PKC Inhibition Improves Human Penile Vascular Function and the NO/cGMP Pathway in Diabetic Erectile Dysfunction: The Role of NADPH Oxidase.

Erectile dysfunction (ED) is a frequent and difficult-to-treat condition in diabetic men. Protein kinase C (PKC) is involved in diabetes-related vascular and cavernosal alterations. We aimed to evaluate the role of PKC in endothelial dysfunction and NO/cGMP impairment associated with diabetic ED in the human corpus cavernosum (CC) and penile resistance arteries (PRAs) and the potential mechanisms involved. Functional responses were determined in the CC and PRAs in patients with non-diabetic ED and diabetic ED undergoing penile prosthesis insertion. PKC activator 12,13-phorbol-dibutyrate (PDBu) impaired endothelial relaxations and cGMP generation in response to acetylcholine in the CC from non-diabetic ED. PDBu also impaired responses to a PDE5 inhibitor, sildenafil, in non-diabetic ED patients. Conversely, a PKC inhibitor, GF109203X, improved endothelial, neurogenic, and PDE5-inhibitor-induced relaxations and cGMP generation only in the CC in diabetic ED patients. Endothelial and PDE5-inhibitor-induced vasodilations of PRAs were potentiated only in diabetes. Improvements in endothelial function in diabetes were also achieved with a specific inhibitor of the PKCß2 isoform or an NADPH-oxidase inhibitor, apocynin, which prevented PDBu-induced impairment in non-diabetic patients. PKC inhibition counteracted NO/cGMP impairment and endothelial dysfunction in diabetes-related ED, potentially improving response to PDE5 inhibition.

DESNUTRICIÓN SECUNDARIA A ENFERMEDAD: PAUTAS PARA UN APROPIADO DIAGNÓSTICO Y ABORDAJE EN NIÑOS PEQUEÑOS EN LA PRÁCTICA CLÍNICA / DISEASE-ASSOCAITED UNDERNUTRITION: GUIDELINES FOR AN ADEQUATE DIAGNOSIS AND MANAGEMENTE OF INFANTS IN THE CLINICAL PRACTICE

La desnutrición secundaria a enfermedad afecta no solo el crecimiento y desarrollo del niño, sino que impacta sobre el pronóstico y la sobrevida. Estos efectos son más graves y dejan secuelas permanentes si la desnutrición afecta el primer año de vida. La definición de esta entidad fue revisada recientemente por asociaciones científicas para identificar mejor a los pacientes, comprender la fisiopatología de la desnutrición y sumar herramientas de diagnóstico y abordaje. El objetivo de la presente revisión es describir aspectos específicos de la desnutrición secundaria a enfermedad y ofrecer pautas para un adecuado diagnóstico, interpretación de su fisiopatología y abordaje de niños pequeños en la práctica clínica pediátrica

Disease-associated undernutrition affects not only the child's growth and development, but also has impact on prognosis and survival. These effects are more severe and produce permanent sequelae if undernutrition affects the first year of life. The definition of this entity has recently been revised by scientific associations to better identify patients, understand the pathophysiology of undernutrition and add diagnostic and management tools. The objective of this review is to describe specific aspects of disease-associated undernutrition secondary to disease and offer guidelines for an adequate diagnosis, interpretation of its pathophysiology, and management of children in clinical practice

Dietary phosphate restriction prevents the appearance of sarcopenia signs in old mice.

BACKGROUND: Sarcopenia is defined by the progressive and generalized loss of muscle mass and function associated with aging. We have previously proposed that aging-related hyperphosphataemia is linked with the appearance of sarcopenia signs. Because there are not effective treatments to prevent sarcopenia, except for resistance exercise, we propose here to analyse whether the dietary restriction of phosphate could be a useful strategy to improve muscle function and structure in an animal model of aging. METHODS: Five-month-old (young), 24-month-old (old) and 28-month-old (geriatric) male C57BL6 mice were used. Old and geriatric mice were divided into two groups, one fed with a standard diet (0.6% phosphate) and the other fed with a low-phosphate (low-P) diet (0.2% phosphate) for 3 or 7 months, respectively. A phosphate binder, Velphoro®, was also supplemented in a group of old mice, mixed with a standard milled diet for 3 months. Muscle mass was measured by the weight of gastrocnemius and tibial muscles, and quality by nuclear magnetic resonance imaging (NMRI) and histological staining assays. Muscle strength was measured by grip test and contractile properties of the tibialis muscle by electrical stimulation of the common peroneal nerve. Gait parameters were analysed during the spontaneous locomotion of the mice with footprinting. Orientation and motor coordination were evaluated using a static rod test. RESULTS: Old mice fed with low-P diet showed reduced serum phosphate concentration (16.46 ± 0.77 mg/dL young; 21.24 ± 0.95 mg/dL old; 17.46 ± 0.82 mg/dL low-P diet). Old mice fed with low-P diet displayed 44% more mass in gastrocnemius muscles with respect to old mice (P = 0.004). NMRI revealed a significant reduction in T2 relaxation time (P = 0.014) and increased magnetization transfer (P = 0.045) and mean diffusivity (P = 0.045) in low-P diet-treated mice compared with their coetaneous. The hypophosphataemic diet increased the fibre size and reduced the fibrotic area by 52% in gastrocnemius muscle with respect to old mice (P = 0.002). Twitch force and tetanic force were significantly increased in old mice fed with the hypophosphataemic diet (P = 0.004 and P = 0.014, respectively). Physical performance was also improved, increasing gait speed by 30% (P = 0.032) and reducing transition time in the static rod by 55% (P = 0.012). Similar results were found when diet was supplemented with Velphoro®. CONCLUSIONS: The dietary restriction of phosphate in old mice improves muscle quantity and quality, muscle strength and physical performance. Similar results were found using the phosphate binder Velphoro®, supporting the role of phosphate in the impairment of muscle structure and function that occurs during aging.

