Search

Resumen: Introducción y objetivos: El control glucémico postprandial es fundamental para conseguir los objetivos metabólicos en pacientes con diabetes mellitus tipo 1 (DM1). La nueva insulina faster aspart presenta un perfil farmacológico caracterizado por una absorción e inicio de acción más rápidos, mayor disponibilidad precoz y menor incremento de la glucosa postprandial. El objetivo principal del estudio fue analizar su eficacia en pacientes con DM1 tratados con un sistema integrado. Pacientes y métodos: Estudio analítico, longitudinal, prospectivo y multicéntrico, evaluando el empleo de faster aspart durante tres meses en pacientes en edad pediátrica con DM1 con sistema integrado MiniMed640G® tratados previamente con insulina aspart. Al inicio y final del estudio se analizaron para posterior comparación: glucosa media, porcentajes de tiempo en objetivo, tiempo en hipoglucemia e hiperglucemia, área bajo la curva (AUC) 180 mg/dL, glucosa media pre y postprandial en comidas principales, necesidades diarias de insulina, porcentaje basal/bolo y HbA1c. Se registraron complicaciones agudas y eventos adversos, y se evaluó grado de satisfacción mediante encuesta. Resultados: Se incluyeron 31 pacientes de 13,49 ± 2,42 años de edad con DM1 de 7,0 ± 3,67 años de evolución. Faster aspart se asoció con menor porcentaje de tiempo en hiperglucemia > 180 mg/dL (25,8 ± 11,3 vs. 22,4 ± 9,5; p = 0,011) y > 250 mg/dL (5,2 ± 4,9 vs. 4,0 ± 3,6; p = 0,04) y AUC > 180 mg/dL (10,8 ± 6,5 vs. 9,3 ± 6,1; p = 0,03), incrementándose el tiempo en objetivo (71,4 ± 10,0 vs. 74,3 ± 9,2; p = 0,03) sin aumentar hipoglucemias. Las necesidades de insulina, porcentajes basal/bolo y HbA1c no se modificaron significativamente. Faster aspart fue bien tolerada y valorada por los participantes. Conclusiones: Faster aspart consigue un mejor control glucémico, aumentando el tiempo de glucosa en objetivo en niños y adolescentes con DM1 en tratamiento con un sistema integrado. Abstract: Background and aims: Post-prandial glucose control is essential to achieve metabolic goals in patients with type 1 diabetes mellitus (T1DM). The new «faster aspart» insulin has a pharmacological profile noted for its faster absorption and onset of action, and increased early availability, resulting in improved blood glucose control after meals. The main objective of the study was to analyse the efficacy of «faster aspart» vs. «insulin aspart» in children and adolescents with DM1 on sensor-augmented pump treatment. Patients and methods: Multicentre, longitudinal and prospective analytical trial evaluating the use of faster aspart insulin for three months in children with T1DM with MiniMed640G® sensor-augmented pumps previously treated with aspart insulin. At the beginning and end of the study the following variables were analysed for subsequent comparison: mean sensor glucose, percentage of time in range, hypoglycaemia and hyperglycaemia, area under the curve (AUC) 180 mg/dL, mean sensor glucose pre and postprandial in main meals, daily insulin requirements, basal/bolus percentage, and HbA1c. Acute complications, adverse events and satisfaction survey were assessed. Results: The study included 31 patients with a mean of 13.49 ± 2.42 years of age and with T1DM of 7.0 ± 3.67 years of onset. The use of faster aspart was associated with lower time in hyperglycaemia > 180 mg/dL (25.8 ± 11.3 vs. 22.4 ± 9.5; p = 0.011) and > 250 mg/dL (5.2 ± 4.9 vs. 4.0 ± 3.6; p = 0.04), lower AUC > 180 mg/dL (10.8 ± 6.5 vs. 9.3 ± 6.1; p = 0.03), and increased time in range (71.4 ± 10.0 vs. 74.3 ± 9.2; p = 0.03). No significant changes in hypoglycaemia, HbA1c, insulin requirements, and basal/bolus percentages were detected. Faster aspart was safe and well-evaluated by patients and caregivers. Conclusions: Faster aspart achieves better glycaemic control by increasing glucose time in range in children and adolescents with T1DM on treatment with sensor-augmented pumps.

Considering the high prevalence of obesity and the lack of effective response to non-surgical treatments, bariatric surgery (BS) has been established as an increasingly frequent alternative, with implications on the physical, psychological and social level, highlighting the changes related to body image (BI). The objective of this study was to describe changes in BI expressed by young women undergoing BC. Based on a qualitative methodology, in-depth interviews were conducted with 10 women between 18 and 24 years. The results were grouped in Pre-BC: body dissatisfaction as motivation, low awareness of the obesity condition, shame of the body, frustration and difficulties with dressing; and Post-BS: body satisfaction associated with self-confidence, change in peer relations, new aspects of appearance, clothing associated with identity, difficulties in adapting to a new BI, and health team as support for adaptation. It is concluded that body satisfaction is a central aspect that affects individual and social wellbeing. Post-CB begins a process of adaptation to a new body scheme, with greater body satisfaction, but with difficulties related to body perception.ResumenDada la alta prevalencia de obesidad y la pobre efectividad de los tratamientos no quirúrgicos, la cirugía bariátrica (CB) constituye una alternativa cada vez más frecuente, con implicaciones a nivel físico, psicológico y social, entre las que destacan aquellas relativas a la imagen corporal (IC). El objetivo de este estudio fue describir los cambios en la IC manifestados por mujeres jóvenes sometidas a CB. Con base a una metodología cualitativa, se llevaron a cabo entrevistas a profundidad a 10 mujeres de entre 18 y 24 años de edad. Los resultados fueron categorizados en Pre-CB: insatisfacción corporal como motivación, baja conciencia de la condición de obesidad, vergüenza por el cuerpo, frustración y dificultades con la vestimenta; y Post-CB: satisfacción corporal (SC) asociada a autoconfianza, cambio en las relaciones con pares, nuevos aspectos de la apariencia, vestimenta asociada a identidad, dificultades en la adaptación a la nueva IC y equipo de salud como apoyo para la adaptación. Se concluye que la SC es un aspecto central que incide en el bienestar individual y social. Post-CB se inicia un proceso de adaptación a un nuevo esquema corporal, con mayor SC, pero con dificultades relacionadas a la percepción corporal.

