Search

Targeting mitochondrial metabolism represents a promising approach for cancer treatment. Here, we investigated the mitotoxic potential of the polybrominated diphenyl ether bromoxib, a natural compound isolated from the marine sponge Dysidea family. We could show that bromoxib comprised strong cytotoxicity in different leukemia and lymphoma cell lines (such as HL60, HPBALL, Jurkat, K562, KOPTK1, MOLT4, SUPB15 and Ramos), but also in solid tumor cell lines (such as glioblastoma cell lines SJ-GBM2 and TP365MG). Bromoxib activated the mitochondrial death pathway as evidenced by the rapid translocation of Bax to the mitochondria and the subsequent mitochondrial release of Smac. Accordingly, bromoxib-induced apoptosis was blocked in caspase 9 deficient Jurkat cells and Jurkat cells overexpressing the antiapoptotic protein Bcl-2. In addition, we could show that bromoxib functioned as an uncoupler of the electron transport chain with similar rapid kinetics as CCCP in terms of dissipation of the mitochondrial membrane potential (ΔΨm), processing of the dynamin-like GTPase OPA1 and subsequent fragmentation of mitochondria. Beyond that, bromoxib strongly abrogated ATP production via glycolysis as well as oxidative phosphorylation (OXPHOS) by targeting electron transport chain complexes II, III, and V (ATP-synthase) in Ramos lymphoma cells. Thus, bromoxib's potential to act on both cytosolic glycolysis and mitochondrial respiration renders it a promising agent for the treatment of leukemia and lymphoma., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

After the meeting held by the Spanish Contact Dermatitis and Skin Allergy Research Group (GEIDAC) back in October 2021, changes were suggested to the Spanish Standard Series patch testing. Hydroxyethyl methacrylate (2% pet.), textile dye mixt (6.6% pet.), linalool hydroperoxide (1% pet.), and limonene hydroperoxide (0.3% pet.) were, then, added to the series that agreed upon in 2016. Ethyldiamine and phenoxyethanol were excluded. Methyldibromoglutaronitrile, the mixture of sesquiterpene lactones, and hydroxyisohexyl 3-cyclohexene (Lyral) were also added to the extended Spanish series of 2022., (Copyright © 2024 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Psoriasis is a chronic inflammatory dermatosis whose clinical and topographic distribution requires differential diagnosis, or the possible association with allergic contact dermatitis (ACD), requiring patch testing (PT) as part of the diagnostic procedure., Objectives: To describe the epidemiological, clinical, and allergic profile of patients with a primary or secondary diagnosis of psoriasis undergoing PT and compare them with patients with a diagnosis of ACD at the end of the diagnostic process., Methods: Cross-sectional study with data from REIDAC from 2018 through 2023 of selected patients with a diagnosis of psoriasis and/or ACD., Results: A total of 11 502 patients were included, 513 of whom had been diagnosed with primary or secondary psoriasis, 3640 with ACD, and 108 with both diseases. Men were more predominant in the groups of patients with psoriasis, psoriasis+ACD, and lesions were more predominantly seen in the hands with little association with atopic factors vs the ACD group. The rate of positivity in PT to the 2022 Spanish battery of allergens was lower in the group with psoriasis only in 27% of the patients. The most common allergens found in the psoriasis group were also the most common ones found in the overall ACD population., Conclusions: Overall, 36.2% of psoriatic patients tested positive in PT to the 2022 Spanish battery of allergens, which proved that this association is not uncommon. Overall, psoriatic patients had a higher mean age, were more predominantly men, and showed more hand involvement., (Copyright © 2024 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

The study aimed to assess the impact of an attachment-based intervention on adolescent adaptation to parental divorce. The Adolescent Adjustment Pilot Program to Parental Divorce (AAPPD) employed an experimental group format, targeting improvements in various adaptation indicators (life satisfaction, positive affect, and negative affect). The sample comprised 30 Chilean adolescents aged 12 to 16 (M = 13.6, SD = 1.35), with 60% females and 40% males. After the intervention, the adolescents showed a decrease in negative affect at 6 and 12 months. However, no differences were identified in other dimensions of subjective well-being considered as indicators of divorce adaptation. The findings prompt discussion on theoretical and clinical implications., (© 2024. The Author(s).)

Defined as the unpleasant sensation that causes the desire to scratch, pruritus is the most common skin symptom associated with uremia and appears in almost half of patients with advanced chronic kidney disease (CKD). Beyond its direct impact on quality of life, CKD-associated pruritus (CKD-aP) is an independent predictor of mortality that also has a synergistic effect with other quality of life-related symptoms, such as insomnia, depression, and anxiety. Although different mechanisms have been proposed to explain the origin of Pa-ERC, its etiopathogenesis is still not fully understood. Since new therapeutic targets have been identified and several clinical trials have recently shown promising results, our current understanding of the interrelationships has expanded significantly and the pathophysiological mechanisms underlying CKD-aP are now considered to be multifactorial. The potential triggers of pruritus in patients with CKD are discussed in this review, including hypotheses about skin xerosis, accumulation of uremic toxins, dysregulation of the immune system and systemic inflammation, uremic neuropathy, and imbalances in the endogenous opioid system. Other non-uremic causes of pruritus are also discussed, with the aim of guiding the physicians to apply an adequate aetiopathogenic approach to CKD-aP in their day-to-day clinical practice., (Copyright © 2022 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: To explore the experiences of people with persistent COVID in the Basque Country more than a year after the start of the pandemic, in order to understand the health and social impact it has, as well as to detect possible areas for improvement in the care that these people receive in order to develop health programms to support their recovery., Method: Qualitative phenomenological study. In-depth interviews will be carried out as a data collection technique until saturation of the discourse. Patients of legal age who present persistent COVID symptomatology with an evolution time of more than 12 weeks were included. Contact with the patients was made through the Basque Long COVID Collective. The interviews were carried out and recorded through the ZOOM application. After the literal transcription of the interviews, the thematic analysis will be carried out, identifying the first units of meaning and assigning codes that will later be grouped into the different categories., Results: 20 patients participated. A total of three main categories emerged from the analysis of the discourses: 1) affecting/impacting patients' quality of life; 2) identifying improvements in healthcare; and 3) comforting aspects., Conclusions: This study shows the significant impact on the quality of life suffered by these people. It is necessary to design health policies that favour a personalised, comprehensive and multidisciplinary approach to these patients., (Copyright © 2022 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.)

