Long-Term Effects of Adipose-Derived Stem Cells for the Treatment of Bilateral Limbal Stem Cell Deficiency.

PURPOSE: To determine the safety and feasibility of human autologous adipose tissue-derived adult mesenchymal stem cells (ASCs) for ocular surface regeneration in patients with bilateral limbal stem-cell deficiency (LSCD). METHODS: A phase IIa clinical trial was designed (https://Clinicaltrials.gov, NCT01808378) with 8 patients, 3 of whom had aniridia, 2 meibomian glands diseases, 2 multiple surgeries and 1 chronic chemical injury. The therapeutic protocol was as follows: 6-mm of central corneal epithelium was removed, 400,000 ASCs were injected into each limboconjunctival quadrant, 400,000 ASCs were suspended over the cornea for 20 min, and finally the cornea was covered with an amniotic membrane patch. RESULTS: No adverse events were detected after a mean of 86,5 months of follow-up. One year after surgery, 6 of the 8 transplants were scored as successful, five patients had improved uncorrected visual acuity (mean of 12 letters), two patients presented epithelial defects (also present at baseline) and the mean percentage of corneal neovascularization was of 28.75% (36.98%, at baseline). Re-examination 24 months after treatment disclosed preserved efficacy in 4 patients. At the last visit (after a mean of 86,5 months of follow up) epithelial defects were absent in all patients although improvement in all of the variables was only maintained in patient 3 (meibomian glands agenesia). CONCLUSION: ASCs are a feasible and conservative therapy for treating bilateral LSCD. The therapeutic effect differs between etiologies and diminishes over time.

Fiebre y exantema tras picadura de garrapata / Fever and rash after tick bite

Las garrapatas duras se han convertido en los principales vectores de enfermedades infecciosas en el mundo industrializado, pudiendo transmitir a través de su picadura bacterias, virus y protozoos, además de causar procesos alérgicos y tóxicos. Dentro de las enfermedades transmitidas por garrapatas, las más frecuentes en nuestro medio son: la fiebre botonosa mediterránea, la enfermedad de Lyme y la enfermedad de Debonel/Tibola. La fiebre botonosa mediterránea es la rickettsiosis más frecuente en Europa. Se ha observado un aumento de los casos en los últimos años, en probable relación con el aumento de temperatura global. (AU)

Hard ticks have become the main vectors of infectious diseases in the industrialized world, being able to transmit bacteria, viruses and protozoa through their bite, as well as causing allergic and toxic processes. Among the tick-borne disease the most frequent in our setting are boutonneuse fever, Lyme disease and Debonel/Tibola disease. Boutonneuse fever is the most common rickettsiosis in Europe. An increase in cases has been observed in recent years, probably related to the increase in global temperature. (AU)

Zinc deficiency and a high-fat diet during growth: Metabolic and adipocyte alterations in rats.

BACKGROUND AND AIMS: To evaluate the effects of a high-fat diet during post-weaning growth on intermediate metabolism and retroperitoneal adipose tissue, in adult male rats exposed to adequate or deficient zinc intake during prenatal and postnatal life. METHODS AND RESULTS: Female Wistar rats were fed low- or control-zinc diets from pregnancy to offspring weaning. Male offspring born from control mothers were fed either control or high-fat, control-zinc diets for 60 days. Male offspring born from zinc deficient mothers were fed either low-zinc or high-fat, low-zinc diets for 60 days. At 74 days of life, oral glucose tolerance test was performed. In 81-day-old offspring, blood pressure, lipid profile, plasmatic lipid peroxidation and serum adiponectin level were determined. In retroperitoneal adipose tissue, we evaluated oxidative stress, morphology and adipocytokines mRNA expression. Low-zinc diet induced adipocytes hypertrophy, increased oxidative stress, and decreased adiponectin mRNA expression in adipose tissue. Low-zinc diet increased systolic blood pressure, triglyceridemia, plasmatic lipid peroxidation and glycemia at 3 h after glucose overload. Animals fed high-fat or high-fat, low-zinc diets showed adipocytes hypertrophy, decreased adiponectin mRNA expression, and increased leptin mRNA expression and oxidative stress in adipose tissue. They also exhibited decreased serum adiponectin levels, increased triglyceridemia, plasmatic lipid peroxidation and area under the oral glucose tolerance curve. High-fat, low-zinc diet induced greater alterations in adipocyte hypertrophy, leptin mRNA expression and glucose tolerance test than high-fat diet. CONCLUSION: Zinc deficiency since early stages of intrauterine life could increase susceptibility to metabolic alterations induced by high-fat diets during postnatal life.

Antimicrobial Stewardship Programs (ASPS) in pediatric primary care.

