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Biomedical subjects

M Vermeer

Publications and source records attributed to M Vermeer.

14 recordsLinked to original sources
PubMed2005

A 2-bp deletion in the GJA1 gene is associated with oculo-dento-digital dysplasia with palmoplantar keratoderma.

Oculo-dento-digital dysplasia (ODDD, OMIM no. 164210) is a pleiotropic disorder characterized mainly by ocular anomalies, varying degrees of finger and toe syndactyly, and enamel defects. It is caused by missense mutations in the gene coding for the gap junction protein connexin 43 or GJA1. Other types of mutations have so far not been reported. Here we describe a Dutch kindred with ODDD showing a new symptom, palmoplantar keratoderma, and associated with a novel 2-bp deletion mutation of GJA1. The dinucleotide deletion 780_781delTG is located in the cytoplasmic C-terminal loop and leads to a frameshift. This is predicted to lead to the production of a slightly truncated protein with 46 incorrect amino acids in the C-terminal cytoplasmic loop (C260fsX307). This novel mutation may explain the presence of skin symptoms.

Abnormalities, Multiple↗
PubMed2001

Space-geodetic constraints on glacial isostatic adjustment in Fennoscandia.

Analysis of Global Positioning System (GPS) data demonstrates that ongoing three-dimensional crustal deformation in Fennoscandia is dominated by glacial isostatic adjustment. Our comparison of these GPS observations with numerical predictions yields an Earth model that satisfies independent geologic constraints and bounds both the average viscosity in the upper mantle (5 x 10(20) to 1 x 10(21) pascal seconds) and the elastic thickness of the lithosphere (90 to 170 kilometers). We combined GPS-derived radial motions with Fennoscandian tide gauge records to estimate a regional sea surface rise of 2.1 +/- 0.3 mm/year. Furthermore, ongoing horizontal tectonic motions greater than approximately 1 mm/year are ruled out on the basis of the GPS-derived three-dimensional crustal velocity field.

Journal Article↗
PubMed1997

Effects of TNF alpha on verocytotoxin cytotoxicity in purified human glomerular microvascular endothelial cells.

In the pathogenesis of the hemolytic uremic syndrome (HUS), endothelial damage of glomeruli and arterioles of the kidney appears to play a central role. Previous studies have shown that verocytotoxin-1 (VT-1) cytotoxicity on human vein endothelial cells require additional stimuli, in particular the inflammatory mediator tumor necrosis factor alpha (TNF alpha). In this study the effects of VT on human glomerular microvascular endothelial cells (GMVEC) were examined. A reproducible method was developed for the isolation and purification of large numbers of highly purified GMVEC. The obtained GMVEC were over 99% pure; their endothelial origin was demonstrated by the expression of the endothelial antigens von Willebrand factor, EN-4, PECAM-1 and V,E-cadherin. Upon stimulation with TNF alpha the cells expressed the endothelial-specific adhesion molecule E-selectin. A limited number of fenestral structures was observed by scanning electron microscopy (SEM), suggesting glomerular origin of the endothelial cells. Cytotoxicity of VT-1 to GMVEC was evaluated by determination of the number of viable adherent cells and by assay of overall protein synthesis after exposure to varying concentrations of VT-1. In non-stimulated GMVEC, cytotoxicity of VT-1 was inversely related to the degree and duration of confluence, subconfluent cells being the most sensitive. In highly confluent GMVEC, VT cytotoxicity required pre-exposure of the cells to the inflammatory mediator TNF alpha, which induced an increase in the number of VT receptors on GMVEC. Thin layer chromatography of extracted glycolipids from the GMVEC showed binding of VT-1 to globotriaosylceramide (Gb3), known to be the functional receptor for VT. There were no major differences in protein synthesis inhibition with equal concentrations VT-1 and VT-2. In conclusion, in this study we provide a reproducible method to isolate, purify and culture well characterized human GMVEC on a routine basis. In vitro studies with these GMVEC demonstrate that VT cytotoxicity depends on the degree of confluence and the additional preexposure to the inflammatory mediator TNF alpha. These observations provide further insight into the complex events that may occur in glomeruli in the pathogenesis of HUS.

Bacterial Toxins↗
PubMed1995

Tumor necrosis factor alpha induces endothelial galactosyl transferase activity and verocytotoxin receptors. Role of specific tumor necrosis factor receptors and protein kinase C.

