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I Dijkstra

Publications and source records attributed to I Dijkstra.

13 recordsLinked to original sources
PubMed2002

Functional expression of CXCR3 in cultured mouse and human astrocytes and microglia.

It has been established recently that inflammation of the CNS is accompanied by an expression of chemokines within the CNS. Several lines of evidence suggest that chemokines within the CNS initiate and orchestrate the infiltration of the inflamed brain by blood leukocytes. It is also known that endogenous cells of the CNS express functional chemokine receptors, raising the possibility that chemokines may be involved in intercellular signalling between brain cells during brain inflammation. It was shown recently that two chemokine ligands for CXCR3 are induced rapidly in damaged neurons. Little is known yet on the function of neuronal chemokine expression. In order to investigate whether neuronal chemokines contribute to endogenous signalling within the CNS we investigated possible expression of CXCR3 in glial cells. Reverse transcription-polymerase chain reaction experiments and in situ hybridization analysis showed that cultured astrocytes and microglia from both mouse and human sources express CXCR3 mRNA. Protein expression of CXCR3 in both cell types was detected by immunocytochemistry. Moreover, stimulation of cultured glial cells with chemokine ligands for CXCR3 induced intracellular calcium transients and chemotaxis, indicating the functional expression of CXCR3. These results indicate that glial cells in culture functionally express the chemokine receptor CXCR3. Since it has been shown that brain damage rapidly induces expression of neuronal chemokines that activate CXCR3, we suggest that glial CXCR3 might contribute to an intercellular signalling system in the CNS related to pathological conditions.

Animals↗
PubMed1998

Reduced activity of hypothalamic corticotropin-releasing hormone neurons in transgenic mice with impaired glucocorticoid receptor function.

Loss of central glucocorticoid receptor (GR) function is thought to be involved in the development of neuroendocrine and psychiatric disorders associated with corticotropin-releasing hormone (CRH) hyperactivity. The possible causal relationship between defective GR function and altered activity of CRH neurons was studied in transgenic mice (TG) expressing antisense RNA against GR. Immunocytochemical studies showed significant reductions in CRH immunoreactive neurons in the paraventricular nucleus (PVN) and in CRH and vasopressin (AVP) stores in the external zone of the median eminence. Concomitantly, stimulus-evoked CRH secretion from mediobasal hypothalami of TG mice in vitro was reduced significantly. However, CRH mRNA levels in the PVN of TG mice were marginally lower than those in wild-type (WT) mice. 125I-CRH binding autoradiography revealed no differences between WT and TG animals in any of the brain regions that were studied. Basal plasma corticosterone (cort) levels and 125I-CRH binding, CRH-R1 mRNA, POMC mRNA, and POMC hnRNA levels in the anterior pituitary gland were similar in WT and TG mice. Intraperitoneal injection of interleukin-1beta (IL-1beta) increased plasma cort levels, CRH mRNA in the PVN, and anterior pituitary POMC hnRNA similarly in WT and TG mice. The injection of saline significantly reduced anterior pituitary CRH-R1 mRNA levels in WT mice, but not in TG mice, whereas IL-1beta produced a decrease in these mRNA levels in both strains. The data show that long-term GR dysfunction can be associated with reduced activity of CRH neurons in the PVN and decreased sensitivity of pituitary CRH-R1 mRNA to stimulus-induced downregulation. Moreover, the hypothalamic changes observed in this model suggest that impaired GR function, at least if present since early embryonic life, does not necessarily result in CRH hyperexpression characteristics of disorders such as major depression.

Animals↗
PubMed1996

Diurnal variation in resting levels of corticosterone is not mediated by variation in adrenal responsiveness to adrenocorticotropin but involves splanchnic nerve integrity.

To study possible mechanisms controlling diurnal changes in corticosterone (CORT) levels, we tested the CORT responses to ACTH in the morning (AM) and evening (PM) in male Wistar and Sprague-Dawley rats. Rat ACTH-(1-39) or human ACTH-(1-24) (3.75-15 ng/rat) was given as an iv bolus or an intraarterial infusion to (un)anesthetized rats treated with dexamethasone (0.1-0.5 mg/kg, 2-6 h before ACTH). In all conditions studied, no AM/PM differences in CORT responses were found when ACTH was given in vehicle (pH 4.3-7). This contrasts with earlier studies in which ACTH was given in a strongly acid vehicle (pH 1-1.9). Administration of ACTH in such acid vehicle confirmed the reported AM/PM differences in CORT responses (P < 0.05). Because alterations in splanchnic nerve activity can modulate ACTH-induced CORT secretion, we studied the effect of splanchnic nerve transection (SPLNX) on the diurnal change in resting CORT levels in unilaterally adrenalectomized rats. SPLNX reduced resting CORT concentrations in the PM (approximately 50%; P < 0.05), but not in the AM. SPLNX did not abolish the acid vehicle-associated AM/PM differences in CORT responses to ACTH. We conclude that 1) diurnal variation in adrenal responsiveness to ACTH per se does not exist in this rat model; 2) the strongly acid vehicle interacts with ACTH-induced CORT secretion; 3) the PM rise in plasma CORT depends on the integrity of the sympathetic neural input to the adrenal gland.

