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The aim of this study was to analyse a personal and social responsibility programme in students and their family&rsquo, s perceptions relative to responsibility, prosocial behaviours, empathy, violence perception and physical activity levels. A sample consisting of 57 physical education students between 11 and 14 years old (mean (M) = 11.93, standard deviation (SD) = 0.73) that included 32 of their parents (M = 49.31, SD = 6.39) was distributed into experimental and control groups. The main results indicate that there were initial significant differences in favour of the control group for personal and social responsibility compared to the experimental group and they disappeared at the end of the treatment. There was an increase in antisocial behaviours for the control group at the end of the treatment. The experimental group also enhanced the values in violence perception for both students and families as compared to the control group. These results seem contradictory, which may be due in part to a short-time intervention programme and a low number of participants in the sample. More studies will clarify the improvements this kind of programme can bring to the variables studied.

The purpose of this study is to describe the characteristics of older patients treated with psychotropic medicines and the associated factors and to assess their inappropriate use. An observational, prospective study was carried out in 672 elderly patients admitted to seven hospitals for a year. A comparison of sociodemographic characteristics, geriatric variables, multimorbidity and the number of prescribed medicines taken in the preceding month before hospitalization between patients treated with psychotropics and those not treated was performed. To assess factors associated with psychotropics, multivariate logistic regression analyses were performed. Inappropriate use was assessed using the Beers and the STOPP criteria. A total of 57.5 % patients (median [Q1-Q3] age 81.7 [78.2-86.1], 65.7 % female) were treated with psychotropics (44.2 % anxiolytics, 22.6 % antidepressants and 10.8 % antipsychotics). Independent factors associated with the use of psychotropics were female gender (OR = 2.3; CI 95 %,1.6-3.5), some degree of disability on admission (slight [OR = 2.2; 1.2-4.2], moderate [OR = 3.2, 1.6-6.6], severe [OR = 3.4; 1.4-8] and very severe [OR = 5.1; 2.0-12.8]) and polypharmacy (5-9 medicines [OR = 3.0; 1.3-6.9] and a parts per thousand yen10 medicines [OR = 6.0; 2.7-13.6]). The associated factors varied depending on the different types of psychotropics. In patients treated with psychotropics, the percentage of those with at least one Beers (61.6 %) or at least one STOPP (71.4 %) criteria was significantly higher in comparison with those not treated with psychotropics (30.7 and 47.7 %, respectively, p < 0.001). Psychotropics are widely used in the elderly population and often their use is inappropriate. Female gender, a poor functional status and polypharmacy, are the characteristics linked to their use. Interventional strategies should be focused on patients with these characteristics.

Background Fine-needle aspiration biopsy (FNAB) is the reference procedure for thyroid nodule evaluation. Its main limitations are inadequate samples, which should be less than 20%. Objective To analyze the learning curve of the procedure by comparing the results of a non-experienced endocrinologist (endocrinologist 2) to those of an experienced one (endocrinologist 1). Material and methods Sixty FNABs were analyzed from February to June 2016. Each endocrinologist made 2 punctures of every nodule in a random order. This order and the professional making every puncture were unknown to the pathologist who examined the samples. Results Endocrinologist 1 had a higher percentage of diagnoses than endocrinologist 2 (82% vs. 72%, p = 0.015). In the first 20 FNABs, the difference between both physicians was remarkable and statistically significant (80% vs. 50%, p = 0.047). In the following 20 FNABs, the difference narrowed and was not statistically significant (90% vs. 65%, p = 0.058). In the final 20 FNABs, the difference was minimal and not statistically significant (75% vs. 70%, p = 0.723). Conclusions The learning curve of ultrasound-guided FNAB may be completed in a suitable environment by performing it at least 60 times. Although the guidelines recommend at least 3 punctures per nodule, 2 are enough to achieve an accurate percentage of diagnoses.

To analyse potentially inappropriate prescribing (PIP) in elderly polypathological patients (PP).Multicentre observational, prospective study of 672 patients aged 75 years and older hospitalised in Internal Medicine between April 2011 and March 2012. The Beers, STOPP-START and ACOVE criteria were used to detect potentially inappropriate prescribing and the results of PP and non-PP patients were compared.Of the 672 patients included, 419 (62%) were polypathological, of which 89.3% met PIP criteria versus 79.4% of non-polypathological patients (p0.01). 40.3% of polypathological patients met at least one Beers criteria, 62.8% at least one STOPP criteria, 62.3% at least one START criteria and 65.6% at least one ACOVE criteria. The rate of potentially inappropriate prescribing was higher in polypathological patients regardless of the tool used.Given the high rate of potentially inappropriate prescribing in polypathological patients, strategies to improve prescribing adequacy must be developed.

