Exercise and insulin resistance in PCOS: muscle insulin signalling and fibrosis.

OBJECTIVE: Mechanisms of insulin resistance in polycystic ovary syndrome (PCOS) remain ill defined, contributing to sub-optimal therapies. Recognising skeletal muscle plays a key role in glucose homeostasis we investigated early insulin signalling, its association with aberrant transforming growth factor ß (TGFß)-regulated tissue fibrosis. We also explored the impact of aerobic exercise on these molecular pathways. METHODS: A secondary analysis from a cross-sectional study was undertaken in women with (n = 30) or without (n = 29) PCOS across lean and overweight BMIs. A subset of participants with (n = 8) or without (n = 8) PCOS who were overweight completed 12 weeks of aerobic exercise training. Muscle was sampled before and 30 min into a euglycaemic-hyperinsulinaemic clamp pre and post training. RESULTS: We found reduced signalling in PCOS of mechanistic target of rapamycin (mTOR). Exercise training augmented but did not completely rescue this signalling defect in women with PCOS. Genes in the TGFß signalling network were upregulated in skeletal muscle in the overweight women with PCOS but were unresponsive to exercise training except for genes encoding LOX, collagen 1 and 3. CONCLUSIONS: We provide new insights into defects in early insulin signalling, tissue fibrosis, and hyperandrogenism in PCOS-specific insulin resistance in lean and overweight women. PCOS-specific insulin signalling defects were isolated to mTOR, while gene expression implicated TGFß ligand regulating a fibrosis in the PCOS-obesity synergy in insulin resistance and altered responses to exercise. Interestingly, there was little evidence for hyperandrogenism as a mechanism for insulin resistance.

Glucose regulation of a cell cycle gene module is selectively lost in mouse pancreatic islets during ageing.

AIMS/HYPOTHESIS: Transcriptional networks in beta cells are modulated by extracellular signals such as glucose, thereby ensuring beta cell adaptation to systemic insulin demands. Ageing is a main risk factor for type 2 diabetes and has been associated with perturbed expression of genes essential for beta cell function. We aimed to uncover glucose-dependent gene modules in mouse pancreatic islets and investigate how this regulation is affected by ageing. METHODS: Global gene expression was assessed in pancreatic islets from young and aged wild-type and Cdkn2a (Ink4a/Arf)-deficient mice exposed to different glucose concentrations. Gene modules were identified by gene ontology and gene set enrichment analysis. RESULTS: Gene expression profiling revealed that variations in glucose levels have a widespread and highly dynamic impact on the islet transcriptome. Stimulatory glucose levels induced the expression of highly beta cell-selective genes and repressed the expression of ubiquitous genes involved in stress and antiproliferative responses, and in organelle biogenesis. Interestingly, a module comprising cell cycle genes was significantly induced between non-stimulatory and stimulatory glucose concentrations. Unexpectedly, glucose regulation of gene expression was broadly maintained in islets from old mice. However, glucose induction of mitotic genes was selectively lost in aged islets and was not even restored in the absence of the cell cycle inhibitors p16(INK4a) and p19(ARF), which have been implicated in the restricted proliferative capacity of beta cells with advanced age. CONCLUSIONS/INTERPRETATION: Glucose-dependent transcriptional networks in islets are globally conserved during ageing, with the exception of the ability of stimulatory glucose levels to induce a cell cycle gene module.

[Guidelines of the Spanish Society of Cardiology on requirements and equipment in electrophysiology]. / Guías de práctica clínica de la Sociedad Española de Cardiología sobre requerimientos y equipamiento en electrofisiología.

Due to the enormous qualitative and quantitative evolution that clinical electrophysiology has experienced over the past years, specific Units dedicated to the management of patients with cardiac arrhythmias have been created. In these guidelines, the minimum technical and human needs of an Arrhythmia Unit are discussed.

[Sudden cardiac death out of the hospital and early defibrillation]. / Muerte súbita cardíaca extrahospitalaria y desfibrilación precoz.

