Functional structure of a high resolution thyroid nodule unit. Economic impact and results of its implementation in an Endocrinology department.

BACKGROUND AND OBJECTIVE: The high incidence of nodular thyroid pathology has led to growing concern about the economic impact that this pathology represents on the healthcare system. There are conclusive data about the cost-effectiveness of high-resolution units for nodular thyroid pathology; however, their implementation is not homogeneous in the Endocrinology and Nutrition services of our country. The objective of the present study was to evaluate the economic impact of the implementation of the high-resolution thyroid nodule unit (HRTNU) in our center. PATIENTS AND METHODS: The present work is a prospective, observational and descriptive study carried out in 1314 patients (82% women, mean age 58 years ds = 11) evaluated at the HRTNU during the period of August 2022-August 2023. Demographic data (age and sex) were analyzed, referral center and consultation type, number of total consultations and neck ultrasound performed, number of fine needle aspiration (FNAB) performed, and cytology results were analyzed. RESULTS: In the period from August 2022 to August 2023, a total of 1314 patients were evaluated (neck ultrasound and clinical consultation) and a total of 133 FNAB were performed, of which only 2.26% were non-diagnostic. Compared to the percentage of unsatisfactory FNAB from the previous year August 2021-July 2022 of 25%, a mean saving of 9931.43 euros was estimated. 84.47% of the patients evaluated for the first time by the HRTNU were discharged, estimating a mean saving of 133,200 euros. CONCLUSIONS: The implementation of a HRTNU at the Endocrinology and Nutrition departments, coordinated with primary and specialized care, is a cost-effectiveness alternative, as it reduces the number of medical consultations and is accompanied by a higher rate of diagnostic FNAB.

Treatment with 1.25% cholesterol enriched diet produces severe fatty liver disease characterized by advanced fibrosis and inflammation and impaired autophagy in mice.

Non-alcoholic fatty liver disease (NAFLD) is reaching pandemic proportions due to overnutrition. The understanding of advanced stages that recapitulate the human pathology is of great importance to get a better mechanistic insight. We hypothesized that feeding of WT (C57BL) mice with a diet containing a high content of fat (21%), sugar (41.5%) and 1.25% of cholesterol (called from now on high fat, sucrose and cholesterol diet, HFSCD) will reproduce the characteristics of disease severity. Analysis of 16 weeks HFSCD-fed mice demonstrated increased liver weight and plasmatic liver damage markers compared with control diet (CD)-fed mice. HFSCD-fed mice developed greater hepatic triglyceride, cholesterol and NEFA content, inflammation and NAFLD activity score (NAS) indicating an advanced disease. HFSCD-fed mice displayed augmented hepatic total CD3+ T and Th9 lymphocytes, as well as reduced Th2 lymphocytes and CD206 anti-inflammatory macrophages. Moreover, T cells and anti-inflammatory macrophages correlated positively and inversely, respectively, with intrahepatic cholesterol content. Consistently, circulating cytotoxic CD8+ T lymphocytes, Th1, and B cell levels were elevated in HFSCD-fed WT mice. Hepatic and adipose tissue expression analysis demonstrated changes in fibrotic and metabolic genes related with cholesterol, triglycerides, and fatty acid synthesis in HFSCD-fed WT. These mice also exhibited reduced antioxidant capacity and autophagy and elevated ERK signaling pathway activation and CHOP levels. Our results indicate that the feeding with a cholesterol-enriched diet in WT mice produces an advanced NAFLD stage with fibrosis, characterized by deficient autophagy and ER stress along with inflammasome activation partially via ERK pathway activation.

Machine Learning Model in Obesity to Predict Weight Loss One Year after Bariatric Surgery: A Pilot Study.

Roux-en-Y gastric bypass (RYGB) is a treatment for severe obesity. However, many patients have insufficient total weight loss (TWL) after RYGB. Although multiple factors have been involved, their influence is incompletely known. The aim of this exploratory study was to evaluate the feasibility and reliability of the use of machine learning (ML) techniques to estimate the success in weight loss after RYGP, based on clinical, anthropometric and biochemical data, in order to identify morbidly obese patients with poor weight responses. We retrospectively analyzed 118 patients, who underwent RYGB at the Hospital Clínico Universitario of Valencia (Spain) between 2013 and 2017. We applied a ML approach using local linear embedding (LLE) as a tool for the evaluation and classification of the main parameters in conjunction with evolutionary algorithms for the optimization and adjustment of the parameter model. The variables associated with one-year postoperative %TWL were obstructive sleep apnea, osteoarthritis, insulin treatment, preoperative weight, insulin resistance index, apolipoprotein A, uric acid, complement component 3, and vitamin B12. The model correctly classified 71.4% of subjects with TWL < 30% although 36.4% with TWL ≥ 30% were incorrectly classified as "unsuccessful procedures". The ML-model processed moderate discriminatory precision in the validation set. Thus, in severe obesity, ML-models can be useful to assist in the selection of patients before bariatric surgery.

