Mesenchymal Stem Cells from Familial Alzheimer's Patients Express MicroRNA Differently.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the predominant form of dementia globally. No reliable diagnostic, predictive techniques, or curative interventions are available. MicroRNAs (miRNAs) are vital to controlling gene expression, making them valuable biomarkers for diagnosis and prognosis. This study examines the transcriptome of olfactory ecto-mesenchymal stem cells (MSCs) derived from individuals with the PSEN1(A431E) mutation (Jalisco mutation). The aim is to determine whether this mutation affects the transcriptome and expression profile of miRNAs and their target genes at different stages of asymptomatic, presymptomatic, and symptomatic conditions. Expression microarrays compare the MSCs from mutation carriers with those from healthy donors. The results indicate a distinct variation in the expression of miRNAs and mRNAs among different symptomatologic groups and between individuals with the mutation. Using bioinformatics tools allows us to identify target genes for miRNAs, which in turn affect various biological processes and pathways. These include the cell cycle, senescence, transcription, and pathways involved in regulating the pluripotency of stem cells. These processes are closely linked to inter- and intracellular communication, vital for cellular functioning. These findings can enhance our comprehension and monitoring of the disease's physiological processes, identify new disorder indicators, and develop innovative treatments and diagnostic tools for preventing or treating AD.

The nuclear receptor Nurr1 is preferentially expressed in human pro-inflammatory macrophages and limits their inflammatory profile.

Nurr1 is a member of the orphan nuclear receptor family NR4A (nuclear receptor subfamily 4 group A) that modulates inflammation in several cell lineages, both positively and negatively. Macrophages are key regulators of inflammatory responses, yet information about the role of Nurr1 in human macrophages is scarce. Here we examined Nurr1 expression and activity in steady state and activated human macrophages. Pro- and anti-inflammatory macrophages were generated in vitro by culture of blood monocytes with granulocyte/macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF), respectively. Nurr1 expression was predominant in macrophages with the pro-inflammatory phenotype. Nurr1 activation with the agonists 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane (C-DIM12) or isoxazolo-pyridinone 7e (IP7e) did not globally modify the polarization status of pro-inflammatory macrophages, but they decreased their production of TNF, IL-1ß, IL-6, IL-8, IL-12 p40, CCL2, IFN-ß, and reactive oxygen species, with variable potencies. Conversely, Nurr1 deficient macrophages increased the expression of transcripts encoding inflammatory mediators, particularly that of IL6, IFNB1, and CCL2. Mechanistically, endogenous Nurr1 interacted with NF-κB p65 in basal conditions and upon lipopolysaccharide (LPS)-mediated activation. C-DIM12 stabilized those complexes in cells exposed to LPS and concurrently decreased NF-κB transcriptional activity and p65 nuclear translocation. Expression of high levels of Nurr1 was associated with a subset of dermal macrophages that display enhanced levels of TNF and lower expression of the anti-inflammatory marker CD163L1 in skin lesions from patients with bullous pemphigoid (BP), a chronic inflammatory autoimmune blistering disorder. These results suggest that Nurr1 expression is linked with the pro-inflammatory phenotype of human macrophages, both in vivo and in vitro, where it may constitute a brake to attenuate the synthesis of inflammatory mediators.

The Proteome Profile of Olfactory Ecto-Mesenchymal Stem Cells-Derived from Patients with Familial Alzheimer's Disease Reveals New Insights for AD Study.

Alzheimer's disease (AD), the most common neurodegenerative disease and the first cause of dementia worldwide, has no effective treatment, and its pathological mechanisms are not yet fully understood. We conducted this study to explore the proteomic differences associated with Familial Alzheimer's Disease (FAD) in olfactory ecto-mesenchymal stem cells (MSCs) derived from PSEN1 (A431E) mutation carriers compared with healthy donors paired by age and gender through two label-free liquid chromatography-mass spectrometry approaches. The first analysis compared carrier 1 (patient with symptoms, P1) and its control (healthy donor, C1), and the second compared carrier 2 (patient with pre-symptoms, P2) with its respective control cells (C2) to evaluate whether the protein alterations presented in the symptomatic carrier were also present in the pre-symptom stages. Finally, we analyzed the differentially expressed proteins (DEPs) for biological and functional enrichment. These proteins showed impaired expression in a stage-dependent manner and are involved in energy metabolism, vesicle transport, actin cytoskeleton, cell proliferation, and proteostasis pathways, in line with previous AD reports. Our study is the first to conduct a proteomic analysis of MSCs from the Jalisco FAD patients in two stages of the disease (symptomatic and presymptomatic), showing these cells as a new and excellent in vitro model for future AD studies.

NAT2 global landscape: Genetic diversity and acetylation statuses from a systematic review.

