Autophagy is Involved in Cardiac Remodeling in Response to Environmental Temperature Change.

Objectives: To study the reversibility of cold-induced cardiac hypertrophy and the role of autophagy in this process. Background: Chronic exposure to cold is known to cause cardiac hypertrophy independent of blood pressure elevation. The reversibility of this process and the molecular mechanisms involved are unknown. Methods: Studies were performed in two-month-old mice exposed to cold (4°C) for 24 h or 10 days. After exposure, the animals were returned to room temperature (21°C) for 24 h or 1 week. Results: We found that chronic cold exposure significantly increased the heart weight/tibia length (HW/TL) ratio, the mean area of cardiomyocytes, and the expression of hypertrophy markers, but significantly decreased the expression of genes involved in fatty acid oxidation. Echocardiographic measurements confirmed hypertrophy development after chronic cold exposure. One week of deacclimation for cold-exposed mice fully reverted the morphological, functional, and gene expression indicators of cardiac hypertrophy. Experiments involving injection of leupeptin at 1 h before sacrifice (to block autophagic flux) indicated that cardiac autophagy was repressed under cold exposure and re-activated during the first 24 h after mice were returned to room temperature. Pharmacological blockage of autophagy for 1 week using chloroquine in mice subjected to deacclimation from cold significantly inhibited the reversion of cardiac hypertrophy. Conclusion: Our data indicate that mice exposed to cold develop a marked cardiac hypertrophy that is reversed after 1 week of deacclimation. We propose that autophagy is a major mechanism underlying the heart remodeling seen in response to cold exposure and its posterior reversion after deacclimation.

Inflammation of brown/beige adipose tissues in obesity and metabolic disease.

Many of the comorbidities of obesity, including type 2 diabetes and cardiovascular diseases, are related to the low-grade chronic inflammation of white adipose tissue. Under white adipocyte stress, local infiltration of immune cells and enhanced production of pro-inflammatory cytokines together reduce metabolic flexibility and lead to insulin resistance in obesity. Whereas white adipocytes act in energy storage, brown and beige adipocytes specialize in energy expenditure. Brown and beige activity protects against obesity and associated metabolic disorders, such as hyperglycaemia and hyperlipidaemia. Compared to white fat, brown adipose tissue depots are less susceptible to developing local inflammation in response to obesity; however, strong obesogenic insults ultimately induce a locally pro-inflammatory environment in brown fat. This condition directly alters the thermogenic activity of brown fat by impairing its energy expenditure mechanism and uptake of glucose for use as a fuel substrate. Pro-inflammatory cytokines also impair beige adipogenesis, which occurs mainly in subcutaneous adipose tissue. There is evidence that inflammatory processes occurring in perivascular adipose tissues alter their brown-versus-white plasticity, impair the extent of browning in these depots and favour the local release of vasculature damaging signals. In summary, the targeting of brown and beige adipose tissues by pro-inflammatory signals and the subsequent impairment of their thermogenic and metabolite draining activities appears to represent obesity-driven disturbances that contribute to metabolic syndrome and cardiovascular alterations in obesity.

Autophagic control of cardiac steatosis through FGF21 in obesity-associated cardiomyopathy.

OBJECTIVE: High-fat diet-induced obesity leads to the development of hypertrophy and heart failure through poorly understood molecular mechanisms. We have recently shown that fibroblast growth factor-21 (FGF21) is produced by the heart and exerts protective effects that prevent cardiac hypertrophy development and oxidative stress. The aim of this study was to determine the effects of FGF21 on the cardiomyopathy associated with obesity development. RESULTS: Fgf21-/- mice showed an enhanced increase in the heart weight/tibia length (HW/TL) ratio in response to the high-fat diet. In keeping with this, echocardiographic measurements confirmed enhanced cardiac hypertrophy in Fgf21-/- mice. At the cellular level, the area of cardiomyocytes was increased in Fgf21-/- mice fed a high-fat diet. Furthermore, a high-fat diet induced fatty acid oxidation in the hearts of Fgf21-/- mice accompanied by an increase in cardiac oxidative stress. Oil-red O staining revealed the presence of higher amounts of lipid droplets in the hearts of Fgf21-/- mice fed a high-fat diet relative to wt mice fed this same diet. Finally, Fgf21-/- mice fed a high-fat diet showed impaired cardiac autophagy and signs of inactive cardiac lipophagy, suggesting that FGF21 promotes autophagy in cardiomyocytes. CONCLUSIONS: Our data indicate that a lack of FGF21 enhances the susceptibility of mice to the development of obesity-related cardiomyopathy. Furthermore, we demonstrate that this cardiac dysfunction is associated with deleterious lipid accumulation in the heart. An impaired ability of FGF21 to promote autophagy/lipophagy may contribute to lipid accumulation and cardiac derangements.

