DNA facilitates heterodimerization between human transcription factors FoxP1 and FoxP2 by increasing their conformational flexibility.

Transcription factors regulate gene expression by binding to DNA. They have disordered regions and specific DNA-binding domains. Binding to DNA causes structural changes, including folding and interactions with other molecules. The FoxP subfamily of transcription factors in humans is unique because they can form heterotypic interactions without DNA. However, it is unclear how they form heterodimers and how DNA binding affects their function. We used computational and experimental methods to study the structural changes in FoxP1's DNA-binding domain when it forms a heterodimer with FoxP2. We found that FoxP1 has complex and diverse conformational dynamics, transitioning between compact and extended states. Surprisingly, DNA binding increases the flexibility of FoxP1, contrary to the typical folding-upon-binding mechanism. In addition, we observed a 3-fold increase in the rate of heterodimerization after FoxP1 binds to DNA. These findings emphasize the importance of structural flexibility in promoting heterodimerization to form transcriptional complexes.

Domain tethering impacts dimerization and DNA-mediated allostery in the human transcription factor FoxP1.

Transcription factors are multidomain proteins with specific DNA binding and regulatory domains. In the human FoxP subfamily (FoxP1, FoxP2, FoxP3, and FoxP4) of transcription factors, a 90 residue-long disordered region links a Leucine Zipper (ZIP)-known to form coiled-coil dimers-and a Forkhead (FKH) domain-known to form domain swapping dimers. We used replica exchange discrete molecular dynamics simulations, single-molecule fluorescence experiments, and other biophysical tools to understand how domain tethering in FoxP1 impacts dimerization at ZIP and FKH domains and how DNA binding allosterically regulates their dimerization. We found that domain tethering promotes FoxP1 dimerization but inhibits a FKH domain-swapped structure. Furthermore, our findings indicate that the linker mediates the mutual organization and dynamics of ZIP and FKH domains, forming closed and open states with and without interdomain contacts, thus highlighting the role of the linkers in multidomain proteins. Finally, we found that DNA allosterically promotes structural changes that decrease the dimerization propensity of FoxP1. We postulate that, upon DNA binding, the interdomain linker plays a crucial role in the gene regulatory function of FoxP1.

Honrar el juramento hipocrático / Honor the Hippocratic Oath

"No llevar otro propósito que el bien y la salud a los enfermos" fue la base del juramento que Hipócrates trasmitió a sus discípulos. Recordarlo nos hace necesariamente reflexionar sobre el rol de los médicos para mantener este principio ético que, a más de dos milenios de vigencia, continúa siendo el motor que impulsa nuestra práctica cotidiana. Asistimos a una era extraordinaria con el desarrollo exponencial de nuevos conocimientos. Se estima que la humanidad cada 2 años duplica la información y probablemente estos lapsos se reduzcan a solo 11 horas en las próximas décadas, de acuerdo a algunos pronósticos.

[Relación entre enfermedad cardiovascular y renal en una muestra de pacientes con diabetes del mundo real]. / Association between cardiovascular disease and kidney disease in a sample of real-world diabetes patients

Objectives: Kidney disease is one of the microvascular complications of diabetes mellitus (DM) with little research and a strong association with cardiovascular disease (CVD). The objective of this study is to characterize the prevalence of kidney disease in a population of patients with type 2 diabetes who attend outpatient control by cardiology, to evaluate its degree of investigation and whether its presence impacts on the achievement of therapeutic goals and use of antidiabetics with cardiovascular and kidney protective effect. Methods: Cross-sectional, observational and multicenter study, carried out in 44 centers in Argentina between May and July 2019. Results: A population with 693 patients with DM was included. The prevalence of CVD was 47.5% (329 patients) and that of microvascular disease was 42.3%. Albuminuria was evaluated only in 46.2% of the patients and was significantly higher in the group with renal impairment (RI). The presence of CVD in patients with RI was greater than in those without RI (64.8% vs. 42.2%; p = 0.0001). The presence of albuminuria was associated with a higher prevalence of CVD. The achievement of therapeutic goals was scarce and no differences were evidenced based on the presence of RI, except for the LDL goal. Low prescription of antidiabetic drugs with proven cardiovascular and kidney benefit was observed. Conclusions: This study highlights the importance of the active search for kidney disease in patients with DM, exposing the low scope of therapeutic goals and the prescription of antidiabetic drugs with cardiovascular and kidney benefit.

