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Background: Dysregulation of the hypothalamic-pituitary-adrenal axis has been suggested as an independent risk factor for ischemic heart disease. The aim of our study was to evaluate whether two markers of the hypothalamic-pituitary-adrenal axis activity, the level of salivary cortisol and the diurnal salivary cortisol pattern, are associated with atherosclerosis of the carotid arteries in an elderly population., Methods and Results: A total of 1866 participants of the Rotterdam Study, a population-based cohort study in the elderly, provided four salivary cortisol samples throughout 1 d, and underwent ultrasonography to examine the presence of plaques in the common, internal, and bifurcation sites of both carotid arteries. Two summary measures of the separate cortisol values were computed: area under the curve (AUC), which is a measure of total cortisol exposure while awake; and the slope, which is a measure of diurnal cortisol decline., Results: Total cortisol exposure while awake (AUC) was associated with higher plaque scores (beta = 0.08 per sd of AUC, 95% confidence interval 0.00-0.16; P = 0.04) in a fully adjusted linear regression model. Persons with an AUC in the highest tertile had a higher number of plaques of carotid arteries compared with those in the lowest tertile (3.08 vs. 2.80, 95% confidence interval of difference 0.09-0.48; P = 0.005). There was no relation between diurnal cortisol decline and plaque score., Conclusion: Our results support the hypothesis that increased total cortisol exposure is independently associated with atherosclerosis of the carotid arteries.

Objective: The objective of the study was to assess whether weekly administration of 40 mg pegvisomant (PEG-V) improves quality of life (QoL) and metabolic parameters in acromegalic patients with normal age-adjusted IGF-I concentrations during long-acting somatostatin analog (SSA) treatment., Design: This was a prospective, investigator-initiated, double blind, placebo-controlled, crossover study. Twenty acromegalic subjects received either PEG-V or placebo for two consecutive treatment periods of 16 wk, separated by a washout period of 4 wk. Efficacy was assessed as change between baseline and end of each treatment period. QoL was assessed by the Acromegaly Quality of Life Questionnaire (AcroQoL) and the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ)., Results: The AcroQoL (P = 0.008) and AcroQoL physical (P = 0.002) improved significantly after PEG-V was added. The addition of PEG-V also significantly improved the PASQ (P = 0.038) and the single PASQ questions, perspiration (P = 0.024), soft tissue swelling (P = 0.036), and overall health status (P = 0.035). No significant change in Z-score of IGF-I (P = 0.34) was observed during addition of PEG-V. Transient liver enzyme elevations were observed in five subjects (25%)., Conclusion: Improvement in quality of life was observed without significant change in IGF-I after the addition of 40 mg pegvisomant weekly to monthly SSA therapy in acromegalic patients who had normalized IGF-I on SSA monotherapy. These data question the current recommendations in how to assess disease activity in acromegaly. Moreover, the findings question the validity of the current approach of medical treatment in which pegvisomant is used only when SSA therapy has failed to normalize IGF-I.

Unlabelled: Chronic exposure to hypercortisolism has significant impact on patient's health and health-related quality of life (HRQoL), as demonstrated with generic questionnaires. We have developed a disease-generated questionnaire to evaluate HRQoL in patients with Cushing's syndrome (CS; CushingQoL)., Objective: Validate the CushingQoL questionnaire in patients with CS in clinical practice conditions., Design: Observational, international, cross-sectional study., Methods: A total of 125 patients were recruited by 14 investigators from Spain, France, Germany, The Netherlands, and Italy over a 2-month period. Clinical and hormonal data were collected and correlated with results of the generic short form 36 (SF-36) questionnaire, a question on self-perceived general health status and the CushingQoL score., Results: A total of 107 patients were pituitary-dependent and 18 adrenal-dependent CS; 104 (83%) were females, mean age 45 years (range 20-73 years); 39 (31%) were currently hypercortisolemic; and 47 (38%) adrenal insufficient. In clinical practice, CushingQoL was feasible (117; 94% of patients fully responded to the questionnaire in a mean time of 4 min), reliable (Crohnbach's alpha=0.87), and valid (factorial analysis demonstrated unidimensionality and Rasch analysis lead to a final version with 12 items). A significant (P<0.001) correlation was observed between CushingQoL score and patients self-perceived general health status and dimensions of SF-36 (Pearson's correlation coefficient > or =0.597). Patients with current hypercortisolism scored worse (lower) than those without (44+/-22 vs 56+/-21, P=0.004). Linear regression analysis identified female gender and hypercortisolism as significant predictors for worse QoL., Conclusion: CushingQoL is useful to evaluate HRQoL in patients with CS and correlates with clinical parameters.

