Maarten O. van Aken

Disease-specific impairments in quality of life during long-term follow-up of patients with different pituitary adenomas

Objectiveu2002 Quality of life (QoL) is impaired in patients treated for pituitary adenomas. However, differences in age and gender distributions hamper a proper comparison of QoL. Therefore, we compared age‐ and gender‐specific standard deviations (SD) scores (Z‐scores) of QoL parameters in patients treated for pituitary adenomas.

Automated Measurement of Salivary Cortisol

A new serum cortisol assay was introduced on the Elecsys (Roche), a random access analyzer, with reportedly good performance in the low (nmol/L) concentration range (preliminary data provided by the manufacturer) and with low cross-reactivity with cortisone [0.3% at 2.7 μmol/L cortisone (package insert)]. This prompted us to evaluate the performance of this new assay for the measurement of salivary cortisol.nnFor this study, saliva samples were collected with a Salivette® (Sarstedt), with an insert containing a sterile polyester swab for collection of the saliva, yielding a clear and particle-free sample. The salivettes were used according to the instructions provided by the manufacturer. Samples collected this way are stable at room temperature for at least a week and, therefore, offer the opportunity to collect samples at home (1)(2). Salivettes containing saliva were centrifuged at 2000 g for 10 min, and the filtrates were stored frozen (−20 °C). Before analysis, the samples were thawed, mixed, and placed on the Elecsys analyzer without pretreatment.nnThe Roche cortisol assay is a competitive electrochemiluminescence immunoassay (ECLIA) that uses a sheep polyclonal antibody. Endogenous cortisol contained in the sample is liberated from …

Morbidly Obese Human Subjects Have Increased Peripheral Blood CD4+ T Cells With Skewing Toward a Treg- and Th2-Dominated Phenotype

Obesity is associated with local T-cell abnormalities in adipose tissue. Systemic obesity-related abnormalities in the peripheral blood T-cell compartment are not well defined. In this study, we investigated the peripheral blood T-cell compartment of morbidly obese and lean subjects. We determined all major T-cell subpopulations via six-color flow cytometry, including CD8+ and CD4+ T cells, CD4+ T-helper (Th) subpopulations, and natural CD4+CD25+FoxP3+ T-regulatory (Treg) cells. Moreover, molecular analyses to assess thymic output, T-cell proliferation (T-cell receptor excision circle analysis), and T-cell receptor-β (TCRB) repertoire (GeneScan analysis) were performed. In addition, we determined plasma levels of proinflammatory cytokines and cytokines associated with Th subpopulations and T-cell proliferation. Morbidly obese subjects had a selective increase in peripheral blood CD4+ naive, memory, natural CD4+CD25+FoxP3+ Treg, and Th2 T cells, whereas CD8+ T cells were normal. CD4+ and CD8+ T-cell proliferation was increased, whereas the TCRB repertoire was not significantly altered. Plasma levels of cytokines CCL5 and IL-7 were elevated. CD4+ T-cell numbers correlated positively with fasting insulin levels. The peripheral blood T-cell compartment of morbidly obese subjects is characterized by increased homeostatic T-cell proliferation to which cytokines IL-7 and CCL5, among others, might contribute. This is associated with increased CD4+ T cells, with skewing toward a Treg- and Th2-dominated phenotype, suggesting a more anti-inflammatory set point.

Somatostatin receptor imaging for neuroendocrine tumors

Tumors and metastases that express the somatostatin receptor subtypes sst2 sst3 or sst5 can be visualized in vivo after injection of radiolabeled octapeptide somatostatin analogs, like 111In-pentetreotide. 111In-pentetreotide scintigraphy also allows for more accurate staging of the disease by demonstrating tumor sites, which were not shown by conventional imaging. 111In-pentetreotide scintigraphy may also detect resectable tumors that would have remained unrecognized using conventional radiological imaging techniques; it may prevent surgery with curative intent in those patients whose tumors have metastasized to a greater extend than could be detected with conventional radiological imaging and it may be used to select patients for treatment with the currently available octapeptide somatostatin analogs or with tumor targeted radioactive treatment with radiolabelled somatostatin analogs.111In-pentetreotide scintigraphy has also been used to select patients with pituitary tumors for medical treatment with octapeptide analogs, but its clinical usefulness for this purpose seems to be limited. It further allows scar tissue to be differentiated from tumor recurrence after the pituitary surgery or radiotherapy. However, a large variety of lesions in and around the pituitary region also express somatostatin receptors and, therefore, can be visualized by 111In-pentetreotide scintigraphy.

