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espanolEl cancer de mama representa la principal causa de muerte por tumores malignos en mujeres. Se considera una entidad multifactorial, con una clara vinculacion con los factores hormonales y reproductivos de las pacientes. La presentacion clinica mas habitual es la existencia de una masa indolora a nivel local. Su diagnostico se basa en la triada de valoracion clinica, prueba de imagen y biopsia, destacando la mamografia como prueba esencial del cribado poblacional. Su pronostico se relaciona con el subtipo biologico y el estadio tumoral al diagnostico. Los objetivos y la modalidad de tratamiento varian en funcion del estadio tumoral. En el tratamiento de estadios precoces, el cual persigue una intencion curativa, ademas de los tratamientos locales con cirugia y radioterapia, destaca el sistemico adyuvante o neoadyuvante, con quimioterapia, hormonoterapia, tratamiento biologico y/o combinaciones de estos. En presencia de enfermedad metastasica, el objetivo del mismo es paliativo. En esta situacion, a las terapias clasicas con quimioterapia y hormonoterapia, se les ha asociado en los ultimos anos otras nuevas terapias. EnglishBreast cancer represents the main cause of death from malignant tumors in women. It is considered a multifactorial entity, linked to the hormonal and reproductive factors of the patients. The most common clinical presentation is the presence of a painless mass in the breast. The diagnosis is based on the triad of clinical assessment, imaging test and biopsy, highlighting mammography as an essential test in population screening. The prognosis depends on the biological subtype and the tumor stage at diagnosis. The objectives and the modality of treatment varies depending on the tumor stage. In the treatment of early stages, which has a curative intention, local treatment with surgery and radiotherapy is important, as well as adjuvant or neoadjuvant systemic treatment with chemotherapy, hormone therapy, biological treatment and/or combinations of them. In the presence of metastatic disease, the goal of treatment is palliative. In this situation, classic therapies with chemotherapy and hormonal therapy have been joined in recent years by the incorporation of new therapies.

espanolEn torno al 2% de los canceres de endometrio, el 7% de los canceres de mama y el 15% de los canceres de ovario son hereditarios. Identificar a estas pacientes resulta fundamental de cara a la prevencion del desarrollo de cancer en el futuro, en ellas y otros miembros de la familia, pero tambien para un apropiado tratamiento de la enfermedad. En base a la evidencia cientifica actual y a las recomendaciones de las guias de practica clinica, proponemos un algoritmo para facilitar el diagnostico de sospecha de cancer hereditario y la apropiada derivacion de dichas pacientes a unidades de consejo genetico (CG). EnglishAbout 2% of endometrial cancers, 7% of breast cancers and 15% of ovarian cancers are hereditary. In order to prevent cancer development and to set up the proper treatment, it is mandatory to identify those patients and their relatives. According with current scientific evidence and clinical practice guidelines, we propose an algorithm to facilitate the diagnosis of suspected inherited cancer and the appropriate referral of patients to hereditary cancer genetic counseling units (HCGCUs).

Coronary artery disease (CAD) is the most common cardiovascular disorder. Vascular surgery strategies for coronary revascularization (either percutaneous or open) show a high rate of failure because of restenosis of the vessel, due to phenotypic switch of vascular smooth muscle cells (VSMCs) leading to proliferation and migration. We have previously reported that the inhibition of Kv1.3 channel function with selective blockers represents an effective strategy for the prevention of restenosis in human vessels used for coronary angioplasty procedures. However, delivery systems for controlled release of these drugs have not been investigated. Here we tested the efficacy of several formulations of elastin like recombinamers (ELRs) hydrogels to deliver the Kv1.3 blocker PAP-1 in various restenosis models. The dose and time course of PAP-1 release from ELRs click hydrogels was able to inhibit human VSMC proliferation in vitro as well as remodeling of human vessels in organ culture and restenosis in in vivo models. We conclude that this combination of active compound and advanced delivery method could improve the outcomes of vascular surgery in patients., The authors are grateful for financial support from the European Social Fund (ESF) and the European Regional Development Fund (ERDF), as well as grants from the EU H2020-NMP-2014-646075), the Spanish Ministerio de Economia y Competitividad MINECO (grants BFU2016-75360-R, DTS19/00162, MAT2016-79435-R, MAT2016-78903-R and RTI2018-096320-B-C22), the Junta de Castilla y León (grants VA114P17 and VA317P18), the CIBER-BBN, the JCyL and the Instituto de Salud Carlos III under the “Network Center of Regenerative Medicine and Cellular Therapy of Castilla and Leon”. S. Moreno-Estar and S. Serrano are predoctoral fellows of the Junta de Castilla y León and M. Arévalo-Martínez is predoctoral fellow of UVa-Santander.

© 2020 Published by Elsevier Inc, The modulation of voltage-gated K+ (Kv) channels, involved in cell proliferation, arises as a potential therapeutic approach for the prevention of intimal hyperplasia present in in-stent restenosis (ISR) and allograft vasculopathy (AV). We studied the effect of PAP-1, a selective blocker of Kv1.3 channels, on development of intimal hyperplasia in vitro and in vivo in 2 porcine models of vascular injury. In vitro phenotypic modulation of VSMCs was associated to an increased functional expression of Kv1.3 channels, and only selective Kv1.3 channel blockers were able to inhibit porcine VSMC proliferation. The therapeutic potential of PAP-1 was then evaluated in vivo in swine models of ISR and AV. At 15-days follow-up, morphometric analysis demonstrated a substantial reduction of luminal stenosis in the allografts treated with PAP-1 (autograft 2.72 ± 1.79 vs allograft 10.32 ± 1.92 vs allograft + polymer 13.54 ± 8.59 vs allograft + polymer + PAP-1 3.06 ± 1.08 % of luminal stenosis; P = 0.006) in the swine model of femoral artery transplant. In the pig model of coronary ISR, using a prototype of PAP-1-eluting stent, no differences were observed regarding % of stenosis compared to control stents (31 ± 13 % vs 37 ± 18%, respectively; P = 0.372) at 28-days follow-up. PAP-1 treatment was safe and did not impair vascular healing in terms of delayed endothelialization, inflammation or thrombosis. However, an incomplete release of PAP-1 from stents was documented. We conclude that the use of selective Kv1.3 blockers represents a promising therapeutic approach for the prevention of intimal hyperplasia in AV, although further studies to improve their delivery method are needed to elucidate its potential in ISR., This work was supported by a Translational Research Project on Cardiology (2015) of the Sociedad Española de Cardiología and Fondo de Investigación Sanitario Instituto de Salud Carlos III (PI11/00225) to M. Roqué; BFU2016-75360-R from the Ministerio de Economía y Competitividad (MINECO) to M.T. Pérez-García and J.R. López-López; Junta de Castilla y León Grant VA114P17 to M.T. Pérez-García; and the CERCA Programme of the Generalitat de Catalunya.

