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Biomedical subjects

A Staal

Publications and source records attributed to A Staal.

At least 19 recordsLinked to original sources
PubMed2002

[The treatment of carpal tunnel syndrome].

The invasive treatment of carpal tunnel syndrome is only indicated if the symptoms persistently interfere with the normal lifestyle (for a period of at least several months), and if the diagnosis has been established beyond reasonable doubt. The standard treatment still consists of an open surgical cleavage of the transverse carpal ligament (with an incision distal to the transverse crease of the wrist). Between 75 and 90% of patients obtain long-term relief as a result of the operation. Endoscopic release may result in a more rapid recovery. However, it is more often associated with complications than the conventional operation, and it requires new equipment and extensive training. The injection of corticosteroids near the carpal tunnel is reasonably safe and also effective, albeit mostly just in the short term; in most patients the symptoms recur within a few months.

Adrenal Cortex Hormones↗
PubMed2000

Molecular characterization of celtix-1, a bromodomain protein interacting with the transcription factor interferon regulatory factor 2.

Transcriptional control at the G1/S-phase transition of the cell cycle requires functional interactions of multimeric promoter regulatory complexes that contain DNA binding proteins, transcriptional cofactors, and/or chromatin modifying enzymes. Transcriptional regulation of the human histone H4/n gene (FO108) is mediated by Interferon Regulatory Factor-2 (IRF-2), as well as other histone gene promoter factors. To identify proteins that interact with cell-cycle regulatory factors, we performed yeast two-hybrid analysis with IRF-2 and identified a novel human protein termed Celtix-1 which binds to IRF-2. Celtix-1 contains several phylogenetically conserved domains, including a bromodomain, which is found in a number of transcriptional cofactors. Using a panel of IRF-2 deletion mutants in yeast two-hybrid assays, we established that Celtix-1 contacts the C-terminus of IRF-2. Celtix-1 directly interacts with IRF-2 based on binding studies with glutathione S-transferase (GST)/IRF-2 fusion proteins, and immunofluorescence studies suggest that Celtix-1 and IRF-2 associate in situ. Celtix-1 is distributed throughout the nucleus in a heterodisperse pattern. A subset of Celtix-1 colocalizes with the hyperacetylated forms of histones H3 and H4, as well as with the hyperphosphorylated, transcriptionally active form of RNA polymerase II. We conclude that the bromodomain protein Celtix-1 is a novel IRF-2 interacting protein that associates with transcriptionally active chromatin in situ.

Cell Line↗
PubMed1998

Selective expression of specific histone H4 genes reflects distinctions in transcription factor interactions with divergent H4 promoter elements.

Expression of many histone H4 genes is stringently controlled during the cell cycle to maintain a functional coupling of histone biosynthesis with DNA replication. The histone H4 multigene family provides a paradigm for understanding cell cycle control of gene transcription. All functional histone H4 gene copies are highly conserved in the mRNA coding region. However, the putative promoter regions of these H4 genes are divergent. We analyzed three representative mouse H4 genes to assess whether variation in H4 promoter sequences has functional consequences for the relative level and temporal control of expression of distinct H4 genes. Using S1 nuclease protection assays with gene-specific probes and RNA from synchronized cells, we show that the mRNA level of each H4 gene is temporally coupled to DNA synthesis. However, there are differences in the relative mRNA levels of these three H4 gene copies in several cell types. Based on gel shift assays, nucleotide variations in the promoters of these H4 genes preclude or reduce binding of several histone gene transcription factors, including IRF2, HiNF-D, SP-1 and/or YY1. Therefore, differential regulation of H4 genes is directly attributable to evolutionary divergence in H4 promoter organization which dictates the potential for regulatory interactions with cognate H4 transcription factors. This regulatory flexibility in H4 promoter organization may maximize options for transcriptional control of histone H4 gene expression in response to the onset of DNA synthesis and cell cycle progression in a broad spectrum of cell types and developmental stages.

3T3 Cells↗
PubMed1998

Regulation of osteocalcin production and bone resorption by 1,25-dihydroxyvitamin D3 in mouse long bones: interaction with the bone-derived growth factors TGF-beta and IGF-I.

