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Objectives: To analyse the hospital admissions for bleeding events associated with treatment with direct oral anticoagulants (DOACs). To describe the characteristics and outcomes of those patients., Methods: A retrospective observational study was carried out in the framework of an integral risk management plan of drugs and proactive pharmacovigilance of hospital admissions for bleeding associated with apixaban, dabigatran and rivaroxaban from April 2015 through December 2016. Cases were identified using the information management tool of Orion Clinic (hospital electronic medical history) and by reviewing the hospital discharge reports. Various biometric, clinical and pharmacotherapeutic variables of each patient were registered., Results: 37 hospitalisation episodes for DOAC-induced bleeding in 32 patients (15 received rivaroxaban, 9 apixaban and 8 dabigatran) were detected, representing an incidence rate of 3.44 per 100 person-years (95% CI 2.35 to 4.86). The most common bleeding site was gastrointestinal (27 cases, 73.0%). Intracranial bleeding was rare (three cases, 8.1%). Four patients (12.5%) were receiving DOACs at full doses and had a 'dose reduction indication'. The mean (SD) length of stay was 8.4 (5.2) days. Three patients (8.1%) died during the hospitalisation. Among bleeding episodes without fatal outcome, DOACs were stopped in 14 cases, continued in 14 cases, switched for another DOAC in two cases and the dose was reduced in four cases., Conclusions: DOACs are associated with serious bleeding events that require hospitalisation. The risk/benefit ratio assessment considering patient preferences and an individualised follow-up, especially in patients who are elderly, polymedicated or have impaired renal function, can help to reinforce the safe use of DOACs., Competing Interests: Competing interests: None declared.

Objectives: To analyse the risk factors of gastropathy caused by using non-steroidal anti-inflammatory drugs (NSAIDs) in detected hospital admissions and to analyse the use of gastroprotective treatment concerning these risk factors., Methods: A retrospective observational study was carried out in the framework of an integral risk management plan of drugs and proactive pharmacovigilance of hospital admissions for NSAID-induced gastropathy occurring between 2011 and 2015. Cases were identified after reviewing the ICD-9 codes related to NSAID-induced gastropathy in hospital discharge reports. Various biometric, clinical and pharmacotherapeutic variables of each patient were registered. The gastroprotective criteria set out in the therapeutic decision algorithm of the Valencian Health System were followed., Results: 62 hospital admissions for NSAID-induced gastropathy were detected. The mean length of stay was 5.3±3.8 days. Ibuprofen was the most prevalent NSAID (28 cases, 45.2%). 24 cases (38.7%) took NSAIDs in the week before hospitalisation. The prevalence of relevant risk factors for gastropathy were age >60 years (37 cases, 59.7%), concomitant medication (24 cases, 38.7%) and a history of peptic ulcer (9 cases, 14.5%). 41 patients (66.1%) met gastroprotective major criteria, 18 of whom (43.9%) were using a proton pump inhibitor following a prevention plan., Conclusions: In this study all relevant gastroprotective criteria were associated with the use of gastroprotection in detected hospital admissions for NSAID-induced gastropathy. However, a lack of gastroprotection was observed in a large number of detected cases with the criteria to use it. The feedback of our results to health area agents can serve to reinforce the safe use of NSAIDs., Competing Interests: Competing interests: None declared.

Introduction: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERα transcriptional regulatory plasticity. Herein we identify VAV3 as a critical component in this process., Methods: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERα was evaluated by molecular docking analyses, an agonist fluoligand assay and short hairpin (sh)RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot analysis of signaling and proliferation markers, and shRNA-mediated protein depletion in viability and clonogenic assays, were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine its association with therapeutic response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression., Results: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase), but instead was likely a result of binding to ERα. VAV3 was selectively reduced upon exposure to YC-1 or ERα depletion, and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 × 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy., Conclusions: This study proposes VAV3 as a biomarker and a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.