Introduction and objectives It is now generally accepted that angiogenesis is crucial in tumour growth. However, controversy still exists regarding the prognostic significance of angiogenesis in head and neck carcinomas. The aim of this paper is to determine the prognostic significance of angiogenesis in a homogeneously treated group of supraglottic squamous cell carcinomas. Material and methods Hundred eight patients surgically treated for squamous cell carcinoma of the supraglottic larynx were studied. Angiogenesis was estimated in the primary tumour and in the nodal metastases by determining microvessel density using the “hot spot” method. Anti-CD34 antibody was used to stain blood vessels. Results The mean microvessel density in primary tumours was 72 (34) vessels/mm2 and 58.5 (31.5) vessels/mm2 in nodal metastases. No correlation was found between microvessel density in the primary tumours and the corresponding nodal metastasis (P = .195). No significant differences in microvessel density were observed in relation to clinico-pathological parameters or survival (P = .19). Conclusions Our results suggest that microvessel density is not a useful prognostic marker in surgically treated supraglottic squamous cell carcinomas.

Introduction and objectives The successive acquisition of molecular alterations determines tumour progression. During this progression, the development of nodal metastases is one of the most important prognostic factors in laryngeal squamous cell carcinomas. The aim of this study is to analyze if, in these carcinomas, the molecular alterations in the nodal metastases are different from those present in the primary tumour. Material and method Paired samples of primary tumour and nodal metastases from 51 patients with squamous cell carcinoma of the supraglottic larynx were studied. Using immunohistochemistry, we analyzed the expression of p53, E-cadherin, FAK, annexin A2, and HIF-1αproteins. In addition, the apoptotic index (measuring activated caspase-3) and the degree of vascularization (identified by CD34 antigen expression) were also studied. Results Aclose correlation in the expression of the proteins studied was observed in the nodal metastases and the corresponding primary tumour, with the exception of HIF-1αexpression and the degree of vascularization. Conclusions Most of the molecular alterations in the nodal metastases are already present in the primary tumour, suggesting that these alterations are early events in carcinogenesis.

Aims To assess inappropriate prescribing in older people with diabetes mellitus during the month prior to a hospitalization, using tools on potentially inappropriate medicines (PIMs) and potential prescribing omissions (PPOs) and comparing inappropriate prescribing in patients with without diabetes. Methods In an observational, prospective multicentric study, we assessed inappropriate prescribing in 672 patients aged 75 years and older during hospital admission. The Beers, Screening Tool of Older Person's Prescriptions (STOPP) and Screening Tool to Alert Doctors to Right Treatment (START) criteria and Assessing Care of Vulnerable Elders (ACOVE-3) medicine quality indicators were used. We analysed demographic and clinical factors associated with inappropriate prescribing. Results Of 672 patients, 249 (mean age 82.4 years, 62.9% female) had a diagnosis of diabetes mellitus. The mean number of prescribing drugs per patient with diabetes was 12.6 (4.5) vs. 9.4 (4.3) in patients without diabetes (P < 0.001). Of those patients with diabetes, 74.2% used 10 or more medications; 54.5% of patients with diabetes had at least one Beers-listed PIM, 68.1% had at least one STOPP-listed PIM, 64.6% had at least one START-listed PPO and 62.8% had at least one ACOVE-3-listed PPO. Except for the Beers criteria, these prevalences were significantly higher in patients with diabetes than in those without. After excluding diabetes-related items from these tools, only STOPP-listed PIMs remained significantly higher among patients with diabetes (P = 0.04). Conclusions Polypharmacy is common among older patients with diabetes mellitus. Inappropriate prescribing is higher in older patients with diabetes, even when diabetes-related treatment is excluded from the inappropriate prescribing evaluation.

