Suchergebnisse

Introduction The evidence on the relationship between breast cancer and different types of antihypertensive drugs taken for at least 5 years is limited and inconsistent. Furthermore, the debate has recently been fueled again with new data reporting an increased risk of breast cancer among women with a long history of use of antihypertensive drugs compared with nonusers. Methods In this case-control study, we report the antihypertensive drugs–breast cancer relationship in 1,736 breast cancer cases and 1,895 healthy controls; results are reported stratifying by the women's characteristics (i.e., menopausal status or body mass index category) tumor characteristics and length of use of antihypertensive drugs. Results The relationship among breast cancer and use of calcium channel blockers (CCB) for 5 or more years had odds ratio (OR) = 1.77 (95% CI, 0.99 to 3.17). Stratifying by BMI, the OR increased significantly in the group with BMI ≥ 25 (OR 2.54, 95% CI, 1.24 to 5.22). CCBs were even more strongly associated with more aggressive tumors, (OR for invasive tumors = 1.96, 95% CI = 1.09 to 3.53; OR for non ductal cancers = 3.97, 95% CI = 1.73 to 9.05; OR for Erbb2+ cancer = 2.97, 95% CI: 1.20 to 7.32). On the other hand, premenopausal women were the only group in which angiotensin II receptor blockers may be associated with breast cancer (OR = 4.27, 95% CI = 1.32 to 13.84) but this could not be identified with any type or stage. Use of angiotensin-converting-enzyme inhibitors, beta blockers and diuretics were not associated with risk. Conclusions In this large population-based study we found that long term use of calcium channel blockers is associated with some subtypes of breast cancer (and with breast cancer in overweight women). ; The study was partially funded by the "Accion Transversal del Cancer" project, approved by the Spanish Council of Ministers on the 11th October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PI09/00773-Cantabria, PI09/01286-Leon, PI09/01903-Valencia, PI09/02078-Huelva, PI09/01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219), by the Fundacion Marques de Valdecilla (API 10/09), by the ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economia y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII) and Red Tematica de Investigacion del Cancer (RTICC) del ISCIII (RD12/0036/0036)), by the Junta de Castilla y Leon (LE22A10-2), by the Consejeria de Salud of the Junta de Andalucia (2009-S0143), by the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), by the Recercaixa (2010ACUP 00310), by the Regional Government of the Basque Country, by the European Commission grants FOOD-CT-2006-036224-HIWATE, by the Spanish Association Against Cancer (AECC) Scientific Foundation and by the Catalan Government DURSI grant 2009SGR1489.

