A Mouse Model of Glycogen Storage Disease Type IX-Beta: A Role for Phkb in Glycogenolysis.

Glycogen storage disease type IX (GSD-IX) constitutes nearly a quarter of all GSDs. This ketotic form of GSD is caused by mutations in phosphorylase kinase (PhK), which is composed of four subunits (α, ß, γ, δ). PhK is required for the activation of the liver isoform of glycogen phosphorylase (PYGL), which generates free glucose-1-phosphate monomers to be used as energy via cleavage of the α -(1,4) glycosidic linkages in glycogen chains. Mutations in any of the PhK subunits can negatively affect the regulatory and catalytic activity of PhK during glycogenolysis. To understand the pathogenesis of GSD-IX-beta, we characterized a newly created PHKB knockout (Phkb−/−) mouse model. In this study, we assessed fasting blood glucose and ketone levels, serum metabolite concentrations, glycogen phosphorylase activity, and gene expression of gluconeogenic genes and fibrotic genes. Phkb−/− mice displayed hepatomegaly with lower fasting blood glucose concentrations. Phkb−/− mice showed partial liver glycogen phosphorylase activity and increased sensitivity to pyruvate, indicative of partial glycogenolytic activity and upregulation of gluconeogenesis. Additionally, gene expression analysis demonstrated increased lipid metabolism in Phkb−/− mice. Gene expression analysis and liver histology in the livers of old Phkb−/− mice (>40 weeks) showed minimal profibrogenic features when analyzed with age-matched wild-type (WT) mice. Collectively, the Phkb−/− mouse recapitulates mild clinical features in patients with GSD-IX-beta. Metabolic and molecular analysis confirmed that Phkb−/− mice were capable of sustaining energy homeostasis during prolonged fasting by using partial glycogenolysis, increased gluconeogenesis, and potentially fatty acid oxidation in the liver.

Exosomal MicroRNAs as Potential Biomarkers of Hepatic Injury and Kidney Disease in Glycogen Storage Disease Type Ia Patients.

Glycogen storage disease type Ia (GSDIa) is an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-α (G6Pase-α). Affected individuals develop renal and liver complications, including the development of hepatocellular adenoma/carcinoma and kidney failure. The purpose of this study was to identify potential biomarkers of the evolution of the disease in GSDIa patients. To this end, we analyzed the expression of exosomal microRNAs (Exo-miRs) in the plasma exosomes of 45 patients aged 6 to 63 years. Plasma from age-matched normal individuals were used as controls. We found that the altered expression of several Exo-miRs correlates with the pathologic state of the patients and might help to monitor the progression of the disease and the development of late GSDIa-associated complications.

Liver Glycogen Phosphorylase Deficiency Leads to Profibrogenic Phenotype in a Murine Model of Glycogen Storage Disease Type VI.

Mutations in the liver glycogen phosphorylase (Pygl) gene are associated with the diagnosis of glycogen storage disease type VI (GSD-VI). To understand the pathogenesis of GSD-VI, we generated a mouse model with Pygl deficiency (Pygl -/-). Pygl -/- mice exhibit hepatomegaly, excessive hepatic glycogen accumulation, and low hepatic free glucose along with lower fasting blood glucose levels and elevated blood ketone bodies. Hepatic glycogen accumulation in Pygl -/- mice increases with age. Masson's trichrome and picrosirius red staining revealed minimal to mild collagen deposition in periportal, subcapsular, and/or perisinusoidal areas in the livers of old Pygl -/- mice (>40 weeks). Consistently, immunohistochemical analysis showed the number of cells positive for alpha smooth muscle actin (α-SMA), a marker of activated hepatic stellate cells, was increased in the livers of old Pygl -/- mice compared with those of age-matched wild-type (WT) mice. Furthermore, old Pygl -/- mice had inflammatory infiltrates associated with hepatic vessels in their livers along with up-regulated hepatic messenger RNA levels of C-C chemokine ligand 5 (Ccl5/Rantes) and monocyte chemoattractant protein 1 (Mcp-1), indicating inflammation, while age-matched WT mice did not. Serum levels of aspartate aminotransferase and alanine aminotransferase were elevated in old Pygl -/- mice, indicating liver damage. Conclusion: Pygl deficiency results in progressive accumulation of hepatic glycogen with age and liver damage, inflammation, and collagen deposition, which can increase the risk of liver fibrosis. Collectively, the Pygl-deficient mouse recapitulates clinical features in patients with GSD-VI and provides a model to elucidate the mechanisms underlying hepatic complications associated with defective glycogen metabolism.

Long-term safety and efficacy of AAV gene therapy in the canine model of glycogen storage disease type Ia.

