mg) groups. No differences in adiposity or glycemic control changes were seen between groups. Conclusions An energy-unrestricted MedDiet supplemented with EVOO, a food with potent antioxidant and anti-inflammatory properties, is associated with a reduced prevalence of hepatic steatosis in older individuals at high cardiovascular risk.

A novel tiotropium bromide monodose capsule dry powder inhaler (DPI) formulation and device have been developed. The formulation was based on a spray-dried matrix that enhances the aerosolizaton properties, allowing a less active tiotropium metered dose (13 µg/capsule) while maintaining the same delivered dose (10 µg/actuation). This study describes the pharmacokinetic bioequivalence to the reference product. This randomized, two-stage, crossover, semi-replicate (three-way) study was performed in healthy volunteers. In each study period, subjects received a single dose of two capsules (20 μg delivered dose) of the study medication, separated by a 14-day washout period: tiotropium 10 μg delivered dose (Laboratorios Liconsa, Spain) and Spiriva HandiHaler® (Boehringer Ingelheim Pharma GmbH & Co KG, Germany). Blood samples were obtained up to 48 h post-dose to evaluate the comparative bioavailability. Tiotropium was measured in plasma by means of dual stage liquid–liquid extraction followed by the two-dimensional ultra-high performance liquid chromatography sensitive sub-pg/mL bioanalytical method. The main pharmacokinetic parameters were maximum plasma concentration (C max), area under the concentration–time curve (AUC) from time zero hours to the last observed concentration at time t (AUC t ), and AUC from time zero hours to 30 min (AUC0.5). Bioequivalence was accepted if the 90.20 % confidence interval (CI) for the ratio test/reference of the primary pharmacokinetic parameters lay within the acceptance range of 80–125 %. Safety assessment was a secondary endpoint. A total of 30 subjects were randomized and bioequivalence was demonstrated for all primary pharmacokinetic parameters: C max (CI 87.26–106.60 %), AUC t (CI 101.33–111.64 %), and AUC0.5 (CI 97.95–113.49 %). Both study treatments were well tolerated (four non-serious adverse events [AEs] were reported in four subjects: one AE before any product administration, two AEs after test product administration; and one AE after reference product administration). Both products containing tiotropium 10 µg delivered-dose DPI were bioequivalent and showed good tolerability and a similar safety profile.

[Background]: Inflammation is known to be related to the leading causes of death including cardiovascular disease, several types of cancer, obesity, type 2 diabetes, depression-suicide and other chronic diseases. In the context of whole dietary patterns, the Dietary Inflammatory Index (DII®) was developed to appraise the inflammatory potential of the diet. [Objective]: We prospectively assessed the association between DII scores and all-cause mortality in two large Spanish cohorts and valuated the consistency of findings across these two cohorts and results published based on other cohorts., [Design]: We assessed 18,566 participants in the “Seguimiento Universidad de Navarra” (SUN) cohort followed-up during 188,891 person-years and 6790 participants in the “PREvencion con DIeta MEDiterránea” (PREDIMED) randomized trial representing 30,233 person-years of follow-up. DII scores were calculated in both cohorts from validated FFQs. Higher DII scores corresponded to more proinflammatory diets. A total of 230 and 302 deaths occurred in SUN and PREDIMED, respectively. In a random-effect meta-analysis we included 12 prospective studies (SUN, PREDIMED and 10 additional studies) that assessed the association between DII scores and all-cause mortality., [Results]: After adjusting for a wide array of potential confounders, the comparison between extreme quartiles of the DII showed a positive and significant association with all-cause mortality in both the SUN (hazard ratio [HR] = 1.85; 95% CI: 1.15, 2.98; P-trend = 0.004) and the PREDIMED cohort (HR = 1.42; 95% CI: 1.00, 2.02; P-trend = 0.009). In the meta-analysis of 12 cohorts, the DII was significantly associated with an increase of 23% in all-cause mortality (95% CI: 16%–32%, for the highest vs lowest category of DII)., [Conclusion]: Our results provide strong and consistent support for the hypothesis that a pro-inflammatory diet is associated with increased all-cause mortality. The SUN cohort and PREDIMED trial were registered at clinicaltrials.gov as NCT02669602 and at isrctn.com as ISRCTN35739639, respectively., Supported by the official funding agency for biomedical research of the Spanish Government, Instituto de Salud Carlos III (ISCIII), through grants provided to research networks specifically developed for the trial (RTIC G03/140, to R.E.; RTIC RD 06/0045, to Miguel A. Martínez-González) and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (Proyecto de Investigación (PI) 04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, PI13/00615, PI13/01090, PI14/01668, PI14/01798, PI14/01764), Ministerio de Ciencia e Innovación (Recursos y teconologia agroalimentarias(AGL)-2009-13906-C02 and AGL2010-22319-C03 and AGL2013-49083-C3-1- R), Fundación Mapfre 2010, the Consejería de Salud de la Junta de Andalucía (PI0105/2007), the Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (Generalitat Valenciana Ayuda Complementaria (GVACOMP) 06109, GVACOMP2010-181, GVACOMP2011-151), Conselleria de Sanitat y, PI14/01764 AP; Atención Primaria (CS) 2010-AP-111, and CS2011-AP-042), and Regional Government of Navarra (P27/2011).). Drs. Shivappa and Hébert were supported by grant number R44DK103377 from the United States National Institute of Diabetes and Digestive and Kidney Diseases.

