M. de Castro

Discordant nadir GH after oral glucose and IGF-I levels on treated acromegaly: refining the biochemical markers of mild disease activity.

Biochemical markers for remission on acromegaly activity are controversial. We studied a subset of treated acromegalic patients with discordant nadir GH levels after oral glucose tolerance test (oGTT) and IGF-I values to refine the current consensus on acromegaly remission. We also compared GH results by two GH immunoassays. From a cohort of 75 treated acromegalic patients, we studied 13 patients who presented an elevated IGF-I despite post-oGTT nadir GH of < or =1 microg/l. The 12-h daytime GH profile (GH-12 h), nadir GH after oGTT, and basal IGF-I levels were studied in patients and controls. Bland-Altman method showed high concordance between GH assays. Acromegalic patients showed higher mean GH-12 h values (0.71+/-0.36 vs. 0.31+/-0.28 microg/l; p<0.05) and nadir GH after oGTT (0.48+/-0.32 vs. 0.097+/-0.002 microg/l; p<0.05) as compared to controls. Nadir GH correlated with mean GH-12 h (r=0.92, p<0.05). The mean GH-12 h value from upper 95% CI of controls (0.54 microg/l) would correspond to a theoretical normal nadir GH of < or =0.27 microg/l. Patients with GH nadir < or =0.3 microg/l had IGF-I between 100-130% ULNR (percentage of upper limit of normal range) and mean GH-12 h of 0.35+/-0.15, and patients with GH nadir >0.3 and < or =1 microg/l had IGF-I >130% ULNR and mean GH-12 h of 0.93+/-0.24 microg/l. Our data integrate daytime GH secretion, nadir GH after oGTT, and plasma IGF-I concentrations showing a continuum of mild residual activity in a subgroup of treated acromegaly with nadir GH values < or =1 microg/l. The degree of increased IGF-I levels and nadir GH after oGTT are correlated with the subtle abnormalities of daytime GH secretion.

Mineralocorticoid receptor p.I180V polymorphism: Association with body mass index and LDL-cholesterol levels

Background/Aims: Aldosterone and the mineralocorticoid receptor (MR) play a major role in sodium balance and blood pressure control. They are also involved in adipocyte metabolism. The aim of this study was to analyze the association between the MR p.I180V polymorphism with hypertension and markers of cardiovascular risk. Design and methods: Case-control study nested within a cohort of 2063 subjects followed since birth to date. All subjects (age 23–25 yr old) from the entire cohort with systolic and diastolic hypertension (no.=126) were paired with 398 normotensive controls. MR p. I180V genotype association with anthropometric and biochemical markers of cardiometabolic risk was tested. Results: There was a significant association of the MR p. I180V genotype with body mass index (BMI) and LDL-cholesterol level (p<0.01). Hypertensive subjects carrying the polymorphic G allele (AG or GG genotypes) presented significantly higher BMI (30.0±6.0 vs 28.7±5.6 kg/m2; p<0.01) and higher LDL-cholesterol (139.9±60.3 vs 109.9±35.5 mg/dl; p<0.01). The frequency of the polymorphism MR p.I180V was similar between hypertensive subjects and controls (p=0.15). Conclusions: The MR p.I180V polymorphism seems to be associated with cardiovascular risk factors including BMI and LDL-cholesterol levels. This original in vivo finding reinforces the role of MR in adipocyte biology and in cardiovascular disease.

The effect of adrenalectomy on Fos expression in vasopressinergic and oxytocinergic neurons in response to stress in the rat

This study evaluated the responses of vasopressin (AVP) and oxytocin (OT) neurons to alterations in hypothalamo–pituitary axis activity by adrenalectomy (ADX) or after restraint stress compared with basal conditions. Wistar male rats were perfuse-fixed by cardiac perfusion under anesthesia 3 h, 1, 3 and 14 days after ADX or Sham surgery. Coronal hypothalamic sections were used for evaluation of Fos, AVP and OT expression by immunohistochemistry. Under basal conditions and after stress, Fos-AVP double labeling showed no difference in the magnocellular subdivisions of the paraventricular nuclei (PVN) or in the supraoptic nuclei (SON), suggesting that the magnocellular AVP system is unlikely to contribute to ACTH secretion after restraint in both Sham and ADX rats. Fos–AVP double labeling in the parvocellular medial paraventricular nucleus (PaMP) in ADX groups was increased after 3 h in basal conditions, and in all periods after restraint stress. There were no differences between Sham and ADX groups in Fos–OT double labeling in any subdivision of the PVN; however, in the SON, the number of Fos–OT double labeled cells was increased at all time-points after stress in the ADX group. Fos expression was increased in the PaMP after 3 h and after restraint stress in the Sham and ADX groups, especially in the ADX group. In conclusion, Fos expression in different cell populations of the PVN can be differentially regulated by short- and long-term absence of glucocorticoid negative feedback and also by stress-related excitatory and/or inhibitory neural inputs. The Fos–AVP double labeling findings in the PaMP also indicate a minor participation of these vasopressinergic neurons in the regulation of the HPA axis after ADX.