New Perspectives for Low Muscle Mass Quantity/Quality Assessment in Probable Sarcopenic Older Adults: An Exploratory Analysis Study.

BACKGROUND: Low muscle mass quantity/quality is needed to confirm sarcopenia diagnosis; however, no validated cut-off points exist. This study aimed to determine the diagnostic accuracy of sarcopenia through muscle mass quantity/quality parameters, using the bioimpedance analysis (BIA), isokinetic, and ultrasound tools in probable sarcopenic community-dwelling older adults (≥60 years). Also, it aimed to suggest possible new cut-off points to confirm sarcopenia diagnosis. METHODS: A cross-sectional exploratory analysis study was performed with probable sarcopenic and non-sarcopenic older adults. BIA, isokinetic, and ultrasound parameters were evaluated. The protocol was registered on ClinicalTrials.gov (NCT05485402). RESULTS: A total of 50 individuals were included, 38 with probable sarcopenia (69.63 ± 4.14 years; 7 men and 31 women) and 12 non-sarcopenic (67.58 ± 4.54 years; 7 men and 5 women). The phase angle (cut-off: 5.10° men, p = 0.003; 4.95° women, p < 0.001), peak torque (cut-off: 66.75 Newtons-meters (N-m) men, p < 0.001; 48.35 N-m women, p < 0.001), total work (cut-off: 64.00 Joules (J) men, p = 0.007; 54.70 J women, p = 0.001), and mean power (cut-off: 87.8 Watts (W) men, p = 0.003; 48.95 W women, p = 0.008) in leg extension, as well as the the forearm muscle thickness (cut-off: 1.41 cm (cm) men, p = 0.017; 0.94 cm women, p = 0.041), had great diagnostic accuracy in both sexes. CONCLUSIONS: The phase angle, peak torque, total work, and mean power in leg extension, as well as forearm muscle thickness, had great diagnostic accuracy in regard to sarcopenia, and the suggested cut-off points could lead to the confirmation of sarcopenia diagnosis, but more studies are needed to confirm this.

Prevención cardiovascular en la diabetes mellitus. ¿Es adecuado hablar de riesgo moderado o intermedio? / Cardiovascular prevention in diabetes mellitus. Is it appropriate to speak of moderate or intermediate risk?

La diabetes, especialmente la tipo 2, está considerada como una situación de riesgo de enfermedad cardiovascular aterosclerosa (ECVA). Los sujetos con diabetes tipo 2 tienen una mortalidad por ECVA 3 veces superior a la de la población general, atribuida a la hiperglucemia y a la frecuente asociación de otros factores de riesgo cardiovascular, como la dislipidemia aterogénica. Numerosas sociedades científicas han establecido una clasificación de riesgo de ECVA en la diabetes basada en 3 grados (moderado, alto y muy alto). Los objetivos del control de la dislipidemia están claramente definidos y aceptados, y varían dependiendo del riesgo cardiovascular previamente establecido. En el riesgo moderado o intermedio, las guías proponen una intervención menos intensiva, manteniendo cifras de c-LDL<100mg/dL y de c-no-HDL<130mg/dL, y esperar 10 años hasta alcanzar la categoría de alto riesgo para iniciar un tratamiento más intensivo. Sin embargo, durante la década de seguimiento preconizada en las guías, el depósito de colesterol en la pared arterial va aumentando, facilitando el desarrollo de una placa de ateroma inestable e inflamatoria, y el desarrollo de ECVA. Alternativamente, se podría considerar desde el inicio que la diabetes conlleva una situación de alto riesgo y el objetivo debería ser c-LDL<70mg/dL. Además, mantener cifras de c-LDL<70mg/dL contribuye a reducir y estabilizar la placa de ateroma, evitando o disminuyendo episodios de mortalidad por ECVA durante esos años de evolución de la diabetes. ¿Deberíamos mantener los objetivos propuestos en los sujetos con diabetes y riesgo moderado durante una década hasta alcanzar la fase de alto riesgo cardiovascular o, por el contrario, adoptar desde el inicio una postura más intensiva buscando reducir el riesgo cardiovascular en la mayoría de los pacientes con diabetes? ¿Es mejor esperar o prevenir con medidas terapéuticas efectivas desde el primer momento? (AU)

