PDE4 cyclic nucleotide phosphodiesterases regulate cAMP abundance in cells and thereby regulate numerous processes, including cell growth and differentiation. The rat PDE4A5 isoform (human homologue PDE4A4) interacts with the AIP protein (also called XAP2 or ARA-9). Germline mutations in AIP occur in approximately 20% of patients with Familial Isolated Pituitary Adenoma (FIPA) and 20% of childhood-onset simplex somatotroph adenomas. We therefore examined the protein expression of PDE4A4 and the closely-related isoform PDE4A8 in normal human pituitary tissue and in pituitary adenomas. PDE4A4 had low expression in normal pituitary, but was significantly over-expressed in somatotroph, lactotroph, corticotroph and clinically non-functioning gonadotroph adenomas (P<0.0001 for all subtypes). Likewise, PDE4A8 was expressed in normal pituitary and was also significantly over-expressed in the adenoma subtypes (P<0.0001 for all). Among the different adenoma subtypes, corticotroph and lactotroph adenomas were the highest and lowest expressed for PDE4A4, respectively, whereas the opposite was observed for PDE4A8. Naturally occurring oncogenic variants in AIP were shown by a two-hybrid assay to disrupt the ability of AIP to interact with PDE4A5. A reverse-two-hybrid screen identified numerous additional variants in the TPR region of AIP that also disrupted its ability to interact with PDE4A5. The expression of PDE4A4 and PDE4A8 in normal pituitary, their increased expression in adenomatous pituitary cells where AIP is meant to participate, and the disruption of the PDE4A4-AIP interaction by AIP mutants may play a role in pituitary tumorigenesis.

Conclusion-sTfR appear to be elevated and related to the degree of anaemia and to the inflammatory process in RA. Reduced sTfR levels in patients with RA compared with patients with irondeficiency anaemia may indicate a reduced erythropoietic activity in RA.

No abstract

Type 4 phosphodiesterases (PDE4s) of the large PDE enzyme superfamily have unique specificity for cAMP and may, therefore, be relevant for somatotroph tumorigenesis. Somatotroph adenomas typically overexpress PDEs probably as part of a compensatory mechanism to reduce cAMP levels. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein, coded by a tumour suppressor gene mutated in a subgroup of familial isolated pituitary adenomas (FIPAs). PDE4A8 is the closest related isoform of PDE4A4. We aimed to evaluate the expression of both PDE4A4 and PDE4A8 in GH cells of AIP-mutated adenomas and compare their expression with that in GH cells from sporadic AIP-mutation negative GH-secreting adenomas, where we had shown previously that both PDE4A4 and PDE4A8 isoforms had been over-expressed. Confocal immunofluorescence analysis showed that both PDE4A8 and PDE4A4 had lower expression in AIP-mutated somatotropinoma samples compared to sporadic GH-secreting tumours (P < 0.0001 for both). Based on the association of low PDE4A4 and PDE4A8 expression with germline AIP-mutations positive samples we suggest that lack of AIP hinders the upregulation of PDE4A8 and PDE4A4 protein seen in sporadic somatotrophinomas. These data point to a unique disturbance of the cAMP-PDE pathway in AIP-mutation positive adenomas, which may help to explain their well-described poor response to somatostatin analogues.

Prolactinomas are prolactin-secreting neoplasias accounting for 40% of the pituitary adenomas. Much is known about the effects of prolactinomas on the reproductive system, but few data are yet available regarding their induced changes on metabolism. This study was aimed at evaluating patients with prolactinomas for insulin resistance and adiponectinemia. Forty patients with prolactinoma were allocated to 2 different groups according to disease control: 20 with uncontrolled disease (UPRL) and 20 with controlled disease in the last 6 months (CPRL). Forty healthy individuals (CG) matched for age, sex, and body mass index were taken as controls. Patients with prolactinoma were compared both as a one group and according to disease control with CG. All subjects were evaluated for waist/hip ratio (WHR), blood pressure, lipid profile, fasting glucose, homeostasis assessment model of insulin resistance (HOMAIR), and adiponectin. Patients with prolactinomas (UPRL+CPRL) showed higher insulin (p<0.05) and HOMAIR (p<0.05), alongside with lower adiponectin levels (p<0.01) than matched controls. When UPRL was compared to CPRL and CG, UPRL was disclosed as a subgroup of significant altered metabolic profile as related to WHR (p<0.01 for comparisons), high-density lipoprotein cholesterol (p<0.05 for comparisons), triglycerides (p<0.05 for comparisons), HOMAIR (p<0.05 and p<0.01, respectively), and adiponectin (p<0.01 for comparisons). All these metabolic abnormalities, except hypoadiponectinemia (p<0.01), were not observed in CPRL. These data suggest that prolactinomas are associated with hypoadiponectinemia, which is further exacerbated in uncontrolled patients when insulin resistance is also prominent.

