Kaempferol protects against cardiovascular abnormalities induced by nitric oxide deficiency in rats by suppressing the TNF-α pathway.

Kaempferol is a natural flavonoid compound that exhibits various pharmacological actions. However, there are few reports regarding the role of kaempferol in cardiovascular abnormalities. This study aimed to assess whether kaempferol could prevent cardiovascular malfunction and hypertrophy provoked by chronic inhibition of nitric oxide (NO) formation in rats. Rats (180-200 g) were treated daily with Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) (40 mg/kg, in drinking water) for five weeks concomitant with kaempferol (oral administration) at a dose of 20 mg/kg or 40 mg/kg or lisinopril (5 mg/kg). Kaempferol partially prevented the progression of hypertension provoked by NO inhibition (p < 0.05). Left ventricular malfunction and hypertrophy present in hypertensive rats were alleviated by concurrent administration of kaempferol (p < 0.05). Furthermore, L-NAME rats had increased sympathetic nerve-mediated vasoconstriction and decreased acetylcholine-induced vasorelaxation and aortic wall thickening, which were resolved by kaempferol treatment (p < 0.05). Kaempferol restored tissue superoxide formation, malondialdehyde, catalase activity, plasma nitric oxide metabolites, tumor necrosis factor-alpha (TNF-α) and interleukin-6 in L-NAME rats (p < 0.05). Overexpression of tumor necrosis factor receptor 2 (TNFR2), phosphatidylinositol 3-kinases (PI3K), AKT serine/threonine kinase 1 (Akt1) and smad2/3 in heart tissue and upregulation of tumor necrosis factor receptor 1 (TNFR1), phosphorylated nuclear factor-kappaB (p-NF-κB) and transforming growth factor beta 1 (TGF-ß1) in vascular tissue were suppressed by kaempferol (p < 0.05). In conclusion, kaempferol exerts antihypertensive, cardioprotective, antioxidant, and anti-inflammatory effects in NO-dependent hypertensive rats. The underlying mechanisms of kaempferol in preventing cardiovascular changes induced by L-NAME were due to the suppression of the TNF-α pathway.

Complementary Role of Oxytocin and Vasopressin in Cardiovascular Regulation.

The neurons secreting oxytocin (OXY) and vasopressin (AVP) are located mainly in the supraoptic, paraventricular, and suprachiasmatic nucleus of the brain. Oxytocinergic and vasopressinergic projections reach several regions of the brain and the spinal cord. Both peptides are released from axons, soma, and dendrites and modulate the excitability of other neuroregulatory pathways. The synthesis and action of OXY and AVP in the peripheral organs (eye, heart, gastrointestinal system) is being investigated. The secretion of OXY and AVP is influenced by changes in body fluid osmolality, blood volume, blood pressure, hypoxia, and stress. Vasopressin interacts with three subtypes of receptors: V1aR, V1bR, and V2R whereas oxytocin activates its own OXTR and V1aR receptors. AVP and OXY receptors are present in several regions of the brain (cortex, hypothalamus, pons, medulla, and cerebellum) and in the peripheral organs (heart, lungs, carotid bodies, kidneys, adrenal glands, pancreas, gastrointestinal tract, ovaries, uterus, thymus). Hypertension, myocardial infarction, and coexisting factors, such as pain and stress, have a significant impact on the secretion of oxytocin and vasopressin and on the expression of their receptors. The inappropriate regulation of oxytocin and vasopressin secretion during ischemia, hypoxia/hypercapnia, inflammation, pain, and stress may play a significant role in the pathogenesis of cardiovascular diseases.

Peripheral Vascular Abnormalities in Anorexia Nervosa: A Psycho-Neuro-Immune-Metabolic Connection.

Immune, neuroendocrine, and autonomic nervous system dysregulation in anorexia nervosa lead to cardiovascular complications that can potentially result in increased morbidity and mortality. It is suggested that a complex non-invasive assessment of cardiovascular autonomic regulation-cardiac vagal control, sympathetic vascular activity, and cardiovascular reflex control-could represent a promising tool for early diagnosis, personalized therapy, and monitoring of therapeutic interventions in anorexia nervosa particularly at a vulnerable adolescent age. In this view, we recommend to consider in the diagnostic route, at least in the subset of patients with peripheral microvascular symptoms, a nailfold video-capillaroscopy as an easy not invasive tool for the early assessing of possible cardiovascular involvement.