Funder: Instituto Nacional de Salud, Bogotá, Colombia, Salmonella Typhi (S. Typhi) is the causative agent of typhoid fever; a systemic disease affecting ~20 million people per year globally. There are little data regarding the contemporary epidemiology of typhoid in Latin America. Consequently, we aimed to describe some recent epidemiological aspects of typhoid in Colombia using cases reported to the National Public Health Surveillance System (Sivigila) between 2012 and 2015. Over the four-year reporting period there were 836 culture confirmed cases of typhoid in Colombia, with the majority (676/836; 80.1%) of reported cases originated from only seven departments. We further characterized 402 S. Typhi isolates with available corresponding data recovered from various departments of Colombia through antimicrobial susceptibility testing and molecular subtyping. The majority (235/402; 58.5%) of these typhoid cases occurred in males and were most commonly reported in those aged between 10 and 29 years (218/402; 54.2%); there were three (0.74%) reported fatalities. The overwhelming preponderance (339/402; 84.3%) of S. Typhi were susceptible to all tested antimicrobials. The most common antimicrobial to which the organisms exhibited non-susceptibility was ampicillin (30/402;7.5%), followed by nalidixic acid (23/402, 5.7%). Molecular subtyping identified substantial genetic diversity, which was well distributed across the country. Despite the diffuse pattern of S. Typhi genotypes, we identified various geographical hotspots of disease associated with local dominant genotypes. Notably, we found limited overlap of Colombian genotypes with organisms reported in other Latin American countries. Our work highlights a substantial burden of typhoid in Colombia, characterized by sustained transmission in some regions and limited epidemics in other departments. The disease is widely distributed across the country and associated with multiple antimicrobial susceptible genotypes that appear to be restricted to Colombia. This study provides a current perspective for typhoid in Latin America and highlights the importance of pathogen-specific surveillance to add insight into the limited epidemiology of typhoid in this region.

Use of glyburide in gestational diabetes (GDM) has raised concerns about fetal and neonatal side effects, including increased birth weight. Placental nutrient transport is a key determinant of fetal growth, however the effect of glyburide on placental nutrient transporters is largely unknown. We hypothesized that glyburide treatment in GDM pregnancies is associated with increased expression of nutrient transporters in the syncytiotrophoblast plasma membranes. We collected placentas from GDM pregnancies who delivered at term and were treated with either diet modification (n = 15) or glyburide (n = 8). Syncytiotrophoblast microvillous (MVM) and basal (BM) plasma membranes were isolated and expression of glucose (glucose transporter 1; GLUT1), amino acid (sodium-coupled neutral amino acid transporter 2; SNAT2 and L-type amino acid transporter 1; LAT1) and fatty acid (fatty acid translocase; FAT/CD36, fatty acid transporter 2 and 4; FATP2, FATP4) transporters was determined by Western blot. Additionally, we determined GLUT1 expression by confocal microscopy in cultured primary human trophoblasts (PHT) after exposure to glyburide. Birth weight was higher in the glyburide-treated group as compared to diet-treated GDM women (3764 ± 126 g vs. 3386 ± 75 g; p 0.05). GLUT1 expression was increased in both MVM (+50%; p 0.01) and BM (+75%; p 0.01). In contrast, MVM FAT/CD36 (-65%; p = 0.01) and FATP2 (-65%; p = 0.02) protein expression was reduced in mothers treated with glyburide. Glyburide increased membrane expression of GLUT1 in a dose-dependent manner in cultured PHT. This data is the first to show that glyburide increases GLUT1 expression in syncytiotrophoblast MVM and BM in GDM pregnancies, and may promote transplacental glucose delivery contributing to fetal overgrowth.

Introduction Cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy (HIPEC) has recently been established as the treatment of choice for selected patients with peritoneal carcinomatosis of colonic origin. Until recently, the simultaneous presence of peritoneal and hepatic dissemination has been considered a contraindication for surgery. The aim of this paper is to analyze the morbidity, mortality and survival of patients with simultaneous peritoneal and hepatic resection with HIPEC for peritoneal carcinomatosis secondary to colon cancer. Methods Between January 2010 and January 2015, 61 patients were operated on, 16 had simultaneous peritoneal and hepatic dissemination (group RH+), and 45 presented only peritoneal dissemination (group RH−). Results There were no differences between the groups in terms of demographic data, length of surgery and extension of peritoneal disease. Postoperative grade III–V complications were significantly higher in the RH+ group (56.3 vs 26.6%; P =0.032). For the whole group, mortality rate was 3.2% (two patients in group RH−, and none in group RH+). Patients with liver resection had a longer postoperative stay (14.4 vs 23.1 days) ( P =.027). Median overall survival was 33 months for RH−, and 36 for RH+ group. Median disease-free survival was 16 months for RH−, and 24 months for RH+ group. Conclusions Simultaneous peritoneal cytoreduction and hepatic resection resulted in a significantly higher Clavien grade III–V morbidity and a longer hospital stay, although the results are similar to other major abdominal interventions. The application of multimodal oncological and surgical treatment may obtain similar long-term survival results in both groups.

