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Background Nonagenarians are mostly denied from different therapeutic strategies due to high preoperative risk. We present the results of nonagenarians with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Methods Our retrospective analysis include baseline and procedural data along with clinical outcome. Clinical follow-up was performed in all patients after TAVR. Results Out of 689 patients, 33 nonagenarians with a mean age of 90.9 ± 1.4 years suffering from severe AS and elevated comorbidity index (logistic EuroSCORE of 16.3 ± 9.6%, STS score 11.1 ± 9.9%) underwent TAVR between September 2009 and July 2016 using self-expanding prosthesis. Baseline transthoracic echocardiography reported a mean aortic valve area (AVA) of 0.64 ± 0.12 cm2 with a mean pressure gradient of 56.1 ± 16.1 mmHg. Five (16.2%) patients had postprocedural moderate/severe aortic regurgitation. One patient died intraoperally due to ventricular perforation during predilatation, while two patients died within the first 30 days, one due to cardiogenic shock and the other due to pneumonia. No patient experienced a myocardial infarction or a stroke, while ten (30.3%) required permanent pacemaker placement. At follow-up (mean 20.3 months, range 1–78 months), all cause and cardiovascular mortality was 24.2% and 15.1%, respectively. Two patients presented heart failure and 12 (40%) had exertional dyspnea. By echo, mean valve area was 1.72 ± 0.12 cm2 and mean gradient 11.2 ± 1.4 mmHg. Two patients (16.7%) presented moderate aortic regurgitation. Conclusion Our case series demonstrate that even with elevated comorbidity index, clinical endpoints and valve-associated results are relatively favorable in nonagenarians treated with TAVR.

Pluripotent stem cells are promising source of cells for tissue engineering, regenerative medicine and drug discovery applications. The process of stem cell differentiation is regulated by multi-parametric cues from the surrounding microenvironment, one of the critical one being cell interaction with extracellular matrix (ECM). The ECM is a complex tissue-specific structure which is an important physiological regulator of stem cell function and fate. Recapitulating this native ECM microenvironment niche is best facilitated by decellularized tissue/organ derived ECM, which can faithfully reproduce the physiological environment with high fidelity to in vivo condition and promote tissue-specific cellular development and maturation. Recognizing the need for organ specific ECM in a 3D culture environment in driving phenotypic differentiation and maturation of hPSCs, we fabricated an ECM array platform using native-mimicry ECM from decellularized organs (namely pancreas, liver and heart), which allows cell-ECM interactions in both 2D and 3D configuration. The ECM array was integrated with rapid quantitative imaging for a systematic investigation of matrix protein profiles and sensitive measurement of cell-ECM interaction during hPSC differentiation. We tested our platform by elucidating the role of the three different organ-specific ECM in supporting induced pancreatic differentiation of hPSCs. While the focus of this report is on pancreatic differentiation, the developed platform is versatile to be applied to characterize any lineage specific differentiation.

RESUMEN Introducción: El acceso radial se ha asociado a numerosos beneficios en angioplastia coronaria en comparación con el acceso femoral. Sin embargo, múltiples registros internacionales han reportado una escasa adherencia a esta técnica. Objetivos: Evaluar la seguridad, la eficacia y la eficiencia operativa de la angioplastia coronaria según la vía de acceso utilizada y el cuadro clínico del paciente. Métodos: Análisis de registro, unicéntrico y retrospectivo de los pacientes con enfermedad coronaria tratados con angioplastia coronaria desde marzo de 2009 a junio de 2018, según el acceso vascular. Se aplicó un modelo de regresión de Cox ajustado para evaluar la relación entre la vía de acceso y el riesgo de eventos cardiovasculares mayores y un modelo de regresión logística para evaluar la relación con el sangrado mayor y las complicaciones del acceso vascular. La eficiencia operativa se evaluó mediante la medición del tiempo de internación total y los costos totales asociados a esta. Resultados: Se incluyeron 8155 angioplastias coronarias (seguimiento promedio 1448,6 ± 714,1 días), mediante acceso radial (n = 5706) o acceso femoral (n = 2449). A los 30 días, el riesgo de eventos cardiovasculares mayores se redujo significativamente con el acceso radial (HR 0,66 [0,5-0,88], p = 0,004), a expensas de una reducción de la mortalidad total. A su vez, el acceso radial redujo significativamente el riesgo de sangrado mayor (HR 0,33 [0,16- 0,67], p = 0,002) y de complicaciones del acceso vascular (HR 0,72 [0,53-0,98], p = 0,038). Se observó una interacción significativa entre la vía de acceso y el riesgo de eventos según el cuadro clínico al ingreso. Se observó una reducción significativa del tiempo total de internación (≈30%) y de sus costos totales (≈15%) mediante el uso del acceso radial. Conclusiones: El uso del acceso radial en angioplastia coronaria es seguro y eficaz en comparación con el acceso femoral, con menores tasas de eventos cardiovasculares mayores a los 30 días, como, así también, un menor riesgo de sangrado mayor y complicaciones del acceso vascular. Asimismo, el acceso radial se asoció con una mayor eficiencia operativa durante la internación. ABSTRACT Background: Radial access has been associated with many advantages in percutaneous coronary intervention compared with femoral access. However, many international registries have reported poor adherence to this technique. Objectives: The aim of this study was to evaluate the safety, efficacy and operational efficiency of percutaneous coronary intervention according to the access site and the clinical presentation of the patient. Methods: A single-center, retrospective registry of patientis with coronary artery disease undergoing percutaneous coronary intervention was conducted from March 2009 to June 2018 according to the vascular access. A Cox proportional-hazards model was used to analyze the association between vascular access and risk of major cardiovascular eventis, and a logistic regression model was applied to assess the relationship between major bleeding and access site complications. Total hospital stay and total hospitalization costis were measured to evaluate the operational efficiency. Resultis: A total of 8,155 percutaneous coronary interventions (mean follow-up of 1,448.6±714.1 days), via radial access (n=5,706) or femoral access (n=2,449), were included in the study. At 30 days, the risk of major cardiovascular eventis was significantly lower with the radial access (HR 0.66 [0.5-0.88], p=0.004), at the expense of a reduction in all-cause mortal-ity In addition, radial access significantly reduced the risk of major bleeding (HR 0.33 [0.16-0.67], p=0.002) and access site complications (HR 0.72 [0.53-0.98], p=0.038). A significant interaction was observed between the vascular access site and the risk of eventis according to the clinical presentation at admission. Use of radial access was associated with a significant reduction in the length of total hospital stay (≈30%) and total hospitalization costis (≈15%). Conclusions: The use of radial access in percutaneous coronary intervention was safe and effective compared with the femoral access, with lower rates of major cardiovascular eventis at 30 days, lower risk of major bleeding and of access site complications. Moreover, radial access was associated with greater operational efficiency during hospitalization.