Diabetes, especially type 2, is considered a risk situation for atherosclerotic cardiovascular disease (ASCVD). Subjects with diabetes type 2 have a mortality rate due to ASCVD 3 times higher than that found in the general population, attributed to hyperglycemia and the frequent association of other cardiovascular risk factors, such as atherogenic dyslipidemia. Numerous scientific societies have established a risk classification for ASCVD in diabetes based on 3 degrees (moderate, high and very high). The objectives of dyslipidemia control are clearly defined and accepted, and vary depending on the previously established cardiovascular risk. In moderate or intermediate risk, the guidelines propose a less intensive intervention, maintaining LDL-C levels<100mg/dL and NO-HDL-C levels<130mg/dL, and waiting 10 years until reaching the high-risk category to initiate more intensive treatment. However, during the decade of follow-up recommended in the guidelines, cholesterol deposition in the arterial wall increases, facilitating the development of an unstable and inflammatory atheromatous plaque, and the development of ASCVD. Alternatively, diabetes could be considered from the outset to be a high-risk situation and the goal should be LDL-C<70mg/dL. Furthermore, maintaining LDL-C levels<70mg/dL contributes to reducing and stabilizing atheromatous plaque, avoiding or reducing mortality episodes due to ASCVD during those years of diabetes evolution. Should we maintain the proposed objectives in subjects with diabetes and moderate risk for a decade until reaching the high cardiovascular risk phase or, on the contrary, should we adopt a more intensive stance from the beginning seeking to reduce cardiovascular risk in the majority of patients with diabetes? Is it better to wait or prevent with effective therapeutic measures from the first moment? (AU)

SEA 2024 Standards for Global Control of Vascular Risk. / Estándares de la Sociedad Española de Arteriosclerosis 2024 para el control global del riesgo vascular.

One of the objectives of the Spanish Society of Arteriosclerosis is to contribute to the knowledge, prevention and treatment of vascular diseases, which are the leading cause of death in Spain and entail a high degree of disability and health expenditure. Atherosclerosis is a multifactorial disease and its prevention requires a global approach that takes into account the associated risk factors. This document summarises the current evidence and includes recommendations for patients with established vascular disease or at high vascular risk: it reviews the symptoms and signs to evaluate, the laboratory and imaging procedures to request routinely or in special situations, and includes the estimation of vascular risk, diagnostic criteria for entities that are vascular risk factors, and general and specific recommendations for their treatment. Finally, it presents aspects that are not usually referenced in the literature, such as the organisation of a vascular risk consultation.

Improved lipid-lowering treatment and reduction in cardiovascular disease burden in homozygous familial hypercholesterolemia: The SAFEHEART follow-up study.

AIM: We aimed to describe clinical and genetic characteristics, lipid-lowering treatment and atherosclerotic cardiovascular disease (ASCVD) outcomes over a long-term follow-up in homozygous familial hypercholesterolemia (HoFH). METHODS: SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) is a long-term study in molecularly diagnosed FH. Data analyzed in HoFH were prospectively obtained from 2004 until 2022. ASCVD events, lipid profile and lipid-lowering treatment were determined. RESULTS: Thirty-nine HoFH patients were analyzed. The mean age was 42 ± 20 years and nineteen (49%) were women. Median follow-up was 11 years (IQR 6,18). Median age at genetic diagnosis was 24 years (IQR 8,42). At enrolment, 33% had ASCVD and 18% had aortic valve disease. Patients with new ASCVD events and aortic valve disease at follow-up were six (15%), and one (3%), respectively. Median untreated LDL-C levels were 555 mg/dL (IQ 413,800), and median LDL-C levels at last follow-up was 122 mg/dL (IQR 91,172). Most patients (92%) were on high intensity statins and ezetimibe, 28% with PCSK9i, 26% with lomitapide, and 23% with lipoprotein-apheresis. Fourteen patients (36%) attained an LDL-C level below 100 mg/dL, and 10% attained an LDL-C below 70 mg/dL in secondary prevention. Patients with null/null variants were youngers, had higher untreated LDL-C and had the first ASCVD event earlier. Free-event survival is longer in patients with defective variant compared with those patients with at least one null variant (p=0.02). CONCLUSIONS: HoFH is a severe life threating disease with a high genetic and phenotypic variability. The improvement in lipid-lowering treatment and LDL-C levels have contributed to reduce ASCVD events.