Purpose The objective of this study is to analyse the relative survival with breast cancer in women diagnosed after new treatments were generalised and to ascertain the current efect that tumour characteristics such as grade, stage or subtype have on survival as well as the new AJCC-pathological prognostic score. Methods The breast cancer MCC-Spain follow-up study is a prospective cohort study of 1685 incident breast cancer cases. Women between 20 and 85 years old were recruited between the years 2008 and 2013 in 18 hospitals located in 10 Spanish provinces and they have been followed until 2017/2018. Relative survival was estimated after 3, 5 and 8 years of follow-up using Ederer II method. In addition, Weibull regression adjusted by age, hospital, grade and stage was used to investigate prognosis factors. Results Among components of TNM staging system, tumour size greater than 50 mm (i.e. T3 or T4) more than doubled the risk of dying, while N3 nodal involvement and presence of metastasis had a huge efect on mortality. The AJCC pathological prognostic score strongly correlated with survival; thus, hazard ratios increased as the score rose, being 2.31, 4.00, 4.94, 7.92, 2.26, 14.9 and 58.9 for scores IB, IIA, IIB, IIIA, IIIB, IIIC and IV, respectively. Conclusion Both TNM staging and histological/molecular biomarkers are associated with overall survival in Spanish women with breast cancer; when both are combined in the AJCC pathological prognosis score, the prognostic value improved with risk indices that increased rapidly as the pathological prognosis score increased ; Biological samples were stored at the biobanks supported by Instituto de Salud Carlos III- FEDER: Parc de Salut MAR Biobank (MARBiobanc) (RD09/0076/00036), 'Biobanco La Fe' (RD 09 0076/00021) and FISABIO Biobank (RD09 0076/00058), as well as at the Public Health Laboratory of Gipuzkoa, the Basque Biobank, the ICOBIOBANC (sponsored by the Catalan Institute of Oncology), the IUOPA Biobank of the University of Oviedo and the ISCIII Biobank. SNP genotyping services were provided by the Spanish 'Centro Nacional de Genotipado' (CEGEN-ISCIII). We thank all the subjects who participated in the study and all MCC-Spain collaborators. This work was supported by the 'Acción Transversal del Cancer', approved by the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III, co-founded by FEDER funds – 'a way to build Europe' (grants PI08/1770, PI08/0533, PI08/1359, PI09/00773, PI09/01286, PI09/01903, PI09/02078, PI09/01662, PI11/01403, PI11/01889, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/00613 and PI15/00069). Support was also provided by the Fundación Marqués de Valdecilla (grant API 10/09); the Junta de Castilla y León (grant LE22A10-2); the Consejería de Salud of the Junta de Andalucía (2009-S0143); the Conselleria de Sanitat of the Generalitat Valenciana (grant AP 061/10); the Recercaixa (grant 2010ACUP 00310); the Regional Government of the Basque Country; the Consejería de Sanidad de la Región de Murcia; European Commission grants FOOD-CT-2006–036224-HIWATE; the Spanish Association Against Cancer (AECC) Scientifc Foundation; the Catalan Government DURSI (grant 2014SGR647); the Fundación Caja de Ahorros de Asturias; the University of Oviedo; Societat Catalana de Digestologia; and COST action BM1206 Eucolongene.

The study was partially funded by the "Accion Transversal del Cancer" approved by the Spanish Council of Ministers on the 11th October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PI09/00773-Cantabria, PI09/01286-Leon, PI09/01903-Valencia, PI09/02078-Huelva, PI09/01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI15/00069), by the Fundacion Marques de Valdecilla (API 10/09), by the ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economia y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII) and Red Tematica de Investigacion del Cancer (RTICC) del ISCIII (RD12/0036/0036)), by the Junta de Castilla y Leon (LE22A10-2), by the Consejeria de Salud of the Junta de Andalucia (2009-S0143), by the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), by the Recercaixa (2010ACUP 00310), by the Regional Government of the Basque Country, by the European Commission grants FOOD-CT-2006-036224-HIWATE, by the Spanish Association Against Cancer (AECC) Scientific Foundation and by the Catalan Government DURSI grant 2009SGR1489.

A breast-risk score, published in 2016, was developed in white-American women using 92 genetic variants (GRS92), modifiable and non-modifiable risk factors. With the aim of validating the score in the Spanish population, 1,732 breast cancer cases and 1,910 controls were studied. The GRS92, modifiable and non-modifiable risk factor scores were estimated via logistic regression. SNPs without available genotyping were simulated as in the aforementioned 2016 study. The full model score was obtained by combining GRS92, modifiable and non-modifiable risk factor scores. Score performances were tested via the area under the ROC curve (AUROC), net reclassification index (NRI) and integrated discrimination improvement (IDI). Compared with non-modifiable and modifiable factor scores, GRS92 had higher discrimination power (AUROC: 0.6195, 0.5885 and 0.5214, respectively). Adding the non-modifiable factor score to GRS92 improved patient classification by 23.6% (NRI = 0.236), while the modifiable factor score only improved it by 7.2%. The full model AUROC reached 0.6244. A simulation study showed the ability of the full model for identifying women at high risk for breast cancer. In conclusion, a model combining genetic and risk factors can be used for stratifying women by their breast cancer risk, which can be applied to individualizing genetic counseling and screening recommendations. ; The study was partially funded by the "Accion Transversal del Cancer" project, approved by the Spanish Council of Ministers on the 11th October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PI09/00773-Cantabria, PI09/01286-Leon, PI09/01903-Valencia, PI09/02078-Huelva, PI09/01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219), by the Fundacion Marques de Valdecilla (API 10/09), by the ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economia y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII) and Red Tematica de Investigacion del Cancer (RTICC) del ISCIII (RD12/0036/0036)), by the Junta de Castilla y Leon (LE22A10-2), by the Consejeria de Salud of the Junta de Andalucia (2009-S0143), by the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), by the Recercaixa (2010ACUP 00310), by the Regional Government of the Basque Country, by the European Commission grants FOOD-CT-2006-036224-HIWATE, by the Spanish Association Against Cancer (AECC) Scientific Foundation and by the Catalan Government DURSI grant 2009SGR1489.