Introduction: The objective of the study was to estimate the level of exposure of children under the age of 18 to second-hand smoke (SHS) inside motor vehicles., Methods: A prevalence study was conducted on the exposure of children under the age of 18 to SHS in motor vehicles in Lleida (Spain). The population was the users of private motor vehicles. The sample was random, and the data were collected by direct observation. The study variables were: the age and sex of the driver, whether the driver was smoking, and the presence of an exposed passenger under the age of 18., Results: A total of 1600 vehicles were observed, 134 of which (8.4%) were carrying a child. In 8 of these 134 vehicles (6%; 95% CI: 2.5-11.0) a child was exposed to SHS. In all these cases, the driver was a male (P=0.02), and in 75% of cases he was over 40 years old., Conclusions: The rate of child exposure to SHS is very high. There is, therefore, a case for organising campaigns to prevent smoking tobacco inside motor vehicles in the presence of children in Spain., (Copyright © 2012 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.)

Unlabelled: The existing literature describing the clinicopathological features and behaviour of matrix-producing (MP) malignant breast tumours presents conflicting results. As a consequence it remains uncertain whether these tumours should be treated as sarcoma and managed by a specialist sarcoma team or treated using the same principles as conventional ductal carcinoma, a dilemma that prompted this study. Improved understanding of the clinicopathological characteristics of primary mammary MP-sarcomas, namely osteosarcoma and chondrosarcoma, is required., Methods: In this large international multicenter series of malignant MP-tumours of the breast (no = 101) with follow-up information has been assessed and their outcome is compared to other subtypes of metaplastic breast carcinoma (MBC) (no = 253) and to grade, lymph node and hormone receptor-matched ductal breast carcinomas (no = 258)., Results: The majority of MP-cancers were associated with epithelial features, which supports the concept that the majority of, if not almost all, primary MP breast sarcomas are of epithelial in origin (MBC). 21% showed nodal metastasis and the distribution of distant metastases resembled conventional mammary carcinoma. The prognosis of MP-MBC is comparable to matched ductal breast carcinoma and slightly better than other subtypes of MBC. Advanced stage (T3&T4) and development of recurrences were predictors of shorter survival in MP-MBC while grade and vascular invasion were not., Conclusion: Most malignant MP breast tumours are variants of MBC. MP-MBC with predominant mesenchymal components behaves similar to ductal carcinomas and although data on their response to systemic therapy is limited, there is no evidence that they should be managed differently from other forms of triple negative breast cancer., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To determine the prevalence of smoking among drivers of private vehicles in the city of Lleida (Spain)., Methods: A random sample of 1600 cars passing through six intersections regulated by traffic lights were selected. The variables were age, sex, smoking driver, adult passengers, intersection (urban/interurban), day (working day/weekend), hour (morning/evening) and simultaneous smokers. We calculated the prevalence of smoking drivers and the corresponding odds ratios (ORs), adjusted for the potential confounding variables, as well as their 95% confidence intervals (95% CI)., Results: The prevalence was 6.0% (95% CI: 4.9-7.3) and was higher in men (6.4%), in the group aged 41 to 60 years (6.9%), and in unaccompanied drivers (6.5%). The probability of the driver smoking increased if there was a smoking passenger (aOR=10.8; 95% CI: 3.6-32.5). The frequency of smoking drivers was higher on working days (aOR=1.7; 95% CI: 1.0-2.8) and in the morning (aOR=1.6; 95% CI: 1.0-2.4)., Conclusions: The prevalence of smoking drivers can be considered dangerously high. We recommend avoiding smoking while driving., (Copyright © 2011 SESPAS. Published by Elsevier Espana. All rights reserved.)