Organoids, which exhibit spontaneous organ specific organization, function, and multi-cellular complexity, are in essence the in vitro reproduction of specific in vivo organ systems. Recent work has demonstrated human pluripotent stem cells (hPSCs) as a viable regenerative cell source for tissue-specific organoid engineering. This is especially relevant for engineering islet organoids, due to the recent advances in generating functional beta-like cells from human pluripotent stem cells. In this study, we report specific engineering of regenerative islet organoids of precise size and cellular heterogeneity, using a novel hydrogel system, Amikagel. Amikagel facilitated controlled and spontaneous aggregation of human embryonic stem cell derived pancreatic progenitor cells (hESC-PP) into robust homogeneous spheroids. This platform further allowed fine control over the integration of multiple cell populations to produce heterogeneous spheroids, which is a necessity for complex organoid engineering. Amikagel induced hESC-PP spheroid formation enhanced pancreatic islet-specific Pdx-1 and NKX6.1 gene and protein expression, while also increasing the percentage of committed population. hESC-PP spheroids were further induced towards mature beta-like cells which demonstrated increased Beta-cell specific INS1 gene and C-peptide protein expression along with functional insulin production in response to in vitro glucose challenge. Further integration of hESC-PP with biologically relevant supporting endothelial cells resulted in multicellular organoids which demonstrated spontaneous maturation towards islet-specific INS1 gene and C-peptide protein expression along with a significantly developed extracellular matrix support system. These findings establish Amikagel -facilitated platform ideal for islet organoid engineering.

Human embryonic stem cells (hESCs) are characterized by both their pluripotency and ability to self-renew, rendering them attractive for treatment of degenerative diseases. The cues necessary to induce hESC differentiation to a desired lineage can be categorized as either chemical or biophysical in nature. While chemical cues are used as primary inducers of differentiation, biophysical cues have been found to augment the process. In this regard, we have designed a novel chitosan nanoparticle augmented encapsulated alginate (CNPEA) platform which can not only augment, but induce differentiation of hESCs into the definitive endoderm (DE) lineage in the absence of specific soluble chemical inducers. These endoderm cells were comparable in phenotype with chemically driven DE cells and remained amenable to further maturation into pancreatic lineages. This study demonstrates the feasibility of carefully designed and tailored nanomaterials inducing differentiation, and moreover demonstrating the possibility of replacing growth factors by material cues.

Basement membranes (BMs) are thin sheets of extracellular matrix that outline epithelia, muscle fibers, blood vessels and peripheral nerves. The current view of BM structure and functions is based mainly on transmission electron microscopy imaging, in vitro protein binding assays, and phenotype analysis of human patients, mutant mice and invertebrata. Recently, MS-based protein analysis, biomechanical testing and cell adhesion assays with in vivo derived BMs have led to new and unexpected insights. Proteomic analysis combined with ultrastructural studies showed that many BMs undergo compositional and structural changes with advancing age. Atomic force microscopy measurements in combination with phenotype analysis have revealed an altered mechanical stiffness that correlates with specific BM pathologies in mutant mice and human patients. Atomic force microscopy-based height measurements strongly suggest that BMs are more than two-fold thicker than previously estimated, providing greater freedom for modelling the large protein polymers within BMs. In addition, data gathered using BMs extracted from mutant mice showed that laminin has a crucial role in BM stability. Finally, recent evidence demonstrate that BMs are bi-functionally organized, leading to the proposition that BM-sidedness contributes to the alternating epithelial and stromal tissue arrangements that are found in all metazoan species. We propose that BMs are ancient structures with tissue-organizing functions and were essential in the evolution of metazoan species.