Oral mucositis is one of the most common side effects in cancer patients receiving systemic antineoplastics. However, the underlying biological mechanisms leading to this condition are still unclear. For this reason, it has been hypothesised that systemic antineoplastics may cause an imbalance on the oral microbiota that subsequently triggers oral mucosa damage. A systematic review was performed following the PRISMA protocol and the PICO question established was: patients diagnosed with cancer, who are candidates for receiving systemic antineoplastics (P=Patients), that undergo oral microbiome determinations (I=Intervention), before and after systemic antineoplastics administration (C=Comparison), to analyse changes in the oral microbiome composition (O=Outcome). The bibliographic search was carried out in PubMed and other scientific repositories. Out of 166 obtained articles, only 5 met eligibility criteria. Acute myeloid leukaemia (AML) was the most frequent type of cancer (40 %) among the participants. Only one of the studies included a control group of healthy subjects. Heterogeneity in the protocols and approaches of the included studies hindered a detailed comparison of the outcomes. However, it was stated that a decrease in bacteria ? diversity is often associated with oral mucositis. On the other hand, fungal diversity was not associated with oral mucositis although ? diversity was lower at baseline on patients developing oral candidiasis. There is insufficient scientific evidence of oral microbiological changes in patients undergoing systemic antineoplastics. Further investigations ought to be carried out to identify microorganisms that might play a key role in the pathogenesis of oral mucosa damage in patients undergoing systemic antineoplastics.

Producción Científica, Objectives: Restenosis after vessel angioplasty due to dedifferentiation of the vascular smooth muscle cells (VSMCs) limits the success of surgical treatment of vascular occlusions. Type 2 diabetes (T2DM) has a major impact on restenosis, with patients exhibiting more aggressive forms of vascular disease and poorer outcomes after surgery. Kv1.3 channels are critical players in VSMC proliferation. Kv1.3 blockers inhibit VSMCs MEK/ERK signalling and prevent vessel restenosis. We hypothesize that dysregulation of microRNAs (miR) play critical roles in adverse remodelling, contributing to Kv1.3 blockers efficacy in T2DM VSMCs. Methods and results: We used clinically relevant in vivo models of vascular risk factors (VRF) and vessels and VSMCs from T2DM patients. Results: Human T2DM vessels showed increased remodelling, and changes persisted in culture, with augmented VSMCs migration and proliferation. Moreover, there were downregulation of PI3K/AKT/mTOR and upregulation of MEK/ERK pathways, with increased miR-126 expression. The inhibitory effects of Kv1.3 blockers on remodelling were significantly enhanced in T2DM VSMCs and in VRF model. Finally, miR-126 overexpression confered “diabetic” phenotype to non-T2DM VSMCs by downregulating PI3K/AKT axis. Conclusions: miR-126 plays crucial roles in T2DM VSMC metabolic memory through activation of MEK/ERK pathway, enhancing the efficacy of Kv1.3 blockers in the prevention of restenosis in T2DM patients., Ministerio de Economía, Industria y Competitividad (grant BFU2016-75360-R and SAF2016-77871-C2-1-R), Junta de Castilla y León (grants VA114P17; VA172P20 and CLU-2019-02), Novo Nordisk Foundation (grant 34366), Swedish Research Council (grants 2017–00860 and 2020-01145), Swedish Heart and Lung Foundation (grant 20200322)

espanolEl cancer de mama es uno de los tumores en los que antes y en mayor numero se ha incorporado la utilizacion de biomarcadores en la practica clinica. Diferenciamos entre marcadores pronosticos y predictivos de respuesta, aunque algunos de ellos pertenecen a ambos grupos. Desde los clasicos detectados por inmunohistoquimica (como son los receptores de estrogenos, progesterona, HER2 y Ki67) hasta los actuales en desarrollo basados principalmente en expresion genetica (BRCA, PI3K) y del sistema inmune (PD-L1, TILS), los biomarcadores son fundamentales para la clasificacion de la enfermedad y la eleccion de los tratamientos. Ademas, plataformas moleculares y de biopsia liquida estan en proceso de validacion clinica actualmente. EnglishBreast cancer is one of the tumor types in which the use of biomarkers has been earlier incorporated into clinical practice and in the greatest number. Biomarkers are classified into two groups: prognostic markers and predictive response markers, but some of them belong to both groups. Biomarkers, including immunohistochemistry markers (like estrogen, progesterone receptors, HER2 and Ki67) and current ones based mainly on gene (BRCA, PI3K) and immune system (PD-L1, TILS) expression, are essential in disease classification and treatment choice. Nowadays, molecular and liquid-biopsy platforms, are being validated.

The Transient Receptor Potential Melastatin 3 (TRPM3) is a Ca2+-permeable non-selective cation channel activated by the neurosteroid pregnenolone sulfate (PS). This compound was previously shown to contract mouse aorta by activating TRPM3 in vascular smooth muscle cells (VSMC), and proposed as therapeutic modulator of vascular functions. However, PS effects and the role of TRPM3 in resistance arteries remain unknown. Thus, we aimed at determining the localization and physiological role of TRPM3 in mouse mesenteric arteries. Real-time qPCR experiments, anatomical localization using immunofluorescence microscopy and patch-clamp recordings in isolated VSMC showed that TRPM3 expression in mesenteric arteries is restricted to perivascular nerves. Pressure myography experiments in wild type (WT) mouse arteries showed that PS vasodilates with a concentration-dependence that was best fit by two Hill components (effective concentrations, EC50, of 14 and 100 μM). The low EC50 component was absent in preparations from Trpm3 knockout (KO) mice and in WT arteries in the presence of the CGRP receptor antagonist BIBN 4096. TRPM3-dependent vasodilation was partially inhibited by a cocktail of K+ channel blockers, and not mediated by β-adrenergic signaling. We conclude that, contrary to what was found in aorta, PS dilates mesenteric arteries, partly via an activation of TRPM3 that triggers CGRP release from perivascular nerve endings and a subsequent activation of K+ channels in VSMC. We propose that TRPM3 is implicated in the regulation of the tone of resistance arteries and that its activation by yet unidentified endogenous damage-associated molecules lead to protective vasodilation responses in mesenteric arteries., This work was supported by grants from the Fund for Scientific Research Flanders (FWO, G.0C68.15, Belgium) to KT, the Ministerio de Economía y Competitividad (BFU2013-45867-R and BFU2016-75360-R, Spain) to JRLL and MTPG and Junta de Castilla y León(VA114P17, Spain) to MTPG. Y.A.A. is a Postdoctoral Fellow of the FWO (Belgium).

