Lung Transplant Immunomodulation with Genetically Engineered Mesenchymal Stromal Cells-Therapeutic Window for Interleukin-10.

Lung transplantation results are compromised by ischemia-reperfusion injury and alloimmune responses. Ex vivo lung perfusion (EVLP) is used to assess marginal donor lungs before transplantation but is also an excellent platform to apply novel therapeutics. We investigated donor lung immunomodulation using genetically engineered mesenchymal stromal cells with augmented production of human anti-inflammatory hIL-10 (MSCsIL-10). Pig lungs were placed on EVLP for 6 h and randomized to control (n = 7), intravascular delivery of 20 × 106 (n = 5, low dose) or 40 × 106 human MSCs IL-10 (n = 6, high dose). Subsequently, single-lung transplantation was performed, and recipient pigs were monitored for 3 days. hIL-10 secretion was measured during EVLP and after transplantation, and immunological effects were assessed by cytokine profile, T and myeloid cell characterization and mixed lymphocyte reaction. MSCIL-10 therapy rapidly increased hIL-10 during EVLP and resulted in transient hIL-10 elevation after lung transplantation. MSCIL-10 delivery did not affect lung function but was associated with dose-related immunomodulatory effects, with the low dose resulting in a beneficial decrease in apoptosis and lower macrophage activation, but the high MSCIL-10 dose resulting in inflammation and cytotoxic CD8+ T cell activation. MSCIL-10 therapy during EVLP results in a rapid and transient perioperative hIL-10 increase and has a therapeutic window for its immunomodulatory effects.

Engineered mesenchymal stromal cell therapy during human lung ex vivo lung perfusion is compromised by acidic lung microenvironment.

Ex vivo lung perfusion (EVLP) is an excellent platform to apply novel therapeutics, such as gene and cell therapies, before lung transplantation. We investigated the concept of human donor lung engineering during EVLP by combining gene and cell therapies. Premodified cryopreserved mesenchymal stromal cells with augmented anti-inflammatory interleukin-10 production (MSCIL-10) were administered during EVLP to human lungs that had various degrees of underlying lung injury. Cryopreserved MSCIL-10 had excellent viability, and they immediately and efficiently elevated perfusate and lung tissue IL-10 levels during EVLP. However, MSCIL-10 function was compromised by the poor metabolic conditions present in the most damaged lungs. Similarly, exposing cultured MSCIL-10 to poor metabolic, and especially acidic, conditions decreased their IL-10 production. In conclusion, we found that "off-the-shelf" MSCIL-10 therapy of human lungs during EVLP is safe and feasible, and results in rapid IL-10 elevation, and that the acidic target-tissue microenvironment may compromise the efficacy of cell-based therapies.

Human Umbilical Cord Perivascular Cells and Human Bone Marrow Mesenchymal Stromal Cells Transplanted Intramuscularly Respond to a Distant Source of Inflammation.

Intravenously administered mesenchymal stromal cells (MSCs) are rapidly entrapped in the lungs, where they display an anti-inflammatory phenotype. Intramuscular (IM) delivery provides an increased MSC dwell-time, which could result in a sustained modulation of an inflammatory milieu. We studied the therapeutic effects of IM delivered MSCs to treat a distant (contralateral) inflammation, and compared the efficacy of neonatal (umbilical cord) and adult bone marrow MSCs (BMMSCs). Inflammation decreased over 48 h, but neonatal cells showed an earlier response than BMMSCs. Tumor necrosis factor-induced gene-6 (TSG-6) was released at the site of MSC delivery, while neutrophil infiltration was abrogated and inflammation reduced at the contralateral site. MSCs did not distribute to the organs or to the site of inflammation. Thus, IM delivery presents a promising alternative for the treatment of inflammation, and neonatal MSCs may represent a stronger candidate than those derived from adult BM to treat inflammatory diseases.