Abstract Background Cantabria (Spain) has one of the highest prevalence of smoking among women of the European Union. The objectives are to assess the trend of smoking during pregnancy in a five-year period and the determinants of smoking cessation during pregnancy in Cantabria. Methods A 1/6 random sample of all women delivering at the reference hospital of the region for the period 1998–2002 was drawn, 1559 women. Information was obtained from personal interview, clinical chart, and prenatal care records. In the analysis relative risks and 95% confidence intervals were estimated. Multivariable analysis was carried out using stepwise logistic regression. Results Smoking prior to pregnancy decreased from 53.6% in 1998 to 39.4% in 2002. A decrease in smoking cessation among women smoking at the beginning of pregnancy was observed, from 37.3% in 1998 to 20.6% in 2002. The mean number of cigarettes/day (cig/d) before pregnancy remained constant, around 16 cig/d, whereas a slight trend to increase over time was seen, from 7.7 to 8.9 cig/d. In univariate analysis two variables favoured significantly smoking cessation, although they were not included in the stepwise logistic regression analysis, a higher education level and to be married. The logistic regression model included five significant predictors (also significant in univariate analysis): intensity of smoking, number of previous pregnancies, partner's smoking status, calendar year of study period (these four variables favoured smoking continuation), and adequate prenatal care (which increased smoking cessation). Conclusion The frequency of smoking among pregnant women is very high in Cantabria. As smoking cessation rate has decreased over time, a change in prenatal care programme on smoking counseling is needed. Several determinants of smoking cessation, such as smoking before pregnancy and partner's smoking, should be also addressed by community programmes.

The effect of the applied stress on the deformation and crack nucleation and propagation mechanisms of a gamma-TiAl intermetallic alloy (Ti-45Al-2Nb-2Mn (at. pct)-0.8 vol. pct TiB2) was examined by means of in situ tensile (constant strain rate) and tensile-creep (constant load) experiments performed at 973 K (700 °C) using a scanning electron microscope. Colony boundary cracking developed during the secondary stage in creep tests at 300 and 400 MPa and during the tertiary stage of the creep tests performed at higher stresses. Colony boundary cracking was also observed in the constant strain rate tensile test. Interlamellar ledges were only found during the tensile-creep tests at high stresses (sigma > 400 MPa) and during the constant strain rate tensile test. Quantitative measurements of the nature of the crack propagation path along secondary cracks and along the primary crack indicated that colony boundaries were preferential sites for crack propagation under all the conditions investigated. The frequency of interlamellar cracking increased with stress, but this fracture mechanism was always of secondary importance. Translamellar cracking was only observed along the primary crack. ; Funding from the Spanish Ministry of Science and Innovation through projects (MAT2009-14547-C02-01 and MAT2009-14547-C02-02) is acknowledged. The Madrid Regional Government partially supported this project through the ESTRUMAT grant (P2009/MAT-1585). CJB acknowledges the support from the Spanish Ministry of Education for his sabbatical stay in Madrid (SAB2009-0045). ; Publicado

