Stimulatory effects of ghrelin on circulating somatostatin and pancreatic polypeptide levels

Ghrelin, the recently identified endogenous ligand of the GH secretagogue receptor, is a gut-brain peptide with endocrine, orexigenic, and gastrointestinal effects. In rodents it increases circulating gastrin and insulin levels, whereas in man it appears to decrease insulin secretion despite a rise in blood glucose levels. The aim of the present study was to evaluate the effects of ghrelin administration on total circulating somatostatin (SS), pancreatic polypeptide (PP), and gastrin levels compared with those elicited on insulin, glucose, and GH. Eight healthy volunteers of normal weight (four women and four men) were injected with 3.3 \u3bcg/kg ghrelin or saline after an overnight fast on 2 different days. Blood was taken every 15 min for 1 h and then every 30 min for 2 h. As expected, ghrelin injection elicited a prompt GH and glucose increase with a peak at 30 min and an insulin decrease with a nadir at 60 min. Gastrin concentrations were not modified, whereas significant rises were observed in both SS (in a biphasic pattern with peaks at 15 and 120 min) and PP (which increased promptly with a peak at 15 min). A significant negative correlation was found between SS (first peak) and insulin changes (r = -0.86; P < 0.01). In conclusion, this study clearly demonstrates that ghrelin stimulates SS and PP release in man. Although the underlying mechanisms and biological significance of these pharmacological effects remain to be elucidated, a causal relationship between the SS increase and the insulin changes may be hypothesized. Finally, these findings strongly support ghrelin's postulated role in linking the endocrine control of energy balance and growth with the regulation of gastrointestinal functions

A capacity framework for strengthening science, education and practice of scaling innovation

This concept note is developed by the CGIAR Initiative for Diversification in East and Southern Africa (Ukama Ustawi). It highlights the significance of strengthening capacity in the science and practice of scaling innovation. The lack of a comprehensive and realistic understanding of innovation and scaling processes, coupled with limited scaling knowledge and capacity across individual, organizational and system levels hinder the effective scaling of innovations. Consequently, many promising initiatives fail to reach their full potential and address systemic issues at scale

Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study.

BACKGROUND: The clinical course of advanced adrenocortical carcinoma (ACC) is heterogeneous. Our study aimed primarily to refine and make headway in the prognostic stratification of advanced ACC. PATIENTS AND METHODS: Patients with advanced ENSAT ACC (stage III or stage IV) at diagnosis registered between 2000 and 2009 in the ENSAT database were enrolled. The primary end point was overall survival (OS). Parameters of potential prognostic relevance were selected. Univariate and multivariate analyses were carried out: model 1 'before surgery'; model 2 'post-surgery'. RESULTS: Four hundred and forty-four patients with advanced ENSAT ACC (stage III: 210; stage IV: 234) were analyzed. After a median follow-up of 55.2 months, the median OS was 24 months. A modified ENSAT (mENSAT) classification was validated: stage III (invasion of surrounding tissues/organs or the vena renalis/cava) and stage IVa, IVb, IVc (2, 3 or >3 metastatic organs, including N, respectively). Two- or 5-year OS was 73%, 46%, 26% and 15% or 50%, 15%, 14% and 2% for stages III, IVa, IVb and IVc, respectively. In the multivariate analysis, mENSAT stages (stages IVa, IVb, or IVc, respectively) were significantly correlated with OS (P 6 and/or Ki67 ≥20%, P = 0.06) in model 2. CONCLUSION: The mENSAT classification and GRAS parameters (Grade, R status, Age and Symptoms) were found to best stratify the prognosis of patients with advanced ACC

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Relationship of edge localized mode burst times with divertor flux loop signal phase in JET