Thermogenic activation represses autophagy in brown adipose tissue.

BACKGROUND: Brown adipose tissue (BAT) thermogenesis is an adaptive process, essential for energy expenditure and involved in the control of obesity. Obesity is associated with abnormally increased autophagy in white adipose tissue. Autophagy has been proposed as relevant for brown-vs-white adipocyte differentiation; however, its role in the response of BAT to thermogenic activation is unknown. METHODS: The effects of thermogenic activation on autophagy in BAT were analyzed in vivo by exposing mice to 24 h cold condition. The effects of norepinephrine (NE), cAMP and modulators of lysosomal activity were determined in differentiated brown adipocytes in the primary culture. Transcript expression was quantified by real-time PCR, and specific proteins were determined by immunoblot. Transmission electron microscopy, as well as confocal microscopy analysis after incubation with specific antibodies or reagents coupled to fluorescent emission, were performed in BAT and cultured brown adipocytes, respectively. RESULTS: Autophagy is repressed in association with cold-induced thermogenic activation of BAT in mice. This effect was mimicked by NE action in brown adipocytes, acting mainly through a cAMP-dependent protein kinase A pathway. Inhibition of autophagy in brown adipocytes leads to an increase in UCP1 protein and uncoupled respiration, suggesting a repressing role for autophagy in relation to the activity of BAT thermogenic machinery. Under basal conditions, brown adipocytes show signs of active lipophagy, which is suppressed by a cAMP-mediated thermogenic stimulus. CONCLUSIONS: Our results show a noradrenergic-mediated inverse relationship between autophagy and thermogenic activity in BAT and point toward autophagy repression as a component of brown adipocyte adaptive mechanisms to activate thermogenesis.

Non-sympathetic control of brown adipose tissue.

The thermogenic activity of brown adipose tissue (BAT) in the organism is tightly regulated through different processes, from short-term induction of uncoupling protein-1-mediated mitochondrial proton conductance to complex processes of BAT recruitment, and appearance of the beige/brite adipocytes in white adipose tissue (WAT), the so-called browning process. The sympathetic nervous system is classically recognized as the main mediator of BAT activation. However, novel factors capable of activating BAT through non-sympathetic mechanisms have been recently identified. Among them are members of the bone morphogenetic protein family, with likely autocrine actions, and activators of nuclear hormone receptors, especially vitamin A derivatives. Multiple endocrine factors released by peripheral tissues that act on BAT have also been identified. Some are natriuretic peptides of cardiac origin, whereas others include irisin, originating in skeletal muscle, and fibroblast growth factor-21, mainly produced in the liver. These factors have cell-autonomous effects in brown adipocytes, but indirect effects in vivo that modulate sympathetic activity toward BAT cannot be excluded. Moreover, these factors can affect to different extents such as the activation of existing BAT, the induction of browning in WAT or both. The identification of non-sympathetic controllers of BAT activity is of special biomedical interest as a prerequisite for developing pharmacological tools that influence BAT activity without the side effects of sympathomimetics.

Genetic ablation of macrohistone H2A1 leads to increased leanness, glucose tolerance and energy expenditure in mice fed a high-fat diet.

