RESUMEN
Obesity is the pandemic of the 21st century. Obesity comorbidities, including hypertension, dyslipidaemia and glucose intolerance define metabolic syndrome, which increases mortality risk and decreases the quality of life. Compared with lifestyles (diet and physical activity) and pharmacological interventions, bariatric surgery is by far the most effective treatment for obesity and its comorbidities. This minimally invasive surgical treatment is based on an increase of satiety (by hormonal regulation and decreasing stomach volume) or a decrease in nutrient retention (gastric and/or intestinal resection). Bariatric surgery has widely demonstrated a beneficial effect on excess body weight loss, cardiovascular risk, dyslipidaemia, non-alcoholic fatty liver disease or glucose homeostasis, among other obesity-related metabolic diseases. This review describes current efforts for the implementation of bariatric surgery in metabolic syndrome, which are mainly focused on the formulation of key definition criteria for targeting the most suitable population for this therapeutic approach. Patients should undergo appropriate nutritional and psychological follow up in order to achieve and maintain weight loss milestones and a healthy metabolic status.
Asunto(s)
Cirugía Bariátrica , Síndrome Metabólico/cirugía , Obesidad/cirugía , Adolescente , Cuidados Posteriores , Cirugía Bariátrica/efectos adversos , Cirugía Bariátrica/métodos , Endoscopía Gastrointestinal , Humanos , Síndrome Metabólico/etiología , Obesidad/complicacionesRESUMEN
BACKGROUND: Maternal obesity increases offspring propensity to metabolic dysfunctions and to non-alcoholic fatty liver disease (NAFLD), which may lead to cirrhosis or liver cancer. The circadian clock is a transcriptional/epigenetic molecular machinery synchronising physiological processes to coordinate energy utilisation within a 24-h light/dark period. Alterations in rhythmicity have profound effects on metabolic pathways, which we sought to investigate in offspring with programmed NAFLD. METHODS: Mice were fed a standard or an obesogenic diet (OD), before and throughout pregnancy, and during lactation. Offspring were weaned onto standard or an OD at 3 weeks postpartum and housed in 12:12 light/dark conditions. Biochemical and histological indicators of NAFLD and fibrosis, analysis of canonical clock genes with methylation status and locomotor activity were investigated at 6 months. RESULTS: We show that maternal obesity interacts with an obesogenic post-weaning diet to promote the development of NAFLD with disruption of canonical metabolic rhythmicity gene expression in the liver. We demonstrate hypermethylation of BMAL-1 (brain and muscle Arnt like-1) and Per2 promoter regions and altered 24-h rhythmicity of hepatic pro-inflammatory and fibrogenic mediators. CONCLUSIONS: These data implicate disordered circadian rhythms in NAFLD and suggest that disruption of this system during critical developmental periods may be responsible for the onset of chronic liver disease in adulthood.
Asunto(s)
Factores de Transcripción ARNTL/metabolismo , Ritmo Circadiano , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Animales , Animales Recién Nacidos , Metilación de ADN , Modelos Animales de Enfermedad , Femenino , Lactancia , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/patología , Proteínas Circadianas Period/metabolismo , EmbarazoRESUMEN
BACKGROUND AND AIMS: Hepatic stellate cells (HSC) are activated by liver injury to become proliferative fibrogenic myofibroblasts. This process may be regulated by the sympathetic nervous system (SNS) but the mechanisms involved are unclear. METHODS: We studied cultured HSC and intact mice with liver injury to test the hypothesis that HSC respond to and produce SNS neurotransmitters to promote fibrogenesis. RESULTS: HSC expressed adrenoceptors, catecholamine biosynthetic enzymes, released norepinephrine (NE), and were growth inhibited by alpha- and beta-adrenoceptor antagonists. HSC from dopamine beta-hydroxylase deficient (Dbh(-/-)) mice, which cannot make NE, grew poorly in culture and were rescued by NE. Inhibitor studies demonstrated that this effect was mediated via G protein coupled adrenoceptors, mitogen activated kinases, and phosphatidylinositol 3-kinase. Injury related fibrogenic responses were inhibited in Dbh(-/-) mice, as evidenced by reduced hepatic accumulation of alpha-smooth muscle actin(+ve) HSC and decreased induction of transforming growth factor beta1 (TGF-beta1) and collagen. Treatment with isoprenaline rescued HSC activation. HSC were also reduced in leptin deficient ob/ob mice which have reduced NE levels and are resistant to hepatic fibrosis. Treating ob/ob mice with NE induced HSC proliferation, upregulated hepatic TGF-beta1 and collagen, and increased liver fibrosis. CONCLUSIONS: HSC are hepatic neuroglia that produce and respond to SNS neurotransmitters to promote hepatic fibrosis.