Towards a smoke-free world? South America became the first 100% smoke-free subregion in the Americas.

Almost 20 years after the launching by the Pan American Health Organization of its "Smoke-Free Americas" initiative in 2001, in December 2020, South America became the first subregion in the Americas to accomplish 100% smoke-free environments in line with Article 8 of the World Health Organization Framework Convention on Tobacco Control (FCTC). Some of these countries adopted legal measures that are more robust than others, including in their laws specific outdoor places in the smoking ban (like Argentina and Uruguay) and/or novel nicotine and tobacco products under their scope (like Ecuador and Paraguay). The 10 countries took different paths to adopt this public health measure, either through executive or legislative measures or a combination of both. A few countries, like Argentina, Brazil, and Venezuela, started at the subnational level and then moved on to the national level, similar to the rest of the countries. For achieving this milestone, an adequate context was crucial: the broad ratification of the FCTC and the relevance given to the human right to health, civil society efforts, commitments made by intergovernmental bodies, media and communication strategies, and the development of scientific evidence. Countries faced obstacles, including the well-known interference of the tobacco industry, which among other strategies used litigation; however, courts and judges upheld comprehensive legal measures on smoke-free environments. The process by which South America achieved this milestone represents a role model for other subregions of the Americas and the world.

Casi 20 años después del lanzamiento de la iniciativa "América libre de humo" de la Organización Panamericana de la Salud en el año 2001, en diciembre del 2020, América del Sur se convirtió en la primera subregión de la Región de las Américas en lograr que 100% de los entornos sean libres de humo, en consonancia con el Artículo 8 del Convenio Marco para el Control del Tabaco de la Organización Mundial de la Salud (CMCT). Algunos de países de la subregión adoptaron medidas legales más sólidas e incluyeron en su legislación la prohibición de fumar en lugares al aire libre concretos (como Argentina y Uruguay) o de introducir nuevos productos de nicotina y tabaco en su alcance jurídico (como Ecuador y Paraguay). Los diez países tomaron diferentes caminos para adoptar esta medida de salud pública, ya fuera mediante disposiciones ejecutivas, legislativas o una combinación de ambas. Algunos países, como Argentina, Brasil y Venezuela, empezaron a nivel subnacional y luego, de un modo similar al del resto de países, pasaron al nivel nacional.Para lograr este hito fue crucial un contexto adecuado: una amplia ratificación del CMCT y la relevancia dada al derecho humano a la salud, los esfuerzos de la sociedad civil, los compromisos asumidos por los órganos intergubernamentales, los medios y las estrategias de comunicación, y el progreso de la evidencia científica. Los países se enfrentaron a obstáculos, entre ellos la conocida interferencia de la industria tabacalera, que entre otras estrategias empleó el uso de litigios; sin embargo, distintos tribunales y jueces respaldaron medidas legales integrales de ambientes libres de humo de tabaco.El proceso mediante el cual América del Sur ha logrado este objetivo representa un modelo a seguir para otras subregiones de las Región de las Américas y el mundo.

Em dezembro de 2020, quase 20 anos depois do lançamento da iniciativa "Américas sem Fumo" pela Organização Pan-Americana da Saúde, em 2001, a América do Sul tornou-se a primeira sub-região das Américas a alcançar ambientes 100% livres de fumaça de tabaco, em conformidade com o Artigo 8 da Convenção-Quadro para o Controle do Tabaco da Organização Mundial da Saúde (CQCT). Alguns desses países adotaram medidas legais mais robustas que outros, com a inclusão da proibição de fumar em determinados locais ao ar livre (como Argentina e Uruguai) e/ou de novos produtos de nicotina e tabaco no escopo de suas leis (como Equador e Paraguai). Os dez países seguiram caminhos diferentes ao adotarem essa medida de saúde pública, por meio de medidas executivas ou legislativas ou ainda por uma combinação de ambas. Alguns países, como Argentina, Brasil e Venezuela, começaram no âmbito subnacional e depois passaram ao âmbito nacional, de maneira semelhante aos demais países.Para alcançar esse marco, foi crucial ter um contexto adequado: a ampla ratificação da CQCT, bem como a importância dada ao direito humano à saúde, os esforços da sociedade civil, os compromissos assumidos por organismos intergovernamentais, as estratégias de mídia e comunicação e o desenvolvimento de evidências científicas. Os países enfrentaram obstáculos, incluindo a conhecida interferência da indústria do tabaco, que, entre outras estratégias, recorreu ao litígio; entretanto, os tribunais e juízes mantiveram medidas legais abrangentes sobre ambientes livres de fumo.O processo pelo qual a América do Sul alcançou esse marco constitui um exemplo para outras sub-regiões das Américas e para o mundo.