Resumen Introduccion La citorreduccion con quimioterapia intraperitoneal hipertermica (HIPEC) se ha postulado como tratamiento de eleccion en pacientes seleccionados con carcinomatosis peritoneal por cancer de colon. La presencia simultanea de diseminacion peritoneal y hepatica ha sido considerada una contraindicacion para esta cirugia. El objetivo del presente estudio es analizar la morbimortalidad y supervivencia de los pacientes con carcinomatosis peritoneal por cancer de colon, intervenidos mediante una citorreduccion peritoneal y reseccion hepatica simultanea con HIPEC. Metodos Entre enero de 2010 y enero de 2015 se intervinieron 61 pacientes, 45 pacientes con carcinomatosis peritoneal (grupo RH−) y 16 con carcinomatosis peritoneal y metastasis hepaticas (grupo RH+). Resultados No hubo diferencias significativas entre los 2 grupos en los datos demograficos, ASA, duracion de la intervencion, ni extension de la enfermedad peritoneal. Las complicaciones postoperatorias Clavien III-V fueron significativamente superiores en el grupo RH+ (56,3 vs. 26,6%; p = 0,03). La mortalidad global de la serie fue del 3,2% (2 pacientes en el grupo RH− y ninguno en el grupo RH+). Los pacientes con reseccion hepatica presentaron una estancia hospitalaria significativamente mas larga (14,4 vs. 23,1 dias; p = 0,027). La mediana estimada de supervivencia global fue de 33 meses para RH− y de 36 meses para RH+, y la de supervivencia libre de enfermedad fue de 16 meses para RH− y de 24 para RH+. Conclusiones La citorreduccion peritoneal con reseccion hepatica simultanea presenta una morbilidad postoperatoria y una estancia hospitalaria significativamente mayores, aunque las cifras son similares a las de otras cirugias abdominales mayores. La aplicacion de un tratamiento oncologico y quirurgico multimodal permite obtener resultados de supervivencia similares en ambos grupos.

// Aroa Baragano Raneros 1 , Alfredo Minguela Puras 2 , Ramon M. Rodriguez 1 , Enrique Colado 3 , Teresa Bernal 3 , Eduardo Anguita 4 , Adela Vasco Mogorron 2 , Alberto Chaparro Gil 4 , Jose Ramon Vidal-Castineira 1 , Leonardo Marquez-Kisinousky 1 , Paula Diaz Bulnes 1 , Amelia Martinez Marin 5 , Maria Carmen Garcia Garay 6 , Beatriz Suarez-Alvarez 1, * , Carlos Lopez-Larrea 1, * 1 Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain 2 Immunology Service, Instituto Murciano de Investigacion Biosanitaria (IMIB), Hospital Clinico Universitario Virgen de la Arrixaca, Murcia, Spain 3 Department of Hematology, Hospital Universitario Central de Asturias, Oviedo, Spain 4 Hematology Department, Hospital Clinico San Carlos, Instituto de Investigacion Sanitaria San Carlos (IdISSC), Department of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain 5 Hematology Service, Hospital Clinico Universitario Virgen de la Arrixaca, Murcia, Spain 6 Hematology Service, Hospital General Universitario Santa Lucia, Cartagena, Murcia, Spain * These authors have contributed equally to this work Correspondence to: Carlos Lopez-Larrea, email: inmuno@hca.es Beatriz Suarez-Alvarez, email: bsuarez@hca.es Keywords: acute myeloid leukemia (AML), DNA methylation, NKG2DL, NKG2D, TIMP3 Received: September 16, 2016 Accepted: March 16, 2017 Published: March 29, 2017 ABSTRACT Acute myeloid leukemia (AML) is a disease with great morphological and genetic heterogeneity, which complicates its prognosis and treatment. The hypomethylating agents azacitidine (Vidaza ® , AZA) and decitabine (Dacogen ® , DAC) have been approved for the treatment of AML patients, but their mechanisms of action are poorly understood. Natural killer (NK) cells play an important role in the recognition of AML blasts through the interaction of the activating NKG2D receptor with its ligands (NKG2DL: MICA/B and ULBPs1-3). However, soluble NKG2DL (sNKG2DL) can be released from the cell surface, impairing immune recognition. Here, we examined whether hypomethylating agents modulate the release of sNKG2DL from AML cells. Results demonstrated that AZA- and DAC-treated AML cells reduce the release of sNKG2DL, preventing downregulation of NKG2D receptor on the cell surface and promoting immune recognition mediated by NKG2D-NKG2DL engagement. We show that the shedding of MICA, MICB and ULBP2 is inhibited by the increased expression of TIMP3, an ADAM17 inhibitor, after DAC treatment. The TIMP3 gene is highly methylated in AML cells lines and in AML patients (25.5%), in which it is significantly associated with an adverse cytogenetic prognosis of the disease. Overall, TIMP3 could be a target of the demethylating treatments in AML patients, leading to a decrease in MICA, MICB and ULBP2 shedding and the enhancement of the lytic activity of NK cells through the immune recognition mediated by the NKG2D receptor.

Dosing insulin is like a dance. The insulin dose is initially calculated, and then the blood glucose levels must be evaluated, in order to increase or decrease the insulin dose responsible for that blood glucose value. The goal is not to go chasing after the blood glucose has risen but to prevent its rise. For this, one must carefully take into account the quality and quantity of a given meal (and its carbohydrate content), the activity level, the patient’s health status, and how other medications could affect the blood glucose levels.