The PREDIMED (PREvención con DIeta MEDiterránea) multicenter, randomized, primary prevention trial assessed the long-term effects of the Mediterranean diet (MeDiet) on clinical events of cardiovascular disease (CVD). We randomized 7447 men and women at high CVD risk into three diets: MeDiet supplemented with extra-virgin olive oil (EVOO), MeDiet supplemented with nuts, and control diet (advice on a low-fat diet). No energy restriction and no special intervention on physical activity were applied. We observed 288 CVD events (a composite of myocardial infarction, stroke or CVD death) during a median time of 4.8years; hazard ratios were 0.70 (95% CI, 0.53-0.91) for the MeDiet+EVOO and 0.70 (CI, 0.53-0.94) for the MeDiet+nuts compared to the control group. Respective hazard ratios for incident diabetes (273 cases) among 3541 non-diabetic participants were 0.60 (0.43-0.85) and 0.82 (0.61-1.10) for MeDiet+EVOO and MeDiet+nuts, respectively versus control. Significant improvements in classical and emerging CVD risk factors also supported a favorable effect of both MeDiets on blood pressure, insulin sensitivity, lipid profiles, lipoprotein particles, inflammation, oxidative stress, and carotid atherosclerosis. In nutrigenomic studies beneficial effects of the intervention with MedDiets showed interactions with several genetic variants (TCF7L2, APOA2, MLXIPL, LPL, FTO, M4CR, COX-2, GCKR and SERPINE1) with respect to intermediate and final phenotypes. Thus, the PREDIMED trial provided strong evidence that a vegetable-based MeDiet rich in unsaturated fat and polyphenols can be a sustainable and ideal model for CVD prevention. Supported by the official funding agency for biomedical research of the Spanish government, Instituto de Salud Carlos III (ISCIII), through grants provided to research networks specifically developed for the trial/n(RTIC G03/140, to Dr. Estruch; RTIC RD 06/0045, to Dr. Martínez-González) and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (PI04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/ 0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/ 02505 and PI13/01090), Ministerio de Ciencia e Innovación (AGL-2009-13906-C02 and AGL2010-22319-C03), Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVACOMP2010-181, GVACOMP2011-151, ACOMP/2013/165, ACOMP/2013/159, CS2010-AP-111, and CS2011-AP-042), and Regional Government of Navarra (P27/2011).

The dissection of S116 in more than 1500 individuals from Atlantic Europe and the Iberian Peninsula has provided important clues about the controversial evolutionary history of M269. First, the results do not point to an origin of M269 in the Franco–Cantabrian refuge, owing to the lack of sublineage diversity within M269, which supports the new theories proposing its origin in Eastern Europe. Second, S116 shows frequency peaks and spatial distribution that differ from those previously proposed, indicating an origin farther west, and it also shows a high frequency in the Atlantic coastline. Third, an outstanding frequency of the DF27 sublineage has been found in Iberia, with a restricted distribution pattern inside this peninsula and a frequency maximum in the area of the Franco–Cantabrian refuge. This entire panorama indicates an old arrival of M269 into Western Europe, because it has generated at least two episodes of expansion in the Franco–Cantabrian area. This study demonstrates the importance of continuing the dissection of the M269 lineage in different European populations because the discovery and study of new sublineages can adjust or even completely revise the theories about European peopling, as has been the case for the place of origin of M269.

To show the clinical development of OrnibelRandomised, single dose, 2-period, 2-sequence, 2-stage crossover, comparative bioavailability study conducted in 40 healthy female subjects. All subjects received both treatments for 28 days in each of two periods, separated by a 28 days washout. OrnibelBioequivalence was demonstrated in the first stage as the 94.12% Confidence Intervals of the primary parameters laid within the 80-125% acceptance range for both etonogestrel (COrnibel

Background & aims: Legumes, a low-energy, nutrient-dense and low glycemic index food, have shown beneficial effects on glycemic control and adiposity. As such, legumes are widely recommended in diabetic diets, even though there is little evidence that their consumption protects against type 2 diabetes. Therefore the aim of the present study was to examine the associations between consumption of total legumes and specific subtypes, and type 2 diabetes risk. We also investigated the effect of theoretically substituting legumes for other protein- or carbohydrate-rich foods. Methods: Prospective assessment of 3349 participants in the PREvención con DIeta MEDiterránea (PREDIMED) study without type 2 diabetes at baseline. Dietary information was assessed at baseline and yearly during follow-up. We used Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for type-2 diabetes incidence according to quartiles of cumulative average consumption of total legumes, lentils, chickpeas, dry beans and fresh peas. Results: During a median follow-up of 4.3 years, 266 new cases of type 2 diabetes occurred. Individuals in the highest quartile of total legume and lentil consumption had a lower risk of diabetes than those in the lowest quartile (HR: 0.65; 95% CI: 0.43, 0.96; P-trend = 0.04; and HR: 0.67; 95% CI: 0.46–0.98; P-trend = 0.05, respectively). A borderline significant association was also observed for chickpeas consumption (HR 0.68; 95% CI: 0.46, 1.00; P-trend = 0.06). Substitutions of half a serving/day of legumes for similar servings of eggs, bread, rice or baked potato was associated with lower risk of diabetes incidence. Conclusions: A frequent consumption of legumes, particularly lentils, in the context of a Mediterranean diet, may provide benefits on type 2 diabetes prevention in older adults at high cardiovascular risk. Trial registration: The trial is registered at http://www.controlled-trials.com (ISRCTN35739639). Registration date: 5th October 2005., The authors disclose no conflict of interest related with the article. Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBEROBN) is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds (CB06/03). Supported by the official funding agency for biomedical research of the Spanish government, ISCIII, through grants provided to research networks specifically developed for the trial (RTIC G03/140 and RD 06/0045) through CIBEROBN, and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–FondoEuropeo de Desarrollo Regional (PI04–2239, PI05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, and PI11/02505; PI13/00462), Ministerio de Ciencia e Innovación (AGL-2009–13906-C02 and AGL2010–22319-C03), Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, and CS2011-AP-042), and the Navarra Regional Government (27/2011). The Fundación Patrimonio Comunal Olivarero and Hojiblanca SA (Málaga, Spain), California Walnut Commission (Sacramento, CA), Borges SA (Reus, Spain), and Morella Nuts SA (Reus, Spain) donated the olive oil, walnuts, almonds, and hazelnuts, respectively, used in the study. None of the funding sources played a role in the design, collection, analysis or interpretation of the data or in the decision to submit the manuscript for publication. Acknowledgements: The authors thank all the participants for their collaboration, all the PREDIMED personnel for their assistance and all the personnel of affiliated primary care centers for making the study possible. CIBEROBN is an initiative of ISCIII, Spain.