Adrenal Glands↗
PubMed1995

Subdiaphragmatic vagotomy suppresses endotoxin-induced activation of hypothalamic corticotropin-releasing hormone neurons and ACTH secretion.

In order to assess the possibility that endotoxin-induced activation of the hypothalamus-pituitary-adrenal (HPA) axis is mediated by vagal afferents, we studied the effects of transection of the vagal nerves on endotoxin-induced Fos expression in hypothalamic corticotropin-releasing hormone (CRH) neurons and plasma ACTH and corticosterone responses. Groups of rats were subjected to sham surgery, complete subdiaphragmatic vagotomy (SVGX), or selective transection of the hepatic branch (HVGX). Two weeks after surgery, endotoxin or saline was injected i.p. and rats were sacrificed by decapitation two hours later. SVGX blocked or attenuated the ACTH response to 20 and 250 micrograms/kg endotoxin, respectively. HVGX did not suppress the ACTH response to either endotoxin dose. In addition, corticosterone responses were not affected by SVGX or HVGX. The endotoxin-induced Fos expression in CRH neurons was suppressed in SVGX, but not in HVGX animals. These observations lead us to postulate that the CRH and ACTH responses to a low dose of endotoxin are mediated by vagal afferents. The responses to a high dose of endotoxin involve additional neuronal or humoral pathways.

Adrenocorticotropic Hormone↗
PubMed1992

Further evidence for dominant inheritance at the chromosome 15q11-13 locus in familial Angelman syndrome.

Eleven patients with Angelman syndrome (AS) and their parents from 5 families have been studied with high resolution chromosome analysis and molecular probes from region 15q11-13 in an attempt to elucidate the mode of inheritance in familial AS. No deletions were detected. All families were informative with a combination of different short arm cytogenetic markers. All sets of sibs inherited the same maternal chromosome 15, but in 3 families sibs inherited different paternal 15s. Analysis of 6 polymorphic DNA markers supported the conclusion that AS sibs inherit the same maternal 15, but often different paternal 15s. These data make autosomal recessive inheritance at a 15q11-13 locus very unlikely and support the hypothesis that familial AS is due to maternal transmission of a mutation within 15q11-13.

Angelman Syndrome↗
PubMed1992

Consideration of the use of 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5- alpha-androstan-3-one (4MA), a 5 alpha-reductase inhibitor, in prostate cancer therapy.

We investigated the effect of 17 beta-N,N-diethylcarbamoyl-4-methyl-4aza- 5 alpha-androstan-3-one (4MA), a 5 alpha-reductase inhibitor, on growth inhibition of androgen-sensitive rat prostatic tumour (R3327-H) and correlated it with changes in weight of normal androgen target tissues and with levels of androgens. Groups of male Copenhagen rats were treated for 28 days with a daily injection of various, increasing doses of 4MA (0.01-4.0 mg/day) and the results were compared with control (vehicle-treated) and with castrated animals. 4MA decreased tumour growth rate in a dose-dependent manner, which was reflected in a decreased incorporation of BrdUrd in DNA of glandular epithelial cells in the tumour. Normal prostate wet weight was also decreased after high-dose 4MA treatment while serum testosterone levels were not affected by 4MA treatment. Contrary to expectations, however, tissue levels of dihydrotestosterone in tumour and ventral prostate were still considerable in 4MA-treated animals. The tumour-inhibiting action of 4MA, therefore, has to be interpreted as not being purely due to 5 alpha-reductase inhibition. On the other hand, it was not possible to demonstrate any direct tumoricidal effect of 4MA in vitro. The relevance of these findings in terms of the endocrine mechanism of action of 4MA on tumour growth is discussed.

5-alpha Reductase Inhibitors↗
PubMed1990

Assignment of X-linked hydrocephalus to Xq28 by linkage analysis.