Context: Increased mortality in patients with pituitary tumors after surgical treatment has been reported. However, it is unknown to what extent excess mortality is caused by pituitary tumors and their treatment in general and to what extent by previous exposure to hormonal overproduction., Objective: The aim of the study was to compare mortality between patients treated for Cushing's disease and nonfunctioning pituitary macroadenomas (NFMAs)., Design: This was a follow-up study., Patients: We included 248 consecutive patients with pituitary adenomas treated by transsphenoidal surgery in our hospital for NFMAs (n = 174) and ACTH-producing adenomas (n = 74). The mean duration of follow-up after surgery was 10.1 +/- 7.2 yr for the whole cohort., Outcome Measures: The standardized mortality ratio (SMR) was calculated for the whole cohort and also for the two diseases separately. Cox regression analysis was used to compare mortality in patients with Cushing's disease with NFMA patients., Results: Patients with Cushing's disease (39.1 +/- 16.1 yr) were significantly younger at time of operation than NFMA patients (55.3 +/- 13.4 yr). The SMR for the whole cohort was 1.41 [95% confidence interval (CI), 1.05-1.86]. The SMR in NFMA patients was 1.24 (95% CI, 0.85-1.74) vs. 2.39 (95% CI, 1.22-3.9) in patients with Cushing's disease. In patients with Cushing's disease, compared with NFMAs, the age-adjusted mortality was significantly increased: hazard ratio 2.35 (95% CI, 1.13-4.09, P = 0.008)., Conclusions: Mortality in patients previously treated for Cushing's disease is increased, compared with patients treated for NFMAs. This implies that previous, transient overexposure to cortisol is associated with increased mortality.

Objective: To investigate predictors for externalizing behaviors and minor unintentional injuries in toddlers and to examine whether common risk factors can be identified., Methods: Linear regression models were used to investigate the contributions of predictors belonging to the domains of child characteristics and parental characteristics. Participants were 117 boys (M = 16.9 months) and their parents., Results: Two common risk factors for externalizing behaviors and minor injuries were identified: maternal low conscientiousness and paternal low self-control. In addition, children's inhibitory control and dispositional frustration as well as maternal externalizing symptoms contributed independently to children's externalizing behaviors., Conclusions: Results supply some evidence for the interrelatedness of negative outcomes and on the existence of common risk factors. Interventions could aim to address these common risk factors in order to pursue a number of goals at the same time, instead of focusing on only one type of negative outcome.

We report on a patient with acromegaly who developed severe drug-induced hepatitis during combined treatment with the long-acting somatostatin-analog octreotide and the GH receptor antagonist pegvisomant. The hepatic enzyme disturbances normalized after discontinuation of pegvisomant. After rechallenge with monotherapy pegvisomant, however, the hepatic enzyme disturbances reappeared within a few weeks, indicating that most likely pegvisomant alone and not the long-acting somatostatin analog or the combination of these two drugs was responsible for this case of drug-induced hepatitis. Clinicians should be aware of this potential severe adverse drug reaction and therefore frequent control of hepatic enzymes is mandatory during treatment with pegvisomant.

