Biomedical subjects
Publications and source records attributed to C Hutter.
We present a simple method for discerning the evolution from vibrational to rotational structure in nuclei as a function of spin. The prescription is applied to the yrast cascades in the A approximately 110 region and a clear transition from vibrational to rotational motion is found.
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Embryonal stem (ES) cells that are homozygous null for the beta(1) integrin subunit fail to differentiate into keratinocytes in vitro but do differentiate in teratomas and wild-type/beta(1)-null chimeric mice. The failure of beta(1)-null ES cells to differentiate in culture might be the result of defective extracellular matrix assembly or reduced sensitivity to soluble inducing factors. By culturing embryoid bodies on dead, deepidermized human dermis (DED) we showed that epidermal basement membrane did not induce beta(1)-null ES cells to undergo keratinocyte differentiation and did not stimulate the differentiation of wild-type ES cells. Coculture with epidermal keratinocytes also had no effect. However, when human dermal fibroblasts were incorporated into DED, the number of epidermal cysts formed by wild-type ES cells increased dramatically, and small groups of keratin 14-positive cells differentiated from beta(1)-null ES cells. Fibroblast-conditioned medium stimulated differentiation of K14-positive cells in wild-type and beta(1)-null embryoid bodies. Of a range of growth factors tested, KGF, FGF10, and TGFalpha all stimulated differentiation of keratin 14-positive beta(1)-null cells, and KGF and FGF10 were shown to be produced by the fibroblasts used in coculture experiments. The effects of the growth factors on wild-type ES cells were much less pronounced, suggesting that the concentrations of inducing factors already present in the medium were not limiting for wild-type cells. We conclude that the lack of beta(1) integrins decreases the sensitivity of ES cells to soluble factors that induce keratinocyte differentiation.
Long-term application of the phorbol ester phorbol 12,13-dibutyrate (PDBu) inhibits the proliferation of human venous endothelial cells. The cyclin-dependent kinase inhibitor p21cip1 is a potential candidate mediating the PDBu-induced delayed entry of the cells into S-phase (by approximately 10 h when compared with cells stimulated with basic fibroblast growth factor (bFGF)). Levels of p21cip1 (protein and mRNA) rapidly rise (within approximately 2 h) in endothelial cells treated with the active isomer beta-PDBu, but not with alpha-PDBu; this effect is blocked by the mitogen-activated protein kinase kinase-1 (Mek1) inhibitor PD098059 and by the protein kinase C (PKC) antagonists GF109203X and rottlerin (selective for PKC-delta), but not Gö 6976 (selective for Ca2+-dependent PKC isoforms). Rapamycin blocks the PDBu-induced accumulation of p21cip1 (but not of the cognate mRNA), indicating an action of PKC on p21(cip1) mRNA translation. If endothelial cells are recruited into the cell cycle by bFGF, p21cip1 mRNA and protein levels rise initially (within 2 h) and decline subsequently such that p21cip1 drops to a minimum prior to the initiation of DNA synthesis (i.e. after approximately 12 h). In bFGF-stimulated cells, changes in p21cip1 mRNA and protein are strictly linked. In contrast, the levels of p21cip1 mRNA decline substantially (>10 h) before the protein decreases in PDBu-stimulated cells. Thus, PKC (presumably PKC-delta) regulates the amounts of p21cip1 in endothelial cells at the level of mRNA accumulation and translation, leading to a rapid and robust induction; following persistent PKC activation, p21(cip1) remains elevated despite reduced mRNA levels, indicating an enhanced stability of the protein. The bFGF-mediated increase in p21cip1 is blocked by the Mek1 inhibitor, but not by GF109203X; hence, in endothelial cells, induction of p21cip1 by PKC- and growth factor-dependent signaling is achieved by distinct pathways that converge and require activation of the mitogen-activated protein kinase cascade. The beta-PDBu-induced delayed S-phase entry and drop in p21cip1 are reversed if GF109203X is added 4 h after beta-PDBu to prevent persistent PKC activation. These observations indicate a cause and effect relation between sustained p21cip1 elevations and the delay in S-phase entry induced by beta-PDBu.
Alterations in G-protein-controlled signalling pathways (primarily pathways controlled by Gs and Gi) have been reported to occur in animal models of diabetes mellitus. We have therefore studied the effect of a long-term exposure of human umbilical vein endothelial cells to elevated concentrations of glucose on expression and function of G-protein subunits and endothelial NO synthase. Long-term incubation in high glucose (30 mM for 15 days) did not affect the levels of Gialpha-2, Gqalpha, the splice variants (long and short form) of Gsalpha, and the G-protein beta-subunits or adenylate cyclase activity; basal, as well as isoprenaline-, forskolin- and guanosine 5'-[gamma-thio]triphosphate-stimulated enzyme activities were comparable in high- and low-glucose-treated cells, thus ruling out any functional changes in the stimulatory pathway. Pretreatment of endothelial cells with pertussis toxin blocked a substantial fraction (50%) of the mitogenic response to serum factor(s) which depend(s) of functional Gi2. The sensitivity of cells cultured in high glucose was comparable with that of the paired controls maintained in normal glucose (EC50 = 3.1 +/- 0.5 and 3.3 +/- 0.4 ng/ml respectively). Similarly, we failed to detect any differences in endothelial NO synthase expression, or intracellular distribution and basal activity of the enzyme in endothelial cells cultured in high glucose. Stimulation of NO synthase in intact cells revealed a comparable response to the calcium ionophore (A23187). In contrast, stimulation with histamine (which acts via H1-receptors predominantly coupled to Gq) resulted in a significantly increased response in the cells maintained in high glucose. These data are suggestive of an altered H1-histamine receptor-Gq-phospholipase C pathway in endothelial cells cultured in high glucose concentrations, but rule out any glucose-induced functional changes in Gs- and Gi-controlled signalling pathways.
