RESUMEN
BACKGROUND: Evidence suggests that autism and schizophrenia share similarities in genetic, neuropsychological and behavioural aspects. Although both disorders are associated with theory of mind (ToM) impairments, a few studies have directly compared ToM between autism patients and schizophrenia patients. This study aimed to investigate to what extent high-functioning autism patients and schizophrenia patients share and differ in ToM performance. METHODS: Thirty high-functioning autism patients, 30 schizophrenia patients and 30 healthy individuals were recruited. Participants were matched in age, gender and estimated intelligence quotient. The verbal-based Faux Pas Task and the visual-based Yoni Task were utilised to examine first- and higher-order, affective and cognitive ToM. The task/item difficulty of two paradigms was examined using mixed model analyses of variance (ANOVAs). Multiple ANOVAs and mixed model ANOVAs were used to examine group differences in ToM. RESULTS: The Faux Pas Task was more difficult than the Yoni Task. High-functioning autism patients showed more severely impaired verbal-based ToM in the Faux Pas Task, but shared similar visual-based ToM impairments in the Yoni Task with schizophrenia patients. CONCLUSIONS: The findings that individuals with high-functioning autism shared similar but more severe impairments in verbal ToM than individuals with schizophrenia support the autism-schizophrenia continuum. The finding that verbal-based but not visual-based ToM was more impaired in high-functioning autism patients than schizophrenia patients could be attributable to the varied task/item difficulty between the two paradigms.
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Trastorno Autístico/psicología , Psicología del Esquizofrénico , Teoría de la Mente , Adulto , Estudios de Casos y Controles , Femenino , Hong Kong , Hospitales Psiquiátricos , Humanos , Pruebas de Inteligencia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pruebas Neuropsicológicas , Análisis y Desempeño de TareasRESUMEN
BACKGROUND: The sympathetic nervous system regulates energy metabolism via ß-adrenoreceptors. Therapeutic exploitation of previous ß2-adrenegic agonists for metabolic benefits has been hindered by cross stimulation of cardiac ß1-adrenoceptor, causing tachycardia. Formoterol is a novel highly ß2-selective adrenergic agonist and holds promise as a ß2-agonist that could impart selective beneficial metabolic effects. OBJECTIVE: To investigate the metabolic effects of formoterol on energy and substrate metabolism. PARTICIPANTS: Healthy volunteers. DESIGN: (1) Dose-finding study, step-wise incremental design of weekly administration of 80, 160 and 320 µg daily of formoterol in four subjects and, (2) metabolic study, an open-label metabolic evaluation of 1-week treatment in eight men using a dose determined from (1). MAIN OUTCOME: Resting energy expenditure (EE), diet-induced thermogenesis (DIT) and fat oxidation (Fox) using indirect calorimetry, heart rate and plasma non-esterified fatty acid (NEFA) levels. RESULTS: In the dose-finding study, all three doses increased resting EE and Fox with the 320 µg dose significantly increasing heart rate. In the metabolic study, the selected 160 µg daily dose increased resting EE by 13 ± 2% (P<0.001) and Fox by 23 ± 4% (P<0.01), but not DIT. Plasma NEFA levels rose by 16 ± 2% (P<0.01). Heart rate did not change significantly. Out of the eight subjects, six reported tremor and palpitation, two lost appetite and one suffered from insomnia. CONCLUSIONS: At a dose of 160 µg per day, formoterol increases resting EE and fat utilization without inducing tachycardia. From this first metabolic evaluation in humans, we conclude that formoterol imparts beneficial metabolic changes that may be exploited for therapy of obesity.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Metabolismo Energético/efectos de los fármacos , Etanolaminas/administración & dosificación , Etanolaminas/farmacología , Termogénesis/efectos de los fármacos , Adulto , Calorimetría Indirecta , Dieta , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Ácidos Grasos no Esterificados/metabolismo , Fumarato de Formoterol , Frecuencia Cardíaca , Humanos , Masculino , Oxidación-Reducción , Resultado del TratamientoRESUMEN