espanolIntroduccion: El bypass gastrico es una de las cirugias mas frecuentes en la obesidad. La intususcepcion intestinal es una de las complicaciones mas raras cuya incidencia en la literatura esta aumentando. Presentacion del caso: Se expone el caso de una mujer intervenida de bypass gastrico que sufre cuadro de intususcepcion intestinal inversa a los nueve anos precisando reseccion intestinal. Posteriormente presenta a los 3 meses nuevo episodio realizandose desinvaginacion. Cuatro anos despues de la ultima intervencion es operada por nuevo episodio de intususcepcion intestinal, cursando todos ellos con invaginacion retrograda. Conclusion: La intususcepcion intestinal tras bypass gastrico es una complicacion rara, que se puede presentar de manera recidivante, precisando un tratamiento quirurgico, por lo que todo cirujano debe tenerlo presente. EnglishIntroduction: Gastric bypass is one of the most common surgeries in obesity. Intestinal intussusception is one of the rarest complications whose incidence in the literature is increasing Presentation of the case: We present a case of a woman undergone gastric bypass surgery who suffers from a case of inverse intestinal intussusception nine years after the gastric bypass, requiring intestinal resection. Subsequently, three months later, she suffered a new episode performing a disinvagination. Four years after the last intervention, it was operated for a new episode of intestinal intussusception, all of them were retrograde invagination. Conclusion: Intestinal intussusception after gastric bypass is a rare complication, which can occur recurrently, requiring surgical treatment, so all surgeons should keep it in mind.

Obesity in pregnancy is associated with increased fetal growth and adiposity, which, in part, is determined by transplacental nutrient supply. Trophoblast uptake and intracellular trafficking of lipids are dependent on placental fatty acid transport proteins (FATP), translocase (FAT/CD36), and fatty acid binding proteins (FABP). We hypothesized that maternal obesity in mice leads to increased placental expression of FAT/CD36, FATPs, and FABPs, and lipid accumulation in the fetal liver. C57/BL6J female mice were fed either a control (C; n = 10) or an obesogenic (OB; n = 10) high-fat, high-sugar diet before mating and throughout pregnancy. At E18.5, placentas and fetal livers were collected. Trophoblast plasma membranes (TPM) were isolated from placental homogenates. Expression of FAT/CD36 and FATP (TPM) and FABP (homogenates) was determined by immunoblotting. Gene expression was assessed by RT-quantitative PCR. Sections of fetal livers were stained for Oil Red O, and lipid droplets were quantified. TPM protein expression of FAT/CD36, FATP 2, and FATP 4 was comparable between C and OB groups. Conversely, TPM FATP 6 expression was increased by 35% in OB compared with C placentas without changes in mRNA expression. FABPs 1, 3–5 and PPARγ were expressed in homogenates, and FABP 3 expression increased 27% in OB compared with C placentas; however, no changes were observed in mRNA expression. Lipid droplet accumulation was 10-fold higher in the livers of fetuses from OB compared with C group. We propose that increased lipid transport capacity in obese mice promotes transplacental fatty acid transport and contributes to excess lipid accumulation in the fetal liver.

Objectives The objective of this study was to evaluate the proficiency of Spanish laboratories with respect to accurate susceptibility testing and the detection and interpretation of quinolone resistance phenotypes in Enterobacteriaceae. Methods Thirteen strains of Enterobacteriaceae were sent to 62 participating centres throughout Spain; strains harboured GyrA/ParC modifications, reduced permeability and/or plasmid-mediated quinolone resistance genes. The centres were requested to evaluate nalidixic acid and five quinolones, provide raw/interpreted clinical categories and to detect/infer resistance mechanisms. Consensus results from reference centres were used to assign minor, major and very major errors (mEs, MEs and VMEs, respectively). Results Susceptibility testing in the participating centres was frequently performed using the MicroScan WalkAway, Vitek 2 and Wider systems (48%, 30% and 8%, respectively). CLSI/EUCAST breakpoints were used in 71%/29% of the determinations. The percentage of VMEs for all quinolones was well below 2%. Only ofloxacin and moxifloxacin showed higher values for raw VMEs (6.6%), which decreased to 0% and 2.9%, respectively, in the interpreted VMEs. These errors were particularly associated with the CC-03 strain [qnrS2 + aac(6′)-Ib-cr]. For MEs, percentages were always Conclusions The use of different breakpoints and methods, the complexity of mutation-driven and transferable resistance mechanisms and the absence of specific tests for detecting low-level resistance lead to high variability and represent a challenge to accuracy in susceptibility testing, particularly in strains with MICs on the border of clinical breakpoints.

