Insights into the molecular function of the inactivating mutations of B-Raf involving the DFG motif.

BRAF gene mutations have been associated with human cancers. Among the naturally occurring mutations, two that involve amino acids of the conserved DFG motif in the activation loop (D594V and G596R), appear to be inactivating. Aim of this study was to analyze the molecular mechanisms involved in the loss of function of B-Raf inactivating mutation G596R.

Recent advances in adrenal autoimmunity.

Autoimmune Addison's disease (AAD) results from the immune-mediated destruction of adrenocortical cells. AAD is a major component of the autoimmune polyendocrine syndromes type 1 (APS 1) and type 2. The adrenal autoimmune process is made evident by the apperance of circulating autoantibodies against the steroidogenic enzyme 21-hydroxylase.

Portal vein glucose sensors do not play a major role in modulating physiological responses to insulin-induced hypoglycemia in humans.

Objective: Experimental data from animal studies indicate that portal vein glucose sensors play a key role in the responses to slow-fall hypoglycemia. However, their role in modulating these responses in humans is not well understood. The aim of the present study was to examine in humans the potential role of portal vein glucose sensors in physiological responses to insulin-induced hypoglycemia mimicking the slow fall of insulin-treated diabetic subjects.

Effect of oral amino acids on counterregulatory responses and cognitive function during insulin-induced hypoglycemia in nondiabetic and type 1 diabetic people.

Objective: Amino acids stimulate glucagon responses to hypoglycemia and may be utilized by the brain. The aim of this study was to assess the responses to hypoglycemia in nondiabetic and type 1 diabetic subjects after ingestion of an amino acid mixture.

Research Design And Methods: Ten nondiabetic and 10 diabetic type 1 subjects were studied on three different occasions during intravenous insulin (2 mU .

Identification of differentially expressed proteins in papillary thyroid carcinomas with V600E mutation of BRAF.

BRAF, a serine/threonine kinase of the RAF family, is a downstream transducer of the RAS-regulated MAPK pathway. V600E mutation of BRAF protein is the most common genetic alteration occurring in papillary thyroid carcinomas and is prognostic of poor clinicopathological outcomes. Protein expression in the subclass of PTC bearing the BRAF(V600E) mutation was investigated by using 2-DE and MS/MS techniques and compared to that of matched normal thyroid tissues from seven patients.

Mapping of human autoantibody epitopes on aromatic L-amino acid decarboxylase.

Context: Aromatic l-amino acid decarboxylase (AADC) is target of autoantibodies in autoimmune polyendocrine syndrome I (APS I), especially in patients with autoimmune hepatitis. Little information is currently available on AADC autoantibody epitopes and on the interrelation between autoantibody-mediated inhibition of enzymatic activity and epitope specificity.

Design: We tested the immunoreactivity of full-length porcine AADC and of eight fragments of the enzyme with human serum from 18 patients with APS I, 199 with non-APS I autoimmune Addison's disease, 124 with type 1 diabetes mellitus, 36 with Graves' disease, and 141 healthy control subjects, and we evaluated the autoantibody-mediated enzymatic inhibition.

Exercise and diabetes.

Physical activity activates has acute and chronic effects on glucose, lipid and protein metabolism. In type 1 diabetic subjects, the lack of the physiological inhibition of insulin secretion during exercise results in a potential risk of hypoglycemia. On the other hand, exercise-induced activation of counterregulatory hormones might trigger an acute metabolic derangement in severe insulin-deficient subjects.

Genotyping of an Italian papillary thyroid carcinoma cohort revealed high prevalence of BRAF mutations, absence of RAS mutations and allowed the detection of a new mutation of BRAF oncoprotein (BRAF(V599lns)).

Objectives: The genes RET and RAS, and more recently BRAF, have been shown to be frequently mutated in human papillary thyroid carcinomas (PTC). The aim of this study was to genotype for these mutations a cohort of thyroid tumours collected at our institutions.

Design And Patients: Thyroid tumours removed from 51 subjects were analysed, including 43 PTC and 8 non-PTC tumours [3 follicular adenomas (FA), 4 follicular carcinomas (FTC) and 1 anaplastic carcinoma (AC)].

