Chondrogenic Differentiation of Human Mesenchymal Stem Cells via SOX9 Delivery in Cationic Niosomes.

Gene transfer to mesenchymal stem cells constitutes a powerful approach to promote their differentiation into the appropriate cartilage phenotype. Although viral vectors represent gold standard vehicles, because of their high efficiency, their use is precluded by important concerns including an elevated immunogenicity and the possibility of insertional mutagenesis. Therefore, the development of new and efficient non-viral vectors is under active investigation. In the present study, we developed new non-viral carriers based on niosomes to promote the effective chondrogenesis of human MSCs. Two different niosome formulations were prepared by varying their composition on non-ionic surfactant, polysorbate 80 solely (P80), or combined with poloxamer 407 (P80PX). The best niosome formulation was proven to transfer a plasmid, encoding for the potent chondrogenic transcription factor SOX9 in hMSC aggregate cultures. Transfection of hMSC aggregates via nioplexes resulted in an increased chondrogenic differentiation with reduced hypertrophy. These results highlight the potential of niosome formulations for gene therapy approaches focused on cartilage repair.

Should we pay more attention to low creatinine levels? / ¿Debemos prestar más atención a la creatinina baja?

A review is made of the basic aspects of creatine/creatinine metabolism and the close relationship between creatinine and muscle mass, which makes the former a biochemical marker of the latter. Emphasis is placed on the current prognostic value of both the low urinary excretion of creatinine and low serum creatinine levels in different clinical settings in which sarcopenia probably plays a significant role in morbidity and mortality.

Male precocious puberty described in literature of the Spanish Golden Age.

Aristotle was the first author who described the existence of abnormalities in the timing of human puberty. In the classic Greek-Roman period, Pliny the Elder and Phlegon of Tralles described the first individual cases of precocious puberty in children. During the Middle Ages, precocious puberty in the male (but not in the female) was ignored. We present what is, to our knowledge, the first full description in European literature of male precocious puberty and its consequences in an adult. This case is included in a book of the miscellaneous genre of Spanish Renaissance literature (Jardin de Flores Curiosas) written by Antonio de Torquemada in the sixteenth century.

Searching for a nutritional screening tool. The value of an analytical method when staff trained in clinical nutrition is not available.

INTRODUCTION: Disease-related malnutrition (DRM) is highly prevalent. Various European resolutions urge to screen and treat DRM. No policy in this regard has yet been developed in Extremadura (Spain). OBJECTIVES: To assess the prevalence of DRM (defined as NRS 2002≥3) using an analytical method (FILNUT), and to compare it with the official rate. RESULTS: FILNUT scores≥3 showed values of sensitivity (S) and positive predictive value (PPV) of 82.3% and 72.3% respectively. No statistically significant differences were found between men and women using this tool. FILNUT showed a significantly higher sensitivity for detecting malnutrition in medical - as compared to surgical - diseases when low scores were used. The estimated prevalence of DRM was 21.4%. Prevalence of DRM is much greater than officially reported. CONCLUSIONS: FILNUT scores≥3 show high sensitivity and PPV for detecting DRM, and is a good alternative as a nutritional screening tool to detect malnutrition at our center.

Financial impact of disease-related malnutrition at the San Pedro de Alcántara hospital. Estimated cost savings associated to a specialized nutritional survey. / Impacto económico de la desnutrición relacionada con la enfermedad en el hospital San Pedro de Alcántara. Estimación del ahorro asociado a una atención nutricional especializada de calidad.

INTRODUCTION AND OBJECTIVES: DRM is a highly prevalent condition in Spanish hospitals and is associated to increased healthcare costs. Costs associated to DRM were calculated using the methods of the PREDyCES study. The potential savings derived from specialized nutritional treatment were calculated by extrapolating the results of the SNAQ strategy. RESULTS: Median cost per procedure in patients with DRM was €9,679.85, with a final cost of €28,700,775.2. The cost of each patient with DRM was 2.63 times higher than the cost of patients with no DRM. The potential cost saving associated to specialized nutritional treatment was estimated at €1,682,317.28 (5.86% of total cost associated to DRM). CONCLUSIONS: Patients with DRM showed a higher consumption of financial resources as compared to well-nourished patients. Specialized nutritional treatment is a potential cost-saving procedure.