Light deficiency in Apoe-/-mice increases atheroma plaque size and vulnerability by modulating local immunity.

Previous research suggests a potential involvement of the cytokine LIGHT (TNFSF14) in atherosclerosis. In this study, the genetic inactivation of Light in Apolipoprotein E deficient mice (male and female C57BL) augmented plaque size and vulnerability while decreasing Treg cells. Human and mouse transcriptomic results demonstrated deranged immune pathways in human atheromas with low LIGHT expression levels and in Light-deficient murine atheromas. In agreement with this, in vitro LIGHT-treatment of human lymphocytes, induced an elevation of Treg cell prevalence while proteomic analysis showed a downregulation of apoptotic and leukocyte cytotoxic pathways. Consistently, Light-deficient mouse lesions displayed increased plaque apoptosis and detrimental adventitial T-lymphocyte aggregates. Altogether suggested that LIGHT could promote a Treg prevalence in the local immunity to prevent the generation of vulnerable plaques via decreased cytotoxic microenvironment and apoptosis. Light gene delivery in Apoe-/-Light-/- mice, through bone marrow transplantation approaches, consistently diminished lesion size and restored local plaque immunity. Altogether demonstrate that Light-deficiency promotes atheroma plaque progression, at least in part through local loss of immune homeostasis and increased apoptosis. This study suggest that therapies based on the local delivery of LIGHT within plaques might therefore prevent immune cell derangement and advanced atherosclerosis.

Association of carotid atheroma plaque with IL-18 levels and with polymorphisms in the IL-18 receptor gene in a Mediterranean population. / Asociación de la placa de ateroma carotídea con los niveles plasmáticos de IL-18 y con polimorfismos en el gen del receptor de la IL-18 en la población mediterránea.

BACKGROUND: Atherosclerosis is an inflammatory disease. Interleukin 18 (IL-18) is an inflammatory molecule that has been linked to the development of atherosclerosis and cardiovascular disease. OBJECTIVE: To evaluate the possible relationship between plasma levels of IL-18 and the presence of atherosclerosis evaluated at the carotid level, as well as to analyze the possible modulation by different polymorphisms in a Mediterranean population. MATERIAL AND METHODS: Seven hundred and forty-six individuals from the metropolitan area of Valencia were included, recruited over a period of 2 years. Hydrocarbon and lipid metabolism parameters were determined using standard methodology and IL-18 using ELISA. In addition, carotid ultrasound was performed and the genotype of four SNPs related to the IL-18 signaling pathway was analyzed. RESULTS: Patients with higher plasma levels of IL-18 had other associated cardiovascular risk factors. Elevated IL-18 levels were significantly associated with higher carotid IMT and the presence of atheromatous plaques. The genotype with the A allele of the SNP rs2287037 was associated with a higher prevalence of carotid atheromatous plaque. On the contrary, the genotype with the C allele of the SNP rs2293224 was associated with a lower prevalence of atheromatous plaque. CONCLUSIONS: High levels of IL-18 were significantly associated with a higher carotid IMT and the presence of atheromatous plaques, which appear to be influenced by genetic factors, as evidenced by associations between SNPs in the IL-18 receptor gene and the presence of atheroma plaque.

Cardiovascular prevention in diabetes mellitus. Is it appropriate to speak of moderate or intermediate risk? / Prevención cardiovascular en la diabetes mellitus. ¿Es adecuado hablar de riesgo moderado o intermedio?

Diabetes, especially type 2, is considered a risk situation for atherosclerotic cardiovascular disease (ASCVD). Subjects with diabetes type 2 have a mortality rate due to ASCVD 3 times higher than that found in the general population, attributed to hyperglycemia and the frequent association of other cardiovascular risk factors, such as atherogenic dyslipidemia. Numerous scientific societies have established a risk classification for ASCVD in diabetes based on 3 degrees (moderate, high and very high). The objectives of dyslipidemia control are clearly defined and accepted, and vary depending on the previously established cardiovascular risk. In moderate or intermediate risk, the guidelines propose a less intensive intervention, maintaining LDL-C levels<100mg/dL and NO-HDL-C levels<130mg/dL, and waiting 10 years until reaching the high-risk category to initiate more intensive treatment. However, during the decade of follow-up recommended in the guidelines, cholesterol deposition in the arterial wall increases, facilitating the development of an unstable and inflammatory atheromatous plaque, and the development of ASCVD. Alternatively, diabetes could be considered from the outset to be a high-risk situation and the goal should be LDL-C<70mg/dL. Furthermore, maintaining LDL-C levels<70mg/dL contributes to reducing and stabilizing atheromatous plaque, avoiding or reducing mortality episodes due to ASCVD during those years of diabetes evolution. Should we maintain the proposed objectives in subjects with diabetes and moderate risk for a decade until reaching the high cardiovascular risk phase or, on the contrary, should we adopt a more intensive stance from the beginning seeking to reduce cardiovascular risk in the majority of patients with diabetes? Is it better to wait or prevent with effective therapeutic measures from the first moment?