Metabolic and endocrine effects of physiological increments in plasma ghrelin concentrations.

Background: Growing evidence indicates that the administration of large amounts of ghrelin to humans increases circulating concentrations of several pituitary and adrenal hormones, induces hyperglycemia and reduces serum insulin concentrations. At present, it is not known whether physiological increments in plasma ghrelin concentrations affect glucose kinetics or hormone concentrations in humans.

Methods And Results: We compared the effects of two- and three-fold increments in plasma ghrelin concentrations in eight healthy subjects during a 2 h intravenous infusion of 7.

Make your diabetic patients walk: long-term impact of different amounts of physical activity on type 2 diabetes.

Objective: To establish the impact of different amounts of increased energy expenditure on type 2 diabetes care.

Research Design And Methods: Post hoc analysis of long-term effects of different amounts of increased energy expenditure (metabolic equivalents [METS] per hour per week) through voluntary aerobic physical activity was performed in 179 type 2 diabetic subjects (age 62 +/- 1 years [mean +/- SE]) randomized to a physical activity counseling intervention. Subjects were followed for 2 years and divided into six groups based on their increments in METs per hour per week: group 0 (no activity, n = 28), group 1-10 (6.

Elevated serum interferon-gamma-inducible chemokine-10/CXC chemokine ligand-10 in autoimmune primary adrenal insufficiency and in vitro expression in human adrenal cells primary cultures after stimulation with proinflammatory cytokines.

Chemokines are a large family of cytokines involved in the pathogenesis of inflammatory and autoimmune diseases. Among CXC chemokines, CXC chemokine ligand 10 (CXCL10) has been identified to play an important role in several endocrinological autoimmune diseases, such as Hashimoto's thyroiditis, Graves' disease, and type 1 diabetes mellitus. Although the mechanisms leading to glandular autoimmune process may be at least in part shared by different endocrine organs, the role of CXCL10 in autoimmune adrenal insufficiency is unknown.

BRAF(V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas.

Activating mutations of BRAF have been identified in a variety of human cancers, most notably melanomas and papillary thyroid carcinomas (PTCs). The aim of the present study was to disclose the role of BRAF mutations in thyroid carcinoma development. Seventy-two thyroid tumors, including 60 PTCs, six follicular adenomas, five follicular carcinomas, and one anaplastic carcinoma, were studied.

Italian addison network study: update of diagnostic criteria for the etiological classification of primary adrenal insufficiency.

Primary adrenal insufficiency (PAI) is clinically evident in one in 8000 individuals. A correct etiological classification is critical for correct disease management. To update the diagnostic criteria for the etiological classification of PAI, a multicentric network was established in Italy, and 222 patients with PAI were studied.

Insulin is required for prandial ghrelin suppression in humans.

Accumulating evidence indicates that ghrelin plays a role in regulating food intake and energy homeostasis. In normal subjects, circulating ghrelin concentrations decrease after meal ingestion and increase progressively before meals. At present, it is not clear whether nutrients suppress the plasma ghrelin concentration directly or indirectly by stimulating insulin secretion.

Ret/PTC activation does not influence clinical and pathological features of adult papillary thyroid carcinomas.

Objective: RET proto-oncogene rearrangements (ret/PTCs) represent the most common genetic alterations found in papillary thyroid carcinomas (PTCs). Correlation of ret/PTC expression with clinical outcome is controversial. The aim of the present study was to analyze the frequency of RET rearrangements in adult PTCs, and to investigate if ret/PTCs influence biological behavior and clinical features of the cancers.

Validation of a counseling strategy to promote the adoption and the maintenance of physical activity by type 2 diabetic subjects.

Objective: There is enough evidence that physical activity is an effective therapeutic tool in the management of type 2 diabetes. The present study was designed to validate a counseling strategy that could be used by physicians in their daily outpatient practice to promote the adoption and maintenance of physical activity by type 2 diabetic subjects.