Introducción: La prevalencia de la obesidad entre los adolescentes ha aumentado con el paso de los años, lo que supone un reto en salud pública.Objetivo: Determinar el grado de asociación de las horas de sueño y los hábitos alimentarios como factores determinantes de la obesidad enadolescentes de un país europeo y otro sudamericano. Materiales y métodos: Se estudió la duración del sueño, la adherencia a la dieta mediterráneamediante el índice KIDMED, los hábitos alimentarios y el estudio de antropometría para la composición corporal de 272 adolescentes. Resultados:De los 272 adolescentes, 164 eran españoles y 108 argentinos, con edades entre los 11-16 años. El 42% de la muestra argentina presentaba excesoponderal, el 53,3% normopeso y el 4,8% bajo peso. En España, el 39% sobrepeso u obesidad, el 54,3% normopeso y el 6,7% bajo peso. La muestraespañola presentaba mayor adherencia a la dieta mediterránea. Con respecto a la duración del sueño, se reflejaron diferencias significativas: un 18%de la muestra adolescente española y un 57% de Argentina llegaba a dormir 8h diarias. No se encontró relación estadísticamente significativa entrelas horas de sueño y la nutrición sobre el sobrepeso u obesidad de los adolescentes. Aquellos adolescentes que seguían unos hábitos alimentarios máscercanos a la Dieta Mediterránea presentaban mejores valores de IMC. Conclusiones: En general, los adolescentes argentinos tenían peores hábitosalimentarios y mayor exceso ponderal que la muestra española. Introduction: Obesity in adolescence has been increasing over the years, which is a challenge in public health. Objective: To determine the association degree of sleep and eating habits as determinants of obesity in adolescents in a European and South American country. Materials and methods: The study was conducted in a sample of 272 adolescents, 164 Spanish and 108 Argentines, aged 11-16 years. Sleep duration, adherence to the Mediterranean diet by KIDMED index, eating habits and anthropometry study for body composition was studied. Results: 42% of Argentina’s sample had excess weight, 53.3% normal weight and 4.8% underweight. In Spain, 39% was overweight or obese, 54.3% normal weight and 6.7% underweight. The Spanish sample had better adherence to the Mediterranean diet. Regarding sleep duration, significant differences were reflected: 18% of Spanish adolescents and 57% of Argentines came to sleep 8 hours a day. No statistically significant relationship between hours of sleep and nutrition in overweight or obese adolescents was found. Those who were closest to a Mediterranean diet eating habits had better BMI values. Conclusions: In general, Argentine teenagers had worse eating habits and greater excess weight than Spanish sample. Fil: San Mauro Martín, Ismael. Centros de Investigación en Nutrición y Salud; España Fil: Paredes Barato, Víctor. Centros de Investigación en Nutrición y Salud; España Fil: Lacunza, Ana Betina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán; Argentina. Universidad Nacional de Tucumán. Facultad de Psicología; Argentina Fil: Garicano Vilar, Elena. Centros de Investigación en Nutrición y Salud; España Fil: Brasero Escolano, Silvia. Centros de Investigación en Nutrición y Salud; España Fil: Sal, Francisco Javier. Universidad del Norte Santo Tomás de Aquino. Facultad de Ciencias de la Salud; Argentina Fil: Díaz Molina,Paula. Centros de Investigación en Nutrición y Salud; España Fil: Cordobés Rol, Marta. Centros de Investigación en Nutrición y Salud; España Fil: Bermejo de las Heras, Sara. Centros de Investigación en Nutrición y Salud; España Fil: León, Joana. Centros de Investigación en Nutrición y Salud; España Fil: Ciudad Cabañas, María José. Universidad Complutense de Madrid; España Fil: Caballero, Silvina Valeria. Universidad Nacional de Tucumán; Argentina Fil: Salazar Burgos, Ramiro Joaquín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán; Argentina. Universidad Nacional de Tucumán; Argentina Fil: Collado Yurrita, Luis. Universidad Complutense de Madrid; España

Objective: The aim of this study is to evaluate the effect of preeclampsia on the level of lipid peroxidation, activity and expression of both plasma membrane Ca2+- and Na+, K+-ATPases in syncytiotrophoblast. Methods: The level of lipid peroxidation was estimated by measuring TBARS. ATPase activities were quantified by a colorimetric method measuring the amount of inorganic phosphate during the assay. Expression of Ca2+- and Na+, K+-ATPases in syncytiotrophoblast plasma membranes and term placenta tissue sections was investigated using Western blot and immunohistochemistry, respectively. Results: Our results show a higher level of lipid peroxidation of syncytiotrophoblast plasma membranes from preeclamptic, as compared to uncomplicated pregnant women. Preeclampsia also significantly reduced the activity of Ca2+- and Na+, K+-ATPases; however, expression of both ATPases was unaffected. Conclusion: Our findings suggest that the reduction of Ca2+- and Na+, K+-ATPase activities during preeclampsia could be at ...

Acidic fibroblast growth factor (FGF1) and neuregulin-1 (NRG1) are growth factors involved in cardiac development and regeneration. Microparticles (MPs) mediate cytokine sustained release, and can be utilized to overcome issues related to the limited therapeutic protein stability during systemic administration. We sought to examine whether the administration of microparticles (MPs) containing FGF1 and NRG1 could promote cardiac regeneration in a myocardial infarction (MI) rat model. We investigated the possible underlying mechanisms contributing to the beneficial effects of this therapy, especially those linked to endogenous regeneration. FGF1- and NRG1-loaded MPs were prepared using a multiple emulsion solvent evaporation technique. Seventy-three female Sprague-Dawley rats underwent permanent left anterior descending coronary artery occlusion, and MPs were intramyocardially injected in the peri-infarcted zone four days later. Cardiac function, heart tissue remodeling, revascularization, apoptosis, cardiomyocyte proliferation, and stem cell homing were evaluated one week and three months after treatment. MPs were shown to efficiently encapsulate FGF1 and NRG1, releasing the bioactive proteins in a sustained manner. Three months after treatment, a statistically significant improvement in cardiac function was detected in rats treated with growth factor-loaded MPs (FGF1, NRG1, or FGF1/NRG1). The therapy led to inhibition of cardiac remodeling with smaller infarct size, a lower fibrosis degree and induction of tissue revascularization. Cardiomyocyte proliferation and progenitor cell recruitment were detected. Our data support the therapeutic benefit of NRG1 and FGF1 when combined with protein delivery systems for cardiac regeneration. This approach could be scaled up for use in pre-clinical and clinical studies.

Tissue engineering is a promising strategy to promote heart regeneration after a myocardial infarction (MI). In this study, we investigated the reparative potential of a system that combines adipose-derived stem cells (ADSCs) with microparticles (MPs) loaded with neuregulin (NRG), named ADSC-NRG-MPs, on a rat MI model. First, cells were attached to the surface of MPs encapsulating NRG and coated with a 1:1 mixture of collagen and poly-d-lysine. One week after in vivo administration, the system favored the shift of macrophage expression from a pro-inflammatory to a regenerative phenotype. At long-term, the adhesion of ADSCs to MPs resulted in an increased cell engraftment, with cells being detectable in the tissue up to three months. In consonance, better tissue repair was observed in the animals treated with cells attached to MPs, which presented thicker left ventricles than the animals treated with ADSCs alone. Moreover, the presence of NRG in the system promoted a more complete regeneration, reducing the infarct size and stimulating cardiomyocyte proliferation. Regarding vasculogenesis, the presence of ADSCs and NRG-MPs alone stimulated vessel formation when compared to the control group, but the combination of both induced the largest vasculogenic effect, promoting the formation of both arterioles and capillaries. Importantly, only when ADSCs were administered adhered to MPs, they were incorporated into newly formed vessels. Collectively, these findings demonstrate that the combination of ADSCs, MPs and NRG favored a synergy for inducing a greater and more complete improvement in heart regeneration and provided strong evidence to move forward with preclinical studies with this strategy.