BACKGROUND/OBJECTIVES: In the context of obesity, epigenetic mechanisms regulate cell-specific chromatin plasticity, perpetuating gene expression responses to nutrient excess. MacroH2A1, a variant of histone H2A, emerged as a key chromatin regulator sensing small nutrients during cell proliferation and differentiation. Mice genetically ablated for macroH2A1 (knockout (KO)) do not show overt phenotypes under a standard diet. Our objective was to analyse the in vivo role of macroH2A1 in response to nutritional excess. METHODS: Twelve-week-old whole-body macroH2A1 KO male mice were given a high-fat diet (60% energy from lard) for 12 weeks until being killed, and examined for glucose and insulin tolerance, and for body fat composition. Energy expenditure was assessed using metabolic cages and by measuring the expression levels of genes involved in thermogenesis in the brown adipose tissue (BAT) or in adipogenesis in the visceral adipose tissue (VAT). RESULTS: Under a chow diet, macroH2A1 KO mice did not differ from their wild-type (WT) littermates for body weight, and for sensitivity to glucose or insulin. However, KO mice displayed decreased heat production (P<0.05), and enhanced total activity during the night (P<0.01). These activities related to protection against diet-induced obesity in KO mice, which displayed decreased body weight owing to a specific decrease in fat mass (P<0.05), increased tolerance to glucose (P<0.05), and enhanced total activity during the day (P<0.05), compared with WT mice. KO mice displayed increased expression of thermogenic genes (Ucp1, P<0.05; Glut4, P<0.05; Cox4, P<0.01) in BAT and a decreased expression of adipogenic genes (Pparγ, P<0.05; Fabp4, P<0.05; Glut4, P<0.05) in VAT compared with WT mice, indicative of augmented energy expenditure. CONCLUSIONS: Genetic eviction of macroH2A1 confers protection against diet-induced obesity and metabolic derangements in mice. Inhibition of macroH2A1 might be a helpful strategy for epigenetic therapy of obesity.

Programa de Salud para niños y adolescentes con síndrome de Down / Health Program for children and adolescents with Down’s syndrome

Los problemas específicos de salud que presentan los niños con síndrome de Down deben ser objeto de atención por los pediatras. Para integrar estos cuidados con los propios de la edad, diversas organizaciones pediátricas han elaborado programas de salud para personas con síndrome de Down. En ellos se puntualiza sobre las necesidades específicas de los pacientes con trisomía 21, añadiéndolas a las propias de las diversas edades. Los programas de salud suponen una ayuda importante para la atención pediátrica a este grupo poblacional (AU)

Special attention should be given by the pediatricians to the specific health problems that children with Down’s Syndrome have. In order to integrate these cares into those cares characteristic for their age, different pediatric organizations have elaborated health programs for persons with Down’s Syndrome. In these, the specific needs of the patients with trisomy 21 are highlighted, adding these to those characteristic for the different ages. The health programs suppose an important aid for the pediatric care to this population group (AU)

[Analgesia for childbirth in a patient with factor V Leiden mutation]. / Analgesia para trabajo de parto en paciente con mutación del factor V Leiden.

Factor V Leiden mutation is the most common congenital thrombophilic disorder, affecting between 5% and 8% of the Caucasian population. Pregnancy creates a state of hypercoagulability and all factors that increase the risk of thrombosis should be considered, as they may be cumulative. In recent years, the diagnosis of new allelic variants of thrombophilic states have increased the incidence of pregnant women receiving anticoagulant therapy, with the anesthetic considerations that implies. We report the case of a 33-year-old woman with heterozygous Leiden factor V mutation who was admitted with spontaneous amniorrhexis in the 38th week of gestation. She was taking low molecular weight heparin therapy. An epidural catheter was inserted to provide analgesia for labor, with all safety precautions to prevent an epidural hematoma. Epidural anesthesia is the technique of choice for obstetric labor in patients with hypercoagulability because of its effects of favoring blood flow and inhibiting clot formation.