A phase relationship is identified between sequential edge localized modes (ELMs) occurrence times in a set of H-mode tokamak plasmas to the voltage measured in full flux azimuthal loops in the divertor region. We focus on plasmas in the Joint European Torus where a steady H-mode is sustained over several seconds, during which ELMs are observed in the Be II emission at the divertor. The ELMs analysed arise from intrinsic ELMing, in that there is no deliberate intent to control the ELMing process by external means. We use ELM timings derived from the Be II signal to perform direct time domain analysis of the full flux loop VLD2 and VLD3 signals, which provide a high cadence global measurement proportional to the voltage induced by changes in poloidal magnetic flux. Specifically, we examine how the time interval between pairs of successive ELMs is linked to the time-evolving phase of the full flux loop signals. Each ELM produces a clear early pulse in the full flux loop signals, whose peak time is used to condition our analysis. The arrival time of the following ELM, relative to this pulse, is found to fall into one of two categories: (i) prompt ELMs, which are directly paced by the initial response seen in the flux loop signals; and (ii) all other ELMs, which occur after the initial response of the full flux loop signals has decayed in amplitude. The times at which ELMs in category (ii) occur, relative to the first ELM of the pair, are clustered at times when the instantaneous phase of the full flux loop signal is close to its value at the time of the first ELM

New therapeutic options for acromegaly

Acromegaly is a slowly developing disfiguring disease characterized by chronic growth hormone (GH) and insulin-like growth factor-I (IGF-I) excess and caused by a pituitary somatotroph adenoma. It is associated to 2- to 3 fold increased mortality, compared to normal population, mostly due to cardiovascular and cerebro-vascular diseases, and to several co-morbid systemic illnesses, such as diabetes mellitus, hypertension, severe arthropathies, a specific cardio-myopathy, goitre, sleep-apnoea, intractable headache. The morbidity and excess mortality of acromegaly are usually the consequence of the metabolic actions of excess GH and IGF-I secretion, while only in rare patients mortality is due to the mass effects of the pituitary tumour. Since, serum IGF-I concentrations within age-adjusted normal range, and a tight GH control have to be achieved to normalize life-expectancy in these patients, an aggressive, and often multi-modality treatment is required for acromegaly. In recent years, new drugs, and new formulations of old drugs, have been developed that are able to effectively inhibit GH secretion or GH action, and may represent important adjuncts or even alternatives to the traditional approaches of surgery and radiotherapy. This review briefly summarizes the therapeutic options nowadays available for acromegaly. A brief note about innovative drugs under study, is also given

Adequacy of current postglucose GH nadir limit (< 1 microg/l) to define long-lasting remission of acromegalic disease

Objective: Some authors proposed to lower the present postglucose GH nadir cut-off (i.e. 0.26 \u3bcg/l in 24 patients (Group B). Group B had only slightly higher IGF-1 SDS (0.4 \ub1 1.0 vs. - 0.1 \ub1 1.0, P = ns) and lower body mass index (BMI) than Group A (26.2 \ub1 2.4 vs. 30.6 \ub1 4.5 kg/m2, P < 0.005). GH nadir positively correlated with IGF-1 (P < 0.05, r = 0.32) and negatively with BMI (P < 0.05, r = 0.42). In Phase 2, all patients had IGF-1 levels in the normal range and GH nadir < 1 \u3bcg/l, both parameters being even lower than those found at the time of remission. No patient had either clinical or neuroradiological evidence of disease recurrence. Conclusions: The current GH nadir limit is still adequate to define both short- and long-lasting remission of acromegaly, independently of the type of definitive treatment. Patients with the lowest GH nadir should probably be monitored long-term for adequacy of their GH secretion

Growth hormone therapy in GH-deficient adults: continuous vs alternate-days treatment