Purpose The aim of this study was to determine whether addition of plasma rich in growth factors (PRGF) improves functional and structural outcomes after arthroscopic repair of full-thickness rotator cuff tears. Methods The study design was independent (investigator-sponsored), randomized in parallel groups, double-blind, and controlled with a conventional surgical technique clinical trial. Sixty-nine patients with rotator cuff tears were included. Subsequently, 6 patients in whom less than 50% footprint coverage of the repair was possible were excluded. Before arthroscopic repair, patients were randomly assigned to receive PRGF at the end of arthroscopy (injected first in the repaired area and then spread over the tendon suture) or only conventional surgery. Efficacy was evaluated 1 year after surgery using functional (UCLA score) and structural (arthro-MRI) assessments. Results The baseline UCLA scores of the PRGF (14.9; 95% confidence interval [CI]: 13.7 to 16.12) and control (13.2; 95% CI: 13.3 to 16.3) groups were similar. After surgery, both groups showed an improvement in UCLA score, without significant differences between groups (23.2; CI 95%: 20.8 to 25.7, and 23.8; 95% CI: 21.0 to 26.7, respectively). Furthermore, no significant differences were observed in satisfaction 1 year after surgery. Tendon healing evaluated with arthro-magnetic resonance imaging showed total healing in 40% of cases, partial healing in 30%, and lack of healing in 30%, again with no significant differences between groups. No adverse events were recorded. Conclusions The present clinical trial does not support the use of plasma rich in growth factors in the arthroscopic repair of rotator cuff tears because no differences in rotator cuff healing or improvements in function were observed in the 1-year postsurgical clinical and radiological follow-up assessments. Level of Evidence Level I, randomized, double-blind, controlled clinical trial.

BACKGROUND AND AIM: We tested the hypothesis that an intervention with a Mediterranean diet (MeDiet) could mitigate the well-known harmful effects of abdominal obesity on cardiovascular health. METHODS AND RESULTS: We assessed the relationship between baseline waist-to-height ratio (WHtR) and major cardiovascular events during a median follow-up of 4.8 years in the Prevention with Mediterranean Diet (PREDIMED) randomized primary prevention trial, which tested a MeDiet against a control diet (advice on a low-fat diet). We also examined whether the MeDiet intervention was able to counteract the detrimental cardiovascular effects of an increased WHtR. The trial included 7447 participants (55-80 years old, 57% women) at high cardiovascular risk but free of cardiovascular disease (CVD) at enrollment. An increased risk of CVD events (myocardial infarction, stroke, or cardiovascular death) was apparent for the highest versus the lowest quartile of WHtR (multivariable-adjusted hazard ratio: 1.98) (95% confidence interval: 1.10-3.57; linear trend: p = 0.019) only in the control-diet group, but not in the two groups allocated to intervention with MeDiet (p for interaction = 0.034). This apparent interaction suggesting that the intervention counterbalanced the detrimental cardiovascular effects of adiposity was also significant for body mass index (BMI) (p = 0.01) and waist circumference (p = 0.043). CONCLUSIONS: The MeDiet may counteract the harmful effects of increased adiposity on the risk of CVD. Supported by the official funding agency for biomedical research of the Spanish government, Instituto de Salud Carlos III (ISCIII), through specific grants (RTIC G03/140; RTIC-RD 06/0045, to Prof. Martínez-González and CIBERobn), and by Fondo de Investigación Sanitaria eISCIII (PI04-2239, PI05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, and/nP11/02505), Ministerio Ciencia e Innovación (AGL-2009-13906-C02 and AGL2010-22319-C03), Fundación Mapfre 2010, Consejería Salud Junta de Andalucía (PI0105/2007), Health Department of Catalonia, Generalitat Valenciana (ACOMP06109, GVACOMP2010-181, GVACOMP2011-151, CS2010-AP-111, and CS2011-AP-042), and Regional Government of Navarra (P27/2011). ET is supported by a Rio Hortega post-residency fellow of the ISCIII

The placenta is an important source of leptin production that contributes to the state of hyperleptinemia observed in pregnant women. Moreover, the synthesis of leptin and its receptors by syncytiotrophoblast cells suggests a potential paracrine or autocrine action of leptin in the placenta. In the present study we examined the effect of gestational hormones, human chorionic gonadotropin (hCG), human placental lactogen (hPL), progesterone and estradiol, on in vitro leptin release by human term trophoblast cells in culture. Placentas at term were obtained immediately after delivery from mothers with uncomplicated pregnancies. Leptin levels were measured by enzyme-linked immunosorbent assay in culture media of trophoblasts maintained in monolayer culture for 24, 48 and 72 h with different hormonal treatments or placebo. Treatment with hPL and progesterone led to a time- and dose-dependent decrease in leptin release that was statistically significant after 24 h, with a maximal effect after 72 h of incubation. In contrast, incubation with estradiol and hCG did not have exhibit any effect on leptin secretion at any of the doses and times assayed in this work. The results obtained in this study support that leptin can be considered a gestational hormone implied in the endocrine function of the placenta and that its secretion is at least partially regulated by steroid and peptidic reproductive hormones in trophoblast cells in vitro. © 2005 Taylor & Francis Group Ltd.

Summary Background Although immunotherapy clearly demonstrated the benefit of reducing allergic symptoms, it has the drawback of adverse events, mainly systemic reactions that could be very inconvenient for patients and even life-threatening. Objective The aim of the present study was to assess the incidence of systemic reactions to immunotherapy in a large number of patients, and its potential relationship with the characteristics of therapy, such as allergen composition or manufacturing laboratory. Methods This study analysed the administration of specific immunotherapy during a period of 5 years, involving 1212 patients affected by respiratory hypersensitivity or hymenoptera venom anaphylaxis. Commercial extracts were supplied by five different laboratories. All the patients were attended at an out-clinic immunotherapy unit by the same experienced staff. Immunotherapy was given following a conventional schedule, modified according the usual recommendations. Results A total of 250 adverse reactions have been recorded, resulting in a frequency of 0.84% over the total number of injections. Seventy-nine of them (32%) were systemic reactions (0.27% SR/injection). The 79 systemic reactions were observed in 60 patients (5% of the patients). The frequency of systemic reactions was significantly lower (P

Ten X chromosome markers (DXS6789, DXS6809, DXS7132, DXS7133, DXS7423, DXS8378, DXS9898, DXS9902, GATA172D05, and GATA31E08) were analyzed in a sample of 185 unrelated autochthonous Basques from Navarre. Deviations from Hardy–Weinberg equilibrium and linkage disequilibrium between markers were not observed at any loci. Combined power of discrimination was 0.999999999 (females) and 0.999998764 (males). Mean exclusion chance was 0.99999463 (trios) and 0.999761591 (duos). Pairwise genetic distances (Fst) of X-STR frequencies indicate significant differences in the allele frequency distribution between the autochthonous Basques from Navarre and American and Iberian populations except with the Basque Country.