Impacto del empleo de umbrales específicos de referencia en el diagnóstico de las alteraciones funcionales tiroideas en la mujer gestante / Impact of using specific reference intervals on the diagnosis of thyroid dysfunction during pregnancy

Objetivo: Establecer los umbrales específicos de referencia de cada uno de los parámetros de función tiroidea en cada trimestre de la gestación y determinar el impacto del uso de umbrales no específicos en el diagnóstico de las alteraciones funcionales en el primer trimestre. Métodos: Entre enero y septiembre de 2014 se contactaron 759 mujeres embarazadas con edad mayor de 18 años y sin alteraciones funcionales tiroideas conocidas. Tras excluir a todas las pacientes que no completaron el seguimiento durante toda la gestación y las que presentaron inmunidad tiroidea positiva, 411 gestantes configuraron nuestra población de referencia. Se determinaron los niveles de TSH, T4L y T3L en cada trimestre, los anticuerpos antiperoxidasa tiroidea y antitiroglobulina en el primero y se recogió una muestra de orina en los trimestres primero y tercero para la determinación del yodo urinario. Resultados: Un total de 411 gestantes completaron el seguimiento en los 3 trimestres. Un 38,69% consumían sal yodada y un 72,20% suplementos yodados. Los valores de referencia de TSH expresados como mediana y percentiles 2,5 y 97,5 fueron: 1,53 μUI/ml (0,26-3,95), 1,90 μUI/ml (0,78-3,85) y 1,89 μUI/ml (0,71-3,61) en el primer, segundo y tercer trimestre, respectivamente. El nivel de yoduria fue de 171,31 μg/l (90,7-274,9) en el primer trimestre y de 190,37 μg/l (96,44-360,38) en el tercero. La aplicación en el primer trimestre de los umbrales propuestos por las sociedades internacionales ocasionaría una clasificación errónea del 19,8% de las gestantes en relación con su función tiroidea, mientras que los umbrales no específicos de nuestro laboratorio lo harían en el 8,52%. Conclusiones: La utilización de umbrales no específicos para el diagnóstico de las alteraciones funcionales tiroideas durante la gestación ocasiona un importante porcentaje de errores de clasificación, contribuyendo a una atención inadecuada.

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Effects of aripiprazole, quetiapine and ziprasidone on plasma prolactin levels in individuals with first episode nonaffective psychosis: Analysis of a randomized open-label 1year study.

RATIONALE: Hyperprolactinemia is considered a troubling adverse effect of antipsychotics. Direct comparisons among second generation antipsychotics are scant in clinical practice. We hypothesize prolactin-sparing second-generation antipsychotics may have differential effects on prolactin levels and that they may be influenced by sex. OBJECTIVES: To explore the differential effect of three widely used prolactin-sparing antipsychotics, aripiprazole, quetiapine and ziprasidone, on prolactin plasma levels in first episode non-affective psychosis during a 1year of treatment. METHOD: From October 2005 to January 2011 a prospective, randomized, open-label study was undertaken. 141 patients who were randomly allocated to aripiprazole (N=56), quetiapine (N=36) or ziprasidone (N=49) were analyzed. The main outcome was differences in prolactin plasma levels over 1year follow-up among the three antipsychotics. Prolactin levels had a skewed distribution and therefore they were log-transformed before statistical analyses. RESULTS: Male patients on aripiprazole had a lower risk of suffering an increase on prolactin plasma levels (N=71; F=12.645; p<0.001). There was a gender effect with smaller changes in mean prolactin values only in males. Aripiprazole had a reduced risk of hyperprolactinemia (aripiprazole 19.6%) compared to quetiapine (44.4%) and ziprasidone (32.7%) (p=0.038); and quite similar findings were found when investigating males (p=0.040). No significant differences were found in females. The percentages of mild prolactin excess were: 14.3% on aripiprazole, 36.1% on quetiapine and 18.4% on ziprasidone (χ2=6.611 p=0.037). CONCLUSIONS: Our findings provide additional evidence of differential effects of three sparing-prolactin antipsychotics on prolactin release and may help clinicians to decide among therapeutic options.

Benefits of early specialized nutritional support in malnourished patients. / Beneficios del soporte nutricional especializado precoz en pacientes con criterios de desnutrición.