Bone cells produce multiple growth factors that have effects on bone metabolism and can be incorporated into the bone matrix. Interplay between these bone-derived growth factors and calciotropic hormones has been demonstrated in cultured bone cells. The present study was designed to extend these observations by examining the interactions between either transforming growth factor-beta (TGF-beta) or insulin-like growth factor-I (IGF-I) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in a mouse long bone culture model with respect to osteocalcin production and bone resorption. In contrast to the stimulation in rat and human, in the fetal mouse long bone cultures, 1,25(OH)2D3 caused a dose-dependent inhibition of osteocalcin production. Both the osteocalcin content in the culture medium and in the extracts of the long bones was reduced by 1,25(OH)2D3. This effect was not specific for fetal bone because 1,25(OH)2D3 also reduced osteocalcin production by the neonatal mouse osteoblast cell line MC3T3. TGF-beta inhibited whereas IGF-I dose-dependently increased osteocalcin production in mouse long bones. The combination of TGF-beta and 1,25(OH)2D3 did not result in a significantly different effect compared with each of these compounds alone. The IGF-I effect was completely blocked by 1,25(OH)2D3. In the same long bones as used for the osteocalcin measurements, we performed bone resorption analyses. Opposite to its effect on osteocalcin, 1,25(OH)2D3 dose-dependently stimulated bone resorption. TGF-beta reduced and IGF-I did not change basal (i.e., in the absence of hormones) bone resorption. Our results show that 1,25(OH)2D3-enhanced bone resorption is dose-dependently inhibited by TGF-beta and IGF-I. Regression analysis demonstrated a significant negative correlation between 1,25(OH)2D3-induced bone resorption and osteocalcin production. The specificity for their effect on 1,25(OH)2D3-stimulated bone resorption was assessed by testing the effects of TGF-beta and IGF-I in combination with parathyroid hormone (PTH). Like 1,25(OH)2D3, PTH dose-dependently stimulates bone resorption. However, PTH-stimulated bone resorption was not affected by TGF-beta. Like 1,25(OH)2D3-stimulated bone resorption, IGF-I inhibited the PTH effect but at a 10-fold higher concentration compared with 1,25(OH)2D3. In conclusion, the present study demonstrates growth factor-specific interactions with 1,25(OH)2D3 in the control of osteocalcin production and bone. With respect to bone resorption, these interactions are also hormone specific. The present data thereby support and extend the previous observations that interactions between 1,25(OH)2D3 and bone-derived growth factors play an important role in the control of bone metabolism. These data together with the fact that TGF-beta and IGF-I are present in the bone matrix and potentially can be released during bone resorption support the concept that growth factors may control the effects of calciotropic hormones in bone in a localized and possibly temporal manner. Finally, in contrast to human and rat, in mice 1,25(OH)2D3 reduces osteocalcin production and this reduction is paralleled by stimulation of bone resorption by 1,25(OH)2D3. These data thereby show a dissociation between osteocalcin production and bone resorption.

Animals↗
PubMed1997

Consequences of vitamin D receptor regulation for the 1,25-dihydroxyvitamin D3-induced 24-hydroxylase activity in osteoblast-like cells: initiation of the C24-oxidation pathway.

A direct relationship between vitamin D receptor (VDR) level and target cell responsiveness to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) has been shown in osteoblast-like cell lines. However, we previously found an inverse relationship between the TGF beta-induced VDR up-regulation and subsequent 1,25-(OH)2D3-induced biological responses. A clear inhibition of the 1,25-(OH)2D3-induced stimulation of osteocalcin and osteopontin expression was observed. A biological response that has formerly been shown to be coupled to VDR level is 24-hydroxylase activity. This enzyme initiates the C24 oxidation of the side-chain, followed by cleavage and ultimate metabolic clearance of both 25-(OH)D3 and its metabolite 1,25-(OH)2D3. With UMR 106 (rat) and MG 63 (human) osteoblast-like cells, we show that after preincubation with TGF beta, which causes an increase in VDR level, 1,25-(OH)2D3 induction of 24-hydroxylase activity is also stimulated. In addition, we provide evidence that variations in VDR level induced by other means (PTH, EGF, medium change) are also closely associated with 1,25-(OH)2D3-induced 24-hydroxylase activity. Furthermore, we show that in MG 63 cells, but not in UMR 106 cells, TGF beta itself was able to increase the activity of the enzyme 24-hydroxylase. As 24-hydroxylation is the initial step in the further C24 oxidation of 1,25-(OH)2D3, our results indicate a close coupling of VDR level and the degradation of its ligand, 1,25-(OH)2D3. This mechanism may provide an important regulatory feedback in the action of 1,25-(OH)2D3 at target tissue/cell level.

