Search

Background and Aim: Differential diagnosis between Cushing's Disease (CD) and Ectopic ACTH Syndrome (EAS) may be a pitfall for endocrinologists. The increasing use in clinical practice of chromatography and mass spectrometry improves the measurement of urinary free cortisol (UFF) and cortisone (UFE). We have recently observed that cortisol to cortisone ratio (FEr) was higher in a small series of EAS; in this study we collected a larger number of ACTH-dependent Cushing's Syndrome (CS) to study the role of FEr to characterize the source of corticotropin secretion., Materials and Methods: High-pressure liquid chromatography with UV detection (HPLC-UV, n=35) or liquid chromatography-tandem mass spectrometry (LC-MS/MS, n=72) were used to measure UFF, UFE and FEr in 83 patients with CD and 24 with EAS., Results: UFF, UFE and FEr levels were higher in EAS than in CD (UFF: 6671 vs 549 nmol/24 hours; UFE: 2069 vs 464 nmol/24 hours; FEr: 4.13 vs 0.97; all P<.001). FEr >1.15 (the best ROC-based threshold) was able to distinguish CD from EAS with 75% sensitivity (SE) and 75% specificity (SP), AUC 0.811; results were similar between HPLC-UV (SE 73%, SP 79%, AUC 0.708) and LC-MS/MS (SE 77%, SP 73%, AUC 0.834; P=.727). The diagnostic accuracy of FEr was similar to that of CRH test or high-dose dexamethasone suppression test (respectively P=.171 and P=.683), also combined. Finally, FEr was able to increase the number of correct diagnosis in patients with discordant dynamic tests., Conclusions: Urinary FEr >1.15 was able to suggest EAS, with a diagnostic accuracy similar to that of other dynamic tests proposed to study ACTH-dependent CS., (© 2017 John Wiley & Sons Ltd.)

Purpose: Pasireotide is a multi-receptor-targeted somatostatin analogue approved in the EU and in the US for the treatment of adults with Cushing's disease (CD). Pasireotide has a safety profile similar to other somatostatin analogues with the exception of hyperglycemia. In this report and literature review, the current understanding of predicting a positive treatment response to pasireotide in CD and the management of diabetes mellitus (DM) during pasireotide treatment are discussed and analyzed., Case Presentation: We report a case of a 55-year-old woman with CD and DM who benefitted from long-term pasireotide. The patient, who was enrolled in a phase III trial of the drug, showed early clinical improvements with pasireotide [900 μg subcutaneously twice daily (bid)] but was classified as a non-responder as urinary free cortisol (UFC) levels, were not normalized. Continuation of pasireotide for 12 months at an increased dose (1,200 μg bid) normalized UFC levels and restored cortisol rhythm. The initial deterioration in her blood glucose was managed with insulin and metformin; however, after 12 months' treatment with pasireotide her DM was well controlled with oral hypoglycemic agents. Five years later, the patient is still receiving pasireotide (300 μg bid) with no loss of clinical or biochemical efficacy and with continued glycemic control., Conclusions: This case presentation indicates that uncontrolled UFC levels during the first few months of pasireotide treatment as well as worsening of glycemic control in patients with CD and DM are not always predictive of the efficacy and tolerability and appears to support the long-term continuation of pasireotide.

Purpose: Late night salivary cortisol (LNSC) is useful for diagnosing hypercortisolism and monitoring patients with Cushing's disease (CD) following pituitary surgery. It may also be a better index of cortisol secretion than serum cortisol or urinary free cortisol (UFC). No data regarding the role of LNSC in the early monitoring of patients with CD receiving drug therapy has been published. We investigated the value of LNSC in monitoring the short-term efficacy of pasireotide., Methods: Seven patients who were enrolled in a phase II study investigating the efficacy of pasireotide in CD (CSOM230B2208) were included in this analysis. Patients self-administered subcutaneous pasireotide 600 μg bid for 15 days. LNSC and UFC levels were assessed at baseline and day 15., Results: At baseline, all patients had elevated LNSC which was correlated significantly with UFC levels (r = 0.97, P = .0002). At day 15, LNSC was reduced in six patients. LNSC decreases were observed from day 1 (-20%) and persisted until day 15 (overall mean reduction from baseline -51%), with the greatest decrease on day 5 (-58%). At day 15, UFC levels were decreased in all patients and normalized in one that restored also salivary cortisol rhythm., Conclusions: In patients with CD, pasireotide rapidly reduced and normalized both UFC and LNSC levels. LNSC may be a simple, non-invasive biomarker to assess the early response to pasireotide, particularly in determining whether cortisol rhythm is normalized in patients with normalized UFC levels. Further studies are warranted.