RESUMEN: Introducción: Actualmente no hay consenso sobre el manejo anestésico más adecuado en el implante valvular aórtico percutáneo por vía transfemoral. Aunque se ha demostrado la factibilidad de concretar el procedimiento bajo anestesia local con sedación consciente o sin esta, los resultados clínicos reportados son controvertidos. Objetivos: Evaluar la seguridad y eficacia del implante valvular aórtico percutáneo por vía transfemoral realizado bajo anestesia general versus anestesia local con sedación consciente. Material y métodos: Análisis unicéntrico y retrospectivo de los pacientes con estenosis aórtica grave sintomática con alto riesgo quirúrgico sometidos a un implante valvular aórtico percutáneo por vía transfemoral desde marzo de 2009 a diciembre de 2016, según el manejo anestésico. Los desenlaces de seguridad y eficacia fueron evaluados a 30 días según las definiciones del Valve Academic Research Consortium-2. Además, se evaluaron los principales tiempos durante la internación. Resultados: Se incluyeron 121 pacientes (Edad 83,2 ± 5,7 años, hombres 48,8%), tratados con un implante valvular aórtico percutáneo por vía transfemoral bajo anestesia general (n = 55, 45,5%) o anestesia local con sedación consciente (n = 66, 54,5%). No se observaron diferencias significativas en los resultados intraprocedimiento ni en los desenlaces de seguridad y eficacia a 30 días. La mortalidad a 30 días fue del 7,3% en el grupo AG y del 3% en el grupo anestesia local con sedación consciente 3%, p log-rank 0,28 (mortalidad global 5%). La necesidad de conversión a anestesia general se presentó en 2 pacientes (3%), por complicaciones vasculares mayores durante el procedimiento. El grupo anestesia local con sedación consciente presentó menor tiempo total de procedimiento, internación en unidad de cuidados intensivos e internación total. Conclusión: El implante valvular aórtico percutáneo por vía transfemoral realizado bajo anestesia local con sedación consciente, parece ser una alternativa segura y eficaz al uso de anestesia general. Abstract: Background: Currently, there is no consensus about the most adequate anesthetic management in transfemoral transcatheter aortic valve replacement. Although it has been shown that local anesthesia (LA) with or without conscious sedation is feasible, clinical results are controversial. Objective: The aim of this study was to evaluate the safety and efficacy of transfemoral transcatheter aortic valve replacement performed under general anesthesia versus local anesthesia with conscious sedation. Methods: This was a single-center, retrospective study of high risk patients with severe aortic stenosis undergoing transfemoral transcatheter aortic valve replacement between March 2009 and December 2016. The population was divided according to anesthetic management. Safety and efficacy outcomes were evaluated at 30-days and were classified according to definitions of the Valve Academic Research Consortium-2. In addition, key times during hospitalization were evaluated. Results: A total of 121 patients undergoing transfemoral transcatheter aortic valve replacement under general anesthesia (n=55, 45.5%) or local anesthesia with conscious sedation (n=66, 54.5%). were included in this analysis. Mean age was 83.2±5.7 years and 48.8% were men. There were no differences in either the procedural result or in the 30-day efficacy and safety outcomes. The rate of death at 30-days was 7.3% in the group with general anesthesia and 3% in the local anesthesia with conscious sedation group (log-rank p 0.28). The need of conversion to general anesthesia was 3% (2 patients), in all cases due to major vascular complications during the procedure. In the local anesthesia with conscious sedation group shorter procedural time, intensive care unit and hospital length of stay were observed. Conclusions: Transfemoral transcatheter aortic valve replacement performed under local anesthesia with conscious sedation seems to be a safe and effective alternative to the use of general anesthesia.