Evaluation of biological production of lactic acid in a synthetic medium and in Aloe vera (L.) Burm. f. processing by-products / Evaluation of biological production of lactic acid in a synthetic medium and in Aloe vera (L.) Burm. f. processing by-products / Avaliação da produção biológica de ácido lático em um meio sintético e no processamento de subprodutos de Aloe vera (L.) Burm. f.

This study evaluated lactic acid production through batch fermentation in a bioreactor with Thermoanaerobacter sp. strain USBA-018 and a chemically defined culture medium and with hydrolyzed pressed extract of Aloe vera peel (AHE). The strain USBA-018 fermented various sugars, but its primary end-product was L-lactic acid. Factors which influenced L- lactic acid production were pH, addition of yeast extract (YE) and manganese chloride. Under the most favorable growing conditions for the production of lactic acid, yield (Yp/s) increased from 0.66 to 0.96 g/g with a productivity (Qp) of 0.62 g.l-1.h and a maximum lactic acid concentration of 178 mM at 26 hours of fermentation. When AHE was used, 93.3 mM, or 0.175 g.l-1.h, was obtained. These results show the potential for transformation of sugars that strain USBA-018 offers, but additional studies are needed to find out if different strategies using AHE as carbon source can produce large enough quantities of lactic acid to allow AHE to become a low-cost alternative substrate.

Este estudio evaluó la producción de ácido láctico de la cepa de Thermoanaerobacter sp. USBA-018 en un biorreactor de fermentación por lotes, utilizando como medios de cultivo una formulación químicamente definida y un extracto prensado e hidrolizado de cáscara de Aloe vera (AHE). La cepa USBA-018 fermentó varios azúcares, pero su principal producto final fue L-ácido láctico. Los factores que influyeron en la producción de L-ácido láctico fueron pH, adición de extracto de levadura (YE) y de cloruro de manganeso. Bajo las condiciones más favorables de crecimiento para la producción de ácido láctico el rendimiento (Yp/s) aumentó de 0.66 a 0.96 g/g, con una productividad (Qp) de 0.62 g.l-1.h y una máxima concentración de ácido láctico de 178 mM a las 26 horas de fermentación. Cuando se usó AHE, se obtuvieron 93.3 mM, o 0.175 g.l-1.h. Estos resultados muestran el potencial de transformación de azúcares que ofrece la cepa USBA-018, pero se requieren estudios adicionales para determinar si diferentes estrategias de uso de AHE como fuente de carbono producen cantidades suficientemente grandes de ácido láctico como para permitir que el AHE se convierta en un sustrato alternativo de bajo costo.

Este estudo avaliou a produção de ácido lático por meio de fermentação descontinua em um biorreator com Thermoanaerobacter sp. cepa USBA-018 e um meio de cultura químicamente definido e com extrato hidrolisado de casca de Aloe vera (AHE). A cepa USBA-018 fermentou vários acucares, mas seu produto final primàrio foi L-ácido lático. Os fatores que influenciaram a produção de L-ácido lático foram o pH, adição de extrato de levedura (YE) e cloreto de manganès. Sob as condicoes de crescimento mais favoráveis para a produção de ácido lático, o rendimento (Yp/S) aumentou de 0,66 a 0,96 g/g com uma produtividade (Q) de 0,62 g.L4.h e um máximo de concentração de ácido lático de 178 mM em 26 horas de fermentação. Quando o AHE foi utilizado, se obteve 93,3 mM ou 0,175 g.L-1.h. Estes resultados mostram o potencial para transformação de acucares que a cepa USBA-018 oferece, entretanto estudos adicionais sáo necessários para descobrir se diferentes estrategias utilizando o AHE como fonte de carbonos podem produzir quantidades de ácido lático grandes o suficiente para permitir que AHE se converta em um substrato alternativo de baixo custo.