We have updated recommendations on 12 controversial topics that were published in the 2013 National Consensus on the diagnosis, risk stratification and treatment of patients with pulmonary embolism (PE). A comprehensive review of the literature was performed for each topic, and each recommendation was evaluated in two teleconferences. For diagnosis, we recommend against using the Pulmonary Embolism Rule Out Criteria (PERC) rule as the only test to rule out PE, and we recommend using a D-dimer cutoff adjusted to age to rule out PE. We suggest using computed tomography pulmonary angiogram as the imaging test of choice for the majority of patients with suspected PE. We recommend using direct oral anticoagulants (over vitamin K antagonists) for the vast majority of patients with acute PE, and we suggest using anticoagulation for patients with isolated subsegmental PE. We recommend against inserting an inferior cava filter for the majority of patients with PE, and we recommend using full-dose systemic thrombolytic therapy for PE patients requiring reperfusion. The decision to stop anticoagulants at 3 months or to treat indefinitely mainly depends on the presence (or absence) and type of risk factor for venous thromboembolism, and we recommend against thrombophilia testing to decide duration of anticoagulation. Finally, we suggest against extensive screening for occult cancer in patients with PE., (Copyright © 2021 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background & Aims: Individuals with non- or minimally verbal autism (nvASD) are primarily characterized by a severe speech production deficit, with speech limited to no or only a few words by school age. Significant unclarity remains over variability in language profiles across the lifespan, the nature of the language impairment seen, and (dis-) associations between linguistic and nonverbal cognitive measures., Methods: To address these questions, we recruited both a school-age and an adult group with nvASD (total N = 49) and investigated relations between expressive and receptive language, and between these and nonverbal intelligence quotient (NVIQ) and sense-making capacities (the ComFor test)., Results: Results revealed limited variation across this sample in receptive language, which in turn predicted expressive language levels. Importantly, an upward trend in verbal mental age (VMA) across increasing chronological age was seen in the youngsters (only). A radical dissociation between NVIQ and both expressive and receptive language transpired as well, and a subset of individuals with normal NVIQ were comparable in terms of any other cognitive aspect. Sense-making reached symbolic levels in 62.2% of the sample and loaded on both verbal and nonverbal factors., Conclusions: These patterns inform theories of nvASD by revealing an impairment that is not conceptualizable as one of expressive language only, sharply limits learning opportunities across the lifespan, and cannot be compensated for by nonverbal cognition., Implications: These findings stress the need to seize developmental opportunities that may disappear when youngsters turn into adults, via therapies that specifically target language as a central cognitive system comprising both production and comprehension., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Introduction: Studies which focus on the process of acculturation in the lifestyles, nutritional status and health of immigrants from the Community of Portuguese-Speaking Countries (CPLP) in the Iberian Peninsula are still scarce. This study aims to explore the influence of the acculturation process and dietary acculturation on the lifestyle and nutritional and health status of CPLP immigrants in Portugal and Spain, focusing on two Iberian contexts: Lisbon Metropolitan Area and the Basque Country., Methods and Analysis: A mixed methods sequential explanatory design, combining cross-sectional studies and semistructured interviews. Official data will also be analysed. Primary data will be collected through a questionnaire and assessment of nutritional status and body composition. The estimated samples sizes are 1061 adults (≥18 years old) in the Lisbon Metropolitan Area and 573 in the Basque Country. Time-location sampling will be used for the quantitative component and non-probabilistic sampling for the qualitative component. If safety conditions are not guaranteed due to the COVID-19 pandemic, online studies will be conducted. The semistructured interviews will complement the questionnaire data and extend knowledge about the process of acculturation of CPLP immigrants and their relationship with eating habits and physical activity. Thematic analysis will be used for qualitative data. Triangulation of data derived from different methods will be carried out. An integrative approach will be used to address potential discrepancies in findings and limitations inherent to the study design. As inter-method discrepancies may occur, triangulation protocol will be used, elaborating a 'convergence coding matrix' to display findings emerging from each component of the study., Ethics and Dissemination: Ethical approval was obtained through the IHMT Ethics Council (Doc No 20/2020), Portugal, and it was submitted to the Ethics Committee of the UPV/EHU (Doc No under revision), Spain., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Standard patch test series must be updated using objective data on allergen sensitization. The Spanish standard series was last updated in 2016 and the European series in 2019, and the inclusion of several emerging allergens needs to be evaluated., Material and Methods: We conducted a prospective, observational, multicenter study of consecutive patients from the registry of the Spanish Contact Dermatitis and Skin Allergy Research Group (GEIDAC) who were patch tested in 2019 and 2020 with linalool hydroperoxide, limonene hydroperoxide, 2-hydroxyethyl-methacrylate, benzisothiazolinone, octylisothiazolinone, textile dye mix (TDM), sodium metabisulfite, propolis, bronopol, Compositae mix II, diazolidinyl urea, imidazolidinyl urea, decyl glucoside, and lauryl glucoside., Results: We analyzed data for 4654 patients tested with diazolidinyl urea, imidazolidinyl urea, and bronopol, and 1890 tested with the other allergens. The values for the MOAHLFA index components were 30% for male, 18% for occupational dermatitis, 15% for atopic dermatitis, 29% for hand, 6.5% for leg, 23% for face, and 68% for age > 40 years. Sensitization rates above 1% were observed for 7 allergens: linalool hydroperoxide, 2-hydroxyethyl-methacrylate, benzisothiazolinone, limonene hydroperoxide, TDM, sodium metabisulfite, and propolis. Three allergens had a current relevance rate of over 1%: linalool hydroperoxide, 2-hydroxyethyl-methacrylat, and limonene hydroperoxide. Benzisothiazolinone and TDM had a relevance rate of between 0.9% and 1%., Conclusions: Our results indicate that 7 new allergens should be considered when extending the Spanish standard patch test series. The data from our series could be helpful for guiding the next extension of the European baseline series., (Copyright © 2021 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: To estimate the incidence and analyze any cancer-associated factors in patients with systemic lupus erythematosus (SLE), differentiating between hormone-sensitive (HS) and non-HS cancers., Methods: This was a retrospective multicenter study of a patient cohort from the Systemic Lupus Erythematosus Registry of the Spanish Society of Rheumatology. Included were the first cancer post-SLE diagnosis, clinical and sociodemographic information, cumulative damage, severity, comorbidities, treatments, and refractoriness. Cancers were classified as HS (prostate, breast, endometrium, and ovarian) and non-HS (the remainder). The standardized incidence ratio (SIR) was calculated and logistic regression models were built., Results: A total of 3,539 patients (90.4% women) were included, 154 of whom had cancer (91% female), and 44 had HS cancer (100% female). The cancer SIR was 1.37 (95% confidence interval [95% CI] 1.15-1.59), with higher values in women age <65 years (SIR 2.38 [95% CI 1.84-2.91]). The SIR in women with HS versus non-HS cancer was 1.02 (95% CI 0.13-1.91) and 1.93 (95% CI 0.98-2.89). In HS versus non-HS cancers, SLE diagnostic age (odds ratio [OR] 1.04 [P = 0.002] versus 1.04 [P = 0.019]), and period of disease evolution (OR 1.01 [P < 0.001] versus 1.00 [P = 0.029]) were associated with cancer. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (OR 1.27 [P = 0.022]) and angiotensin-converting enzyme (ACE) inhibitor prescriptions (OR 2.87 [P = 0.048]) were associated with non-HS cancers., Conclusion: Cancer incidence in patients with SLE was higher than in the Spanish population, particularly among young women. This increase might be due to non-HS cancers, which would be associated with SLE involving greater cumulative damage where more ACE inhibitors are prescribed., (© 2019, American College of Rheumatology.)