The deformation and fracture mechanisms of a nearly lamellar Ti-45Al-2Nb-2Mn (at. pct) + 0.8 vol pct TiB₂ intermetallic, processed into an actual low-pressure turbine blade, were examined by means of in situ tensile and tensile-creep experiments performed inside a scanning electron microscope (SEM). Low elongation-to-failure and brittle fracture were observed at room temperature, while the larger elongations-to-failure at high temperature facilitated the observation of the onset and propagation of damage. It was found that the dominant damage mechanisms at high temperature depended on the applied stress level. Interlamellar cracking was observed only above 390 MPa, which suggests that there is a threshold below which this mechanism is inhibited. Failure during creep tests at 250 MPa was controlled by intercolony cracking. The in situ observations demonstrated that the colony boundaries are damage nucleation and propagation sites during tensile creep, and they seem to be the weakest link in the microstructure for the tertiary creep stage. Therefore, it is proposed that interlamellar areas are critical zones for fracture at higher stresses, whereas lower stress, high-temperature creep conditions lead to intercolony cracking and fracture. ; The authors are grateful to Industria de Turbo Propulsores, S.A. for supplying the intermetallic blades. Funding from the Spanish Ministry of Science and Innovation through projects MAT2009-14547-C02-01 and MAT2009-14547-C02-02 is acknowledged. The Madrid Regional Government supported this project partially through the ESTRUMAT grant P2009/MAT-1585. C.J.B. acknowledges the support from Grant SAB2009-0045 from the Spanish Ministry of Education for his sabbatical stage in Madrid. ; Publicado

Research on the risk of motor vehicle injuries and their relationship with the amount of travel has been only partially analyzed. The few individual exposure assessments are related to very specific subsets of the driving and traveling populations. This study analyzes the relationship between kilometers traveled and hospitalization due to motor vehicle injuries. Twelve thousand three hundred and sixty nine Spanish university graduates from the Seguimiento Universidad de Navarra multipurpose cohort study were evaluated. They had not been hospitalized due to motor vehicle injuries at baseline and were followed up to eight years. Biannual questionnaires allowed for self‐reporting of kilometers traveled in motor vehicles, together with incidence of hospitalization. Covariates in the Cox regression models included age and gender and baseline use of safety belt while driving, driving a vehicle with driver‐side airbag, driving a motorcycle, and drinking and driving. There were 49,766 participant‐years with an average yearly travel of 7,828 km per person‐year. Thirty‐six subjects reported a first hospitalization event during this time. The adjusted hazard ratio per additional kilometer traveled was 1.00005 (95% confidence interval 1.000013 to 1.000086). Even the smallest of reductions in the amount of kilometers traveled (from an average of 3,250 km per year to 1,000) has a statistically significant protective effect on the likelihood of sustaining hospitalization due to motor vehicle injury (aHR 0.9, 95% CI 0.78 to 0.98). In light of current policies aimed to reduce motorized traffic due to environmental concerns, it may be appropriate to consider the additional health benefit related to reductions in injuries.

This work aims to contribute to a further understanding of the fundamentals of crystallographic slip and grain boundary sliding in the gamma-TiAl Ti-45Al-2Nb-2Mn (at%)-0.8 vol%TiB2 intermetallic alloy, by means of in situ high-temperature tensile testing combined with electron backscatter diffraction (EBSD). Several microstructures, containing different fractions and sizes of lamellar colonies and equiaxed gamma-grains, were fabricated by either centrifugal casting or powder metallurgy, followed by heat treatment at 1300 °C and furnace cooling. in situ tensile and tensile-creep experiments were performed in a scanning electron microscope (SEM) at temperatures ranging from 580 °C to 700 °C. EBSD was carried out in selected regions before and after straining. Our results suggest that, during constant strain rate tests, true twin gamma/gamma interfaces are the weakest barriers to dislocations and, thus, that the relevant length scale might be influenced by the distance between non-true twin boundaries. Under creep conditions both grain/colony boundary sliding (G/CBS) and crystallographic slip are observed to contribute to deformation. The incidence of boundary sliding is particularly high in gamma grains of duplex microstructures. The slip activity during creep deformation in different microstructures was evaluated by trace analysis. Special emphasis was placed in distinguishing the compliance of different slip events with the Schmid law with respect to the applied stress. ; Funding from the Spanish Ministry of Science and Innovation through projects (MAT2009-14547-C02-01 and MAT2009-14547-C02-02) is acknowledged. The Madrid Regional Government partially supported this project through the ESTRUMAT grant (P2009/MAT-1585). We also acknowledge financial support from the Spanish Ministry of Economy and Competitiveness through grant MAT2012-31889.