Research Design And Methods: The long-term (2-year) efficacy of the behavioral approach (n = 182) was compared with usual care treatment (n = 158) in two matched, randomized groups of patients with type 2 diabetes who had been referred to our Outpatient Diabetes Center.

Dehydroepiandrosterone, 17alpha-hydroxyprogesterone and aldosterone responses to the low-dose (1 micro g) ACTH test in subjects with preclinical adrenal autoimmunity.

Objective: The appearance of 21-hydroxylase autoantibodies (21OHAbs) identifies subjects with preclinical adrenal insufficiency. In 21OHAb-positive subjects, the adrenocortical function is best evaluated by peak cortisol (F) levels after the low-dose (1 micro g) ACTH stimulation test (LDT). No information is currently available on the correlation between F and other adrenocortical hormone responses to the LDT in subjects with an ongoing autoimmune adrenal process.

Ghrelin is not necessary for adequate hormonal counterregulation of insulin-induced hypoglycemia.

Ghrelin is a novel enteric hormone that stimulates growth hormone (GH), ACTH, and epinephrine; augments plasma glucose; and increases food intake by inducing the feeling of hunger. These characteristics make ghrelin a potential counterregulatory hormone. At present, it is not known whether ghrelin increases in response to insulin-induced hypoglycemia.

[Prevalence of the neuroendocrine phenotype in thymus neoplasms].

To determine the prevalence of neuroendocrine differentiation in human thymic neoplasms, which are unusual tumours that may range from well-differentiated to overtly malignant, poorly differentiated lesions, an immunohistochemical study was conducted in 23 thymic neoplasms re-classified on the basis of the new 1999 WHO classification. Immunohistochemical evidence of neuroendocrine differentiation in the form of reactivity to the markers synaptophysin, neuron-specific enolase and chromogranin A was found in 6 of 23 tissues (26%). Two of 3 patients with thymic carcinoids (or well-differentiated thymic neuroendocrine carcinoma) were affected by multiple endocrine neoplasia type 1 (MEN-1).

Steroid-cell autoantibodies are preferentially expressed in women with premature ovarian failure who have adrenal autoimmunity.

Objective: To determine the prevalence of steroid-cell autoantibodies, 3beta-hydroxysteroid dehydrogenase (3beta-HSD) antibodies, 17alpha-hydroxylase (17alpha-OH) antibodies, and P450 side-chain cleavage antibodies in premature ovarian failure.

Design: Cross-sectional, observational study.

Setting: Academic research hospitals.

Short-term treatment with low doses of recombinant human GH stimulates lipolysis in visceral obese men.

This study was designed to explore whether low doses of recombinant human (rh)GH affect lipid, glucose, or protein metabolism in men with visceral obesity. Four different studies were performed in six, otherwise healthy, obese men (age, 42 +/- 3; body mass index, 33 +/- 1 kg/m(2); waist circumference, 111 +/- 3 cm; mean +/- SEM). Lipid, glucose, and protein kinetics was estimated by infusing stable isotopes (glycerol, glucose, leucine) in the basal state and after 1 wk of treatment with sc bedtime injections of either placebo, 2.

Autoantibodies in autoimmune polyendocrine syndrome type II.

The autoimmune polyendocrine syndrome type II (APS-II) is characterized by the association of autoimmune Addison's disease with thyroid autoimmune diseases or type-1 diabetes mellitus. 21-Hydroxylase autoantibodies enable the accurate diagnosis of autoimmune Addison's disease and, in patients with other endocrine autoimmune diseases, identify subjects at high risk for clinical adrenal insufficiency. 17 alpha-Hydroxylase (17OH) and side-chain-cleavage enzyme (P450scc) are target autoantigens of steroid-cell autoantibodies, and in women with Addison's disease, 17OH autoantibodies and P450scc autoantibodies are markers of increased risk for premature ovarian failure.

Continuous subcutaneous glucose monitoring in diabetic patients: a multicenter analysis.

Objective: To evaluate the accuracy of a new subcutaneous glucose sensor (Glucoday; A. Menarini Diagnostics) compared with venous blood glucose measurement in type 1 and type 2 diabetic patients.

Research Design: A multicenter study was performed in 70 diabetic patients.