Context:
Cushing's disease (CD) is accompanied by an increased risk of venous thromboembolism. Surgery is the primary treatment of CD.
Objective:
The aim of the study was to compare hemostatic ...parameters between patients with CD and controls and to evaluate the effect of medical treatment of CD on hemostasis.
Design and Setting:
During 80 d, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline, and ketoconazole, which suppresses adrenocortical steroidogenesis, at four university medical centers in The Netherlands.
Patients:
Seventeen patients with de novo, residual, or recurrent CD were included.
Main Outcome Measures:
We measured urinary free cortisol and parameters of coagulation and fibrinolysis.
Results:
Patients with CD had significantly higher body mass index (P < 0.001), shortened activated partial thromboplastin time (P < 0.01), and higher levels of fibrinogen, Factor VIII, and protein S activity (P < 0.05) compared to healthy control subjects. In addition, fibrinolytic capacity was impaired in patients with CD as reflected by prolonged clot lysis time (P < 0.001) and higher levels of plasminogen activator inhibitor type 1, thrombin-activatable fibrinolysis inhibitor, and α2-antiplasmin (P < 0.01). There were no statistically significant differences in von Willebrand factor:antigen, antithrombin, and protein C activity. After 80 d, 15 of 17 patients had normalized urinary free cortisol excretion. Despite biochemical remission, only slight decreases in antithrombin (P < 0.01) and thrombin-activatable fibrinolysis inhibitor (P < 0.05) levels were observed. Other parameters of coagulation and fibrinolysis did not change significantly.
Conclusions:
The hypercoagulable state in patients with CD, which is explained by both increased production of procoagulant factors and impaired fibrinolysis, is not reversible upon short-term biochemical remission after successful medical therapy. This may have implications for the duration of anticoagulant prophylaxis in patients with (cured) CD.
Context:
Corticotroph pituitary adenomas often highly express the dopamine 2 receptor (D2R) and somatostatin receptor subtype 5 (sst5). The sst2 expression is relatively low, likely resulting from ...downregulating effects of high cortisol levels. This may explain why the sst2-preferring somatostatin analog octreotide, compared with the multi–receptor-targeting somatostatin analog pasireotide, is generally ineffective in Cushing's disease.
Objective:
Our objective was to compare sst and D2R expression levels between adenomas from patients with elevated and normalized preoperative urinary free cortisol excretion.
Patients and Design:
Corticotroph adenoma tissue was examined from patients from group 1 (n = 22; elevated preoperative urinary free cortisol) and group 2 (n = 11; mean duration of preoperative normocortisolism 10 weeks). Somatotroph adenoma tissue from 10 acromegalic patients was examined to compare receptor expression profiles.
Main Outcome Measures:
We evaluated receptor mRNA and protein expression levels and effects of octreotide, pasireotide, and cabergoline on ACTH secretion by cultured human corticotroph adenoma cells.
Results:
The sst2 mRNA expression in group 2 was 10-fold higher than in group 1 (P < .01), even comparable to that in somatotroph adenomas. There were no statistically significant differences in sst5 and D2R mRNA expression or in sst2, sst5, and D2R protein expression between both groups of corticotroph adenomas. In responders, octreotide (n = 2 out of 4; −30.5% ± 10.4%) was less potent than pasireotide (n = 5 out of 6; −47.0% ± 4.2%) and cabergoline (n = 3 out of 4; −41.9% ± 3.1%) with respect to inhibition of ACTH secretion by adenomas from group 2.
Conclusions:
After achieving normocortisolism induced by medical therapy, cortisol-mediated sst2 downregulation on corticotroph adenomas appears to be a reversible process at the mRNA but not at the protein level. Octreotide remains less potent than pasireotide and cabergoline with respect to in vitro inhibition of ACTH secretion. Whether sustained normocortisolism induced by medical therapy induces re-expression of functional sst2 protein in corticotroph adenomas and whether this increases the ACTH-lowering potency of octreotide remains to be established.
Context: Low IGF-I signaling activity prolongs lifespan in certain animal models, but the precise role of IGF-I in human survival remains controversial. The IGF-I kinase receptor activation assay is ...a novel method for measuring IGF-I bioactivity in human serum. We speculated that determination of circulating IGF-I bioactivity is more informative than levels of immunoreactive IGF-I.
