Renal denervation reduces atrial remodeling in hypertensive rats with metabolic syndrome

Atrial fibrillation (AF) is highly prevalent in hypertensive patients with metabolic syndrome and is related to inflammation and activation of the sympathoadrenergic system. The multi-ligand Receptor-for-Advanced-Glycation-End-products (RAGE) activates inflammation-associated tissue remodeling and is regulated by the sympathetic nervous system. Its counterpart, soluble RAGE (sRAGE), serves as anti-inflammatory decoy receptor with protective properties. We investigated the effect of sympathetic modulation by renal denervation (RDN) on atrial remodeling, RAGE/sRAGE and RAGE ligands in metabolic syndrome. RDN was performed in spontaneously hypertensive obese rats (SHRob) with metabolic syndrome compared with lean spontaneously hypertensive rats (SHR) and with normotensive non-obese control rats. Blood pressure and heart rate were measured by telemetry. The animals were killed 12 weeks after RDN. Left atrial (LA) and right atrial (RA) remodeling was assessed by histological analysis and collagen types. Sympathetic innervation was measured by tyrosine hydroxylase staining of atrial nerve fibers, RAGE/sRAGE, RAGE ligands, cytokine expressions and inflammatory infiltrates were analyzed by Western blot and immunofluorescence staining. LA sympathetic nerve fiber density was higher in SHRob (+44%) versus controls and reduced after RDN (-64% versus SHRob). RAGE was increased (+718%) and sRAGE decreased (− 62%) in SHRob as compared with controls. RDN reduced RAGE expression (− 61% versus SHRob), significantly increased sRAGE levels (+162%) and induced a significant decrease in RAGE ligand levels in SHRob (− 57% CML and − 51% HMGB1) with reduced pro-inflammatory NFkB activation (− 96%), IL-6 production (− 55%) and reduced inflammatory infiltrates. This led to a reduction in atrial fibrosis (− 33%), collagen type I content (− 72%), accompanied by reduced LA myocyte hypertrophy (− 21%). Transfection experiments on H9C2 cardiomyoblasts demonstrated that RAGE is directly involved in fibrosis formation by influencing cellular production of collagen type I. In conclusion, suppression of renal sympathetic nerve activity by RDN prevents atrial remodeling in metabolic syndrome by reducing atrial sympathetic innervation and by modulating RAGE/sRAGE balance and reducing pro-inflammatory and pro-fibrotic RAGE ligands, which provides a potential therapeutic mechanism to reduce the development of AF

A framework to develop adapted treatment regimens to manage pediatric cancer in low- and middle-income countries: The Pediatric Oncology in Developing Countries (PODC) Committee of the International Pediatric Oncology Society (SIOP)

Many children with cancer in low- and middle-income countries are treated in hospitals lacking key infrastructure, including diagnostic capabilities, imaging modalities, treatment components, supportive care, and personnel. Childhood cancer treatment regimens adapted to local conditions provide an opportunity to cure as many children as possible with the available resources, while working to improve services and supportive care. This paper from the Adapted Treatment Regimens Working Group of the Pediatric Oncology in Developing Countries committee of the International Society of Pediatric Oncology outlines the design, development, implementation, and evaluation of adapted regimens and specifies levels of services needed to deliver them.Fil: Howard, Scott C.. University of Tennessee; Estados UnidosFil: Davidson, Alan. University of Cape Town; SudáfricaFil: Luna Fineman, Sandra. University of Colorado; Estados UnidosFil: Israels, Trijn. Vrije Unviversiteit Brussel; BélgicaFil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Universidad de Barcelona; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Lam, Catherine G.. St. Jude Children's Research Hospital; Estados UnidosFil: Hunger, Stephen P.. University of Pennsylvania; Estados UnidosFil: Bailey, Simon. Royal Victoria Infirmary Paediatric Neuro‐Oncology and Paediatric Oncology; Reino UnidoFil: Ribeiro, Raul C.. St. Jude Children's Research Hospital; Estados UnidosFil: Arora, Ramandeep S.. Max Super‐Specialty Hospital. Department of Medical Oncology; IndiaFil: Pedrosa, Francisco. Real Hospital Português Real Oncopediatría; BrasilFil: Harif, Mhamed. Hôpital 20. Department of Hematology ; MarruecosFil: Metzger, Monika L.. St. Jude Children's Research Hospital; Estados Unido