Objetivos: La enfermedad renal es una de las complicaciones microvasculares de la diabetes mellitus (DM) con escasa pesquisa y gran relación con enfermedad cardiovascular (ECV). El objetivo de este trabajo es caracterizar la prevalencia de enfermedad renal en una población de pacientes con diabetes tipo 2 que concurren a control ambulatorio por cardiología, determinar su grado de pesquisa y su posible efecto en el alcance de los objetivos terapéuticos y en el uso de los antidiabéticos con efecto protector cardiorrenal. Métodos: Estudio de corte transversal, observacional y multicéntrico realizado en 44 centros de Argentina entre mayo y julio de 2019. Resultados: Se incluyó a 693 pacientes con una prevalencia de ECV establecida de 47.5% (329 pacientes) y de enfermedad microvascular de 42.3%. La albuminuria se valoró sólo en el 46.2% de los pacientes y fue significativamente mayor en el grupo con IR. La ECV en pacientes con IR fue mayor que en aquéllos sin IR (64.8% vs. 42.2%; p = 0.0001). La presencia de albuminuria se acompañó de mayor prevalencia de ECV. El alcance de los objetivos terapéuticos fue escaso y no se reconocieron diferencias en función de la IR, a excepción del objetivo de LDL. Se observó baja prescripción de fármacos antidiabéticos con probado beneficio cardiorrenal. Conclusiones: El trabajo resalta la importancia de la búsqueda activa de la enfermedad renal en pacientes con diabetes, lo que revela el bajo alcance de los objetivos terapéuticos y la prescripción de fármacos antidiabéticos con beneficio cardiorrenal.

[Efectos del aislamiento social, preventivo y obligatorio en pacientes con diabetes tipo 2].

Objetivo: Evaluar el impacto del aislamiento social, preventivo y obligatorio sobre al aumento de peso, el nivel de actividad física, la adherencia al tratamiento y la inmunización antigripal y antineumocócica en pacientes con diabetes tipo 2 (DM2). Método: Se realizó un seguimiento telefónico de pacientes con DM2 luego de al menos 100 días de comienzo del aislamiento. Se compararon dos regiones agrupadas en relación con el número de casos: región 1, más de 150 casos/100, 000 habitantes, y región 2, más de 150 casos/100,000 habitantes. Resultados: Se contactaron 454 pacientes con DM2. El 42% reportaron incremento de peso y el 7% refirió haber aumentado más de 5 kg. En relación con la actividad física, se observó un promedio más bajo en la región 1 (367.5 [0-5698] MET/sem) que en la región 2 (720 [0-7066] MET/sem) (p = 0.0009). La adherencia al tratamiento farmacológico disminuyó en forma global, pero aumentó en las zonas de mayor circulación viral. Por otra parte, hubo un incremento de vacunación antigripal y antineumocócica, alcanzando coberturas del 80% y el 70%, respectivamente. Conclusiones: En una población de alto riesgo cardiovascular y con una prevalencia de sobrepeso/obesidad elevada, el aislamiento social, preventivo y obligatorio se asoció con ganancia de peso y menos actividad física, lo que podría resultar deletéreo sobre la salud cardiovascular de los pacientes con DM2. Por otro lado, se observan algunos aspectos positivos, como el aumento de las inmunizaciones y el incremento de la adherencia en las zonas más afectadas.

Características clínicas y control cardiometabólico de personas con diabetes en el consultorio de cardiología en la República Argentina / Clinical Characteristics and Cardiometabolic Control of Persons with Diabetes in the Cardiology Office in Argentina