Infections with verocytotoxin (VT) producing Escherichia coli have been strongly implicated in the epidemic form of hemolytic uremic syndrome (HUS). Endothelial damage plays a central role in the pathogenesis of HUS. In vitro studies have shown that VT can damage endothelial cells after interaction with its cellular receptor globotriaosylceramide (GbOse3cer). Cytokines, such as tumor necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1) can potentiate the toxic effect of VT by inducing a protein-synthesis dependent increase in VT receptors on endothelial cells. In this study, the mechanisms underlying the increase in endothelial VT receptors induced by TNF alpha were studied in more detail. To investigate which proteins were involved in this induction, endothelial cells were incubated with and without TNF alpha in the presence of 14C-galactose or 14C-glucose. Thin-layer chromatography (TLC) analysis of the glycolipid extracts of these cells demonstrated a markedly enhanced incorporation of 14C-galactose in GbOse3cer and other galactose-containing glycolipids, suggesting that TNF alpha enhanced galactosyl-transferase activity. To examine the role of the two recently cloned TNF-receptors (TNFR-p75 and TNFR-p55) in the TNF alpha-induced increase in GbOse3cer in human endothelial cells, cells were incubated with TNF alpha, the TNFR-p55 selective R32W-S86T-TNF alpha-mutant, or the TNFR-p75 selective D143N-A145R-TNF alpha-mutant. The effect of TNF alpha activation, determined by binding-experiments with 125I-VT-1, could be largely, but not completely mimicked by R32W-S86T-TNF alpha. Although incubation of cells with D143N-A145R-TNF alpha did not show an increase in VT-1 binding, the monoclonal antibody utr-1, which prevents binding to TNFR-p75, decreased the TNF alpha-induced VT-1 binding. Activation of protein kinase C (PKC) by phorbol ester increases the expression of VT-1 receptors; this effect was prevented by the PKC inhibitor Ro31-8220 and by homologous desensitization by pretreatment with phorbol ester. In contrast, the presence of the protein kinase inhibitor Ro31-8220 or desensitization of PKC activity reduced the TNF alpha-induced increase in VT-1 receptors maximally by 50% and 24%, respectively. Comparable reductions in overall protein synthesis and the synthesis of E-selectin and plasminogen activator inhibitor-1 (PAI-1) were observed. This suggests an effect on general protein synthesis rather than a specific effect of PKC in the signal transduction pathway, by which TNF alpha induces VT-1 receptors. Our results indicate that TNF alpha can increase the VT-1 receptors on endothelial cells by inducing galactosyl-transferase activity, that this action of TNF alpha mainly occurs via the TNFR-p55; and that PKC activation increases expression of VT-1 receptors by a separate mechanism that acts additively to the TNF alpha-induced increase in VT-1 receptors.

Autoradiography↗
PubMed1994

Genistein reduces tumor necrosis factor alpha-induced plasminogen activator inhibitor-1 transcription but not urokinase expression in human endothelial cells.

The plasminogen activator inhibitor PAI-1 is markedly elevated in vivo and in vitro upon exposure to the inflammatory mediators tumor necrosis factor alpha (TNF alpha), interleukin-1 (IL-1), and bacterial lipopolysaccharide. Here we report that the isoflavone compound genistein prevents the increase in synthesis of PAI-1 induced by these inflammatory mediators in human endothelial cells in vitro, and partially reduces the basal PAI-1 production by these cells. These effects of genistein were accompanied by a decrease in PAI-1 mRNA and in a suppression of the PAI-1 transcription rate as shown by run-on assay. A specific action of genistein, probably by inhibiting a tyrosine protein kinase, is likely, because the structural genistein analogue daidzein, which has a low tyrosine protein kinase inhibitor activity, did not inhibit PAI-1 synthesis. Vanadate, a tyrosine protein phosphatase inhibitor, increased PAI-1 production. The effect of genistein on PAI-1 synthesis was rather selective. Herbimycin A also reduced PAI-1 synthesis, but several other tyrosine protein kinase inhibitors, namely tyrphostin A47, methyl-2,5-dihydroxy-cinnamate, and compound 5, were unable to do so. All these tyrosine protein kinase inhibitors reduced basic fibroblast growth factor (b-FGF)-induced [3H]thymidine incorporation in endothelial cells. This indicates that the effect of genistein on PAI-1 transcription proceeds independently of its effect on mitogenesis. In contrast to TNF-alpha-induced PAI-1 production, the transcription and synthesis of urokinase-type plasminogen activator (u-PA) was not inhibited by genistein. A TNF-alpha-mutant (Trp32Thr86TNF alpha) that specifically recognizes the 55-kD TNF-receptor, mimicked the effects of TNF alpha on both PAI-1 and u-PA. Because genistein affected PAI-1, but not u-PA induced by this mutant, involvement of different TNF-receptors cannot underlie the difference in the effects of genistein on PAI-1 and u-PA synthesis. Because genistein also inhibited PAI-1 induction by thrombin and IL-4, it is likely that genistein does not act on a TNF alpha-receptor-coupled protein kinase but on the signal transduction pathway enhancing PAI-1 transcription. Our results suggest that the TNF alpha-induced signal transduction pathway of PAI-1 transcription involves a genistein-sensitive step that is not involved in the induction of u-PA by TNF alpha. Given the limited sensitivity to several other tyrosine protein kinase inhibitors, this genistein-sensitive step may be a potential target for pharmacologic intervention to reduce elevated plasma PAI-1 levels.