24,25-Dihydroxyvitamin D 3↗
PubMed1996

Antagonistic effects of transforming growth factor-beta on vitamin D3 enhancement of osteocalcin and osteopontin transcription: reduced interactions of vitamin D receptor/retinoid X receptor complexes with vitamin E response elements.

Osteocalcin and osteopontin are noncollagenous proteins secreted by osteoblasts and regulated by a complex interplay of systemic and locally produced factors, including growth factors and steroid hormones. We investigated the mechanism by which transforming growth factor-beta (TGF beta) inhibits 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3)-enhanced expression of the osteocalcin (OC) and osteopontin (OP) genes. ROS 17/2.8 cells, in which both genes are expressed, were transfected with reporter constructs driven by native (i.e. wild-type) rat OC and mouse OP promoters. TGF beta abrogated the 1,25-(OH)2D3 enhanced transcription of both the OC and OP genes. The inhibitory TGF beta response for each requires vitamin D response element (VDRE) sequences, although there are additional contributions from proximal basal regulatory elements. These transcriptional effects were further investigated for contribution of the trans-activating factors, which interact with OC and OP VDREs, involving the vitamin D receptor (VDR) and retinoid X receptor (RXR). Gel mobility shift assays show that TGF beta significantly reduces induction of the heterodimers VDR/RXR complexes in 1,25-(OH)2D3-treated ROS 17/2.8 cells. However, Western blot and ligand binding analysis reveal that TGF beta does not affect nuclear availability of the VDR. We also show that activator protein-1 activity is up-regulated by TGF beta; thus, activator protein-1 binding sites in the OC promoter may potentially contribute to inhibitory effects of TGF beta on basal transcription. Our studies demonstrate that the inhibitory action of TGF beta on the 1,25-(OH)2D3 enhancement of OC and OP transcription in osteoblastic cells results from modulations of protein-DNA interactions at the OC and OP VDRE, which cannot be accounted for by changes in VDR protein levels. As OC and OP participate in bone turnover, our results provide insight into the contributions of TGF beta and 1,25-(OH)2D3 to VDR-mediated gene regulatory mechanism operative in bone formation and/or resorption events.

Animals↗
PubMed1996

Distinct conformations of vitamin D receptor/retinoid X receptor-alpha heterodimers are specified by dinucleotide differences in the vitamin D-responsive elements of the osteocalcin and osteopontin genes.

The 1 alpha,25-dihydroxyvitamin D3 (VD3)-dependent stimulation of osteocalcin (OC) and osteopontin (OP) gene transcription in bone tissue is mediated by interactions of trans-activating factors with distinct VD3-responsive elements (VDREs). Sequence variation between the OC- and OP-VDRE steroid hormone half-elements provides the potential for recognition by distinct hormone receptor homo- and heterodimers. However, the exact composition of endogenous VD3- induced complexes recognizing the OC- and OP-VDREs in osteoblasts has not been definitively established. To determine the identity of these complexes, we performed gel shift immunoassays with nuclear proteins from ROS 17/ 2.8 osteoblastic cells using a panel of monoclonal antibodies. We show that VD3- inducible complexes interacting with the OC- and OP-VDREs represent two distinct heterodimeric complexes, each composed of the vitamin D receptor (VDR) and the retinoid X receptor-alpha (RXR). The OC- and OP-VDR/RXR alpha heterodimers are immunoreactive with RXR antibodies and several antibodies directed against the ligand-binding domain of the VDR. However, while the OC-VDRE complex is also efficiently recognized by specific monoclonal antibodies contacting epitopes in or near the VDR DNA-binding domain (DBD) (between amino acids 57-164), the OP-VDRE complex is not efficiently recognized by these antibodies. By systematically introducing a series of point-mutations in the OC-VDRE, we find that two internal nucleotides of the proximal OC-VDRE half-site (nucleotide -449 and -448; 5'-AGGACA) determine differences in VDR immunoreactivity. These results are consistent with the well established polarity of RXR heterodimer binding to bipartite hormone response elements, with the VDR recognizing the 3'-half-element. Furthermore, our data suggest that the DBD of the VDR adopts different protein conformations when contacting distinct VDREs. Distinctions between the OC- and OP-VDR/RXR alpha complexes may reflect specialized requirements for VD3 regulation of OC and OP gene expression in response to physiological cues mediating osteoblast differentiation.

Animals↗
PubMed1994

Transforming growth factor beta-induced dissociation between vitamin D receptor level and 1,25-dihydroxyvitamin D3 action in osteoblast-like cells.