Arylamine N-acetyltransferase 2 has been related to drug side effects and cancer susceptibility; its protein structure and acetylation capacity results from the polymorphism's arrays on the NAT2 gene. Absorption, distribution, metabolism, and excretion, cornerstones of the pharmacological effects, have shown diversity patterns across populations, ethnic groups, and even interethnic variation. Although the 1000 Genomes Project database has portrayed the global diversity of the NAT2 polymorphisms, several populations and ethnicities remain underrepresented, limiting the comprehensive picture of its variation. The NAT2 clinical entails require a detailed landscape of its striking diversity. This systematic review spans the genetic and acetylation patterns from 164 articles from October 1992 to October 2020. Descriptive studies and controls from observational studies expanded the NAT2 diversity landscape. Our study included 243 different populations and 101 ethnic minorities, and, for the first time, we presented the global patterns in the Middle Eastern populations. Europeans, including its derived populations, and East Asians have been the most studied genetic backgrounds. Contrary to the popular perception, Africans, Latinos and Native Americans have been significantly represented in recent years. NAT2*4, *5B, and *6A were the most frequent haplotypes globally. Nonetheless, the distribution of *5B and *7B were less and more frequent in Asians, respectively. Regarding the acetylator status, East Asians and Native Americans harboured the highest frequencies of the fast phenotype, followed by South Europeans. Central Asia, the Middle East, and West European populations were the major carriers of the slow acetylator status. The detailed panorama presented herein, expands the knowledge about the diversity patterns to genetic and acetylation levels. These data could help clarify the controversial findings between acetylator states and the susceptibility to diseases and reinforce the utility of NAT2 in precision medicine.

The Nurr7 agonist Cytosporone B differentially regulates inflammatory responses in human polarized macrophages.

The orphan nuclear receptor Nur77 is involved in diverse cellular processes such as inflammation, proliferation, differentiation and survival. Stimuli like lipopolysaccharide (LPS) and tumor necrosis factor (TNF) increase Nur77 expression in human and murine macrophages, and it has been proposed that Nur77 plays a major role in dampening the inflammatory response. Here, we evaluated the expression and function of Nur77 in human anti-inflammatory and pro-inflammatory macrophages derived from blood monocytes cultured with macrophage colony-stimulating factor (M-MDMs) or granulocyte/macrophage colony-stimulating factor (GM-MDMs), respectively. Nur77 mRNA expression was significantly enhanced in M-MDMs compared with GM-MDMs, both constitutively and upon exposure to Toll-like receptor (TLR)2, 3, and 4 ligands. Nur77 activation with the agonist Cytosporone B (CsnB) significantly suppressed the production of TNF, interleukin (IL)-1ß, IL-6, and IL-8 in GM-MDMs stimulated with LPS. In contrast, it tended to enhance the production of the anti-inflammatory cytokine IL-10. This effect was associated with reduced NF-κB p65 nuclear translocation. Similarly, Nur77 knockdown enhanced TNF production in GM-MDMs. CsnB effectively stimulated the transactivation activity of Nur77 in M-MDMs, but it did not alter cytokine synthesis or p65 nuclear translocation. However, Nur77 seemed to have a role in maintaining the anti-inflammatory profile of M-MDMs, since Nur77-deficient M-MDMs constitutively produced higher levels of TNF transcripts. Thus, in the absence of exogenous agonists, Nur77 activity favors the anti-inflammatory function of M-MDMs, whereas agonistic activation of this receptor preferentially drives attenuation of inflammation in inflammatory macrophages.

Coronary stent and prolonged dual antiplatelet therapy. A longitudinal study.

INTRODUCTION: In current European guidelines for the management of myocardial infarction after coronary stent placement, there is no consensus on dual antiplatelet therapy (DAPT) ideal duration to prevent stent thrombosis-restenosis without significantly increasing the bleeding risk. OBJECTIVE: To report the percentage of major bleeding and presence of major cardiovascular events associated with prolonged DAPT in patients recruited at the National Institute of Cardiology, treated with primary percutaneous coronary intervention and stent. METHODS: A longitudinal, prospective, observational, non-experimental, descriptive study was carried out. Patients were recruited from November 2016 to December 2017. RESULTS: One hundred and thirty-five patients with a mean age of 57 ± 10 years who completed the three-year follow-up were selected. Obesity and hypertension stood out as the main risk factors. After using DAPT for three years, 3.7% of mortality, 1.48% of major bleeding, and 4.4% of thrombosis-restenosis were recorded. CONCLUSIONS: Prolonged use of DAPT would be justified by the high incidence of thrombosis-restenosis, without a significant increase in bleeding risk, as well as a decrease in major cardiovascular events.

INTRODUCCIÓN: En las guías actuales europeas para el manejo del infarto de miocardio posterior a la colocación de endoprótesis coronaria (stent), no existe consenso sobre la duración ideal de la terapia antiagregante plaquetaria dual (DAPT, dual antiplatelet therapy) para prevenir la trombosis-reestenosis del stent sin aumentar el riesgo significativo de sangrado. OBJETIVO: Reportar el porcentaje de sangrado mayor y de eventos cardiovasculares mayores asociados a la DAPT prolongada en pacientes atendidos en el Instituto Nacional de Cardiología y tratados con intervención coronaria percutánea primaria y stent. MÉTODOS: Se realizó un estudio longitudinal, prospectivo observacional y descriptivo no experimental. Los pacientes fueron captados de noviembre de 2016 a diciembre de 2017. RESULTADOS: Fueron seleccionados 135 pacientes con una media de edad de 57 ± 10 años, quienes cumplieron un seguimiento clínico por tres años. La obesidad y la hipertensión destacaron como principales factores de riesgo. Posterior al uso de DAPT durante tres años, se registró 3.7 % de mortalidad, 1.48 % de sangrado mayor y 4.4 % de trombosis-reestenosis. CONCLUSIONES: El uso prolongado de DAPT estaría justificado por la alta incidencia de trombosis-reestenosis, sin incremento significativo en el riesgo de sangrado y con disminución de los eventos cardiovasculares mayores.