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiere, y los autores pertenecientes a la UAM, Background We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC). Patients and methods VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and 1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m2 then 250 mg/m2 weekly) plus FOLFIRI [irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 (bolus) then 2400 mg/m2 (46-h continuous infusion) every 2 weeks]. The primary endpoint was progression-free survival (PFS). All analyses were exploratory. Results Two hundred and forty patients with BRAF/PIK3CA wild-type (n = 196) or BRAF- and/or PIK3CA-mutated tumours (n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF/PIK3CA wild-type and BRAF/PIK3CA-mutated tumours, respectively [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602]. In the BRAF- and/or PIK3CA-mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF/PI3KCA-mutated (n = 8), BRAF-mutated/PI3KCA wild-type (n = 16) and BRAF wild-type/PI3KCA-mutated (n = 20) tumours, respectively (P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF/PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF/PIK3CA-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups. Conclusions BRAF/PIK3CA status influences outcomes in patients with RAS wild-type mCRC but does not appear to assist with the selection of first-line targeted therapy, This work was supported by Roche Farma S.A (no grant number). Medical writing support was funded by Roche Farma S.A and provided by H. Lamb and L. Miller of Miller Medical Communications Ltd.

© The Author(s) 2021., Exposure to Gram-negative bacterial LPS exacerbates host immune responses and may lead to sepsis, a life-threatening condition. Despite its high mortality and morbidity, no drugs specifically directed to treating sepsis are currently available. Using human cell genetic depletion, pharmacological inhibition, live-cell microscopy and organelle-targeted molecular sensors we present evidence that the channel TRPC3 is activated intracellularly during macrophage exposure to LPS and is essential for Ca2+ release from internal stores. In this manner, TRPC3 participates in cytosolic Ca2+ elevations, activation of the transcription factor NF-κB and cytokine upregulation. We also report that TRPC3 is activated by diacylglycerol generated by the phosphatidic acid phosphatase lipin-1. In accord with this, lipin-1-deficient cells exhibit reduced Ca2+ responses to LPS challenge. Finally, pharmacological inhibition of TRPC3 reduces systemic inflammation induced by LPS in mice. Collectively, our study unveils a central component of LPS-triggered Ca2+ signaling that involves intracellular sensing of lipin-1-derived DAG by TRPC3, and opens new opportunities for the development of strategies to treat LPS-driven inflammation., This work was supported by the Spanish Ministry of Economy, Industry, and Competitiveness (grant SAF2016-80883-R) and the Spanish Ministry of Science and Innovation (grants PID2019-105989RB-I00 and PID2020-118517RB-I00), and the Regional Government of Castile and Leon (grants CSI141P20 and VA172P20, co-financed by the European Union through the European Regional Development Fund). Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas (CIBERDEM) is an initiative of Instituto de Salud Carlos III.

Chronic kidney disease (CKD) significantly increases cardiovascular risk. In advanced CKD stages, accumulation of toxic circulating metabolites and mineral metabolism alterations triggers vascular calcification, characterized by vascular smooth muscle cell (VSMC) transdifferentiation and loss of the contractile phenotype. Phenotypic modulation of VSMC occurs with significant changes in gene expression. Even though ion channels are an integral component of VSMC function, the effects of uremia on ion channel remodeling has not been explored. We used an in vitro model of uremia-induced calcification of human aorta smooth muscle cells (HASMCs) to study the expression of 92 ion channel subunit genes. Uremic serum-induced extensive remodeling of ion channel expression consistent with loss of excitability but different from the one previously associated with transition from contractile to proliferative phenotypes. Among the ion channels tested, we found increased abundance and activity of voltage-dependent K+ channel Kv1.3. Enhanced Kv1.3 expression was also detected in aorta from a mouse model of CKD. Pharmacological inhibition or genetic ablation of Kv1.3 decreased the amount of calcium phosphate deposition induced by uremia, supporting an important role for this channel on uremia-induced VSMC calcification.

The voltage-dependent potassium channel Kv1.3 has been implicated in proliferation in many cell types, based on the observation that Kv1.3 blockers inhibited proliferation. By modulating membrane potential, cell volume, and/or Ca2+ influx, K+ channels can influence cell cycle progression. Also, noncanonical channel functions could contribute to modulate cell proliferation independent of K+ efflux. The specificity of the requirement of Kv1.3 channels for proliferation suggests the involvement of molecule-specific interactions, but the underlying mechanisms are poorly identified. Heterologous expression of Kv1.3 channels in HEK cells has been shown to increase proliferation independently of K+ fluxes. Likewise, some of the molecular determinants of Kv1.3-induced proliferation have been located in the C-terminus region, where individual point mutations of putative phosphorylation sites (Y447A and S459A) abolished Kv1.3-induced proliferation. Here, we investigated the mechanisms linking Kv1.3 channels to proliferation exploring the correlation between Kv1.3 voltage-dependent molecular dynamics and cell cycle progression. Using transfected HEK cells, we analyzed both the effect of changes in resting membrane potential on Kv1.3-induced proliferation and the effect of mutated Kv1.3 channels with altered voltage dependence of gating. We conclude that voltage-dependent transitions of Kv1.3 channels enable the activation of proliferative pathways. We also found that Kv1.3 associated with IQGAP3, a scaffold protein involved in proliferation, and that membrane depolarization facilitates their interaction. The functional contribution of Kv1.3-IQGAP3 interplay to cell proliferation was demonstrated both in HEK cells and in vascular smooth muscle cells. Our data indicate that voltage-dependent conformational changes of Kv1.3 are an essential element in Kv1.3-induced proliferation., Secretaría de Estado de Investigación,Desarrollo e Innovación,Grant/Award Numbers: BFU2016‐75360‐R,SEV‐2015‐0505; Consejería de Educación,Junta de Castilla y León,Grant/Award Number: VA114P17