Towards a smoke-free world? South America became the first 100% smoke-free subregion in the Americas

[ABSTRACT]. Almost 20 years after the launching by the Pan American Health Organization of its “Smoke-Free Americas” initiative in 2001, in December 2020, South America became the first subregion in the Americas to accomplish 100% smoke-free environments in line with Article 8 of the World Health Organization Framework Convention on Tobacco Control (FCTC). Some of these countries adopted legal measures that are more robust than others, including in their laws specific outdoor places in the smoking ban (like Argentina and Uruguay) and/or novel nicotine and tobacco products under their scope (like Ecuador and Paraguay). The 10 countries took different paths to adopt this public health measure, either through executive or legislative measures or a combination of both. A few countries, like Argentina, Brazil, and Venezuela, started at the subnational level and then moved on to the national level, similar to the rest of the countries. For achieving this milestone, an adequate context was crucial: the broad ratification of the FCTC and the rele- vance given to the human right to health, civil society efforts, commitments made by intergovernmental bodies, media and communication strategies, and the development of scientific evidence. Countries faced obstacles, including the well-known interference of the tobacco industry, which among other strategies used litigation; however, courts and judges upheld comprehensive legal measures on smoke-free environments. The process by which South America achieved this milestone represents a role model for other subregions of the Americas and the world.

[RESUMEN]. Casi 20 años después del lanzamiento de la iniciativa "América libre de humo" de la Organización Panameri- cana de la Salud en el año 2001, en diciembre del 2020, América del Sur se convirtió en la primera subregión de la Región de las Américas en lograr que 100% de los entornos sean libres de humo, en consonancia con el Artículo 8 del Convenio Marco para el Control del Tabaco de la Organización Mundial de la Salud (CMCT). Algunos de países de la subregión adoptaron medidas legales más sólidas e incluyeron en su legislación la prohibición de fumar en lugares al aire libre concretos (como Argentina y Uruguay) o de introducir nuevos productos de nicotina y tabaco en su alcance jurídico (como Ecuador y Paraguay). Los diez países tomaron diferentes caminos para adoptar esta medida de salud pública, ya fuera mediante disposiciones ejecutivas, legislativas o una combinación de ambas. Algunos países, como Argentina, Brasil y Venezuela, empezaron a nivel subnacional y luego, de un modo similar al del resto de países, pasaron al nivel nacional. Para lograr este hito fue crucial un contexto adecuado: una amplia ratificación del CMCT y la relevancia dada al derecho humano a la salud, los esfuerzos de la sociedad civil, los compromisos asumidos por los órganos intergubernamentales, los medios y las estrategias de comunicación, y el progreso de la evidencia científica. Los países se enfrentaron a obstáculos, entre ellos la conocida interferencia de la industria tabacalera, que entre otras estrategias empleó el uso de litigios; sin embargo, distintos tribunales y jueces respaldaron medi- das legales integrales de ambientes libres de humo de tabaco. El proceso mediante el cual América del Sur ha logrado este objetivo representa un modelo a seguir para otras subregiones de las Región de las Américas y el mundo.

[RESUMO]. Em dezembro de 2020, quase 20 anos depois do lançamento da iniciativa “Américas sem Fumo” pela Organização Pan-Americana da Saúde, em 2001, a América do Sul tornou-se a primeira sub-região das Américas a alcançar ambientes 100% livres de fumaça de tabaco, em conformidade com o Artigo 8 da Con- venção-Quadro para o Controle do Tabaco da Organização Mundial da Saúde (CQCT). Alguns desses países adotaram medidas legais mais robustas que outros, com a inclusão da proibição de fumar em determinados locais ao ar livre (como Argentina e Uruguai) e/ou de novos produtos de nicotina e tabaco no escopo de suas leis (como Equador e Paraguai). Os dez países seguiram caminhos diferentes ao adotarem essa medida de saúde pública, por meio de medidas executivas ou legislativas ou ainda por uma combinação de ambas. Alguns países, como Argentina, Brasil e Venezuela, começaram no âmbito subnacional e depois passaram ao âmbito nacional, de maneira semelhante aos demais países. Para alcançar esse marco, foi crucial ter um contexto adequado: a ampla ratificação da CQCT, bem como a importância dada ao direito humano à saúde, os esforços da sociedade civil, os compromissos assumidos por organismos intergovernamentais, as estratégias de mídia e comunicação e o desenvolvimento de evi- dências científicas. Os países enfrentaram obstáculos, incluindo a conhecida interferência da indústria do tabaco, que, entre outras estratégias, recorreu ao litígio; entretanto, os tribunais e juízes mantiveram medidas legais abrangentes sobre ambientes livres de fumo. O processo pelo qual a América do Sul alcançou esse marco constitui um exemplo para outras sub-regiões das Américas e para o mundo.

Effect of Physical Activity/Exercise on Oxidative Stress and Inflammation in Muscle and Vascular Aging.

Functional status is considered the main determinant of healthy aging. Impairment in skeletal muscle and the cardiovascular system, two interrelated systems, results in compromised functional status in aging. Increased oxidative stress and inflammation in older subjects constitute the background for skeletal muscle and cardiovascular system alterations. Aged skeletal muscle mass and strength impairment is related to anabolic resistance, mitochondrial dysfunction, increased oxidative stress and inflammation as well as a reduced antioxidant response and myokine profile. Arterial stiffness and endothelial function stand out as the main cardiovascular alterations related to aging, where increased systemic and vascular oxidative stress and inflammation play a key role. Physical activity and exercise training arise as modifiable determinants of functional outcomes in older persons. Exercise enhances antioxidant response, decreases age-related oxidative stress and pro-inflammatory signals, and promotes the activation of anabolic and mitochondrial biogenesis pathways in skeletal muscle. Additionally, exercise improves endothelial function and arterial stiffness by reducing inflammatory and oxidative damage signaling in vascular tissue together with an increase in antioxidant enzymes and nitric oxide availability, globally promoting functional performance and healthy aging. This review focuses on the role of oxidative stress and inflammation in aged musculoskeletal and vascular systems and how physical activity/exercise influences functional status in the elderly.