Antibiotic resistance is a major threat to global health. Optimizing the use of antibiotics is a key measure to prevent and control this problem. Antimicrobial Stewardship Programs (ASPs) are designed to improve clinical outcomes, minimize adverse effects and protect patients, and to ensure the administration of cost-effective treatments. Inappropriate use of antibiotics also occurs in pediatric clinical practice. For this reason, ASPs should include specific objectives and strategies aimed at pediatricians and families. Implementing these programs requires the involvement of institutions and policy makers, healthcare providers as well as individuals, adapting them to the characteristics of each healthcare setting. Pediatric primary care (PPC) faces specific issues such as high demand and immediacy, scarce specialized professional resources, difficulties to access regular training and to obtain feedback. This requires the design of specific policies and strategies to achieve the objectives, including structural and organizational measures, improvement of the information flow and accessibility to frequent trainings. These programs should reach all health professionals, promoting regular trainings, prescription support tools and supplying diagnostic tests, with adequate coordination between health care levels. Periodic evaluations and surveillance tools are useful to assess the impact of the actions taken and to provide feedback to health providers in order to adapt and improve their clinical practice to meet ASPs objectives.

Programas de optimización del uso de antibióticos (PROA) en pediatría de atención primaria / Antimicrobial Stewardship Programs (ASPS) in pediatric primary care

La resistencia a antibióticos supone una amenaza para la salud pública a nivel mundial. Su estrecha relación con el consumo de antibióticos hace necesaria la adopción de medidas para optimizar su uso. Los programas de optimización del uso de antibióticos (PROA) se diseñan para mejorar los resultados clínicos de los pacientes con infecciones, minimizar los efectos adversos asociados a su uso y garantizar la administración de tratamientos costo-eficientes. En la práctica clínica pediátrica el uso inadecuado de antibióticos es una realidad. Es por ello que los PROA deben incluir objetivos y estrategias específicos dirigidos a familias y pediatras. La implementación de estos programas requiere la implicación de instituciones, profesionales y población, adaptándolos a las características de cada ámbito asistencial. La atención primaria (AP) pediátrica presenta unas peculiaridades organizativas y asistenciales (hiperdemanda e inmediatez, escasos recursos profesionales especializados, dificultades en el acceso a la formación continuada y a la retroalimentación informativa) que exigen el diseño de medidas y estrategias propias para conseguir los objetivos fijados, que incluyan medidas estructurales, organizativas, de flujo de información y de formación continuada. Es necesario que estos programas alcancen a todos los profesionales, abordando la formación continuada, las herramientas de apoyo a la prescripción y el acceso a pruebas diagnósticas, con la adecuada coordinación interniveles. Se debe evaluar periódicamente el impacto de las distintas acciones en los objetivos planteados. La información generada debe revertir a los profesionales para que puedan adaptar su práctica clínica a la consecución óptima de los objetivos. (AU)

Antibiotic resistance is a major threat to global health. Optimizing the use of antibiotics is a key measure to prevent and control this problem. Antimicrobial Stewardship Programs (ASPs) are designed to improve clinical outcomes, minimize adverse effects and protect patients, and to ensure the administration of cost-effective treatments. Inappropriate use of antibiotics also occurs in pediatric clinical practice. For this reason, ASPs should include specific objectives and strategies aimed at pediatricians and families. Implementing these programs requires the involvement of institutions and policy makers, healthcare providers as well as individuals, adapting them to the characteristics of each healthcare setting. Pediatric primary care (PPC) faces specific issues such as high demand and immediacy, scarce specialized professional resources, difficulties to access regular training and to obtain feedback. This requires the design of specific policies and strategies to achieve the objectives, including structural and organizational measures, improvement of the information flow and accessibility to frequent trainings. These programs should reach all health professionals, promoting regular trainings, prescription support tools and supplying diagnostic tests, with adequate coordination between health care levels. Periodic evaluations and surveillance tools are useful to assess the impact of the actions taken and to provide feedback to health providers in order to adapt and improve their clinical practice to meet ASPs objectives. (AU)

Estudio diagnóstico de tos ferina mediante técnica de PCR en consultas de Atención Primaria / Diagnostic study of pertussis using PCR in primary care clinics