The rs4783961 and rs708272 genetic variants of the CETP gene are associated with coronary artery disease, but not with restenosis after coronary stenting / Los polimorfismos rs4783961 y rs708272 del gen CETP son asociados con la enfermedad arterial coronaria y no con la restenosis tras el implante de un stent coronario

Abstract Objective: We evaluated whether cholesteryl ester transfer protein (CETP) gene polymorphisms are associated with the presence of coronary artery disease (CAD) and/or restenosis in patients with coronary stent. Methods: Two polymorphisms of the CETP gene [−971 A/G (rs4783961), and Taq1B A/G (rs708272)] were genotyped by 5'exonuclease TaqMan assays in 219 patients with CAD (66 patients with restenosis and 153 without restenosis) and 607 control individuals. Results: The distribution of polymorphisms was similar in patients with and without restenosis. However, when the whole group of patients (with and without restenosis) was compared to healthy controls, under dominant model, the G allele of the Taq1B A/G polymorphism was associated with increased risk of CAD (odds ratio [OR] = 1.48, pCDom = 0.032). In the same way, under codominant, dominant, and additive models, the A allele of the −971 A/G polymorphisms was associated with an increased risk of developing CAD (OR = 2.03, pCCo-dom = 0.022, OR = 1.83, pCDom = 0.008, and OR = 1.39, pCAdd = 0.011, respectively). In addition, the linkage disequilibrium showed that the "AG" haplotype was associated with increased risk of developing CAD (OR = 1.28, p = 0.03). Conclusion: This study demonstrates that CETP Taq1B A/G and CETP −971 A/G polymorphisms are associated with an increased risk of developing CAD, but no association with restenosis was observed.

Resumen Objetivo: Evaluamos si los polimorfismos del gen CETP están asociados con la presencia de enfermedad arterial coronaria (EAC) y/o restenosis en pacientes con stent coronario. Métodos: En este estudio se genotiparon dos polimorfismos del gen CETP [−971 A/G (rs4783961) y Taq1B A/G (rs708272)] mediante ensayos de 5'exonucleasa TaqMan en 219 pacientes con EAC (66 pacientes con restenosis y 153 sin restenosis), y 607 individuos de control. Resultados: La distribución de polimorfismos fue similar en pacientes con y sin restenosis. Sin embargo, cuando se comparó todo el grupo de pacientes (con y sin restenosis) con controles sanos, bajo el modelo dominante el alelo G del polimorfismo Taq1B A/G se asocia con un mayor riesgo de EAC (OR = 1.48, pCDom = 0.032). De la misma manera, bajo los modelos co-dominante, dominante y aditivo, el alelo A de los polimorfismos −971 A/G se asocia con un mayor riesgo de desarrollar EAC (OR = 2.03, pCCo-dom = 0.022, OR = 1.83, pCDom = 0,008 y OR = 1.39, pCAdd = 0.011, respectivamente). Adicionalmente, el desequilibrio de ligamiento mostró que el haplotipo "AG" se asocia con un mayor riesgo de desarrollar EAC (OR = 1.28, p = 0.03). Conclusión: En resumen, este estudio demuestra que los polimorfismos CETP Taq1B A/G y CETP −971 A/G están asociados con un mayor riesgo de desarrollar CAD, pero no se observó asociación con restenosis.

Endoprótesis coronaria y doble terapia antiplaquetaria prolongada. Un estudio longitudinal / Coronary stent and prolonged dual antiplatelet therapy. A longitudinal study

Resumen Introducción: En las guías actuales europeas para el manejo del infarto de miocardio posterior a la colocación de endoprótesis coronaria (stent), no existe consenso sobre la duración ideal de la terapia antiagregante plaquetaria dual (DAPT, dual antiplatelet therapy) para prevenir la trombosis-reestenosis del stent sin aumentar el riesgo significativo de sangrado. Objetivo: Reportar el porcentaje de sangrado mayor y de eventos cardiovasculares mayores asociados a la DAPT prolongada en pacientes atendidos en el Instituto Nacional de Cardiología y tratados con intervención coronaria percutánea primaria y stent. Métodos: Se realizó un estudio longitudinal, prospectivo observacional y descriptivo no experimental. Los pacientes fueron captados de noviembre de 2016 a diciembre de 2017. Resultados: Fueron seleccionados 135 pacientes con una media de edad de 57 ± 10 años, quienes cumplieron un seguimiento clínico por tres años. La obesidad y la hipertensión destacaron como principales factores de riesgo. Posterior al uso de DAPT durante tres años, se registró 3.7 % de mortalidad, 1.48 % de sangrado mayor y 4.4 % de trombosis-reestenosis. Conclusiones: El uso prolongado de DAPT estaría justificado por la alta incidencia de trombosis-reestenosis, sin incremento significativo en el riesgo de sangrado y con disminución de los eventos cardiovasculares mayores.