OBJECTIVE: To date no clinical trials have evaluated the role of dietary patterns on the incidence of microvascular diabetes complications. We hypothesized that a nutritional intervention based on the Mediterranean diet (MedDiet) would have greater protective effect on diabetic retinopathy and nephropathy than a low-fat control diet. RESEARCH DESIGN AND METHODS: This was a post hoc analysis of a cohort of patients with type 2 diabetes participating in the PREvención con DIeta MEDiterránea (PREDIMED) study, a multicenter randomized nutritional intervention trial conducted in a population at high cardiovascular risk. Individuals with type 2 diabetes who were free of microvascular complications at enrollment (n = 3,614, aged 55-80 years) were randomly assigned to one of three dietary interventions: MedDiet supplemented with extravirgin olive oil (MedDiet+EVOO), MedDiet supplemented with mixed nuts (MedDiet+Nuts), or a low-fat control diet. Two independent outcomes were considered: new onset of diabetic retinopathy and nephropathy. Hazard ratios (HRs) were calculated using multivariable-adjusted Cox regression./nRESULTS: During a median follow-up of 6.0 years, we identified 74 new cases of retinopathy and 168 of nephropathy. Compared with the control diet, multivariable-adjusted HRs for diabetic retinopathy were 0.56 (95% CI 0.32-0.97) for the MedDiet+EVOO and 0.63 (0.35-1.11) for the MedDiet+Nuts. No between-group differences were found for nephropathy. When the yearly updated information on adherence to the MedDiet was considered, the HR for retinopathy in the highest versus the lowest quintile was 0.34 (0.13-0.89; P = 0.001 for trend). No significant associations were found for nephropathy. CONCLUSIONS: A MedDiet enriched with EVOO may protect against diabetic retinopathy but not diabetic nephropathy. CIBEROBN is an initiative of ISCIII, Spain. Supported by the official funding agency for biomedical research of the Spanish government, Instituto de Salud Carlos III (ISCIII), through grants provided to research networks specifically developed for the trial (RTIC G03/140, to Ramón Estruch; RTIC RD 06/0045, to Miguel Martínez-González and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición [CIBEROBN]), and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, and P11/02505; PI13/00462), Ministerio de Ciencia e Innovación (AGL-2009–13906-C02 and AGL2010–22319-C03), Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, and CS2011-AP-042), and Regional Government of Navarra (P27/2011). The Fundación Patrimonio Comunal Olivarero and Hojiblanca SA (Málaga, Spain), California Walnut/nCommission (Sacramento, CA), Borges SA (Reus, Spain), and Morella Nuts SA (Reus, Spain) donated the olive oil, walnuts, almonds, and hazelnuts, respectively, used in the study. None of the funding sources played a role in the design, collection, analysis or interpretation of the data, or in the decision to submit the manuscript for publication

Background - The PREDIMED (Prevención con Dieta Mediterránea) randomized primary prevention trial showed that a Mediterranean diet enriched with either extravirgin olive oil or mixed nuts reduces the incidence of stroke, myocardial infarction, and cardiovascular mortality. We assessed the effect of these diets on the incidence of atrial fibrillation in the PREDIMED trial. Methods and Results - Participants were randomly assigned to 1 of 3 diets: Mediterranean diet supplemented with extravirgin olive oil, Mediterranean diet supplemented with mixed nuts, or advice to follow a low-fat diet (control group). Incident atrial fibrillation was adjudicated during follow-up by an events committee blinded to dietary group allocation. Among 6705 participants without prevalent atrial fibrillation at randomization, we observed 72 new cases of atrial fibrillation in the Mediterranean diet with extravirgin olive oil group, 82 in the Mediterranean diet with mixed nuts group, and 92 in the control group after median follow-up of 4.7 years. The Mediterranean diet with extravirgin olive oil significantly reduced the risk of atrial fibrillation (hazard ratio, 0.62; 95% confidence interval, 0.45-0.85 compared with the control group). No effect was found for the Mediterranean diet with nuts (hazard ratio, 0.89; 95% confidence interval, 0.65-1.20). Conclusions - In the absence of proven interventions for the primary prevention of atrial fibrillation, this post hoc analysis of the PREDIMED trial suggests that extravirgin olive oil in the context of a Mediterranean dietary pattern may reduce the risk of atrial fibrillation. © 2014 American Heart Association, Inc., The PREDIMED trial was supported by the Official funding agency for Biomedical Research of the Spanish Government (Spanish analogous institution to the NIH: Instituto de Salud Carlos III, through grants provided to research networks specifically developed for the trial: RTIC G03/140 (Coordinator: R Estruch, MD, PhD), and RTIC RD 06/0045 (Coordinatos: MA Martínez-González, MD, PhD). All investigator of the PREDIMED t rial belong to Centro de Investigación Biomédica en Red (CIBER), an initiative of Instituto de Salud Carlos III. We also acknowledge the grants from NIH 1R01HL118264-01, Fondo de Investigación Sanitaria - Fondo Europeo de Desarrollo Regional (PI04/0233, PI05/0976, PI07/0240 , PI10/01407, PI10/02658 and PI11/00049) and Consejería de Salud de la Junta de Andalucía (PI0105/2007).