Comparison of GLP-1 receptor agonists and other Glucose-Lowering agents on cardiovascular outcomes in individuals with type 2 diabetes and Obesity: A Spanish Real-World Population-Based study.

AIMS: Assess the impact of glucagon-like peptide receptor agonists (GLP-1RA) compared to other glucose-lowering agents on cardiovascular outcomes in individuals with type 2 diabetes and obesity in a Spanish metropolitan area. METHODS: A retrospective population-based type 2 diabetes cohort was identified from the Valencia Clinic-Malvarrosa Department electronic databases (2014-2019). Study groups included GLP-1RA, sodium-glucose co-transporter-2 inhibitors (SGLT2i), Insulin, and Miscellany (other glucose-lowering agents). 1:1:1:1 propensity score matching was conducted. The primary outcome was a composite of major adverse cardiovascular events (4-point MACE) comprising myocardial infarction, stroke, all-cause mortality, and heart failure. Secondary outcomes included individual 4-point MACE components. Hazard ratios were estimated using Cox regression analyses against the Miscellany group. RESULTS: From 26,944 subjects, 1,848 adults were selected per group. GLP-1RA did not show a significant reduction in 4-point MACE risk (HR 1.05 [95%CI 0.82-1.34]). SGLT2i significantly reduced the risk of heart failure (HR 0.16 [95%CI 0.05-0.54]) and atrial fibrillation (HR 0.58, [95%CI 0.35-0.95]). The Insulin group exhibited a higher risk for 4-point MACE and most individual outcomes compared to GLP-1RA and SGLT2i. CONCLUSIONS: Our findings do not provide evidence of a reduced cardiovascular risk, as assessed by 4-point MACE, with GLP-1RA. In contrast, SGLT2i demonstrated protective effects against heart failure and atrial fibrillation.

Low Muscle Mass Is Associated with Poorer Glycemic Control and Higher Oxidative Stress in Older Patients with Type 2 Diabetes.

Body composition changes that occur during aging, such as loss of lean mass, are unfavorable at metabolic level and they can explain, in part, the appearance of certain age-associated diseases such as type 2 diabetes (T2D). Separately, T2D is associated with an increase in oxidative stress (OS) which negatively affects skeletal muscle. Our aim was to study the differences in clinical and nutritional parameters, disease control, and OS in a cohort of older patients with T2D classified according to the amount of lean mass they had. We included 100 adults older than 65 years with T2D. We found that women with low fat-free mass and muscle mass have worse T2D metabolic control. Moreover, the patients with a low percentile of muscle mass present a high value of OS. The study shows that the presence of low lean mass (LM) in the geriatric population diagnosed with T2D is associated with poorer glycemic control and greater OS.

Real-World Evaluation of GLP-1 Receptor Agonist Therapy Persistence, Adherence and Therapeutic Inertia Among Obese Adults with Type 2 Diabetes.