Abstract Introduction: In current European guidelines for the management of myocardial infarction after coronary stent placement, there is no consensus on dual antiplatelet therapy (DAPT) ideal duration to prevent stent thrombosis-restenosis without significantly increasing the bleeding risk. Objective: To report the percentage of major bleeding and presence of major cardiovascular events associated with prolonged DAPT in patients recruited at the National Institute of Cardiology, treated with primary percutaneous coronary intervention and stent. Methods: A longitudinal, prospective, observational, non-experimental, descriptive study was carried out. Patients were recruited from November 2016 to December 2017. Results: One-hundred and thirty-five patients with a mean age of 57 ± 10 years who completed the three-year follow-up were selected. Obesity and hypertension stood out as the main risk factors. After using DAPT for three years, 3.7% of mortality, 1.48% of major bleeding, and 4.4% of thrombosis-restenosis were recorded. Conclusions: Prolonged use of DAPT would be justified by the high incidence of thrombosis-restenosis, without a significant increase in bleeding risk, as well as a decrease in major cardiovascular events.

Tuning HAuCl4/Sodium Citrate Stoichiometry to Fabricate Chitosan-Au Nanocomposites.

Nanocomposite engineering of biosensors, biomaterials, and flexible electronics demand a highly tunable synthesis of precursor materials to achieve enhanced or desired properties. However, this process remains limited due to the need for proper synthesis-property strategies. Herein, we report on the ability to synthesize chitosan-gold nanocomposite thin films (CS/AuNP) with tunable properties by chemically reducing HAuCl4 in chitosan solutions and different HAuCl4/sodium citrate molar relationships. The structure, electrical, and relaxation properties of nanocomposites have been investigated as a function of HAuCl4/sodium citrate molar relation. It was shown that gold particle size, conductivity, Vogel temperature (glass transition), and water content strongly depend upon HAuCl4/sodium citrate relationships. Two relaxation processes have been observed in nanocomposites; the α-relaxation process, related to a glass transition in wet CS/AuNP films, and the σ-relaxation related to the local diffusion process of ions in a disordered system. The ability to fine-tune both α- and σ-relaxations may be exploited in the proper design of functional materials for biosensors, biomaterials, and flexible electronics applications.

The rs4783961 and rs708272 genetic variants of the CETP gene are associated with coronary artery disease, but not with restenosis after coronary stenting.

OBJECTIVE: We evaluated whether cholesteryl ester transfer protein (CETP) gene polymorphisms are associated with the presence of coronary artery disease (CAD) and/or restenosis in patients with coronary stent. METHODS: Two polymorphisms of the CETP gene [-971 A/G (rs4783961), and Taq1B A/G (rs708272)] were genotyped by 5'exonuclease TaqMan assays in 219 patients with CAD (66 patients with restenosis and 153 without restenosis) and 607 control individuals. RESULTS: The distribution of polymorphisms was similar in patients with and without restenosis. However, when the whole group of patients (with and without restenosis) was compared to healthy controls, under dominant model, the G allele of the Taq1B A/G polymorphism was associated with increased risk of CAD (odds ratio [OR] = 1.48, pCDom = 0.032). In the same way, under codominant, dominant, and additive models, the A allele of the -971 A/G polymorphisms was associated with an increased risk of developing CAD (OR = 2.03, pCCo-dom = 0.022, OR = 1.83, pCDom = 0.008, and OR = 1.39, pCAdd = 0.011, respectively). In addition, the linkage disequilibrium showed that the "AG" haplotype was associated with increased risk of developing CAD (OR = 1.28, p = 0.03). CONCLUSION: This study demonstrates that CETP Taq1B A/G and CETP -971 A/G polymorphisms are associated with an increased risk of developing CAD, but no association with restenosis was observed.

OBJETIVO: Evaluamos si los polimorfismos del gen CETP están asociados con la presencia de enfermedad arterial coronaria (EAC) y/o restenosis en pacientes con stent coronario. MÉTODOS: En este estudio se genotiparon dos polimorfismos del gen CETP [−971 A/G (rs4783961) y Taq1B A/G (rs708272)] mediante ensayos de 5'exonucleasa TaqMan en 219 pacientes con EAC (66 pacientes con restenosis y 153 sin restenosis), y 607 individuos de control. RESULTADOS: La distribución de polimorfismos fue similar en pacientes con y sin restenosis. Sin embargo, cuando se comparó todo el grupo de pacientes (con y sin restenosis) con controles sanos, bajo el modelo dominante el alelo G del polimorfismo Taq1B A/G se asocia con un mayor riesgo de EAC (OR = 1.48, pCDom = 0.032). De la misma manera, bajo los modelos co-dominante, dominante y aditivo, el alelo A de los polimorfismos −971 A/G se asocia con un mayor riesgo de desarrollar EAC (OR = 2.03, pCCo-dom = 0.022, OR = 1.83, pCDom = 0,008 y OR = 1.39, pCAdd = 0.011, respectivamente). Adicionalmente, el desequilibrio de ligamiento mostró que el haplotipo "AG" se asocia con un mayor riesgo de desarrollar EAC (OR = 1.28, p = 0.03). CONCLUSIÓN: En resumen, este estudio demuestra que los polimorfismos CETP Taq1B A/G y CETP −971 A/G están asociados con un mayor riesgo de desarrollar CAD, pero no se observó asociación con restenosis.