In the present report, we have compared 12 months of rhGH therapy given daily (D) at the beginning and then on alternate days (A) to 20 subjects with severe adult-onset GH deficiency (GHD). Aim of the study was to establish whether the lower frequency injection regimen is as effective as the daily dose. Measurements included: IGF-I levels, body composition (BF%), lipid profile, insulin sensitivity by homeostasis model assessment (HOMA-IR) and quantitative insulin check index (QUICKI), as well as thyroid function. Evaluation on A therapy was performed both 12 and 36 hours after the last rhGH injection. The final rhGH dose was 0.3 \ub1 0.1 mg/day. During A, the dose used in D was doubled and given on alternate days. Recombinant hGH given during the A period induced changes in IGF-I levels, BF% and lipid profile comparable to daily treatment. HOMA-IR increased similarly after both regimens, though QUICKI did not significantly change. A significant reduction in serum FT4 levels occurred after both D and A therapy, so that an adjustment of L-T4 replacement dose in 5 of 20 patients was necessary. No differences were found in the various parameters after 12 and 36 hours post rhGH injection. In conclusion, rhGH therapy given on alternate days is clinically effective and may result in improved patient compliance. Monitoring glucose tolerance and thyroid function while on rhGH is essential

Evaluation of insulin resistance in acromegalic patients before and after treatment with somatostatin analogues

Many studies have recently shown that simple computer-solved indices, based on fasting glucose and insulin levels, closely mirror the euglycemic clamp technique in studying insulin resistance or pancreatic insulin secretion. Few data are at present available on the evaluation of these novel indices in acromegalic patients, known to be GH-dependent insulin-resistant subjects, in particular during medical treatment with somatostatin analogues. Indeed, these drugs are able to inhibit not only GH and IGF-I levels, but also insulin and glucagon pancreatic secretion, with contrasting effects on glucose metabolism. In this study, insulin resistance was evaluated by the homeostasis model assessment (HOMA-IR) and insulin sensitivity by quantitative insulin check index (QUICKI) in 27 normoglycemic acromegalic patients, before and after 6-month therapy with somatostatin analogues (lanreotide-SR 30-60 mg every 7-28 days in 15 and octreotide-LAR 20-30 mg every 28 days in 12). Thirty-five age- and sex-matched healthy subjects and 17 surgically treated acromegalic patients (5 cured and 12 not cured) were studied as control groups. Before medical treatment, HOMA-IR was higher in acromegalic patients than in healthy controls (4\ub13 vs 1.7\ub10.7, p<0.05), while QUICKI was lower (0.33\ub10.04 vs 0.36\ub10.03, p<0.05). During medical therapy, HOMA-IR decreased to 2.4\ub11.6 (p<0.05) and became similar to that recorded in both healthy subjects and surgically treated patients. However, fasting glucose was increased and fasting insulin was decreased. QUICKI did not significantly change from basal values. No differences were observed between patients who normalized or not hormonal levels. The effects of the 2 drugs, though higher glucose levels were seen in patients treated with octreotide-LAR. In conclusion, this study demonstrates that medical treatment is able to improve insulin resistance, even if only successful surgery is able to completely normalize both HOMA-IR and QUICKI

An unusual case of recurrent autoimmune hypophysitis

Autoimmune hypophysitis (AH) is an inflammatory disease that can present either as empty sella or as pituitary mass. A 16-years-old girl was admitted at our Unit for primary amenorrhea. A pituitary MRI performed 2 years before for severe headache demonstrated a large sellar and suprasellar lesion. As a craniopharyngioma was suspected, the consultant neurosurgeon suggested the removal of the lesion. Two months later, a preoperative MRI showed the disappearance of the lesion and a residual empty sella, figure consistent with AH. When the patient came at our observation, basal and dynamic testing documented a state of hypopituitarism, high titers of antipituitary antibodies and a partial empty sella at MRI. Hormonal replacement therapy was started, obtaining a good clinical and biochemical control. Four years later, severe headache and a MRI suggestive of pituitary adenoma recurred. A relapse of the autoimmune phenomenon seemed the most feasible hypothesis. A MRI performed 3 months later did not show any pituitary lesion and empty sella was again described. This patient represents one of the few reported cases of recurrent hypophysitis and demonstrates that both pituitary enlargement and empty-sella can be seen in the same patient at different times of his history