OBJECTIVE: Ageing is associated with frailty and decreased anabolic hormones, insulin-like growth factor-I (IGF-I) and testosterone. We hypothesized that components of the IGF-I system, in conjunction with testosterone, modulate frailty risk in the elderly. We examined associations between IGF-I, its binding proteins IGFBP1 and IGFBP3 and testosterone with frailty in men. DESIGN: Observational study of 3 447 community-dwelling men aged 70-89 years assessed in 2001-04, with 1 654 reassessed in 2008-09. METHODS: Baseline total IGF-I, IGFBP1, IGFBP3 and testosterone were assayed. Frailty was assessed using the FRAIL scale, comprising 5 domains: fatigue; difficulty climbing stairs; difficulty walking >100 m; >5 illnesses; weight loss >5%. Men with ≥ 3 domains were considered frail. RESULTS: At baseline, 527 men (15·3%) were frail. Frail men had lower IGFBP3 (3 630 ng/ml vs not frail: 3 800 ng/ml, P < 0·001) and comparable IGFBP1 (23·5 vs 21·5 ng/ml, P = 0·09). In multivariate analyses, higher IGFBP1 was associated with increased prevalence of frailty (highest vs lowest quartile Q4:Q1, adjusted odds ratio [OR] = 1·39, 95% CI = 1·03-1·88). New-onset frailty arose in 260 (17·5%) of 1 484 men. Lower baseline IGF-I predicted new-onset frailty (Q1:Q4 OR = 1·48, 95% CI = 1·00-2·20) as did higher IGFBP1 (Q4:Q1 OR = 1·59, 95% CI = 1·01-2·50). Men with both IGF-I and free testosterone in Q1 had greater odds of prevalent frailty (OR = 2·13, 95% CI = 1·54-2·95). CONCLUSIONS: Older men with higher IGFBP1 level, or both lower IGF-I and testosterone, are more likely to be frail, while those with lower IGF-I and higher IGFBP1 are more likely to become frail. Components of the IGF-I system may be biomarkers or independent predictors of frailty.
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Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Testosterona/sangre , Anciano , Anciano de 80 o más Años , Anciano Frágil , Humanos , MasculinoRESUMEN
BACKGROUND: Sympathetic activation is an important metabolic adaptation limiting weight gain. Propensity of weight gain associated with ß-blocker therapy in the obese modern population is unknown. OBJECTIVE: To determine whether chronic ß-blocker therapy reduces energy expenditure (EE) and increases body weight. METHODS: We undertook (i) a mechanistic study comparing EE, diet-induced thermogenesis and habitual activity between healthy volunteers (n=11) with uncomplicated hypertension treated with a ß-blocker and anthropometrically matched controls (n=19) and (ii) three cross-sectional studies comparing body weight, body mass index (BMI) and waist circumference between ß-blocker treated and untreated patients from ambulatory patients attending (a) diabetes outpatient clinic (n=214), (b) hypertension outpatient (n=84) and (c) participants in a multi-centre type 2 diabetes trial (ADVANCE) (n=11140). RESULTS: Among weight-matched ß-blocker users, diet-induced thermogenesis, fat oxidation rate and weekly habitual activity were lower by 50% (P<0.01), 32% (P=0.04) and 30% (P<0.01), respectively, compared with controls. In ß-blocker treated patients, the adjusted mean body weight was 9.2 ± 1.2 kg (P=0.0002) higher among those attending the diabetes clinic, 17.2 ± 3.2 kg (P=0.004) higher among those attending the hypertension clinic and 5.2 ± 0.7 kg (P=0.0003) higher at baseline among participants in the ADVANCE trial compared with patients not treated with ß-blockers. BMI displayed a similar difference. CONCLUSIONS: EE is reduced and body weight increased in chronic ß-blocker users. We hypothesise that chronic ß-blockade causes obesity by blunting EE.