Psychological distress and unsatisfied information needs in heart failure patients and ventricular dysfunction without previously diagnosed psychiatric disorder. Cross-sectional study in a national reference center / Distrés psicológico y necesidades de información insatisfechas en pacientes con insuficiencia cardiaca y disfunción ventricular sin trastorno psiquiátrico previamente diagnosticado. Estudio transversal en un centro de referencia nacional.

Introduction: Heart failure (HF) is a chronic disease that acutely and progressively reduces physical functionality. The patient commonly suffers from intermittent relapses that increase the likelihood of comorbidities such as chronic insomnia, cognitive impairment, alterations in sexual response, psychological distress, symptoms of anxiety and depression disorder, and decreased self-care behaviors. The objective of this study was to identify the main needs for psychological support in patients with HF. Methodology: A descriptive, cross-sectional and analytical study was carried out. Participants were selected through consecutive non-probability samples. 150 patients with a diagnosis of HF who attended the Specialized Center for Heart Failure at the National Institute of Cardiology "Ignacio Chávez" were evaluated from November 2018 to April 2019, applying the inventories: Quality of life in patients with HF (Minnesota), Hospital Anxiety and Depression Scale (HADS), psychological distress thermometer (visual analog scale) and the HF Patient Information Needs Inventory. Results: 33% of the patients perceive a high level of psychological distress that requires immediate assistance and 26.6% report a medium level that requires monitoring. The main information needs reported by the patients were information on taking medications (53.7%) and managing psychological distress (43.9%). Conclusion: Active assessment of psychological distress and unmet information needs is relevant in patients with heart failure, thus highlighting the importance of their identification and the correct design and application of evidence-based interventions aimed at their resolution.

Introducción: La insuficiencia cardiaca crónica (ICC) es una enfermedad que reduce de manera aguda y progresiva la funcionalidad física. El paciente comúnmente sufre de recaídas intermitentes que aumentan la probabilidad de comorbilidades como insomnio crónico, deterioro cognitivo, alteraciones en la respuesta sexual, estrés psicológico, síntomas de trastorno de ansiedad y depresión y disminución de las conductas de autocuidado. Objetivo: Identificar las principales necesidades de apoyo psicológico en pacientes con IC. Metodología: Se realizó un estudio descriptivo, transversal y analítico. Se evaluaron 150 pacientes con ICC del Centro Especializado en Insuficiencia Cardiaca del Instituto Nacional de Cardiología Ignacio Chávez de noviembre de 2018 a abril de 2019. Se aplicaron los inventarios: Calidad de vida en pacientes con IC (Minnesota), Escala de Ansiedad y Depresión Hospitalaria (HADS), termómetro del distrés psicológico (escala analógica visual) y el Inventario de Necesidades de Información del Paciente con IC. Resultados: Treinta y tres por ciento de los pacientes perciben un nivel alto de distrés psicológico que requiere asistencia inmediata y el 26.6% reporta un nivel medio que requiere monitoreo. Las principales necesidades de información reportadas por los pacientes fueron información sobre la toma de medicamentos (53.7%) y manejo del estrés psicológico (43.9%). Conclusión: En pacientes con IC es relevante la valoración activa de distrés psicológico y necesidades de información no cubiertas, resaltando de este modo la importancia de su identificación y el correcto diseño y aplicación de intervenciones basadas en la evidencia enfocadas a su resolución.

Design and manufacture of a coronary stent INC-1 and initial tests in experimental animal model.

In this paper, we describe our coronary stent (INC-1) design and development, the way that we found the specific characteristics needed for our device including biophysics aspects, design, finite element testing, manufacturing, and mechanic trials, we submitted and animal models experiences. The stent platform was cobalt-chromium L605 (Co-Cr), with struts thickness of 80 µm, balloon expandable. We placed the coronary stent INC-1 on a rabbit and dog models so we can evaluate efficacy and security of the device in relationship to its biomechanical properties including navigation capacity, traceability, symmetric expansion, and safety, as well as endothelial attachment, thrombogenicity, and lack of involvement of secondary branches in these models. We succeeded in efficacy and safety of the device after fluoroscopy-guided implant proving excellent capacity of release system, traceability, fluoroscopic visualization, symmetric expansion, and complete endothelial attach. Furthermore, we obtained a good post-implant balloon withdrawal, functional integrity, and no vascular complications. We observed adequate clinical evolution 3 weeks after the stent implantation.