Towards a smoke-free world? South America became the first 100% smoke-free subregion in the Americas / ¿Hacia un mundo libre de humo? América del Sur se convierte en la primera subregión 100% libre de humo en la Región de las Américas / Rumo a um mundo livre de fumo? A América do Sul tornou-se a primeira sub-região 100% livre de fumaça de tabaco nas Américas

ABSTRACT Almost 20 years after the launching by the Pan American Health Organization of its "Smoke-Free Americas" initiative in 2001, in December 2020, South America became the first subregion in the Americas to accomplish 100% smoke-free environments in line with Article 8 of the World Health Organization Framework Convention on Tobacco Control (FCTC). Some of these countries adopted legal measures that are more robust than others, including in their laws specific outdoor places in the smoking ban (like Argentina and Uruguay) and/or novel nicotine and tobacco products under their scope (like Ecuador and Paraguay). The 10 countries took different paths to adopt this public health measure, either through executive or legislative measures or a combination of both. A few countries, like Argentina, Brazil, and Venezuela, started at the subnational level and then moved on to the national level, similar to the rest of the countries. For achieving this milestone, an adequate context was crucial: the broad ratification of the FCTC and the relevance given to the human right to health, civil society efforts, commitments made by intergovernmental bodies, media and communication strategies, and the development of scientific evidence. Countries faced obstacles, including the well-known interference of the tobacco industry, which among other strategies used litigation; however, courts and judges upheld comprehensive legal measures on smoke-free environments. The process by which South America achieved this milestone represents a role model for other subregions of the Americas and the world.

RESUMEN Casi 20 años después del lanzamiento de la iniciativa "América libre de humo" de la Organización Panamericana de la Salud en el año 2001, en diciembre del 2020, América del Sur se convirtió en la primera subregión de la Región de las Américas en lograr que 100% de los entornos sean libres de humo, en consonancia con el Artículo 8 del Convenio Marco para el Control del Tabaco de la Organización Mundial de la Salud (CMCT). Algunos de países de la subregión adoptaron medidas legales más sólidas e incluyeron en su legislación la prohibición de fumar en lugares al aire libre concretos (como Argentina y Uruguay) o de introducir nuevos productos de nicotina y tabaco en su alcance jurídico (como Ecuador y Paraguay). Los diez países tomaron diferentes caminos para adoptar esta medida de salud pública, ya fuera mediante disposiciones ejecutivas, legislativas o una combinación de ambas. Algunos países, como Argentina, Brasil y Venezuela, empezaron a nivel subnacional y luego, de un modo similar al del resto de países, pasaron al nivel nacional. Para lograr este hito fue crucial un contexto adecuado: una amplia ratificación del CMCT y la relevancia dada al derecho humano a la salud, los esfuerzos de la sociedad civil, los compromisos asumidos por los órganos intergubernamentales, los medios y las estrategias de comunicación, y el progreso de la evidencia científica. Los países se enfrentaron a obstáculos, entre ellos la conocida interferencia de la industria tabacalera, que entre otras estrategias empleó el uso de litigios; sin embargo, distintos tribunales y jueces respaldaron medidas legales integrales de ambientes libres de humo de tabaco. El proceso mediante el cual América del Sur ha logrado este objetivo representa un modelo a seguir para otras subregiones de las Región de las Américas y el mundo.

RESUMO Em dezembro de 2020, quase 20 anos depois do lançamento da iniciativa "Américas sem Fumo" pela Organização Pan-Americana da Saúde, em 2001, a América do Sul tornou-se a primeira sub-região das Américas a alcançar ambientes 100% livres de fumaça de tabaco, em conformidade com o Artigo 8 da Convenção-Quadro para o Controle do Tabaco da Organização Mundial da Saúde (CQCT). Alguns desses países adotaram medidas legais mais robustas que outros, com a inclusão da proibição de fumar em determinados locais ao ar livre (como Argentina e Uruguai) e/ou de novos produtos de nicotina e tabaco no escopo de suas leis (como Equador e Paraguai). Os dez países seguiram caminhos diferentes ao adotarem essa medida de saúde pública, por meio de medidas executivas ou legislativas ou ainda por uma combinação de ambas. Alguns países, como Argentina, Brasil e Venezuela, começaram no âmbito subnacional e depois passaram ao âmbito nacional, de maneira semelhante aos demais países. Para alcançar esse marco, foi crucial ter um contexto adequado: a ampla ratificação da CQCT, bem como a importância dada ao direito humano à saúde, os esforços da sociedade civil, os compromissos assumidos por organismos intergovernamentais, as estratégias de mídia e comunicação e o desenvolvimento de evidências científicas. Os países enfrentaram obstáculos, incluindo a conhecida interferência da indústria do tabaco, que, entre outras estratégias, recorreu ao litígio; entretanto, os tribunais e juízes mantiveram medidas legais abrangentes sobre ambientes livres de fumo. O processo pelo qual a América do Sul alcançou esse marco constitui um exemplo para outras sub-regiões das Américas e para o mundo.