Macrophage Depletion Improves Endothelial Insulin Resistance and Protects against Cardiovascular Injury in Salt-Sensitive Hypertension.

Vascular endothelial insulin signaling is critical for the maintenance of vascular and metabolic homeostasis. We have previously shown that in hypertensive Dahl rats, impaired vascular insulin action is linked to angiotensin II activation of the NFκB inflammatory pathway. Macrophage polarization (M1) has implicated in hypertensive and metabolic diseases. Here, we investigated the effect of macrophage depletion using liposome-encapsulated clodronate (LEC) on endothelial insulin resistance and cardiovascular remodeling in Dahl salt-sensitive (DS) rats. High salt intake (HS) for 5 weeks increased systolic blood pressure (SBP: 192 ± 5 vs. 144 ± 4 mmHg in NS, p < 0.05), aortic and cardiac hypertrophy, cardiac fibrosis, and impaired acetylcholine- and insulin-induced vasorelaxation, accompanied by impaired insulin activation of endothelial nitric oxide synthases (eNOS)/NO signaling. HS rats had a significant increase in CD68 (a monocyte/macrophage marker) expression in the aorta and the heart. LEC reduced SBP (168 ± 5 mmHg, p < 0.05) and cardiovascular injury and improved acetylcholine- and insulin-mediated vasorelaxation and insulin signaling molecules with a reduction in the macrophage infiltration in the aorta and the heart. HS rats also manifested an increase in the aortic expressions of inflammatory cytokines, including the ratio of phosphorylated inhibitory kappa B (Iκb)/Iκb, tumor necrosis factor α, and phosphorylated c-Jun N-terminal kinase (JNK) and oxidative stress, which were reduced in HS/LEC rats. Our results suggest that in salt-sensitive hypertension, macrophage may importantly contribute to endothelial insulin resistance, vascular inflammation, and injury. These findings support the idea that macrophages may be a new target for immunotherapy of vasculopathy in hypertensive and metabolic disorders.

Phenotypic features of ciliary dyskinesia among patients with congenital cardiovascular malformations.

BACKGROUND: Cilia are cell membrane-bound organelles responsible for airway mucus clearance, establishment of left-right organ asymmetry, cardiogenesis, and many other functions in utero. Phenotypic features suggestive of respiratory ciliary dyskinesia among patients with heterotaxy syndrome, defined as complex cardiovascular malformations (CVM) and situs ambiguus (SA), has not been adequately explored. OBJECTIVES: We hypothesized that there is a greater incidence of phenotypic features consistent with ciliary dyskinesia among patients with heterotaxy syndrome compared to patients with other CVM and laterality defects without heterotaxy syndrome. METHODS: Thirty six subjects were identified by medical record search and divided into four groups based on situs status and type of CVM as follows: SA and complex CVM (group 1); SA and simple CVM (group 2); situs solitus and complex CVM (group 3); and situs solitus and simple CVM (group 4). Phenotype was assessed with a clinical questionnaire, nasal nitric oxide (NO) level, and pulmonary function testing. Those with complex CVM underwent additional testing for variants in genes involved in ciliary structure and function. RESULTS: The mean nasal NO level was significantly lower among all subjects with complex CVM regardless of situs anomalies (groups 1 and 3). There was no significant difference in respiratory symptoms or lung function among the four groups. No bi-allelic genetic mutations were detected among patients with complex CVM. CONCLUSIONS: This study identified a relatively lower mean nasal NO level, suggestive of relative ciliary dyskinesia, among subjects with complex CVM. Pulmonary function and clinical symptoms did not reflect significant pulmonary disease among those with complex CVM.

Constitutive activation of the PI3K-AKT pathway and cardiovascular abnormalities in an individual with Kosaki overgrowth syndrome.