Introducción: El seudoaneurisma es una complicación ocasional (0,05-0,5%) de los procedimientos intervencionistas cuando se utiliza el acceso femoral. El cierre con inyección local de trombina como alternativa al tratamiento quirúrgico luego de compresión manual fallida cuenta con escasos registros. Objetivo: Evaluar la seguridad y eficacia del cierre del seudoaneurisma femoral iatrogénico mediante la inyección local de trombina guiada por ecografía Doppler. Material y métodos: Entre marzo de 2007 y junio de 2016 se incluyeron 32 pacientes para tratamiento con inyección de trombina. Resultados: La edad media fue de 64,3 ± 10,2 años. La mayoría de los seudoaneurismas estuvieron asociados con la realización de cateterismos coronarios diagnósticos o terapéuticos (59,3%). Siete pacientes habían recibido tratamiento anticoagulante y 21 doble antiagregación plaquetaria. En todos los casos se intentó previamente el cierre por compresión manual. La media del diámetro mayor de los seudoaneurismas fue de 38 mm. Luego del tratamiento, la trombosis inmediata del saco ocurrió en 28 pacientes (87,5%), mientras que 4 pacientes requirieron una segunda inyección, lo que determinó un éxito del 96,8%. En un solo paciente este tratamiento no fue efectivo, con posterior conversión a reparación quirúrgica programada. La dosis media de trombina fue de 450 unidades. Un único paciente presentó complicación trombótica venosa que requirió terapia anticoagulante, con buena evolución clínica. Conclusión: El tratamiento del seudoaneurisma con inyección local de trombina guiada con eco-Doppler fue una alternativa terapéutica segura y eficaz para pacientes con seudoaneurisma femoral refractarios a la compresión manual. Background: Pseudoaneurysm is a rare complication (0.05-0.5%) after interventional procedures using femoral access. There are few registries of local thrombin injection for pseudoaneurysm closure as an alternative treatment to surgery after failed manual compression. Objective: The aim of this study was to evaluate the safety and efficacy of iatrogenic femoral pseudoaneurysm closure with Doppler ultrasound-guided local thrombin injection. Methods: Thirty-two patients were included for thrombin injection treatment between March 2007 and June 2016. Results: Mean age was 64.3±10.2 years. Most pseudoaneurysms were associated with diagnostic or therapeutic cardiac cath-eterizations (59.3%). Seven patients had received anticoagulant treatment and 21, double antiplatelet therapy. In all cases, prior closure was attempted by manual compression. Mean pseudoaneurysm major diameter was 38 mm. Following treatment, immediate pseudoaneurysm sac thrombosis occurred in 28 patients (87.5%), while 4 patients required a second injection, resulting in 96.8% success rate. Treatment was not effective in only one patient, with subsequent conversion to programmed surgical repair. Mean thrombin dose was 450 units. Only one patient presented with venous thrombosis complication requir-ing anticoagulant therapy, with good clinical outcome. Conclusion: Doppler ultrasound-guided local thrombin injection was a safe and effective therapeutic alternative for pseudoa-neurysm treatment in patients with femoral pseudoaneurysm refractory to manual compression.

Objectives To assess the mortality in patients with diabetes mellitus (DM) following percutaneous coronary intervention (PCI) according to their insulin requirement and PCI setting (elective, urgent, and emergency). Background DM is a major risk factor to develop coronary artery disease (CAD). It is unclear if meticulous glycemic control and aggressive risk factor management in patients with DM has improved outcomes following PCI. Methods Retrospective analysis of prospectively collected data on 9,224 patients treated with PCI at a regional tertiary center between 2008 and 2011. Results About 7,652 patients were nondiabetics (non‐DM), 1,116 had non‐insulin treated diabetes mellitus (NITDM) and 456 had ITDM. Multi‐vessel coronary artery disease, renal impairment and non‐coronary vascular disease were more prevalent in DM patients. Overall 30‐day mortality rate was 2.4%. In a logistic regression model, the adjusted odds ratios (95% confidence intervals [CI]) for 30‐day mortality were 1.28 (0.81–2.03, P = 0.34) in NITDM and 2.82 (1.61–4.94, P

γ2 adaptin is homologous to γ1, but is only expressed in vertebrates while γ1 is found in all eukaryotes. We know little about γ2 functions and their relation to γ1. γ1 is an adaptin of the heterotetrameric AP-1 complexes, which sort proteins in and do form clathrin-coated transport vesicles and they also regulate maturation of early endosomes. γ1 knockout mice develop only to blastocysts and thus γ2 does not compensate γ1-deficiency in development. γ2 has not been classified as a clathrin-coated vesicle adaptor protein in proteome analyses and functions for monomeric γ2 in endosomal protein sorting have been proposed, but adaptin interaction studies suggested formation of heterotetrameric AP-1/γ2 complexes. We detected γ2 at the trans-Golgi network, on peripheral vesicles and identified γ2 clathrin-coated vesicles in mice. Ubiquitous σ1A and tissue-specific σ1B adaptins bind γ2 and γ1. σ1B knockout in mice does not effect γ1/σ1A AP-1 levels, but γ2/σ1A AP-1 levels are increased in brain and adipocytes. Also γ2 is essential in development. In zebrafish AP-1/γ2 and AP-1/γ1 fulfill different, essential functions in brain and the vascular system.

The σ1 subunit of the AP-1 clathrin-coated-vesicle adaptor-protein complex is expressed as three isoforms. Tissues express σ1A and one of the σ1B and σ1C isoforms. Brain is the tissue with the highest σ1A and σ1B expression. σ1B-deficiency leads to severe mental retardation, accumulation of early endosomes in synapses and fewer synaptic vesicles, whose recycling is slowed down. AP-1/σ1A and AP-1/σ1B regulate maturation of these early endosomes into multivesicular body late endosomes, thereby controlling synaptic vesicle protein transport into a degradative pathway. σ1A binds ArfGAP1 and with higher affinity brain-specific ArfGAP1, which bind Rabex-5. AP-1/σ1A-ArfGAP1-Rabex-5 complex formation leads to more endosomal Rabex-5 and enhanced, Rab5GTP-stimulated Vps34 PI3-kinase activity, which is essential for multivesicular body endosome formation. Formation of AP-1/σ1A-ArfGAP1-Rabex-5 complexes is prevented by σ1B binding of Rabex-5 and the amount of endosomal Rabex-5 is reduced. AP-1 complexes differentially regulate endosome maturation and coordinate protein recycling and degradation, revealing a novel molecular mechanism by which they regulate protein transport besides their established function in clathrin-coated-vesicle formation.