[Clinical guidelines for the managment of intestinal failure secondary to pediatric short bowel syndrome]. / Guía clínica para el manejo de la falla intestinal secundaria a síndrome de intestino corto en pediatría.

Intestinal failure secondary to short bowel syndrome in pediatrics, is a rare condition with high morbimortality. A follow up multidisciplinary team is necessary to minimize complications and optimize the intestinal rehabilitation. There are no gold standard guidelines for the management of this group of complex patients. The development of clinical guidelines may contribute for an adequate management of patients with intestinal failure and short bowel syndrome. This Clinical Guideline for the Management was developed by 16 experts based on modified Delphi methodology. The meetings were held at the Argentinian Association of Enteral and Parenteral Nutrition (Asociación Argentina de Nutrición Enteral y Parenteral); the topics analyzed were definitions, epidemiology, enteral and parenteral nutrition, pharmacological and surgical treatments, and criteria for referring patients to intestinal rehabilitation centers. The document is aimed to provide basic scientific knowledge for medical institutions, health providers, healthcare providers, patients and families.

La falla intestinal secundaria a síndrome de intestino corto en pediatría es una entidad poco frecuente, de alta morbimortalidad. Requiere de un equipo interdisciplinario para su abordaje, lo cual ha demostrado que disminuye la morbimortalidad y aumenta la posibilidad de que los pacientes logren la autonomía intestinal. Existe una falta de evidencia científica en diferentes abordajes de la patología. Consideramos necesario el desarrollo de esta Guía para el Manejo Clínico construida sobre la base de la metodología Delphi modificada, en la Asociación Argentina de Nutrición Enteral y Parenteral, por 16 expertos que se reunieron para discutir y consensuar los principales aspectos de tratamiento clínico. Se analizaron 4 aspectos: definiciones y epidemiología; nutrición enteral, nutrición parenteral; tratamientos farmacológicos y quirúrgicos, y criterios de derivación a centros de alta complejidad. Sin duda este documento será de utilidad para los pacientes, los profesionales y las instituciones, así como para los diferentes financiadores del sistema de salud.

Hyperphosphatemia-Induced Oxidant/Antioxidant Imbalance Impairs Vascular Relaxation and Induces Inflammation and Fibrosis in Old Mice.

Aging impairs vascular function, but the mechanisms involved are unknown. The aim of this study was to analyze whether aging-related hyperphosphatemia is implied in this effect by elucidating the role of oxidative stress. C57BL6 mice that were aged 5 months (young) and 24 months (old), receiving a standard (0.6%) or low-phosphate (0.2%) diet, were used. Isolated mesenteric arteries from old mice showed diminished endothelium-dependent vascular relaxation by the down-regulation of NOS3 expression, increased inflammation and increased fibrosis in isolated aortas, compared to those isolated from young mice. In parallel, increased Nox4 expression and reduced Nrf2, Sod2-Mn and Gpx1 were found in the aortas from old mice, resulting in oxidant/antioxidant imbalance. The low-phosphate diet improved vascular function and oxidant/antioxidant balance in old mice. Mechanisms were analyzed in endothelial (EC) and vascular smooth muscle cells (SMCs) treated with the phosphate donor ß-glycerophosphate (BGP). In EC, BGP increased Nox4 expression and ROS production, which reduced NOS3 expression via NFκB. BGP also increased inflammation in EC. In SMC, BGP increased Collagen I and fibronectin expression by priming ROS production and NFκB activity. In conclusion, hyperphosphatemia reduced endothelium-dependent vascular relaxation and increased inflammation and vascular fibrosis through an impairment of oxidant/antioxidant balance in old mice. A low-phosphate diet achieved improvements in the vascular function in old mice.

Aging-related hyperphosphatemia impairs myogenic differentiation and enhances fibrosis in skeletal muscle.

BACKGROUND: Hyperphosphatemia has been related to the development of sarcopenia in aging mice. We describe the intracellular mechanisms involved in the impairment of the myogenic differentiation promoted by hyperphosphatemia and analyse these mechanisms in the muscle from older mice. METHODS: C2 C12 cells were grown in 2% horse serum in order to promote myogenic differentiation, in the presence or absence of 10 mM beta-glycerophosphate (BGP) for 7 days. Troponin T, paired box 7 (Pax-7), myogenic factor 5 (Myf5), myogenic differentiation 1 (MyoD), myogenin (MyoG), myocyte enhancer factor 2 (MEF2C), P300/CBP-associated factor (PCAF), histone deacetylase 1 (HDAC1), fibronectin, vimentin, and collagen I were analysed at 48, 72, and 168 h, by western blotting or by immunofluorescence staining visualized by confocal microscopy. Studies in mice were performed in 5- and 24-month-old C57BL6 mice. Three months before sacrifice, 21-month-old mice were fed with a standard diet or a low phosphate diet, containing 0.6% or 0.2% phosphate, respectively. Serum phosphate concentration was assessed by a colorimetric method and forelimb strength by a grip test. Fibrosis was observed in the tibialis anterior muscle by Sirius Red staining. In gastrocnemius muscle, MyoG, MEF2C, and fibronectin expressions were analysed by western blotting. RESULTS: Cells differentiated in the presence of BGP showed near five times less expression of troponin T and kept higher levels of Pax-7 than control cells indicating a reduced myogenic differentiation. BGP reduced Myf5 about 50% and diminished MyoD transcriptional activity by increasing the expression of HDAC1 and reducing the expression of PCAF. Consequently, BGP reduced to 50% the expression of MyoG and MEF2C. A significant increase in the expression of fibrosis markers as collagen I, vimentin, and fibronectin was found in cells treated with BGP. In mice, serum phosphate (17.24 ± 0.77 mg/dL young; 23.23 ± 0.81 mg/dL old; 19.09 ± 0.75 mg/dL old with low phosphate diet) correlates negatively (r = -0.515, P = 0.001) with the muscular strength (3.13 ± 0.07 gf/g young; 1.70 ± 0.12 gf/g old; 2.10 ± 0.09 gf/g old with low phosphate diet) and with the expression of MyoG (r = -0.535, P = 0.007) and positively with the expression of fibronectin (r = 0.503, P = 0.001) in gastrocnemius muscle. The tibialis anterior muscle from old mice showed muscular fibrosis. Older mice fed with a low phosphate diet showed improved muscular parameters relative to control mice of similar age. CONCLUSIONS: Hyperphosphatemia impairs myogenic differentiation, by inhibiting the transcriptional activity of MyoD, and enhances the expression of fibrotic genes in cultured myoblasts. Experiments carried out in older mice demonstrate a close relationship between age-related hyperphosphatemia and the decrease in the expression of myogenic factors and the increase in factors related to muscle fibrosis.