In recent decades, research into the effects of virtual reality on different neurological disorders has increased exponentially. Yet, the literature focused on the beneficial effects of virtual reality on cognitive impairment in elderly people is limited.To explore the application of virtual reality as a preventive, diagnostic or therapeutic tool for cognitive impairment in elderly people.A literature search was conducted in the Medline and Web of Science databases, including all the literature published from their inception up until December 2019.Of the 270 publications found, 15 met the inclusion criteria: two examined the effect of virtual reality as a tool for the prevention of cognitive impairment, six looked at its possible applications in diagnosis, and seven explored its effectiveness as a form of treatment.There is evidence of the potential effect of virtual reality as a preventive strategy against the development of cognitive impairment in elderly people. There is also evidence of its applicability as a diagnostic tool for detecting the development of mild cognitive impairment or dementia, and of its effectiveness as a treatment, since it improves the cognitive functioning of elderly people with cognitive impairment. Further studies are needed that are more methodologically robust and have long follow-up times in order to examine the real impact of virtual reality and to be able to generalise its application in different areas of the management of cognitive impairment.Realidad virtual como herramienta de prevención, diagnóstico y tratamiento del deterioro cognitivo en personas mayores: revisión sistemática.Introducción. En las últimas décadas, se ha incrementado exponencialmente la investigación sobre los efectos de la realidad virtual en diferentes trastornos neurológicos. Sin embargo, la bibliografía centrada en los beneficios de la realidad virtual sobre el deterioro cognitivo en personas mayores es limitada. Objetivo. Explorar la aplicación de la realidad virtual como herramienta preventiva, diagnóstica o de tratamiento del deterioro cognitivo en personas mayores. Pacientes y métodos. Se llevó a cabo una búsqueda bibliográfica en las bases de datos Medline y Web of Science, incluyendo toda la bibliografía publicada desde sus inicios hasta diciembre de 2019. Resultados. De las 270 publicaciones encontradas, 15 cumplieron los criterios de inclusión: dos examinaron el efecto de la realidad virtual como herramienta de prevención del deterioro cognitivo; seis, su aplicabilidad diagnóstica; y siete, su efectividad como tratamiento. Conclusiones. Existe evidencia del potencial efecto de la realidad virtual como estrategia preventiva frente al desarrollo de deterioro cognitivo en personas mayores. Existe también evidencia de su aplicabilidad como herramienta diagnóstica de detección de desarrollo de deterioro cognitivo leve o demencia, y de su efectividad como tratamiento, ya que mejora el funcionamiento cognitivo de personas mayores con deterioro cognitivo. Son necesarios futuros estudios metodológicamente más robustos y con amplios tiempos de seguimiento para examinar el impacto real de la realidad virtual y poder generalizar su aplicación en los diferentes ámbitos de manejo del deterioro cognitivo.

[Objective]: We have previously described that changes in the expression of Kv channels associate to phenotypic modulation (PM), so that Kv1.3/Kv1.5 ratio is a landmark of vascular smooth muscle cells phenotype. Moreover, we demonstrated that the Kv1.3 functional expression is relevant for PM in several types of vascular lesions. Here, we explore the efficacy of Kv1.3 inhibition for the prevention of remodeling in human vessels, and the mechanisms linking the switch in Kv1.3 /Kv1.5 ratio to PM., [Approach and Results]: Vascular remodeling was explored using organ culture and primary cultures of vascular smooth muscle cells obtained from human vessels. We studied the effects of Kv1.3 inhibition on serum-induced remodeling, as well as the impact of viral vector-mediated overexpression of Kv channels or myocardin knock-down. Kv1.3 blockade prevented remodeling by inhibiting proliferation, migration, and extracellular matrix secretion. PM activated Kv1.3 via downregulation of Kv1.5. Hence, both Kv1.3 blockers and Kv1.5 overexpression inhibited remodeling in a nonadditive fashion. Finally, myocardin knock-down induced vessel remodeling and Kv1.5 downregulation and myocardin overexpression increased Kv1.5, while Kv1.5 overexpression inhibited PM without changing myocardin expression., [Conclusions]: We demonstrate that Kv1.5 channel gene is a myocardin-regulated, vascular smooth muscle cells contractile marker. Kv1.5 downregulation upon PM leaves Kv1.3 as the dominant Kv1 channel expressed in dedifferentiated cells. We demonstrated that the inhibition of Kv1.3 channel function with selective blockers or by preventing Kv1.5 downregulation can represent an effective, novel strategy for the prevention of intimal hyperplasia and restenosis of the human vessels used for coronary angioplasty procedures., This work was supported by grant BFU2016-75360-R from the Ministerio de Economía y Competitividad (MINECO), to M.T. Pérez-García and J.R. López-López and Junta de Castilla y León Grant VA114P17 to M.T. Pérez-García. N. García-Mateo was supported by FIS PI15/00064 from the Instituto de Salud Carlos III. M. Arévalo-Martínez and J. Serna are predoctoral fellows of the UVa-Santander, and S. Moreno-Estar is a predoctoral fellow of the JCyL. K. Swärd was supported by the Swedish Research Council (2017-01225_3).