BACKGROUND: Viral mediated gene therapy has progressed after overcoming early failures, and gene therapy has now been approved for several conditions in Europe and the USA. Glycogen storage disease (GSD) type Ia, caused by a deficiency of glucose-6-phosphatase-α, has been viewed as an outstanding candidate for gene therapy. This follow-up report describes the long-term outcome for the naturally occurring GSD-Ia dogs treated with rAAV-GPE-hG6PC-mediated gene therapy. METHODS: A total of seven dogs were treated with rAAV-GPE-hG6PC-mediated gene therapy. The first four dogs were treated at birth, and three dogs were treated between 2 and 6 months of age to assess the efficacy and safety in animals with mature livers. Blood and urine samples, radiographic studies, histological evaluation, and biodistribution were assessed. RESULTS: Gene therapy improved survival in the GSD-Ia dogs. With treatment, the biochemical studies normalized for the duration of the study (up to 7 years). None of the rAAV-GPE-hG6PC-treated dogs had focal hepatic lesions or renal abnormalities. Dogs treated at birth required a second dose of rAAV after 2-4 months; gene therapy after hepatic maturation resulted in improved efficacy after a single dose. CONCLUSION: rAAV-GPE-hG6PC treatment in GSD-Ia dogs was found to be safe and efficacious. GSD-Ia is an attractive target for human gene therapy since it is a monogenic disorder with limited tissue involvement. Blood glucose and lactate monitoring can be used to assess effectiveness and as a biomarker of success. GSD-Ia can also serve as a model for other hepatic monogenic disorders.

Cuidados enfermeros al paciente portador de drenaje torácico / Nursing care for patient with thoracic drainage

El drenaje torácico consiste en la colocación de una sonda en el espacio pleural para evacuar la presencia de aire, líquido o sangre, lo cual produce un colapso pulmonar de grado variable con repercusión clínica en función de la reserva ventilatoria previa del paciente y el grado de colapso. Existen varios modelos de tubos torácicos, así como de sistemas de drenaje pleural. Los sistemas cerrados de drenaje torácico actuales son desechables y garantizan un manejo óptimo y seguro para el paciente. Los cuidados de Enfermería son fundamentales durante todo el proceso de instauración de dichos drenajes, tanto en la preparación del paciente, inserción y mantenimiento adecuado para el éxito del tratamiento, como durante la extracción y posterior atención, por lo que conocerlos principios técnicos básicos para una correcta utilización permitirá un mantenimiento eficaz y eficiente del sistema de drenaje y el control, el seguimiento y la evaluación del paciente

Thoracic drainage consists of placing a tube in the pleural cavity to evacuate air, fluid or blood, which leads to pulmonary collapse of a variable degree with a clinical repercussion depending on the patient’s previous ventilation reserve and the extent of collapse. There are several models of thoracic tubes, as well as pleural drainage systems. Current thoracic closed drainage systems are disposable and guarantee optimal and safe patient management. Nursing care is fundamental throughout the process of placement of drainage systems, both in terms of preparation of the patient, insertion and proper maintenance for the success of the treatment, as well as the removal and after-care; therefore, knowledge of the basic technical principles for correct use thereof will enable effective and efficient maintenance of the drainage system and the control, follow-up and evaluation of the patient

Administración de nutrición enteral. Uso de bombas de infusión / Administration of enteral nutrition. Use of infusion pumps

La nutrición enteral (NE) constituye una técnica de nutrición artificial que permite la administración por vía digestiva de una mezcla definida de nutrientes y agua, por medio de sondas implantadas por vía nasal o por enterostomías (por ejemplo, por gastrostomía). Siempre que el paciente presente limitaciones para la ingesta oral voluntaria o la deglución de los nutrientes, y siempre que la capacidad del aparato digestivo permita absorber los nutrientes, se recurrirá a la administración a través de una sonda. La preocupación por el estado nutricional de los pacientes es una realidad cada vez más presente entre los profesionales de la sanidad, ya que se ha demostrado la relación directa entre la malnutrición y la morbimortalidad de los pacientes hospitalizados. La nutrición enteral se ha convertido en un procedimiento útil para el tratamiento de estos pacientes, que reduce su morbimortalidad. La NE puede administrarse por bomba de infusión, por goteo gravitatorio (menor uso clínico) y a través de jeringa (bolus), teniendo en cuenta la velocidad de la misma, lo que evita un gran número de complicaciones (suelen deberse a administraciones demasiado rápidas). En consecuencia, el método empleado se ajustará a las necesidades de cada paciente, considerando, asimismo, la tolerancia y su riesgo de aspiración. En este trabajo nos centraremos en la administración de la NE mediante bomba de infusión haciendo hincapié en la disminución de complicaciones con esta metodología frente a la administración por bolus (jeringa) (AU)