MUC5B rs35705950 (G/T) is strongly associated with idiopathic pulmonary fibrosis (IPF) and also contributes to the risk of interstitial lung disease (ILD) in rheumatoid arthritis (RA-ILD) and chronic hypersensitivity pneumonitis (CHP). Due to this, we evaluated the implication of MUC5B rs35705950 in antisynthetase syndrome (ASSD), a pathology characterised by a high ILD incidence. 160 patients with ASSD (142 with ILD associated with ASSD [ASSD-ILD+]), 232 with ILD unrelated to ASSD (comprising 161 IPF, 27 RA-ILD and 44 CHP) and 534 healthy controls were genotyped. MUC5B rs35705950 frequency did not significantly differ between ASSD-ILD+ patients and healthy controls nor when ASSD patients were stratified according to the presence/absence of anti Jo-1 antibodies or ILD. No significant differences in MUC5B rs35705950 were also observed in ASSD-ILD+ patients with a usual interstitial pneumonia (UIP) pattern when compared to those with a non-UIP pattern. However, a statistically significant decrease of MUC5B rs35705950 GT, TT and T frequencies in ASSD-ILD+ patients compared to patients with ILD unrelated to ASSD was observed. In summary, our study does not support a role of MUC5B rs35705950 in ASSD. It also indicates that there are genetic differences between ILD associated with and that unrelated to ASSD.

Objective: To assess the efficacy of the ProMIC, multidisciplinary program for patients admitted at hospital because of heart failure (HF) programme, in reducing the HF-related readmission rate., Desing: Quasi-experimental research with control group., Settings: Twelve primary health care centres and 3 hospitals from the Basque Country., Participants: Aged 40 years old or above patients admitted for HF with a New York Heart Association functional class II to IV., Interventions: Patients in the intervention group carried out the ProMIC programme, a structured clinical intervention based on clinical guidelines and on the chronic care model. Control group received usual care., Main Measurements: The rate of readmission for HF and health-related quality of life RESULTS: One hundred fifty five patients were included in ProMIC group and 129 in control group. 45 rehospitalisation due to heart failure happened in ProMIC versus 75 in control group (adjusted hazard ratio=0.59, CI 95%: 0.36-0.98; P=.049). There were significant differences in specific quality of life al 6 months. No significant differences were found in rehospitalisation due to all causes, due to cardiovascular causes, visits to emergency room, mortality, the combined variable of these events, the functional capacity or quality of life at 12 months of follow up., Conclusions: ProMIC reduces significantly heart failure rehospitalisation and improve quality of life al 6 months of follow up. No significant differences were found in the rests of variables., (Copyright © 2018 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

When listeners misperceive words in noise, do they report words that are more common? Lexical frequency differences between misperceived and target words in English and Spanish were examined for five masker types. Misperceptions had a higher lexical frequency in the presence of pure energetic maskers, but frequency effects were reduced or absent for informational maskers. The tendency to report more common words increased with the degree of energetic masking, suggesting that uncertainty about segment identity provides a role for lexical frequency. However, acoustic-phonetic information from an informational masker may additionally constrain lexical choice.