The human placental syncytiotrophoblast (hSTB) is a polarized epithelial structure, without paracellular routes, forming the main barrier for materno–fetal exchange. There is ample evidence suggesting the presence of potassium (K + ) channels in the placental apical membrane; which could contribute to membrane potential and volume regulation. We have therefore examined the K + currents of isolated apical membranes from human term placenta using electrophysiological methods: reconstitution of ion channels from apical membranes into giant liposomes (single channel recordings, patch clamp method) or their functional transplantation into Xenopus laevis oocytes (total currents recording, voltage clamp method). Single channel recording experiments show the presence of K + channels in the hSTB microvillous membrane sensitive to Tetraethylammonium (TEA) and Barium (Ba +2 ). Patch current activity was diminished 50% and 70% by 20 mmol/L TEA and 5 mmol/L Ba +2 respectively. The more frequent conductance was approximately 73 pS, however several levels of current were detected suggesting the presence of more than one type of K + channel. In addition, sodium (Na + ) sensitivity was detected in the patch current thus, over 10 mmol/L Na + reduced the seal current to 38%. These results were corroborated by the total current experiments where the K + current elicited in injected oocytes with apical purified membrane was blocked by Ba +2 and TEA. The total current was also affected by Na + , becoming larger when a Na + -free solution was used. Our results show the existence of at least two types of Ba +2 -sensitive K + channels including a TEA sensitive sub-population, and some of them Na + sensitive K + channels. These channels could be the conductive pathways proposed previously for this cation in placental hSTB. Our novel contribution has been to successfully obtain K + channel recordings in systems suitable for electrophysiological studies of isolated apical membranes.

Human chorionic gonadotropin (hCG) is a key autocrine/paracrine regulator of placental syncytiotrophoblast, the transport epithelium of the human placenta. Syncytiotrophoblast hCG secretion is modulated by the partial pressure of oxygen (pO2), reactive oxygen species (ROS) and potassium (K+) channels. Here we test the hypothesis that K+ channels mediate the effects of pO2 and ROS on hCG secretion. Placental villous explants from normal term pregnancies were cultured for 6 days at 6% (normoxia), 21% (hyperoxia) or 1% (hypoxia) pO2. On days 3-5, explants were treated with 5mM 4-aminopyridine (4-AP) or tetraethylammonium (TEA), blockers of pO2-sensitive voltage-gated K+ (KV) channels, or ROS (10-1000μM H2O2). hCG secretion and lactate dehydrogenase (LDH) release, a marker of necrosis, were determined daily. At day 6, hCG and LDH were measured in tissue lysate and 86Rb (K+) efflux assessed to estimate syncytiotrophoblast K+ permeability. hCG secretion and 86Rb efflux were significantly greater in explants maintained in 21% pO2 than normoxia. 4-AP/TEA inhibited hCG secretion to a greater extent at 21% than 6% and 1% pO2, and reduced 86Rb efflux at 21% but not 6% pO2. LDH release and tissue LDH/hCG were similar in 6%, 21% and 1% pO2 and unaffected by 4-AP/TEA. H2O2 stimulated 86Rb efflux and hCG secretion at normoxia but decreased 86Rb efflux, without affecting hCG secretion, at 21% pO2. 4-AP/TEA-sensitive K+ channels participate in pO2-sensitive hCG secretion from syncytiotrophoblast. ROS effects on both hCG secretion and 86Rb efflux are pO2-dependent but causal links between the two remain to be established.

The placenta mediates maternal-fetal exchange and has historically been regarded as a passive conduit for nutrients. However, emerging evidence suggests that the placenta actively responds to nutritional and metabolic signals from the mother and the fetus. We propose that the placenta integrates a multitude of maternal and fetal nutritional cues with information from intrinsic nutrient-sensing signaling pathways to match fetal demand with maternal supply by regulating maternal physiology, placental growth, and nutrient transport. This process, which we have called placental nutrient sensing, ensures optimal allocation of resources between the mother and the fetus to maximize the chances for propagation of parental genes without jeopardizing maternal health. We suggest that these mechanisms have evolved because of the evolutionary pressures of maternal undernutrition, which result in decreased placental growth and down-regulation of nutrient transporters, thereby limiting fetal growth to ensure maternal survival. These regulatory loops may also function in response to maternal overnutrition, leading to increased placental growth and nutrient transport in cases of maternal obesity or gestational diabetes. Thus, placental nutrient sensing modulates maternal-fetal resource allocation to increase the likelihood of reproductive success. This model implies that the placenta plays a critical role in mediating fetal programming and determining lifelong health.

Regulation of human placental syncytiotrophoblast renewal by cytotrophoblast migration, aggregation/fusion and differentiation is essential for successful pregnancy. In several tissues, these events are regulated by intermediate conductance Ca2+-activated K+ channels (IKCa), in part through their ability to regulate cell volume. We used cytotrophoblasts in primary culture to test the hypotheses that IKCa participate in the formation of multinucleated syncytiotrophoblast and in syncytiotrophoblast volume homeostasis. Cytotrophoblasts were isolated from normal term placentas and cultured for 66 h. This preparation recreates syncytiotrophoblast formation in vivo, as mononucleate cells (15 h) fuse into multinucleate syncytia (66 h) concomitant with elevated secretion of human chorionic gonadotropin (hCG). Cells were treated with the IKCa inhibitor TRAM-34 (10 µM) or activator DCEBIO (100 µM). Culture medium was collected to measure hCG secretion and cells fixed for immunofluorescence with anti-IKCa and anti-desmoplakin antibodies to assess IKCa expression and multinucleation respectively. K+ channel activity was assessed by measuring 86Rb efflux at 66 h. IKCa immunostaining was evident in nucleus, cytoplasm and surface of mono- and multinucleate cells. DCEBIO increased 86Rb efflux 8.3-fold above control and this was inhibited by TRAM-34 (85%; p