Paracrine signaling through receptor activator of NF-κB (RANK) pathway mediates the expansion of mammary epithelia that occurs during pregnancy, and activation of RANK pathway promotes mammary tumorigenesis in mice. In this study we extend these previous data to human cells and show that the RANK pathway promotes the development of mammary stem cells and breast cancer. Overexpression of RANK (FL-RANK) in a panel of tumoral and normal human mammary cells induces the expression of breast cancer stem and basal/stem cell markers. High levels of RANK in untransformed MCF10A cells induce changes associated with both stemness and transformation, including mammary gland reconstitution, epithelial-mesenchymal transition (EMT), increased migration, and anchorage-independent growth. In addition, spheroids of RANK overexpressing MCF10A cells display disrupted acinar formation, impair growth arrest and polarization, and luminal filling. RANK overexpression in tumor cells with nonfunctional BRCA1 enhances invasiveness in acinar cultures and increases tumorigenesis and metastasis in immunodeficient mice. High levels of RANK were found in human primary breast adenocarcinomas that lack expression of the hormone receptors, estrogen and progesterone, and in tumors with high pathologic grade and proliferation index; high RANK/RANKL expression was significantly associated with metastatic tumors. Together, our findings show that RANK promotes tumor initiation, progression, and metastasis in human mammary epithelial cells by increasing the population of CD44(+)CD24(-) cells, inducing stemness and EMT. These results suggest that RANK expression in primary breast cancer associates with poor prognosis., (©2012 AACR)

Intracellular signaling mediated by the receptor activator of nuclear factor-κB [Rank, encoded by the tumor necrosis factor receptor superfamily, member 11a (Tnfrsf11a) gene] is fundamental for mammary gland development in mice, regulating the expansion of stem and progenitor cell compartments. Conversely, Rank overexpression in mice promotes abnormal proliferation and impairs differentiation, leading to an increased incidence of tumorigenesis. Here, we show that a common genetic variant near the 5'-end of TNFRSF11A, rs7226991, is associated with breast cancer risk in the general population and among carriers of mutations in the breast cancer 2, early onset (BRCA2) gene. Akin to the results of the Cancer and Genetics Markers of Susceptibility initiative, combined analysis of rs7226991 in two Spanish case-control studies (1,365 controls and 1,323 cases in total) revealed a significant association with risk: odds ratio (OR) = 0.88, 95% confidence interval (CI) 0.78-0.98, P (trend) = 0.025. Subsequent examination of BRCA1 (n = 1,017) and BRCA2 (n = 885) mutation carriers revealed a consistent association in the latter group: weighted hazard ratio ((w)HR) = 0.70; 95% CI 0.55-0.88; and P (trend) = 0.003; compared to BRCA1 mutation carriers, (w)HR = 0.91; 95% CI 0.76-1.10; and P (trend) = 0.33. The results of this study need to be replicated in other populations and with larger numbers of BRCA1/2 mutation carriers.

Introduction: Appendiceal diverticula are uncommon, with an incidence of less than 1% in surgical specimens. We report a series of 14 patients with diverticular disease of the cecal appendix., Patients and Method: A total of 547 patients with a clinical diagnosis of acute appendicitis underwent surgery over 4 years. Of these, 11 patients showed acute appendiceal diverticulitis at histological examination, and three patients showed diverticulosis associated with appendicitis. Clinical features were compared between the group of patients with diverticular disease and the group with acute appendicitis. Statistical analysis was performed using Students t-test and the chi-squared test., Results: The overall incidence of appendiceal diverticula was 2.6%, and 2% of cases had acute diverticulitis. In the group with diverticular disease, the mean age and the percentage of patients under clinical observation before the decision to perform surgery was made were significantly higher. There was a nonsignificant predominance of male over female patients and no differences were found in mean white cell count. No radiological investigations were performed in the diverticular group., Conclusions: The incidence of appendiceal diverticula was much higher in our series than that reported in the literature. We found no clinical or perioperative data that would serve to differentiate acute diverticulitis from acute appendicitis.