Analgesia para trabajo de parto en paciente con mutación del factor V Leiden / Analgesia for childbirth in a patient with Factor V Leiden mutation

La mutación del factor V Leiden, es la forma más frecuente de trastorno trombofílico congénito, afectando al 5-8% de la población caucasiana. La gestación supone, en sí misma, un estado de hipercoagulabilidad que nos debe llevar a prestar especial atención a todos aquellos factores de riesgo trombótico que puedan sumarse. En los últimos años, el diagnóstico de las nuevas variantes alélicas de los estados trombofílicos, ha incrementado la incidencia de gestantes que reciben anticoagulación con las consideraciones anestésicas que ello conlleva. Presentamos el caso de una mujer de 33 años de edad, portadora heterocigoto de una mutación en el gen del factor V Leiden, en tratamiento con heparina de bajo peso molecular, que ingresa por amniorrexis espontánea a la semana 38 de gestación. La paciente requirió analgesia para el trabajo de parto, por lo que se le colocó un catéter epidural cumpliendo los protocolos de seguridad y prevención del hematoma epidural. La anestesia epidural es la técnica de elección para analgesia del trabajo de parto, en las pacientes con hipercoagulabilidad, por sus efectos sobre la reología vascular y su efecto antitrombótico

Factor V Leiden mutation is the most common congenital thrombophilic disorder, affecting between 5% and 8% of the Caucasian population. Pregnancy creates a state of hypercoagulability and all factors that increase the risk of thrombosis should be considered, as they may be cumulative. In recent years, the diagnosis of new allelic variants of thrombophilic states have increased the incidence of pregnant women receiving anticoagulant therapy, with the anesthetic considerations that implies. We report the case of a 33-year-old woman with heterozygous Leiden factor V mutation who was admitted with spontaneous amniorrhexis in the 38th week of gestation. She was taking low molecular weight heparin therapy. An epidural catheter was inserted to provide analgesia for labor, with all safety precautions to prevent an epidural hematoma. Epidural anesthesia is the technique of choice for obstetric labor in patients with hypercoagulability because of its effects of favoring blood flow and inhibiting clot formation

Seroprevalence of varicella among children and adolescents in Valencia, Spain. Reliability of the parent's reported history and the medical file for identification of potential candidates for vaccination.

This study assessed the seroprevalence of varicella antibodies in children and adolescents in Spain and evaluated the reliability of two methods for detecting susceptible individuals: (1) parental-reported history of varicella and (2) medically-documented histories maintained by the pediatrician. A total of 186 children (6 to 15 years of age) were recruited in 13 pediatric offices of Valencia, Spain. A brief case report form was completed including previous history of varicella referred by the parents, and a 5 mL blood sample was obtained. The pediatrician medical file was reviewed for antecedent of varicella. The overall prevalence of varicella antibodies was 84% and 88% in the 6-9 years and 10-15 years age brackets, respectively. The predictive value of a negative history of varicella disease was 48% by parental recall (52% "false negative"), and only 26% by medical record (74% "false negative"). However, the positive predictive value of a positive parental reported history or a positive medically-documented history was 95%. The most effective strategy for varicella vaccination of older children and adolescents in Spain will be to immunize those individuals with a lack of positive (unknown or negative) history of disease.

[Epidemiology and burden of acute otitis media in Valencia (Spain)]. / Epidemiología e impacto de la otitis media aguda en la Comunidad Valenciana.