Poly-lactide-co-glycolide (PLGA) microparticles emerged as one of the most promising strategies to achieve site-specific drug delivery. Although these microparticles have been demonstrated to be effective in several wound healing models, their potential in cardiac regeneration has not yet been fully assessed. The present work sought to explore PLGA microparticles as cardiac drug delivery systems. PLGA microparticles were prepared by Total Recirculation One-Machine System (TROMS) after the formation of a multiple emulsion. Microparticles of different size were prepared and characterized to select the most suitable size for intramyocardial administration. Next, the potential of PLGA microparticles for administration in the heart was assessed in a MI rat model. Particle biodegradation over time and myocardial tissue reaction were studied by routine staining and confocal microscopy. Results showed that microparticles with a diameter of 5 μm were the most compatible with intramyocardial administration in terms of injectability through a 29-gauge needle and tissue response. Particles were present in the heart tissue for up to three months post-implantation and no particle migration towards other solid organs was observed, demonstrating good myocardial retention. CD68 immunolabeling revealed 31%, 47% and below 4% microparticle uptake by macrophages one week, one month and three months after injection, respectively (P

Myocardial infarction (MI) is the leading cause of death worldwide and extensive research has therefore been performed to find a cure. Neuregulin-1 (NRG) is a growth factor involved in cardiac repair after MI. We previously described how biocompatible and biodegradable microparticles, which are able to release NRG in a sustained manner, represent a valuable approach to avoid problems related to the short half-life after systemic administration of proteins. The effectiveness of this strategy could be improved by combining NRG with several cytokines involved in cardiac regeneration. The present study investigates the potential feasibility of using NRG-releasing particle scaffold combined with adipose derived stem cells (ADSC) as a multiple growth factor delivery-based tissue engineering strategy for implantation in the infarcted myocardium. NRG-releasing particle scaffolds with a suitable size for intramyocardial implantation were prepared by TROMS. Next, ADSC were adhered to particle scaffolds and their potential for heart administration was assessed in a MI rat model. NRG was successfully encapsulated reaching encapsulation efficiencies of 92.58 ± 3.84 %. NRG maintained its biological activity after the microencapsulation process. ADSC cells adhered efficiently to particle scaffolds within a few hours. The ADSC-cytokine delivery system developed proved to be compatible with intramyocardial administration in terms of injectability through a 23-gauge needle and tissue response. Interestingly, ADSC-scaffolds were present in the peri-infarted tissue two weeks after implantation. This proof of concept study provides important evidence required for future effectiveness studies and for the translation of this approach.

Background Patients with chronic pain frequently display comorbid depression, but the impact of this concurrence is often underestimated and mistreated. The aim of this study was to determine the prevalence of unrecognized major depression and other mood disorders and comorbid unexplained chronic pain in primary care settings and to explore the associated factors. Also, to compare the use of health services by patients with unexplained chronic pain, both with and without mood disorder comorbidity. Methods A cross-sectional study was carried out in a sample of primary care centers. 3189 patients consulting for "unexplained chronic pain" were assessed by the Visual Analogue Scales (VAS) and the Primary Care Evaluation of Mental Disorders (PRIME-MD) questionnaire. Results We report: a) a high prevalence of unrecognized mood disorders in patients suffering from unexplained chronic pain complaints (80.4%: CI 95%: 79.0%; 81.8%); b) a greater susceptibility of women to mood disorders (OR adjusted = 1.48; CI 95%:1.22; 1.81); c) a direct relationship between the prevalence of mood disorders and the duration of pain (OR adjusted = 1.01; CI 95%: 1.01; 1.02) d) a higher comorbidity with depression if the pain etiology was unknown (OR adjusted = 1.74; CI 95%: 1.45; 2.10) and, e) an increased use of health care services in patients with such a comorbidity (p < 0.0001). Conclusions The prevalence of undiagnosed mood disorders in patients with unexplained chronic pain in primary care is very high, leading to dissatisfaction with treatment processes and poorer outcomes. Consequently, it seems necessary to explore this condition more regularly in general practice in order to reach accurate diagnoses and to select the appropriate treatment.