Introducción: La tos ferina es una infección respiratoria causada por bacterias del género Bordetella, principalmente por las especies pertussis y parapertussis. A pesar de las altas coberturas vacunales en países desarrollados, está considerada como una enfermedad reemergente existiendo, además, una infranotificación y un infradiagnóstico especialmente en los pacientes que no precisan derivación hospitalaria. Material y métodos: Estudio descriptivo, prospectivo y multicéntrico de diagnóstico de casos de tos ferina, así como el estudio de sus contactos en 17 consultas de pediatría de Atención Primaria (AP) mediante la toma de muestras para realización de técnicas de reacción en cadena de la polimerasa (PCR) a lo largo de cuatro años y tras la implantación de la vacunación sistemática de la tos ferina en el embarazo. Resultados: Se diagnostican un total de 50 pacientes; la tasa de incidencia estimada en estos años fue superior a las publicadas en edad pediátrica. Un 14% de los casos sucedieron en menores de un año. La media de edad fue de 6,7 años. La tos estuvo presente en el 100% de los casos, seguida de los vómitos y rinorrea como síntomas más frecuentes. Sólo un paciente precisó ingreso y ninguno falleció ni presentó complicaciones. Bordetella pertussis (B. pertussis) (BP) fue el agente causal predominante. Sólo un 40% conocía la fuente de contagio. En un 26% de los casos se comprobó mediante PCR tos ferina en sus contactos y en un 46% se sospechó clínicamente, aunque sin confirmación microbiológica. Conclusiones: El acceso a pruebas diagnósticas (PCR) para tos ferina en AP permite optimizar su diagnóstico y tratamiento, cortar la cadena de transmisión, conocer las tasas de incidencia reales y valorar el impacto de la vacunación sistemática de las embarazadas en esta enfermedad. (AU)

Introduction: Pertussis is a respiratory infection caused by bacteria of the genus Bordetella, mainly pertussis and parapertussis species. Despite the high vaccination coverage in developed countries, it is considered a re-emerging disease that is also underreported and underdiagnosed, especially in patients who do not require hospital referral. Material and methods: Descriptive, prospective and multicentre study of pertussis diagnosis and contact investigation in 17 primary care paediatric clinics through collection of samples for polymerase chain reaction (PCR) testing over a period of 4 years and after the implementation of routine vaccination against pertussis during pregnancy. Results: Pertussis was diagnosed in a total of 50 patients; the estimated incidence in these years was higher compared to previous rates in the paediatric age group. Fourteen percent of the cases occurred in children aged less than 1 year. The mean age was 6.7 years. Cough was present in 100% of cases, followed in frequency by vomiting and rhinorrhoea. Only 1 patient required hospital admission, and none died or developed complications. B. pertussis was the predominant causative agent. Only 40% knew the source of infection. In 26% of the cases, pertussis was confirmed in contacts of the patient by PCR, and in 46% it was suspected based on the clinical presentation but without microbiological confirmation. Conclusions: Access to diagnostic tests (PCR) for pertussis in primary care allows us to optimise its diagnosis and treatment, to break the chain of transmission, to know the real incidence rates and to assess the impact of routine vaccination of pregnant women on this disease. (AU)

Diagnostic study of pertussis using PCR in primary care clinics.

INTRODUCTION: Pertussis is a respiratory infection caused by bacteria of the genus Bordetella, mainly pertussis and parapertussis species. Despite the high vaccination coverage in developed countries, it is considered a re-emerging disease that is also underreported and underdiagnosed, especially in patients who do not require hospital referral. MATERIAL AND METHODS: Descriptive, prospective and multicentre study of pertussis diagnosis and contact investigation in 17 primary care paediatric clinics through collection of samples for polymerase chain reaction (PCR) testing over a period of 4 years and after the implementation of routine vaccination against pertussis during pregnancy. RESULTS: Pertussis was diagnosed in a total of 50 patients; the estimated incidence in these years was higher compared to previous rates in the paediatric age group. Fourteen percent of the cases occurred in children aged less than 1 year. The mean age was 6.7 years. Cough was present in 100% of cases, followed in frequency by vomiting and rhinorrhoea. Only 1 patient required hospital admission, and none died or developed complications. B. pertussis was the predominant causative agent. Only 40% knew the source of infection. In 26% of the cases, pertussis was confirmed in contacts of the patient by PCR, and in 46% it was suspected based on the clinical presentation but without microbiological confirmation. CONCLUSIONS: Access to diagnostic tests (PCR) for pertussis in primary care allows us to optimise its diagnosis and treatment, to break the chain of transmission, to know the real incidence rates and to assess the impact of routine vaccination of pregnant women on this disease.

Impact of Zinc Deficiency During Prenatal and/or Postnatal Life on Cardiovascular and Metabolic Diseases: Experimental and Clinical Evidence.