Key points Canonical transient receptor potential (TRPC)3 and TRPC6 channels of vascular smooth muscle cells (VSMCs) mediate stretch- or agonist-induced cationic fluxes, contributing to membrane potential and vascular tone. Native TRPC3/C6 channels can form homo- or heterotetrameric complexes, which can hinder individual TRPC channel properties. The possibility that the differences in their association pattern may change their contribution to vascular tone in hypertension is unexplored. Functional characterization of heterologously expressed channels showed that TRPC6-containing complexes exhibited Pyr3/Pyr10-sensitive currents, whereas TRPC3-mediated currents were blocked by anti-TRPC3 antibodies. VSMCs from hypertensive (blood pressure high; BPH) mice have larger cationic basal currents insensitive to Pyr10 and sensitive to anti-TRPC3 antibodies. Consistently, myography studies showed a larger Pyr3/10-induced vasodilatation in BPN (blood pressure normal) mesenteric arteries. We conclude that the increased TRPC3 channel expression in BPH VSMCs leads to changes in TRPC3/C6 heteromultimeric assembly, with a higher TRPC3 channel contribution favouring depolarization of hypertensive VSMCs. Abstract Increased vascular tone in essential hypertension involves a sustained rise in total peripheral resistance. A model has been proposed in which the combination of membrane depolarization and higher L-type Ca2+ channel activity generates augmented Ca2+ influx into vascular smooth muscle cells (VSMCs), contraction and vasoconstriction. The search for culprit ion channels responsible for membrane depolarization has provided several candidates, including members of the canonical transient receptor potential (TRPC) family. TRPC3 and TRPC6 are diacylglycerol-activated, non-selective cationic channels contributing to stretch- or agonist-induced depolarization. Conflicting information exists regarding changes in TRPC3/TRPC6 functional expression in hypertension. However, although TRPC3-TRPC6 channels can heteromultimerize, the possibility that differences in their association pattern may change their functional contribution to vascular tone is largely unexplored. We probe this hypothesis using a model of essential hypertension (BPH mice; blood pressure high) and its normotensive control (BPN mice; blood pressure normal). First, non-selective cationic currents through homo- and heterotetramers recorded from transfected Chinese hamster ovary cells indicated that TRPC currents were sensitive to the selective antagonist Pyr10 only when TRPC6 was present, whereas intracellular anti-TRPC3 antibody selectively blocked TRPC3-mediated currents. In mesenteric VSMCs, basal and agonist-induced currents were more sensitive to Pyr3 and Pyr10 in BPN cells. Consistently, myography studies showed a larger Pyr3/10-induced vasodilatation in BPN mesenteric arteries. mRNA and protein expression data supported changes in TRPC3 and TRPC6 proportions and assembly, with a higher TRPC3 channel contribution in BPH VSMCs that could favour cell depolarization. These differences in functional and pharmacological properties of TRPC3 and TRPC6 channels, depending on their assembly, could represent novel therapeutical opportunities.

Producción Científica, Changes in voltage-dependent potassium channels (Kv channels) associate to proliferation in many cell types, including transfected HEK293 cells. In this system Kv1.5 overexpression decreases proliferation, whereas Kv1.3 expression increases it independently of K+ fluxes. To identify Kv1.3 domains involved in a proliferation-associated signaling mechanism(s), we constructed chimeric Kv1.3-Kv1.5 channels and point-mutant Kv1.3 channels, which were expressed as GFP- or cherry-fusion proteins. We studied their trafficking and functional expression, combining immunocytochemical and electrophysiological methods, and their impact on cell proliferation. We found that the C terminus is necessary for Kv1.3-induced proliferation. We distinguished two residues (Tyr-447 and Ser-459) whose mutation to alanine abolished proliferation. The insertion into Kv1.5 of a sequence comprising these two residues increased proliferation rate. Moreover, Kv1.3 voltage-dependent transitions from closed to open conformation induced MEK-ERK1/2-dependent Tyr-447 phosphorylation. We conclude that the mechanisms for Kv1.3-induced proliferation involve the accessibility of key docking sites at the C terminus. For one of these sites (Tyr-447) we demonstrated the contribution of MEK/ERK-dependent phosphorylation, which is regulated by voltage-induced conformational changes., Ministerio de Economía y Competitividad (MINECO), Instituto de Salud Carlos III y Programa Estatal de Investigación , Fundación Ramón Areces y Consejería de Sanidad de la Junta de Castilla y León.

Genetic Improvement (GI) performs a search at the level of source code to find the best variant of a baseline system that improves non-functional properties while maintaining functionality with noticeable results in several domains. There a many aspects of this general approach that are currently being explored. In particular, this work deals to the way in which the search is guided to efficiently explore the search space of possible software versions in which GI operates. The proposal is to integrate Novelty Search (NS) within the GISMOE GI framework to improve KinectFusion, which is a vision-based Simultaneous Localization and Mapping (SLAM) system that is used for augmented reality, autonomous vehicle navigation, and many other real-world applications. This is one of a small set of works that have successfully combined NS with a GP system, and the first time that it has been used for software improvement. To achieve this, we propose a new behaviour descriptor for SLAM algorithms, based on state-of-the-art benchmarking and present results that show that NS can produce significant improvement gains in a GI setting, when considering execution time and trajectory estimation as the main performance criteria.

Producción Científica, Patients with chronic kidney disease (CKD) have a markedly increased incidence of cardiovascular disease (CVD). The high concentration of circulating uremic toxins and alterations in mineral metabolism and hormone levels produce vascular wall remodeling and significant vascular damage. Medial calcification is an early vascular event in CKD patients and is associated to apoptosis or necrosis and trans-differentiation of vascular smooth muscle cells (VSMC) to an osteogenic phenotype. VSMC obtained from bovine or rat aorta and cultured in the presence of increased inorganic phosphate (Pi) have been extensively used to study these processes. In this study we used human aortic VSMC primary cultures to compare the effects of increased Pi to treatment with serum obtained from uremic patients. Uremic serum induced calcification, trans-differentiation and phenotypic remodeling even with normal Pi levels. In spite of similar calcification kinetics, there were fundamental differences in osteochondrogenic marker expression and alkaline phosphatase induction between Pi and uremic serum-treated cells. Moreover, high Pi induced a dramatic decrease in cell viability, while uremic serum preserved it. In summary, our data suggests that primary cultures of human VSMC treated with serum from uremic patients provides a more informative model for the study of vascular calcification secondary to CKD., Ministerio de Economía, Industria y Competitividad (grant BFU2016-78374-R, BFU2013-45867-R and BFU2016-75360-R), Instituto de Salud Carlos III (grant PI13/01726)

