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L. J. Hellebrekers, E. Lagerweij, H. W. de Vries and Tj. B. Van Wimersma Greidanus

Abstract. Experiments were performed in conscious dogs, in order to study the possibility of dopaminergic or opioid modulation of the osmolality-regulated release of AVP. Hypertonic saline (20%), infused during a period of 2 h at a rate of 0.03 ml· kg−1 · min−1, induced a significant AVP response, which was not influenced by prior administration of bromocriptine or naloxone. Data presented in this report, therefore, are not in support of a dopaminergic or opioid modulation of the osmolality-regulated AVP release in dogs. The results demonstrate a great consistency in individual plasma osmolality-plasma AVP relationships, next to a large inter-individual variation.

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L.J. Hellebrekers, E. Lagerweij, H W. de Vries and Tj. B. van Wimersma Greidanus

Abstract. The possibility of a dopaminergic and/or opioid modulation of the volume-regulated release of AVP was investigated in conscious dogs. Either bromocriptine, 10 μg/kg body weight po, or naloxone, 0.1 mg/kg body weight iv, was administered prior to induction of nonhypotensive hypovolemia. Volume contraction of 15 ml/kg body weight was induced gradually, over a period of 30 min. Basal plasma AVP levels in the bromocriptine group were not significantly different from control group values. Bromocriptine administration significantly augmented AVP release following volume contraction. Mean arterial pressure in the bromocriptine group decreased to a slightly, but significantly, lower level than that in the control group. Mean arterial pressures, however, did not adequately explain the magnitude of the AVP response in the bromocriptine group. In the naloxone group, neither baseline levels, nor AVP values following volume contraction, differed significantly from respective control group values. In conclusion, the results suggest the possibility of a stimulatory role for endogenous dopamine in the volume-regulated, but not the basal, release of AVP in conscious dogs.

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Sophie J van Asselt, Adrienne H Brouwers, Hendrik M van Dullemen, Eric J van der Jagt, Alfons H Bongaerts, Klaas P Koopmans, Ido P Kema, Bernard A Zonnenberg, Henri J Timmers, Wouter W de Herder, Wim J Sluiter, Elisabeth G de Vries and Thera P Links

Background

Patients with von Hippel-Lindau (VHL) disease are prone to develop pancreatic neuroendocrine tumors (pNETs). However, the best imaging technique for early detection of pNETs in VHL is currently unknown. In a head-to-head comparison, we evaluated endoscopic ultrasound (EUS) and 11C-5-hydroxytryptophan positron emission tomography (11C-5-HTP PET) compared with conventional screening techniques for early detection of pancreatic solid lesions in VHL patients.

Methods

We conducted a cross-sectional, prospective study in 22 patients at a tertiary care university medical center. Patients with VHL mutation or with one VHL manifestation and a mutation carrier as first-degree family member, with recent screening by abdominal computed tomography (CT) or magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS), were eligible. Patients underwent EUS by linear Pentax echoendoscope and Hitachi EUB-525, and 11C-5-HTP PET. Patient-based and lesion-based positivity for pancreatic solid lesions were calculated for all imaging techniques with a composite reference standard.

Results

In 10 of the 22 patients, 20 pancreatic solid lesions were detected: 17 with EUS (P < 0.05 vs CT/MRI+ SRS), 3 with 11C-5-HTP PET, 3 with SRS, 9 with CT/MRI, and 9 with CT/MRI + SRS. EUS evaluations showed solid lesions with a median size of 9.7 mm (range 2.9–55 mm) and most of them were homogeneous, hypoechoic, isoelastic, and hypervascular. Moreover, EUS detected multiple pancreatic cysts in 18 patients with a median of 4 cysts (range 1–30).

Conclusions

EUS is superior to CT/MRI + SRS for detecting pancreatic solid lesions in VHL disease.11C-5-HTP PET has no value as a screening method in this setting. EUS performs well in early detection of pNETs, but its role in VHL surveillance is unclear.