Objective To evaluate whether brown adipose tissue (BAT) activity is altered in women with polycystic ovary syndrome (PCOS), and whether BAT activity correlates with plasma levels of irisin, a myokine that can induce BAT formation. Design We performed a cross-sectional study including women with PCOS (n = 45) and a healthy control group (n = 25) matched by age and body mass index (BMI). Methods BAT activity was measured using 18F-FDG positron emission tomography-computed tomography (PET-CT) and plasma irisin levels were measured by a validated enzyme immunoassay. Results Total BAT activity was significantly reduced in women with PCOS (maximal standardized uptake value (SUVmax): median 7.4 g/mL, interquartile range 0.9–15.4) compared to controls (median 13.0 g/mL, interquartile range 4.7–18.4, P = 0.047). However, this difference was no longer significant after adjustment for waist circumference, a surrogate marker of central adiposity. In the PCOS group, BAT activity correlated negatively with BMI (Spearman’s r = −0.630, P = 0.000) and waist circumference (r = −0.592, P = 0.000) but not with plasma irisin levels. Conclusions BAT activity was reduced in women with PCOS possibly due to increased central adiposity. In PCOS women, BAT activity did not correlate with plasma irisin levels.

Polycystic ovary syndrome (PCOS) is a chronic dysfunction associated with obesity and metabolic disorders that can be ameliorated by treatment with metformin. Brown adipose tissue (BAT) has been recently identified in adult humans, and irisin is a myokine that induces BAT formation. The aim of this randomized controlled trial was to evaluate whether a short term treatment with metformin alters BAT activity and plasma irisin levels in women with PCOS. The participants were randomly assigned to receive metformin (1500 mg/day, n=21) or placebo (n=24) during 60 days. BAT activity was assessed by 18F-FDG positron emission tomography-computed tomography (PET-CT) and plasma irisin levels were measured by enzyme immunoassay. The groups were similar in age, body measures, metabolic profile and PCOS phenotypes. BAT activity did not change significantly in the women treated with metformin (median Δ SUVmax=–0.06 g/ml, interquartile interval –2.81 to 0.24 g/ml, p=0.484, Wilcoxon’s test) or placebo (median Δ SUVmax=0.98 g/ml, interquartile interval –2.94 to 4.60 g/ml, p=0.386). In addition, plasma irisin levels remained unchanged in the groups treated with metformin (median Δ=–98 ng/ml, interquartile interval –366 to 60 ng/ml, p=0.310) and placebo (median Δ=28 ng/ml, interquartile interval –1260 to 215 ng/ml, p=0.650). These results suggest that in PCOS women BAT activity and plasma irisin levels may not change after a brief treatment with metformin.

Background Pulmonary Hypertension (PH) impacts negatively on patients’ health-related quality of life (HRQoL). The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) was the first PH-specific and validated instrument for use in different languages worldwide. This report describes the adaptation and psychometric validation of the CAMPHOR into Brazilian Portuguese language. Methods The translation and validation process included a bilingual and lay panel translation; cognitive debriefing interviews; psychometric testing in two repeated times assessing internal consistency, reproducibility and validity of the questionnaire. The Nottingham Health Profile (NHP) questionnaire was used as a comparator to test for convergent validity. Results The translation captured the same concepts as the English questionnaire and produced a comprehensive instrument in a Brazilian-Portuguese version expressing common, natural language. The psychometric evaluation involved 102 patients (48.8 ± 14.5 years, 80,4% female]. Cronbach’s alpha coefficients were above 0.9 on all three CAMPHOR scales. There was excellent test-retest reliability (coefficients above 0.85 on all scales). CAMPHOR Symptoms scale and Activities scale correlated highly with Physical Mobility section and CAMPHOR QoL scale was strongly associated with the Emotional Reactions and Social Isolation sections of NHP. There was a significant association between gender and perceived general health (p < 0.05). There were significant differences in CAMPHOR scale scores between patients who differed according to their perceived disease severity and general health. Conclusions The present CAMPHOR version demonstrated good psychometric properties and provides a reliable instrument for assessing HRQL and QoL in Brazilian PH patients, addressing patients’ perspective of their illness in a comprehensive way.