En esta publicación se describen el diseño y el desarrollo de un stent coronario (INC-1), la forma en que se determinaron las características biofísicas deseadas, el diseño y las pruebas computacionales por elemento finito, su fabricación, así como las pruebas mecánicas a las que se sometió el prototipo y por último las primeras experiencias en modelos animales. La plataforma del stent desarrollado fue de cobalto y cromo L605 (Co-Cr), con struts de 80 µm de grosor, expandido por balón. La colocación del stent coronario INC-1 se realizó en un modelo de conejo y uno canino con el objetivo de evaluar el éxito técnico y de seguridad del stent en relación con las propiedades biomecánicas (capacidad de navegación, maniobrabilidad, expansión simétrica del stent) y de seguridad (fijación a la pared vascular y ausencia de compromiso de ramas secundarias y formación de trombos en el momento de la colocación del stent en el modelo animal). Se obtuvo éxito técnico y de seguridad del stent después del implante guiado por fluoroscopia, lo que demostró adecuada capacidad del sistema liberador, excelente maniobrabilidad, adecuada visualización fluoroscópica, expansión simétrica y fijación completa a la pared vascular, capacidad para retirar el balón desinflado después del implante, e integridad funcional y sin complicaciones vasculares. La evolución clínica fue favorable a tres semanas del seguimiento planeado.

Design, manufacture and initial tests of a drug-eluting coronary stent.

INTRODUCTION: A drug-eluting coronary stent is being developed at the National Institute of Cardiology of Mexico for the treatment of ischemic heart disease. OBJECTIVE: To establish the best animal model for the tests, to show the advances in the drug-eluting stent prototype, to assess two drugs' antiproliferative activity and histological results. METHOD: Smooth muscle cell culture tests were performed in order to assess sirolimus and paclitaxel antiproliferative properties. The drugs were encapsulated inside the polymeric matrix of the stents. Rabbits and pigs were used as animal models. RESULTS: Sirolimus and paclitaxel showed an inhibitory effect, which was higher for the latter. Infrared spectroscopy and light and optical microscopy showed that the drug/polymer layer properly adhered to the stent. At a four-week follow-up, both animal models showed satisfactory clinical evolution and adequate histological response, although the porcine model was shown to be more suitable for future protocols. CONCLUSIONS: Preliminary tests of the drug-eluting stent provided bases for the development of a study protocol with an adequate number of pigs and with clinical angiographic and histopathological three-month follow-up.

INTRODUCCIÓN: En el Instituto Nacional de Cardiología de México se desarrolla una endoprótesis (stent) coronaria liberadora de fármacos para el tratamiento de la cardiopatía isquémica. OBJETIVO: Establecer el mejor modelo animal para las pruebas, mostrar los avances en el prototipo del stent liberador de fármacos, evaluar la actividad antiproliferativa de dos fármacos y los resultados histológicos. MÉTODO: Se realizaron cultivos de células de músculo liso para evaluar las propiedades antiproliferativas de sirolimus y paclitaxel. Los fármacos fueron encapsulados en el interior de la matriz polimérica de los stents. Se emplearon conejos y cerdos como modelos animales. RESULTADOS: Sirolimus y paclitaxel mostraron efecto inhibitorio, mayor en el segundo. La espectroscopia infrarroja y la microscopia óptica y electrónica mostraron que la capa del polímero con el fármaco se adhería adecuadamente al stent. A las cuatro semanas de seguimiento, ambos modelos animales mostraron evolución clínica satisfactoria y adecuada respuesta histológica, si bien el modelo porcino resultó más conveniente para protocolos futuros. CONCLUSIONES: Las pruebas preliminares del stent liberador de fármaco brindó bases para desarrollar el protocolo con un número adecuado en cerdos y con seguimiento clínico angiográfico e histopatológico a tres meses.

Design, manufacture and initial tests of a drug-eluting coronary stent / Diseño, fabricación y pruebas iniciales de una endoprótesis coronaria liberadora de fármaco

Abstract Introduction: A drug-eluting coronary stent is being developed at the National Institute of Cardiology of Mexico for the treatment of ischemic heart disease. Objective: To establish the best animal model for the tests, to show the advances in the drug-eluting stent prototype, to assess two drugs’ antiproliferative activity and histological results. Method: Smooth muscle cell culture tests were performed in order to assess sirolimus and paclitaxel antiproliferative properties. The drugs were encapsulated inside the polymeric matrix of the stents. Rabbits and pigs were used as animal models. Results: Sirolimus and paclitaxel showed an inhibitory effect, which was higher for the latter. Infrared spectroscopy and light and optical microscopy showed that the drug/polymer layer properly adhered to the stent. At a four-week follow-up, both animal models showed satisfactory clinical evolution and adequate histological response, although the porcine model was shown to be more suitable for future protocols. Conclusions: Preliminary tests of the drug-eluting stent provided bases for the development of a study protocol with an adequate number of pigs and with clinical angiographic and histopathological three-month follow-up.

Resumen Introducción: En el Instituto Nacional de Cardiología de México se desarrolla una endoprótesis (stent) coronaria liberadora de fármacos para el tratamiento de la cardiopatía isquémica. Objetivo: Establecer el mejor modelo animal para las pruebas, mostrar los avances en el prototipo del stent liberador de fármacos, evaluar la actividad antiproliferativa de dos fármacos y los resultados histológicos. Método: Se realizaron cultivos de células de músculo liso para evaluar las propiedades antiproliferativas de sirolimus y paclitaxel. Los fármacos fueron encapsulados en el interior de la matriz polimérica de los stents. Se emplearon conejos y cerdos como modelos animales. Resultados: Sirolimus y paclitaxel mostraron efecto inhibitorio, mayor en el segundo. La espectroscopia infrarroja y la microscopia óptica y electrónica mostraron que la capa del polímero con el fármaco se adhería adecuadamente al stent. A las cuatro semanas de seguimiento, ambos modelos animales mostraron evolución clínica satisfactoria y adecuada respuesta histológica, si bien el modelo porcino resultó más conveniente para protocolos futuros. Conclusiones: Las pruebas preliminares del stent liberador de fármaco brindó bases para desarrollar el protocolo con un número adecuado en cerdos y con seguimiento clínico angiográfico e histopatológico a tres meses.