Cochlea-scaled entropy (CSE) was proposed as a signal-based metric for automatic detection of speech regions most important for intelligibility, but its proposed superiority over traditional linguistic and psychoacoustical characterisations was not subsequently confirmed. This paper shows that the CSE concept is closely related to intensity and as such captures similar speech regions. However, a slight but significant advantage of a CSE over an intensity-based characterisation was observed, associated with a time difference between the two metrics, suggesting that the CSE index may capture dynamical properties of the speech signal crucial for intelligibility.

Speakers adjust their voice when talking in noise (known as Lombard speech), facilitating speech comprehension. Recent neurobiological models of speech perception emphasize the role of amplitude modulations in speech-in-noise comprehension, helping neural oscillators to "track" the attended speech. This study tested whether talkers produce more pronounced amplitude modulations in noise. Across four different corpora, modulation spectra showed greater power in amplitude modulations below 4 Hz in Lombard speech compared to matching plain speech. This suggests that noise-induced speech contains more pronounced amplitude modulations, potentially helping the listening brain to entrain to the attended talker, aiding comprehension.

Objective: Despite cautions by professional associations, benzodiazepines (BZD) and Z hypnotics (BZD/Z) are widely prescribed to older adults who are particularly susceptible to insomnia and anxiety, but who are also more sensitive to drugs adverse events. In this study, we assessed the prescription of BZD/Z drugs in a sample of older adults (≥65) who presented for emergency care after a fall., Methods: We collected the type, number and dose of BZD/Z drugs prescribed and explored gender differences in the prescription., Results: BZD/Z drugs were prescribed to 43.6% of the sample (n=654) and more frequently to women; 78.4% of prescriptions were for BZD/Z drugs with a short half-life. The majority of patients (83.5%) were prescribed only one type of BZD/Z, but 16.5% had been prescribed multiple BZD/Z drugs, with no gender difference. Doses higher than those recommended for older adults were prescribed to 58% of patients, being the doses significantly higher for men compared to women (70.0% vs 53.1%)., Conclusions: Over 40% of older adults presenting for emergency care after a fall had previously been prescribed BZD/Z drugs. Some important gender differences in the prescription of BZD/Z drugs were seen, especially prescription above the recommended dose and of drugs with a long-half life., (Copyright © 2017 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.)

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

We evaluated the impact of a workplace 'sit less, move more' programme (Walk@WorkSpain, W@WS, 19-week) on self-reported activity-related energy expenditure (AREE) in Spanish office employees (n = 264; 42 ± 10 years; 171 female) randomly assigned to Intervention (IG; used W@WS; n = 129) or comparison groups (CGs; n = 135). A linear mixed model assessed changes in METs-min/wk of total, vigorous, moderate and light physical activity (IPAQ short form) between baseline and 2 months follow-up. Over the CG, IG significantly increased light intensity AREE (P = 0.027). W@WS secured sustained increases on AREE-but not on achieving PA recommendations-providing translational evidence that active living in office employees can be increased., (© The Author 2017. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Algorithmic modifications to the durational structure of speech designed to avoid intervals of intense masking lead to increases in intelligibility, but the basis for such gains is not clear. The current study addressed the possibility that the reduced information load produced by speech rate slowing might explain some or all of the benefits of durational modifications. The study also investigated the influence of masker stationarity on the effectiveness of durational changes. Listeners identified keywords in sentences that had undergone linear and nonlinear speech rate changes resulting in overall temporal lengthening in the presence of stationary and fluctuating maskers. Relative to unmodified speech, a slower speech rate produced no intelligibility gains for the stationary masker, suggesting that a reduction in information rate does not underlie intelligibility benefits of durationally modified speech. However, both linear and nonlinear modifications led to substantial intelligibility increases in fluctuating noise. One possibility is that overall increases in speech duration provide no new phonetic information in stationary masking conditions, but that temporal fluctuations in the background increase the likelihood of glimpsing additional salient speech cues. Alternatively, listeners may have benefitted from an increase in the difference in speech rates between the target and background.

This work attempts to study the way higher music graduate students segment a contemporary music work, Itinerant, and to understand the influence of musical feature on segmentation. It attempts to test the theory stating that saliences contribute to organising the music surface. The 42 students listened to the work several times and, in real time, they were requested to indicate the places on the score where they perceived structural boundaries. This work is characterised by its linearity, which could hinder identification of saliences and thereby, the establishment of structural boundaries. The participants show stability in the points of segmentation chosen. The results show significant coincidences among the participants in strategic places of the work, which leads us to conclude, in line with other researches, although in a work with different characteristics, that listeners can find a structural organisation in contemporary music that could allow them to understand it.