INTRODUCTION: In type 2 diabetes (T2D), key barriers to optimal glycaemic control include lack of persistence with treatment, reduced medication adherence and therapeutic inertia. This study aimed to assess the impact of these barriers in obese adults with type 2 diabetes treated with a GLP-1 receptor agonist (GLP-1RA) and compare them against other glucose-lowering agents in a real-world setting. METHODS: A retrospective study was conducted using electronic medical records from 2014 to 2019 for adults with T2D at the Valencia Clínico-Malvarrosa Department of Health (Valencia, Spain). Four study groups were established: all GLP-1RA users, SGLT2i users, insulin users and other glucose-lowering agent users (miscellany group). To account for imbalance between groups, propensity score matching (PSM) including age, gender and pre-existing cardiovascular disease was performed. Chi-square tests were used for comparisons between groups. Time to first intensification was calculated using competing risk analysis. RESULTS: Among the 26,944 adults with T2D, 7392 individuals were selected following PSM, with 1848 patients in each group. At 2 years, GLP-1RA users were less persistent than non-users (48.4% versus 72.7%, p < 0.0001) but more adherent (73.8% versus 68.9%, respectively, p < 0.0001). A greater proportion of persistent GLP-1RA users than non-persistent users exhibited reduced HbA1c (40.5% versus 18.6%, respectively, p < 0.0001), but no differences in cardiovascular outcomes and death were found. Overall, therapeutic inertia was observed in 38.0% of the study population. The large majority of GLP-1RA users received treatment intensification, whereas only 50.0% of GLP-1RA non-users were intensified. CONCLUSION: Under real-life conditions, obese adults with T2D persistently treated with GLP-1RA showed improved glycaemic control. Despite benefits, persistence with GLP-1RA was limited after 2 years. Additionally, therapeutic inertia occurred in two out of three study participants. Strategies to facilitate medication adherence, persistence and treatment intensification in people with T2D should be made a priority in order to achieve and maintain glycaemic targets and improve outcomes in this population. TRAIL REGISTRATION: Study registered in clinicaltrials.org with the identifier NCT05535322.

Vascular smooth muscle cell phenotype is modulated by ligands of the lymphotoxin beta receptor and the tumor necrosis factor receptor / El fenotipo de las células de músculo liso vascular es modulado por los ligandos del receptor de la linfotoxina beta y del receptor del factor de necrosis tumoral

Objective: Vascular smooth muscle cells (VSMCs) undergo a phenotypic-switching process during the generation of unstable atheroma plaques. In this investigation, the potential implication of the tumor necrosis factor superfamily (TNFSF) ligands, in the gene expression signature associated with VSMC plasticity was studied. Material and methods: Human aortic (ha)VSMCs were obtained commercially and treated with the cytokine TNFSF14, also called LIGHT, the lymphotoxin alpha (LTα), the heterotrimer LTα1β2 or with vehicle for 72h. The effect of the different treatments on gene expression was analyzed by quantitative PCR and included the study of genes associated with myofibroblast-like cell function, osteochondrogenesis, pluripotency, lymphorganogenesis and macrophage-like cell function. Results: HaVSMCs displayed a change in myofibroblast-like cell genes which consisted in reduced COL1A1 and TGFB1 mRNA levels when treated with LTα or LIGHT and with augmented MMP9 expression levels when treated with LTα. LTα and LIGHT treatments also diminished the expression of genes associated with osteochondrogenesis and pluripotency SOX9, CKIT, and KLF4. By contrary, all the above genes were no affected by the treatment with the trimer LTα1β2. In addition, haVSMC treatment with LTα, LTα1β2 and LIGHT altered lymphorganogenic cytokine gene expression which consisted of augmented CCL20 and CCL21 mRNA levels by LTα and a reduction in the gene expression of CCL21 and CXCL13 by LIGHT and LTα1β2 respectively. Neither, LTα or LIGHT or LTα1β2 treatments affected the expression of macrophage-like cell markers in haVSMC. Conclusions: Altogether, indicates that the TNFSF ligands through their interconnected network of signaling, are important in the preservation of VSMC identity against the acquisition of a genetic expression signature compatible with functional cellular plasticity.(AU)

Objetivo: La transición de placa de ateroma estable a placa inestable implica, entre otros procesos, un cambio fenotípico de las células del músculo liso vascular (CMLVs). En esta investigación, se estudió el posible papel de los ligandos de la superfamilia del factor de necrosis tumoral (TNFSF), en los cambios de expresión génica asociada a la plasticidad de las CMLVs. Materiales y métodos: Las CMLVs de aorta humana (CMLVah) se obtuvieron comercialmente y se trataron con la citoquina TNFSF14, también llamada LIGHT, la linfotoxina alfa (LTα), el heterotrímero LTα1β2 o con vehículo durante 72 horas. El efecto de los diferentes tratamientos se analizó mediante el estudio de la expresión génica por PCR cuantitativa e incluyó genes asociados con fenotipo miofibroblástico, osteocondrogénico, genes de pluripotencia, genes de linforganogénesis y genes característicos de macrófagos. Resultados: El estudio de genes asociados a fenotipo miofibroblástico en las CMLVah reveló una reducción de la expresión génica de COL1A1 y TGFB1 tras el tratamiento con LTα o LIGHT mientras que el tratamiento con LTα aumentó los niveles de mRNA de MMP9. LTα y LIGHT también disminuyeron la expresión de genes de osteocondrogénesis y pluripotencia como SOX9, CKIT y KLF4. Por el contrario, la expresión de los genes anteriores no se vio afectada por el tratamiento con el trímero LTα1β2. El tratamiento de las CMLVah con LTα, LTα1β2 y LIGHT alteró la expresión génica de citoquinas linforganogénicas con una expresión aumentada de los genes CCL20 y CCL21 por LTα y una reducción de los niveles de mRNA de CCL21 y CXCL13 por LIGHT y LTα1β2, respectivamente. Ninguno de los tres tratamientos alteró la expresión de genes típicos de macrófagos en las CMLVah. Conclusiones: La presente investigación indica que los ligandos de la familia de los TNFSF a través de su red de señalización...(AU)