Background & aimsMetabolic syndrome (MetS) has become an important public concern due to its increasing prevalence. An altered fatty acid composition has been associated with MetS, but the Mediterranean diet has been shown to have a protective effect. The aim of the present study was to analyze the influence of a Mediterranean dietary pattern, as assessed by the biomarkers of food supplied, on the plasma fatty acid composition and its relation with MetS after 1 year of intervention.MethodsA total of 424 subjects were randomly selected from the PREDIMED randomized dietary trial after completing a 1-year intervention program. Participants aged 55 to 80 years and at high risk of cardiovascular disease were randomly assigned to three dietary interventions: Mediterranean diet supplemented with virgin olive oil or nuts, or a low-fat diet.ResultsAfter 1 year of intervention participants in the virgin olive oil group showed significantly increased plasma concentrations of palmitic and oleic acids, but reduced proportions of margaric, stearic, and linoleic acids. In turn, subjects in the nut group showed significantly increased levels of palmitic, linoleic, and α-linolenic acids, but reduced proportions of myristic, margaric, palmitoleic, and dihommo-γ-linoleic acids. Increases in the biomarkers of foods supplied to the Mediterranean diet groups, i.e., oleic and α-linolenic acids, were beneficially associated with the incidence, reversion and prevalence of MetS. No weight changes were observed among participants.ConclusionsThe nut and olive oil diets induced a fatty acid composition that has been shown to be beneficial in the face of MetS. Therefore, a Mediterranean diet rich in fats of vegetable origin may be a useful tool for the management of MetS without the need for concerns over weight gain due to its high fat content.Trial registrationControlled-Trials.com ISRCTN35739639.

© 2014 Canadian Medical Association or its licensors. Results: Over 4.8 years of follow-up, metabolic syndrome developed in 960 (50.0%) of the 1919 participants who did not have the condition at baseline. The risk of developing metabolic syndrome did not differ between participants assigned to the control diet and those assigned to either of the Mediterranean diets (control v. olive oil HR 1.10, 95% CI 0.94-1.30, p = 0.231; control v. nuts HR 1.08, 95% CI 0.92- 1.27, p = 0.3). Reversion occurred in 958 (28.2%) of the 3392 participants who had metabolic syndrome at baseline. Compared with the control group, participants on either Mediterranean diet were more likely to undergo reversion (control v. olive oil HR 1.35, 95% CI 1.15-1.58, p ≤ 0.001; control v. nuts HR 1.28, 95% CI 1.08-1.51, p ≤ 0.001). Participants in the group receiving olive oil supplementation showed significant decreases in both central obesity and high fasting glucose (p = 0.02); participants in the group supplemented with nuts showed a significant decrease in central obesity. Interpretation: A Mediterranean diet supplemented with either extra virgin olive oil or nuts is not associated with the onset of metabolic syndrome, but such diets are more likely to cause reversion of the condition. An energy-unrestricted Mediterranean diet may be useful in reducing the risks of central obesity and hyperglycemia in people at high risk of cardiovascular disease. Trial registration: ClinicalTrials. gov, no. ISRCTN35739639. Background: Little evidence exists on the effect of an energy-unrestricted healthy diet on metabolic syndrome. We evaluated the long-term effect of Mediterranean diets ad libitum on the incidence or reversion of metabolic syndrome. Methods: We performed a secondary analysis of the PREDIMED trial - a multicentre, randomized trial done between October 2003 and December 2010 that involved men and women (age 55-80 yr) at high risk for cardiovascular disease. Participants were randomly assigned to 1 of 3 dietary interventions: a Mediterranean diet supplemented with extravirgin olive oil, a Mediterranean diet supplemented with nuts or advice on following a low-fat diet (the control group). The interventions did not include increased physical activity or weight loss as a goal. We analyzed available data from 5801 participants. We determined the effect of diet on incidence and reversion of metabolic syndrome using Cox regression analysis to calculate hazard ratios (HRs) and 95% confidence intervals (CIs)., CIBERobn is an initiative of ISCIII, Spain. Supported by the official funding agency for biomedical research of the Spanish government, Instituto de Salud Carlos III (ISCIII), through grants provided to research networks specifically developed for the trial (RTIC G03/140, to Ramón Estruch; RTIC RD 06/0045, to Miguel Martínez-González and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición [CIBERobn]), and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, and P11/02505; PI13/00462), Ministerio de Ciencia e Innovación (AGL-2009–13906-C02 and AGL2010–22319-C03), Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, and CS2011-AP-042), and Regional Government of Navarra (P27/2011). None of the funding sources played a role in the design, collection, analysis or interpretation of the data or in the decision to submit the manuscript for publication.

9 p. The European genetic landscape has been shaped by several human migrations occurred since Paleolithic times. The accumulation of archaeological records and the concordance of different lines of genetic evidence during the last two decades have triggered an interesting debate concerning the role of ancient settlers from the Franco-Cantabrian region in the postglacial resettlement of Europe. Among the Franco-Cantabrian populations, Basques are regarded as one of the oldest and more intriguing human groups of Europe. Recent data on complete mitochondrial DNA genomes focused on macrohaplogroup R0 revealed that Basques harbor some autochthonous lineages, suggesting a genetic continuity since pre-Neolithic times. However, excluding haplogroup H, the most representative lineage of macrohaplogroup R0, the majority of maternal lineages of this area remains virtually unexplored, so that further refinement of the mtDNA phylogeny based on analyses at the highest level of resolution is crucial for a better understanding of the European prehistory. We thus explored the maternal ancestry of 548 autochthonous individuals from various Franco-Cantabrian populations and sequenced 76 mitogenomes of the most representative lineages. Interestingly, we identified three mtDNA haplogroups, U5b1f, J1c5c1 and V22, that proved to be representative of Franco-Cantabria, notably of the Basque population. The seclusion and diversity of these female genetic lineages support a local origin in the Franco-Cantabrian area during the Mesolithic of southwestern Europe, similar to 10,000 years before present (YBP), with signals of expansions at similar to 3,500 YBP. These findings provide robust evidence of a partial genetic continuity between contemporary autochthonous populations from the Franco-Cantabrian region, specifically the Basques, and Paleolithic/Mesolithic hunter-gatherer groups. Furthermore, our results raise the current proportion (approximate to 15%) of the Franco-Cantabrian maternal gene pool with a putative pre-Neolithic origin to approximate to 35%, further supporting the notion of a predominant Paleolithic genetic substrate in extant European populations. Funds were provided by the Basque Government (Grupo Consolidado IT-424-07) and a grant from the University of the Basque Country UPV/EHU (ELDUNANOTEK UFI11/32). Leire Palencia is a PhD student granted by the Basque Government (Dpto. de Educacion, Universidades e Investigacion). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