Enteral nutrition (NE) is a technique of artificial nutrition that enables management by digestive tract of a defined mixture of nutrients and water, by means of probes implanted nasally or by enterostomies (eg: gastrostomy). Whenever the patient present limitations for voluntary oral ingestion or swallowing of the nutrients, and digestive capacity permitted to absorb nutrients, will draw the administration through a tube. Concern for the nutritional status of the patients is a more present reality among health professionals have demonstrated the direct relationship between malnutrition and morbidity and mortality of hospitalized patients. Enteral nutrition has become a useful procedure for the treatment of these patients, reducing their morbidity and mortality. The NE can be administered by infusion by gravity drip (less clinical use) pump and syringe (bolus), taking into account the speed of it, thus avoiding a large number of complications (usually due to too rapid administrations), so the method employed will be adjusted to the needs of each patient, whereas, the tolerance and its risk of aspiration. In this paper we will focus on the NE by infusion pump administration emphasizing the reduction of complications with this methodology against the administration by bolus (syringe) (AU)

Cribado neonatal en la Comunidad Autónoma de Aragón. Guía práctica / Newborn Screening in the Autonomous Community of Aragon. Practical Guidelines

En todas las comunidades autónomas se llevan a cabo programas de detección precoz de enfermedades metabólicas, endocrinas y congénitas, reduciéndose así la morbimortalidad y discapacidades asociadas al detectarse enfermedades que no se manifiestan clínicamente en el momento del nacimiento, sino que lo hacen posteriormente y que, si no son diagnosticadas y tratadas a tiempo, dejan secuelas neurológicas importantes. Se trata de una técnica sencilla realizada por enfermeras/os, pero para la que se precisa de una formación adecuada, dado que todavía se refiere por parte de los laboratorios de cribado neonatal la recepción de muestras mal impregnadas, en las que no puede asegurarse el volumen absorbido de sangre, bien por muestra insuficiente o inadecuadamente embebida. El objetivo de este artículo es revisar la técnica de recogida de muestras a fin de contribuir a mejorar el conocimiento de enfermeros/as en cuanto a la punción del talón del recién nacido para mejorar la calidad de las muestras de gotas de sangre obtenidas

Early detection screening programs for metabolic, endocrine and congenital diseases are conducted in all autonomous communities, thus reducing the morbimortality and disabilities associated, by detecting diseases that present no clinical symptoms at the time of birth but subsequently, and which will leave major neurological consequences if not diagnosed and treated on time. This is an easy technique, conducted by nurses, but which requires adequate training, because there are still claims by newborn screening labs regarding the reception of poorly impregnated samples, where the volume of blood absorption cannot be ensured, either due to insufficient sample or inadequate soaking. The objective of this article is to review the technique of sample collection, in order to contribute to improving the knowledge of nurses regarding the newborn heel prick, for an improvement in the quality of the blood drop samples obtained

[ADMINISTRATION OF ENTERAL NUTRITION. USE OF INFUSION PUMPS]. / Administración de nutrición enteral. USO DE BOMBAS DE INFUSIÓN.

Enteral nutrition (NE) is a technique of artificial nutrition that enables management by digestive tract of a defined mixture of nutrients and water, by means of probes implanted nasally or by enterostomies (eg: gastrostomy). Whenever the patient present limitations for voluntary oral ingestion or swallowing of the nutrients, and digestive capacity permitted to absorb nutrients, will draw the administration through a tube. Concern for the nutritional status of the patients is a more present reality among health professionals have demonstrated the direct relationship between malnutrition and morbidity and mortality of hospitalized patients. Enteral nutrition has become a useful procedure for the treatment of these patients, reducing their morbidity and mortality. The NE can be administered by infusion by gravity drip (less clinical use) pump and syringe (bolus), taking into account the speed of it, thus avoiding a large number of complications (usually due to too rapid administrations), so the method employed will be adjusted to the needs of each patient, whereas, the tolerance and its risk of aspiration. In this paper we will focus on the NE by infusion pump administration emphasizing the reduction of complications with this methodology against the administration by bolus (syringe).

Disfagia en fase aguda del ictus / Dysphagia in acute phase of ictus. usefulness of the volume-viscosity test in a district hospital