Downregulation of Melanocortin-4 Receptor during Refeeding and its Modulation by Adrenalectomy in Rats

Melanocortin system and corticotropin releasing hormone (CRH) are implicated in the control of feeding behavior. Besides its anorexigenic effect on food intake, CRH is one of the most important regulators of hypothalamic-pituitary-adrenal (HPA) axis activity. Therefore, there could be an interplay between HPA axis activity and melanocortin system. We investigated the expression of melanocortin-4 receptor (MC4-R) mRNA in the hypothalamus of rats after 14 days of food restriction or after a fasting-refeeding regimen, in sham or adrenalectomized rats. Male Wistar rats were subjected to free access to food or food ingestion restricted for 2 h a day (8-10 AM) during 14 d, when plasma corticosterone, ACTH, insulin, leptin concentrations, and MC4-R mRNA expression were determined before and after refeeding. Another set of rats was fasted for 48 h, followed by refeeding during 2 or 4 h on the seventh day after adrenalectomy (ADX) or sham surgery. On the day of the experiment, rats were anesthetized and perfused and the brain processed for MC4-R mRNA by in situ hybridization. Long-term reduction of food intake, either secondary to food restriction or adrenalectomy, reduced body weight gain and also leptin and insulin plasma concentrations. Food ingestion reduced MC4-R expression in the paraventricular nucleus in naive rats subjected to food restriction and also in sham rats fasted for 48 h. However, after ADX, MC4-R expression was not changed by refeeding. In conclusion, the present data indicate that MC4-R expression is downregulated by food ingestion and this response could be modulated by glucocorticoid withdrawal.

Intracranial Castleman’s disease presenting as hypopituitarism

Castleman’s disease is an atypical lymphoproliferative disorder that may present as a localized or multicentric form. The involvement of the central nervous system is rare. We describe here a case of Castleman’s disease with involvement of the hypothalamus and meninges, presenting as hypopituitarism. Radiological and clinical pathological features are emphasized and a review of the literature is presented.

An Analytical Evaluation of Objective Measures Behavior for Generalized Association Rules

The association rule mining task identifies all the intrinsic associations among the items contained in data and leads to only specialized knowledge. To overcome this problem the generalized association rules appeared. This type of rule associates not only the items contained in data, but also some items encoded into a given taxonomy. Therefore, the techniques used to obtain generalized association rules are very useful since they provide a more general view of the domain. However, a problem found when using these techniques is how to identify the most useful rules to avoid overload the user with a huge amount of patterns. Nowadays, the researches use objective evaluation measures to evaluate and select the most interesting knowledge to the user. Despite the fact these measures have been studied by many researches to evaluate many types of rules (for example, classification and traditional association rules), it is important to study these measures in the context of generalized rules. Thus, this paper presents an analytical evaluation to understand the behavior of some objective measures when applied in a set of generalized rules. Many relations were obtained to express the behavior of these measures, what represents a meaningful contribution to the post-processing data mining area

The interaction of plasma renin activity and plasma atrial natriuretic peptide in 21-hydroxylase deficiency patients

Plasma renin activity (PRA) determination is the main index used to evaluate the mineralocorticoid control in 21-hydroxylase deficiency (21-OHD). PRA values within or at the upper limit of the age-appropriate range, or values <5 or 10 ng/ml/h have been regarded as adequate control. Atrial natriuretic peptide (ANP) has opposite actions to those of angiotensin II/aldosterone, and could help to understand the hydrosaline homeostasis in 21-OHD. We studied the interaction between PRA and ANP levels in 10 controls and 26 patients with 21-OHD under corticoid treatment. Patients were divided into two groups according to PRA levels, < or ≥5 ng/ml/h, irrespective of the clinical form of 21-OHD. Blood samples for determination of PRA and ANP levels were taken after 30 min in the sitting position (basal), after 30 min in the recumbent position and after 15 min of 20° head-down tilting. ANP levels (pg/ml) in the basal, supine and after head-down tilting position were 25.9±1.6, 42.7±7.4 and 54.3±5.5 in controls; 28.5±2.1, 38.3±2.1 and 48.8±4.1 in the group with PRA levels <5 ng/ml/h, and 20.9±1.9, 26.6±2.5 and 34.6±3.1 in the group with PRAlevels ≥5 ng/ml/h, respectively. Basal and after head-down tilting ANP plasma levels were similar between the controls and the group with PRA levels <5 ng/ml/h. However, the group of patients with PRA levels ≥5 ng/ml/h showed lower basal and stimulated ANP levels compared to the control group (p<0.05). The decreased plasma ANP levels in the basal condition and after head-down tilting indicate a chronic contraction of the extracellular volume in 21-OHD patients with increased PRA levels. Therefore, mineralocorticoid deficiency is counteracted by decreased ANP secretion in order to preserve fluid and electrolyte homeostasis.

Absence of TERT promoter mutations in pituitary adenomas

Ethical approval All procedures performed involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. This study was approved by the Institutional Review Board of the University Hospital of the Ribeirao Preto Medical School, University of Sao Paulo, Brazil (Process n° 11071/2013).

The higher expression of α and β isoforms of the human glucocorticoid receptor in leukemic B-progenitors compared to normal CD10+ BM cells does not correlate with methylprednisolone-induced apoptosis

The higher expression of α and β isoforms of the human glucocorticoid receptor in leukemic B-progenitors compared to normal CD10 + BM cells does not correlate with methylprednisolone-induced apoptosis