Kosaki overgrowth syndrome is a recently described syndrome characterized by distinctive facial features, brain white matter lesions, and developmental delay. Germline activating heterozygous PDGFRB mutations have been reported in this condition. Systemic connective tissue-type findings have been described in some individuals. We describe a 19-year-old Caucasian female with a history of hydrocephalus, Dandy-Walker malformation, cervical spine arachnoid cyst, progressive scoliosis, and overgrowth. Her physical exam included distinctive craniofacial dysmorphism, as well as soft and hyperextensible skin. Cardiovascular imaging during adolescence revealed saccular aneurysms in both coronary artery systems and subtle tortuosity of the cervical vertebral arteries. Exome sequencing trio analysis identified a de novo previously reported pathogenic variant in PDGFRB, c.1696T>C (p.[Trp566Arg]). Further functional studies included platelet-derived growth factor cellular metabolic pathway activity that confirmed the variant causes a constitutive activation of the PI3K-AKT pathway. This is the first report to characterize the activating nature of this PDGFRB variant. We also highlight the connective tissue findings seen in Kosaki overgrowth syndrome and recommend baseline echocardiographic evaluation in all individuals with this condition with particular emphasis on coronary arteries.

Loss of CXCL12/CXCR4 signalling impacts several aspects of cardiovascular development but does not exacerbate Tbx1 haploinsufficiency.

The CXCL12-CXCR4 pathway has crucial roles in stem cell homing and maintenance, neuronal guidance, cancer progression, inflammation, remote-conditioning, cell migration and development. Recently, work in chick suggested that signalling via CXCR4 in neural crest cells (NCCs) has a role in the 22q11.2 deletion syndrome (22q11.2DS), a disorder where haploinsufficiency of the transcription factor TBX1 is responsible for the major structural defects. We tested this idea in mouse models. Our analysis of genes with altered expression in Tbx1 mutant mouse models showed down-regulation of Cxcl12 in pharyngeal surface ectoderm and rostral mesoderm, both tissues with the potential to signal to migrating NCCs. Conditional mutagenesis of Tbx1 in the pharyngeal surface ectoderm is associated with hypo/aplasia of the 4th pharyngeal arch artery (PAA) and interruption of the aortic arch type B (IAA-B), the cardiovascular defect most typical of 22q11.2DS. We therefore analysed constitutive mouse mutants of the ligand (CXCL12) and receptor (CXCR4) components of the pathway, in addition to ectodermal conditionals of Cxcl12 and NCC conditionals of Cxcr4. However, none of these typical 22q11.2DS features were detected in constitutively or conditionally mutant embryos. Instead, duplicated carotid arteries were observed, a phenotype recapitulated in Tie-2Cre (endothelial) conditional knock outs of Cxcr4. Previous studies have demonstrated genetic interaction between signalling pathways and Tbx1 haploinsufficiency e.g. FGF, WNT, SMAD-dependent. We therefore tested for possible epistasis between Tbx1 and the CXCL12 signalling axis by examining Tbx1 and Cxcl12 double heterozygotes as well as Tbx1/Cxcl12/Cxcr4 triple heterozygotes, but failed to identify any exacerbation of the Tbx1 haploinsufficient arch artery phenotype. We conclude that CXCL12 signalling via NCC/CXCR4 has no major role in the genesis of the Tbx1 loss of function phenotype. Instead, the pathway has a distinct effect on remodelling of head vessels and interventricular septation mediated via CXCL12 signalling from the pharyngeal surface ectoderm and second heart field to endothelial cells.

Integrin ß1 activity is required for cardiovascular formation in zebrafish.

Integrins are transmembrane molecules that facilitate cell-to-cell and cell-to-extracellular matrix (ECM) interactions. Integrin molecules are heterodimers that consist of α- and ß-subunits. The integrin ß1 gene is widely expressed in vivo and is the major ß molecule in many tissues; however, tissue-specific roles of integrin ß1 are still elusive. In this study, we investigated integrin ß1 function in endothelial cells of zebrafish. An integrin ß1b mutant zebrafish exhibited morphological abnormalities in blood vessel formation, cephalic hemorrhage and a decreased responsiveness to tactile stimulation during development. To determine the role of integrin ß1b in vascular formation, we developed a Gal4/UAS-mediated conditional inactivation of integrin ß1 by expressing the cytoplasmic region of integrin ß1 that acts as a dominant-negative (DN) isoform. Expression of integrin ß1 DN in endothelial cells induced blood vessel abnormalities as in integrin ß1b mutants. These results show that endothelial cells require integrin activity for the formation and/or maintenance of blood vessels in zebrafish. Furthermore, our time-lapse recording visualized the breakpoint of cephalic vessels and the hemorrhage onset. Taken together, our tissue-specific inactivation of integrin ß1 in zebrafish is powerful tools for functional analysis of integrin ß1 in developing tissues.