Objective: Our objective was to study IGF-I bioactivity in relation to human survival.
Design, Setting, and Study Participants: We conducted a prospective observational study at a clinical research center at a university hospital of 376 healthy elderly men (aged 73–94 yr).
Main Outcome Measures: IGF-I bioactivity was determined by the IGF-I kinase receptor activation assay. Total and free IGF-I were determined by IGF-I immunoassays. Mortality was registered during follow-up (mean 82 months).
Results: During the follow-up period of 8.6 yr, 170 men (45%) died. Survival of subjects in the highest quartile of IGF-I bioactivity was significantly better than in the lowest quartile, both in the total study group hazard ratio (HR) = 1.8; 95% confidence interval (95% CI) = 1.2–2.8; P = 0.01 as well as in subgroups having a medical history of cardiovascular disease (HR = 2.4; 95% CI = 1.3–4.3; P = 0.003) or a high inflammatory risk profile (HR = 2.3; 95% CI = 1.2–4.5; P = 0.01). Significant relationships were not observed for total or free IGF-I.
Conclusion: Our study suggests that a relatively high circulating IGF-I bioactivity in elderly men is associated with extended survival and with reduced cardiovascular risk.
Context:
Two patients presented with Cushing's syndrome due to ectopic ACTH secretion. Initial localization studies included computed tomography, magnetic resonance imaging, and octreoscans ...(111In-pentreotide scintigraphy), which were negative in both patients. They were treated with the glucocorticoid receptor antagonist mifepristone, with improvement in their clinical symptoms. Follow-up octreoscans after, respectively, 6 and 12 months showed the unequivocal presence of a bronchial carcinoid in both patients.
Objective:
The objective of the study was to correlate in vivo and in vitro findings in patients with ectopic ACTH-producing syndrome.
Methods:
We determined the expression of somatostatin and dopamine receptors by immunohistochemistry (patients 1 and 2), quantitative PCR, and in vitro culturing of tumor cells (patient 1 only).
In Vitro Results:
Both tumors were strongly positive for somatostatin receptor type 2 (sst2) on immunohistochemistry, whereas one of the tumors (patient 1) was also dopamine receptor subtype 2 (D2) positive on both immunohistochemistry and quantitative PCR. Octreotide (a sst2 preferring analog) and cabergoline (D2 agonist) both decreased the ACTH levels in the cultured tumor cells of patient 1.
Conclusion:
We describe two patients with ACTH-producing bronchial carcinoids, in whom a direct down-regulatory effect of glucocorticoid levels on tumoral sst2 receptor expression is suggested by a remarkable change in octreoscan status after successful mifepristone therapy. Further studies will have to demonstrate whether glucocorticoid lowering or antagonizing therapy may be used to improve the diagnostic accuracy of somatostatin receptor scintigraphy in patients with ectopic ACTH production of unknown primary origin.
Abstract
Objectives
AmpC-β-lactamase production is an under-recognized antibiotic resistance mechanism that renders Gram-negative bacteria resistant to common β-lactam antibiotics, similar to the ...well-known ESBLs. For infection control purposes, it is important to be able to discriminate between plasmid-mediated AmpC (pAmpC) production and chromosomal-mediated AmpC (cAmpC) hyperproduction in Gram-negative bacteria as pAmpC requires isolation precautions to minimize the risk of horizontal gene transmission. Detecting pAmpC in Escherichia coli is challenging, as both pAmpC production and cAmpC hyperproduction may lead to third-generation cephalosporin resistance.
Methods
We tested a collection of E. coli strains suspected to produce AmpC. Elaborate susceptibility testing for third-generation cephalosporins, WGS and machine learning were used to develop an algorithm to determine ampC genotypes in E. coli. WGS was applied to detect pampC genes, cAmpC hyperproducers and STs.
Results
In total, 172 E. coli strains (n=75 ST) were divided into a training set and two validation sets. Ninety strains were pampC positive, the predominant gene being blaCMY-2 (86.7%), followed by blaDHA-1 (7.8%), and 59 strains were cAmpC hyperproducers. The algorithm used a cefotaxime MIC value above 6 mg/L to identify pampC-positive E. coli and an MIC value of 0.5 mg/L to discriminate between cAmpC-hyperproducing and non-cAmpC-hyperproducing E. coli strains. Accuracy was 0.88 (95% CI=0.79–0.94) on the training set, 0.79 (95% CI=0.64–0.89) on validation set 1 and 0.85 (95% CI=0.71–0.94) on validation set 2.
