A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex

Bilateral adrenocortical hyperplasia (BAH) is the second most common cause of corticotropin-independent Cushing syndrome (CS). Genetic forms of BAH have been associated with complex syndromes such as Carney Complex and McCune-Albright syndrome or may present as isolated micronodular adrenocortical disease (iMAD) usually in children and young adults with CS. A genome-wide association study identified inactivating phosphodiesterase (PDE) 11A (PDE11A)-sequencing defects as low-penetrance predisposing factors for iMAD and related abnormalities; we also described a mutation (c.914A > C/H305P) in cyclic AMP (cAMP)-specific PDE8B, in a patient with iMAD. In this study we further characterize this mutation; we also found a novel PDE8B isoform that is highly expressed in the adrenal gland. This mutation is shown to significantly affect the ability of the protein to degrade cAMP in vitro. Tumor tissues from patients with iMAD and no mutations in the coding PDE8B sequence or any other related genes (PRKAR1A, PDE11A) showed downregulated PDE8B expression (compared to normal adrenal cortex). Pde8b is detectable in the adrenal gland of newborn mice and is widely expressed in other mouse tissues. We conclude that PDE8B is another PDE gene linked to iMAD; it is a candidate causative gene for other adrenocortical lesions linked to the cAMP signaling pathway and possibly for tumors in other tissues.     

Lone noncompaction in Leber's hereditary optic neuropathy

The association of Leber's hereditary optic neuropathy (LHON) and left ventricular non-compaction in the absence of other neurologic or cardiac abnormalities has not been reported. In a 19-year-old man with deteriorating visual acuity, first in the right and two weeks later also in the left eye, LHON was diagnosed, based upon reduced visual acuity, abnormal visually evoked potentials, hyperaemia of the papilla, hyperaemia of the peripapillary capillaries, peripapillary teleangiectasias, congested peripapillary veins, complete central scotoma and spotted partial defects of the remaining visual field. No other ophthalmologic abnormalities were detected. Because of frequent cardiac involvement in LHON a thorough cardiologic investigation was carried out. The cardiovascular history was uneventful. Clinical cardiologic examination and ECG were normal. Transthoracic echocardiography, however, revealed left ventricular noncompaction in the apex and the lateral wall. No other cardiac abnormalities were found. In conclusion, LHON without other neurological abnormalities may be associated with lone left ventricular noncompaction. Patients with LHON should undergo a cardiologic investigation.     

Differential roles of 2, 6, and 8 carbon ceramides on the modulation of gap junctional communication and apoptosis during carcinogenesis

The inhibition of apoptosis and gap junctional intercellular communication (GJIC) has been implicated in tumor promotion. Ionizing radiation and oxidative toxicants activate sphingomyelinases resulting in the release of ceramides that control cell proliferation and apoptosis. A rat liver epithelial cell line treated with ceramides containing a 6 (C6) or 8 (C8) carbon acyl-group were potent inhibitors of GJIC and apoptosis, whereas a C2-ceramide was only a weak inhibitor of GJIC and strong inducer of apoptosis. Apoptosis induced by either serum deprivation or C2-ceramide was inhibited by the GJIC inhibitory C8-ceramide. In conclusion, these results suggest that a chronic release of ceramides with acyl groups larger than C6 might act as tumor promoters.     

Parenteral diclofenac infusion significantly decreases brain-tissue oxygen tension in patients with poor-grade aneurysmal subarachnoid hemorrhage

Introduction

Diclofenac, a nonsteroidal antiinflammatory drug, is commonly used as antipyretic therapy in intensive care. The purpose of this study was to investigate the effects of parenteral diclofenac infusion on brain homeostasis, including brain-tissue oxygen tension (P_btO₂) and brain metabolism after aneurysmal subarachnoid hemorrhage (aSAH).

Methods

We conducted a prospective, observational study with retrospective analysis of 21 consecutive aSAH patients with multimodal neuromonitoring. Cerebral perfusion pressure (CPP), mean arterial pressure (MAP), intracranial pressure (ICP), body temperature, and P_btO₂ were analyzed after parenteral diclofenac infusion administered over a 34-minute period (20 to 45 IQR). Data are given as mean ± standard error of mean and median with interquartile range (IQR), as appropriate. Time-series data were analyzed by using a general linear model extended by generalized estimation equations (GEEs).