Single Nucleotide Polymorphisms in the G-Protein Coupled Receptor Kinase 5 (GRK5) Gene are associated with Plasma LDL-Cholesterol Levels in Humans.

Genetically modified mice models suggest an important role for G-protein-coupled receptor kinase 5 (GRK5) in the pathophysiology of obesity and related disorders. We investigated whether single nucleotide polymorphisms (SNPs) in the gene encoding GRK5 affect cardiometabolic traits in humans. We genotyped 3 common SNPs in intron 1 (rs1980030, rs10466210, rs9325562) and one SNP in intron 3 (rs10886471) of GRK5 in 2332 subjects at risk for type 2 diabetes. Total- and visceral fat mass were measured by magnetic resonance (MR) tomography and liver fat content by 1H-MR spectroscopy. Insulin secretion and sensitivity were estimated during an OGTT and measured during the euglycemic, hyperinsulinemic clamp (n = 498). Carriers of the minor allele of rs10466210 and rs1980030 had higher total- and LDL-cholesterol levels (p = 0.0018 and p = 0.0031, respectively, for rs10466210; p = 0.0035 and p = 0.0081, respectively, for rs1980030), independently of gender, age, BMI and lipid-lowering drugs. The effects of rs10466210 withstood Bonferroni correction. Similar associations were observed with apolipoprotein B levels (p = 0.0034 and p = 0.0122, respectively). Carriers of the minor allele of rs10466210 additionally displayed a trend for higher intima-media thickness of the carotid artery (p = 0.075). GRK5 may represent a novel target for strategies aiming at lowering LDL-cholesterol levels and at modifying cardiovascular risk.

Sirenomelia: A Multi-systemic Polytopic Field Defect with Ongoing Controversies.

The most impressive phenotypic appearance of sirenomelia is the presence of a 180°-rotated, axially positioned, single lower limb. Associated gastrointestinal and genitourinary anomalies are almost always present. This rare anomaly is still the subject of ongoing controversies concerning its nosology, pathogenesis, and possible genetic etiology. Sirenomelia can be part of a syndromic continuum, overlapping with other complex conditions including caudal dysgenesis and VATER/VACTERL/VACTERL-H associations, which could all be part of a heterogeneous spectrum, and originate from an early defect in blastogenesis. It is imaginable that different "primary field defects," whether or not genetically based, induce a spectrum of caudal malformations. In the current study, we review the contemporary hypotheses and conceptual approaches regarding the etiology and pathogenesis of sirenomelia, especially in the context of concomitant conditions. To expand on the latter, we included the external and internal dysmorphology of one third trimester sirenomelic fetus from our anatomical museum collection, in which multiple concomitant but discordant anomalies were observed compared with classic sirenomelia, and was diagnosed as VACTERL-H association with sirenomelia. Birth Defects Research 109:791-804, 2017. © 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc.

Reduced dosage of ß-catenin provides significant rescue of cardiac outflow tract anomalies in a Tbx1 conditional null mouse model of 22q11.2 deletion syndrome.

The 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome; DiGeorge syndrome) is a congenital anomaly disorder in which haploinsufficiency of TBX1, encoding a T-box transcription factor, is the major candidate for cardiac outflow tract (OFT) malformations. Inactivation of Tbx1 in the anterior heart field (AHF) mesoderm in the mouse results in premature expression of pro-differentiation genes and a persistent truncus arteriosus (PTA) in which septation does not form between the aorta and pulmonary trunk. Canonical Wnt/ß-catenin has major roles in cardiac OFT development that may act upstream of Tbx1. Consistent with an antagonistic relationship, we found the opposite gene expression changes occurred in the AHF in ß-catenin loss of function embryos compared to Tbx1 loss of function embryos, providing an opportunity to test for genetic rescue. When both alleles of Tbx1 and one allele of ß-catenin were inactivated in the Mef2c-AHF-Cre domain, 61% of them (n = 34) showed partial or complete rescue of the PTA defect. Upregulated genes that were oppositely changed in expression in individual mutant embryos were normalized in significantly rescued embryos. Further, ß-catenin was increased in expression when Tbx1 was inactivated, suggesting that there may be a negative feedback loop between canonical Wnt and Tbx1 in the AHF to allow the formation of the OFT. We suggest that alteration of this balance may contribute to variable expressivity in 22q11.2DS.