Outcome of children with nodular lymphocyte predominant Hodgkin lymphoma - a children's cancer and leukemia group report

This report describes the clinical outcomes and follow-up records of 42 children with nodular lymphocyte predominant Hodgkin lymphoma (LPHL) treated on United Kingdom Children’s Cancer Study Group (UKCCSG) HD1 (1982–1992) and HD2 protocols (1992–2000). The clinical records of 42 children with LPHL treated between 1982 and 2000 were reviewed retrospectively. All 42 had histology reviewed centrally and confirmed as LPHL by an expert panel. In both trials, only patients with stage IA disease had the option of being treated with either involved field radiation alone or combination chemotherapy consisting of chlorambucil, vinblastine, procarbazine and prednisolone (ChlVPP). Patients with all other stages were treated with ChlVPP chemotherapy. Thirty-five patients (83%) presented with early stage disease (Stages I & II). All 42 patients achieved a complete remission (CR). Six children relapsed after primary therapy. The 5- and 10-year relapse-free survival rates were 87% and 82% respectively. Forty-one are currently alive in CR. In conclusion, children with low-stage LPHL treated between 1982 and 2000 according to the UK strategy for classical Hodgkin lymphoma (HL) had an excellent prognosis. There have been no second malignancies or transformations to B-cell non-Hodgkin lymphoma

Renal Denervation Prevents Atrial Arrhythmogenic Substrate Development in CKD

BACKGROUND: In patients with chronic kidney disease (CKD), atrial fibrillation (AF) is highly prevalent and represents a major risk factor for stroke and death. CKD is associated with atrial proarrhythmic remodeling and activation of the sympathetic nervous system. Whether reduction of the sympathetic nerve activity by renal denervation (RDN) inhibits AF vulnerability in CKD is unknown. METHODS: Left atrial (LA) fibrosis was analyzed in samples from patients with AF and concomitant CKD (estimated glomerular filtration rate [eGFR], <60 mL/min per 1.73 m2) using picrosirius red and compared with AF patients without CKD and patients with sinus rhythm with and without CKD. In a translational approach, male Sprague Dawley rats were fed with 0.25% adenine (AD)-containing chow for 16 weeks to induce CKD. At week 5, AD-fed rats underwent RDN or sham operation (AD). Rats on normal chow served as control. After 16 weeks, cardiac function and AF susceptibility were assessed by echocardiography, radiotelemetry, electrophysiological mapping, and burst stimulation, respectively. LA tissue was histologically analyzed for sympathetic innervation using tyrosine hydroxylase staining, and LA fibrosis was determined using picrosirius red. RESULTS: Sirius red staining demonstrated significantly increased LA fibrosis in patients with AF+CKD compared with AF without CKD or sinus rhythm. In rats, AD demonstrated LA structural changes with enhanced sympathetic innervation compared with control. In AD, LA enlargement was associated with prolonged duration of induced AF episodes, impaired LA conduction latency, and increased absolute conduction inhomogeneity. RDN treatment improved LA remodeling and reduced LA diameter compared with sham-operated AD. Furthermore, RDN decreased AF susceptibility and ameliorated LA conduction latency and absolute conduction inhomogeneity, independent of blood pressure reduction and renal function. CONCLUSIONS: In an experimental rat model of CKD, RDN inhibited progression of atrial structural and electrophysiological remodeling. Therefore, RDN represents a potential therapeutic tool to reduce the risk of AF in CKD, independent of changes in renal function and blood pressure