This review summarizes the latest findings, from animal models and clinical studies, regarding the cardiovascular and metabolic consequences in adult life of zinc deficiency (ZD) during prenatal and early postnatal life. The effect of zinc supplementation (ZS) and new insights about sex differences in the phenotype and severity of cardiovascular and metabolic alterations are also discussed. Zinc has antioxidant, anti-inflammatory, and antiapoptotic properties and regulates the activity of enzymes involved in regulation of the metabolic, cardiovascular, and renal systems. Maternal ZD is associated with intrauterine growth restriction and low birth weight (LBW). Breast-fed preterm infants are at risk of ZD due to lower zinc uptake during fetal life and reduced gut absorption capacity. ZS is most likely to increase growth in preterm infants and survival in LBW infants in countries where ZD is prevalent. Studies performed in rats revealed that moderate ZD during prenatal and/or early postnatal growth is a risk factor for the development of hypertension, cardiovascular and renal alterations, obesity, and diabetes in adult life. An adequate zinc diet during postweaning life does not always prevent the cardiovascular and metabolic alterations induced by zinc restriction during fetal and lactation periods. Male rats are more susceptible to this injury than females, and some of the mechanisms involved include: 1) alterations in organogenesis, 2) activation of oxidative, apoptotic, and inflammatory processes, 3) dysfunction of nitric oxide and renin-angiotensin-aldosterone systems, 4) changes in glucose and lipid metabolism, and 5) adipose tissue dysfunction. Safeguarding body zinc requirements during pregnancy, lactation, and growth periods could become a new target in the prevention and treatment of cardiovascular and metabolic disorders. Further research is needed to elucidate the efficacy of ZS during early stages of growth to prevent the development of these diseases later in life.

Programación intrauterina de enfermedad en la vida adulta: identificación de genes cardinales asociados a hipertensión arterial, obesidad y síndrome metabólico / Intrauterine Programming of Adult Disease: Identification of Cardinal Genes Associated with Hypertension, Obesity and Metabolic Syndrome

RESUMEN Introducción: La restricción del crecimiento intrauterino es una alteración del desarrollo fetal que se caracteriza por una tasa de crecimiento durante la etapa fetal que es menor al potencial genético de crecimiento para la edad gestacional. Esta condición plantea una carga importante para la salud pública, ya que aumenta la morbimortalidad de la descendencia, a corto y a largo plazo, particularmente, por asociarse al desarrollo de enfermedad cardiovascular y metabólica en la vida adulta. Objetivos: Mediante el uso de herramientas bioinformáticas nos propusimos identificar posibles genes cardinales involucrados en la restricción del crecimiento intrauterino asociados al desarrollo de obesidad, hipertensión arterial y síndrome metabólico. Material y métodos: Obtuvimos un total de 343 genes involucrados en los fenotipos de interés e identificamos 20 genes que resultaron significativamente relevantes en el análisis de la red de interacción. Particularmente, cuatro de estos genes identificados codifican para factores de crecimiento o sus receptores, VEGFA, PDGFRB, IGF1R y EGFR. Además, identificamos genes relacionados con la insulina y el control de la homeostasis cardiovascular, como son el CTNNB1, APP, MYC y MDMD2. Por otra parte, el análisis de clústeres permitió reconocer los términos de ontología genética más significativos, entre los que se destacan aquellos relacionados con procesos biológicos de proliferación y muerte celular programada, de comunicación intercelular, del metabolismo proteico, y de desarrollo del sistema cardiovascular. Conclusiones: Los genes hallados en este estudio podrían ser de utilidad como biomarcadores putativos de la presencia de alteraciones cardiovasculares y metabólicas asociadas a la restricción del crecimiento intrauterino o potenciales blancos terapéuticos de estrategias de tratamiento orientadas al genotipo del paciente.

ABSTRACT Background: Intrauterine growth restriction is an abnormal fetal development characterized by a fetal growth rate lower than the potential genetic growth for the gestational age. This condition represents a major burden for public health systems, as it increases short and long-term morbidity and mortality in the offspring, particularly because of its association with the development of cardiovascular and metabolic disease in adult life. Objectives: The aim of the present study was to identify possible cardinal genes involved in intrauterine growth restriction associated with the development of obesity, hypertension and metabolic syndrome using bioinformatics tools. Methods: A total of 343 genes involved in the phenotypes of interest were obtained and 20 genes were identified as significantly relevant in the interaction network analysis. Specifically, four of these identified genes encode for growth factors or their receptors, VEGFA, PDGFRB, IGF1R and EGFR. We also identified genes related to insulin and cardiovascular homeostasis as CTNNB1, APP, MYC and MDMD2. Cluster analysis provided the most significant gene ontology terms, including those related to the biological processes of proliferation and programmed cell death, intercellular communication, protein metabolism and development of the cardiovascular system. Conclusions: The genes found in this study could be useful as putative biomarkers for the presence of cardiovascular and metabolic disorders associated with intrauterine growth restriction, or as potential therapeutic targets for treatment strategies directed to the patient's genotype.

Cardiac morphological and functional changes induced by C-type natriuretic peptide are different in normotensive and spontaneously hypertensive rats.

