Adaptation and validation of the quality of life assessment of the Cambridge pulmonary hypertension outcome review (CAMPHOR) for Brazil.

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.

Phosphodiesterases and cAMP Pathway in Pituitary Diseases.

Human phosphodiesterases (PDEs) comprise a complex superfamily of enzymes derived from 24 genes separated into 11 PDE gene families (PDEs 1-11), expressed in different tissues and cells, including heart and brain. The isoforms PDE4, PDE7, and PDE8 are specific for the second messenger cAMP, which is responsible for mediating diverse physiological actions involving different hormones and neurotransmitters. The cAMP pathway plays an important role in the development and function of endocrine tissues while phosphodiesterases are responsible for ensuring the appropriate intensity of the actions of this pathway by hydrolyzing cAMP to its inactive form 5'-AMP. PDE1, PDE2, PDE4, and PDE11A are highly expressed in the pituitary, and overexpression of some PDE4 isoforms have been demonstrated in different pituitary adenoma subtypes. This observed over-expression in pituitary adenomas, although of unknown etiology, has been considered a compensatory response to tumorigenesis. PDE4A4/5 has a unique interaction with the co-chaperone aryl hydrocarbon receptor-interacting protein (AIP), a protein implicated in somatotroph tumorigenesis via germline loss-of-function mutations. Based on the association of low PDE4A4 expression with germline AIP-mutation-positive samples, the available data suggest that lack of AIP hinders the upregulation of PDE4A4 protein seen in sporadic somatotrophinomas. This unique disturbance of the cAMP-PDE pathway observed in the majority of AIP-mutation positive adenomas could contribute to their well-described poor response to somatostatin analogs and may support a role in tumorigenesis.

Reduced protein expression of the phosphodiesterases PDE4A4 and PDE4A8 in AIP mutation positive somatotroph adenomas.

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.