Resumen es: Introduccion El tratamiento antiagregante dual con aspirina y clopidogrel constituye un tratamiento esencial para la prevencion de eventos isquemicos en ...

Key Points Diabetes mellitus (DM) is a multisystem disorder and a recognized risk factor for coronary artery disease (CAD) and DM patient are particularly challenging for revascularization. In this “real world” retrospective study post-PCI DM patients showed a high risk profile compared to the non-DM group, given by the higher prevalence of cardiovascular risk factors, multiple vessel disease, and renal dysfunction, with the highest rates seen in the ITDM. Only ITDM patients present higher 30-day mortality compared to non-DM patients in the urgent and primary PCI setting. Also ITDM, but not those NITDM patients, had an increased long-term mortality in the overall cohort and in all PCI setting.

BACKGROUND The relationship of the ischemic time to primary angioplasty and the quality of myocardial reperfusion according to infarcted territory among patients with ST-segment elevation myocardial infarction (STEMI) is unclear. METHODS This study consisted of 140 patients with STEMI within 12 h from the symptom onset and undergoing a primary angioplasty from the Protection of Distal Embolization in High-Risk Patients with Acute ST-Segment Elevation Myocardial Infarction Trial. ST-segment resolution (STR) at 60 min was analyzed by an independent corelab using continuous ST monitoring. Patients were divided according to anterior (n=74) and nonanterior (n=64) locations and according to ischemic time in quartiles (

Type 1 diabetes affects more than a million people in the United States and many more across the world. While pharmaceutical interventions and insulin supplementation are the most commonplace treatment of diabetes, these are not essentially cures and can potentially lead to long-term complications. Transplantation of insulin-producing Islets of Langerhans from donor pancreas has been established as a promising alternative to diabetes therapy. While successful islet transplantation has the potential of providing a cure, the primary hurdles to be overcome for it to be clinically viable are the scarcity of donor islets and immune rejection of transplanted islets. Recent advances in stem cell culture and differentiation techniques have established stem cells as a likely source of transplantable islets. Different stem cell sources have been induced toward pancreatic differentiation using specific chemical perturbations along with use of specific substrates. An approach to overcoming the second hurdle of immune rejection of transplantable islets is to encapsulate the islets in specific biomaterials. In this review, we discuss the extensive use of various substrates for pancreatic differentiation of different stem cell sources, along with different biomaterial designs used for islet transplantation.

Purpose Some forms of congenital muscular dystrophy are associated with cortical and retinal dysplasias. Protein O-mannose N-acetylglucosaminyltransferase 1 (POMGnT1) knockout mice, one of the mouse models of muscular dystrophy, exhibit a thinner retina with reduced density of retinal ganglion cells. This study is aimed to further characterize the knockout retina, with special emphasis on the inner limiting membrane, the basement membrane of the retina. Methods Immunofluorescence staining and transmission electron microscopy were used to analyze the retinas. Atomic force microscopy was performed on the inner limiting membrane preparations to examine their mechanical properties. Results The inner limiting membrane of the knockout mice exhibited frequent breaks with protrusions of the Müller glial processes and ectopic placement of retinal ganglion cells into the vitreous humor. Disruptions in inner limiting membrane integrity developmentally precede the cellular abnormalities. Regions of disrupted inner limiting membrane were also associated with molecular abnormalities of Müller glia that included diminished presence of the integral membrane proteins Kir4.1 (an inwardly rectifying potassium channel) and aquaporin-4. When measured with atomic force microscopy, the POMGnT1 knockout mouse inner limiting membrane (ILM) exhibited significantly reduced Young’s modulus and is therefore mechanically weaker than the ILM from controls. Conclusions Deficiency of POMGnT1-mediated glycosylation of dystroglycan is implicated in reduced stiffness of the ILM. The weakened ILM results in the disruption of the membrane and subsequent reduction in retinal integrity.

RESUMENIntroducciónEl pronóstico de los pacientes que sufren un infarto agudo de miocardio con supradesniveldel ST (IAMST) ha mejorado notoriamente, en particular como resultado de la terapia dereperfusión. A pesar de estos avances, los pacientes con diabetes mellitus (DM) constituyenun grupo de alto riesgo. La hiperglucemia en pacientes con IAMST se asocia con peor pronóstico, independientemente del diagnóstico previo de DM.ObjetivoEvaluar el valor pronóstico de la glucemia en ayunas (GA) durante un IAMST tratado conangioplastia primaria.Material y métodosDe 227 pacientes con diagnóstico de IAMST se excluyeron 31 con DM y 7 derivados paraterapia de rescate tardío. Se registraron la glucemia en la admisión (GAd) y la GA; la población se dividió según la GA en: grupo A ³ 110 mg/dl (hiperglucémicos) y grupo B < 110 mg/dl (normoglucémicos).ResultadosLa población en estudio quedó conformada por 189 pacientes. La edad fue de 62,1 ± 10,5años, sexo masculino 82%, tabaquistas 40%, el tiempo dolor-balón fue de 2,75 horas (25-75% intercuartiles 2-4,75), el porcentaje con clasificación de Killip & Kimball (KK) ³ 3 fuedel 12,1% y el 38% presentaron localización anterior. Se registraron 15 (7,9%) muertesintrahospitalarias, todas en pacientes hiperglucémicos. Por análisis multivariado, lospredictores independientes de mortalidad intrahospitalaria fueron la edad (p = 0,048) y laGA como variable continua (p = 0,002). Para los eventos cardíacos mayores (muerte, reIAMe insuficiencia cardíaca), la clasificación de KK ³ 3 (p = 0,001), la GA (p = 0,001) y eldeterioro moderado/grave de la función sistólica (p = 0,016) fueron sus únicos predictoresindependientes. La GAd no resultó predictora independiente de muerte o de eventos cardíacosmayores.ConclusionesLos resultados del presente estudio sugieren que la GA posee valor pronóstico a corto plazoen pacientes no diabéticos que cursan un IAMST. La GA identifica tempranamente y enforma sencilla a una población de riesgo alto.REV ARGENT CARDIOL 2009;77:361-366.