RESUMEN Introducción: La cardiología tiene un rol protagónico en el control y el tratamiento de las personas con diabetes mellitus tipo 2 (DM2). No contamos con datos epidemiológicos locales acerca de los pacientes con DM2 asistidos por la especialidad. Objetivos: Evaluar las características clínicas, enfermedad cardiovascular (ECV) y tratamiento de personas con DM2 en el consultorio de cardiología. Material y métodos: Se realizó un estudio observacional en 17 provincias de la Argentina durante 3 meses. Resultados: Se incluyeron 694 pacientes. La edad media fue de 64.7 ± 10.5 años, con un tiempo de evolución de la DM2 de 10.7 ± 9.3 años, índice de masa corporal de 32 ± 5,9 kg/m2, HbA1c de 7,3 ± 1,6 % y tensión arterial 135/80 mmHg. El 70% de los pacientes presentaba 2 o más factores de riesgo. El 48,1% presentaba ECV y el 40,9% enfermedad microvascular (31,4% nefropatía, 10,5% retinopatía, 8,3% neuropatía, 3,3% pie diabético). El 57,3% se encontraban con antiagregantes, 84,3% con inhibidores del sistema renina/angiotensina/aldosterona (iECAS/ARAII), 79,5% con estatinas. Asimismo, el 85,9% recibía metformina, seguido de inhibidores de la dipeptidil peptidasa-4 (iDDP4) (24,1%), insulina (22,2%), sulfonilureas (SU) (14,3%), inhibidores del cotransportador sodio-glucosa tipo 2 (iSGLT2) (9,8%), agonistas del receptor glucagón like (arGLP1) (3%) y glitazonas (1,3%). El 55,9% tenía HbA1c < = 7%, 61,7% TA <140/90 mmHg, 58,5% LDL <100 mg/dl y 28,5% LDL <70 mg/dl. Conclusiones: La mayoría de los pacientes con DM2 presentaba dos o más factores de riesgo cardiovasculares y una elevada prevalencia de complicaciones asociadas. Observamos un bajo alcance de los objetivos terapéuticos, así como también un bajo uso de fármacos con beneficio cardiovascular.

ABSTRACT Background: Cardiology has a leading role in the control and treatment of persons with type 2 diabetes mellitus (DM2). We do not have local epidemiological data about patients with DM2 treated by cardiologists. Objectives: The aim of this study was to evaluate the clinical characteristics, cardiovascular disease (CVD) and treatment of patients with DM2 attending a cardiology office. Methods: We conducted and observational study in 17 provinces of Argentina during three months. Results: A total of 694 patients were included in the study. Mean age was 64.7±10.5 years, time of disease progression 10.7±9.3 years, body mass index 32±5.9 kg/m2, HbA1c 7.3%±1.6, and blood pressure 135/80 mm Hg. Seventy percent of the patients presented two or more risk factors, 48.1% had CVD and microvascular disease was present in 40.9% of cases (kidney disease in 31.4%, retinopathy in 10.5%, neuropathy in 8.3% and diabetic foot in 3.3%). Patients were receiving antiplatelet agents in 57.3% of cases, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs/ARBs) in 84.3% and 79.5% were treated with statins. Hypoglycemic agents included metformin in 85.9% of patients, dipeptidyl peptidase 4 (DPP4) inhibitors in 24.1%, sulfonylureas (SU) in 14.3%, sodium-glucose co-transporter 2 (SGLT2) inhibitors in 9.8%, glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in 3% and glitazones in 1.3%. HbA1C levels ≤7% were achieved by 55.9% of patients, BP <140/90 mm Hg by 61.7%, and LDL-C <100 mg/dL by 58.5% and <70 mg/dL by 28.5%. Conclusions: Most patients with DM2 presented two or more cardiovascular risk factors and a high prevalence of associated complications. Treatment goals were achieved by a low number of patients and the use of medications with demonstrated cardiovascular benefit was low.

Intrinsically Disordered Regions of the DNA-Binding Domain of Human FoxP1 Facilitate Domain Swapping.

Forkhead box P (FoxP) proteins are unique transcription factors that spatiotemporally regulate gene expression by tethering two chromosome loci together via functional domain-swapped dimers formed through their DNA-binding domains. Further, the differential kinetics on this dimerization mechanism underlie an intricate gene regulation network at physiological conditions. Nonetheless, poor understanding of the structural dynamics and steps of the association process impedes to link the functional domain swapping to human-associated diseases. Here, we have characterized the DNA-binding domain of human FoxP1 by integrating single-molecule Förster resonance energy transfer and hydrogen-deuterium exchange mass spectrometry data with molecular dynamics simulations. Our results confirm the formation of a previously postulated domain-swapped (DS) FoxP1 dimer in solution and reveal the presence of highly populated, heterogeneous, and locally disordered dimeric intermediates along the dimer dissociation pathway. The unique features of FoxP1 provide a glimpse of how intrinsically disordered regions can facilitate domain swapping oligomerization and other tightly regulated association mechanisms relevant in biological processes.