Free access

Sarina G Kant, Iveta Cervenkova, Lukas Balek, Lukas Trantirek, Gijs W E Santen, Martine C de Vries, Hermine A van Duyvenvoorde, Michiel J R van der Wielen, Annemieke J M H Verkerk, André G Uitterlinden, Sabine E Hannema, Jan M Wit, Wilma Oostdijk, Pavel Krejci and Monique Losekoot

Objective

Mutations of the fibroblast growth factor receptor 3 (FGFR3) cause various forms of short stature, of which the least severe phenotype is hypochondroplasia, mainly characterized by disproportionate short stature. Testing for an FGFR3 mutation is currently not part of routine diagnostic testing in children with short stature without disproportion.

Design

A three-generation family A with dominantly transmitted proportionate short stature was studied by whole-exome sequencing to identify the causal gene mutation. Functional studies and protein modeling studies were performed to confirm the pathogenicity of the mutation found in FGFR3. We performed Sanger sequencing in a second family B with dominant proportionate short stature and identified a rare variant in FGFR3.

Methods

Exome sequencing and/or Sanger sequencing was performed, followed by functional studies using transfection of the mutant FGFR3 into cultured cells; homology modeling was used to construct a three-dimensional model of the two FGFR3 variants.

Results

A novel p.M528I mutation in FGFR3 was detected in family A, which segregates with short stature and proved to be activating in vitro. In family B, a rare variant (p.F384L) was found in FGFR3, which did not segregate with short stature and showed normal functionality in vitro compared with WT.

Conclusions

Proportionate short stature can be caused by a mutation in F GFR3. Sequencing of this gene can be considered in patients with short stature, especially when there is an autosomal dominant pattern of inheritance. However, functional studies and segregation studies should be performed before concluding that a variant is pathogenic.

Free access

M Engels, K Gehrmann, H Falhammar, E A Webb, A Nordenström, F C Sweep, P N Span, A E van Herwaarden, J Rohayem, A Richter-Unruh, C Bouvattier, B Köhler, B B Kortmann, W Arlt, N Roeleveld, N Reisch, N M M L Stikkelbroeck, H L Claahsen-van der Grinten and dsd-LIFE group

Context

Current knowledge on gonadal function in congenital adrenal hyperplasia (CAH) is mostly limited to single-center/country studies enrolling small patient numbers. Overall data indicate that gonadal function can be compromised in men with CAH.

Objective

To determine gonadal function in men with CAH within the European ‘dsd-LIFE’ cohort.

Design

Cross-sectional clinical outcome study, including retrospective data from medical records.

Methods

Fourteen academic hospitals included 121 men with CAH aged 16–68 years. Main outcome measures were serum hormone concentrations, semen parameters and imaging data of the testes.

Results

At the time of assessment, 14/69 patients had a serum testosterone concentration below the reference range; 7 of those were hypogonadotropic, 6 normogonadotropic and 1 hypergonadotropic. In contrast, among the patients with normal serum testosterone (55/69), 4 were hypogonadotropic, 44 normogonadotropic and 7 hypergonadotropic. The association of decreased testosterone with reduced gonadotropin concentrations (odds ratio (OR) = 12.8 (2.9–57.3)) was weaker than the association between serum androstenedione/testosterone ratio ≥1 and reduced gonadotropin concentrations (OR = 39.3 (2.1–732.4)). Evaluation of sperm quality revealed decreased sperm concentrations (15/39), motility (13/37) and abnormal morphology (4/28). Testicular adrenal rest tumor (TART)s were present in 39/80 patients, with a higher prevalence in patients with the most severe genotype (14/18) and in patients with increased current 17-hydroxyprogesterone 20/35) or androstenedione (12/18) serum concentrations. Forty-three children were fathered by 26/113 patients.

Conclusions

Men with CAH have a high risk of developing hypothalamic-pituitary-gonadal disturbances and spermatogenic abnormalities. Regular assessment of endocrine gonadal function and imaging for TART development are recommended, in addition to measures for fertility protection.