s / Placenta 35 (2014) A1eA112 A97 mouse knockout models of impaired sulfonation of structural molecules important for foetal development. Conclusion: Our novel mouse model is providing valuable insight into the critical role of placental sulphate transporters in meeting foetal nutrient demands during gestation. P2.115-N. PLACENTAL URIC ACID TRANSPORTER GLUT9 IS MODULATED BY FREE IODINE Benjamin P. Luscher , Michael Fine , Camilla Marini , Benjamin Clemencon , Christiane Albrecht , Matthias A. Hediger , Daniel V. Surbek , Marc U. Baumann a,b Department of Obstetrics and Gynecology, University Hospital of Bern, Bern, Switzerland; Department of Clinical Research, University of Bern, Bern, Switzerland; c Institute for Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland Objectives: Materno-fetal transplacental transport is crucial for the fetal well-being. The altered expression of placental transport proteins under specific pathophysiological conditions may affect the intrauterine environment. Pre-eclampsia is often associated with high maternal uric acid serum levels. The regulation of the placental uric transport system and its transporter glucose transporter (GLUT)-9 are not fully understood yet. The aim of this study was to investigate the placental urate transport and to characterize its transporter GLUT9. Methods: In this study we used a transepithelial transport (Transwell®) model to assess uric acid transport activity. Electrophysiological techniques and radioactive ligand up-take assays were used to measure transport activity of GLUT9 expressed in Xenopus oocytes. Results: In the Transwell/ model uric acid is transported across the BeWo choriocarcinoma cell monolayer with 530 pmol/min at the linear stage. We could successfully over-express GLUT9 using the Xenopus laevis oocytes expression system. Chloride modulates the urate transport system: interestingly replacing chloride with iodine resulted in a complete loss of urate transport activity. We determined the IC50 of iodine at 30uM concentration. In radioactiveup-takeexperiments iodinehadnoeffectonuric acid transport. Conclusions: In vitro the “materno-fetal” transport of uric acid is slow. This indicates that in vivo the child is protected from short-term fluctuations of maternal uric acid serum concentrations. The different results regarding iodine-mediated regulation of GLUT9 transport activity between electrophysiological and radioactive ligand uptake experiments may suggest that iodine does not directly inhibit uric acid transport, but changes the mode of up-take from an electrogenic to an electroneutral transport. GLUT9 is not an uric acid uniporter, there are more ions involved in the transport. This may allow regulating uric acid transport by the change from an active to a passive transport. P2.116. UPTAKE MECHANISM OF AN ESTRIOL PRECURSOR, 16a-HYDROXY DEHYDROEPIANDROSTERONE SULFATE, AT THE BASAL PLASMA MEMBRANE OF HUMAN TERM PLACENTA Masatoshi Tomi , Hiromi Eguchi , Tomohiro Nishimura , Tetsuo Maruyama , Emi Nakashima a Keio University Faculty of Pharmacy, Tokyo, Japan; Keio University School of Medicine, Tokyo, Japan Objectives: Estriol is mostly secreted from placental syncytiotrophoblasts during pregnancy. 16a-Hydroxy dehydroepiandrosterone sulfate (16a-OH DHEAS) is an estriol precursor, which is synthesized by fetal liver-specific CYP3A7 (16a-hydroxylase). To achieve placental estriol synthesis, syncytiotrophoblasts require organic anion transporter(s) for 16a-OH DHEAS uptake at the basal plasma membrane (BM) facing fetal circulation. The purpose of this study is to clarify the mechanism underlying 16a-OH DHEAS uptake at the BM of human placental syncytiotrophoblasts. Methods: The uptake of [3H]16a-OH DHEAS was characterized using basal-enriched plasma membrane vesicles (BMVs) derived from human term placenta. The expression of transporters in BMVs was determined by western blot analysis. Results:Proteinexpressionsof organic anion transporter (OAT)4 (SLC22A11) and organic anion transporting polypeptide 2B1 (SLCO2B1)were enriched in human placental BMVs compared with crude membrane fractions, which is consistent with immunohistochemical observations of the basal localization of these transporters in syncytiotrophoblasts. Uptake of [3H]16a-OH DHEAS by BMVs was sodiumand chloride-independent and was trans-stimulated by preloaded glutarate. The uptake of [3H]16a-OH DHEAS was significantly cis-inhibited byDHEAS, estrone sulfate, andbromosulfophthalein, but not by cyclosporin A, tetraethylammonium, p-aminohippuric acid, and cimetidine. These transport characteristics of [3H]16a-OHDHEAS are in good agreement with those in human OAT4-transfected COS7 cells. Conclusion: OAT4 expressed at the basal plasma membrane of the syncytiotrophoblast appears to play a predominant role in the placental uptake of 16a-OH DHEAS from the fetal circulation and contribute to estriol synthesis during pregnancy. P2.117. NANOPARTICLE INTERACTION WITH EARLY HUMAN PLACENTA: PLACENTAL BARRIER MATTERS? Liudmila Nikitina , Gottfried Dohr , Herbert Juch a,b a Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria; b Institute of Human Genetic, Medical University of Graz, Graz

INTRODUCCION: Las fracturas acetabulares pueden causar artrosis degenerativa de la cadera. La incidencia de artrosis post traumática tras fracturas acetabulares ha sido reportada entre el 12% y el 57% y la osteonecrosis cefálica femoral entre un 2% al 40% luego de una luxo fractura de cadera. La fractura acetabular con frecuencia es ocasionada por traumas importantes en accidentes en la vía pública, laborales o deportivos y los pacientes por lo general se presentan para el reemplazo total de cadera (RTC) a una edad mas temprana que la población artrósica general. Se describe y analiza una serie de casos de RTC post fractura de acetabulo, y se la comparó con un grupo de RTC en pacientes con patologías degenerativas.MATERIALES Y METODOS: Se evaluaron 19 casos tratados en forma quirúrgica de RTC con copa acetabular no cementada secundario a artrosis post traumática como secuela de fracturas de acetábulo. La edad promedio al momento de la artroplastía fue de 52,2 años (19 - 83). La edad al momento de la fractura fue de 47,9 años (16 - 81). El tiempo promedio entre la fractura de acetábulo y el reemplazo total de cadera fue de 52,4 meses (4 - 360). El seguimiento promedio fue de 4,25 años.RESULTADOS: En los RTC post fracturas acetabulares no se registró ningún tipo de aflojamiento de los componentes protésicos radiográficos. En ningún caso se registró infección. El Score de Harris promedió 89.3 (57 – 99). El grupo control con RTC por patologías degenerativas tuvo un seguimiento de 4,9 años; su Score de Harris fue de 94,1 puntos (78 – 100). En este grupo no encontramos signos de infección ni signos de aflojamientos clínicos ni radiográficos. No hubo diferencias significativas con el Score de Harris (p= 0,24) entre ambos grupos.CONCLUSION: El RTC para una artrosis post traumática como secuela de una fractura de acetábulo es un procedimiento mas dificultoso que una artroplastía de rutina en un paciente con una enfermedad degenerativa. En un corto plazo no existen diferencias clínicas ni radiográficas en los RTC con copas acetabulares no cementadas en pacientes con artrosis post traumáticas comparadas con pacientes con patologías degenerativas.