Annexin A1 (ANXA1) protein expression was evaluated by Western blot in a series of 32 head and neck squamous cell carcinomas (HNSCCs) in a search for molecular alterations that could serve as useful diagnostic/prognostic markers. ANXA1 down-regulation was observed in 24 cases (75%) compared with patient-matched normal epithelium. In relation to clinicopathological variables, ANXA1 down-regulation was significantly associated with advanced T stages (P = 0.029), locoregional lymph node metastases (P = 0.038), advanced disease stage (P = 0.006), hypopharyngeal localization (P = 0.038), and poor histological differentiation (P = 0.005). ANXA1 expression was also analyzed by immunohistochemistry in paraffin-embedded sections from 22 of 32 HNSCCs and 8 premalignant lesions. All dysplastic tissues showed significantly reduced ANXA1 expression compared to a strong positive signal observed in adjacent normal epithelia (except basal and suprabasal cells). A close association was observed between ANXA1 expression and the histological grade in HNSCC. Well-differentiated tumors presented a positive ANXA1 signal in highly keratinized areas whereas moderately and poorly differentiated tumors exhibited very weak or negative staining. Our findings clearly identify ANXA1 as an effective differentiation marker for the histopathological grading of HNSCCs and for the detection of epithelial dysplasia.

In the search for differences between ERalpha and ERbeta, we analyzed the interaction of both receptors with calmodulin (CaM) and demonstrated that ERalpha but not ERbeta directly interacts with CaM. Using transiently transfected HeLa cells, we examined the effect of the CaM antagonist N-(6-aminohexyl)-5-chloro-naphthalene sulfonilamide hydrochloride (W7) on the transactivation properties of ERalpha and ERbeta in promoters containing either estrogen response elements or activator protein 1 elements. Transactivation by ERalpha was dose-dependently inhibited by W7, whereas that of ERbeta was not inhibited or even activated at low W7 concentrations. In agreement with these results, transactivation of an estrogen response element containing promoter in MCF-7 cells (which express a high ERalpha/ERbeta ratio) was also inhibited by W7. In contrast, transactivation in T47D cells (which express a low ERalpha/ERbeta ratio) was not affected by this CaM antagonist. The sensitivity of MCF-7 cells to W7 was abolished when cells were transfected with increasing amounts of ERbeta, indicating that the sensitivity to CaM antagonists of estrogen-responsive tissues correlates with a high ERalpha/ERbeta ratio. Finally, substitution of lysine residues 302 and 303 of ERalpha for glycine rendered a mutant ERalpha unable to interact with CaM whose transactivation activity became insensitive to W7. Our results indicate that CaM antagonists are selective modulators of ER able to inhibit ERalpha-mediated activity, whereas ERbeta actions were not affected or even potentiated by W7.