Purpose: Fracture risk data following curative treatment of Cushing's syndrome (CS) are scarce and the role of bisphosphonates in bone recovery after remission is controversial. We evaluated the effects of hypercortisolism remission in bone recovery in CS. Then, we assessed if the FRAX(®) algorithm calculated before the cure can predict fracture risk after cure., Methods: Thirty-six patients with CS were retrospectively investigated. Bone turnover markers, bone mineral density (BMD) at the lumbar spine (L1-L4) and left femur (both neck and total hip were considered), and fracture risk using FRAX(®) algorithm with femoral neck BMD were evaluated at diagnosis and after a median follow-up of 24 months (range 12-108 months) from hypercortisolism remission. Data about bone active therapy were analyzed., Results: Hypercortisolism remission was associated with the improvement of all densitometric parameters and with the reduction of fracture risk. The percentage change in BMD and the fracture risk were not significantly different in bisphosphonate-treated vs. untreated patients. During follow-up, three fractured patients at baseline exhibited a new vertebral fracture. A baseline 10-year probability of major osteoporotic fractures (FRAX(®) Major) of 17 % was able to predict the occurrence of a new vertebral fracture during follow-up after cure with 100 % sensitivity, 77 % specificity, 81 % positive predictive value and 100 % negative predictive value., Conclusions: Osteoporosis and fracture risk may be reversible after curative treatment of CS, regardless of bisphosphonate therapy. We suggest applying the FRAX(®) algorithm to all active CS patients using a baseline FRAX(®) Major of 17 % as "intervention threshold".

We compared changes in the morphology of mitochondrial cristae with those in the blood and adrenal content of steroid hormones after the stimulation or inhibition of steroidogenesis. Rats were treated with adrenocorticotrophic hormone or angiotensin II to elicit steroidogenesis and with dexamethasone to inhibit it. Blood and adrenal glands were collected after several time intervals for measurements of steroids and their main intermediates. In the zona fasciculata, mitochondrial ultrastructure was investigated by high resolution scanning electron microscopy. We found that the morphometric data correlated well with the measurements of hyper- or hypo-activity of steroidogenesis over short periods of time (4 h) but not over longer observation times. A peculiar finding was that, contrary to previous reports, 11-deoxycortisol was present in adult rat adrenal tissue.

Aim:   To determine the influence of a family carer on haemodialyzed patients''adherence'., Background:   There is extensive evidence showing that successful treatment of patients with end-stage renal disease is directly related to patients''adherence'. The parameters indicative of a good adherence are potassium and phosphate serum levels and the interdialytic weight gain. Haemodialyzed patients may have scarce adherence to food and fluid intake restrictions, and medications schedule., Design:   Case-control study carried out in a haemodialysis centre in Italy., Data Sources:   The data were collected during 2010., Methods:   A total of 72 subjects with end-stage renal disease participated in the study. The subjects assisted by a family carer were identified as cases (n = 36), whereas those who did not have a family carer, as controls (n = 36). All subjects were followed up (4 months) and checked up regarding interdialytic weight gain, and serum levels of potassium and phosphate. Important differences in potassium and phosphate serum level and interdialytic weight gain between the two groups were evaluated separately using a repeated measures anova test., Results:   Participants in the case group showed significantly lower phosphate and potassium serum levels and a lower interdialytic weight gain during follow-up when compared to controls., Conclusions:   The presence of a family carer improves patients' adherence, particularly as far as phosphate levels are concerned, since phosphate intake plays a fundamental role in avoiding long-term complications in end-stage renal disease patients., (© 2012 Blackwell Publishing Ltd.)