OBJECTIVE: Inflammation and fibrosis are key mechanisms in cardiovascular remodeling. C-type natriuretic peptide (CNP) is an endothelium-derived factor with a cardiovascular protective role, although its in-vivo effect on cardiac remodeling linked to hypertension has not been investigated. The aim of this study was to determine the effects of chronic administration of CNP on inflammatory and fibrotic cardiac mechanisms in normotensive Wistar rats and spontaneously hypertensive rats (SHR). METHODS: Twelve-week-old male SHR and normotensive rats were infused with CNP (0.75 µg/h/100 g) or isotonic saline (NaCl 0.9%) for 14 days (subcutaneous micro-osmotic pumps). Echocardiograms and electrocardiograms were performed, and SBP was measured. After treatment, transforming growth factor-beta 1, Smad proteins, tumor necrosis factor-alpha, interleukin-1 and interleukin-6, nitric oxide (NO) system and 2-thiobarbituric acid-reactive substances were evaluated in left ventricle. Histological studies were also performed. RESULTS: SHR showed lower cardiac output with signs of fibrosis and hypertrophy in left ventricle, higher NO-system activity and more oxidative damage, as well as higher pro-inflammatory and pro-fibrotic markers than normotensive rats. Chronic CNP treatment-attenuated hypertension and ventricular hypertrophy in SHR, with no changes in normotensive rats. In left ventricle, CNP induced an anti-inflammatory and antifibrotic response, decreasing both pro-fibrotic and pro-inflammatory cytokines in SHR. In addition, CNP reduced oxidative damage as well as collagen content, and upregulated the NO system in both groups. CONCLUSION: Chronic CNP treatment appears to attenuate hypertension and associated end-organ damage in the heart by reducing inflammation and fibrosis.

Fetal and postnatal zinc restriction: sex differences in the renal renin-angiotensin system of newborn and adult Wistar rats.

This study aimed to evaluate renal morphology and the renal renin-angiotensin system in 6- and 81-day-old male and female offspring exposed to zinc deficiency during fetal life, lactation and/or postnatal growth. Female Wistar rats were fed low- or control zinc diets from pregnancy to offspring weaning. Afterwards, offspring were fed a low- or a control zinc diet until 81 days of life. In 6- and/or 81-day-old offspring, we evaluated systolic blood pressure, renal morphology, renal angiotensin II and angiotensin 1-7 concentration, and AT1 and AT2 receptors and angiotensin-converting enzymes protein and/or mRNA expression. At 6 days, zinc-deficient male offspring showed decreased glomerular filtration areas, remodelling of renal arteries, greater number of renal apoptotic cells, increased levels of Angiotensin II, higher Angiotensin II/Angiotensin 1-7 ratio and increased angiotensin-converting enzyme 1, AT1 and AT2 receptors mRNA and/or protein expression. Exacerbation of the renal Ang II/AT1 receptor axis and remodelling of renal arteries were also observed in adult zinc-deficient male offspring. An adequate zinc diet during post-weaning life did not improve all the alterations induced by zinc deficiency in early stages of development. Female offspring would appear to be less sensitive to zinc deficiency with no increase in blood pressure or significant alterations in renal morphology and the renin-angiotensin system. Moderate zinc deficiency during critical periods of prenatal and postnatal development leads to early morphological renal alterations and to permanent and long-term changes in the renal renin-angiotensin system that could predispose to renal and cardiovascular diseases in adult life.

Manejo del paciente pediátrico ante sospecha de infección por el nuevo coronavirus SARS-CoV-2 en atención primaria (COVID-19). AEPap-SEIP/AEP-SEPEAP / No disponible

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Chronic treatment with C-type natriuretic peptide impacts differently in the aorta of normotensive and hypertensive rats.

The aim of this study was to determine whether exogenous administration of C-type natriuretic peptide (CNP) induces functional and morphological vascular changes in spontaneously hypertensive rats (SHR) compared with normotensive rats. Male 12-week-old normotensive Wistar and SHR were administered with saline (NaCl 0.9%) or CNP (0.75 µg/h/100 g) for 14 days (subcutaneous micro-osmotic pumps). Systolic blood pressure (SBP) was measured in awake animals and renal parameters were evaluated. After decapitation, the aorta was removed, and vascular morphology, profibrotic markers, and vascular reactivity were measured. In addition, nitric oxide (NO) system and oxidative stress were evaluated. After 14-days of treatment, CNP effectively reduced SBP in SHR without changes in renal function. CNP attenuated vascular remodeling in hypertensive rats, diminishing both profibrotic and pro-inflammatory cytokines. Also, CNP activated the vascular NO system and exerted an antioxidant effect in aortic tissue of both groups, diminishing superoxide production and thiobarbituric acid-reactive substances, and increasing glutathione content. These results show that chronic treatment with CNP attenuates the vascular damage development in a model of essential hypertension, inducing changes in fibrotic, inflammatory, oxidative, and NO pathways that could contribute to beneficial long-term effects on vascular morphology, extracellular matrix composition, and function. The knowledge of these effects of CNP could lead to improved therapeutic strategies to not only control BP but also reduce vascular damage, primarily responsible for the risk of cardiovascular events.