Specific macrophage subsets accumulate in human subcutaneous and omental fat depots during obesity.

Obesity is a chronic inflammatory disease associated with adipose tissue macrophage (ATM) activation. ATMs from lean mice contribute to tissue homeostasis by their M2-oriented polarization, whereas obesity leads to an increase of M1 inflammatory ATMs that underlies obesity-related metabolic disorders. In humans, studies characterizing ATMs and their functional status are limited. Here we investigated ATM phenotype in visceral (VAT) and subcutaneous (SAT) adipose tissue from healthy lean and obese individuals using two molecules previously identified as markers of M1-like and M2-like/tissue-resident macrophages, the C-type lectin CLEC5A and the scavenger receptor CD163L1, respectively. CD163L1 was expressed by the majority of ATMs, and CD163L1+ ATM density was greater with respect to cells expressing the pan-macrophage markers CD68 or CD11b. ATM counts in SAT, but not in VAT, increased in obese compared to lean individuals, measured with the three markers. Accordingly, CD163L1, CD68 and ITGAM gene expression was significantly enhanced in obese with respect to control individuals only in SAT. CLEC5A+ ATMs had a proinflammatory profile and were abundant in the lean VAT, but their density diminished in obesity. The only ATM subset that increased its counts in the obese VAT had a mixed M1-like (CD11c+ CD163- CD209- ) and M2-like (CLEC5A- CD206+ ) phenotype. ATM expansion was dominated by a subset of M2-like macrophages (CD11c- CLEC5A- CD163+ CD206+ CD209+ ) in the obese SAT, with a minor contribution of a CD11c+ CLEC5A- ATM subpopulation. Thus, both SAT and VAT seems to limit inflammation during obesity by differentially altering their ATM subset composition.

Design and manufacture of a coronary stent INC-1 and initial tests in experimental animal model / Diseño y fabricación del stent coronario INC-1y pruebas iniciales en animales de experimentación

Abstract In this paper, we describe our coronary stent (INC-1) design and development, the way that we found the specific characteristics needed for our device including biophysics aspects, design, finite element testing, manufacturing, and mechanic trials, we submitted and animal models experiences. The stent platform was cobalt-chromium L605 (Co-Cr), with struts thickness of 80 μm, balloon expandable. We placed the coronary stent INC-1 on a rabbit and dog models so we can evaluate efficacy and security of the device in relationship to its biomechanical properties including navigation capacity, traceability, symmetric expansion, and safety, as well as endothelial attachment, thrombogenicity, and lack of involvement of secondary branches in these models. We succeeded in efficacy and safety of the device after fluoroscopy-guided implant proving excellent capacity of release system, traceability, fluoroscopic visualization, symmetric expansion, and complete endothelial attach. Furthermore, we obtained a good post-implant balloon withdrawal, functional integrity, and no vascular complications. We observed adequate clinical evolution 3 weeks after the stent implantation.

Resumen En esta publicación se describen el diseño y el desarrollo de un stent coronario (INC-1), la forma en que se determinaron las características biofísicas deseadas, el diseño y las pruebas computacionales por elemento finito, su fabricación, así como las pruebas mecánicas a las que se sometió el prototipo y por último las primeras experiencias en modelos animales. La plataforma del stent desarrollado fue de cobalto y cromo L605 (Co-Cr), con struts de 80 μm de grosor, expandido por balón. La colocación del stent coronario INC-1 se realizó en un modelo de conejo y uno canino con el objetivo de evaluar el éxito técnico y de seguridad del stent en relación con las propiedades biomecánicas (capacidad de navegación, maniobrabilidad, expansión simétrica del stent) y de seguridad (fijación a la pared vascular y ausencia de compromiso de ramas secundarias y formación de trombos en el momento de la colocación del stent en el modelo animal). Se obtuvo éxito técnico y de seguridad del stent después del implante guiado por fluoroscopia, lo que demostró adecuada capacidad del sistema liberador, excelente maniobrabilidad, adecuada visualización fluoroscópica, expansión simétrica y fijación completa a la pared vascular, capacidad para retirar el balón desinflado después del implante, e integridad funcional y sin complicaciones vasculares. La evolución clínica fue favorable a tres semanas del seguimiento planeado.

Design and manufacture of a coronary stent INC-1 and initial tests in experimental animal model.

In this paper we describe our coronary stent (INC-1) design and development, the way that we found the specific characteristics needed for our device including biophysics aspects, design, finite element testing, manufacturing and mechanic trials we submitted and animal models experiences. The stent platform was cobalt-chromium L605 (Co-Cr), with struts thickness of 80 µm, balloon expandable. We placed the coronary stent INC-1 on a rabbit and dog models so we can evaluate efficacy and security of the device in relationship to its biomechanical properties including navigation capacity, traceability, symmetric expansion and safety. As well as endothelial attachment, thrombogenicity and lack of involvement of secondary branches in these models. We succeeded in efficacy and safety of the device after fluoroscopy-guided implant proving excellent capacity of release system, traceability, fluoroscopic visualization, symmetric expansion and complete endothelial attach. Also, we obtained a good post-implant balloon withdrawal, functional integrity and no vascular complications. We observed adequate clinical evolution 3 weeks after the stent implantation.