INTRODUCTION AND OBJECTIVE: Disease related malnutrition (DRM) is highly prevalent in Spain, affecting 23% of in-hospital patients, and is associated with clinical complications. Specialized nutritional support (SNS) can reduce these complications. MATERIAL AND METHODS: Prospective study carried out in standard clinical practice conditions to test if SNS during the first 5 days of hospitalization, or subsequently, was associated to a lower length of stay or reduced complications in patients with a NRS-2002 score≥3 points. RESULTS: In the group of patients who initiated early SNS, the length of stay was 8.83 days shorter than in the group with a later introduction (95% CI 3.55-14.10); nevertheless, the higher prevalence of male and oncological patients in this group could have impacted the results. A tendency towards a statistically significant lower mortality rate and a reduced amount of total complications was described. CONCLUSION: The early introduction of SNS (within the first 5 days of hospitalization) in patients with DRM was associated with a 32.4% reduction in the length of stay.

[Not Available]. / Impacto de la adecuada codificación de la desnutrición y procesos asociados sobre el índice case-mix en patologías médicas y quirúrgicas.

Introducción: la clasificación por procesos según el sistema de los grupos relacionados con el diagnóstico permite clasificar los diferentes procesos acorde a un consumo de recursos equivalentes. La complejidad de los procesos según el índice case-mix permite solicitar un mayor o menor presupuesto para la atención de los pacientes. La desnutrición tiene capacidad para aumentar el índice case-mix si bien en muchos casos este diagnóstico y el de los procesos nutricionales no se realizan de forma adecuada. Objetivo: determinar si la adecuada codificación de la desnutrición es capaz de aumentar el índice case-mix y si este aumento es dependiente de la documentación del mismo por un médico especialista, el tipo de proceso o el servicio de ingreso. Resultados: en una serie aleatorizada de 100 pacientes, la documentación de desnutrición y procesos asociados por parte de un médico especialista en Endocrinología y Nutrición produjo un aumento de 0,68 puntos en el índice case-mix (IC95: 0,48-0,88). El impacto fue mayor en procesos médicos que en quirúrgicos (0,42 puntos [IC95: 0,03-0,81]). Por servicios, el impacto fue positivo en Medicina Interna y Cirugía General. El tamaño muestral para el cálculo del resto de servicios no alcanzó tamaño muestral suficiente. Conclusión: el aumento de recursos humanos (médicos especialistas en Endocrinología y Nutrición) es viable en términos de gestión por el aumento del índice case-mix dependiente de su presencia en un contexto de práctica clínica habitual, no de investigación.

Differences in quality standards when prescribing nutritional support: Differences between specialist and non-specialist physicians.

UNLABELLED: Adequate nutritional support includes many different aspects, but poor understanding of clinical nutrition by health care professionales often results in an inadequate prescription. MATERIAL AND METHODS: A study was conducted to compare enteral and parenteral nutritional support plans prescribed by specialist and non-specialist physicians. RESULTS: Non-specialist physicians recorded anthropometric data from only 13.3% of patients, and none of them performed nutritional assessments. Protein amounts provided by non-specialist physicians were lower than estimated based on ESPEN (10.29g of nitrogen vs 14.62; P<.001). Differences were not statistically significant in the specialist group (14.88g of nitrogen; P=.072). Calorie and glutamine provision and laboratory controls prescribed by specialists were significantly closer to those recommended by clinical guidelines. CONCLUSION: Nutritional support prescribed by specialists in endocrinology and nutrition at San Pedro de Alcántara Hospital was closer to clinical practice guideline standards and of higher quality as compared to that prescribed by non-specialists.

ß-Arrestin scaffolds and signaling elements essential for the obestatin/GPR39 system that determine the myogenic program in human myoblast cells.