We studied the involvement of chemokines that bind to G protein-coupled receptors in the migration of skin homing T cells across a bilayer vascular construct (BVC) consisting of a fibroblast matrix underneath an activated endothelial (EC) monolayer. Based on the expression of the cutaneous lymphocyte-associated antigen (CLA), a skin homing receptor, CD45R0+ T cells freshly isolated from blood or HUT-78 cutaneous T lymphoma cells were separated into CLA+ and CLA- subpopulations. These T cells were incubated on interleukin (IL)-1 beta and tumor necrosis factor-alpha-activated EC, and the number of transmigrated cells was determined. The chemokine IL-8 was selectively involved in the enhanced migration of CLA+ T cells across activated EC as demonstrated by blocking antibody to IL-8 but not to GRO-alpha, MCP-1 and RANTES. Identical results were obtained with both human umbilical vein EC (HUVEC) and microvascular skin EC (HDMEC). Pertussis toxin selectively inhibited the enhanced transendothelial migration (TEM) of CLA+ T cells, suggesting that CLA-dependent TEM depends on Gi protein-transmitted signals. Moreover, the IL-8 receptor B (IL-8RB) appeared to be functionally involved in TEM, as demonstrated by receptor desensitization with the CXC chemokines IL-8 and GRO-alpha and by blocking the IL-8RB with specific monoclonal antibodies. Although only the IL-8RB was involved in CLA-dependent TEM, mRNA encoding IL-8RA and IL-8RB was expressed by both CLA+ and CLA- T cells. This correlated with IL-8RA and IL-8RB surface expression on these cells. Thus, the IL-8RB is selectively functional in TEM of T cells expressing the skin homing receptor CLA. Our results demonstrate a critical role for IL-8 and possibly other IL-8RB ligands in addition to the IL-8RB in TEM and suggest the involvement of these molecules in the homing of specific T cells to inflamed skin.

The cutaneous lymphocyte-associated antigen (CLA) is the major T cell ligand for the vascular adhesion molecule E-selectin, and it has been proposed to be involved in the selective targeting of memory T cells reactive with skin-associated Ag to cutaneous inflammatory sites. To further investigate the relation of CLA and cutaneous T cell responses, we analyzed the CLA phenotype of circulating memory T cells in patients with allergic contact dermatitis and atopic dermatitis (AD) alone vs in patients manifesting bronchopulmonary atopy (asthma with or without AD) and nonallergic individuals. Significant T cell proliferative responses to Ni, a contact allergen, and to the house dust mite (HDM), an allergen to which sensitization is often observed in AD and/or asthma, was noted only in allergic and atopic individuals, respectively. When the minor circulating CLA+CD3+CD45RO+ subset was separated from the major CLA-CD3+CD45RO+ subpopulation in Ni-sensitive subjects, the Ni-dependent memory T cell response was largely confined to the CLA+ subset. A similar restriction of the T cell proliferative response to the CLA+ memory subset was observed for HDM in patients with AD alone. In HDM-sensitive patients with asthma with or without AD, however, the CLA- subset exhibited a strong antigen-dependent proliferation, in contrast to patients with AD alone, whose CLA- subset proliferated very weakly to HDM. In asthma with or without AD, the HDM-dependent proliferation slightly predominated in the CLA- when compared to the CLA+ subset. The functional linkage between CLA expression and disease-associated T cell effector function in AD was also demonstrated by the finding that the circulating CLA+ T cell subset in AD patients, but not nonatopic controls, selectively showed both evidence of prior activation (human histocompatibility antigen-DR expression) and spontaneous production of interleukin 4 but not interferon-gamma. Taken together, these observations demonstrate the correlation of CLA expression on circulating memory T cells and disease-associated memory T cell responses in cutaneous hypersensitivity, and they suggest the existence of mechanisms capable of sorting particular T cell Ag specificities and lymphokine patterns into homing receptor-defined memory subsets.