In the present study the interaction between a locally produced factor in bone, transforming growth factor beta (TGF beta) and a systemic regulator of bone metabolism, 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) was investigated. In rat (UMR 106, ROS 17/2.8) and human (MG-63) osteoblastic cell lines and in isolated fetal rat osteoblasts TGF beta caused a comparable increase in vitamin D receptor (VDR) level. A maximum was observed after 6 h at 1 ng/ml TGF beta. Scatchard analysis revealed that up-regulation of VDR is due to an increase in receptor number and not to a change in affinity. This was supported by Northern blot analysis which showed a dose- and time-dependent increase in VDR mRNA by TGF beta. To assess the significance of the TGF beta-induced increase in VDR level for 1,25-(OH)2D3 effects cells were preincubated with TGF for 4 h (causing a 2-3-fold increase of the VDR level) and subsequently incubated with 1,25-(OH)2D3 for 4 h and 24 h. TGF beta preincubation potently inhibited subsequent 1,25-(OH)2D3 stimulation of osteocalcin production in both ROS 17/2.8 and MG-63 cells on protein as well as mRNA level. A similar inhibition by TGF beta was observed on the 1,25-(OH)2D3-induced increase in osteopontin mRNA. The current study demonstrates dissociation between regulation of VDR level and modulation of two 1,25-(OH)2D3 biological responses by TGF beta in osteoblast-like cell lines of different origin. This dissociation shows that, besides interaction at VDR level also at other levels in the cell interaction(s) exist between TGF beta and 1,25-(OH)2D3. Besides, these data emphasize the potential importance of the interplay of locally produced factors and systemic calciotrophic hormones in the regulation of bone metabolism.

Animals↗
PubMed1992

Evidence for the functional involvement of protein kinase C in the action of 1,25-dihydroxyvitamin D3 in bone.

In the present study the involvement of protein kinase C in the action of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on osteoblast-like cells and in the stimulation of in vitro bone resorption by 1,25(OH)2D3 was examined. Incubation for 24 h with 1,25(OH)2D3 potently stimulated osteocalcin synthesis by ROS 17/2.8 cells. This stimulation was inhibited (30-70% inhibition) by 25 microM of the protein kinase C (PKC) inhibitors 1-O-hexadecyl-2-O-methyl-rac-glycerol (AMG) and sphingosine without affecting basal osteocalcin synthesis. 1,25(OH)2D3-stimulated osteocalcin secretion by nontransformed isolated fetal rat osteoblasts was also inhibited (30-55%) by AMG. Also, AMG inhibited 10(-9) M 1,25(OH)2D3-induced up-regulation of vitamin D receptor in ROS 17/2.8 cells. Activation of PKC with phorbol 12-myristate 13-acetate (PMA) did not cause an increase in osteocalcin secretion, while only a small increase in cellular content of osteocalcin in ROS 17/2.8 cells was observed. Addition of PMA together with 1,25(OH)2D3 did not change the response to 1,25(OH)2D3. The PKC inhibitors were not toxic for the cells. 1,25(OH)2D3 did not stimulate diacylglycerol production in ROS 17/2.8 cells up to 5 min after administration. However, 4- and 24-h incubation with 10 nM 1,25(OH)2D3 increased phorbol ester binding in ROS 17/2.8 cells. 1,25(OH)2D3 potently stimulated bone resorption after 3 and 6 days of culture in fetal mouse long bones and calvaria. Both the PKC inhibitors AMG (25 microM) and staurosporine (50 nM) strongly inhibited (60-86% inhibition) 1,25(OH)2D3-stimulated bone resorption without affecting basal 45Ca release. These effects were not due to a cytotoxic effect of both PKC inhibitors. Nor is it likely that the effects of AMG and staurosporine are due to inhibition of cell proliferation as hydroxyurea did not affect 1,25(OH)2D3-stimulated bone resorption. The inhibition of 1,25(OH)2D3-stimulated bone resorption by PKC inhibitors suggests that besides osteocalcin synthesis PKC is also involved in other responses of 1,25(OH)2D3 in bone. 1,25(OH)2D3 does not directly activate PKC via an increase in diacylglycerol production but more likely via an increase in PKC. Together, the present study demonstrates a functional involvement of PKC in the action of 1,25(OH)2D3 in bone and bone cells which may have consequences for the development of 1,25(OH)2D3 analogs, e.g. with less hypercalcemic and relatively more antiproliferative activity.

Alkaloids↗
PubMed1991

'Atypical TIAs' may herald cardiac rather than cerebral events.