X-linked recessive hydrocephalus (HSAS) occurs at a frequency of approximately 1 per 30,000 male births and consists of hydrocephalus, stenosis of the aqueduct of Sylvius, mental retardation, spastic paraparesis, and clasped thumbs. Prenatal diagnosis of affected males by ultrasonographic detection of hydrocephalus is unreliable because hydrocephalus may be absent antenatally. Furthermore, carrier detection in females is not possible because they are asymptomatic. Using four families segregating HSAS, we performed linkage analysis with a panel of X-linked probes that detect restriction fragment length polymorphisms. We report here that HSAS, in all tested families, is closely linked to marker loci mapping in Xq28 (DXS52, lod = 6.52 at theta of 0.03; F8, lod = 4.32 at theta of 0.00; DXS15, lod = 3.40 at theta of 0.00). These data assign HSAS to the gene-dense chromosomal band Xq28 and allow for both prenatal diagnosis and carrier detection by linkage analysis.

Blotting, Southern↗
PubMed1990

[Angelman's happy puppet syndrome].

The Angelman ('happy puppet') syndrome is clinically characterized by severe mental retardation without any development of speech, a happy disposition with paroxysms of laughter, a stiff-atactic gait with arms in flexion and abduction, epileptic seizures, EEG-abnormalities, and some dysmorphic features like prognathism, macrosomia, tongue protrusion and brachycephaly and/or microcephaly. The genetic background is still obscure, but in some patients with this syndrome small deletions in the long arm of chromosome 15 have been found. So further investigation of this probably rather frequent syndrome seems appropriate.

Child↗
PubMed1988

Activation of fatty acid oxidation in the Silver-Russell syndrome and the Brachmann-de Lange syndrome.

We describe a similar metabolic pattern of hyperketosis, ketonaciduria, and C6-C12 dicarboxylic aciduria in a patient with the Silver-Russell syndrome and a patient with the Brachmann-de Lange syndrome. Fasting blood levels of beta-hydroxybutyrate and acetoacetate were significantly higher than in age-matched controls, and both patients showed massive urinary excretion of beta-hydroxybutyrate, acetoacetate and C6-C12 dicarboxylic acids.

3-Hydroxybutyric Acid↗
PubMed1987

Recurrence risk in the Angelman ("happy puppet") syndrome.

We report on two sibs with Angelman "happy puppet" syndrome. Out of 48 families reported in the literature, this is only the fourth family with affected sibs. A review of the literature shows a low but not negligible recurrence risk. Different explanations for this are discussed.

Child↗
PubMed1987

X-linked hydrocephalus.

We report on a family with X-linked hydrocephalus: progressive increase in head circumference (OFC) led to the diagnosis in 3 patients; however, in 5 with normal OFC, the initial diagnosis had been "nonspecific" mental retardation, until identification of relatedness between 3 macrocephalic boys suggested segregation of a major Mendelian gene. Moderate to severe hydrocephaly was present in all macrocephalic patients and in 3 of the 5 with normal OFC, but CT-scan of the brain did not show aqueductal stenosis in any of them. We stress the importance of a brain CT-scan in every male with "nonspecific" mental retardation, especially in cases with X-linked inheritance, because confirmation of X-linkage has important genetic counseling consequences.

Adolescent↗
PubMedDate not supplied

Inhibition of 3 beta-hydroxysteroid-dehydrogenase: an approach for prostate cancer treatment?

Over 80% of clinically manifested prostate cancers respond to androgen withdrawal. Several alternatives to castration have been explored. Since a growth promoting role for androstenedione has been suggested, we investigated the effect of inhibition of 3 beta-hydroxy-steroid-dehydrogenase (3 beta-HSD), a key enzyme involved in the biosynthesis of practically all steroids. In a previous study a reduced proliferation rate of androgen responsive R3327-H tumor was demonstrated after in vivo treatment with 17 beta-N,N-diethylcarbamoyl-4-aza-5 alpha-androstan-3-one (4MA) - a putative 5 alpha-reductase inhibitor. In the present investigation 3 beta-HSD enzyme activity derived from human placenta, testis and ovarian cancer cell line and from rat testis was determined using radiolabeled dehydroepiandrosterone (DHEA) or pregnenolone. Among different synthetic compounds known to interfere with steroidogenesis, only 4MA was shown to potently inhibit in vitro 3 beta-HSD activity from all tissue sources. 4MA was administered to male Copenhagen rats bearing R3327-H androgen dependent prostate tumors and levels of different androgens in serum and prostate tumor were measured using reversed phase HPLC and radioimmunoassay. The decreased content of androstenedione in serum and tumor tissue with DHEA accumulation in prostate tumor tissue showed an effective 3 beta-HSD inhibition by 4MA occurring in vivo as well. These observations unequivocally demonstrate a 3 beta-HSD inhibiting effect of 4MA in vitro as well as in vivo and point to a role for androstenedione in the promotion of cell proliferation in androgen sensitive tumors. 3 beta-HSD dependent androstenedione production could thus constitute a proper target -eventually combined with other endocrine treatment - for the treatment of hormone dependent prostate cancer.

3-Hydroxysteroid Dehydrogenases↗