Generalized arteriolar vasospasm and subsequent damage to vascular endothelium are fundamental to the development of preeclampsia. A possible mechanism underlying this involves increased deportation of trophoblast cells into maternal venous circulation with 5-hydroxytryptamine (serotonin, 5-HT) release as a consequence of platelet aggregation onto these fragments. Ketanserin, a 5-HT(2) receptor blocker, has been used successfully to treat preeclampsia. An examination of the therapeutic role of ketanserin indicates that there should now be a much more detailed assessment of serotonin antagonists in the treatment and prophylaxis of preeclampsia and eclampsia.
Evidence on aetiology in multiple sclerosis suggests that the prevalence depends on the interaction of two factors, diet and exposure to visible sunlight. The dietary features which may be beneficial include supplementation with fish oils, avoidance of saturated fats, and the associated intake of antioxidants with unsaturated fatty acids. Inhibition, by antioxidants, of the enzyme lipoxygenase inhibits leukotriene synthesis, and the presence of fish oils leads to the production of leukotrienes with less inflammatory properties. This is of particular importance in the retina where leukotrienes might be the underlying cause of retrobulbar neuritis. The antioxidant properties of vitamin A may also lead to inhibition of leukotriene synthesis. Visible solar radiation could be of benefit therefore by releasing vitamin A from visual pigment rhodopsin. The interaction of these two factors may explain the epidemiological observations on the prevalence of multiple sclerosis.
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Monoclonal antibodies (mAbs) can discriminate phagocytes (mAb, RFD7+), antigen presenting cells (mAb, RFD1+) and suppressor macrophages (mAbs, RFD1+RFD7+). Here we compare proportions of these subsets in normal mucosa and investigate changes associated with inflammatory disease. Biopsies were obtained from normal and inflamed lung, gut and skin. Cryostat sections were then analysed using mAbs RFD1 and RFD7. At normal mucosal surfaces the RFD1+RFD7+ suppressor cells consistently formed a major population: lung, RFD1+ 11.4%, RFD7+ 43.3%, RFD1+RFD7+ 45.2% and in gut, RFD1+ 37%, RFD7+ 12%, RFD1+RFD7+ 51% while in the skin the three subsets were in relatively equal proportions (RFD1+ 30%, RFD7+ 37%, RFD1+RFD7+ 33%). In inflamed eczematous skin the percentage of RFD1+RFD7+ increased at the expense of RFD1+ and RFD7+ cells whereas in inflamed mucosa the RFD1+RFD7+ population was significantly reduced (asthmatic lung 29%, RFD1+RFD7+, colitis 31% RFD1+RFD7+). In the lung this reduction was concomitant with a rise in RFD1+ cells while in the gut the RFD7+ population increased. It is concluded that balance of macrophage subsets may be customised at mucosal surfaces to sustain suppression of T cell reactivity. Inflammation here is associated with a loss of this suppression.
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Measurement of carcinoembryonal (CEA) levels in pleural fluid are suggested to improve the unsatisfactory sensitivity of pleural cytology in the differential diagnosis of malignant pleural effusions. We evaluated simultaneously determined pleural and serum CEA levels in 117 patients with pleural effusions of different aetiology (74 malignant, 30 inflammatory exudates and 13 transudates) by use of an enzyme immunoassay (EIA). Despite considerable scatter, pleural levels of CEA in malignant effusions were significantly higher (p less than 0.001) than the values in benign effusions. Using a cut off level of 5 ng/ml, 41% (= sensitivity) of malignant pleural effusions showed elevated concentrations of CEA. Only one out of 43 benign effusions showed a level of 5 ng/ml, which is equivalent to a specificity of 98%. However, malignant effusions due to small cell lung cancer, pleural mesothelioma and metastasising ovarian carcinoma never showed elevated levels of CEA. Highest pleural values of CEA were observed in cases of alveolar cell or adenocarcinoma of the lung or metastasising breast cancer. Although pleural and serum CEA levels correlated significantly (rs = 0.77), the evaluation of serum CEA levels alone yielded a lower sensitivity (36%) and specificity (93%) than pleural levels. 77% of cases with malignant pleural effusions showing elevated pleural CEA levels were characterized by an increased ratio Pleura/Serum greater than 1, particularly in effusions due to lung cancer. The CEA ratio was significantly higher (p less than 0.05) in patients with malignant than with benign effusions. EIA appears to be more specific by avoiding false positive results in benign effusions as compared with determination by conventional RIA. In conclusion, evaluation of pleural CEA levels in patients with malignant effusions by using an EIA because of its high specificity is a valuable adjunct to pleural cytology in improving the diagnosis of malignant effusions. However, a normal CEA level in either pleural effusion or in serum is of no clinical significance. Simultaneous measurement in pleural effusion and serum is of greater value.
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DNA-microarrays allow the analysis of almost the complete gene expression program of tumor samples and normal control samples in a single experiment. This allows the processing of a large number of samples in a reasonable short time. Tumor specific gene expression profiles can be used for molecular tumor classification and as a new diagnostic tool. In addition, the identification of tumor specific genes can help to understand the biology of tumor cells and identified genes can be used for the development of new therapeutic strategies. However, the huge amount of data generated by DNA-microarrays creates new challenges for data analysis. In addition, accuracy and reproducibility of the available techniques require complementary methods for verification of DNA-microarray data.