Guía clínica para el manejo de la falla intestinal secundaria a síndrome de intestino corto en pediatría / Clinical guidelines for the managment of intestinal failure secondary to pediatric short bowel syndrome

La falla intestinal secundaria a síndrome de intestino corto en pediatría es una entidad poco frecuente, de alta morbimortalidad. Requiere de un equipo interdisciplinario para su abordaje, lo cual ha demostrado que disminuye la morbimortalidad y aumenta la posibilidad de que los pacientes logren la autonomía intestinal. Existe una falta de evidencia científica en diferentes abordajes de la patología. Consideramos necesario el desarrollo de esta Guía para el Manejo Clínico construida sobre la base de la metodología Delphi modificada, en la Asociación Argentina de Nutrición Enteral y Parenteral, por 16 expertos que se reunieron para discutir y consensuar los principales aspectos de tratamiento clínico. Se analizaron 4 aspectos: definiciones y epidemiología; nutrición enteral, nutrición parenteral; tratamientos farmacológicos y quirúrgicos,y criterios de derivación a centros de alta complejidad. Sin duda este documento será de utilidad para los pacientes, los profesionales y las instituciones, así como para los diferentes financiadores del sistema de salud.

Intestinal failure secondary to short bowel syndrome in pediatrics, is a rare condition with high morbimortality. A follow up multidisciplinary team is necessary to minimize complications and optimize the intestinal rehabilitation. There are no gold standard guidelines for the management of this group of complex patients. The development of clinical guidelines may contribute for an adequate management of patients with intestinal failure and short bowel syndrome. This Clinical Guideline for the Management was developed by 16 experts based on modified Delphi methodology. The meetings were held at the Argentinian Association of Enteral and Parenteral Nutrition (Asociación Argentina de Nutrición Enteral y Parenteral); the topics analyzed were definitions, epidemiology, enteral and parenteral nutrition, pharmacological and surgical treatments, and criteria for referring patients to intestinal rehabilitation centers. The document is aimed to provide basic scientific knowledge for medical institutions, health providers, healthcare providers, patients and families.

Uraemic toxins impair skeletal muscle regeneration by inhibiting myoblast proliferation, reducing myogenic differentiation, and promoting muscular fibrosis.

Uraemic toxins increase in serum parallel to a decline in the glomerular filtration rate and the development of sarcopenia in patients with chronic kidney disease (CKD). This study analyses the role of uraemic toxins in sarcopenia at different stages of CKD, evaluating changes in the muscular regeneration process. Cultured C2C12 cells were incubated with a combination of indoxyl sulphate and p-cresol at high doses (100 µg/mL) or low doses (25 µg/mL and 10 µg/mL) resembling late or early CKD stages, respectively. Cell proliferation (analysed by scratch assays and flow cytometry) was inhibited only by high doses of uraemic toxins, which inactivated the cdc2-cyclin B complex, inhibiting mitosis and inducing apoptosis (analysed by annexin V staining). By contrast, low doses of uraemic toxins did not affect proliferation, but reduced myogenic differentiation, primed with 2% horse serum, by inhibiting myogenin expression and promoting fibro-adipogenic differentiation. Finally, to assess the in vivo relevance of these results, studies were performed in gastrocnemii from uraemic rats, which showed higher collagen expression and lower myosin heavy chain expression than those from healthy rats. In conclusion, uraemic toxins impair the skeletal muscular regeneration process, even at low concentrations, suggesting that sarcopenia can progress from the early stages of CKD.

Regional Alterations in Cortical Sulcal Depth in Living Fetuses with Down Syndrome.