© 2013 Massachusetts Medical Society, [Background]: Observational cohort studies and a secondary prevention trial have shown an inverse association between adherence to the Mediterranean diet and cardiovascular risk. We conducted a randomized trial of this diet pattern for the primary prevention of cardiovascular events., [Methods]: In a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years., [Results]: A total of 7447 persons were enrolled (age range, 55 to 80 years); 57% were women. The two Mediterranean-diet groups had good adherence to the intervention, according to self-reported intake and biomarker analyses. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, versus the control group (109 events). No diet-related adverse effects were reported., [Conclusions]: Among persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events., Supported by the official funding agency for biomedical research of the Spanish government, Instituto de Salud Carlos III (ISCIII), through grants provided to research networks specifically developed for the trial (RTIC G03/140, to Dr. Estruch; RTIC RD 06/0045, to Dr. Martínez-González and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición [CIBERobn]), and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (PI04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, and P11/02505), Ministerio de Ciencia e Innovación (AGL-2009-13906-C02 and AGL2010-22319-C03), Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVACOMP2010-181, GVACOMP2011-151, CS2010-AP-111, and CS2011-AP-042), and Regional Government of Navarra (P27/2011).

Background Alcoholic beverages are widely consumed. Depression, the most prevalent mental disorder worldwide, has been related to alcohol intake. We aimed to prospectively assess the association between alcohol intake and incident depression using repeated measurements of alcohol intake. Methods We followed-up 5,505 high-risk men and women (55 to 80 y) of the PREDIMED Trial for up to seven years. Participants were initially free of depression or a history of depression, and did not have any history of alcohol-related problems. A 137-item validated food frequency questionnaire administered by a dietician was repeated annually to assess alcohol intake. Participants were classified as incident cases of depression when they reported a new clinical diagnosis of depression, and/or initiated the use of antidepressant drugs. Cox regression analyses were fitted over 23,655 person-years. Results Moderate alcohol intake within the range of 5 to 15 g/day was significantly associated with lower risk of incident depression (hazard ratio (HR) and 95% confidence interval (95% CI) = 0.72 (0.53 to 0.98) versus abstainers). Specifically, wine consumption in the range of two to seven drinks/week was significantly associated with lower rates of depression (HR (95% CI) = 0.68 (0.47 to 0.98)). Conclusions Moderate consumption of wine may reduce the incidence of depression, while heavy drinkers seem to be at higher risk.

Background: Pollutants and other stressing factors like mold infection might increase the production of pathogen-related proteins in plants. Since this is invoked as one of the causes for the high prevalence of allergic diseases in developed countries, we aimed to determine the potential effect of environmental pollution, with or without mold infection of the trees, on the allergenic potency of pine pollen (Pinus radiata). Methods: Pine pollen samples were recovered from three selected areas: low polluted (A), highly polluted (B) and highly polluted and infected with fungi (Spheropsis sapinea) (C). The allergenic potency of pollen from areas A, B or C were compared in vivo in 35 pine pollen-allergic patients by skin prick test and specific IgE (sIgE) quantification. Pollen was also analyzed in vitro by SDS-PAGE immunoblotting, RAST inhibition and cDNA-AFLP (amplified fragment length polymorphism) to compare differences in proteins and mRNA expression. Results: The allergenic potency measured by prick test, sIgE and RAST inhibition was greater in pollen A, which was exposed to smaller amounts of NOx, PM10 and SO2 but greater amounts of O3. No differences were found in IgE-binding bands in immunoblotting or densitometry of the bands. In cDNA-AFLP, three homologous transcript-derived fragments were expressed in samples B only, with an expressed sequence tag related with stress-regulated gene expression. Conclusions: A greater allergenic potency, in terms of skin tests and sIgE, is observed in pine pollen coming from unpolluted areas. We consider that this fact might be related to a higher exposure to ozone, resulting in a greater expression of allergenic proteins.

Background Natural rubber latex allergy is a common and unsolved health problem. Since the avoidance of exposure is very difficult, immunotherapy is strongly recommended, but before its use in patients, it is essential to prove the efficacy and safety of extracts. The aim of the present randomised, double-blind, placebo-controlled clinical trial was to assess the efficacy and tolerability of latex sublingual immunotherapy in adult patients undergoing permanent latex avoidance. Methods Twenty-eight adult latex-allergic patients (5 males and 23 females), with mean age of 39 years (range 24-57) were randomized to receive a commercial latex-sublingual immunotherapy or placebo during one year, followed by another year of open, active therapy. The following outcomes were measured at baseline and at the end of first and second year of follow-up: skin prick test, gloves-use score, conjunctival challenge test, total and specific IgE, basophil activation test, and adverse reactions monitoring. Results No significant difference in any of the efficacy in vivo variables was observed between active and placebo groups at the end of the placebo-controlled phase, nor when each group was compared with their baseline values at the end of the two year-study. An improvement in the average percentage of basophils activated was observed. During the induction phase, 4 reactions in the active group and 5 in the placebo group were recorded. During the maintenance phase, two patients dropped out due to pruritus and to acute dermatitis respectively. Conclusion Further studies are needed to evaluate latex-sublingual immunotherapy, since efficacy could not be demonstrated in adult patients with avoidance of the allergen. Trial registration number ACTRN12611000543987