OBJECTIVE: To assess the burden (incidence, treatment and complications) of acute otitis media (AOM) and otitis media with effusion (OME) in children younger than 5 years of age from Valencia, Spain. SUBJECT AND METHODS: We performed a retrospective cohort study of 1,399 children followed-up for the first 5 years of life. Seventeen pediatricians reviewed the medical records of their patients born in 1995 and 1996 and followed-up from birth until the age of 5 years. For each child, the number of otitis episodes, treatment, complications, and surgical interventions was obtained. RESULTS: There were 2,961 episodes of AOM in the first 5 years of life (2.23 cases/child). Four hundred seventy-six cases (16.1 %) occurred before 1 year of age and 1,346 between the first and second year of life (45.5 %). By the third year of life, 59.8 % had had at least one episode. In most children (80.9 %), diagnosis was made in primary care and required a median of 1.81 visits/episode for follow-up. A total of 94.5 % were treated with antibiotics (amoxicillin-clavulanate 38.8 %, cefuroxime 14.3 %, clarithromycin 8.2 % and amoxicillin 5.9 %) and 8.5 % required a change of antibiotic therapy. Two hundred seventeen children (15.2 %) had at least one episode of OME. Twenty-six patients (1.8 %, 95 % CI: 1.2-2.7 %) required insertion of ventilation tubes. Twenty-four patients (1.7 %) had secondary hypoacusis. There was one case of meningitis and two cases of chronic otorrhea. No cases of mastoiditis were recorded. CONCLUSIONS: The incidence of AOM in Valencia is 40,014 episodes/100,000 children younger than 5 years/year (95 % CI: 39,700-40,300). It represents a significant burden due to the large number of visits, antibiotic use, associated surgical procedures and need for auditory rehabilitation.

Epidemiología e impacto de la otitis media aguda en la Comunidad Valenciana / Epidemiology and burden of acute otitis media in Valencia (Spain)

Objetivo: Estimar el impacto (incidencia, tratamiento y complicaciones) de la otitis media aguda (OMA) y la otitis media serosa (OMS) en los niños menores de 5 años de la Comunidad Valenciana (España). Sujetos y métodos: Cohorte retrospectiva de 1.399 niños seguidos durante los primeros 5 años de vida. Diecisiete pediatras revisaron las historias clínicas de sus pacientes nacidos en 1995 y 1996, controlados desde su nacimiento hasta los 5 años. Se obtuvo de cada niño el número de episodios de otitis, tratamiento, complicaciones e intervenciones quirúrgicas requeridas. Resultados: Hubo 2.961 episodios de OMA en los primeros 5 años de vida (2,23 casos/niño), 476 casos (16,1 por ciento) antes del año y 1.346 entre el primer y segundo año (45,5 por ciento). Al tercer año, el 59,8 por ciento habían presentado al menos un episodio. La mayoría de casos (80,9 por ciento) se diagnosticaron en atención primaria, con 1,81 visitas/episodio de media para su seguimiento. El 94,5 por ciento de los episodios fueron tratados con antibiótico (amoxicilina-ácido clavulánico 38,8 por ciento, cefuroxima-axetilo, 14,3 por ciento; claritromicina, 8,2 por ciento, y amoxicilina 5,9 por ciento). El 8,5 por ciento requirió cambio a un segundo antibiótico. Presentaron al menos un episodio de OMS 217 niños (15,2 por ciento). Necesitaron implantación de tubos de ventilación 26 pacientes (1,8 por ciento, intervalo de confianza del 95 por ciento (IC 95 por ciento), 1,2-2,7). Presentaron hipoacusia secundaria 24 niños (1,7 por ciento). Hubo un caso de meningitis y dos de otorrea crónica. No hubo mastoiditis. Conclusiones: La incidencia de OMA en la Comunidad Valenciana es de 40.014 episodios/100.000 niños menores de 5 años/año (IC 95 por ciento, 39.700-40.300). Supone un gran impacto sanitario por el elevado número de visitas, uso antibiótico, cirugía asociada y necesidad de rehabilitación auditiva (AU)

[Crossed renal ectopia: radiological possibilities of helicoidal CAT]. / Ectopia renal cruzada: posibilidades radiológicas de la TAC helicoidal.

OBJECTIVES: To evaluate the diagnostical possibilities of helicoidal CAT in crossed renal ectopy (CRE) and review 36 cases published in Spain, including our 3 new patients. CLINICAL CASES: We present two women and a man aged between 54 and 82 who were diagnosed of left CRE. One of them showed an ureterocele and other one presented a splenic angiosarcoma. DISCUSSION: Main embriological theories, clinical presentation, associated anomalies and different radiological systems used in the diagnosis of this infrequent congenital malformation are evaluated.