Since most sudden cardiac death victims show neither symptoms before the event nor other signs or risk factors that would have identified them as a high risk population before their cardiac arrest, emergency out-of-hospital medical services must be improved in order to obtain a higher survival in these patients. Early defibrillation is an essential part of the chain of survival that also includes the early identification of the victim, activation of the emergency medical system, immediate arrival of trained personnel who can perform basic cardiopulmonary resuscitation and early initiation of advanced cardiac life support that would raise the survival rate for sudden cardiac arrest victims. Many studies have demonstrated the enormous importance of early defibrillation in patients with a cardiac arrest due to ventricular fibrillation. The most important predictor of survival in these individuals is the time that elapses until electric defibrillation, the longer the time to defbrillation the lower the number of patients who are eventually discharged. Multiple studies have demonstrated that automatic external defibrillation will reduce the time elapsed to defibrillation and thus improve survival. For these reason, public access defibrillation to allow the use of automatic external defibrillators by minimally trained members of the lay public, has received increasing interest on the part of a groving number of companies, cities or countries. The automatic external defibrillaton, as performed by a lay person is being investigated. The liberalization of its application, if is demonstrated to be effective, will need to be accompanied by legal measures to endorse it and appropriate health education, probably during secondary education.

Catheter ablation of repetitive monomorphic ventricular tachycardia from left ventricular outflow tract guided by unipolar mapping.

Repetitive monomorphic ventricular tachycardia from the left ventricular outflow tract is an uncommon arrhythmia. Successful catheter ablation has been previously reported in a few cases, but a large number of applications were usually needed when an approach based on either activation mapping or pace mapping was used. In our patient, the selection of the target point for application was based exclusively on unipolar mapping criteria of the ectopic beats, resulting in a short procedure with successful outcome.

Tilt-table testing and syncope.

Syncope is a common clinical problem with multiple potential causes. Recent studies have delineated the natural history and most frequent causes of recurrent syncopal episodes. The medical history and detailed physical examination are particularly important. Clinical electrophysiologic testing has also played a critical role in assessing causes of syncope, but recent reports suggest that its value lies primarily in treating patients with evident underlying structural heart disease. Among patients without structural heart disease, the neurally mediated forms of syncope, particularly the emotional or vasovagal faint, are by far the most common basis for symptoms. In these patients, head-up tilt-table testing has proved particularly valuable in defining the origin of the problem and in assessing therapeutic alternatives. Protocols for upright tilt-table testing remain in evolution. Nonetheless, current practice suggests that 25-minute tilt-test duration is reasonable if pharmacologic provocation is to be used for further evaluation of patients with negative initial findings. However, for those laboratories that do not favor pharmacologic intervention, a 45-minute tilt-test duration is probably essential. Overall, tilt-table testing has proved relatively sensitive and appropriately specific for the identification of patients susceptible to neurally mediated syncopal syndromes.

[Histiocytosis of Langerhans cells: a study of 40 cases]. / Histiocitosis de células de Langerhans: estudio de 40 casos.

Forty cases of histiocytosis of Langerhans' cells (26 children and 14 adults) were evaluated; 20 were localized forms (with single or multiple bone involvement); another 20 were generalized forms, with organic dysfunction (lung, liver, hemopoietic system) in 7 children. This feature has a poor prognostic significance, as shown by the fact that 3 of these 7 patients died. In 3 patients single skin involvement was found, with spontaneous recovery one month after the diagnosis in one; in one case the single involvement was lymphadenopathic, associated to Hodgkin's lymphoma, and in another it was hypothalamic. These cases of single involvement have been followed up between 1 and 4 years. In 4 of 7 patients with generalized disease a reduction of OKT8 with an increased OKT4: OKT8 ratio was found, as reported in other cases from the literature. This finding gives support to an immunological rather than neoplastic basis for the disease. In all 40 cases the diagnosis was morphological, with positive staining for S-100 protein in 38.