Vascular smooth muscle cell phenotype is modulated by ligands of the lymphotoxin ß receptor and the tumor necrosis factor receptor.

OBJECTIVE: Vascular smooth muscle cells (VSMCs) undergo a phenotypic-switching process during the generation of unstable atheroma plaques. In this investigation, the potential implication of the tumor necrosis factor superfamily (TNFSF) ligands, in the gene expression signature associated with VSMC plasticity was studied. MATERIAL AND METHODS: Human aortic (ha)VSMCs were obtained commercially and treated with the cytokine TNFSF14, also called LIGHT, the lymphotoxin alpha (LTα), the heterotrimer LTα1ß2 or with vehicle for 72h. The effect of the different treatments on gene expression was analyzed by quantitative PCR and included the study of genes associated with myofibroblast-like cell function, osteochondrogenesis, pluripotency, lymphorganogenesis and macrophage-like cell function. RESULTS: HaVSMCs displayed a change in myofibroblast-like cell genes which consisted in reduced COL1A1 and TGFB1 mRNA levels when treated with LTα or LIGHT and with augmented MMP9 expression levels when treated with LTα. LTα and LIGHT treatments also diminished the expression of genes associated with osteochondrogenesis and pluripotency SOX9, CKIT, and KLF4. By contrary, all the above genes were no affected by the treatment with the trimer LTα1ß2. In addition, haVSMC treatment with LTα, LTα1ß2 and LIGHT altered lymphorganogenic cytokine gene expression which consisted of augmented CCL20 and CCL21 mRNA levels by LTα and a reduction in the gene expression of CCL21 and CXCL13 by LIGHT and LTα1ß2 respectively. Neither, LTα or LIGHT or LTα1ß2 treatments affected the expression of macrophage-like cell markers in haVSMC. CONCLUSIONS: Altogether, indicates that the TNFSF ligands through their interconnected network of signaling, are important in the preservation of VSMC identity against the acquisition of a genetic expression signature compatible with functional cellular plasticity.

Effect of personality on blood glucose control in patients with type 1 diabetes.

OBJECTIVE: The diagnosis of type 1 diabetes mellitus (DM1) has a major impact on young people and their families. Psychosocial factors, patient motivation, participation and acceptance of the disease are essential to achieve good blood glucose control. Our aims were to analyse personality traits and how they are related to blood glucose control in patients with DM1. METHODS: Sixty-two patients with DM1 over 18 years of age, with at least one-year disease duration and absence of advanced chronic complications were studied. Clinical, biological and personality parameters were measured. The Millon Index of Personality Styles was administered for personality assessment. RESULTS: Significant correlations between different personality variables and glycated haemoglobin (HbA1c) values were found. Individuals with poor blood glucose control had significantly higher scores on the Feeling-guided (53.6±25.7 vs 36.2±26.8, p=0.021), Innovation-seeking (36.7±24.1 vs 21.9±21.4, p=0.025), Dissenting (41.1±24.4 vs 15.6±16.6, p=0.001), Submissive (41.5±25.1 vs 28.3±14.7, p=0.038) and Dissatisfied (37.5±27.5 vs 19.5±20.2, p=0.015) scales. This psychological profile is characterised by greater focus on emotions and personal values (feeling-guided), the tendency to reject conventional ideas (innovation-seeking), an aversion to complying with norms and a preference for autonomy (unconventional/dissenting), labile self-confidence (submissive/yielding) and expressed disagreement with others (dissatisfied/complaining). Factor analysis based on the main components of the variance yielded four factors. Factor characterised as related to rebelliousness or independent judgement and action was correlated with poor blood glucose control (r=0.402, p<0.05). CONCLUSION: The rebellious or non-conformist personality type is closely associated with poor blood glucose control in patients with DM1.