Introduction: Since its approval by the European Medicines Agency, a great number of patients born small for gestational date have received recombinant growth hormone treatment in Spain. The aim of this study is to analyse its outcome in the setting of ordinary clinical practice., Methods: Information was gathered from the registers of the assessment boards that authorise all growth hormone treatments prescribed in public hospitals in six autonomic communities (regions)., Results: Valid data from 974 patients was obtained. All of them complied with criteria established by the European Medicines Agency. Patients in the sample were smaller in length than weight at birth, with their median target height being below 1 standard deviation (SD), and 23% of them had been delivered prematurely. Treatment was started at 7.2±2.8 years (mean±SD). The mean patient height at start was -3.1±0.8 SD. They gained 0.7±0.2 SD in the first year, and 1.2±0.8 SD after two years. Final height was attained by 8% of the sample, reaching -1.4±0.7 SD., Conclusions: These results are similar to other Spanish and international published studies, and are representative of the current practice in Spain. Despite treatment being started at a late age, adequate growth is observed in the short term and in the final height. Up to a 24% of patients show a poor response in the first year., (Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

For decades, human activities have gradually destroyed the natural habitats of wild grapevine, Vitis vinifera L. subsp. sylvestris (Gmelin) Hegi, and nowadays this species is endangered in southern Europe. In this paper, 94 populations of this species have been localized and characterized in the Andalusian region in the Iberian Peninsula between 1989 and 2013. Location, ecological aspects, and sanitary characteristics are described. Must properties and in vitro tolerance to calcareous conditions were also checked. The paper also contains a global description of female and male individuals. Two hundred individuals from six river basin populations have been sampled, and their genetic structure analyzed by using 25 nuclear microsatellites loci to investigate the gene diversity of wild grape populations in Andalusia at two levels: total individuals and at river basin populations. Also, the genetic relationship of wild and cultivated accessions has been tested. Wild grapevine is considered the ancestor of the cultivated varieties and should be preserved as this material could be used to start breeding programs of cultivated varieties and also to restore riverbank forests, which constitute one of the worst preserved ecosystems in the area., (Copyright © 2017 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.)

The metastasis suppressor KISS1 is reported to be involved in the progression of several solid neoplasias, making it a promising molecular target for controlling their metastasis. The KISS1 sequence contains an N-terminal secretion signal and several dibasic sequences that are proposed to be the proteolytic cleavage sites. We present the first structural characterization of KISS1 by circular dichroism, multi-angle light scattering, small angle X-Ray scattering and NMR spectroscopy. An analysis of the KISS1 backbone NMR chemical shifts does not reveal any preferential conformation and deviation from a random coil ensemble. The backbone 15N transverse relaxation times indicate a mildly reduced mobility for two regions that are rich in bulky residues. The small angle X-ray scattering curve of KISS1 is likewise consistent with a predominantly random coil ensemble, although an ensemble optimization analysis indicates some preference for more extended conformations possibly due to positive charge repulsion between the abundant basic residues. Our results support the hypothesis that KISS1 mostly samples a random coil conformational space, which is consistent with its high susceptibility to proteolysis and the generation of Kisspeptin fragments.

Introduction: Iatrogenic hyperprolactinaemia (IHPRL) has been more frequently related to some antipsychotic drugs that provoke an intense blockade of dopamine D2 receptors. There is a wide variation in clinical practice, and perhaps some more awareness between clinicians is needed. Due to the high frequency of chronic treatment in severe mental patients, careful attention is recommended on the physical risk. IHPRL symptoms could be underestimated without routine examination., Methodology: An intense scientific literature search was performed in order to draw up a multidisciplinary consensus, including different specialists of psychiatry, endocrinology, oncology and internal medicine, and looking for a consensus about clinical risk and detection of IHPRL following evidence-based medicine criteria levels (EBM I- IV)., Results: Short-term symptoms include amenorrhea, galactorrhoea, and sexual dysfunction with decrease of libido and erectile difficulties related to hypogonadism. Medium and long-term symptoms related to oestrogens are observed, including a decrease bone mass density, hypogonadism, early menopause, some types of cancer risk increase (breast and endometrial), cardiovascular risk increase, immune system disorders, lipids, and cognitive dysfunction. Prolactin level, gonadal hormones and vitamin D should be checked in all patients receiving antipsychotics at baseline although early symptoms (amenorrhea-galactorrhoea) may not be observed due to the risk of underestimating other delayed symptoms that may appear in the medium term. Routine examination of sexual dysfunction is recommended due to possible poor patient tolerance and low compliance. Special care is required in children and adolescents, as well as patients with PRL levels >50ng/ml (moderate hyperprolactinaemia). A possible prolactinoma should be investigated in patients with PRL levels >150ng/ml, with special attention to patients with breast/endometrial cancer history. Densitometry should be prescribed for males >50 years old, amenorrhea>6 months, or early menopause to avoid fracture risk., (Copyright © 2016 SEP y SEPB. Published by Elsevier España. All rights reserved.)

Landscapes and features of the everyday world were scarcely represented in Paleolithic art, especially those features associated with the human landscape (huts and campsites). On the contrary, other figurative motifs (especially animals) and signs, traditionally linked to the magic or religious conceptions of these hunter-gatherer societies, are the predominant themes of Upper Paleolithic art. This paper seeks to present an engraved schist slab recently found in the Molí del Salt site (North-eastern Iberia) and dated at the end of the Upper Paleolithic, ca. 13,800 years ago. This slab displays seven semicircular motifs that may be interpreted as the representation of dome-shaped huts. The analysis of individual motifs and the composition, as well as the ethnographic and archeological contextualization, suggests that this engraving is a naturalistic depiction of a hunter-gatherer campsite. Campsites can be considered the first human landscape, the first area of land whose visible features were entirely constructed by humans. Given the social meaning of campsites in hunter-gatherer life-styles, this engraving may be considered one of the first representations of the domestic and social space of a human group.