Glyphosate induces cardiovascular toxicity in Danio rerio.

Glyphosate is a broad spectrum herbicide used aggressively in agricultural practices as well as home garden care. Although labeled "safe" by the chemical industry, doses tested by industry do not mimic chronic exposures to sublethal doses that organisms in the environment are exposed to over long periods of time. Given the widespread uses of and exposure to glyphosate, studies on developmental toxicity are needed. Here we utilize the zebrafish vertebrate model system to study early effects of glyphosate on the developing heart. Treatment by embryo soaking with 50µg/ml glyphosate starting at gastrulation results in structural abnormalities in the atrium and ventricle, irregular heart looping, situs inversus as well as decreased heartbeats by 48h as determined by live imaging and immunohistochemistry. Vasculature in the body was also affected as determined using fli-1 transgenic embryos. To determine if the effects noted at 48h post fertilization are due to early stage alterations in myocardial precursors, we also investigate cardiomyocyte development with a Mef2 antibody and by mef2ca in situ hybridization and find alterations in the Mef2/mef2ca staining patterns during early cardiac patterning stages. We conclude that glyphosate is developmentally toxic to the zebrafish heart.

Especificaciones del servicio de medición y control de la presión arterial mediante MAFC, AMPA y MAPA / Specifications of the arterial pressure measurement and testing service using one-off measurement in community pharmacies, arterial pressure self-measurement and outpatient arterial pressure monitoring

En abril de 2013, la Sociedad Española de Farmacia Familiar y Comunitaria (SEFAC) presentó su propuesta sobre servicios profesionales farmacéuticos (SPF) cuyo fin es cubrir las necesidades relacionadas tanto con la atención de los pacientes que utilizan medicamentos, como con la salud pública. Esta propuesta ofrece un planteamiento sobre la implantación y desarrollo de los SPF con el objetivo de impulsar su prestación por las farmacias comunitarias en los próximos años. De acuerdo con dicha propuesta todos los SPF que constituyen el catálogo de servicios contarán con un documento de especificaciones. El objeto de este documento de especificaciones es definir y caracterizar el servicio de medición y control de la presión arterial con un doble objeto: • Ayudar al farmacéutico comunitario y a sus representantes en el ofrecimiento, prestación, difusión, financiación y concertación de este servicio. • Servir de guía a los farmacéuticos comunitarios que desean implantar este servicio en la farmacia o elaborar un procedimiento normalizado de trabajo para su realización. Este documento se complementa con la Guía de actuación para el farmacéutico comunitario en pacientes con HTA y riesgo cardiovascular (RCV). Documento de consenso GIAF-UGR, SEFAC y SEH-LELHA y con el programa impacHta: formación de SEFAC y SEH-LELHA en hipertensión y riesgo vascular (AU)

In April 2013, the Spanish Family and Community Pharmacy Society (Sociedad Española de Farmacia Familiar y Comunitaria - SEFAC) issued a proposal for professional pharmacy services, with an aim to cover both the needs relating to care for patients on medication and to public health. This proposal put forward an approach for the implementation and development of professional pharmacy services with an aim to roll out this service in community pharmacies in the next few years. In accordance with this proposal, all professional pharmacy services that offer these services will be supported by a specifications document. The purpose of this specifications document is to define and characterize the arterial pressure measurement and testing service with two aims: • To help community pharmacists and their representatives in the offer, provision, promotion, financing and arrangement of this service. • To serve as a guide for community pharmacists who want to implement this service in the pharmacy or to provide a standardized working procedure to do so. This document is accompanied by the procedural guide for community pharmacists for patients with arterial hypertension and cardiovascular risk (Guía de actuación para el farmacéutico comunitario en pacientes con HTA y riesgo cardiovascular (RCV)). Consensus document of GIAF-UGR, SEFAC and SEH-LELHA and the impacHta program: SEFAC and SEH-LELHA training in hypertension and vascular risk (AU)