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Adiposidad/efectos de los fármacos , Antagonistas Adrenérgicos beta/efectos adversos , Antihipertensivos/efectos adversos , Peso Corporal/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Obesidad/inducido químicamente , Absorciometría de Fotón , Antagonistas Adrenérgicos beta/administración & dosificación , Anciano , Antihipertensivos/administración & dosificación , Australia/epidemiología , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Persona de Mediana Edad , Obesidad/epidemiología , Obesidad/metabolismo , Estudios Prospectivos , Encuestas y Cuestionarios , Termogénesis/efectos de los fármacos , Circunferencia de la CinturaRESUMEN
To determine whether peer-reviewed consensus statements have changed clinical practice, we surveyed acromegaly care in specialist centers across the globe, and determined the degree of adherence to published consensus guidelines on acromegaly management. Sixty-five acromegaly experts who participated in the 7th Acromegaly Consensus Workshop in March 2009 responded. Results indicated that the most common referring sources for acromegaly patients were other endocrinologists (in 26% of centers), neurosurgeons (25%) and primary care physicians (21%). In sixty-nine percent of patients, biochemical diagnoses were made by evaluating results of a combination of growth hormone (GH) nadir/basal GH and elevated insulin like growth factor-I (IGF-I) levels. In both Europe and the USA, neurosurgery was the treatment of choice for GH-secreting microadenomas and for macroadenomas with compromised visual function. The most widely used criteria for neurosurgical outcome assessment were combined measurements of IGF-I and GH levels after oral glucose tolerance test (OGTT) 3 months after surgery. Ninety-eight percent of respondents stated that primary treatment with somatostatin receptor ligands (SRLs) was indicated at least sometime during the management of acromegaly patients. In nearly all centers (96%), the use of pegvisomant monotherapy was restricted to patients who had failed to achieve biochemical control with SRL therapy. The observation that most centers followed consensus statement recommendations encourages the future utility of these workshops aimed to create uniform management standards for acromegaly.
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Acromegalia/terapia , Endocrinología/métodos , Endocrinología/tendencias , Práctica Profesional/tendencias , Acromegalia/epidemiología , Australia/epidemiología , Brasil/epidemiología , Canadá/epidemiología , China/epidemiología , Recolección de Datos , Europa (Continente)/epidemiología , Humanos , Internacionalidad , Neurocirugia/métodos , Neurocirugia/estadística & datos numéricos , Nueva Zelanda/epidemiología , Médicos de Atención Primaria , Periodo Posoperatorio , Práctica Profesional/estadística & datos numéricos , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
Paradigms for managing acromegaly have undergone major changes in the past two decades. This has been brought about by combining surgical, pharmacological and radiotherapeutic approaches that provide tight biochemical control to reduce mortality to that of the general population. The biochemical targets for treatment are a growth hormone of <2.5 ng/mL (approximately 7.5 mU/L) and a normal, age-adjusted insulin-like growth factor-1. Until 20 years ago, dopamine agonists were the only class of pharmaceutical agents available to control acromegaly. They have a limited adjunctive role, even with the development of second-generation selective agonists such as cabergoline. Surgery and radiotherapy were the mainstay of acromegaly management before the advent of the effective pharmacological therapies of the modern era: somatostatin analogues and pegvisomant, a growth hormone receptor antagonist. Somatostatin analogues achieve biochemical control in approximately 60% of patients. Pegvisomant, which is available in the USA and Europe and has just been registered in Australia, normalizes insulin-like growth factor-1 in nearly all patients but has no effect on tumour mass. Surgery is an appropriate first-line therapy for microadenomas as the chance of success is high. For large and/or invasive tumours where the prospect of surgical cure is remote, first-line therapy is somatostatin analogue treatment with debulking surgery having an adjunctive role to achieve tight control or to alleviate compression of the optic chiasm. Although acromegaly remains a challenging disease to manage, the expanding range of therapeutic options is likely to result in a better outcome for patients and offers the potential to tailor therapy based on a patient's individual requirements.