Background The Mediterranean food pattern (MeDiet) has been suggested to have beneficial effects on cardiovascular risk factors. Scarcity of assessment of this effect on large samples of patients at high risk is, however, observed. Our objective was to estimate the association between adherence to MeDiet and the prevalence of risk factors in 3204 asymptomatic high-risk patients. Design Cross-sectional assessment of baseline characteristics of participants in a primary prevention trial. Methods Participants were assessed by their usual primary-care physicians to ascertain the prevalence of diet-related cardiovascular risk factors (diabetes, hypertension, dyslipidemia, or obesity) using standard diagnostic criteria. A dietitian interviewed each participant to obtain a 14-point score measuring the degree of adherence to MeDiet. Results Adherence to MeDiet was inversely associated with individual risk factors and, above all, with the clustering of them. The multivariate adjusted odds ratio to present simultaneously the four risk factors for those above the median value of the MeDiet score was 0.67 (95% confidence interval: 0.53–0.85). The multivariate odds ratios for successive categories of adherence to MeDiet were 1 (ref.), 1.03, 0.85, 0.70 and 0.54 (P for trend ≤0.001). Conclusion Following a MeDiet was inversely associated with the clustering of hypertension, diabetes, obesity, and hypercholesterolemia among high-risk patients., The authors acknowledge the Navarra Regional Government (G41/2005), Generalitat Valenciana (ACOMP06109) and Instituto de Salud Carlos III (ISCIII, Spanish Ministry of Health) [Grants FIS-PI040233; FIS-PI042241, FIS-PI050514, FIS-PI050976, FIS-PI052368, FIS-PI042234, FIS-PI041828, FIS-PI051839, FIS-PI070240, RD06/0045/0000, Red Temática PRE-DIMED and CIBEROBN ‘CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03)'] for supporting this study. CIBEROBN (CB06/03) is an initiative of ISCIII.

Background Budesonide has a long history as intranasal drug, with many marketed products. Efforts should be made to demonstrate the therapeutic equivalence and safety comparability between them. Given that systemic availability significantly varies from formulations, the clinical comparability of diverse products comes to be of clinical interest and a regulatory requirement. The aim of the present study was to compare the systemic availability, pharmacodynamic effect, and safety of two intranasal budesonide formulations for the treatment of rhinitis. Methods Eighteen healthy volunteers participated in this randomised, controlled, crossover, clinical trial. On two separated days, subjects received a single dose of 512 μg budesonide (4 puffs per nostril) from each of the assayed devices (Budesonida nasal 64®, Aldo-Union, Spain and Rhinocort 64®, AstraZeneca, Spain). Budesonide availability was determined by the measurement of budesonide plasma concentration. The pharmacodynamic effect on the hypothalamic-adrenal axis was evaluated as both plasma and urine cortisol levels. Adverse events were tabulated and described. Budesonide availability between formulations was compared by the calculation of 90%CI intervals of the ratios of the main pharmacokinetic parameters describing budesonide bioavailability. Plasma cortisol concentration-time curves were compared by means of a GLM for Repeated Measures. Urine cortisol excretion between formulations was compared through the Wilcoxon's test. Results All the enroled volunteers successfully completed the study. Pharmacokinetic parameters were comparable in terms of AUCt (2.6 ± 1.5 vs 2.2 ± 0.7), AUCi (2.9 ± 1.5 vs 2.4 ± 0.7), tmax (0.4 ± 0.1 vs 0.4 ± 0.2), Cmax/AUCi (0.3 ± 0.1 vs 0.3 ± 0.0), and MRT (5.0 ± 1.4 vs 4.5 ± 0.6), but not in the case of Cmax (0.9 ± 0.3 vs 0.7 ± 0.2) and t1/2 (3.7 ± 1.8 vs 2.9 ± 0.4). The pharmacodynamic effects, measured as the effect over plasma and urine cortisol, were also comparables between both formulations. No severe adverse events were reported and tolerance was comparable between formulations. Conclusion The systemic availability of intranasal budesonide was comparable for both formulations in terms of most pharmacokinetic parameters. The pharmacodynamic effect on hypothalamic-pituitary-adrenal axis was also similar. Side effects were scarce and equivalent between the two products. This methodology to compare different budesonide-containing devices is reliable and easy to perform, and should be recommended for similar products intented to be marketed or already on the market. Trial registration No Eudra CT: 2005-003727-39

Autologous Preparation Rich in Growth Factors (PRGF), a small volume of plasma enriched in platelets, is a novel therapeutic strategy for the acceleration of the wound healing of a wide range of tissues because of the continuous release of multiple growth factors, including PDGF-AB, TGF-beta1, IGF-I, HGF, VEGF-A, and EGF. In this article, we have characterized the PRGF preparation and designed a randomized open-label controlled pilot trial to evaluate the effectiveness of PRGF in the treatment of chronic cutaneous ulcers. Results showed that at 8 weeks, the mean percentage of surface healed in the PRGF group was 72.94% +/- 22.25% whereas it was 21.48% +/- 33.56% in the control group (p < 0.05). These results, with the limitations of a pilot study, suggest that topical application of PRGF is more effective than standard therapy in helping a chronic ulcer to heal.

Placenta is an important source of leptin during pregnancy that contributes to the high plasma leptin levels in pregnant women. Leptin and its functional receptors are synthesized in trophoblast cells that, in turn, secrete gestational hormones supporting a paracrine or autocrine role for leptin in the endocrine activity of the placenta. In the present study we examined the effect of leptin on in vitro release of gestational hormones (human chorionic gonadotropin (hCG), human placental lactogen (hPL), progesterone, estrogens and testosterone) by human term placental cells in culture. Placentas at term were obtained immediately after delivery from mothers with uncomplicated pregnancies. Progesterone, hCG, hPL, estradiol, estrone, estriol and testosterone levels were measured by different assays in culture media of cells maintained in monolayer culture after incubation for 12, 24, 48 or 72 h with leptin or placebo. Incubation with leptin did not modify hCG, hPL, progesterone, estriol and estrone secretion for any of the doses and times assayed. However, leptin led to a dose-dependent decrease in estradiol release. This effect was observed when treatment with recombinant human leptin spanned from 12 to 72 h. At this time an increase in testosterone levels was observed in leptin-treated cells versus placebo. These results indicate that leptin can be considered a gestational hormone implied in the endocrine function of the placenta, with an important role in control of the production of steroid reproductive hormones in placental cells in vitro.