Effects of acute administration of acylated and unacylated ghrelin on glucose and insulin concentrations in morbidly obese subjects without overt diabetes

OBJECTIVEnTo investigate the effects of unacylated ghrelin (UAG) and co-administration of acylated ghrelin (AG) and UAG in morbid obesity, a condition characterized by insulin resistance and low GH levels.nnnDESIGN AND METHODnEight morbidly obese non-diabetic subjects were treated with either UAG 200 microg, UAG 100 microg in combination with AG 100 microg (Comb) or placebo in three episodes of 4 consecutive days in a double-blind randomized crossover design. Study medication was administered as daily single i.v. bolus injections at 0900 h after an overnight fast. At 1000 h, a standardized meal was served. Glucose, insulin, GH, free fatty acids (FFA) and ghrelin were measured up to 4 h after administration.nnnRESULTSnInsulin concentrations significantly decreased after acute administration of Comb only, reaching a minimum at 20 min: 58.2 + or - 3.9% of baseline versus 88.7 + or - 7.2 and 92.7 + or - 2.6% after administration of placebo and UAG respectively (P<0.01). After 1 h, insulin concentration had returned to baseline. Glucose concentrations did not change after Comb. However, UAG administration alone did not change glucose, insulin, FFA or GH levels.nnnCONCLUSIONnCo-administration of AG and UAG as a single i.v. bolus injection causes a significant decrease in insulin concentration in non-diabetic subjects suffering from morbid obesity. Since glucose concentration did not change in the first hour after Comb administration, our data suggest a strong improvement in insulin sensitivity. These findings warrant studies in which UAG with or without AG is administered for a longer period of time. Administration of a single bolus injection of UAG did not influence glucose and insulin metabolism.

Risk Factors for Meningitis After Transsphenoidal Surgery

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.

Postoperative metyrapone test in the early assessment of outcome of pituitary surgery for Cushing's disease

The prediction of relapse during the early months after transsphenoidal surgery for Cushings disease remains difficult. We have evaluated the usefulness of the postoperative metyrapone test in this situation.

Profound amplification of secretory-burst mass and anomalous regularity of ACTH secretory process in patients with Nelson's syndrome compared with Cushing's disease

objectiveu2002 As described originally, Nelsons syndrome is characterized by grossly elevated ACTH concentrations, a sellar mass and skin hyperpigmentation emerging in the course of Cushings disease after bilateral adrenalectomy. No detailed studies have defined whether the mechanisms directing ACTH secretion differ in Nelsons syndrome and untreated Cushings disease.

ACTH-independent macronodular adrenocortical hyperplasia reveals prevalent aberrant in vivo and in vitro responses to hormonal stimuli and coupling of arginine-vasopressin type 1a receptor to 11β-hydroxylase.

BackgroundAdrenal Cushing’s syndrome caused by ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) can be accompanied by aberrant responses to hormonal stimuli. We investigated the prevalence of adrenocortical reactions to these stimuli in a large cohort of AIMAH patients, both in vivo and in vitro.MethodsIn vivo cortisol responses to hormonal stimuli were studied in 35 patients with ACTH-independent bilateral adrenal enlargement and (sub-)clinical hypercortisolism. In vitro, the effects of these stimuli on cortisol secretion and steroidogenic enzyme mRNA expression were evaluated in cultured AIMAH and other adrenocortical cells. Arginine-vasopressin (AVP) receptor mRNA levels were determined in the adrenal tissues.ResultsPositive serum cortisol responses to stimuli were detected in 27/35 AIMAH patients tested, with multiple responses within individual patients occurring for up to four stimuli. AVP and metoclopramide were the most prevalent hormonal stimuli triggering positive responses in vivo. Catecholamines induced short-term cortisol production more often in AIMAH cultures compared to other adrenal cells. Short- and long-term incubation with AVP increased cortisol secretion in cultures of AIMAH cells. AVP also increased steroidogenic enzyme mRNA expression, among which an aberrant induction of CYP11B1. AVP type 1a receptor was the only AVPR expressed and levels were high in the AIMAH tissues. AVPR1A expression was related to the AVP-induced stimulation of CYP11B1.ConclusionsMultiple hormonal signals can simultaneously induce hypercortisolism in AIMAH. AVP is the most prevalent eutopic signal and expression of its type 1a receptor was aberrantly linked to CYP11B1 expression.