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al. ; Myc (c-Myc) counteracts p27 effects, and low p27 usually correlates with high Myc expression in human cancer. However there is no information on the co-expression of both genes in chronic lymphocytic leukemia (CLL). We found a lack of correlation between RNA and protein levels of p27 and Myc in CLL cells, so we determined the protein levels by immunoblot in 107 cases of CLL. We observed a high p27 protein expression in CLL compared to normal B cells. Ectopic p27 expression in a CLL-derived cell line resulted in cell death resistance. Surprisingly, Myc expression was very low or undetectable in most CLL cases analyzed, with a clear correlation between high p27 and low Myc protein levels. This was associated with low Skp2 expression, which is consistent with the Skp2 role in p27 degradation and with SKP2 being a Myc target gene. High Myc expression did not correlate with leukemia progression, despite that cell cycle-related Myc target genes were upregulated. However, biochemical analysis showed that the high p27 levels inhibited cyclin-Cdk complexes even in Myc expressing CLL cells. Our data suggest that the combination of high p27 and low Myc is a marker of CLL cells which is mediated by Skp2. ; The work has been funded by grants SAF11-23796 from MINECO and RD12/0036/0033 (to JL), and RD12/0036/0004 (to DC) and RD12/0036/0060 (to MAP) from Instituto Carlos III. These funding was co-sponsored by the European Union FEDER program. JC was recipient of a Fellowship from Fundación Marqués de Valdecilla and from the University of Cantabria. ; Peer Reviewed

Osteoprotegerin (OPG), receptor activator of nuclear factor-ΚB ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have been involved in rheumatoid arthritis (RA) pathophysiology. In this study, we assessed messenger RNA (mRNA) expression of these molecules by qPCR in peripheral blood from 26 patients with RA (12 of them with ischemic heart disease –IHD) and 10 healthy controls. Correlation coefficients between OPG, RANKL and TRAIL expression levels in RA patients and their clinical and demographic characteristics were also evaluated. Whereas OPG and OPG/TRAIL ratio expression were significantly increased in RA patients compared to controls (fold change = 1.79, p = 0.013 and 2.07, p = 0.030, respectively), RANKL/OPG ratio was significantly decreased (fold change = 0.50, p = 0.020). No significant differences were found between patients and controls in RANKL and TRAIL expression. Interestingly, TRAIL expression was significantly higher in RA patients with IHD compared to those without IHD (fold change = 1.46, p = 0.033). Moreover, biologic disease-modifying antirheumatic drugs (DMARDs) significantly decreased RANKL expression in RA patients (p = 0.016). Our study supports an important role of OPG and TRAIL in RA. Furthermore, it highlights an effect of biologic DMARDs in the modulation of RANKL. ; European Union FEDER funds and "Fondo de Investigación Sanitaria" (grant PI12/00060 and PI15/00525) from "Instituto de Salud Carlos III" (ISCIII) (Spain). This work was also partially supported by RETICS Programs RD12/0009 (RIER) from ISCIII (Spain). FG is a recipient of a Sara Borrell postdoctoral fellowship from the "ISCIII" (CD15/00095). RL-M and BU are supported by funds from the RETICS Program (RIER) (RD12/0009/0013). ; Peer reviewed