To evaluate the long-term impact of cured Cushing's disease on subjective well-being, we assessed quality of life by validated health-related questionnaires in 58 patients cured from Cushing's disease by transsphenoidal surgery (n = 58), some of whom received additional radiotherapy (n = 11) and/or bilateral adrenalectomy (n = 3). The mean duration of remission was 13.4 +/- 6.7 yr (range of 2-25 yr). Patient data were compared with a control group of 98 healthy subjects with the same age and sex distribution and with age-adjusted reference values available from the literature. General perceived well-being, measured by the Nottingham Health Profile and the Short Form, was reduced compared with controls for all subscales (P < 0.001). Patients with Cushing's disease had worse scores on subscales of fatigue Multidimensional Fatigue Index and anxiety and depression (Hospital Anxiety and Depression Scale). Compared with reference values from the literature, quality of life was also reduced in the patients according to all questionnaires and all items, except pain (Short Form), sleep (Nottingham Health Profile), and reduced activity (Multidimensional Fatigue Index). Despite conventional hormone replacement therapy, hypopituitarism was an important independent predictor of reduced quality of life. Patients without hypopituitarism (n = 28) showed reduced scores on physical items but normal scores on mental items compared with controls. In conclusion, despite long-term cure of Cushing's disease, patients experience a considerable decrease in quality of life, with physical and psychosocial impairments, especially in the presence of hypopituitarism.

To evaluate the pathophysiology of altered cortisol secretion in patients with primary adrenal hypercortisolism, cortisol secretion was investigated in 12 patients, seven with a unilateral adenoma and five with ACTH-independent macronodular adrenal hyperplasia compared with age- and gender-matched controls and with patients with pituitary-dependent hypercortisolism. Pulsatile secretion was increased 2-fold (P = 0.04), attributable to increased event frequency (P = 0.002). All patients showed a significant diurnal rhythm with a delay in phase shift of 3 h (P = 0.01). Approximate entropy ratio, a feedback-sensitive measure, was increased compared with controls (P = 0.00003) but similar to that of pituitary-dependent hypercortisolism (P = 0.77), denoting loss of autoregulation. Cortisol burst-mass tended to be smaller in patients with ACTH-independent macronodular adrenal hyperplasia than in unilateral adenoma (P = 0.06). In conclusion, increased cortisol secretion in patients with primary adrenal Cushing's syndrome is caused by amplified pulsatile secretion via event frequency modulation. We speculate that partial preservation of secretory regularity and diurnal rhythmicity point to incomplete autonomy of these tumors.

To evaluate possible risk factors for meningitis, we retrospectively reviewed 228 transsphenoidal operations (in which a standard regimen of amoxicillin prophylaxis was used) for sellar pathology. The incidence of meningitis was 3.1% (seven of 228 cases). Cultures of preoperative specimens from the anterior nasal vestibule in three of seven patients yielded Staphylococcus aureus, but none of these patients developed S. aureus meningitis. Two of three patients with significant preoperative paranasal sinus abnormalities developed meningitis compared with only five of 225 patients without significant paranasal sinus abnormalities (P < .005). Three of 22 patients with intraoperative cerebrospinal fluid (CSF) leakage developed meningitis compared with four of 206 patients without intraoperative CSF leakage (P < .05). Six of seven patients with postoperative CSF rhinorrhea and only one of 221 patients without postoperative CSF rhinorrhea developed meningitis (P < .00001). In conclusion, postoperative CSF leakage is an important risk factor for meningitis after transsphenoidal surgery. Cultures of preoperative specimens from the anterior nasal vestibule did not have any predictive value in our study.

Studied developmental and gender differences in distress behavior during separate phases of a medical treatment in 2 cultures. Distress reactions of 175 children with cancer (age 8 months-18 years 7 months) were observed during bone marrow aspirations (BMA) in 2 different treatment centers (one in the United States, one in The Netherlands) using a behavioral checklist (Procedure Behavioral Rating Scale). The BMAs contained a preparatory phase, the actual needle introduction, and a recovery period. In both cultures almost all separate distress behaviors occurred less in older children, except for increasing muscle tension during the actual puncture. Distress was highest during the needle introduction and significantly lower during the preparatory and recovery phases; in addition, somewhat different patterns of distress behavior were found in separate phases. Culture and sex differences were found. The latter were less robust than developmental and phase differences.