Objective: Glucocorticoid receptor (GR) polymorphisms alter glucocorticoid (GC) sensitivity and have been associated with altered metabolic profiles. We evaluate the prevalence of the four GR (NR3C1) polymorphisms BclI, N363S, ER22/23EK, and A3669G in patients with Cushing's syndrome (CS) compared with healthy controls (HC) and we investigate their role in the development of metabolic abnormalities in patients with CS according to their hormonal profile., Patients and Methods: Sixty-one patients with CS and 71 sex- and age-matched HC were genotyped., Results: BclI variant was markedly higher in patients with CS compared with HC (62 vs 41%, P<0.05) while no significant differences were found among other polymorphisms. A very low frequency of N363S and the ER22/23EK was observed. In CS patients, despite the significantly increased levels of morning serum cortisol in BclI carriers compared with wild type no clinical or metabolic differences were found. In contrast, A3669G GR carriers showed a significantly reduced prevalence of type 2 diabetes mellitus compared with wild type (19 vs 68%, P=0.001) despite the higher levels of both serum morning (21.7±6 vs 27.3±8.6 μg/dl, P=0.009) and midnight cortisol (18.8±5.8 vs 24.0±8.0 μg/dl, P=0.01). The negative association between diabetes and A3669G GR polymorphism remained significant when data were adjusted for potential confounding factors., Conclusions: The A3669G polymorphism of the GR gene plays a protective role in patients with CS, attenuating the effects of GC excess on glucose metabolism as shown by their reduced risk of diabetes.

Cimetidine and ranitidine were submitted to eight in vitro assays: their intrinsic activity was evaluated on guinea-pig auricles and ileum, acetylcholine synergism on guinea-pig tracheal muscle, frog rectus abdominis, guinea-pig vas and rat phrenic nerve diaphragm, and antagonism on guinea-pig auricles and rat jejunum estimated at a range of concentrations. Ranitidine alone opposed 1-hyoscyamine antagonism in guinea-pig ileum when acetylcholine was the agonist, but not when the agonist was bethanechol.

The endothelium-dependent acetylcholine, metacholine, carbachol, betanechol, and furtrethonium relaxation values have been measured in vitro for the rabbit aorta, in presence of a high concentration of hexamethonium. The produced EPMR values complete the values that were obtained in a previous experiment under analogous conditions for rat bladder, ileum, iris, stomach, and trachea preparations. The complete set was analyzed by new statistical techniques of data analysis and display, which are both simpler and more precise than the statistical modeling techniques used by us in the past. This has led to new results concerning the clustering of drugs and of receptors, as well as to a characterization of the endothelium receptor.

Zipeprol, a piperazine ethanol derivative, is a non-essential but widely used (paediatric) antitussive, which is not legally considered as being capable of creating dependence or abuse liability. A first group of experimental results was obtained assaying the displacement of 1 nM [3H]naloxone by zipeprol vs morphine on the rat brain homogenate fractions. A second group was carried out on the longitudinal muscle of guinea-pig ileum, using the field stimulation technique, either in the absence or in the presence of naloxone 1 x 10(-5)M or in the absence or in the presence of yohimbine 1 x 10(-5)M. Further investigations concerning the pharmacological and the biochemical characterization of the mechanisms involved in abuse liability were carried out by means of the in vitro inhibition of ACh response on the guinea-pig ileum preparation. The results indicate zipeprol as a moderate opioid agonist, which also shows a direct anticholinergic effect, independent of presynaptic alpha 2 interaction.

A new and automated on-line analysis of the parameters related to the neuromuscular activity is shown. The procedure used to obtain in real time the statistical evaluation of the recorded electrical signals is presented and discussed. The hardware is composed of a PDP-11/73 microcomputer equipped with an analog input/output board. The software is written principally in FORTRAN 77 and also uses MACRO/ASSEMBLY language.