Conclusions
This approach resulted in a pragmatic algorithm for differentiating ampC genotypes in E. coli based on phenotypic susceptibility testing.
Background:
Accumulating evidence suggests that hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA axis) is involved in depression. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) ...converts inert cortisone to active cortisol and is implicated in HPA axis regulation in animal studies. The aim of our study was to identify polymorphisms in 11β-HSD1 gene (HSD11B1) with consistent associations with increased HPA axis activity and relate those polymorphisms to depression.
Methods:
Twelve single-nucleotide polymorphisms (SNPs), including 11 tagging SNPs, were selected using the HapMap database and genotyped in 4228 participants of the population-based Rotterdam Study. The outcome measures were salivary cortisol levels after awakening, 30 min later, at 1700 h, at bedtime, and plasma levels of androstenedione (in women only). SNPs that were significantly associated with cortisol as well as androstenedione levels were also related to incident depression.
Results:
rs11119328 was associated with higher cortisol saliva samples collected at bedtime as well as higher androstenedione levels (P value after correction for multiple testing: 0.01 and 0.04, respectively). Carriers of this polymorphism had an increased risk of an incident depression (hazard ratio 1.28, 95% confidence interval 1.03–1.59). Two other SNPs, which were in high linkage disequilibrium with rs11119328, were related to higher cortisol levels but not with androstenedione levels.
Conclusions:
We identified one SNP, which was associated with increased salivary cortisol levels at nadir as well as higher androstenedione levels. Moreover, this SNP was also associated with a higher risk of an incident depression. This suggests that 11β-HSD1 is implicated in human HPA axis regulation and susceptibility to depression.
Background
Up to 33 per cent of patients with uncomplicated symptomatic cholecystolithiasis report persistent pain after cholecystectomy. The aim of this study was to determine characteristics ...associated with patient‐reported absence of abdominal pain after cholecystectomy, improved abdominal symptoms, and patient‐reported positive cholecystectomy results in a prospective cohort multicentre study.
Methods
Patients aged 18 years or more with symptomatic cholecystolithiasis who had a cholecystectomy between June 2012 and June 2014 in one of three hospitals were included. Before surgery all patients were sent the Gastrointestinal Quality of Life Index (GIQLI) questionnaire and the McGill Pain Questionnaire (MPQ). At 12 weeks after surgery, patients were invited to complete the GIQLI and Patients' Experience of Surgery Questionnaire (PESQ). Logistic regression analyses were performed to determine associations.
Results
Questionnaires were sent to 552 patients and returned by 342 before and after surgery. Postoperative absence of abdominal pain was reported by 60·5 per cent of patients. A high preoperative GIQLI score, episodic pain, and duration of pain of 1 year or less were associated with postoperative absence of pain. These factors showed no association with improved abdominal symptoms (reported by 91·5 per cent of patients) or a positive surgery result (reported by 92·4 per cent).
Conclusion
Preoperative characteristics determine the odds for relief of abdominal pain after cholecystectomy. However, these factors were not associated with patient‐reported improvement of abdominal symptoms or patient‐reported positive cholecystectomy results, highlighting the variation of internal standards and expectations of patients before cholecystectomy.