Fetal and postnatal zinc restriction: Sex differences in metabolic alterations in adult rats.

OBJECTIVE: Intrauterine and postnatal micronutrient malnutrition may program metabolic diseases in adulthood. We examined whether moderate zinc restriction in male and female rats throughout fetal life, lactation, or postweaning growth induces alterations in liver, adipose tissue, and intermediate metabolism. METHODS: Female Wistar rats were fed low-zinc or control zinc diets from pregnancy to offspring weaning. After weaning, male and female offspring were fed either a low-zinc or a control zinc diet. At 74 d of life, oral glucose tolerance tests were performed and serum metabolic profiles were evaluated. Systolic blood pressure and oxidative stress and morphology of liver and retroperitoneal adipose tissue were evaluated in 81 d old offspring. RESULTS: Zinc restriction during prenatal and postnatal life induced an increase in systolic blood pressure, hyperglycemia, hypertriglyceridemia, higher serum glucose levels at 180 min after glucose overload, and greater insulin resistance indexes in male rats. Hepatic histologic studies revealed no morphologic alterations, but an increase in lipid peroxidation and catalase activity were identified in zinc-deficient male rats. Adipose tissue from zinc-deficient male rats had adipocyte hypertrophy, an increase in lipid peroxidation, and a reduction in catalase and glutathione peroxidase activity. Adequate dietary zinc content during postweaning growth reversed basal hyperglycemia, hypertriglyceridemia, insulin resistance indexes, hepatic oxidative stress, and adipocyte hypertrophy. Female rats were less sensitive to the metabolic effects of zinc restriction. CONCLUSIONS: This study strengthens the importance of a balanced intake of zinc during growth to ensure adequate lipid and carbohydrate metabolism in adult life.

Developmental programming of vascular dysfunction by prenatal and postnatal zinc deficiency in male and female rats.

Micronutrient malnutrition during intrauterine and postnatal growth may program cardiovascular diseases in adulthood. We examined whether moderate zinc restriction in male and female rats throughout fetal life, lactation and/or postweaning growth induces alterations that can predispose to the onset of vascular dysfunction in adulthood. Female Wistar rats were fed low- or control zinc diets from pregnancy to offspring weaning. After weaning, offspring were fed either a low- or a control zinc diet until 81 days. We evaluated systolic blood pressure (SBP), thoracic aorta morphology, nitric oxide (NO) system and vascular reactivity in 6- and/or 81-day-old offspring. At day 6, zinc-deficient male and female offspring showed a decrease in aortic NO synthase (NOS) activity accompanied by an increase in oxidative stress. Zinc-deficient 81-day-old male rats exhibited an increase in collagen deposition in tunica media, as well as lower activity of endothelial NOS (eNOS) that could not be reversed with an adequate zinc diet during postweaning life. Zinc deficiency programmed a reduction in eNOS protein expression and higher SBP only in males. Adult zinc-deficient rats of both sexes showed reduced vasodilator response dependent on eNOS activity and impaired aortic vasoconstrictor response to angiotensin-II associated with alterations in intracellular calcium mobilization. Female rats were less sensitive to the effects of zinc deficiency and exhibited higher eNOS activity and/or expression than males, without alterations in SBP or aortic histology. This work strengthens the importance of a balanced intake of micronutrients during perinatal growth to ensure adequate vascular function in adult life.

Cardiac changes in apoptosis, inflammation, oxidative stress, and nitric oxide system induced by prenatal and postnatal zinc deficiency in male and female rats.