Results

One-hundred twenty-three interventions were analyzed. Body temperature decreased from 38.3°C ± 0.05°C by 0.8°C ± 0.06°C (P < 0.001). A 10% decrease in MAP and CPP (P < 0.001) necessitated an increase of vasopressors in 26% (n = 32), colloids in 33% (n = 41), and crystalloids in 5% (n = 7) of interventions. P_btO₂ decreased by 13% from a baseline value of 28.1 ± 2.2 mm Hg, resulting in brain-tissue hypoxia (P_btO₂ <20 mm Hg) in 38% (n = 8) of patients and 35% (n = 43) of interventions. P_btO₂ <30 mm Hg before intervention was associated with brain-tissue hypoxia after parenteral diclofenac infusion (likelihood ratio, 40; AUC, 93%; 95% confidence interval (CI), 87% to 99%; P < 0.001). Cerebral metabolism showed no significant changes after parenteral diclofenac infusion.

Conclusions

Parenteral diclofenac infusion after aSAH effectively reduces body temperature, but may lead to CPP decrease and brain-tissue hypoxia, which were both associated with poor outcome after aSAH.     

Primary pigmented nodular adrenocortical disease reveals insulin-like growth factor binding protein-2 regulation by protein kinase A.

OBJECTIVE: Primary pigmented nodular adrenocortical disease (PPNAD) can occur as an isolated trait or part of Carney complex, a familial lentiginosis-multiple endocrine neoplasia syndrome frequently caused by mutations in PRKAR1A, which encodes the 1alpha regulatory subunit of protein kinase A (PKA). Because alterations in the insulin-like growth factor (IGF) axis, particularly IGF-II and IGF binding protein (IGFBP)-2 overexpression, have been implicated in sporadic adrenocortical tumors, we sought to examine the IGF axis in PPNAD. DESIGN: RNA samples and paraffin-embedded sections were procured from adrenalectomy specimens of patients with PPNAD. Changes in expression of IGF axis components were evaluated by real-time quantitative RT-PCR and immunohistochemistry. NCI-H295R cells were used to study PKA and IGF axis signaling in adrenocortical cells in vitro. RESULTS: IGFBP-2 mRNA level distinguished between the two genetic subtypes of this disease; increased IGFBP-2 expression in PRKAR1A mutation-positive PPNAD tissues was also confirmed by immunohistochemistry. Moreover, PKA inhibitors increased IGFBP-2 expression in NCI-H295R adrenocortical cells, and anti-IGFBP-2 antibody reduced their proliferation. CONCLUSIONS: IGFBP-2 expression is increased in PPNAD caused by PRKAR1A mutations, and in adrenocortical cancer cells. This is the first evidence for PKA-dependent regulation of IGFBP-2 expression in adrenocortical cells.     

Assessment of work intensification by managers and psychological distressed and non-distressed employees: a multilevel comparison

Work intensification is a popular management strategy to increase productivity, but at the possible expense of employee mental stress. This study examines associations between ratings of work intensification and psychological distress, and the level of agreement between compared employee-rated and manager-rated work intensification. Multi-source survey data were collected from 3,064 employees and 573 company managers from the private sector in 2010. Multilevel regression models were used to compare different work intensification ratings across psychological distress strata. Distressed employees rated higher degree of total work intensification compared to non-distressed employees, and on three out of five sub ratings there were an increased prevalence of work intensification in the case group. In general, there was poor agreement between employee and company work intensification rating. Neither manager-rated work intensification nor employee/manager discrepancy in work intensification ratings was associated with psychological distress. Distressed employees had a higher total score of employee/manager agreed work intensification, and a higher prevalence of increased demands of labour productivity. This study demonstrates higher ratings of employee/manager agreed work intensification in distressed employees compared to non-distressed employees, challenging previous findings of reporting bias in distressed employees’ assessment of work environment.