Niveles urinarios de angiotensina-(1-7) y angiotensina II en pacientes con estenosis aórtica de importante repercusión hemodinámica / Urinary levels of angiotensin-(1-7) and angiotensin II in patients with severe aortic stenosis

Objetivo:Reforzar el conocimiento sobre la fisiopatología de la estenosis aórtica. Métodos: Se compararon los niveles urinarios de angiotensina II y angiotensina-(1-7) entre dos muestras: a) 45 pacientes con estenosis aórtica de importante repercusión hemodinámica, sin hipertensión arterial sistémica y con funciones renal y sistólica ventricular izquierda normales; b) grupo de control con 21 voluntarios sin patología cardiovascular. Hipótesis nula: no habría diferencia entre los niveles urinarios. Resultados:El promedio de la concentración urinaria de angiotensina-(1-7) en pacientes con estenosis aórtica fue 2.102 pmoles/mL y de 5.591 pmoles/mL para el grupo control. La media obtenida en concentración urinaria de angiotensina II fue de 0.704 pmoles/mL en los pacientes con estenosis aórtica y 0.185 pmoles/mL en el grupo control. Utilizando la prueba t de Student determinamos que la diferencia en la concentración urinaria de angiotensina-(1-7) (p = 0.633) y la diferencia en la concentración urinaria de angiotensina II (p = 0.631), fueron estadísticamente significativas. Conclusión:Se documentó una diferencia estadísticamente significativa en los niveles urinarios de angiotensina II y angiotensina-(1-7) dentro del grupo de pacientes con estenosis aórtica de importante repercusión hemodinámica.

Objective:Strengthen knowledge about the pathophysiology of aortic stenosis. Methods: Urinary levels of angiotensin-(1-7) and angiotensin II were compared between two samples: A) forty five patients with severe aortic stenosis, without systemic arterial hypertension and with normal kidney and normal left ventricular systolic function; B) control group: twenty one persons without cardiovascular disease. Null hypothesis: there would be no difference between urinary levels. Results: The average of angiotensin-(1-7) urinary concentration in severe aortic stenosis patients was 2.102 pmol/mL and 5.591 pmol/mL for the control group. The average of Ang II was 0.704 pmol/mL and 0.185 pmol/mL respectively. Using t-Student test, we determine that the difference in urinary concentration of angiotensin-(1-7) [p = 0.633] and the difference of angiotensin II (p = 0.631), were statistically significant. Conclusion:documented a statistically significant difference in urinary levels angiotensin II and angiotensin-(1-7) within the group of patients with severe aortic stenosis.

[Penetrating atherosclerotic ulcer of the thoracic aorta: endovascular treatment, hybrid or surgery. A review]. / Aneurisma de aorta torácica por úlcera aterosclerótica penetrante: tratamiento endovascular, hibrido o cirugía. Revisión.

The aortic aneurysm is part of the acute aortic syndromes (AAS). Aortic aneurysms have a weakened tunica media. Acute aneurysm expansion may herald rupture with high morbility and mortality. Five percent of AAS are diagnosed as pentetrating atherosclerotic ulcer which is an ulceration of an atherosclerotic lesion of the aorta that penetrates the internal elastic lamina and allows hematoma formation within the tunica media of the aortic wall. Endovascular treatment is an alternative to surgery and has provided an adequate rate of successful repair. There is another type of treatment which combines surgery and endovascular repair (the hybrid open-endovascular repair) which provides adequate results. The afford mention case is about a patient with a penetrating atherosclerotic ulcer. The hematoma that results from this ulcer extends and self-contains the aneurysm, with a high risk of rupture. We will also describe the aneurysm treatment options.

