Peripheral Insulin Regulates a Broad Network of Gene Expression in Hypothalamus, Hippocampus, and Nucleus Accumbens.

The brain is now recognized as an insulin-sensitive tissue; however, the role of changing insulin concentrations in the peripheral circulation in gene expression in the brain is largely unknown. Here, we performed a hyperinsulinemic-euglycemic clamp on 3-month-old male C57BL/6 mice for 3 h. We show that, in comparison with results in saline-infused controls, increases in peripheral insulin within the physiological range regulate expression of a broad network of genes in the brain. Insulin regulates distinct pathways in the hypothalamus (HTM), hippocampus, and nucleus accumbens. Insulin shows its most robust effect in the HTM and regulates multiple genes involved in neurotransmission, including upregulating expression of multiple subunits of GABA-A receptors, Na+ and K+ channels, and SNARE proteins; differentially modulating glutamate receptors; and suppressing multiple neuropeptides. Insulin also strongly modulates metabolic genes in the HTM, suppressing genes in the glycolysis and pentose phosphate pathways, while increasing expression of genes regulating pyruvate dehydrogenase and long-chain fatty acyl-CoA and cholesterol biosynthesis, thereby rerouting of carbon substrates from glucose metabolism to lipid metabolism required for the biogenesis of membranes for neuronal and glial function and synaptic remodeling. Furthermore, based on the transcriptional signatures, these changes in gene expression involve neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells. Thus, peripheral insulin acutely and potently regulates expression of a broad network of genes involved in neurotransmission and brain metabolism. Dysregulation of these pathways could have dramatic effects in normal physiology and diabetes.

HIPECT4: multicentre, randomized clinical trial to evaluate safety and efficacy of Hyperthermic intra-peritoneal chemotherapy (HIPEC) with Mitomycin C used during surgery for treatment of locally advanced colorectal carcinoma.

BACKGROUND: Local relapse and peritoneal carcinomatosis (PC) for pT4 colon cancer is estimated in 15,6% and 36,7% for 12 months and 36 months from surgical resection respectively, achieving a 5 years overall survival of 6%. There are promising results using prophylactic HIPEC in this group of patients, and it is estimated that up to 26% of all T4 colon cancer could benefit from this treatment with a minimal morbidity. Adjuvant HIPEC is effective to avoid the possibility of peritoneal seeding after surgical resection. Taking into account these results and the cumulative experience in HIPEC use, we will lead a randomized controlled trial to determine the effectiveness and safety of adjuvant treatment with HIPEC vs. standard treatment in patients with colon cancer at high risk of peritoneal recurrence (pT4). METHODS/DESIGN: The aim of this study is to determine the effectiveness and safety of adjuvant HIPEC in preventing the development of PC in patients with colon cancer with a high risk of peritoneal recurrence (cT4). This study will be carried out in 15 Spanish HIPEC centres. Eligible for inclusion are patients who underwent curative resection for cT4NxM0 stage colon cancer. After resection of the primary tumour, 200 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously after the primary resection. Mitomycin C will be used as chemotherapeutic agent, for 60 min at 42-43 °C. Primary endpoint is loco-regional control (LC) in months and the rate of loco-regional control (%LC) at 12 months and 36 months after resection. DISCUSSION: We assumed that adjuvant HIPEC will reduce the expected absolute risk of peritoneal recurrence from 36% to 18% at 36 months for T4 colon-rectal carcinoma. TRIAL REGISTRATION: NCT02614534 ( clinicaltrial.gov ) Nov-2015.

Programación del desfibrilador automático implantable / Programming implantable cardioverter–defibrillators

Los desfibriladores automáticos modernos incluyen entre sus funciones la estimulación antibradicardia, la cardioversión de baja energía y la desfibrilación de alta energía. Tienen, además, criterios adicionales de detección para discriminar en lo posible las arritmias ventriculares de las de origen supraventricular. Son multiprogramables y pueden ser programados para actuar en diferentes zonas de frecuencia de taquicardia, lo que permite tratar de forma diferente cada taquicardia ventricular (TV) que pueda tener un paciente. Esto es particularmente útil en pacientes que presentan TV con ciclos diferentes. La estimulación antitaquicardia disminuye la necesidad de cardioversión o desfibrilación en pacientes con TV. Se han comparado diferentes algoritmos de estimulación con resultados similares. En este capítulo de la monografía se analizan dichos algoritmos y su mejor programación, la necesidad de estimulación antibradicardia y la selección del modo de estimulación, y cómo evitar en lo posible las terapias inapropiadas debidas a arritmias supraventriculares (AU)

Among other functions, modern implantable cardioverter-defibrillators (ICDs) are able to perform antibradycardia pacing, low-energy cardioversion, and highenergy defibrillation. In addition, they can implement a range of different arrhythmia detection criteria that enable them to discriminate, when possible, between ventricular and supraventricular tachycardias. The devices can be programmed in a range of different ways. They can be set to respond differently according to specific tachycardia frequency ranges, thereby enabling each form of tachycardia experienced by the patient to be treated differently. This capability is particularly useful in patients who present with ventricular tachycardias with a number of different cycle lengths. Antitachycardia pacing reduces the need for cardioversion or defibrillation in patients with ventricular tachycardias. Comparison of different pacing algorithms has shown that they give similar results. This part of the monograph contains reviews of the efficacy of these algorithms and how they can be better programmed, of the need for antibradycardia pacing and selection of the most appropriate pacing mode, and of how the administration of inappropriate shocks in response to supraventricular arrhythmias can be avoided (AU)