The literature on inducers in epilepsy and bipolar disorder is seriously contaminated by false negative findings. Part II of this comprehensive review on antiepileptic drug (AED) inducers provides clinicians with further educational material about the complexity of interpreting AED drug-drug interactions. The basic pharmacology of induction is reviewed including the cytochrome P450 (CYP) isoenzymes, the Uridine Diphosphate Glucuronosyltransferases (UGTs), and P-glycoprotein (P-gp). CYP2B6 and CYP3A4 are very sensitive to induction. CYP1A2 is moderately sensitive while CYP2C9 and CYP2C19 are only mildly sensitive. CYP2D6 cannot be induced by medications. Induction of UGT and P-gp are poorly understood. The induction of metabolic enzymes such as CYPs and UGTs, and transporters such as P-gp, implies that the amount of these proteins increases when they are induced; this is almost always explained by increasing synthesis mediated by the so-called nuclear receptors (constitutive androstane, estrogen, glucocorticoid receptors and pregnaneX receptors). Although parti provides correction factors for AEDs, extrapolation from an average to an individual patient may be influenced by administration route, absence of metabolic enzyme for genetic reasons, and presence of inhibitors or other inducers. AED pharmacodynamic DDIs may also be important. Six patients with extreme sensitivity to AED inductive effects are described., (Copyright © 2014 SEP y SEPB. Published by Elsevier España. All rights reserved.)

The literature on inducers in epilepsy and bipolar disorder is seriously contaminated by false negative findings. This is part i of a comprehensive review on antiepileptic drug (AED) inducers using both mechanistic pharmacological and evidence-based medicine to provide practical recommendations to neurologists and psychiatrists concerning how to control for them. Carbamazepine, phenobarbital and phenytoin, are clinically relevant AED inducers; correction factors were calculated for studied induced drugs. These correction factors are rough simplifications for orienting clinicians, since there is great variability in the population regarding inductive effects. As new information is published, the correction factors may need to be modified. Some of the correction factors are so high that the drugs (e.g., bupropion, quetiapine or lurasidone) should not co-prescribed with potent inducers. Clobazam, eslicarbazepine, felbamate, lamotrigine, oxcarbazepine, rufinamide, topiramate, vigabatrin and valproic acid are grouped as mild inducers which may (i)be inducers only in high doses; (ii)frequently combine with inhibitory properties; and (iii)take months to reach maximum effects or de-induction, definitively longer than the potent inducers. Potent inducers, definitively, and mild inducers, possibly, have relevant effects in the endogenous metabolism of (i)sexual hormones, (ii) vitamin D, (iii)thyroid hormones, (iv)lipid metabolism, and (v)folic acid., (Copyright © 2014 SEP y SEPB. Published by Elsevier España. All rights reserved.)

Aim: Weight gain is an important and common side effect of second generation antipsychotics (SGAs). Furthermore, these drugs can induce other side effects associated with higher cardiovascular morbidity and mortality, such as insulin resistance, diabetes or metabolic syndrome. Preliminary studies show that inter-individual genetic differences produce varying degrees of vulnerability to the different SGA-induced side effects. The Second-generation antipsychotic Long-term treatment Metabolic side effects (SLiM) study aims to identify clinical, environmental and genetic factors that explain inter-individual differences in weight gain and metabolic changes in drug-naïve patients after six months of treatment with SGAs., Materials and Methods: The SLIM study is a multicenter, observational, six-month pharmacogenetic study where a cohort of 307 drug-naïve paediatric and adult patients (age range 8.8-90.1 years) and a cohort of 150 age- and sex- matched healthy controls (7.8-73.2 years) were recruited., Results: This paper describes the rationale, objectives and design of the study and provides a description of the sample at baseline., Conclusions: Results from the SLiM study will provide a better understanding of the clinical, environmental, and genetic factors involved in weight gain and metabolic disturbances associated with SGA treatment., (Copyright © 2014 SEP y SEPB. Published by Elsevier España. All rights reserved.)

Ulcerative colitis is a chronic inflammatory bowel disease of unknown etiopathogenesis and increasing incidence in recent years. Perianal complications of ulcerative colitis are rare and seem to be associated with higher extent of inflammation and a more severe course of the disease. The cases of two male patients with severe corticoid-dependent ulcerative colitis of protracted clinical course who developed perianal fistulas and abscesses successfully treated with infliximab are reported. Treatment with infliximab was followed by perianal fistula closure with marked improvement in the quality of life over 2-year follow-up period.