Obestatin/GPR39 signaling stimulates skeletal muscle repair by inducing the expansion of satellite stem cells as well as myofiber hypertrophy. Here, we describe that the obestatin/GPR39 system acts as autocrine/paracrine factor on human myogenesis. Obestatin regulated multiple steps of myogenesis: myoblast proliferation, cell cycle exit, differentiation and recruitment to fuse and form multinucleated hypertrophic myotubes. Obestatin-induced mitogenic action was mediated by ERK1/2 and JunD activity, being orchestrated by a G-dependent mechanism. At a later stage of myogenesis, scaffolding proteins ß-arrestin 1 and 2 were essential for the activation of cell cycle exit and differentiation through the transactivation of the epidermal growth factor receptor (EGFR). Upon obestatin stimulus, ß-arrestins are recruited to the membrane, where they functionally interact with GPR39 leading to Src activation and signalplex formation to EGFR transactivation by matrix metalloproteinases. This signalplex regulated the mitotic arrest by p21 and p57 expression and the mid- to late stages of differentiation through JNK/c-Jun, CAMKII, Akt and p38 pathways. This finding not only provides the first functional activity for ß-arrestins in myogenesis but also identify potential targets for therapeutic approaches by triggering specific signaling arms of the GPR39 signaling involved in myogenesis.

Efficiency, cost-effectiveness and need of inversion in nutritional therapy. Importance of detecting and documenting undernutrition.

Disease Related Malnutrition (DRM) is highly prevalent in Spanish hospitals. WHO estimates that 20-40% of health-associated expenses are lost due to inefficiency. Demonstration that DRM is a component of inefficiency and hiring a specialist physician for its detection and treatment is cost-effective. MATERIAL AND METHODS: Comparison between nutritional diagnosis and procedures detected and encoded at discharge using McNemar test. Recoding of 162 discharge reports including nutritional diagnoses and procedures. Determine changes on Case-Mix Index (IC), cost of procedure and cost procedure/DRG index. Comparison using T-student paired test. RESULTS: Only 10 of 162 diagnoses of malnutrition were coded in delivery statements (p < 0.001). After right codification, IC increased in 103,3 DRG points (p < 0.001). Consequently, procedure cost/DRG index was reduced in 978.81 € (p < 0.001). CONCLUSIONS: DRM is underdiagnosed in our hospital. DRM and nutritional procedures detection by a doctor specialist in clinical nutrition led to a reduction in cost procedure/DRG index of 16.8% of officially established by the Health System. Loss of 16.8% of health expenses, estimated in 424.785,15 € was described. Proper codification would have justified 343.291,2 € reimbursement just for nutritional diagnoses and processes. Both expenses were lost due to system's inefficiency. Those amounts are much higher than cost associated of hiring a specialist in clinical nutrition.

Glutamina: su papel en el paciente crítico / Glutamine: the role in critically ill patients

La glutamina es un aminoácido condicionalmente esencial considerado actualmente como un importante fármaco-nutriente. Niveles plasmáticos bajos de glutamina han demostrado comportarse como un factor independiente de mortalidad en el paciente crítico, y su adición al soporte nutricional ha probado disminuir las complicaciones infecciosas, la mortalidad y la estancia hospitalaria. En los últimos años han aparecido nuevos estudios que indicanla necesidad de individualizar la vía de acceso y la dosis y el período de suplementación para determinados grupos de pacientes candidatos a la suplementación con glutamina, y por otra parte, a tenor de los resultados, es aconsejable evitarla en situaciones deshock hipovolémico inestable, fallo multiorgánico o insu¬ciência renal no sometida a técnicas de depuración.

Glutamine is a conditionally essential aminoacid which is nowadays considered an important pharmaco nutrient. Low serum levels of glutamine have proven to be an independent predictor of mortality in the critically ill patient. Supplementation with glutamine as a part of a nutritional therapy has demonstrated to reduce infectious complications, length of stay in hospital and mortality. Recent new published data show the need to individualize the route, dose, length of supplementation for determined groups of candidate patients to glutamine administration. On the other hand, according to results, glutamine is not recommended in case of unstable hypovolemic shock, multiorgan faillure, or renal failure not subjected to depuration techniques.

[Efficiency, cost-effectiveness and justification of need for investment in nutrition therapy in a hospital of third level; the role of specialists in endocrinology and nutrition and the coding unit]. / Eficiencia, coste-efectividad y justificación de necesidad de inversión en terapia nutricional en un hospital de nivel III; papel conjunto del médico especialista en endocrinología y nutrición y la unidad de codificación.