Ateroembolia de colesterol / Cholesterol atheroembolism

La ateroembolia de colesterol (AEC) es una enfermedad sistémica poco conocida y con un pronóstico sombrío. En estas últimas décadas, su incidencia ha aumentado considerablemente. El diagnóstico es difícil y parte de una alta sospecha clínica, dada la inespecificidad de sus síntomas y el frecuente inicio tardío, semanas después de haber estado expuesto a factores predisponentes (procedimientos endovasculares, tratamiento anticoagulante). Se confirma por la biopsia del órgano afectado. A continuación presentamos un caso clínico de una paciente con AEC de origen espontáneo que presentaba manifestaciones cutáneas, donde la sospecha clínica de esta enfermedad fue la clave para su diagnóstico y un temprano manejo terapéutico (AU)

Cholesterol atheroembolism (CAE) is a rarely known systemic disease with bad prognosis. In the last decades, the incidence of this disorder has increased considerably. The diagnosis is difficult and starts with a clinical suspicion, given the lack of specific symptoms and the frequent late onset during the weeks after exposure of the patient to predisposing factors (angiographic procedures or anticoagulant treatments). It is confirmed by biopsy of the affected organ. Below we report the case of a patient with spontaneous CAE who presented skin manifestations, where clinical suspicion of this disease was the key to diagnosis and early therapeutic management (AU)

p21-Activated Kinase 2 Regulates Endothelial Development and Function through the Bmk1/Erk5 Pathway.

p21-activated kinases (Paks) have been shown to regulate cytoskeleton rearrangements, cell proliferation, attachment, and migration in a variety of cellular contexts, including endothelial cells. However, the role of endothelial Pak in embryo development has not been reported, and currently, there is no consensus on the endothelial function of individual Pak isoforms, in particular p21-activated kinase 2 (Pak2), the main Pak isoform expressed in endothelial cells. In this work, we employ genetic and molecular studies that show that Pak2, but not Pak1, is a critical mediator of development and maintenance of endothelial cell function. Endothelial depletion of Pak2 leads to early embryo lethality due to flawed blood vessel formation in the embryo body and yolk sac. In adult endothelial cells, Pak2 depletion leads to severe apoptosis and acute angiogenesis defects, and in adult mice, endothelial Pak2 deletion leads to increased vascular permeability. Furthermore, ubiquitous Pak2 deletion is lethal in adult mice. We show that many of these defects are mediated through a newly unveiled Pak2/Bmk1 pathway. Our results demonstrate that endothelial Pak2 is essential during embryogenesis and also for adult blood vessel maintenance, and they also pinpoint the Bmk1/Erk5 pathway as a critical mediator of endothelial Pak2 signaling.

Diabetes mellitus y riesgo cardiovascular: recomendaciones del Grupo de Trabajo Diabetes y Enfermedad Cardiovascular de la Sociedad Española de Diabetes (SED, 2015) / Diabetes mellitus and cardiovascular risk: Working group recommendations of Diabetes and Cardiovascular Disease of the Spanish Society of Diabetes (SED, 2015)

El presente documento actualiza las recomendaciones de práctica clínica del manejo de los factores de riesgo cardiovascular (FRCV) en la diabetes mellitus (DM). Es un consenso médico realizado por un panel de expertos independiente de la Sociedad Española de Diabetes (SED). Se han propuesto y actualizado varios consensos de diferentes sociedades científicas o médicas con el fin de mejorar los resultados terapéuticos. La valoración del RCV en la población general puede carecer de sensibilidad para la evaluación individual en determinados grupos de riesgo como los diabéticos. Se revisan los factores de riesgo tradicionales y no tradicionales, así como las estrategias de intervención para el control de los FRCV en los pacientes diabéticos como la dieta, el control ponderal, el ejercicio físico, los hábitos tóxicos, el control glucémico, tensional y lipídico, así como la antiagregación plaquetaria. Confiamos en que estas pautas ayuden a los médicos en la toma de decisiones en su actividad asistencial. Se expone una actualización de los conceptos más relevantes y de mayor interés clínico-práctico y, a su vez realista, para reducir el RCV de los diabéticos como se venía haciendo regularmente por parte del Grupo de Enfermedad Cardiovascular de la SED