Mesa 1: Diabetes mellitus tipo 1 y enfermedad cardiovascular / Table 1: type 1 diabetess mellitus and cardiovascular disease

La principal causa de muerte en personas con diabetes mellitus tipo 1 (DM1) es de origen cardiovascular (CV). La duración de la DM1 es uno de los predictores más importantes para infarto agudo de miocardio (IAM), junto con el colesterol de lipoproteínas de baja densidad (cLDL) y HbA1c. El desarrollo de DM1 antes de los 10 años de edad se asocia con un riesgo 90 veces mayor de IAM en mujeres. En la DM1 habría una mayor contribución de un estado de inflamación sistémica de bajo de grado. La combinación de electrocardiograma de ejercicio y una técnica de imagen proporciona valor diagnóstico para la detección de isquemia miocárdica y pronóstico. La evaluación del riesgo CV en el adulto mayor debe ser individualizado y categorizarlo según funcionalidad y comorbilidades a fin de fijar objetivos de control de factores glucémicos y no glucémicos personalizados. Las personas con enfermedad cardíaca conocida o múltiples factores de riesgo cardiovascular (FRCV) deben tener recomendaciones de ejercicio personalizadas; se recomienda el tratamiento intensificado de la glucemia y de los FRCV asociados. En la población pediátrica y adolescentes con DM1 es esencial la detección y tratamiento precoz de los FRCV a fin de prevenir o retrasar el inicio y progresión de eventos CV

The leading cause of death in type 1 diabetes mellitus (T1DM) is cardiovascular. The duration of diabetes is one of the most important predictors for acute myocardial infarction (AMI), along with low-density lipoprotein cholesterol (cLDL) and HbA1c. Being diagnosed of T1DM before age 10 is been associated with a 90 times higher risk of AMI in women. It has been proposed, that a low-grade systemic inflammation state to be great prompt contributor. The combination of exercise electrocardiogram and an imaging technique provides diagnostic value for myocardial ischemia detection and future prognosis. Cardiovascular risk assessment in the older adult should be individualized by categorizing it, according to functionality and patient's co morbidity and customized glycaemic and non-glycaemic targets. People with known heart disease or multiple cardiovascular risk factors should have personalized exercise recommendations, blood glucose intensified treatment and associated risk factors. In paediatric and adolescent population with T1DM, cardiovascular risk factors early screening, recognition and treatment has become essential to prevent or delay the onset and progression of cardiovascular events.

[Cardiovascular effects of new non-insulinic anti-diabetes drugs]. / Efectos cardiovasculares de los nuevos fármacos no insulínicos en diabetes.

Diabetes mellitus is currently a serious public health problem worldwide, that increases the risk of presenting microvascular and macrovascular complications. Although achieving the recommended blood glucose goals reduces the risk of microvascular complications, the effect of the drugs used to treat hyperglycemia on macrovascular complications and cardiovascular death is a cause for concern. In this context, the regulatory agencies have modified the regulations for the approval of new drugs in diabetes, by adding the need to demonstrate that they are capable of lowering blood glucose levels together with a solid assessment of cardiovascular safety. The objective of this study is to review the cardiovascular effects of the new families of non-insulin drugs, with special emphasis on their effect on the risk of major cardiovascular events. In recent years, it has finally been confirmed that some of the drugs used to treat diabetes are not only safe from a cardiovascular point of view, but have even shown capacity to reduce the risk of cardiovascular disease in type 2 diabetes mellitus. The evidence obtained determined the updating of some current therapeutic guidelines when cardiovascular risk should be considered a fundamental variable at the time of therapeutic choice in patients with diabetes.