Down syndrome (DS) is the most common genetic cause of developmental disabilities. Advanced analysis of brain magnetic resonance imaging (MRI) has been used to find brain abnormalities and their relationship to neurocognitive impairments in children and adolescents with DS. Because genetic factors affect brain development in early fetal life, there is a growing interest in analyzing brains from living fetuses with DS. In this study, we investigated regional sulcal folding depth as well as global cortical gyrification from fetal brain MRIs. Nine fetuses with DS (29.1 ± 4.24 gestational weeks [mean ± standard deviation]) were compared with 17 typically developing [TD] fetuses (28.4 ± 3.44). Fetuses with DS showed lower whole-brain average sulcal depths and gyrification index than TD fetuses. Significant decreases in sulcal depth were found in bilateral Sylvian fissures and right central and parieto-occipital sulci. On the other hand, significantly increased sulcal depth was shown in the left superior temporal sulcus, which is related to atypical hemispheric asymmetry of cortical folding. Moreover, these group differences increased as gestation progressed. This study demonstrates that regional sulcal depth is a sensitive marker for detecting alterations of cortical development in DS during fetal life, which may be associated with later neurocognitive impairment.

Ecosistema intestinal en la infancia: rol de los "bióticos" / Gut ecosystem during infancy: The role of "biotics"

En los últimos años, las evidencias han demostrado la importancia de la microbiota intestinal en la salud del individuo. La dinámica de la colonización temprana y el establecimiento de una comunidad abundante y diversa de microorganismos saludables, a partir de un parto vaginal y lactancia materna, resultan fundamentales en la conformación de una matriz inmunológica saludable. Esta revisión tiene como objetivo describir las evidencias disponibles sobre el desarrollo de la microbiota en el primer año de vida y el actual potencial que ofrece el uso de prebióticos, probióticos, simbióticos y posbióticos durante esta etapa esencial de la vida

In recent years, the evidence has demonstrated the relevance of the gut microbiota in an individual's health. The dynamics of an early colonization and the establishment of a community of plenty, diverse, and healthy microorganisms from a vaginal delivery and breastfeeding are critical for the development of a healthy immune matrix. The objective of this review is to describe the available evidence on microbiota development in the first year of life and the current possibilities offered by prebiotics, probiotics, symbiotics, and postbiotics during such critical stage of life.

Gut ecosystem during infancy: The role of "biotics". / Ecosistema intestinal en la infancia: rol de los "bioticos".

In recent years, the evidence has demonstrated the relevance of the gut microbiota in an individual's health. The dynamics of an early colonization and the establishment of a community of plenty, diverse, and healthy microorganisms from a vaginal delivery and breastfeeding are critical for the development of a healthy immune matrix. The objective of this review is to describe the available evidence on microbiota development in the first year of life and the current possibilities offered by prebiotics, probiotics, symbiotics, and postbiotics during such critical stage of life.

En los últimos años, las evidencias han demostrado la importancia de la microbiota intestinal en la salud del individuo. La dinámica de la colonización temprana y el establecimiento de una comunidad abundante y diversa de microorganismos saludables, a partir de un parto vaginal y lactancia materna, resultan fundamentales en la conformación de una matriz inmunológica saludable. Esta revisión tiene como objetivo describir las evidencias disponibles sobre el desarrollo de la microbiota en el primer año de vida y el actual potencial que ofrece el uso de prebióticos, probióticos, simbióticos y posbióticos durante esta etapa esencial de la vida.

Endothelin-1 induces cellular senescence and fibrosis in cultured myoblasts. A potential mechanism of aging-related sarcopenia.

Endothelial dysfunction, with increased endothelin-1 (ET-1) synthesis, and sarcopenia, characterized by the loss of muscular mass and strength, are two aging-related conditions. However, a relationship between them has not been already established. The aim of this study was to determine whether ET-1 induces senescence and fibrosis in cultured murine myoblasts, which could be involved in the development of sarcopenia related to aging. For this purpose, myoblasts were incubated with ET-1 to assess cellular senescence, analyzed by senescence associated ß-galactosidase activity and p16 expression; and fibrosis, assessed by fibronectin expression. ET-1 induced myoblast senescence and fibrosis through ETA receptor. The use of antioxidants and several antagonists revealed that ET-1 effect on senescence and fibrosis depended on ROS production and activation of PI3K-AKT-GSK pathway. To stress the in vivo relevance of these results, circulating ET-1, muscular strength, muscular fibrosis and p16 expression were measured in male C57Bl6 mice from 5-18-24-months-old. Old mice shown high levels of ET-1 correlated with muscular fibrosis, muscular p16 expression and loss of muscle strength. In conclusion, ET-1 promotes fibrosis and senescence in cultured myoblasts, similar results were found in old mice, suggesting a potential role for ET-1 in the development of sarcopenia related to aging.

High-serum phosphate and parathyroid hormone distinctly regulate bone loss and vascular calcification in experimental chronic kidney disease.

BACKGROUND: In chronic kidney disease (CKD), increases in serum phosphate and parathyroid hormone (PTH) aggravate vascular calcification (VC) and bone loss. This study was designed to discriminate high phosphorus (HP) and PTH contribution to VC and bone loss. METHODS: Nephrectomized rats fed a HP diet underwent either sham operation or parathyroidectomy and PTH 1-34 supplementation to normalize serum PTH. RESULTS: In uraemic rats fed a HP diet, parathyroidectomy with serum PTH 1-34 supplementation resulted in (i) reduced aortic calcium (80%) by attenuating osteogenic differentiation (higher α-actin; reduced Runx2 and BMP2) and increasing the Wnt inhibitor Sclerostin, despite a similar degree of hyperphosphataemia, renal damage and serum Klotho; (ii) prevention of bone loss mostly by attenuating bone resorption and increases in Wnt inhibitors; and (iii) a 70% decrease in serum calcitriol levels despite significantly reduced serum Fgf23, calcium and renal 24-hydroxylase, which questions that Fgf23 is the main regulator of renal calcitriol production. Significantly, when vascular smooth muscle cells (VSMCs) were exposed exclusively to high phosphate and calcium, high PTH enhanced while low PTH attenuated calcium deposition through parathyroid hormone 1 receptor (PTH1R) signalling. CONCLUSIONS: In hyperphosphataemic CKD, a defective suppression of high PTH exacerbates HP-mediated osteogenic VSMC differentiation and reduces vascular levels of anti-calcifying sclerostin.