Aneurisma de aorta torácica por úlcera aterosclerótica penetrante: tratamiento endovascular, hibrido o cirugía: revisión / Penetrating atherosclerotic ulcer of the thoracic aorta: endovascular treatment, hybrid or surgery: a review

The aortic aneurysm is part of the acute aortic syndromes (AAS). Aortic aneurysms have a weakened tunica media. Acute aneurysm expansion may herald rupture with high morbility and mortality. Five percent of AAS are diagnosed as pentetrating atherosclerotic ulcer which is an ulceration of an atherosclerotic lesion of the aorta that penetrates the internal elastic lamina and allows hematoma formation within the tunica media of the aortic wall. Endovascular treatment is an alternative to surgery and has provided an adequate rate of successful repair. There is another type of treatment which combines surgery and endovascular repair (the hybrid open-endovascular repair) which provides adequate results. The afford mention case is about a patient with a penetrating atherosclerotic ulcer. The hematoma that results from this ulcer extends and self-contains the aneurysm, with a high risk of rupture. We will also describe the aneurysm treatment options.

Elevación extrema de la presión arterial (crisis hipertensiva): recomendaciones para su abordaje clínico-terapéutico / Extreme elevation of the blood pressure (hypertensive crisis): recommendations for its clinical-therapeutic approach

From beginnings of last century the hypertensive emergency was defined as the association of acutely elevation from the arterial pressure and the appearance of damage to end organ. At present is recognized the effects of the hypertensive emergency, the aspects of its patophysiology in which are included phenomenon of vasomotricity and the participation of different substances with vasoactives properties. The clinical presentation includes not only the manifestations of the increase of the arterial pressure, the end organ damage too; for this reason the hypertensive emergency needs the immediate reduction of the arterial tension to prevent the damage to specific organs. The treatment in every case will have to be individualized, with a wide knowledge of the characteristics of every medicament to obtain the best results. The diagnosis and treatment of the hypertensive emergencies needs often of the attention of its complications if they have appeared and later, of a treatment of support for the arterial hypertension.

Prevención y tratamiento de la hipertensión arterial sistémica en el paciente con enfermedad arterial coronaria / Prevention and treatment of hypertension and coronary heart disease

The association between arterial systemic hypertension arterial coronary disease has been demonstrated by cumulated evidence of several epidemiological studies. Hypertension is an important independent risk factor for the development of coronary artery disease, vascular cerebral disease and nephropathy. Important advances exist in the knowledge of neurohumoral and hemodynamic factors that come together in the pathophysiology of the hypertension and in the development of coronary disease that allow to establish better strategies not only of treatment, but also of prevention, with the purpose of diminishing the cardiovascular mortality. The spectrum of the coronary artery disease secondary to atherosclerosis is wide and the strategies of treatment of hypertension must be adapted to each particular case. The treatment of both conditions needs of specific limits of agreement to the conditions of the patient and the form of presentation of each one of these disease.

Obstrucción en la vía de salida del ventrículo derecho en la miocardiopatía hipertrófica obstructiva. Informe de un caso y revisión de la literatura / Obstruction of the right ventricular outflow tract on the obstructive hypertrophic cardiomyopathy. Case report and literature review

OHC is a disorder with a broad spectrum of morphological, functional and genetics abnormalities. The Obstruction on the Right Ventricular Outflow (OHCRV) is not expected most of the time, that's way it is not usually detected and rarely mentioned in the cardiological literature. Its clinical presentation may include basically systemic venous hypertension symptoms that come with the hypertrophic cardyomiopathy manifestations. The manifestations of an apparent Right Ventricular Hypertrophic (RVH) in the ECG are probably due to the huge septal vector that activates the septum with a major thickness. The clinical confirmation of the obstruction on the OHCRV produced by a considerable asymmetric septal hypertrophic is easily shown with bidimensional an Doppler echocardiography.