Ectopia renal cruzada: posibilidades radiológicas de la TAC helicoidal / Crossed renal ectopia: Radiological possibilities with helicoida CAT

OBJETIVOS: Evaluar las posibilidades diagnósticas de la TAC helicoidal en la ectopia renal cruzada (ERC) a la vez que se realiza una revisión de 36 casos publicados en España, incluyendo nuestros 3 nuevos pacientes. CASOS CLÍNICOS: Presentamos 2 mujeres y 1 varón con edades comprendidas entre 54 y 82 años, que fueron diagnosticados de ERC izquierda. Uno de ellos mostraba asociadamente un ureterocele ipsilateral y otro presentaba un angiosarcoma esplénico. DISCUSIÓN: Las principales teorías embriogénicas, presentación clínica, anomalías asociadas y distintos medios radiológicos en el diagnóstico de esta infrecuente malformación congénita son evaluados (AU)

[Nephrogenic adenoma of the bladder: metaplasia or embryologic alteration?]. / Adenoma nefrogénico vesical: metaplasia o alteración embriológica?

OBJECTIVES: To present a new case of nephrogenic adenoma of the bladder and to review the current concepts on the etiopathogenesis of this lesion. CLINICAL CASE: Seventy years old female with repetitive haematuria who was diagnosed as having a nephrogenic adenoma of the bladder which was extirpated by cold biopsy forceps. No tumoral relapse was detected after 16 months of follow up. DISCUSSION: In the light of the present knowledges, the origin of nephrogenic adenoma is a phenomenon of urothelial metaplasia due to a chronic irritative stimulus wich would lead a cellular proliferation with potentialities to originate mesonephric tissues and which starting point could be on not completely involutioned mesonephric cellular rests and/or on de-differentiated mature urothelial cells.

Adenoma nefrogénico vesical: ¿metaplasia o alteración embriológica? / Nephrogenic adenoma of the bladder: metaplasia or embriological disturbance?

OBJETIVOS: Presentación de un nuevo caso de adenoma nefrogénico vesical, y revisar los conocimientos actuales sobre la etiopatogenia de esta lesión. CASO CLÍNICO: Mujer de 70 años con hematuria de repetición que es diagnosticada de un adenoma nefrogénico vesical, que fue extirpada mediante biopsia fría. No se ha detectado recidiva de la neoformación tras 16 meses de seguimiento. DISCUSIÓN: A la luz de los conocimientos actuales, el origen del adenoma nefrogénico podría estar en un fenómeno de metaplasia urotelial secundario a un estímulo irritativo crónico, que induciría una proliferación celular con potencialidad para generar tejido mesonéfrico, y cuyo origen podría encontrarse en restos celulares mesonéfri-cos incompletamente involucionados y/o en la desdiferenciación de células uroteliales maduras (AU)

Unusual retrovesical masses in men.

Retrovesical masses in men not related to prostatic carcinoma or hyperplasia is an uncommon pathology. Rare masses or unusual manifestations of those common diseases are a diagnostic dilemma. We review our experience in three unusual retrovesical masses in men: carcinosarcoma filling a giant bladder diverticulum; cystic prostatic carcinoma; and acquired cystic dilatation of the seminal vesicle associated with a prostatic carcinoma that obstructed and invaded the vesicle. We report the imaging findings and review the literature. In our experience, the imaging findings are usually not specific for doing a precise diagnosis and biopsy procedures are necessary.

Port site metastases after laparoscopic cholecystectomy for an unexpected gallbladder carcinoma.

Laparoscopic cholecystectomy is a proven, well-accepted surgical technique for removing the diseased gallbladder and has rapidly become the surgical procedure of choice over conventional open cholecystectomy. Radiologists must be aware of the possibility of inadvertent dissemination of incidental gallbladder cancer during laparoscopic cholecystectomy. We report a case of this unusual complication: a patient with port site metastases after laparoscopic cholecystectomy for an unexpected gallbladder carcinoma at an early stage.