Corticotroph cell hyperplasia as a rare cause of ACTH-dependent Cushing syndrome.

OBJECTIVE: Our aim was to characterise a cohort of patients with Cushing's disease (CD) who did not present pituitary adenoma in magnetic resonance imaging (MRI), needing a catheterisation of the inferior petrosal sinus (CIPS), and to study the pathological findings of the pituitary gland in these subjects after transsphenoidal surgery in order to establish the aetiology of CD. Furthermore, we evaluated possible differences in the features of the diagnosis between hyperplasia and adenoma. SUBJECTS AND METHODS: We included 16 subjects. 17 CIPS were done. Hormonal parameters were measured using standard methods. A microscopic histochemical study following standard procedures and immunohistochemical analysis was performed. The diagnostic criteria for adenoma and hyperplasia were based on the WHO classification. RESULTS: One patient was excluded for presenting an ACTH-producing bronchial neuroendocrine tumour. The 15 subjects with CD have a positive CIPS test indicating hypophyseal ACTH production. After transsphenoidal surgery, 12 patients showed a microadenoma and three (20%) a corticotroph cell hyperplasia. We found four recurrences after the transsphenoidal surgery (26%), with a mean time for recurrence of 105 months. We found that recurrence was more frequent in subjects with hyperplasia, and in those subjects with lower right/left ACTH ratio. CONCLUSION: Our study, which was focused on patients with CD with no pituitary adenoma detected by MRI and a positive CRH test after CIPS, has found that 20% showed corticotroph cell hyperplasia as the cause of CD. Right/left ACTH ratio after CIPS was useful to differentiate adenoma from hyperplasia. This finding may have important prognostic and treatment implications. More studies are necessary to confirm our result.

Novel Therapies for Cardiometabolic Disease: Recent Findings in Studies with Hormone Peptide-Derived G Protein Coupled Receptor Agonists.

The increasing prevalence of obesity and type 2 diabetes (T2DM) is provoking an important socioeconomic burden mainly in the form of cardiovascular disease (CVD). One successful strategy is the so-called metabolic surgery whose beneficial effects are beyond dietary restrictions and weight loss. One key underlying mechanism behind this surgery is the cooperative improved action of the preproglucagon-derived hormones, glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) which exert their functions through G protein-coupled receptors (GPCR). Great success has been reached with therapies based on the GLP-1 receptor monoagonism; therefore, a logical and rational approach is the use of the dual and triagonism of GCPC to achieve complete metabolic homeostasis. The present review describes novel findings regarding the complex biology of the preproglucagon-derived hormones, their signaling, and the drug development of their analogues, especially those acting as dual and triagonists. Moreover, the main investigations into animal models and ongoing clinical trials using these unimolecular dual and triagonists are included which have demonstrated their safety, efficacy, and beneficial effects on the CV system. These therapeutic strategies could greatly impact the treatment of CVD with unprecedented benefits which will be revealed in the next years.

A Very Rare Variant in SREBF2, a Possible Cause of Hypercholesterolemia and Increased Glycemic Levels.

Patients with high cholesterol and glucose levels are at high risk for cardiovascular disease. The Sterol Regulatory Element Binding Protein (SREBP) system regulates genes involved in lipid, cholesterol and glucose pathways. Autosomal Dominant Hypercholesterolemias (ADHs) are a group of diseases with increased cholesterol levels. They affect 1 out of every 500 individuals. About 20-30% of patients do not present any mutation in the known genes (LDLR, APOB and PCSK9). ADHs constitute a good model to identify the genes involved in the alteration of lipid levels or possible therapeutic targets. In this paper, we studied whether a mutation in the SREBP system could be responsible for ADH and other metabolic alterations present in these patients. Forty-one ADH patients without mutations in the main responsible genes were screened by direct sequencing of SREBP system genes. A luciferase reporter assay of the found mutation and an oral glucose tolerance test in carriers and non-carriers were performed. We found a novel mutation in the SREBF2 gene that increases transcription levels and cosegregates with hypercholesterolemia, and we found increased glucose levels in one family. SREBP2 is known to be involved in cholesterol synthesis, plasma levels and glucose metabolism in humans. The found mutation may involve the SREBF2 gene in hypercholesterolemia combined with hyperglycemia.