Objective: To assess the effect of continuous positive airway pressure (CPAP) on 24 hour ambulatory blood pressure monitoring values in a large number of patients with untreated systemic hypertension of new onset and obstructive sleep apnoea., Design: Multicentre, double blind, randomised, placebo controlled trial., Setting: Eleven general hospitals in Spain between 2004 and 2007., Participants: 340 patients recently diagnosed as having systemic hypertension by a general practitioner (systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or both) and an apnoea-hypopnoea index per hour of sleep of >15 events/hour., Intervention: Patients were assigned to CPAP (n=169) or sham CPAP (n=171) for three months. Main outcome measurements Net changes in the different 24 hour ambulatory blood pressure monitoring values from baseline to three months of optimal or sham CPAP., Results: 277 (81%) of the 340 patients randomised were men; the patients had a mean age of 52.4 (SD 10.5) years, a body mass index of 31.9 (5.7), an Epworth sleepiness scale score of 10.1 (4.3), an apnoea-hypopnoea index of 43.5 (24.5). No differences between groups were seen at baseline. Compared with placebo and analysed by intention to treat, the mean 24 hour ambulatory blood pressure of the CPAP group decreased by 1.5 (95% confidence interval: 0.4 to 2.7) mm Hg (P=0.01). The mean 24 hour ambulatory blood pressure monitoring measures decreased by 2.1 mm Hg (0.4 to 3.7) mm Hg (P=0.01) for systolic pressure and 1.3 (0.2 to 2.3) mm Hg (P=0.02) for diastolic blood pressure. Mean nocturnal blood pressure decreased by 2.1 (0.5 to 3.6) mm Hg (P=0.01)., Conclusions: CPAP produced a statistically significant reduction in blood pressure in patients with systemic hypertension and obstructive sleep apnoea. This reduction is small and did not achieve the 3 mm Hg drop in mean 24 hour ambulatory blood pressure that the trial was powered to detect. Consequently, these results may have uncertain clinical relevance. However, taking into account the prevalence of hypertension and the likelihood of comorbidities, the decrease in blood pressure, although minimal, may be beneficial., Trial Registration: Clinical trials NCT00202527.

The aim of this work is to confirm the tetra-factorial validity of the Cuestionario de Autoconcepto Físico (CAF [in English, the Physical Self-concept Questionnaire]) in adulthood and old age from the responses of 1,114 people (39.50% men and 60.50% women), divided into four age groups (24 to 34 years, n= 390; 35 to 49 years, n= 277; 50 to 64 years, n= 330; and over 65, n= 117). The correlations between scales (physical skills, physical fitness, physical attractiveness and strength) are lower than those obtained in previous studies, which supports their being different. However, confirmatory factor analysis supported the tetra-factorial structure primarily in the 24-34 age group.

This research follows the line of investigation opened some years ago about the generalizability studies and variance components applied to soccer. In this investigation, various matches played during the final phase of the last three World Championships (France'98, Korea and Japan'02 and Germany'06) were observed and coded while their interaction contexts were registered. In total, 58 matches were used for this investigation. The following facets were considered: 5 field areas where the 48 contexts are moved or transformed and 7 different types of match result. The results confirm the linear model, which can be generalized to the universe. The resulting 1% of the variance explained by the World Championship facet (1 point when analyzed singly and 14 points when it interacts with the other facets) allows us to confirm that soccer has not changed over the last three World Championships.

A simple and efficient stereoselective synthesis of fluorine containing beta-aminophosphonates by reduction of beta-enaminophosphonates is described. Reduction with sodium cyanborohydride in the presence of zinc chloride and the catalytic hydrogenation of beta-enaminophosphonates gives beta-aminophosphonates. beta-Enaminophosphonates are also used as intermediates for the regioselective synthesis of fluoroalkyl-substituted pyridines.

[reaction: see text] A simple and efficient stereoselective synthesis of aziridine-2-phosphonate 3, and -phosphine oxide 5 by diastereoselective addition of Grignard reagents to 2H-azirine phosphonate 1 and -phosphine oxide 4 is reported. Similarly, the addition of heterocyclic amines and benzenethiol to aziridines 1 and 4 yielded functionalized aziridines 10, 11, and 18. These aziridines are used as intermediates for the regioselective synthesis of beta-aminophosphine oxides 6 and beta-aminophosphonates 7, as well as alpha- aminophosphonates 8. Phenylsulfenyl-substituted alpha-aminophosphorus derivatives 15 and 19 are obtained directly from benzenethiol and 2H-azirine phosphonates 1 and -phosphine oxides 4.

Fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD) are familial prion diseases with autosomal dominant inheritance of the D178N mutation. FFI has been reported in at least 27 pedigrees around the world. Twelve apparently unrelated FFI and fCJD pedigrees with the characteristic D178N mutation have been reported in the Prion Diseases Registry of the Basque Country since 1993. The high incidence of familial prion diseases in this region may reflect a unique ancestral origin of the chromosome carrying this mutation. In order to investigate this putative founder effect, we developed "happy typing", a new approach to the happy mapping method, which consists of the physical isolation of large haploid genomic DNA fragments and their analysis by the Polymerase Chain Reaction in order to perform haplotypic analysis instead of pedigree analysis. Six novel microsatellite markers, located in a 150-kb genomic segment flanking the PRNP gene were characterized for typing haploid DNA fragments of 285 kb in size. A common haplotype was found in patients from the Basque region, strongly suggesting a founder effect. We propose that "happy typing" constitutes an efficient method for determining disease-associated haplotypes, since the analysis of a single affected individual per pedigree should provide sufficient evidence.