Sixty per cent of patients cured
The hypothalamus is a major target for glucocorticoids and a key structure for hypothalamic‐pituitary‐adrenal (HPA) axis setpoint regulation. The enzyme 11β hydroxysteroid dehydrogenase type 1 ...(11βHSD1) modulates glucocorticoid signalling in various tissues at the prereceptor level by converting biologically inactive cortisone to its active form cortisol. The present study aimed to assess 11βHSD1 expression in the human hypothalamus. We studied 11βHSD1 expression in five frozen and four formalin‐fixed, paraffin‐embedded human hypothalami (obtained from the Netherlands Brain Bank) by the polymerase chain reaction and immunocytochemistry, respectively. 11βHSD1 mRNA was expressed in the area of the suprachiasmatic nucleus, which is the biological clock of the brain, in the supraoptic nucleus and paraventricular nucleus (PVN), and in the infundibular nucleus, which is the human homologue of the rodent arcuate nucleus. 11βHSD1 was detected by immunocytochemistry in the same nuclei. In the PVN, neuronal 11βHSD1 immunoreactivity colocalised with corticotrophin‐releasing hormone (CRH), arginine vasopressin and oxytocin, as shown by dual fluorescence staining. Our data demonstrate that 11βHSD1 is widely expressed in the human hypothalamus. Its colocalisation with CRH in the PVN suggests a role in modulation of glucocorticoid feedback of the HPA axis, whereas the expression of 11βHSD1 in additional and functionally diverse hypothalamic nuclei points to a role for the enzyme in the regulation of metabolism, appetite and circadian rhythms.
An in-depth case study approach was followed and data were collected by means of nine semi-structured interviews with experts from six case organizations. Our findings indicate that gamification of ...work can be a promising path for working organizations and can be beneficial to both employers and employees. The success of gamification at the workplace is dependent on whether its implementation is able to fulfill employees’ psychological needs for competence, autonomy, and relatedness. To make the most out of gamification at the workplace, employers, supervisors, and employees themselves should pay ample attention to its conditions (i.e., personal preferences of the employees, their demographic characteristics, their need for psychological safety, and the purposefulness of the game). In addition, seven psychological mechanisms underlying successful performance were found in our empirical work (i.e., competition, intrinsic incentives, extrinsic incentives, choice, social interaction, feedback, and ownership). The properties of gamification schemes that also have to be dealt with by the parties involved comprise their duration and intensity, the inclusion of a facilitator, the type of equipment, and scale referring to the size of the gamification scheme. Finally, our study has provided more insight into the possible effects of gamification schemes (i.e., increased insight in the workflow and, through this, a better understanding of both the employees’ own contributions and of their employers’ contributions to the work processes, the transfer of game elements into work processes, team building enhancement, learning effects, and negative emotions).
Departments of 1 Internal Medicine,
2 Immunology, and 4 Pathology,
Josephine Nefkens Institute, Erasmus MC, 3015 GD Rotterdam, The Netherlands;
and 3 Radiology Department, Washington University
...School of Medicine, St. Louis, Missouri 63110
Submitted 3 February 2003
; accepted in final form 6 April 2003
Increasing evidence suggests that neuropeptides play a role in the
regulatory mechanisms between the neuroendocrine and immune systems. A
differential expression of the five known somatostatin (SS) receptors
(sst 15 ) has been demonstrated in human immune cells and
tissues. However, little is known concerning regulation and expression of
sst 15 and the peptide SS. Therefore, we investigated the
expression and the time-dependent regulation of sst 15 , SS,
and cortistatin (CST), a novel SS-like peptide, in human monocytes (MO),
monocyte-derived macrophages (MP), and dendritic cells (DC) in the basal and
lipopolysaccharide (LPS)-activated state. MO, MP, and DC selectively expressed
sst 2 mRNA. SS mRNA was not detectable, whereas all samples
expressed CST mRNA. Expression levels of sst 2 and CST mRNA showed
marked differences and were in the rank order of MP>>DC>>>MO.
LPS stimulation did not induce expression of SS or sst 1,3,4,5 .
However, sst 2 mRNA expression was upregulated significantly by
stimulation with LPS. CST mRNA was upregulated as well. During differentiation
of MO in MP or DC, time-dependent, significantly increasing sst 2
and CST mRNA levels were found. By confocal microscopy, the presence of
sst 2 receptors was demonstrated on MP, but not on DC. This study
demonstrates for the first time a selective and inducible expression of the
recently discovered CST, as well as sst 2 , in human monocyte-derived
cells, suggesting a role for a CST-sst 2 system rather than a
SS-sst 2 system in these immune cell types.
cellular differentiation; cellular activation; neuropeptides; messenger ribonucleic acid
Address for reprint requests and other correspondence: L. J. Hofland, Dept. of
Internal Medicine, Rm. Bd 240, Erasmus MC, Dr. Molewaterplein 40, 3015 GD,
Rotterdam, The Netherlands (E-mail:
l.hofland{at}erasmusmc.nl ).
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