IntroducciónEl surgimiento de los stents liberadores de droga (SLD) ha disminuido la tasa de reintervención del vaso tratado (RVT). No obstante, incluso con SLD, el tratamiento percutáneo de lesiones en bifurcación aún constituye un desafío debido a una tasa todavía elevada de RVT.ObjetivoEvaluar los resultados clínicos en pacientes con bifurcaciones tratados con SLD o sin éstos en un centro de alto volumen.Material y métodosDesde abril de 2003 hasta agosto de 2006 se realizaron 1.910 angioplastias; 235 (12,3%) pacientes presentaron bifurcaciones.ResultadosLa edad de los pacientes incluidos fue de 62 ± 11 años; el 86% era de sexo masculino, el 19,2% padecía diabetes y el 22,7% tenía cirugía coronaria previa. El 54% de los pacientes presentaron bifurcaciones verdaderas. Se utilizó SLD en el 44,3%; el 22,5% requirió el implante de dos stents (en ambas ramas), mientras que el procedimiento se concluyó con kissing balloon final en el 24,5% de los casos. En el seguimiento alejado (mediana 430 días), la RVT fue del 16,7%, 13,9% con SLD y 17,2% con stent convencional (SC) (p = ns). La tasa de trombosis angiográfica fue del 3%, 1,9% para SLD y 4,6% para stent convencional (p = ns). Las tasas de infarto y muerte cardíaca fueron del 3,4% y del 2,9%, respectivamente, sin diferencias entre los dos grupos. La tasa combinada de muerte cardíaca, infarto, trombosis y RVT fue del 21,7%, 16,3% con SLD y 25,2% con stent convencional (p = 0,04).ConclusiónEl tratamiento percutáneo de lesiones en bifurcación continúa siendo un desafío. Es probable que técnicas más simples con implante de un solo stent, preferentemente SLD, y la implementación de kissing balloon final sea la opción más recomendable en la mayoría de los casos.

Heart valve interstitial cells (VICs) appear to have a dynamic and reversible phenotype, an attribute speculated to be necessary for valve tissue remodeling during times of development and repair. Therefore, we hypothesized that the cytoskeletal (CSK) remodeling capability of the aortic and pulmonary VICs (AVICs and PVICs, respectively), which are dominated by smooth muscle alpha-actin, would exhibit unique contractile behaviors when seeded on collagen gels. Using a porcine cell source, we observed that VIC populations did not contract the gels at early time points (2 and 4 hours) as dermal fibroblasts did, but formed a central cluster of cells prior to contraction. After clustering, VICs appeared to radiate out from the center of the gels, whereas fibroblasts did not migrate but contracted the gels locally. VIC gels treated with transforming growth factor beta1 contracted the gels rapidly, revealing similar sensitivity to the cytokine. Moreover, we evaluated the initial mechanical state of the underlying CSK by comparing AVIC and PVIC stiffness with atomic force microscopy. Not only were AVICs significantly stiffer (p < 0.001) than the PVICs, but they also contracted the gels significantly more at 24 and 48 hours (p < 0.001). Taken together, these findings suggest that the AVICs are capable of inducing greater extra cellular matrix contraction, possibly manifesting in a more pronounced ability to remodel valvular tissues. Moreover, significant mechanobiological differences between AVICs and PVICs exist, and may have implications for understanding native valvular tissue remodeling. Elucidating these differences will also define important functional endpoints in the development of tissue engineering approaches for heart valve repair and replacement.

Basement membranes are sheets of extracellular matrix that separate epithelia from connective tissues and outline muscle fibers and the endothelial lining of blood vessels. A major function of basement membranes is to establish and maintain stable tissue borders, exemplified by frequent vascular breaks and a disrupted pial and retinal surface in mice with mutations or deletions of basement membrane proteins. To directly measure the biomechanical properties of basement membranes, chick and mouse inner limiting membranes were examined by atomic force microscopy. The inner limiting membrane is located at the retinal-vitreal junction and its weakening due to basement membrane protein mutations leads to inner limiting membrane rupture and the invasion of retinal cells into the vitreous. Transmission electron microscopy and western blotting has shown that the inner limiting membrane has an ultrastructure and a protein composition typical for most other basement membranes and, thus, provides a suitable model for determining their biophysical properties. Atomic force microscopy measurements of native chick basement membranes revealed an increase in thickness from 137 nm at embryonic day 4 to 402 nm at embryonic day 9, several times thicker that previously determined by transmission electron microscopy. The change in basement membrane thickness was accompanied by a large increase in apparent Young's modulus from 0.95 MPa to 3.30 MPa. The apparent Young's modulus of the neonatal and adult mouse retinal basement membranes was in a similar range, with 3.81 MPa versus 4.07 MPa, respectively. These results revealed that native basement membranes are much thicker than previously determined. Their high mechanical strength explains why basement membranes are essential in stabilizing blood vessels, muscle fibers and the pial border of the central nervous system.

