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.

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.

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.

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.

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.

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.

Costa Rica's implementation of the Framework Convention on Tobacco Control: Overcoming decades of industry dominance.

OBJECTIVE: To analyze the passage of Costa Rica's 2012 tobacco control law. MATERIALS AND METHODS: Review of legislation, newspaper articles, and key informant interviews. RESULTS: Tobacco control advocates, in close collaboration with international health groups, recruited national, regional and international experts to testify in the Legislative Assembly, implemented grassroots advocacy campaigns, and generated media coverage to enact strong legislation in March 2012 consistent with the World Health Organization Framework Convention on Tobacco Control, despite tobacco industry lobbying efforts that for decades blocked effective tobacco control legislation. CONCLUSION: Costa Rica's experience illustrates how with resources, good strategic planning, aggressive tactics and perseverance tobacco control advocates can overcome tobacco industry opposition in the Legislative Assembly and Executive Branch. This determined approach has positioned Costa Rica to become a regional leader in tobacco control.

Diagnóstico y tratamiento de la esofagitis eosinofílica en niños. Revisión de la literatura y recomendaciones basadas en la evidencia. Grupo de trabajo de la Sociedad Latinoamericana de Gastroenterología, Hepatología y Nutrición pediátrica (SLAGHNP).

During the last twenty years Eosinophilic Esophagitis has become one the most important causes of esophageal disfunction in children, food impactation in adolescents and young adults, therapeutic failure in patients with gastroesophageal reflux disease (GERD) and the most frecuent eosinophilic disease of the gastrointestinal tract. We present recommendations for the diagnosis and treatment of the disease based in a systematic review of the literature.

Fiber in enteral nutrition: why and what for? / La fibra en la nutrición enteral: ¿por qué y para qué?

Enteral formulas containing fiber, designed to be administered orally or by gavage, have been used for decades. Although their indication in the pediatric population does not have a global consensus, knowledge about the benefits of using fiber to promote healthier microbiota has grown in recent years. Different fiber types' physicochemical characteristics (solubility, viscosity, fermentability) determine their functions. The impact of fiber use on preventing specific chronic pathologies (cardiovascular disease, cancer, diabetes) has been reported in epidemiological studies. In controlled studies, changes in stool consistency, intestinal transit, and the composition and function of the microbiota have been observed since fiber produces fermentation metabolites such as short-chain fatty acids, which improve metabolic and immunological aspects. Different pediatric pathologies could benefit from the use of fiber.

Las fórmulas enterales que contienen fibra, diseñadas para ser administradas de forma oral o por sonda, han sido utilizadas durante décadas. Si bien su indicación en población pediátrica no cuenta con un consenso global, el conocimiento sobre los beneficios de la utilización de fibra en relación con el intestino, para promover una microbiota más saludable, ha crecido en los últimos años. Los diferentes tipos de fibra tienen características fisicoquímicas (solubilidad, viscosidad, fermentabilidad) que determinan sus funciones. El impacto del uso de fibra sobre la prevención de ciertas patologías crónicas (enfermedad cardiovascular, cáncer, diabetes) ha sido reportado en estudios epidemiológicos. En estudios controlados, se han observado cambios en la consistencia de las heces, en el tránsito intestinal y en la composición y función de la microbiota, ya que la fibra produce metabolitos de fermentación tales como ácidos grasos de cadena corta, lo cual mejora aspectos metabólicos e inmunológicos. Diferentes patologías pediátricas podrían verse beneficiadas por el uso de fibra.

Gender-specific capacity of insulin resistance proxies to predict functional decline in older adults.

OBJECTIVES: Insulin resistance determined by Homeostasis Model of Insulin Resistance (HOMA-IR) has been associated with functional decline in non-diabetic older subjects. However, insulin is not routinely assessed. The study evaluated the predictive value of non-insulin-dependent IR surrogates on functional decline in non-diabetic older men and women. DESIGN AND PARTICIPANTS: Prospective cohort study over 5 years. The study included 615 older participants from the Toledo Study of Healthy Aging. METHODS: Frailty was assessed by the Frailty Trait Scale-5 (FTS-5) at baseline and after 5 years follow-up. 193 subjects experienced functional decline (2.5-point reduction in the FTS-5 score). Multivariate regression models analysed the effect of five described IR surrogates on functional decline considering potential confounders. RESULTS: Among evaluated IR proxies, triglyceride glucose-body mass index (TyG-BMI) and HOMA-IR were significantly associated with an increased risk of functional decline (odd ratio (95% confidence interval) TyG-BMI: 1.16 (1.05, 1.28), p = 0.0035 and HOMA-IR: 1.59 (1.15, 2.21), p = 0.0056) among all participants. When stratified by gender, HOMA-IR was related to functional decline in men [2.02 (1.13, 3.59), p = 0.0173] and TyG-BMI in women [1.19 (1.05, 1.35), p = 0.0057]. CONCLUSIONS: Only TyG-BMI index mimics the predictive capacity of insulin-based IR marker. The predictive ability of IR indexes is gender-specific, being TyG-BMI the only index able to predict functional decline in women and HOMA-IR in men.