The cutaneous lymphocyte-associated Ag (CLA) is expressed by a subset of circulating memory/effector T cells and by the vast majority of skin-infiltrating T cells. CLA is thought to target skin-associated T cells to inflammatory skin sites by interacting with endothelial cell ligand E-selectin (CD62E). We have examined adhesion molecules involved in the migration of human CLA+ and CLA- memory/effector T lymphocytes through IL-1- and TNF-alpha-activated and nonactivated HUVEC layers under static (nonflow) conditions. CLA-enriched memory/effector T lymphocytes migrated more actively across cytokine-activated HUVEC than CLA-depleted memory/effector T cells. This enhanced migration is dependent on the CLA/E-selectin interaction. mAb to very late Ag-4 (VLA-4) and vascular cell adhesion molecule-1 (VCAM-1) blocked the migration of CLA-enriched, but not of CLA-depleted, T cells across activated HUVEC. The observation that anti-VLA-4 and anti-CLA mAb did not show additional inhibition supports the concept that CLA and VLA-4 are sequentially involved in the extravasation. The fact that only CLA+ T cells were inhibited by the anti-VLA-4 mAb suggests that, in this system, CLA engagement is required for using the VLA-4/VCAM-1 pathway. Our studies demonstrate that CLA+ T cells use LFA-1/intercellular leukocyte adhesion molecule-1 (ICAM-1) for transmigration but that CLA expression is not required for the LFA-1/ICAM-1-dependent transmigration because anti-CD18/CD11a mAbs and anti-ICAM-1 mAbs were able to block T cell migration regardless of the activation state of HUVEC or the CLA expression by T cells. Taken together, our results suggest that CLA has a homing function in conducting the T cell to interact with LFA-1/ICAM-1 and/or VLA-4/VCAM-1; this results in enhanced adhesion and migration across cytokine-activated endothelial cells.

The cutaneous lymphocyte-associated antigen (CLA) is a carbohydrate epitope present on memory/effector T cells that infiltrate inflamed skin. E-selectin is the ligand for CLA and is induced under inflammation on endothelial cells. CLA was originally postulated as a phenotype marker for skin-associated T cells. We studied the specific in vitro response to skin-associated allergens of CLA+ and CLA-CD45RO+ T cells in atopic dermatitis (AD) and contact dermatitis (CD), which represent two well-characterized T cell-mediated cutaneous allergic inflammations. Whereas CLA+ T cells from AD patients preferentially responded to house dust mite (HDM) and CLA+ T cells from nickel CD patients showed an increased response to nickel, CLA-T cells showed very little response in both cases. In contrast, tetanus toxoid, a systemically acting antigen, induced a proliferative response in both CLA+ and CLA- cells. Interestingly the response to HDM in patients with asthma +/- AD was preferentially found in the CLA- subset indicating the involvement of different homing receptors for mucosal tissues. Moreover, CLA+ T cells showed enhanced migration through activated human umbilical vein endothelial cell monolayers compared to CLA- T cells. The CLA binding to E-selectin is initially responsible for the extravasation that also involves VLA-4/VCAM-1 and LFA-1/ICAM-1 interactions. We have recently identified IL-8 as an endothelial cell-derived chemokine and the IL-8 receptor type B which control CLA+ T cell migration. Such a CLA-mediated migration would localize memory/effector T cells that respond to antigens and reach the body through inflamed skin. Our data support the existence of a regionalization of the immune system and in particular of the skin immune system. It may allow an efficient distribution of the immune defense to different sites of the body.

Monomeric IgE bound to the low-affinity receptor for IgE (FcERII-CD23) on EBV-transformed human B cells selectively enhances binding of antigen and therefore presentation to specific T-cell clones. To demonstrate the role of monomeric IgE in antigen focusing, we have made use of a system consisting of human T-cell clones specific for Der-P1 (major allergen of the Dermathophagoides pteronyssinus), Der-P1 coupled to NIP (Der-P1-NIP), and the commercially available chimeric (human-murine) monoclonal IgE antibodies with specificity for the hapten NIP. We have found that monomeric IgE binds to CD23 and remains detectable on the surface of the B cells for a period of at least 16 hours at 37 degrees C. Pulsing of these IgE-anti-NIP (1 microgram/ml) treated B cells for 1 hour at 37 degrees C with low amounts (10 ng/ml) of Der-P1-NIP antigen allows the B cells to stimulate Der-P1-specific T cells. Even with IgE concentrations as low as 20 ng/ml, which were not detectable by immunofluorescence, we were able to induce a significant T-cell response. Furthermore, ongoing specific T-cell-B-cell interactions were not inhibited by the presence of high concentrations of nonspecific IgE molecules (incubated with up to 25 micrograms/ml) on the surface of the B cells. Our data confirm the hypothesis that IgE, bound by either CD23 or the high-affinity receptor for IgE, potentiates the immune response. Therefore, IgE may be seen as the fourth general mechanism for antigen capture by (nonspecific) antigen-presenting cells.