[Purpose]: Breakthrough cancer pain (BTcP) has been shown to be a prevalent and poor prognostic factor for oncologic patients, which remain under diagnosed and undertreated. In 2012, the Spanish Society of Medical Oncology (SEOM) published a clinical practice guideline (CPG) for the treatment of cancer pain which specifically addressed the management of BTcP., [Methods]: Fundación ECO designed a qualitative study using an Internet-based survey to investigate the attitudes toward, compliance with, and use of SEOM Guideline., [Results]: A total of 83 oncologists with a mean experience of 13 years responded. Overall, 82% were aware of different guidelines to manage BTcP. Notably, attitudes toward guidelines were highly positive and there was nearly unanimous agreement that CPG provided the best scientific evidence available (99%), on the minimum information to be gathered for the medical history (100%), on the need for a specific treatment for BTcP (100%), and fentanyl as the first-choice drug (99%). Interestingly, there were discrepancies between what oncologists agreed with and what they do in clinical practice. In fact, 87.6% declare full compliance with SEOM guideline, although adherence to registration of BTcP data in medical records ranged from 30.1 to 91.6% (mean 64.5%); therapeutic management compliance was higher ranging from 75.9 to 91.6%. Main barriers identified were time pressure together with vague statements and limited dissemination of the guidelines., [Conclusion]: Despite oncologist’s clinical practice is increasingly guided by GPC, it suffers from limited compliance, at least in part due to suboptimal statements. Improved dissemination and education are needed to enhance guideline implementation., This study was funded by Kyowa Kirin Farmacéutica S. L.U. through Fundación ECO.

Resumen: Introducción: Los avances en el diagnóstico precoz y tratamiento han propiciado una mayor supervivencia, y en mejores condiciones, de los pacientes con enfermedades metabólicas congénitas (EMC). Estos pueden acudir a los Servicios de Urgencias Pediátricas (SUP) por motivos relacionados o no con su enfermedad. El propósito de este trabajo fue revisar las características de las visitas al SUP de estos pacientes, en un hospital de tercer nivel. Material y métodos: Se desarrolló un estudio observacional retrospectivo en el que se analizaron todas las visitas al SUP del Hospital Infantil La Paz durante los años 2011 y 2012 de pacientes con EMC. Se registraron el tipo de EMC, el motivo de consulta, el tiempo de evolución de los síntomas, la necesidad de ingreso hospitalario y la presencia de descompensación metabólica. Resultados: En total, fueron analizadas 107 visitas, siendo el motivo de consulta más frecuente los procesos respiratorios (30,8%). Cuando la consulta fue por vómitos, los pacientes con trastornos relacionados con las proteínas fueron los que menos tardaron en acudir al SUP. Un tercio de las visitas se siguió de ingreso, siendo la mitad de ellas por descompensación metabólica de la patología de base. Conclusiones: Los pacientes con EMC acudieron al SUP por motivos muy diversos, que en algunos casos fueron causa o consecuencia de una descompensación metabólica aguda que motivó el ingreso hospitalario. Al tratarse de enfermedades con baja prevalencia individual, resulta de interés contar con protocolos diagnóstico-terapéuticos que faciliten una atención óptima. Abstract: Introduction: Advances in the early diagnosis and treatment have led to improved survival, and a better quality of life for patients with inherited metabolic disorders (IMD). They can go to the Pediatric Emergency Services (PES) for reasons unrelated to their disease. The purpose of this study was to review the characteristics of visitors to the PES of these patients in a tertiary hospital. Material and methods: A retrospective observational study was conducted on all visits from patients with IMD to the PES of Hospital Infantil La Paz over the years 2011 and 2012. IMD type, complaint, duration of symptoms, need for hospitalization, and presence of metabolic decompensation was recorded. Results: A total of 107 visits were analyzed, with the most frequent reason being for consultation of respiratory processes (30.8%). When the consultation was for vomiting, patients with protein-related disorders were those who delayed less in going to PES. One third of visitors were admitted, half of them due to metabolic decompensation of the underlying pathology. Conclusions: Patients with IMD came to PES for many different reasons, which in some cases were the cause or consequence of an acute metabolic decompensation that led to hospitalization. Being diseases with low prevalence, it would be useful to have diagnostic and therapeutic protocols in order to provide optimal care.

Investigating the contribution of tropical cyclones to the terrestrial water cycle can help quantify the benefits and hazards caused by the rainfall generated from this type of hydro-meteorological event. Rainfall induced by tropical cyclones can enhance both flood risk and groundwater recharge, and it is therefore important to characterise its minimum, mean and maximum contributions to a region or country’s water balance. This work evaluates the rainfall contribution of tropical depressions, storms and hurricanes across Mexico from 1998 to 2013 using the satellite-derived precipitation dataset TMPA 3B42. Additionally, the sensitivity of rainfall to other datasets was assessed: the national rain gauge observation network, real-time satellite rainfall and a merged product that combines rain gauges with non-calibrated space-borne rainfall measurements. The lower Baja California peninsula had the highest contribution from cyclonic rainfall in relative terms (∼40% of its total annual rainfall), whereas the contributions in the rest of the country showed a low-to-medium dependence on tropical cyclones, with mean values ranging from 0% to 20%. In quantitative terms, southern regions of Mexico can receive more than 2400 mm of cyclonic rainfall during years with significant TC activity. Moreover, (a) the number of tropical cyclones impacting Mexico has been significantly increasing since 1998, but cyclonic contributions in relative and quantitative terms have not been increasing, and (b) wind speed and rainfall intensity during cyclones are not highly correlated. Future work should evaluate the impacts of such contributions on surface and groundwater hydrological processes and connect the knowledge gaps between the magnitude of tropical cyclones, flood hazards, and economic losses.

Kv1.3 channels are involved in the switch to proliferation of normally quiescent cells, being implicated in the control of cell cycle in many different cell types and in many different ways. They modulate membrane potential controlling K+ fluxes, sense changes in potential, and interact with many signaling molecules through their intracellular domains. From a mechanistic point of view, we can describe the role of Kv1.3 channels in proliferation with at least three different models. In the “membrane potential model,” membrane hyperpolarization resulting from Kv1.3 activation provides the driving force for Ca2+ influx required to activate Ca2+-dependent transcription. This model explains most of the data obtained from several cells from the immune system. In the “voltage sensor model,” Kv1.3 channels serve mainly as sensors that transduce electrical signals into biochemical cascades, independently of their effect on membrane potential. Kv1.3-dependent proliferation of vascular smooth muscle cells (VSMCs) could fit this model. Finally, in the “channelosome balance model,” the master switch determining proliferation may be related to the control of the Kv1.3 to Kv1.5 ratio, as described in glial cells and also in VSMCs. Since the three mechanisms cannot function independently, these models are obviously not exclusive. Nevertheless, they could be exploited differentially in different cells and tissues. This large functional flexibility of Kv1.3 channels surely gives a new perspective on their functions beyond their elementary role as ion channels, although a conclusive picture of the mechanisms involved in Kv1.3 signaling to proliferation is yet to be reached., This work was supported by Grants BFU2013-45867-R and BFU2016-75360-R from the Spanish Government.