The Perfect Storm: Applying the Multiple Streams Framework to Understand the Adoption of a WHO Framework Convention on Tobacco Control-Based Policy in Mexico.

BACKGROUND: The aim of this study was to document how Mexico adopted a WHO Framework Convention on Tobacco Control (FCTC)-based national tobacco control law. METHODS: We analyzed publicly available documents and interviewed 14 key stakeholders. We applied the Multiple Streams Framework (MSF) to analyze these findings. RESULTS: Previous attempts to approve comprehensive FCTC-based initiatives failed due to a lack of political will, the tobacco industry's close connections to policymakers, and a lack of health advocacy coordination. Applying the MSF reveals increased attention towards collecting and sharing data to frame the severity of the problem (problem stream). The expansion of a coordinated health advocacy coalition and activities led to increased support for desired FCTC policy solutions (policy stream). The election of President López Obrador and legislative changes led to a deep renewed focus on tobacco control (politics stream). These three streams converged to create a policy window to secure a strong FCTC-based initiative on the political agenda that was ultimately passed. CONCLUSIONS: The Mexican experience illustrates the importance of continued health advocacy and political will in adopting FCTC-based policies. Other countries should follow Mexico's lead by collecting and sharing data through coordinating efforts in order to be prepared to seize political opportunity windows when strong political will is present.

[Cow's milk allergy treatment. An expert consensus]. / Tratamiento de la alergia a la proteína de la leche de vaca. Consenso interdisciplinario de expertos.

The treatment of cow's milk protein allergy is based on the complete elimination of cow's milk protein from the diet. To achieve remission of symptoms and future tolerance, exclusion must be total. In formula fed infants the extensively hydrolysed formula is the most appropriate option in mild or moderate forms, while those based on amino acids are reserved for the most severe cases. The treatment time, the acquisition of tolerance and the moment for the oral provocation test will vary according to the clinical picture, the immunological mechanism involved and the age of the patient. The aim of this consensus has been to reflect the updated knowledge together with the experience of neonatologists, pediatricians, experts in allergy, nutrition and gastroenterology.

El tratamiento de la alergia a las proteínas de la leche de vaca se basa en la eliminación completa de las proteínas de leche de vaca de la dieta del niño y de la madre en los que reciben leche materna. Para lograr la remisión de los síntomas y la tolerancia futura, la exclusión debe ser total. En los niños que reciben fórmula, esta deberá tener hidrolizado extenso de proteínas en las formas leves o moderadas, mientras que aquellas a base de aminoácidos se reservan para los casos más graves. El tiempo de tratamiento, la adquisición de tolerancia y el momento para la prueba de provocación oral van a variar según el cuadro clínico, el mecanismo inmunológico implicado y la edad del paciente. El objetivo de este consenso ha sido reflejar el conocimiento actualizado junto con la experiencia de neonatólogos, pediatras, especialistas en alergia, nutrición y gastroenterología.

[Cow's milk allergy: diagnostic process. Expert consensus]. / Alergia a las proteínas de la leche de vaca: proceso diagnóstico. Consenso interdisciplinario de expertos.

Cow's milk protein can cause food allergy. The different mechanisms of action involved, the clinical variability depending on the stage of pediatric life in which it manifests, leads to difficulties in its approach, with the risk of under- or over-diagnosis. Professionals from various areas intervene in this process and their interaction is recommended. That is why the objective of this consensus has been to reflect the updated knowledge in an interdisciplinary mode, generating recommendations for its correct diagnosis. We have worked with the Delphi method to add to the scientific evidence, the experience from neonatologists, pediatricians, experts in allergy, nutrition and gastroenterology. We think that this interdisciplinary approach will be of practical use and will promote more comprehensive care for these patients.

Las proteínas de la leche de vaca pueden causar alergia alimentaria. Los distintos mecanismos de acción involucrados y la variabilidad clínica según la etapa de la vida pediátrica en la que se manifieste ocasionan dificultades en su abordaje, con riesgo de sub- o sobrediagnóstico. En este proceso, intervienen profesionales de diversas áreas y es recomendable su interacción. Es por ello que el objetivo de este consenso ha sido reflejar el conocimiento actualizado desde la interdisciplina, generando recomendaciones para su correcto diagnóstico. Hemos trabajado con el método de Delphi para sumarle a la evidencia científica, la experiencia proveniente de neonatólogos, pediatras, especialistas en alergia, nutrición y gastroenterología. Pensamos que este enfoque interdisciplinario de trabajo va a resultar de utilidad práctica y promoverá una atención más integral de estos pacientes.

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.

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.

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.

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.

[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.

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.