Efectos cardiovasculares de los nuevos fármacos no insulínicos en diabetes / Cardiovascular effects of new non-insulinic anti-diabetes drugs]

La diabetes mellitus constituye actualmente un grave problema de salud pública a nivel mundial, que incrementa el riesgo de presentar complicaciones tanto microvasculares como macrovasculares. Aunque lograr los objetivos de glucemia recomendados reduce el riesgo de complicaciones microvasculares, el efecto de los fármacos para tratar la hiperglucemia sobre las complicaciones macrovasculares y la muerte cardiovascular es motivo de preocupación. En este contexto, las agencias regulatorias han modificado la normativa para la aprobación de nuevos fármacos en diabetes, de forma que establecen la necesidad de demostrar que son capaces de disminuir la glucemia junto con una evaluación sólida de la seguridad cardiovascular. El objetivo de este trabajo es revisar los efectos cardiovasculares de las nuevas familias de fármacos no insulínicos, en especial en su efecto sobre el riesgo de eventos cardiovasculares mayores. En los últimos años, finalmente, se ha confirmado que algunos fármacos para tratar la diabetes no solo son seguros desde el punto de vista cardiovascular, sino que incluso han mostrado capacidad para reducir el riesgo de enfermedad cardiovascular en la diabetes mellitus tipo 2. La evidencia obtenida ha determinado la actualización de algunas guías terapéuticas vigentes cuando el riesgo cardiovascular debería considerarse una variable fundamental al momento de la elección terapéutica en pacientes con diabetes.

Diabetes mellitus is currently a serious public health problem worldwide, that increases the risk of presenting microvascular and macrovascular complications. Although achieving the recommended blood glucose goals reduces the risk of microvascular complications, the effect of the drugs used to treat hyperglycemia on macrovascular complications and cardiovascular death is a cause for concern. In this context, the regulatory agencies have modified the regulations for the approval of new drugs in diabetes, by adding the need to demonstrate that they are capable of lowering blood glucose levels together with a solid assessment of cardiovascular safety. The objective of this study is to review the cardiovascular effects of the new families of non-insulin drugs, with special emphasis on their effect on the risk of major cardiovascular events. In recent years, it has finally been confirmed that some of the drugs used to treat diabetes are not only safe from a cardiovascular point of view, but have even shown capacity to reduce the risk of cardiovascular disease in type 2 diabetes mellitus. The evidence obtained determined the updating of some current therapeutic guidelines when cardiovascular risk should be considered a fundamental variable at the time of therapeutic choice in patients with diabetes.

Medium-term glycemic control in diabetics before coronary bypass surgery.

The aim of this study was to determine the association between preoperative medium-term (60-90 days) glycemic control, as reflected by glycosylated hemoglobin levels (HbA1c), and the incidence of major complications (mediastinitis, perioperative infarction, heart failure, stroke and kidney failure dialysis) and mortality in diabetic patients undergoing elective coronary artery by-pass graft surgery (CABG). This study suggests that aggressive glycemic control three months before surgery, achieving HbA1c=7% improvement results with less postoperative morbidity and mortality.

Medium-term glycemic control in diabetics before coronary bypass surgery

The aim of this study was to determine the association between preoperative medium-term (60-90 days) glycemic control, as reflected by glycosylated hemoglobin levels (HbA1c), and the incidence of major complications (mediastinitis, perioperative infarction, heart failure, stroke and kidney failure dialysis) and mortality in diabetic patients undergoing elective coronary artery by-pass graft surgery (CABG). This study suggests that aggressive glycemic control three months before surgery, achieving HbA1c ≤ 7% improvement results with less postoperative morbidity and mortality.

El propósito de este estudio fue determinar la asociación entre el control glucémico a mediano plazo, 2-3 meses previos a la cirugía cardiaca, evaluado mediante el dosaje de hemoglobina glicosilada (HbA1c), y la incidencia de muerte y complicaciones mayores (mediastinitis, infarto perioperatorio, insuficiencia cardíaca, accidente cerebrovascular e insuficiencia renal dialítica) en pacientes diabéticos tipo 2. Este estudio sugiere que el control glucémico 3 meses antes de la cirugía en pacientes con diabetes mellitus tipo 2, logrando HbA1c ≤ 7%, mejora los resultados en el posoperatorio observándose menor morbilidad y mortalidad.

Incretins and selective renal sodium-glucose co-transporter 2 inhibitors in hypertension and coronary heart disease.