The present paper updates the Clinical Practice Recommendations for the management of cardiovascular risk factors (CVRF) in diabetes mellitus. This is a medical consensus agreed by an independent panel of experts from the Spanish Society of Diabetes (SED). Several consensuses have been proposed by scientific and medical Societies to achieve clinical goals. However, the risk score for general population may lack sensitivity for individual assessment or for particular groups at risk, such as diabetics. Traditional risk factors together with non-traditional factors are reviewed throughout this paper. Intervention strategies for managing CVRF in the diabetic patient are reviewed in detail: balanced food intake, weight reduction, physical exercise, smoking cessation, reduction in HbA1c, therapy for high blood pressure, obesity, lipid disorders, and platelet anti-aggregation. It is hoped that these guidelines can help clinicians in the decisions of their clinical activity. This regular update by the SED Cardiovascular Disease Group of the most relevant concepts, and of greater practical and realistic clinical interest, is presented in order to reduce CVR of diabetics

Claves para avanzar hacia un rol más activo por parte del paciente con diabetes mellitus tipo 2 en España / Key aspects to moving towards a more active role for the patient with diabetes mellitus type 2 in Spain

OBJETIVOS: La diabetes mellitus tipo 2 (DM2) es un problema de salud pública de primer orden que preocupa a gestores, a profesionales sanitarios y a la sociedad en su conjunto. Contar con un paciente con DM2 más activo y responsable con su salud se perfila como una de las soluciones. Por ello la importancia de impulsar un debate multidisciplinar que aporte ideas y soluciones que contribuyan a conseguir un paciente con DM2 involucrado en su salud. En este artículo se presentan una serie de recomendaciones consensuadas por el Grupo Paciente Activo y Diabetes (PAyDInet). MATERIAL Y MÉTODOS: Se constituyó el grupo de trabajo PAyDInet, en el que participaron diferentes agentes del sistema. Siguiendo la técnica de grupo nominal, se identificaron y priorizaron las barreras, los elementos facilitadores así como iniciativas concretas que fomenten una actitud preventiva y de autocuidado en el paciente con DM2. RESULTADOS: El grupo llegó a un consenso sobre las 3 barreras, 3 elementos facilitadores y 3 iniciativas clave en la consecución de un paciente con DM2 más activo en el manejo de su enfermedad. La configuración actual del sistema sanitario, la necesidad de mejorar la coordinación interprofesional y el desarrollo de la educación diabetológica estructurada constituyen los puntos esenciales identificados por el grupo. CONCLUSIÓN: Es una necesidad ineludible seguir avanzando para situar al paciente como centro del sistema. Un paciente formado e informado en DM2 es una tarea compleja que solo se logrará con nuevas alianzas y la colaboración de todos los agentes. En cualquier caso, el debate y las recomendaciones del grupo PAyDInet aportan una buena aproximación al tema y un excelente punto de partida

OBJECTIVES: Diabetes mellitus type 2 (DM2) is a public health problem of the first order of concern to managers, health professionals and society as a whole. Having a more active and responsible patient with DM2 is emerging as one of the solutions. Hence the importance of promoting a multidisciplinary discussion that provides ideas and solutions that contribute to an active and involved patient with DM2. In this article some consensual recommendations are provided by the working group called Active Patient and Diabetes(PAyDInet by its Spanish initials). METHODS: PAyDInet team was established by gathering agents from different fields of the system. Following the nominal group technique, barriers, facilitators and specific initiatives to promote a preventive attitude and self-care in patients with DM2, were identified and prioritized. RESULTS: The team reached a final consensus on 3 key barriers, 3 enablers and 3 key initiatives to achieve patients with DM2 more active in managing their disease. The configuration of the healthcare system, the need to improve interprofessional coordination, and development of structured diabetes education, are the key points identified by the group. CONCLUSION: It is an inescapable need to move forward to put the patient at the centre of the system. Training and informing a patient on DM2 is a complex task that can only be achieved with new partnerships and collaboration of all stakeholders. In any case, the discussion and recommendations of the group PAyDInet give us a good approach to the subject and an excellent starting point

Requirement of DLG1 for cardiovascular development and tissue elongation during cochlear, enteric, and skeletal development: possible role in convergent extension.