Re-encuesta Nacional de Hipertensión Arterial (RENAHTA): Consolidación Mexicana de los Factores de Riesgo Cardiovascular. Cohorte Nacional de Seguimiento / National Re-survey of Arterial Hypertension (RENAHTA). Mexican consolidation of the cardiovascular risk factors. National Follow-up Cohort

Propósito: A través de una Re-encuesta Nacional sobre Hipertensión Arterial Sistémica (HTAS) y Factores de Riesgo Cardiovascular, en población adulta con HTAS identificada en encuestas nacionales de salud del año 2000; Determinar: 1) Las tasas de morbilidad y mortalidad. 2) La incidencia e interrelación en el tiempo con otros factores de riesgo, tales como Obesidad, Dislipidemia, Diabetes y Tabaquismo. 3) Los principales factores de riesgo asociados a HTAS que influencian la aparición de complicaciones, necesidad y numero de días de hospitalización. 4) El grado de adherencia y tipo de medicación usada por el paciente hipertenso. Métodos: La Re-encuesta Nacional de Hipertensión (RENAHTA) fue realizada en el periodo 2003-2004. La encuesta es tipo III del método paso a paso descrito por la OMS. La población estudiada correspondió en su mayoría (73%) a individuos detectados en encuestas nacionales previas. El muestreo fue ponderado a priori tomando en cuenta una prevalencia nacional promedio de HTAS de 30.05% y su correspondiente para cada estado de la República. Error máximo permisible en la estimación = 0.28, Efecto de diseño = 4.5; y, Tasa de respuesta esperada (0.70). Resultados: De 14 567 como muestra inicial, 1165 (8%) sujetos fueron considerados como no hipertensos o falsos positivos en el año 2000. De los 13,402 pacientes restantes se informaron 335 muertes ocurridas en los primeros 2 años de seguimiento (2000-2002), lo que implicó una mortalidad anual de ˜1.15% en la población hipertensa. Así, 13,067 sobrevivientes, fueron sujetos a análisis. La edad al momento de la re-encuesta fue 45.6 ± 12.6. El (40.5%) fueron hombres (n=5,295), hubo diferencia estadísticamente significativa en la talla, pero no en el peso entre ambos géneros. El control de la HTAS subió de 14.6% en el 2000 a 19.2% en el 2004. Se duplicó la cifra de diabéticos de 16% a 30% (p < .001). El 54% de la población estudiada requirió de hospitalización al menos ...

Objective: Based on a National Re-survey on Hypertension (HTA) and other cardiovascular risk factors performed in Mexico during 2003 and 2004 in the adult population with HTA, as identified in the 2000 National Survey of Health, this study was planed to determine: 1) morbidity and mortality rates; 2) the incidence and interrelation with other risk factors, such as overweight, obesity, dyslipidemia, nephropathy and diabetes; 3) the main risk factors associated to HTA involved in its complications, need for hospitalization and number of days; and, 4) the degree of therapeutical adhesion and the type of antihypertensive drugs used. Methods: The survey was of type III using the step by step method described by WHO. Sampling was weighed a priori taking into account a national prevalence average of HTA of 30.05% and its corresponding rate for each federal state. Permissible maximum error in the estimation = 0.28. Effect of design = 4.5; and, Rate of awaited answer (0.70). Results: From the initial 14,567 interviewed patients, 1,165 (8%) subjects were considered non-hypertensive or false positives at the 2000 survey. From the 13,402 remaining patients, 335 died during the first 2 years of pursuit, which implies an annual mortality of ˜1.15% in the hypertensive population. Thus, 13,067 survivors were subjected to the final analysis. The mean age at the re-survey was 45.6 ± 12.6; 40.5% were men (n = 5,295). There was a statistically significant difference in height, but not in weight between both genders. The control HTAwas raised 14.6% in the year 2000 and 19.2% in 2004. The prevalence of diabetes was duplicated from 16% to 30% (< .001). Fifty four percent of the whole population required hospitalization at least once during the period of study. The rates of overweight, obesity, and dyslipidemia rose significantly (p < 0.05) independently from age, federal state, and gender. Conclusion: RENAHTA shows the impact of hypertension on the morbidity and mortality during the 3.1 ± 1.5 years of follow-up in Mexico. It alerts us on the need to reinforce the strategies of attention and prevention of this crucial risk factor and of screening the dynamic nonlinear interaction between the main cardiovascular risk factors in Mexico. New hypotheses are proposed forthe metabolic syndrome.