Hyperglycemia is associated with an increased risk of cardiovascular disease, and the consequences of intensive therapy may depend on the mechanism of the anti-diabetic agent(s) used to achieve a tight control. In animal models, stable analogues of glucagon-like peptide-1 (GLP-1) were able to reduce body weight and blood pressure and also had favorable effects on ischemia following coronary reperfusion. In a similar way, dipeptidyl peptidase IV (DPP-IV) showed to have favorable effects in animal models of ischemia/reperfusion. This could be due to the fact that DPP-IV inhibitors were able to prevent the breakdown of GLP-1 and glucose-dependent insulinotropic polypeptide, but they also decreased the degradation of several vasoactive peptides. Preclinical data for GLP-1, its derivatives and inhibitors of the DPP-IV enzyme degradation suggests that these agents may be able to, besides controlling glycaemia, induce cardio-protective and vasodilator effects. Notwithstanding the many favorable cardiovascular effects of GLP-1/incretins reported in different studies, many questions remain unanswered due the limited number of studies in human beings that aim to examine the effects of GLP-1 on cardiovascular endpoints. For this reason, long-term trials searching for positive cardiovascular effects are now in process, such as the CAROLINA and CARMELINA trials, which are supported by small pilot studies performed in humans (and many more animal studies) with incretin-based therapies. On the other hand, selective renal sodium-glucose co-transporter 2 inhibitors were also evaluated in the prevention of cardiovascular outcomes in type 2 diabetes. However, it is quite early to draw conclusions, since data on cardiovascular outcomes and cardiovascular death are limited and long-term studies are still ongoing. In this review, we will analyze the mechanisms underlying the cardiovascular effects of incretins and, at the same time, we will present a critical position about the real value of these compounds in the cardiovascular system and its protection.

Hipertensión arterial y diabetes: guías de recomendaciones para la práctica clínica. 2015. Comité de Hipertensión Arterial y otros FRCV-SAD / Hypertension and diabetes. Guidelines for clinical practice. 2015. Hypertension and other FRCV-SAD committee

Introducción: la hipertensión arterial (HA) y la diabetes mellitus (DM) son enfermedades crónicas de alta prevalencia que se encuentran frecuentemente asociadas. Objetivos: brindar los conocimientos para la práctica clínica que favorezcan la toma de decisiones diagnósticas y terapéuticas adecuadas, basadas en las evidencias científicas actuales. Materiales y métodos: utilizando la evidencia disponible, los grandes ensayos clínicos publicados en los últimos cuatro años y la adaptación de los recursos diagnósticos y terapéuticos de nuestro país se elaboraron las presentes “Recomendaciones para la Práctica Clínica”. Conclusiones: la HA aumenta la progresión y el desarrollo de las complicaciones crónicas micro y macrovasculares de la DM. El impacto del tratamiento de la HA es significativo en la reducción de la morbimortalidad de las personas con DM. Por ello, el tratamiento debe ser temprano y las metas de objetivo terapéutico deberán ser individualizadas según grupo etario, comorbilidades y daño de órgano blanco. En todas las personas con HA, tengan o no DM y/o enfermedad renal crónica (ERC), el objetivo es alcanzar una PA <140/90 mmHg. Podrán considerarse objetivos más cercanos a 130/80 mmHg en jóvenes, sin comorbilidades, con larga expectativa de vida y menor tiempo de diagnóstico de DM: en quienes tendrían beneficios a nivel renal o en quienes el riesgo de ACV es sustancial, si se logran sin efectos adversos asociados al tratamiento. Los IECA o ARA II son los fármacos de primera elección excepto en casos de intolerancia o contraindicación. Un bajo porcentaje de personas logra el objetivo terapéutico. La educación es una herramienta fundamental para mejorar la adherencia al tratamiento.

Angioplastía programada en octogenarios con enfermedad coronaria crónica. Resultados hospitalarios y en el seguimiento alejado / Programmed angioplasty in the elderly with chronic coronary disease

Cardiac vascular disease is the main cause of death in the elderly, and this factor is closely related to the increase and severity of the ischemic cardiopathy... The aim of the present report is to show the hospitalary results and the late follow-up in a population of patients older than 80 years, submitted to coronary angioplasty. It is concluded that the revascularization by mean of an elective angioplasty is a valid option for persons age 80 or older, with chronic ischemic cardiopathy, resulting in our experience in a high rate of primary success, and with an acceptable rate of complications