Encapsulation of donor islets using a hydrogel material is a well-studied strategy for islet transplantation, which protects donor islets from the host immune response. Replacement of donor islets by human embryonic stem cell (hESC) derived islets will also require a means of immune-isolating hESCs by encapsulation. However, a critical consideration of hESC differentiation is the effect of surrounding biophysical environment, in this case capsule biophysical properties, on differentiation. The objective of this study, thus, was to evaluate the effect of capsule properties on growth, viability, and differentiation of encapsulated hESCs throughout pancreatic induction. It was observed that even in the presence of soluble chemical cues for pancreatic induction, substrate properties can significantly modulate pancreatic differentiation, hence necessitating careful tuning of capsule properties. Capsules in the range of 4–7 kPa supported cell growth and viability, whereas capsules of higher stiffness suppressed cell growth. While an increase in capsule stiffness enhanced differentiation at the intermediate definitive endoderm (DE) stage, increased stiffness strongly suppressed pancreatic progenitor (PP) induction. Signaling pathway analysis indicated an increase in pSMAD/pAKT levels with substrate stiffness likely the cause of enhancement of DE differentiation. In contrast, sonic hedgehog inhibition was more efficient under softer gel conditions, which is necessary for successful PP differentiation. Statement of Significance Cell replacement therapy for type 1 diabetes (T1D), affecting millions of people worldwide, requires the immunoisolation of insulin-producing islets by encapsulation with a semi-impermeable material. Due to the shortage of donor islets, human pluripotent stem cell (hPSC) derived islets are an attractive alternative. However, properties of the encapsulating substrate are known to influence hPSC cell fate. In this work, we determine the effect of substrate stiffness on growth and pancreatic fate of encapsulated hPSCs. We precisely identify the range of substrate properties conducive for pancreatic cell fate, and also the mechanism by which substrate properties modify the cell signaling pathways and hence cell fate. Such information will be critical in driving regenerative cell therapy for long term treatment of T1D.

Antecedentes Estudios aleatorizados demostraron la superioridad del uso de stents liberadores de droga (SL) sobre el stent convencional (SC). La información en nuestro medio sobre el implante de SL es escasa. Objetivo Comparar los resultados clínicos obtenidos en pacientes sometidos a implante de SL versus SC en un centro terciario de la Argentina. Material y métodos Se incluyeron todos los pacientes sometidos a angioplastia electiva desde abril de 2003 hasta junio de 2005 y se dividieron en dos grupos: los pacientes sometidos a implante de uno o más SL (grupo SL, n = 373) y los sometidos solamente a implante de SC (grupo SC, n = 857). Resultados Las características basales fueron similares entre los dos grupos. En el grupo SL se observó un porcentaje mayor de lesiones en la arteria descendente anterior (50,6 versus 40,6%; p < 0,001) y de lesiones tipo reestenosis intrastent (16,6 versus 8,7%; p < 0,001) junto con un tamaño menor del vaso (3,01 ± 0,57 versus 3,11 ± 0,57; p = 0,068) y una longitud mayor de la lesión (20,6 ± 9,0 versus 15,9 ± 7,8; p < 0,001) que en el grupo SC. En cuanto a los stents implantados, su longitud total fue mayor (36,7 ± 18,1 versus 28,2 ± 17,7; p = 0,002) y su diámetro promedio fue menor en el grupo SL que en el SC (3,09 ± 0,47 versus 3,17 ± 0,44; p = 0,007). Se observó una tasa similar de muerte, infarto y revascularización de urgencia a los 30 días de seguimiento. Al año, en el grupo SL se redujo la incidencia de nuevas revascularizaciones (7,2% versus 11,7%; p > 0,001), gracias a una reducción de la tasa de cirugía coronaria (1,4% versus 5,8%; p = 0,045). Conclusión El uso de SL en un centro terciario de la Argentina demostró que es seguro y, en comparación con el implante de sólo SC, dio por resultado una tasa menor de reintervención, primariamente por haber reducido la tasa de cirugía de revascularización miocárdica

Esistono indicatori in grado di descrivere lo stato dell’innovazione digitale dei territori? È possibile tramite di essi esprimere la dinamicità dei cambiamenti e quindi evidenziare i trend? È quindi misurabile l’impatto delle politiche di innovazione perseguite dalla Pubblica Amministrazione locale? In questo testo si cerca di dare una risposta a queste domande, coinvolgendo esperti, amministratori, imprese, passando per big data, smart city, eGovernment intelligence e ponendo le premesse per la realizzazione di una infrastruttura tecnologica di rilevazione a supporto dei decisori pubblici., Scienza e società, volume 3