Se denomina Accidente Cerebrovascular (ACV) o ictus al trastorno brusco de flujo sanguíneo cerebral que altera de forma transitoria o permanente la función de una determinada región del encéfalo [1]. La Organización Mundial de la Salud (OMS) define el ictus como un «síndrome clínico, presumiblemente de origen vascular, que se caracteriza por el desarrollo rápido de signos de afectación neurológica focal y que duran más de 24 horas o llevan a la muerte». [2] Las enfermedades cerebrovasculares pueden dividirse en dos grandes grupos, según el mecanismo etiopatogénico: ictus isquémicos e ictus hemorrágicos. Los ictus isquémicos representan entre el 80-85 % de todos los ictus y los hemorrágicos entre el 15-20 %. Esta patología tiene una elevada frecuencia de presentación, sobre todo en personas de edad avanzada, una gran repercusión social, un alto índice de mortalidad, ocasiona ingresos prolongados y tiene unos costes sociosanitarios elevados. Constituye la tercera causa de muerte en los países desarrollados después de la cardiopatía isquémica y las neoplasias [1]. En la fase aguda del ictus, la disfagia tiene una prevalencia que se estima entre el 30-70 % y, por sus consecuencias (desnutrición, deshidratación y broncoaspiración), la morbimortalidad en estos pacientes se incrementa [3]. Por este motivo es de gran importancia la aplicación del Método de Exploración Clínica Volumen-Viscosidad (MECV-V) para detectar precozmente alteraciones compatibles con la disfagia (AU)

Cerebrovascular accident (ACV) or ictus is called sudden disorder of cerebral blood flow that temporarily or permanently alters the function of a certain region of the brain. Cerebrovascular diseases can be divided into two groups, according to the mechanism etiopathogenic: ischemic ictus and hemorrhagic ictus [1]. The World Health Organization (WHO) defines ictus as «a clinical syndrome, presumably of vascular origin, characterized by rapidly developing signs of focal neurological impairment lasting more than 24 hours or leading to death» [2]. Ischemic ictus account for between 80-85 % of all ictus and the hemorrhagic between 15-20 %. This pathology has a high frequency of presentation, especially in people of advanced age, a great social impact, to the high rate of mortality, causes prolonged income and has a high social cost. It constitutes the third leading cause of death in developed after ischemic heart disease and malignancies [1]. In the acute phase of ictus, dysphagia have prevalence estimated between 30-70 %, and by its consequences (malnutrition, dehydration and aspiration into lungs), morbidity and mortality in these patients is going to be increased [3]. For this reason, the application of Volume-Viscosity Swallow Test (V-VST) it is of great importance to detect early abnormalities compatible with dysphagia (AU)

Curación de herida traumatológica mediante terapia de presión negativa / Trauma wound healing using negative pressure therapy

El tratamiento con terapia de presión negativa o de vacío cerrada, denominada VAC® por sus siglas en inglés (Vacuum Assisted Closure) supone un cambio en el paradigma de la curación de heridas de origen diverso. El objetivo de este trabajo es mostrar la efectividad de la terapia de vacío en el tratamiento de heridas complejas, mediante la descripción de un caso clínico tratado en el Servicio de Cirugía Ortopédica y Traumatológica del Hospital Ernest Lluch Martín de Calatayud (Zaragoza).Se describen las características de la herida quirúrgica infectada en extremidad inferior derecha en un paciente de 45 años y el tratamiento aplicado desde su ingreso en el hospital. Tras cinco semanas de evolución insatisfactoria se decidió aplicar terapia de vacío, cuyo funcionamiento y proceso de aplicación también son descritos. Dos semanas después, la herida presentaba tejidode granulación y cierre gradual de los bordes distales. El potencial beneficio del uso de la terapia de vacío incluye al paciente, a los profesionales de Enfermería y al sistema

VAC® (Vacuum Assisted Closure) is a negative pressure therapy or closed vacuum therapy that has resulted in a new paradigm for cure of various wound types. Our work was aimed at demonstrating vacuum therapy effectiveness to treat complex wounds with a case presentation corresponding to a patient that was treated at the Department of Orthopedics, Hospital Ernest Lluch Martín, Calatayud, Zaragoza, Spain. Wound characteristics are described: an infected wound in right lower limb in a 45-year-old patient. Applied therapy since hospital admission is reported. After a five-week unsuccessful course, vacuum therapy was applied. Operation and application processes are also described. Two weeks later, granulation tissue and gradual healing at distal margins were observed. Patients, nursing staff, and system can all potentially benefit from vacuum therapy

Is prosodic development correlated with grammatical and lexical development? Evidence from emerging intonation in Catalan and Spanish.

This investigation focuses on the development of intonation patterns in four Catalan-speaking children and two Spanish-speaking children between 0 ; 11 and 2 ; 4. Pitch contours were prosodically analyzed within the Autosegmental Metrical framework in all meaningful utterances, for a total of 6558 utterances. The pragmatic meaning and communicative function were also assessed. Three main conclusions arise from the results. First, the study shows that the Autosegmental Metrical model can be successfully used to transcribe early intonation contours. Second, results reveal that children's emerging intonation is largely independent of grammatical development, and generally it develops well before the appearance of two-word combinations. As for the relationship between lexical and intonational development, the data show that the emergence of intonational grammar is related to the onset of speech and the presence of a small lexicon. Finally, we discuss the implications of these results for the biological hypothesis of intonational production.