PURPOSE: Zinc restriction during fetal and postnatal development could program cardiovascular diseases in adulthood. The aim of this study was to determine the effects of zinc restriction during fetal life, lactation, and/or post-weaning growth on cardiac inflammation, apoptosis, oxidative stress, and nitric oxide system of male and female adult rats. METHODS: Wistar rats were fed a low- or a control zinc diet during pregnancy and up to weaning. Afterward, offspring were fed either a low- or a control zinc diet until 81 days of life. IL-6 and TNF-α levels, TUNEL assay, TGF-ß1 expression, thiobarbituric acid-reactive substances that determine lipoperoxidation damage, NADPH oxidase-dependent superoxide anion production, antioxidant and nitric oxide synthase activity, mRNA and protein expression of endothelial nitric oxide synthase, and serine1177 phosphorylation isoform were determined in left ventricle. RESULTS: Zinc deficiency activated apoptotic and inflammatory processes and decreased TGF-ß1 expression and nitric oxide synthase activity in cardiac tissue of both sexes. Male zinc-deficient rats showed no changes in endothelial nitric oxide synthase expression, but a lower serine1177 phosphorylation. Zinc deficiency induced an increase in antioxidant enzymes activity and no differences in lipoperoxidation products levels in males. Females were less sensitive to this deficiency exhibiting lower increase in apoptosis, lower decrease in expression of TGF-ß1, and higher antioxidant and nitric oxide enzymes activities. A zinc-adequate diet during postnatal life reversed most of these mechanisms. CONCLUSION: Prenatal and postnatal zinc deficiency induces alterations in cardiac apoptotic, inflammatory, oxidative, and nitric oxide pathways that could predispose the onset of cardiovascular diseases in adult life.

Sexual Dimorphic Pattern of Renal Transporters and Electrolyte Homeostasis.

Compared with males, females have lower BP before age 60, blunted hypertensive response to angiotensin II, and a leftward shift in pressure natriuresis. This study tested the concept that this female advantage associates with a distinct sexual dimorphic pattern of transporters along the nephron. We applied quantitative immunoblotting to generate profiles of transporters, channels, claudins, and selected regulators in both sexes and assessed the physiologic consequences of the differences. In rats, females excreted a saline load more rapidly than males did. Compared with the proximal tubule of males, the proximal tubule of females had greater phosphorylation of Na+/H+ exchanger isoform 3 (NHE3), distribution of NHE3 at the base of the microvilli, and less abundant expression of Na+/Pi cotransporter 2, claudin-2, and aquaporin 1. These changes associated with less bicarbonate reabsorption and higher lithium clearance in females. The distal nephrons of females had a higher abundance of total and phosphorylated Na+/Cl- cotransporter (NCC), claudin-7, and cleaved forms of epithelial Na+ channel (ENaC) α and γ subunits, which associated with a lower baseline plasma K+ concentration. A K+-rich meal increased the urinary K+ concentration and decreased the level of renal phosphorylated NCC in females. Notably, we observed similar abundance profiles in female versus male C57BL/6 mice. These results define sexual dimorphic phenotypes along the nephron and suggest that lower proximal reabsorption in female rats expedites excretion of a saline load and enhances NCC and ENaC abundance and activation, which may facilitate K+ secretion and set plasma K+ at a lower level.

Vascular Tone Regulation Induced by C-Type Natriuretic Peptide: Differences in Endothelium-Dependent and -Independent Mechanisms Involved in Normotensive and Spontaneously Hypertensive Rats.

Given that the role of C-type natriuretic peptide (CNP) in the regulation of vascular tone in hypertensive states is unclear, we hypothesized that impaired response of the nitric oxide system to CNP in spontaneously hypertensive rats (SHR) could affect vascular relaxation induced by the peptide in this model of hypertension, and that other endothelial systems or potassium channels opening could also be involved. We examined the effect of CNP on isolated SHR aortas, and the hindlimb vascular resistance (HVR) in response to CNP administration compared to normotensive rats. Aortas were mounted in an isometric organ bath and contracted with phenylephrine. CNP relaxed arteries in a concentration-dependent manner but was less potent in inducing relaxation in SHR. The action of CNP was diminished by removal of the endothelium, inhibition of nitric oxide synthase by Nω-nitro-L-arginine methyl ester, and inhibition of soluble guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one in both groups. In contrast, blockade of cyclooxygenase or subtype 2 bradykinin receptor increased CNP potency only in SHR. In both Wistar and SHR, CNP relaxation was blunted by tetraethylammonium and partially inhibited by BaCl2 and iberiotoxin, indicating that it was due to opening of the Kir and BKCa channels. However, SHR seem to be more sensitive to Kir channel blockade and less sensitive to BKCa channel blockade than normotensive rats. In addition, CNP decreases HVR in Wistar and SHR, but the effect of CNP increasing blood flow was more marked in SHR. We conclude that CNP induces aorta relaxation by activation of the nitric oxide system and opening of potassium channels, but the response to the peptide is impaired in conductance vessel of hypertensive rats.