Asunto(s)
Cirrosis Hepática/fisiopatología , Neurotransmisores/fisiología , Sistema Nervioso Simpático/fisiopatología , Animales , Apoptosis , Comunicación Autocrina , Catecolaminas/biosíntesis , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Proteínas de Unión al GTP/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Norepinefrina/metabolismo , Norepinefrina/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos/metabolismoRESUMEN
BACKGROUND: Helicobacter pylori (HP) testing in young patients with uncomplicated dyspepsia has been recommended. A test and treat strategy for dyspeptics positive for HP is recommended by the European H. pylori Study Group and the American Gastroenterology Association. OBJECTIVES: To assess the rates of re-referral for upper GI endoscopy (OGD) and outpatient (OPD) attendance in uncomplicated dyspeptic patients following assessment of HP status. METHODS: 190 patients under 50 years of age with uncomplicated dyspepsia (without alarm symptoms) referred from general practitioners (GPs) to the gastroenterology department underwent HP urea breath test (UBT). GPs were informed of the results of UBT and recommended eradication therapy if positive, and if negative advised symptomatic treatment with an acid suppressant with/without a prokinetic. The patients were analysed for subsequent attendance at OGD or OPD in the following two years. RESULTS: HP was present in 93 of 190 patients. Twenty of 190 (10.5%) patients subsequently were re-referred and underwent OGD for continuing dyspeptic symptoms; a further 6 were seen in OPD but not endoscoped as they have been judged to have uncomplicated gastro-oesophageal reflux disease. At time of OGD all patients were negative on Campylobacter-like organism (CLO) test for HP. Findings at OGD were normal (9), hiatus hernia (6), gastritis (4) and duodenitis (1). No case of peptic ulcer disease or gastric cancer has been identified. CONCLUSIONS: In this group of dyspeptic patients, adopting a test and treat policy after initial analysis of HP resulted in 10.5% being re-referred for subsequent OGD; findings in those endoscoped were normal or minimal. A test and treat strategy for H. pylori in uncomplicated dyspeptics therefore saves endoscopies and outpatient consultations without missing significant underlying pathology.
Asunto(s)
Dispepsia/microbiología , Esofagoscopía , Infecciones por Helicobacter/diagnóstico , Adolescente , Adulto , Pruebas Respiratorias , Dispepsia/etiología , Femenino , Política de Salud , Helicobacter pylori/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Derivación y Consulta/estadística & datos numéricos , Estudios RetrospectivosRESUMEN
IL-2 release from mouse splenocytes was measured by assaying the IL-2 on an IL-2-dependent cytotoxic T-lymphocyte line in culture (CTLL). Proliferation of the CTLL cells was monitored indirectly with the dye thiazolyl blue. The slow-acting anti-rheumatic drug auranofin at concentrations below 0.1 microM potentiated concanavalin A (Con A)-induced IL-2 release. Similar potentiation of Con A-induced IL-2 release was obtained with D-penicillamine, 1 microM-1 mM, and with the angiotensin-converting enzyme-inhibitor captopril, 10 nM-1 microM. Potentiation of Con A-induced IL-2 release was obtained with concentrations of the drugs likely to be achieved in vivo during therapy. Auranofin but not D-penicillamine and captopril inhibited Con A-induced IL-2 release at high concentrations (greater than 0.3 microM).
Asunto(s)
Auranofina/farmacología , Captopril/farmacología , Interleucina-2/biosíntesis , Penicilamina/farmacología , Animales , Células Cultivadas , Ratones , Bazo/citología , Bazo/efectos de los fármacosRESUMEN
Auranofin (AF), D-penicillamine (D-pen) and thiola are prescribed as disease-modifying drugs in the treatment of rheumatoid arthritis (RA). We have shown here that auranofin, 10(-8) to 10(-6) M, D-penicillamine, 10(-6) to 10(-3) M, thiola, 10(-7) to 10(-3) M, and the tripeptide thiol, glutathione, 10(-6) to 10(-3) M, enhanced f-met-leu-phe-induced lysosomal enzyme release and the phagocytic uptake of bacteria by up to 40%. The previously reported inhibitory effects of AF were only observed at concentrations in excess of those likely to be available to effector cells in vivo. The stimulatory effects of thiola and D-pen occurred at concentrations likely to be available to effector cells in vivo and, therefore, may be of greater clinical relevance. There is evidence that the drugs used in this study exert their effects via a thiol moiety and their therapeutic effect is preceded by an elevation of intracellular thiol levels.
Asunto(s)
Antiinflamatorios/farmacología , Neutrófilos/efectos de los fármacos , Auranofina/farmacología , Fluoresceína-5-Isotiocianato , Fluoresceínas , Glucuronidasa/metabolismo , Humanos , Técnicas In Vitro , L-Lactato Deshidrogenasa/metabolismo , Micrococcus/inmunología , Muramidasa/metabolismo , Neutrófilos/inmunología , Penicilamina/farmacología , Fagocitosis , Tiocianatos , Tiopronina/farmacologíaRESUMEN
In general the in vitro assays of phagocytosis rely on microscope counting or radioisotopic detection of ingested particles or microbiological counting of non-ingested bacteria. A very simple, rapid, highly quantitative method using fluorescein-labelled bacteria was described by Vray et al. (Scand. J. Immunol. (1980) 11, 147) for non-human phagocytes. We report here a modification of this method to increase its sensitivity, to make it more suitable for pharmacological studies. We also provide detailed experimental parameters for its use with human phagocytes. A suspension of fluorescein-labelled bacteria is incubated with human phagocytes; after incubation at 37 degrees C, the reaction is terminated with ice-cold Tyrode buffer solution, and the non-ingested bacteria are removed by lysis with lysozyme and the resultant cell suspension treated with the detergent TX-100. The fluorescence of the suspension is then measured. The modified method is sufficiently sensitive to permit the detection of bi-directional effects on phagocytosis of a known modulator of human phagocyte function.