Background Olive tree pollen is an important cause of inhalant allergy in Mediterranean countries. The major allergen of this pollen, Ole e 1, has caused reactions in the sera of >80% of olive-sensitive patients. Accurate standardization of allergenic products for diagnosis and immunotherapy is essential to guarantee their quality, and measurement of the major allergen content is becoming an important aspect of standardization procedures. Objective To develop a two-site enzyme-linked immunoadsorbent assay (ELISA) for the quantification of Ole e 1. Methods BALB/c mice were immunized with purified natural Ole e 1. After fusion and screening by direct ELISA, one of the monoclonal antibodies (5A3) was selected as the capture antibody in an ELISA for Ole e 1 quantification. Bound allergens were detected by a combination of biotinylated Ole e 1-specific polyclonal rabbit antibody and peroxidase-conjugated streptavidin. This ELISA was subsequently evaluated and compared with other techniques. Results The developed ELISA was highly reproducible and sensitive, with a detection limit of 0.5 ng/mL and a practical range of 1 to 10 ng/mL. The Ole e 1 content ranged from 3 to 50% of the total protein among the nine Olea europaea pollen extracts studied. The assay also detected Ole e 1-like proteins in pollen from other Oleaceae. Correlation was good between the Ole e 1 content determined by ELISA and scanning densitometry and the immunoglobulin E-binding activity of the extracts. Conclusion The described Ole e 1 ELISA is sensitive, reproducible, specific, and reliable, and therefore, can be helpful for standardization of olive pollen extracts intended for clinical use.

Few studies have been published on the efficacy and safety of immunotherapy with fungal extracts, possibly because of difficulties arising from antigenic variability among different strains of fungus. The aim of the study was to analyze changes in the in vivo and in vitro parameters in response to immunotherapy with an Alternaria alternata extract. We studied 28 patients with rhinitis, bronchial asthma, or both caused by Alternaria. The patients were randomized to the active immunotherapy or placebo group, and a conventional schedule of immunotherapy was used. We recorded changes for a year in skin reactivity (skin prick test), conjunctival reactivity (conjunctival provocation test), and in vitro parameters (serum-specific IgE, IgG, IgG1 and IgG4 for A. alternata complete extract and for natural and recombinant Alt a 1). Twenty-three patients completed the study and all attained the maintenance dose. There were no changes in skin reactivity in the active treatment group, and reactivity increased at the end of the study period in the placebo group. Conjunctival sensitivity decreased only in the active treatment group when the maintenance dose was reached. Allergen-specific IgE decreased, and IgG, IgG1 and IgG4 increased in all periods of study in the active treatment group, with no changes in the placebo group. Allergen-specific immunotherapy with the A. alternata extract tested here led to a decrease in conjunctival reactivity and induced a significant immunologic response.

Omalizumab (OmAb) is a humanized anti-IgE antibody approved for the treatment of chronic spontaneous urticaria (CSU). OmAb’s mechanism of action is known to include actions on free IgE and on pre-bound IgE. However, OmAb is equally and rapidly effective against autoimmune and non-autoimmune urticaria where IgE involvement is not clear, suggesting the involvement of additional mechanisms of action. In this study, we sought to investigate the ability of OmAb to inhibit mast cell and basophil degranulation induced by sera from CSU patients. For this purpose, we performed a comparison between the in vitro incubation of sera from CSU patients treated with OmAb and the in vivo administration of OmAb in a clinical trial. We found that OmAb added in vitro to sera from CSU patients did not modify the ability of the sera to induce cell degranulation. Similarly, the sera from patients treated with OmAb in the context of the clinical trial who had a good clinical outcome maintained the capacity to activate mast cells and basophils. Thus, we conclude that the beneficial activity of OmAb does not correlate with the ability of patient sera to induce cell degranulation.

The seeds of Plantago ovata (psyllium, ispaghula) used in the manufacture of bulk laxatives are known to be the cause of occupational allergy (rhinitis, asthma) in health care and pharmaceutical workers.We studied the prevalence of P ovata seed allergy among health care workers in geriatric care homes and compared it with a group of health care professionals not exposed to P ovata seed. Cross reactivity with Plantago lanceolata pollen was also studied.Two groups of health professionals were recruited: 58 health care workers from geriatric care homes who were exposed daily to laxatives containing P ovata and 63 nonexposed health care professionals. The prevalence of allergy and sensitization to P ovata seed was determined based on clinical history, skin prick test, and analysis of specific immunoglobulin (Ig) E. IgE immunoblotting was performed to calculate the molecular weights of the P ovata seed allergens. Cross reactivity to P lanceolata pollen was studied by enzyme allergosorbent test (EAST) and immunoblot inhibition techniques.The prevalence of sensitization and clinical allergy to P ovata seed in the exposed group was 13.8% and 8.6%, respectively. No sensitization was observed in the nonexposed group. IgE-binding proteins of 17, 20, 25, 32-34, 54, 73-77, and97 kDa were identified. EAST inhibition and immunoblot inhibition demonstrated the existence of cross reactivity between P ovata seed and P lanceolata pollen extracts.The rate of sensitization to P ovata seed is high among health care workers in geriatric care homes (13.8%). A mild cross reactivity between P ovata seed and P lanceolata pollen was observed.

Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't; TRIAL REGISTRATION Controlled-Trials.comISRCTN35739639. BACKGROUND The Metabolic Syndrome (MetS) is a cluster of metabolic abnormalities that includes hyperglucemia, hypertension, dyslipidemia and central obesity, conferring an increased risk of cardiovascular disease. The white blood cell (WBC) count has been proposed as a marker for predicting cardiovascular risk. However, few prospective studies have evaluated the relationship between WBC subtypes and risk of MetS. METHODS Participants were recruited from seven PREDIMED study centers. Both a baseline cross-sectional (n = 4,377) and a prospective assessment (n = 1,637) were performed. Participants with MetS at baseline were excluded from the longitudinal analysis. The median follow-up was 3.9 years. Anthropometric measurements, blood pressure, fasting glucose, lipid profile and WBC counts were assessed at baseline and yearly during the follow-up. Participants were categorized by baseline WBC and its subtype count quartiles. Adjusted logistic regression models were fitted to assess the risk of MetS and its components. RESULTS Of the 4,377 participants, 62.6% had MetS at baseline. Compared to the participants in the lowest baseline sex-adjusted quartile of WBC counts, those in the upper quartile showed an increased risk of having MetS (OR, 2.47; 95%CI, 2.03-2.99; P-trend