En esta publicación se describen el diseño y el desarrollo de un stent coronario (INC-1), la forma en que se determinaron las características biofísicas deseadas, el diseño y las pruebas computacionales por elemento finito, su fabricación, así como las pruebas mecánicas a las que se sometió el prototipo y por último las primeras experiencias en modelos animales. La plataforma del stent desarrollado fue de cobalto y cromo L605 (Co-Cr), con struts de 80 µm de grosor, expandido por balón. La colocación del stent coronario INC-1 se realizó en un modelo de conejo y uno canino con el objetivo de evaluar el éxito técnico y de seguridad del stent en relación con las propiedades biomecánicas (capacidad de navegación, maniobrabilidad, expansión simétrica del stent) y de seguridad (fijación a la pared vascular y ausencia de compromiso de ramas secundarias y formación de trombos en el momento de la colocación del stent en el modelo animal). Se obtuvo éxito técnico y de seguridad del stent después del implante guiado por fluoroscopia, lo que demostró adecuada capacidad del sistema liberador, excelente maniobrabilidad, adecuada visualización fluoroscópica, expansión simétrica y fijación completa a la pared vascular, capacidad para retirar el balón desinflado después del implante, e integridad funcional y sin complicaciones vasculares. La evolución clínica fue favorable a tres semanas del seguimiento planeado.

HUMAN PILOT STUDY OF BARE-METAL STENT: INC-01.

BACKGROUND: The cost of performing a percutaneous coronary intervention is considerably high for the patient as well as for health systems, which have promoted the development of local technology to help meet the need for these devices. METHODS: The INC-01 bare-metal stent was developed at the National Institute of Cardiology in Mexico City and was first implanted on porcine models with technical success in 100% of the evaluated parameters. PRESENTATION OF CASES: We present the first three cases of patients with ischemic heart disease, to whom the INC-01 bare-metal stent was implanted. Intracoronary ultrasonography was performed post-stent implantation, showing all the characteristics of implant success during evaluation and clinical follow-up. CONCLUSIONS: Angiography and intracoronary ultrasound were carried out demonstrating that the INC-01 bare-metal stent has physical, biological, and histological characteristics similar to those found in commercial metallic stents.

THE BRANCHED-CHAIN AMINO ACID TRANSAMINASE 1 -23C/G POLYMORPHISM CONFERS PROTECTION AGAINST ACUTE CORONARY SYNDROME.

BACKGROUND: Previous studies have shown an association between polymorphisms of the BAT1-NF-κB inhibitor-like-1 (NFKBIL1)-LTA genomic region and susceptibility to myocardial infarction and acute coronary syndrome (ACS). OBJECTIVE: The objective of the study was to study the role of three polymorphisms in the BAT1, NFKBIL1, and LTA genes on the susceptibility or protection against ACS; we included a group of cases-controls from Central Mexico. METHODS: The BAT1 rs2239527C/G, NFKBIL1 rs2071592T/A, and LTA rs1800683G/A polymorphisms were genotyped using a 5' TaqMan assay in a group of 625 patients with ACS and 617 healthy controls. RESULTS: Under a recessive model, the BAT1 -23C/G (rs2239527) polymorphism showed an association with protection against ACS (odds ratio = 0.56, and p-corrected = 0.019). In contrast, the genotype and allele frequencies of the NFKBIL1 rs2071592T/A and LTA rs1800683G/A polymorphisms were similar between ACS patients and controls and no association was identified. CONCLUSION: Our data suggest an association between the BAT1 -23C/G polymorphism and protection against ACS in Mexican patients.

The branched-chain amino acid transaminase 1 -23c/g polymorphism confers protection against acute coronary syndrome

ABSTRACT Background: Previous studies have shown an association between polymorphisms of the BAT1-NF-κB inhibitor-like-1 (NFKBIL1)-LTA genomic region and susceptibility to myocardial infarction and acute coronary syndrome (ACS). Objective: The objective of the study was to study the role of three polymorphisms in the BAT1, NFKBIL1, and LTA genes on the susceptibility or protection against ACS; we included a group of cases-controls from Central Mexico. Methods: The BAT1 rs2239527C/G, NFKBIL1 rs2071592T/A, and LTA rs1800683G/A polymorphisms were genotyped using a 5' TaqMan assay in a group of 625 patients with ACS and 617 healthy controls. Results: Under a recessive model, the BAT1 -23C/G (rs2239527) polymorphism showed an association with protection against ACS (odds ratio = 0.56, and p-corrected = 0.019). In contrast, the genotype and allele frequencies of the NFKBIL1 rs2071592T/A and LTA rs1800683G/A polymorphisms were similar between ACS patients and controls and no association was identified. Conclusion: Our data suggest an association between the BAT1 -23C/G polymorphism and protection against ACS in Mexican patients.