Respuesta cardiovascular a la administración crónica de péptido natriurético tipo C en ratas espontáneamente hipertensas / Cardiovascular Response to Chronic Administration of C-type Natriuretic Peptide in Spontaneously Hypertensive Rats

Introducción: El péptido natriurético tipo C (CNP) ha cobrado relevancia por sus efectos sobre la regulación de la función y la morfología del corazón y los vasos sanguíneos. Previamente demostramos in vitro que el CNP incrementa la actividad del sistema del óxido nítrico (NO) en ratas espontáneamente hipertensas (SHR). Objetivo: Estudiar el efecto del tratamiento crónico con CNP sobre la presión arterial sistólica (PAS), la función cardíaca y vascular y el sistema del NO en ratas espontáneamente hipertensas y normotensas. Material y métodos: Se emplearon ratas Wistar macho de 12 semanas de edad normotensas y espontáneamente hipertensas. Los animales recibieron infusión crónica de solución salina o CNP (0,75 mg/hora/rata) durante 14 días mediante la implantación de bombas osmóticas subcutáneas. Se midió la PAS y se realizaron un electrocardiograma y un ecocardiograma. Se extrajeron el ventrículo izquierdo y la arteria aorta torácica y se determinó la actividad, con L-[U14C]-arginina, de la óxido nítrico sintasa (NOS) y se realizaron estudios de reactividad vascular. Resultados: La administración crónica de CNP disminuyó la PAS en las SHR. Se observó menor volumen minuto en las SHR y el CNP incrementó dicho volumen, en tanto que no indujo cambios en las ratas normotensas. En las SHR se observó un desequilibrio en las respuestas vasodilatadora y vasoconstrictora en la arteria aorta y el tratamiento con CNP mejoró la función vascular respecto de las ratas normotensas. En ambos tejidos, la actividad de la NOS fue mayor en las SHR y se incrementó con la infusión durante 14 días de CNP. Sin embargo, dicho incremento fue menor en las SHR. Conclusión: El CNP induce cambios a nivel cardiovascular y en el sistema del NO que podrían resultar beneficiosos en este modelo de hipertensión arterial.

Background: C-type natriuretic peptide (CNP) plays an important role in the regulation of cardiovascular function and morphology. We have previously demonstrated that CNP increases nitric oxide (NO) system activity in vivo in spontaneously hypertensive rats (SHR). Objective: The goal of this study is to evaluate the effect of chronic CNP administration on systolic blood pressure (SBP), cardiovascular function and the NO system in spontaneously hypertensive and normotensive rats. Methods: Twelve-week-old normotensive male Wistar rats and SHR were used. They received chronic infusion of saline or CNP (0.75 mg/h/rat) for 14 days via subcutaneously implanted osmotic pumps. Systolic blood pressure was measured and an electrocardiogram and echocardiogram were performed. The left ventricle and the thoracic aorta were resected; nitric oxide synthase (NOS) activity was determined using L-[U14C]-arginine and vascular reactivity was assessed. Results: Chronic administration of CNP decreased SBP in SHR. Cardiac output was lower in SHR and increased with CNP; however, CNP had no effect in normotensive rats. Spontaneously hypertensive rats had unbalanced aortic vasodilation and vasoconstriction responses, and CNP improved the vascular function. Nitric oxide synthase activity was greater in SHR and increased with the 14-day CNP infusion, but this increase was lower than in normotensive rats. Conclusion: C-type natriuretic peptide induces cardiovascular and NO system changes which may be beneficial in this model of hypertension.

Chronic treatment with atrial natriuretic peptide in spontaneously hypertensive rats: beneficial renal effects and sex differences.

OBJECTIVE: The aim of this study was to investigate the effects of chronic treatment with atrial natriuretic peptide (ANP) on renal function, nitric oxide (NO) system, oxidative stress, collagen content and apoptosis in kidneys of spontaneously hypertensive rats (SHR), as well as sex-related differences in the response to the treatment. METHODS: 10 week-old male and female SHR were infused with ANP (100 ng/h/rat) or saline (NaCl 0.9%) for 14 days (subcutaneous osmotic pumps). Systolic blood pressure (SBP) was recorded and diuresis and natriuresis were determined. After treatment, renal NO synthase (NOS) activity and eNOS expression were evaluated. Thiobarbituric acid-reactive substances (TBARS), glutathione concentration and glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were determined in the kidney. Collagen was identified in renal slices by Sirius red staining and apoptosis by Tunel assay. RESULTS: Female SHR showed lower SBP, oxidative stress, collagen content and apoptosis in kidney, and higher renal NOS activity and eNOS protein content, than males. ANP lowered SBP, increased diuresis, natriuresis, renal NOS activity and eNOS expression in both sexes. Renal response to ANP was more marked in females than in males. In kidney, ANP reduced TBARS, renal collagen content and apoptosis, and increased glutathione concentration and activity of GPx and SOD enzymes in both sexes. CONCLUSIONS: Female SHR exhibited less organ damage than males. Chronic ANP treatment would ameliorate hypertension and end-organ damage in the kidney by reducing oxidative stress, increasing NO-system activity, and diminishing collagen content and apoptosis, in both sexes.