The term conjugated linoleic acid (CLA) refers to a series of linoleic acid isomers present in meat and diary products from ruminants that have their double bonds in a conjugated position. The aim of the present work was to study the effects of a CLA isomer, trans-10,cis-12, on cholesterolemia and biliary lithiasis risk in an animal model of diet-induced hypercholesterolemia. For that, two groups of hamsters were fed with a hypercholesterolemic diet supplemented with 0.5% linoleic acid or with the trans-10,cis-12 CLA isomer, respectively. Daily food intake and weight were determined and, 6 weeks later, serum and bile samples were obtained, and livers and spleens were dissected and weighted. Cholesterolemia, hepatic and splenic cholesterol content, and biliary cholesterol phosnolipid and bileacid concentrations were determined; Biliary Lithogenic Index was calculated, and presence of gallstones was assessed. CLA did not modify energetic intake or final body weight, spleen size or spleen cholesterol content, but it did significantly reduce total serum cholesterol (-18%) at the expense of c-LDL (-66%), and it also significantly reduced hepatic content of free cholesterol (-26%), without changes in esterified cholesterol. Besides, CLA produced a 32% increase in biliary cholesterol concentration, a 28% increase in Lithogenic Index, and a higher incidence of biliary lithiasis. Therefore, the present study shows that the CLA trans-10,cis-12 isomer is hypercholesterolemic since it increases, at least in part, cholesterol secretion to the bile. As a consequence, this effect increases the risk for biliary lithiasis.

Functionalized keto-enamines 6 were obtained by nucleophilic addition of enol ethers to the imine moiety of 2-azadienes derived from dehydroaspartic esters 4. Reactions of 2-azadiene 4c containing three electron-withdrawing substituents (CO(2)R) with enol ethers 5 in the presence of lithium perchlorate led to the formation of tetrahydropyridine derivatives 7 in a regio- and stereoselective fashion. 2H-[1,3]-oxazines 10 and pyridine derivatives 12 and 13 were obtained by heterocycloaddition reactions of electron-poor azadienes 4d-g containing two electron-withdrawing substituents (4-O(2)N-C(6)H(4), CO(2)R) in positions 1 and 4 with carbonyl derivatives (ethyl glyoxalate 9a and diethyl ketomalonate 9b) and the electron-deficient olefin tetracyanoethylene 11.

Background and Objectives: Geographical differences in hospitalizations and mortality for heart failure serve to estimate the potential for reducing the associated hospital and demographic burden on the population. Accordingly, the objective of this paper is to analyze the geographic variation in heart failure hospitalizations and mortality in Spain during the period of 1980-1993, and to examine their potential determinants., Methods: Data on the primary diagnosis of heart failure were taken from the National Hospital Morbidity Survey and National Vital Statistics. Information on determinants of heart failure were obtained from large-scale nationally representative surveys conducted by the National Statistics Office., Results: The period of 1980-1993 witnessed a decrease in geographical differences in heart failure hospitalizations and mortality. Theoretically, however, heart failure hospitalizations and mortality among persons aged > or = 45 years could still be further reduced by 60% and 30% respectively. In the period of 1989-1993 heart failure hospitalizations were correlated (p < 0.05) with ischaemic heart disease hospitalizations and the number of beds/1,000 inhabitants. Heart failure mortality showed a statistically significant correlation (p < 0.05) with ischaemic heart disease mortality, illiteracy and unemployed status., Conclusions: There is a great potential for a reduction in the hospital and demographic burden of heart failure in Spain. Control of ischaemic heart disease and a reduction in the geographical differences in socio-economic status would probably contribute to lessening the healthcare burden of heart failure in Spain.

Aims: To describe, for the first time, trends in hospitalization and mortality rates for congestive heart failure in Spain during the period 1980-1993., Methods and Results: Data on primary diagnosis of congestive heart failure were taken from the National Hospital Morbidity Survey and the National Vital Statistics. The number of hospital admissions for congestive heart failure rose by 71% (from 42,965 in 1980 to 73,448 in 1993) and hospitalization rates for congestive heart failure increased by 47% (from 348 per 100,000 in 1980 to 511 per 100,000 in 1993). The rise in hospitalizations was limited to persons aged > or = 65 years, and proved greater among women. Congestive heart failure was the leading cause of hospitalization in persons aged > or = 65 years, accounting for 5% of all hospital admissions in this age group. Age-adjusted congestive heart failure mortality declined by 23%. The decline affected all age groups, with the sole exception of the > or = 80-year group in which mortality rose. Nevertheless, congestive heart failure remained the third leading cause of cardiovascular death., Conclusion: Congestive heart failure represents a significant hospital and demographic burden for the Spanish population. The hospital burden increased substantially in the period 1980-1993, and will continue to do so in future with the growth of the elderly population.

OBJECTIVE: To assess restriction endonuclease analysis (REA) of chromosomal DNA using SalI enzyme, low-concentration (0.4%) agarose gels and digitalized data management of the REA patterns obtained for the typing of clinical Pseudomonas aeruginosa isolates. METHODS: A group of 67 clinical unrelated isolates from 10 Spanish hospitals was used to study the discriminatory power, reproducibility and typeability of REA typing. RESULTS: A SalI REA pattern consisted of a variety (1--10) of restriction bands in the range between 12.2 and 48.5 kb and an unresolvable smear of low-molecular-weight bands. Forty different SalI REA patterns with an index of discrimination of 0.979 were obtained. Low typeability (91.04%) was the major limitation of REA typing. Analysis of blinded subcultures of eight Pseudomonas aeruginosa strains showed the reproducibility of REA typing to be 87.5%. Combined phenotypic typing (O-serotyping and phage typing) performed on the same group of strains showed comparable discrimination but much lower reproducibility. Isolates selected from five clusters of nosocomial infections in hospitals in the UK were typed by REA typing, and the results show high agreement when compared with conventional phenotypic typing methods in distinguishing between strains. CONCLUSIONS: These data underline the usefulness of REA typing enhanced with digitalized data management for the epidemiologic subtyping of clinical Pseudomonas aeruginosa isolates.