LSA is a useful user study technique, it is well known and used to design and evaluate Ubicomp systems. The LSA technique enables researchers to collect data, analyze it, and obtain quantitative and statistical results. A key advantage of using LSA is that it is performed in the user’s environment. However, analyzing large amounts of data is considered by some researchers to be a burden and time consuming, prone to human error. In this paper we explore the use of computer vision techniques to automate the data analysis and coding when using LSA. We present a system that uses facial tracking, object recognition and composite correlation filters to detect the Attention behavior of a subject. Our results indicate that computer vision can automate the LSA technique and reduce the burden of coding data manually by the researcher. The findings from this study reveal emergent practices of the use of our proposed system to automate the evaluation of Ubicomp environments.

Kv channels are present in virtually all VSMCs and strongly influence contractile responses. However, they are also instrumental in the proliferative, migratory, and secretory functions of synthetic, dedifferentiated VSMCs upon PM. In fact, Kv channels not only contribute to all these processes but also are active players in the phenotypic switch itself. This review is focused on the role(s) of Kv channels in VSMC proliferation, which is one of the best characterized functions of dedifferentiated VSMCs. VSMC proliferation is a complex process requiring specific Kv channels at specific time and locations. Their identification is further complicated by their large diversity and the differences in expression across vascular beds. Of interest, both conserved changes in some Kv channels and vascular bed‐specific regulation of others seem to coexist and participate in VSMC proliferation through complementary mechanisms. Such a system will add flexibility to the process while providing the required robustness to preserve this fundamental cellular response., Ministerio de Economía y Competitividad (MINECO), Grant/Award Number: BFU2013- 45867-R and BFU2016-75360-R.

Producción Científica, K+ channels encoded by the ether-a-go-go related gene (ERG1 or KCNH2) are important determinants of the cardiac action potential. Expression of both cardiac isoforms (ERG1a and ERG1b) were identified in murine portal vein and distinctive voltage-gated K+ currents were recorded from single myocytes. The aim of the present study was to ascertain the expression and functional impact of ERG channels in murine arteries., British Heart Foundation (projects PG/06/057/20864 and PG/11/93/21943), Medical Research Council (project MR/K019074/1), Ministerio de Economía, Industria y Competitividad (grants BFU2013-45867-R and BFU2016-75360)

The economic situation showed that the resources devoted to health spending are limited, making rationalisation of their consumption necessary. The relevance of pharmacoeconomic analyses is becoming crucial. The ECO Foundation, promoting the quality of oncology care, set out to analyse the consensus on the new therapeutic targets inclusion and the integration of pharmacoeconomics when evaluating their effectiveness. Study about pharmacoeconomic estimations was performed during the first ECO-Seminar (2010). It was developed using a modified Delphi method, in four stages: (1) committee coordinator establishment, (2) expert-panel selection, (3) preparation and submission of survey (1 question) by email, and (4) analysis of the degree of consensus reached. Results were obtained from surveys completed by 35 experts. Regarding the tolerable annual cost for the approval of new drugs, 68.8 % of the respondents considered a cost per quality-adjusted life year (QALY) gained between €30,000 and 100,000 acceptable (34.4 % €30,000–60,000; 34.4 % €60,000–100,000), 21.9 % of the respondents found costs between €100,000–150,000/QALY and 9.3 % of the respondents found costs above €150,000/QALY acceptable. The costs of new drugs are higher than traditional treatments, making it a priority to identify subgroups of patients with specific molecular profiles as candidates for higher-efficiency-targeted therapies. The allocation of the available resources to the most effective interventions, to achieve the best clinical outcomes with lower costs and best subjective profile possible, allows expenditure to be rationalised. Pharmacoeconomic studies are a basic tool for obtaining better health outcomes according to the available resources, while also considering the other needs of the population.

Cinnamaldehyde (CA), a major component of cinnamon, is known to have important actions in the cardiovascular system, including vasorelaxation and decrease in blood pressure. Although CA-induced activation of the chemosensory cation channel TRPA1 seems to be involved in these phenomena, it has been shown that genetic ablation of Trpa1 is insufficient to abolish CA effects. Here, we confirm that CA relaxes rat aortic rings and report that it has negative inotropic and chronotropic effects on isolated mouse hearts. Considering the major role of L-type Ca(2+) channels in the control of the vascular tone and cardiac contraction, we used whole-cell patch-clamp to test whether CA affects L-type Ca(2+) currents in mouse ventricular cardiomyocytes (VCM, with Ca(2+) as charge carrier) and in mesenteric artery smooth muscle cells (VSMC, with Ba(2+) as charge carrier). We found that CA inhibited L-type currents in both cell types in a concentration-dependent manner, with little voltage-dependent effects. However, CA was more potent in VCM than in VSMC and caused opposite effects on the rate of inactivation. We found these divergences to be at least in part due to the use of different charge carriers. We conclude that CA inhibits L-type Ca(2+) channels and that this effect may contribute to its vasorelaxing action. Importantly, our results demonstrate that TRPA1 is not a specific target of CA and indicate that the inhibition of voltage-gated Ca(2+) channels should be taken into account when using CA to probe the pathophysiological roles of TRPA1.