Purpose: This study aims to assess inappropriate prescribing (IP) to elderly patients during the month prior to hospitalization and to compare different IP criteria. Methods: An observational, prospective and multicentric study was carried out in the internal medicine services of seven Spanish hospitals. Patients aged 75 years and olderwere randomly selected after hospital admission for a year. To assess potentially inappropriate medicines (PIMs), the Beers and STOPP criteria were used and to assess potentially prescribing omissions (PPOs), the START criteria and ACOVE-3 medicine quality indicators were used. An analysis to assess factors associated with IP was performed. Results: 672 patients [median age (Q1-Q3) 82 (79-86) years, 55.9% female] were included. Median prescribed medicines in the month prior to hospitalization were 10(Q1-Q3 7-13). The prevalence of IP was 87.6%, and 54.3% of patients had PIMs and PPOs concurrently. A higher prevalence rate of PIMs was predicted using the STOPP criteria than with the Beers criteria (p < 0.001) and a higher prevalence of PPOs using the ACOVE-3 criteria than using the START criteria (p < 0.001) was observed. Polypharmacy (>= 10 medicines) was the strongest predictor of IP [OR = 11.34 95% confidence interval (CI) 4.96-25.94], PIMs [OR = 14.16, 95% CI 6.44-31.12], Beers-listed PIMs [OR = 8.19, 95% CI 3.01-22.28] and STOPP-listed PIMs [OR = 8.21, 95% CI 3.47-19.44]. PIMs was the strongest predictor of PPOs [OR = 2.79, 95% CI 1.81-4.28]. Conclusions: A high prevalence of polypharmacy and PIMs and PPOs were reported. More than half the patients had simultaneous PIMs and PPOs. The related factors to PIMs and PPOs were different. (c) 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Purpose: There are limited tools to assess potential prescribing omissions (PPOs) or underprescribing in the elderly. The ACOVE project defines comprehensive quality care indicators for older people and some of these indicators focused on appropriate use of medicines. The aim of the present study was to assess the inter-rater reliability between observers using the ACOVE 3 prescribing indicated medications indicators and compare it with the inter-rater reliability obtained for the Screening Tool of Older Person's Prescriptions (STOPP)/Screening Tool to Alert Doctors to Right Treatment (START) criteria. Methods: In the context of an observational and multicentric study of a cohort of 672 patients 75 years and older who were hospitalized in Internal Medicine services of seven Spanish hospitals, an inter-rater reliability study using the ACOVE selected indicators and the STOPP/START criteria was carried out between April 2011 and March 2012. Three patients were randomly selected in each participating hospital, one for each four months of study. Results: A total of 21 patients (mean (SD) age of 84.3 (5.6) years, 57.1% female) were included in the inter-rater reliability study. For the STOPP, START and ACOVE criteria, the median kappa coefficient for the seven hospital analyses was 0.97, 0.92 and 0.95, respectively. Out of 123 total indicators in only 7 (5.7%) was the kappa coefficient value below 0.75. Only for 2 (5.6%) of the 37 studies selected ACOVE quality indicators was the kappa coefficient value less than 0.75. Conclusions: A high inter-rater reliability was obtained for the selected underprescribing quality indicators of ACOVE 3. These quality indicators may be considered a useful tool in detecting underprescribing to the elderly patients. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Esculetin (6,7-dihydroxycoumarin) and daphnetin (7,8-dihydroxycoumarin) are secondary metabolites of plants used in folk medicine. These compounds have showed great antiproliferative activity in several tumor cell lines and have been proposed as potential anticancer agents. However, the estrogenic potential of these two compounds has to date not been reported. The present study compared esculetin and daphnetin on the inhibition of cell proliferation and cell cycle progression of the MCF-7 estrogen-responsive human carcinoma cell line. In vivo and in vitro estrogenic activity for both compounds was also evaluated. Esculetin inhibited cell proliferation after 72 h exposure (IC50=193 ± 6.6 μM), while daphnetin evidenced inhibiting effects starting at 24-h exposure (72 h, IC50=73 ± 4.1 μM). Both effects showed changes in cyclin D1 gene expression. In non-estrogenic conditions (E-screening assay), esculetin produced biphasic response on proliferation of the MCF-7 cells; at 10(-8)-10(-6)M, concentrations induced proliferative effects as EC50=4.07 × 10(-9)M (E(2)=2.91 × 10(-12)M); at higher concentrations (10(-5)-10(-4)M), cell proliferation was inhibited. Relative proliferative effect at E(2) was 52% (E(2)=100), relative proliferative potency was 0.072 (E(2)=100). Additionally, esculetin tested in vivo showed estrogenic effects at 50-100mg/kg doses; relative uterotrophic effect at E(2) was 37%, with relative uterotrophic potency registered at 0.003. In contrast, daphnetin did not induce estrogenic effects in vitro or with in vivo models. The low estrogenic activity of esculetin could prove useful in postmenopausal therapy but not as a safe antitumor agent in estrogen-dependent tumors. Daphnetin-based antiproliferative selectivity with MCF-7 cells showed that daphnetin is a promising antitumoral agent also acting on estrogen dependent tumors.

We investigated the status of the PI 3-kinase/AKT/PTEN signaling pathway in a series of 117 head and neck squamous cell carcinomas (HNSCC) in a search for molecular alterations in genes/proteins with potential prognostic value. For this purpose, PIK3CA and AKT2 gene amplification was assessed by multiplex and Quantitative Real-Time PCR. Protein expression of AKT, p-AKT, p110alpha and PTEN was determined by Western blot. PTEN allelic loss was evaluated by microsatellite analysis. PTEN-exon 5 was screened for point mutations by PCR-SSCP. Homozygous deletions were determined by multiplex PCR. PIK3CA gene was amplified in 43/117 (37%) fresh tumor samples, a frequency that did not differ from that found in archival premalignant tissues: 15/38 (39%); 12/40 (30%) fresh tumors harbored AKT2 gene amplification. AKT was found activated in 6/36 (17%) fresh tumor samples, when compared to their normal tissue counterparts. Of these 6 cases, 1 showed p110alpha overexpression and 5 displayed PTEN protein downregulation. Neither allelic loss (found in 11/77 informative cases) nor point mutations or homozygous deletions accounted for the reduced PTEN protein expression observed in our tumor series. The histologically normal mucosa of 4 patients displayed some of the molecular alterations analyzed. Dysregulation of the PI 3-K/AKT/PTEN pathway might contribute to early HNSCC tumorigenesis and might constitute a potential clinical target. Overall, 17/36 (47%) cases showed at least 1 of the molecular alterations studied here, which makes the PI 3-kinase-initiated signaling pathway one of the most frequently altered in HNSCC.