Hyperphosphatemia Promotes Senescence of Myoblasts by Impairing Autophagy Through Ilk Overexpression, A Possible Mechanism Involved in Sarcopenia.

In mammalians, advancing age is associated with sarcopenia, the progressive and involuntary loss of muscle mass and strength. Hyperphosphatemia is an aging-related condition involved in several pathologies. The aim of this work was to assess whether hyperphosphatemia plays a role in the age-related loss of mass muscle and strength by inducing cellular senescence in murine myoblasts and to explore the intracellular mechanism involved in this effect. Cultured mouse C2C12 cells were treated with 10 mM beta-glycerophosphate (BGP] at different periods of time to induce hyperphosphatemia. BGP promoted cellular senescence after 24 h of treatment, assessed by the increased expression of p53, acetylated-p53 and p21 and senescence associated ß-galactosidase activity. In parallel, BGP increased ILK expression and activity, followed by mTOR activation and autophagy reduction. Knocking-down ILK expression increased autophagy and protected cells from senescence induced by hyperphosphatemia. BGP also reduced the proliferative capacity of cultured myoblasts. Old mice (24-months-old] presented higher serum phosphate concentration, lower forelimb strength, higher expression of p53 and ILK and less autophagy in vastus muscle than young mice (5-months-old]. In conclusion, we propose that hyperphosphatemia induces senescence in cultured myoblasts through ILK overexpression, reducing their proliferative capacity, which could be a mechanism involved in the development of sarcopenia, since old mice showed loss of muscular strength correlated with high serum phosphate concentration and increased levels of ILK and p53.

Hyperphosphatemia induces senescence in human endothelial cells by increasing endothelin-1 production.

Hyperphosphatemia is related to some pathologies, affecting vascular cell behavior. This work analyzes whether high concentration of extracellular phosphate induces endothelial senescence through up-regulation of endothelin-1 (ET-1), exploring the mechanisms involved. The phosphate donor ß-glycerophosphate (BGP) in human endothelial cells increased ET-1 production, endothelin-converting enzyme-1 (ECE-1) protein, and mRNA expression, which depend on the AP-1 activation through ROS production. In parallel, BGP also induced endothelial senescence by increasing p16 expression and the senescence-associated ß-galactosidase (SA-ß-GAL) activity. ET-1 itself was able to induce endothelial senescence, increasing p16 expression and SA-ß-GAL activity. In addition, senescence induced by BGP was blocked when different ET-1 system antagonists were used. BGP increased ROS production at short times, and the presence of antioxidants prevented the effect of BGP on AP1 activation, ECE-1 expression, and endothelial senescence. These findings were confirmed in vivo with two animal models in which phosphate serum levels were increased: seven/eight nephrectomized rats as chronic kidney disease models fed on a high phosphate diet and aged mice. Both models showed hyperphosphatemia, higher levels of ET-1, and up-regulation in aortic ECE-1, suggesting a direct relationship between hyperphosphatemia and ET-1. Present results point to a new and relevant role of hyperphosphatemia on the regulation of ET-1 system and senescence induction at endothelial level, both in endothelial cells and aorta from two animal models. The mechanism involved showed a higher ROS production, which probably activates AP-1 transcription factor and, as a result, ECE-1 expression, increasing ET-1 synthesis, which in consequence induces endothelial senescence.

The importance of continued engagement during the implementation phase of tobacco control policies in a middle-income country: the case of Costa Rica.

OBJECTIVE: To analyse the process of implementing and enforcing smoke-free environments, tobacco advertising, tobacco taxes and health warning labels from Costa Rica's 2012 tobacco control law. METHOD: Review of tobacco control legislation, newspaper articles and interviewing key informants. RESULTS: Despite overcoming decades of tobacco industry dominance to win enactment of a strong tobacco control law in March 2012 consistent with WHO's Framework Convention on Tobacco Control, the tobacco industry and their allies lobbied executive branch authorities for exemptions in smoke-free environments to create public confusion, and continued to report in the media that increasing cigarette taxes led to a rise in illicit trade. In response, tobacco control advocates, with technical support from international health groups, helped strengthen tobacco advertising regulations by prohibiting advertising at the point-of-sale (POS) and banning corporate social responsibility campaigns. The Health Ministry used increased tobacco taxes earmarked for tobacco control to help effectively promote and enforce the law, resulting in high compliance for smoke-free environments, advertising restrictions and health warning label (HWL) regulations. Despite this success, government trade concerns allowed, as of December 2015, POS tobacco advertising, and delayed the release of HWL regulations for 15 months. CONCLUSIONS: The implementation phase continues to be a site of intensive tobacco industry political activity in low and middle-income countries. International support and earmarked tobacco taxes provide important technical and financial assistance to implement tobacco control policies, but more legal expertise is needed to overcome government trade concerns and avoid unnecessary delays in implementation.