Adaptor protein (AP)-1/σ1B(-/-) mice have reduced synaptic-vesicle (SV) recycling and increased endosomes. Mutant mice have impaired spatial memory, and σ1B-deficient humans have a severe mental retardation. In order to define these σ1B(-/-) 'bulk' endosomes and to determine their functions in SV recycling, we developed a protocol to separate them from the majority of the neuronal endosomes. The σ1B(-/-) 'bulk' endosomes proved to be classic early endosomes with an increase in the phospholipid phosphatidylinositol 3-phosphate (PI-3-P), which recruits proteins mediating protein sorting out of early endosomes into different routes. σ1B deficiency induced alterations in the endosomal proteome reveals two major functions: SV protein storage and sorting into endolysosomes. Alternative endosomal recycling pathways are not up-regulated, but certain SV proteins are misrouted. Tetraspanins are enriched in σ1B(-/-) synaptosomes, but not in their endosomes or in their clathrin-coated-vesicles (CCVs), indicating AP-1/σ1B-dependent sorting. Synapses contain also more AP-2 CCV, although it is expected that they contain less due to reduced SV recycling. Coat composition of these AP-2 CCVs is altered, and thus, they represent a subpopulation of AP-2 CCVs. Association of calmodulin-dependent protein kinase (CaMK)-IIα, -δ and casein kinase (CK)-IIα with the endosome/SV pool is altered, as well as 14-3-3η, indicating changes in specific signalling pathways regulating synaptic plasticity. The accumulation of early endosomes and endocytotic AP-2 CCV indicates the regulation of SV recycling via early endosomes by the interdependent regulation of AP-2-mediated endocytosis and AP-1/σ1B-mediated SV reformation.

INTRODUÇÃO: O procedimento de implante transcateter da válvula aórtica (TAVI, do inglês transcatheter aortic valve implantation) representa opção de tratamento em pacientes com estenose valvar aórtica (EA) com risco cirúrgico elevado ou proibitivo. Relatamos nossa experiência usando o sistema autoexpansível Medtronic CoreValve®. MÉTODOS: No período de 2009 a 2013, 51 pacientes consecutivos com EA grave sintomática e risco cirúrgico alto ou proibitivo foram submetidos ao TAVI. Os resultados foram analisados de acordo com os critérios Valve Academic Research Consortium (VARC) -2. RESULTADOS: A média de idades dos pacientes foi 82 ± 6 anos, 49% eram do sexo feminino, 19% diabéticos, 21% tinham insuficiência renal e o EuroSCORE logístico foi 17,4 ± 11,4%. O sucesso do dispositivo foi alcançado em 84,3%. Todos os pacientes tiveram diminuição significativa dos gradientes transaórticos, que foi mantida ao longo do tempo. A internação hospitalar foi de 6 dias (intervalo interquartil: 5-8,8). A mortalidade intra-hospitalar e aos 30 dias foi 7,8% e 9,8%, respectivamente. Implante de marca-passo permanente foi necessário em 32,6% dos casos; acidente cerebrovascular isquêmico ocorreu em 3,9%; e complicações vasculares maiores em 6% dos pacientes. A sobrevivência aos 6 meses e em 1 ano foi 86,3% e 84,4%, respectivamente. A classe funcional NYHA melhorou significativamente após o TAVI e permaneceu baixa no seguimento de médio prazo. CONCLUSÕES: Nesta experiência preliminar, o tratamento de pacientes com EA e risco cirúrgico alto ou proibitivo com TAVI, usando o sistema autoexpansível CoreValve®, foi considerado viável e seguro, e levou à melhoria sustentável dos sintomas cardíacos. Após a superação dos riscos iniciais de morte e de acidente cerebrovascular, o procedimento garantiu um bom resultado clínico, no longo prazo. BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a treatment option for patients with aortic valve stenosis (AS) and high or prohibitive surgical risk. We report our experience using the Medtronic CoreValveTM self-expending system. METHODS: From 2009 to 2013, 51 consecutive patients with severe symptomatic AS and high or prohibitive surgical risk were submitted to TAVI. Results were analyzed according to the criteria of the Valve Academic Research Consortium (VARC) -2. RESULTS: Mean age was 82 ± 6 years, 49% were female, 19% were diabetic, 21% had renal failure and the logistic EuroScore was 17.4 ± 11.4%. The success rate of the device was 84.3%. All of the patients had a significant decrease of transaortic gradients, which was maintained over time. Hospitalization time was 6 days (interquartile range: 5-8,8). In-hospital mortality at 30 days was 7.8% and 9.8%, respectively. Permanent pacemaker implantation was required in 32.6% of the cases, ischemic stroke was observed in 3.9% and major vascular complications in 6% of the patients. Survival at 6 months and 1 year was 86.3% and 84.4%, respectively. NYHA functional class improved significantly after TAVI and remained low in the medium-term follow-up. CONCLUSIONS: In this preliminary experience, the treatment of patients with AS and high or prohibitive surgical risk with TAVI, using the CoreValveTM self-expanding system was feasible and safe and led to sustained improvement of cardiac symptoms. After overcoming the initial risks of death and stroke, the procedure guaranteed good long-term clinical outcomes.