Objective: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased cardiovascular (CV) morbidity and mortality. Since interferon-gamma (IFN-γ) has a direct effect on inflammation, in this study we assessed the potential association of the IFNG functional gene variant rs2430561 with CV disease in patients with RA. Methods: One thousand six hundred and thirty-five patients fulfilling the 1987 American College of Rheumatology classification criteria for RA were genotyped for the IFNG (rs2430561, +874T/A) gene polymorphism using TaqMan genotyping assay. Patients were stratified according to the presence of CV events or not. Logistic regression models to explain the presence of CV disease according to the IFNG rs2430561 allele distribution were performed. The potential influence of this variant in the development of subclinical atherosclerosis was also analyzed in a subgroup of patients with no history of CV events to determine carotid artery intima-media thickness (IMT) (n = 286) and presence of carotid plaques. Levels of the cytokine were determined in a subgroup of patients by ELISA. Results: Adjusted logistic regression model disclosed that presence of the minor allele A was not associated with increased risk of suffering CV events in RA patients. Besides, differences did not achieve statistical significance regarding carotid IMT and presence of carotid plaques in RA patients carrying IFNG rs2430561 variant allele. Levels of IFN-γ were higher in patients who had suffered CV events compared to patients who did not. Conclusion: Our results do not support a role of IFNG rs2430561 (+874T/A) functional gene variant in the development of CV disease in RA patients ; This work was supported by two grants from Fondo de Investigaciones Sanitarias PI06-0024 and PS09/00748 (Spanish National Health System; Ministry of Science and Innovation, Spain Government) and by RETICS Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), National Health System (Spain) within the VI Programa Nacionalde I+D+i 2008–2011 (FEDER). This work was supported in part by grants from the EuropeanIMI BTCure Program. MGB is a beneficiary of a grant from Fundación Española de Reumatología

Objective: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased cardiovascular (CV) mortality. Since CD40-CD154 binding has direct consequences on inflammation process initiation, we aimed to replicate previous findings related to disease susceptibility in Spanish RA population. Furthermore, as the major complication in RA disease patients is the development of CV events due to accelerated atherosclerosis, and elevated levels of CD40L/CD154 are present in patients with acute myocardial infarction, we assessed the potential association of CD40 and CD154/CD40L gene variants with CV risk in Spanish RA patients. Methods: One thousand five hundred and seventy-five patients fulfilling the 1987 ACR classification criteria for RA and 1600 matched controls were genotyped for the CD40 rs1883832, rs4810485 and rs1535045 and CD154 rs3092952 and rs3092920 gene polymorphisms, using predesigned TaqMan single nucleotide polymorphism genotyping assays. Afterwards, we investigated the influence of CD40-CD154 gene variants in the development of CV events. Also, in a subgroup of 273 patients without history of CV events, we assessed the influence of these polymorphisms in the risk of subclinical atherosclerosis determined by carotid ultrasonography. Results: Nominally significant differences in the allele frequencies for the rs1883832 CD40 gene polymorphism between RA patients and controls were found (p = 0.038). Although we did not observe a significant association of CD40-CD154 gene variants with the development of CV events, an ANCOVA model adjusted for sex, age at the time of the ultrasonography assessment, follow-up time, traditional CV risk factors and anti-cyclic citrullinated peptide antibodies disclosed a significant association (p = 0.0047) between CD40 rs1535045 polymorphism and carotid intima media thickness, a surrogate marker of atherosclerosis. Conclusion: Data from our pilot study indicate a potential association of rs1883832 CD40 gene polymorphism with susceptibility to RA. Also, the CD40 rs1535045 gene variant may influence development of subclinical atherosclerosis in RA patients ; This work was supported by two grants from Fondo de Investigaciones Sanitarias PI06-0024 and PS09/00748 (Spanish National Health System; Ministry of Science and Innovation, Spain Government) and by RETICS Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), National Health System (Spain) within the VI Programa Nacional de I+D+i 2008–2011 (FEDER). This work was supported in part by grants from the European IMI BTCure Program. MGB is a beneficiary of a grant from Fundación Española de Reumatología.