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Acromegalia/terapia , Adenoma/cirugía , Antineoplásicos Hormonales/uso terapéutico , Neoplasias Hipofisarias/cirugía , Acromegalia/sangre , Acromegalia/etiología , Adenoma/complicaciones , Agonistas de Dopamina/uso terapéutico , Hormona del Crecimiento/sangre , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Octreótido/uso terapéutico , Péptidos Cíclicos/uso terapéutico , Neoplasias Hipofisarias/complicaciones , Radioterapia , Receptores de Somatotropina/antagonistas & inhibidores , Somatostatina/análogos & derivados , Somatostatina/uso terapéuticoRESUMEN
To investigate whether oestrogen modulates GH secretion and action in adult life, we studied the impact of oestrogen replacement on circulating GH and IGF-I levels in post-menopausal women. Since the liver is the major source of circulating IGF-I and the oral route of oestrogen delivery causes non-physiologic effects on hepatic proteins, we compared the effects of oral and transdermal route of delivery. Oral ethinyl oestradiol administration resulted in a significant fall in mean IGF-I levels and a 3-fold increase in mean 24h GH. Transdermal administration of 17beta oestradiol resulted in a slight increase in serum IGF-I but no change in mean 24h GH levels. To determine whether differences in oestrogen type rather than in the route of delivery caused the different effects on the GH/IGF-I axis, we compared the effects of three oral oestrogen formulations. Ethinyl oestradiol, conjugated equine oestrogen and oestradiol valerate each induced a fall in IGF-I and a rise of mean 24h GH levels in post-menopausal women. To determine the metabolic significance of oestrogen-induced changes on GH/ IGF-I, we compared the effects of 24 weeks each of oral and transdermal oestrogen on energy metabolism and body composition in 18 post menopausal women in an open-label randomised cross-over study. When compared to the transdermal route, oral oestrogen reduced lipid oxidation, increased fat mass and reduced lean body mass. Oestrogen causes distinct, route dependent effects on the somatotrophic axis. The dissociation of the GH/IGF-I axis by the oral route is likely to arise from impaired hepatic IGF-I production which causes increased GH secretion through reduced feedback inhibition. The route of oestrogen therapy confers divergent effects on substrate oxidation and body composition. The suppression of lipid oxidation during oral oestrogen therapy may increase fat mass while the fall in IGF-I may lead to a loss of lean body mass. The route dependent changes in body composition observed during oestrogen replacement therapy may have important implications for post-menopausal health and oestrogen use in general.
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Terapia de Reemplazo de Estrógeno , Estrógenos/administración & dosificación , Hormona de Crecimiento Humana/metabolismo , Glucemia/metabolismo , Composición Corporal/efectos de los fármacos , Huesos/efectos de los fármacos , Femenino , Hormona de Crecimiento Humana/fisiología , Humanos , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , PosmenopausiaRESUMEN
Oral estrogen administration attenuates the metabolic action of growth hormone (GH) in humans. To investigate the mechanism involved, we studied the effects of estrogen on GH signaling through Janus kinase (JAK)2 and the signal transducers and activators of transcription (STATs) in HEK293 cells stably expressing the GH receptor (293GHR), HuH7 (hepatoma) and T-47D (breast cancer) cells. 293GHR cells were transiently transfected with an estrogen receptor-alpha expression plasmid and luciferase reporters with binding elements for STAT3 and STAT5 or the beta-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17beta-estradiol (E(2)) resulted in a dose-dependent reduction in the response of all three reporters to GH to a maximum of 49-66% of control at 100 nM (P < 0.05). No reduction was seen when E(2) was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E(2) suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression. Next, we investigated the role of the suppressors of cytokine signaling (SOCS) in E(2) inhibition. E(2) increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E(2) was absent in cells lacking SOCS-2 but not in those lacking SOCS-1 and SOCS-3. In conclusion, estrogen inhibits GH signaling, an action mediated by SOCS-2. This paper provides evidence for regulatory interaction between a sex steroid and the GHJAKSTAT pathway, in which SOCS-2 plays a central mechanistic role.