Sixty-four patients with atypical transient cerebral or visual symptoms that could not be classified as unequivocal TIAs nor as migraine, epilepsy or neurosis, were followed up for a mean of 3.75 years (range 11 months and 9 years, 240 patient years). Their mean age was 55 years. Only two patients suffered a (non-disabling) stroke, but eight patients had a major cardiac event: fatal myocardial infarction in three, sudden death in one and non-fatal myocardial infarction in four patients. Seven of these eight patients were known to have cardiovascular risk factors. Visual symptoms were relatively benign with regard to cardiac events (2 events in 28 patients), whereas dizziness alone and focal sensory symptoms alone were more strongly associated with subsequent cardiac complications (2 out of 4, and 4 out of 13 patients, respectively). In a control group of 185 patients with 'typical' TIAs or minor strokes, followed for a total of 233 patient years, seven patients had a ischaemic stroke, and only one a cardiac event. Our results suggest that patients with atypical transient cerebral deficits and cardiovascular risk factors may carry a low risk of subsequent stroke, but a high risk of major cardiac events.

Adult↗
PubMed1991

Epidemiology of lissencephaly type I.

In a cooperative study in The Netherlands 22 patients with lissencephaly type I were collected. In the period 1980-1988, the prevalence of lissencephaly type I in the Netherlands was 11.7 per million births (12.2 for females and 11.0 for males). The 5-year survival rate of patients with a complete or nearly complete agyria (grade 1 or 2) in this study was 54% compared to 91% in patients with a mixture of agyria with pachygyria or complete pachygyria (grade 3 or 4).

Abnormalities, Multiple↗
PubMed1991

[Not Available].

Explore the source record for details and available documents.

Crime↗
PubMed1990

Non-familial degenerative disease and atrophy of brainstem and cerebellum. Clinical and CT data in 47 patients.

We studied the clinical features of 47 patients with a non-hereditary degenerative disease and with atrophy of brainstem or cerebellum or both in CT scanning. There was no relation between the CT findings and duration or severity of the disease, nor with the kind of the neurological signs which comprised ataxia, a hypokinetic rigid syndrome, oculomotor abnormalities, upper and lower motor neuron signs, orthostatic hypotension and dementia. The 2 main diagnoses were olivopontocerebellar atrophy (OPCA), or a combination of OPCA and striatonigral degeneration (SND). The differential diagnosis with Parkinson's disease and progressive supranuclear palsy was discussed. We concluded, that a CT scan is warranted in all cases of suspected Parkinson's disease, especially in those without tremor, and in cases of motoneuron disease with broad-based gait. In our patients with mainly hypokinesia and rigidity, levodopa treatment had no or brief beneficial effects. If ataxia predominated, OPCA appeared the most sensible diagnosis; if a hypokinetic-rigid syndrome predominated, the diagnoses SND plus OPCA appeared the most suitable. We assessed the degree of atrophy on CT subjectively, because an interobserver study of 60 normal CT scans, did not produce reliable measurements.

Adult↗
PubMed1989

Anticipation in myotonic dystrophy: fact or fiction?

In 1918 Fleischer reported that after transmission from one generation to the next, myotonic dystrophy has an earlier onset and is more severe. The hypothesis put forward by Penrose in 1948 that 'anticipation' is caused by bias of index case selection was based on theoretical arguments only and has not been supported by clinical observations. This hypothesis was tested in a clinical and genetic study of 14 families with myotonic dystrophy. Excluding index patients, an earlier onset in the child was found in 98% of 61 parent-child pairs. A greater mean difference in age of onset was found with transmission via the father than via the mother. The comparison of the severity of the disease between parents and children was difficult because of the variation in symptoms but, in general, the disease was more severe in the child than in the parent. The penetrance of the abnormal gene was nearly complete in the 14 families combined, leaving little room for the observation of 'complementary' parent-child pairs in the future. Also in retrospect no complementary parent-child pairs were found in the first generations. Fertility was severely reduced only in the very early onset patient group and this selective infertility cannot be responsible for the total amount of anticipation observed. It is therefore concluded that anticipation may be inherent in the transmission of myotonic dystrophy. This has important consequences for genetic counselling.

Adult↗
PubMed1989

Reliability of the diagnosis of a first seizure.

We studied the interrater variability among three neurologists of the diagnosis of a seizure in 100 patients evaluated for a possible "first seizure." We found that use of simple descriptive diagnostic criteria and discussion among the neurologists themselves improved the diagnostic agreement.

Adolescent↗