Cells, Cultured↗
PubMed1993

Ultrastructural studies bearing on the mechanism of UVB-impaired induction of contact hypersensitivity to DNCB in man.

In both murine and human experimental systems, acute, low dose exposure of skin to ultraviolet B light (UVB) impairs the induction of allergic contact dermatitis (ACD) by haptens such as dinitrochlorobenzene (DNCB) in a significant proportion of individuals. By light microscopy, epidermal Langerhans cells (LC) have been reported to be depleted by UVB exposure as well as by epicutaneous hapten application, implying that LC may be the locus of action of the effects of both UVB and DNCB. However, light microscopy can not readily distinguish cell density changes secondary to LC necrosis from changes resulting from down-modulation of expression of LC surface molecules. Using a highly sensitive immunogold electron microscopic approach, we have evaluated the differential effects of UVB and/or DNCB on human epidermal LC. The results reveal that DNCB alone caused significant up-regulation of cell surface HLA class II expression on a very small number of LC, the major fraction of LC expressing normal levels of HLA class II. Furthermore, DNCB alone caused a modest reduction in the density of LC at the treated sites without evidence of cell necrosis. Treatment with UVB alone or UVB exposure followed by DNCB resulted in a reduction in the density of LC, with widespread evidence of LC necrosis. However, the few remaining intact LC were all intensely HLA class II-positive after UVB exposure followed by DNCB, whereas treatment with UVB alone did not result in changes in LC HLA class II expression. The findings that after DNCB painting only a small proportion of the LC were strongly HLA class II-positive, but after UVB exposure followed by DNCB all intact LC displayed significant up-regulation of cell surface HLA class II expression, imply that UVB exposure inhibits the migration of epidermal LC. This is consistent with the view that DNCB fails to induce ACD when hapten is painted on UVB-exposed skin because insufficient LC are available to initiate T cell activation in the draining lymph node.

Cell Count↗
PubMed1991

Effects of ultraviolet B light on cutaneous immune responses of humans with deeply pigmented skin.

The incidence of skin cancers of the basal and squamous cell types is extremely low among genetically black-skinned human beings, whereas these types of skin cancers are common among Caucasians, especially those who live in geographic areas of high sun exposure. Ultraviolet B light (UVB) is thought to be the primary oncogenic agent in sunlight. We have recently demonstrated that acute, low-dose exposure of Caucasian skin to UVB impairs the induction of contact hypersensitivity to dinitrochlorobenzene (DNCB) in approximately 40% of normal individuals. Importantly, this trait--termed UVB susceptibility--was found to be a characteristic of virtually 100% of patients with a history of biopsy-proved skin cancer, implying that UVB susceptibility may be a risk factor for this disease. Because melanin pigment is thought to be protective of some of the deleterious effects of UVB radiation, we have examined the capacity of a low-dose regimen of UVB to alter induction of contact hypersensitivity in individuals with genetically melanized or heavily tanned skin. Our results indicate that UVB radiation depletes heavily pigmented skin of Langerhans cells, just as it does in Caucasian skin. Moreover, UVB-susceptibility exists as a polymorphic trait in individuals with genetically determined black skin, as well as in individuals with heavily tanned skin, and the incidence of this trait is similar to that found among normal Caucasian subjects. Thus, melanin does not appear to protect against the deleterious effects of an acute, low-dose regimen of UVB on induction of cutaneous immunity, and the UVB susceptibility trait is equally well-represented in both black- and Caucasian-skinned individuals. We conclude that although UVB susceptibility may function as a risk factor for skin cancer in Caucasians, it does not function similarly in black-skinned human beings, probably because melanin effectively protects against the mutagenic properties of UVB radiation.

Adult↗
PubMed1990

Functional dichotomy between Langerhans cells that present antigen to naive and to memory/effector T lymphocytes.