Disease Related Malnutrition (DRM) is highly prevalent in Spanish hospitals. WHO estimates that 20-40% of health-associated expenses are lost due to inefficiency. Demonstration that DRM is a component of inefficiency and hiring a specialist physician for its detection and treatment is cost-effective. MATHERIAL AND METHODS: Comparison between nutritional diagnosis and procedures detected and encoded at discharge using McNemar test. Recoding of 55 discharge reports including nutritional diagnoses and procedures. Determine changes on Case-Mix Index (IC), cost of procedure and cost procedure/GRD index. Comparison using Wilcoxon test. RESULTS: Only 2 of 55 diagnoses of malnutrition were coded in delivery statements (p<0,001). After right codification,IC increased in 42,67 GRD points (p<0,05). Consequently, procedure cost/GRD index was reduced in 976,81€ (p<0,05). CONCLUSIONS: DRM is underdiagnosed in our hospital. DRM and nutritional procedures detection by a specialist on endocrinology and nutrition led to a reduction in cost procedure/GRD index of 20% of officially established by the Health System. Loss of 20% of health expenses,estimated in 172690€ was described. Proper codification would have justified 154581€ reimbursement just for nutritional diagnoses and processes. Both expenses were lost due to system's inefficiency. Those amounts are much higher than cost associated of hiring a specialist, so there is no economic reason for denying it.

La desnutrición relacionada con la enfermedad (DRE) es una entidad con alta prevalencia en el medio hospitalario español. Según la OMS, entre el 20 y el 40% del gasto sanitario se pierde por ineficiencia. Demostrar que la DRE es una fuente de ineficiencia y que la contratación de un médico especialista para su detección y tratamiento es coste-efectiva para el sistema. MATERIAL Y MÉTODOS: Comparación de diagnósticos y procedimientos nutricionales detectados y codificados en informes de alta mediante test de McNemar. Recodificación de 55 informes de alta incluyendo diagnósticos y procesos nutricionales. Determinar variaciones en IC, coste proceso, coste proceso/punto GRD tras la recodificación. Comparación con test de Wilcoxon. RESULTADOS: Sólo se codificaron 2 de 55 casos de desnutrición (p<0,001). Tras recodificación el IC aumentó 42,67 puntos (p<0,05), lo que se tradujo en disminución del índice coste proceso/punto GRD en 976,81 € (p<0,05). CONCLUSIONES: La DRE no se detecta adecuadamente en el centro. Su detección y la de los procedimientos nutricionales adecuados en manos de un médico especialista en nutrición produjeron una disminución del índice coste proceso/punto GRD de un 20% respecto al coste oficial del sistema. Se produjo una pérdida de un 20% del gasto sanitario, estimado en 172.690 € exclusivamente por procesos nutricionales. Su adecuada codificación justificaría un reembolso de 154.581€ para la asistencia nutricional. Ambos costes, perdidos por ineficiencia, son superiores a los que implica la contratación de un especialista en endocrinología, por lo que no existe justificación económica para su no contratación.

Action of obestatin in skeletal muscle repair: stem cell expansion, muscle growth, and microenvironment remodeling.

The development of therapeutic strategies for skeletal muscle diseases, such as physical injuries and myopathies, depends on the knowledge of regulatory signals that control the myogenic process. The obestatin/GPR39 system operates as an autocrine signal in the regulation of skeletal myogenesis. Using a mouse model of skeletal muscle regeneration after injury and several cellular strategies, we explored the potential use of obestatin as a therapeutic agent for the treatment of trauma-induced muscle injuries. Our results evidenced that the overexpression of the preproghrelin, and thus obestatin, and GPR39 in skeletal muscle increased regeneration after muscle injury. More importantly, the intramuscular injection of obestatin significantly enhanced muscle regeneration by simulating satellite stem cell expansion as well as myofiber hypertrophy through a kinase hierarchy. Added to the myogenic action, the obestatin administration resulted in an increased expression of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) and the consequent microvascularization, with no effect on collagen deposition in skeletal muscle. Furthermore, the potential inhibition of myostatin during obestatin treatment might contribute to its myogenic action improving muscle growth and regeneration. Overall, our data demonstrate successful improvement of muscle regeneration, indicating obestatin is a potential therapeutic agent for skeletal muscle injury and would benefit other myopathies related to muscle regeneration.

Perioperative nutritional support.