Resumen: Introducción: Evaluar la utilidad de la capnografía para la detección precoz de depresión respiratoria durante los procedimientos de sedoanalgesia. Determinar si la administración de oxígeno durante el procedimiento puede modificar los parámetros monitorizados, retrasando la detección de depresión respiratoria. Material y métodos: Se diseña un estudio prospectivo aleatorizado. Se incluyeron pacientes de 1 a 16 años que precisaron sedoanalgesia para la realización de técnicas diagnósticas y/o terapéuticas, aleatorizando la administración o no de oxígeno suplementario. Todos fueron monitorizados mediante inspección visual, pulsioximetría y capnografía no invasiva, iniciando la monitorización antes de la administración del fármaco y manteniéndola hasta la recuperación completa del estado basal. La variable principal fue la detección de depresión respiratoria definida como apnea, hipoventilación o desaturación. Resultados: Se incluyeron 20 pacientes, de los cuales 11 recibieron oxígeno suplementario. Se objetivó una elevación estadísticamente significativa de los niveles de etCO2 a los 5, 10 y 15 min, comparados con su valor basal. No se detectaron cambios significativos en la media de SatO2. Comparando la evolución de las medias de etCO2 y SatO2 en ambos grupos no se identificaron diferencias estadísticamente significativas. Se registraron 2 casos de depresión respiratoria, detectados precozmente por la capnografía. Existe una correlación estadísticamente significativa entre el nivel de etCO2 a los 5 y 10 min y el grado de sedación alcanzado. Conclusiones: La incorporación de la capnografía a la monitorización rutinaria durante los procedimientos de sedoanalgesia podría mejorar su seguridad. La administración de oxígeno no parece modificar los parámetros monitorizados. Abstract: Introduction: To evaluate the usefulness of capnography for early detection of respiratory depression during sedoanalgesia procedures in the pediatric emergency department. To assess whether the administration of oxygen during the procedure can modify monitored parameters, thus delaying detection of respiratory depression. Material and methods: A prospective randomized study was performed on children between 1 year and 16 years who underwent sedoanalgesia to perform diagnostic or therapeutic procedures. They were randomized into two groups (with or without supplemental oxygen). All patients were monitored by visual inspection, pulse-oximetry and non-invasive capnography. Monitoring was initiated prior to drug administration and continued until complete recovery of baseline. The main study variable was respiratory depression defined as apnea, hypoventilation or oxygen desaturation. Results: Twenty patients were included. Eleven patients were randomized in the supplemental oxygen group. This study showed a statistically significant elevation of EtCO2 levels at 5, 10 and 15 min, compared with baseline. No significant change in the SatO2 mean was detected. No statistically significant differences were identified when comparing etCO2 mean and SatO2 mean in both groups. Two cases of respiratory depression were detected early by capnography. There was a statistically significant correlation between etCO2 at 5 and 10 min, and the degree of sedation achieved. Conclusions: The inclusion of capnography to routine monitoring for adequate sedation procedures could improve safety. Oxygen administration does not appear to modify the parameters monitored.

Supported by Ministerio de Sanidad, ISCIII grant R006/009 (Red Heracles), Ministerio de Ciencia e Innovacion grant BFU2010-15898 (MTPG) and Junta de Castilla y Leon grant VA094A11-2 (JRLL). ST is a fellow of the Spanish MICINN. Work in Dr. L. Fernando Santana’s laboratory was supported by NIH grants HL085870 and P01HL095488.

"The detection and description of locally salient regions is one of the most widely used low-level processes in modern computer vision systems. The general approach relies on the detection of stable and invariant image features that can be uniquely charac- terized using compact descriptors. Many detection and description algorithms have been proposed, most of them derived using different assumptions or problem models. This work presents a comparison of different approaches towards the feature extraction problem, namely: (1) standard computer vision techniques; (2) automatic synthesis techniques based on genetic programming (GP); and (3) a new local descriptor based on composite correlation filtering, proposed for the first time in this paper. The considered methods are evaluated on a difficult real-world problem, vision-based simultaneous localization and mapping (SLAM). Using three experimental scenarios, results indicate that the GP-based methods and the correlation filtering techniques outperform widely used computer vision algorithms such as the Harris and Shi-Tomasi detectors and the Speeded Up Robust Features descriptor."

International audience; Genetic programming (GP) is an evolutionary-based search paradigm that is well suited to automatically solve difficult design problems. The general principles of GP have been used to evolve mathematical functions, models, image operators, programs, and even antennas and lenses. Since GP evolves the syntax and structure of a solution, the evolutionary process can be carried out in one environment and the solution can then be ported to another. However, given the nature of GP it is common that the evolved designs are unorthodox compared to traditional approaches used in the problem domain. Therefore, efficiently porting, improving or optimizing an evolved design might not be a trivial task. In this work we argue that the same GP principles used to evolve the solution can then be used to optimize a particular new implementation of the design, following the Genetic Improvement approach. In particular, this paper presents a case study where evolved image operators are ported from Matlab to OpenCV, and then the source code is optimized an improved using Genetic Improvement of Software for Multiple Objectives (GISMOE). In the example we show that functional behavior is maintained (output image) while improving non-functional properties (computation time). Despite the fact that this first example is a simple case, it clearly illustrates the possibilities of using GP principles in two distinct stages of the software development process, from design to improved implementation.

The increased vascular tone that defines essential hypertension is associated with depolarization of vascular smooth muscle cells (VSMCs) and involves a change in the expression profile of ion channels promoting arterial contraction. As a major regulator of VSMC resting membrane potential (VM), K+ channel activity is an important determinant of vascular tone and vessel diameter. However, hypertension-associated changes in the expression and/or modulation of K+ channels are poorly defined, due to their large molecular diversity and their bed-specific pattern of expression. Moreover, the impact of these changes on the integrated vessel function and their contribution to the development of altered vascular tone under physiological conditions need to be confirmed. Hypertensive (BPH) and normotensive (BPN) mice strains obtained by phenotypic selection were used to explore whether changes in the functional expression of VSMC inward rectifier K+ channels contribute to the more depolarized resting VM and the increased vascular reactivity of hypertensive arteries. We determined the expression levels of inward rectifier K+ channel mRNA in several vascular beds from BPN and BPH animals, and their functional contribution to VSMC excitability and vascular tone in mesenteric arteries. We found a decrease in the expression of Kir2.1, Kir4.1, Kir6.x and SUR2 mRNA in BPH VSMCs, and a decreased functional contribution of both KIR and KATP channels in isolated BPH VSMCs. However, only the effect of KATP channel modulators was impaired when exploring vascular tone, suggesting that decreased functional expression of KATP channels may be an important element in the remodelling of VSMCs in essential hypertension.