The Dlg1 gene encodes a member of the MAGUK protein family involved in the polarization of epithelial cells. Null mutant mice for the Dlg1 gene (Dlg1-/- mice) exhibit respiratory failure and cyanosis, and die soon after birth. However, the cause of this neonatal lethality has not been determined. In the present study, we further examined Dlg1-/- mice and found severe defects in the cardiovascular system, including ventricular septal defect, persistent truncus arteriosus, and double outlet right ventricle, which would cause the neonatal lethality. These cardiovascular phenotypes resemble those of mutant mice lacking planar cell polarity (PCP) genes and support a recent notion that DLG1 is involved in the PCP pathway. We assessed the degree of involvement of DLG1 in the development of other organs, as the cochlea, intestine, and skeleton, in which PCP signaling has been suggested to play a role. In the organ of Corti, tissue elongation was inhibited accompanied by disorganized arrangement of the hair cell rows, while the orientation of the stereocilia bundle was normal. In the sternum, cleft sternum, abnormal calcification pattern of cartilage, and disorganization of chondrocytes were observed. Furthermore, shortening of the intestine, sternum, and long bones of the limbs was observed. These phenotypes of Dlg1-/- mice involving cellular disorganization and insufficient tissue elongation strongly suggest a defect in the convergent extension movements in these mice. Thus, our present results provide a possibility that DLG1 is particularly required for convergent extension among PCP signaling-dependent processes.

Activin-A in diabetes-induced cardiac malformations in embryos.

BACKGROUND: Heart defects are the most common abnormalities in infants of diabetic mothers. Cardiac malformation is associated with altered expression of the genes in the transforming growth factor ß system, including inhibin ßA, which forms activin-A as a homodimer and functions through its effectors, Smad2 and Smad3. This study aimed to investigate the role of activin-A in diabetes-induced cardiac malformations. METHODS: Diabetes mellitus in female mice (C57BL/6J) was induced via intravenous injection of streptozotocin. The expression of inhibin ßA protein and phosphorylation of Smad2 and Smad3 in the embryonic hearts were examined using immunohistochemical, in situ proximity ligation, and immunoblot assays. Embryos and endocardial cushions of nondiabetic mice were cultured in a high concentration of glucose and treated with activin-A. Mitosis was examined using BrdU incorporation assay and immunohistochemistry of phosphorylated histone H3. Migration of the endocardial cells was assessed using a collagen-based cell migration assay. RESULTS: The levels of inhibin ßA expression and Smad2 and Smad3 activation were significantly reduced by maternal diabetes. Treatment with activin-A significantly increased cell proliferation in the myocardium and migration of endocardial cells, compared with those in vehicle-treated high glucose group, to the level in the euglycemic control group. CONCLUSIONS: Maternal diabetes suppresses the expression of inhibin ßA protein, as well as the activation of Smad2 and Smad3. Activin-A rescues cell proliferation in the myocardium and migration of the endocardial cells suppressed by hyperglycemia. The activin-Smad2/3 signaling system appears to play a role in cardiac malformation in diabetic embryopathy.

Polymorphisms in folate-metabolizing genes and risk of having an offspring with congenital anomalies in the West Siberian region of Russia: a case-control study.

OBJECTIVE: Periconceptional folate supplementation prevents a number of congenital anomalies (CA). The aim of our study was to investigate the association of 11 polymorphisms in the folate-metabolizing genes with the risk of having an offspring with CA in the Russian ethnic group. METHOD: We genotyped 280 mothers having a CA-affected pregnancy and 390 control mothers. The most common malformations among the cases were CA of the nervous, urinary, and cardiovascular systems, and these groups were analyzed separately. RESULTS: In the whole group of CA, we revealed the associations of MTHFR C677T and MTR A2756G loci with increased risk of CA-affected pregnancy. In the group of CA of the cardiovascular system, we observed an association of MTHFR A1298C with decreased risk and an association of MTR A2756G with increased risk of CA. After the Bonferroni correction, only the association between the genotype MTR 2756GG and the risk of having a fetus with CA of the cardiovascular system remained statistically significant (OR = 4.99, P = 0.03). CONCLUSION: These findings indicate that locus A2756G in the MTR gene may play a role in susceptibility to CA of the cardiovascular system in West Siberia, but further research is necessary to confirm the association.