The relationship between preoperative malnutrition and morbi-mortality has been documented for years. Despite the existence of tools that allow its detection, and therefore treat this entity, their introduction into clinical practice is not wide-spread. Both perioperative insulin resistance and hyperglycemia are associated with increased perioperative morbidity and length of hospital stay. The intake of carbohydrate-rich drinks 2-4h prior to surgery reduces insulin resistance. In the immediate postoperative period, the enteral route is safe and well tolerated and its early use reduces hospital stay and postoperative complications compared with parenteral nutritional support. Inmunonutrition has been proven effective to decrease postoperative complications and hospital stay. In view of these data we opted for the adoption of these measures replacing bowel rest and the indiscriminate use of postoperative parenteral nutrition.

Edge loading does not increase wear rates of ceramic-on-ceramic and metal-on-polyethylene articulations.

The mal-positioning of total hip arthroplasty components can result in edge loading conditions. Purpose of this study was to determine if the wear rate of ceramic-on-ceramic and metal-on-polyethylene increases under edge loading conditions. The literature was reviewed to determine which of the commonly used hip bearings is the most forgiving to implant mal-orientation. Two 28-mm ceramic-on-ceramic articulations were tested in vitro: pure alumina (PAL) ceramic versus the new alumina-toughened zirconia (ATZ). Two 28-mm metal-on-polyethylene articulations were tested in vitro: conventional ultrahigh molecular weight polyethylene (UHMWPE) versus highly crosslinked polyethylene (HXLPE) stabilized with vitamin E. All bearings were tested at standard and at highest possible inclination angles. Hip simulator tests were run for five million cycles based on N = 3 tests per condition. The average wear rate of ATZ-on-ATZ is 0.024 mm(3) /Mcycles at 45° and 0.018 mm(3) /Mcycles at 65°. Wear rate of PAL-on-PAL is between 0.02 and 0.03 mm(3) /Mcycles at 45°, as well as 65°. The wear rate of UHMWPE was 31 ± 1 mm(3) /Mcycles at an inclination angle of 45° and 26 ± 1 mm(3) /Mcycles at 80°. The wear rate of vitamin E stabilized HXLPE was 5.9 ± 0.2 mm(3) /Mcycles at 45° and 5.8 ± 0.2 mm(3) /Mcycles at 80°. Edge loading does not increase the wear rate of ceramic-on-ceramic and metal-on-polyethylene articulations. The newest biomaterials showed markedly lower wear rates compared with their conventional counterparts. ATZ-on-ATZ showed the lowest wear rate of all tested pairings, but the vitamin E stabilized HXLPE seems to be the most forgiving material when it comes to implant mal-orientation.

The obestatin/GPR39 system is up-regulated by muscle injury and functions as an autocrine regenerative system.

The maintenance and repair of skeletal muscle are attributable to an elaborate interaction between extrinsic and intrinsic regulatory signals that regulate the myogenic process. In the present work, we showed that obestatin, a 23-amino acid peptide encoded by the ghrelin gene, and the GPR39 receptor are expressed in rat skeletal muscle and are up-regulated upon experimental injury. To define their roles in muscle regeneration, L6E9 cells were used to perform in vitro assays. For the in vivo assays, skeletal muscle tissue was obtained from male rats and maintained under continuous subcutaneous infusion of obestatin. In differentiating L6E9 cells, preproghrelin expression and correspondingly obestatin increased during myogenesis being sustained throughout terminal differentiation. Autocrine action was demonstrated by neutralization of the endogenous obestatin secreted by differentiating L6E9 cells using a specific anti-obestatin antibody. Knockdown experiments by preproghrelin siRNA confirmed the contribution of obestatin to the myogenic program. Furthermore, GPR39 siRNA reduced obestatin action and myogenic differentiation. Exogenous obestatin stimulation was also shown to regulate myoblast migration and proliferation. Furthermore, the addition of obestatin to the differentiation medium increased myogenic differentiation of L6E9 cells. The relevance of the actions of obestatin was confirmed in vivo by the up-regulation of Pax-7, MyoD, Myf5, Myf6, myogenin, and myosin heavy chain (MHC) in obestatin-infused rats when compared with saline-infused rats. These data elucidate a novel mechanism whereby the obestatin/GPR39 system is coordinately regulated as part of the myogenic program and operates as an autocrine signal regulating skeletal myogenesis.