The general thrust of this volume is to review the roles of accessory cells in regulating T and B lymphocytes. To that end, we have summarized the evidence that indicates the crucial role that Langerhans cells play in the induction and expression of immunity to antigens that gain access to, or arise within, skin. Langerhans cells accomplish this important goal by their abilities to (a) activate naive T cells to antigens not previously encountered by the host, and (b) activate memory/effector T cells specific for previously encountered antigens. Arguments have been advanced to support the view that the functional properties of Langerhans cells used to present antigens to naive T cells differ substantially from the properties that equip Langerhans cells to activate effector T cells. The arguments are based in part on the fact that Langerhans cells carry out these functions in two very different environments: in the epidermis, and in the draining lymph node. The arguments are also based on results of in vitro experiments that reveal distinct differences in antigen processing and presenting properties of Langerhans cells freshly obtained from mouse and human skin as compared to Langerhans cells that have been cultured in vitro for 2-3 days. We propose that freshly explanted Langerhans cells faithfully reflect the functional program of intraepidermal Langerhans cells, and are able to present antigen to memory/effector T cells that enter the epidermal compartment. To accomplish this task, epidermal LC pick up environmental antigens, process them with great efficiency, and then present them in situ, without further upregulation of "accessory" signals (cell-adhesion molecules, secretion of additional cytokines). They can carry out this function, even in the presence of TGFB--a a cytokine which is constitutively made by keratinocytes, and which we have found to profoundly inhibit antigen presentation by most other types of "professional" antigen-presenting cells. Intraepidermal Langerhans cells are also capable of carrying cutaneous antigens through the dermal epidermal junction and migrating to the draining lymph node. We further propose that cultured Langerhans cells are fated to present antigens to unprimed/naive T cells, and thereby to initiate immune responses to new cutaneous antigens. Cultured LC process antigens less efficiently than fresh cells, but their unique capacity to present antigen effectively to unprimed T cells rests chiefly on the fact that they have significantly upregulated cell surface adhesion molecules, expression of MHC molecules, and secretion of activating cytokines--the "accessory" signals that are required for arousing naive T cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Ultraviolet B light-induced alterations in epidermal Langerhans cells are mediated in part by tumor necrosis factor-alpha.

Acute, low-dose treatment of murine skin with ultraviolet B light (UVB) impairs the induction of contact hypersensitivity to dinitrofluorobenzene, and depletes the epidermis of normally appearing class II MHC positive Langerhans cells. Recent studies with inbred strains of mice have revealed that impairment of contact hypersensitivity by UVB is a polymorphic trait that is polygenically dictated by susceptibility alleles at the Lps and Tnf alpha loci. Since impairment of contact hypersensitivity by UVB has been associated with deleterious effects on Langerhans cells, we have tested the hypotheses that UVB and TNF alpha have similar effects on epidermal Langerhans cells and that TNF alpha is an important mediator of this UVB-induced effect. Our results confirm that both UVB and TNF alpha reduce the density of class II MHC-bearing epidermal cells and alter the morphology (shortened or absent dendrites, rounded shape) of the cells that remain. UVB- and TNF alpha-induced changes are prevented by systemic administration of neutralizing anti-TNF alpha antibodies. Circumstantial evidence, based on time of onset of numerical and morphologic changes among Langerhans cells following epidermal treatment, suggests that TNF alpha is the mediator of UVB-induced changes. Moreover, the ability of intradermally injected TNF alpha to alter Langerhans cells depends, in part, on whether the strain of mouse is of the UVB-susceptible or UVB-resistant phenotype as it pertains to the effect of UVB on contact hypersensitivity.

Animals↗
PubMedDate not supplied

Vastatins inhibit cholesterol ester accumulation in human monocyte-derived macrophages.

Human monocyte-derived macrophages were incubated for 48 hours in Medium 199 with 1% human serum albumin, and with 100 micrograms acetyl low density lipoprotein (LDL) or beta-very low density lipoprotein (beta-VLDL), with or without various concentrations of compactin, lovastatin, simvastatin, or pravastatin. The mass of free (FC) and esterified (CE) cholesterol was determined, as well as the incorporation of [1-14C]acetate in sterols, that of [1-14C]oleate in CE, and that of [methyl-14C]choline in phospholipids. Moreover, we assessed the high-affinity association and degradation of 125I-labeled acetyl LDL. Compactin markedly decreased the cellular accumulation of CE induced by acetyl LDL or beta-VLDL and increased the content of FC. Compactin also decreased the incorporation of [1-14C]oleate in CE (by 70-90%) in incubations with or without added lipoproteins. The half-maximal inhibitory concentration for this effect of compactin was 30 nM. Lovastatin and simvastatin were more potent, but pravastatin was about 100-fold less potent. Although compactin also caused a clear inhibition of cholesterol synthesis in the presence of acetyl LDL, the effect on CE formation did not seem to be related to decreased cholesterol synthesis, since this was already very low in the presence of acetyl LDL. Compactin did not affect the association and degradation of labeled acetyl LDL and also had no effect on the rate of cholesterol loss after preloading the cells with CE by incubation with acetyl LDL. However, compactin had a slight stimulatory effect on the synthesis of phosphatidylcholine and sphingomyelin when compactin was added to incubations in the presence of acetyl LDL.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticholesteremic Agents↗