Melatonin is an indole hormone produced mainly by the pineal gland. We have previously demonstrated that melatonin interferes with estrogen (E(2)) signaling in MCF7 cells by impairing estrogen receptor (ER) pathways. Here we present the characterization of its mechanism of action showing that melatonin is a specific inhibitor of E(2)-induced ERalpha-mediated transcription in both estrogen response element- and AP1-containing promoters, whereas ERbeta-mediated transactivation is not inhibited or even activated at certain promoters. We show that the sensitivity of MCF-7 cells to melatonin depends on the ERalpha/ERbeta ratio, and ectopic expression of ERbeta results in MCF-7 cells becoming insensitive to this hormone. Melatonin acts as a calmodulin antagonist inducing conformational changes in the ERalpha-calmodulin (CaM) complex, thus impairing the binding of E(2).ERalpha.CaM complex to DNA and, therefore, preventing ERalpha-dependent transcription. Moreover the mutant ERalpha (K302G,K303G), unable to bind calmodulin, becomes insensitive to melatonin. The effect of melatonin is specific since other related indoles neither interact with CaM nor inhibit ERalpha-mediated transactivation. Interestingly, melatonin does not affect the binding of coactivators to ERalpha, indicating that melatonin action is different from that of current therapeutic anti-estrogens used in breast cancer therapy. Thus, they target ERalpha at different levels, representing two independent ways to control ERalpha activity. It is, therefore, conceivably a synergistic pharmacological effect of melatonin and current anti-estrogen drugs.

We have isolated and functionally characterized the exon 7-skipped variant (ERΔE7) of estrogen receptor (ER)α, which has emerged as the predominant variant expressed in multiple normal and tumoral tissues. However, to date no function has been established for this variant in mammalian cells. ERΔE7 exhibits a negligible ability to bind ligands, insensitivity to allosteric modulation by estrogen and antiestrogens, and loss of estrogen-dependent interaction with p160 coactivators such as SRC-1 and AIB1. ERΔE7 is able to form heterodimers with both ERα and ERβ in a ligand-independent manner. Transient expression experiments in HeLa cells show that increasing amounts of ERΔE7 result in a progressive inhibition of the estrogen-dependent transcriptional activation by both wild-type ERα and ERβ on estrogen response element-driven promoters. The inhibitory effect of ERΔE7 is due to the inhibition of binding of wild-type receptors to their responsive elements. Surprisingly, the activation function (AF)-1-dependent transactivation triggered by epithelial growth factor and phorbol-12-myristate-13-acetate is also abolished in ERΔE7 despite AF1 integrity, suggesting a cross-talk between AF1 and AF2 regions of the receptor. These results indicate that the naturally occurring variant ERΔE7 is a dominant negative receptor that, when expressed at high levels relative to wild-type ERs, might have profound effects on several estrogen-dependent functions.

The present study shows that melatonin prevents, within the first cell cycle, the estradiol-induced growth of synchronized MCF7 breast cancer cells. By using nuclear extracts of these cells, we first examined the binding of estradiol-estrogen receptor complexes to estrogen-responsive elements and found that the addition of estradiol to whole cells activates the binding of the estrogen receptor to DNA whereas melatonin blocks this interaction. By contrast, melatonin neither affects the binding of estradiol to its receptor nor the receptor nuclear localization. Moreover, we also show that addition of estradiol to nuclear extracts stimulates the binding of estrogen receptor to DNA, but this activation is also prevented by melatonin. The inhibitory effect caused by melatonin is saturable at nanomolar concentrations and does not appear to be mediated by RZR nuclear receptors. The effect is also specific, since indol derivatives do not cause significant inhibition. Furthermore, we provide evidence that melatonin does not interact with the estrogen receptor in the absence of estradiol. Together, these results demonstrate that melatonin interferes with the activation of estrogen receptor by estradiol. The effect of melatonin suggests the presence of a receptor that, upon melatonin addition, destabilizes the binding of the estradiol-estrogen receptor complex to the estrogen responsive element.