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Biomedical subjects

R Müller

Publications and source records attributed to R Müller.

At least 361 records · Page 20Linked to original sources
PubMed1994

Changes in plasma norepinephrine concentration and thrombocyte alpha 2-adrenoceptor density during long-term antihypertensive therapy with nitrendipine and captopril.

Antihypertensive drugs influence the sympathetic nervous system in different ways that may cause adverse or beneficial effects. We treated 48 hypertensive patients with either nitrendipine (10-20 mg twice daily, b.i.d.) or captopril (25-50 mg b.i.d.) for 16 weeks to evaluate changes in plasma catecholamines, platelet alpha 2- and lymphocyte beta 2-adrenoceptors. Blood pressure (BP) decreased from 153/95 to 135/87 mm Hg with captopril and from 155/99 to 137/89 mm Hg with nitrendipine. Treatment with nitrendipine significantly stimulated plasma norepinephrine (NE) from 327 +/- 37 to 446 +/- 50 pg/ml, and treatment with captopril resulted in a significant reduction in platelet alpha 2-adrenoceptor density from 265 +/- 39 to 171 +/- 26 fmol/mg protein. Despite having equal BP-lowering properties, captopril and nitrendipine have different effects on the sympathetic nervous system. Stimulation of plasma NE during long-term treatment with nitrendipine may contribute to possible adverse effects, whereas reduction in alpha 2-adrenoceptors induced by captopril may contribute to the vasodilating effect of angiotensin-converting enzyme (ACE) inhibition.

Adult↗
PubMed1994

Rift Valley fever virus L segment: correction of the sequence and possible functional role of newly identified regions conserved in RNA-dependent polymerases.

The sequence of Rift Valley fever virus L segment that we published in a previous paper was erroneous in the 3'-terminal region of the antigenomic RNA molecule. Here, we have shown that the L segment is in fact 6404 nucleotides long and encodes a polypeptide of 237.7K in the viral complementary sense. Sequence comparisons performed between the RNA-dependent RNA polymerases of 22 negative-stranded RNA viruses revealed the existence of two novel regions located at the amino termini of the proteins and conserved only in the polymerases of bunya- and arenaviruses. In the region conserved in all RNA-dependent polymerases, corresponding to the so-called 'polymerase module', we identified a new motif, designated premotif A, common to all RNA-dependent polymerases, as well as amino acids located in the region between motifs preA and A which are strictly conserved for segmented negative-stranded RNA viruses. Using the recently released coordinates of human immunodeficiency virus reverse transcriptase and the alignment between all RNA-dependent polymerases in the 'polymerase module', we have determined the position of the conserved residues in these polymerases and discuss their possible functions in light of the available structural information.

Amino Acid Sequence↗
PubMed1994

CD7-negative helper T cells accumulate in inflammatory skin lesions.

Recently, we identified a particular T-cell subset in the peripheral blood of normal individuals that lack CD7 expression. In this study we determined the portion of CD7- T cells in the peripheral blood and skin of patients with various inflammatory skin diseases. We found that skin-infiltrating lymphocytes isolated from different benign and malignant skin lesions (n = 20) contain a high portion of CD7- helper T cells, whereas the number of CD7- T cells in the peripheral blood was not altered compared to healthy controls. Cell activation in vitro did not induce CD7 expression in negative T cells but increased CD7 expression in CD7-positive cells. Thus, lack of CD7 expression seems to be a stable characteristic in a major subset of skin-infiltrating lymphocytes. During long-term culture of CD7- helper T-cell clones derived from a psoriasis skin lesion, no phenotypic change in the CD7 phenotype could be monitored by sequential flow-cytometric analyses. No CD7 mRNA could be detected by Northern blot analysis, indicating transcriptional regulation of CD7 expression. The results show that CD7- T cells accumulate in certain inflammatory skin lesions without alteration of the circulating CD7- population. These cells may be identical to or derived from CD7- T cells of the peripheral blood.

Antigens, CD↗
PubMed1994

Reduced lymphocyte beta 2-adrenoceptor density and impaired diastolic left ventricular function in patients with glucocorticoid deficiency.

OBJECTIVE: Patients with adrenal crisis are at risk of severe hypotension not responding to administration of catecholamines. As glucocorticoids may be a prerequisite for intact beta-adrenoceptor function, impaired adrenoceptor activity may explain the hypotension and reduced cardiac performance in adrenal insufficiency. The aim of our study was, therefore, to further elucidate the permissive action of glucocorticoids on adrenergic function and cardiac performance. DESIGN: Prospective randomized controlled study. PATIENTS: Nine patients with adrenal insufficiency were investigated before and 48 hours after glucocorticoid withdrawal. Mineralocorticoid therapy remained unchanged during the study period. MEASUREMENTS: Lymphocyte beta 2-adrenoceptor density, intracellular c-AMP response to isoprenaline, platelet alpha 2-receptor density, plasma catecholamines, serum cortisol, plasma ACTH, echocardiography. RESULTS: Glucocorticoid depletion was demonstrated by a fall in serum cortisol from mean +/- SEM 441 +/- 62 to 45 +/- 18 nmol/l. Glucocorticoid withdrawal decreased lymphocyte beta 2-receptor density from 798 +/- 111 to 498 +/- 54 binding sites/cell (P < 0.05) and the intracellular c-AMP response to isoprenaline from 15.0 +/- 4.2 to 8.2 +/- 1.7 pmol/10(6) cells (P < 0.05). Echocardiography showed impaired diastolic relaxation after glucocorticoid withdrawal with prolongation of the rapid filling period (80.3 +/- 12.5 vs 138.3 +/- 11.8 ms, P < 0.05). Plasma catecholamines, platelet alpha 2-receptor density and systolic left ventricular function were not affected by glucocorticoid deficiency. CONCLUSIONS: This study demonstrates the importance of normal glucocorticoid levels for beta 2-adrenoceptor function and helps to explain the decreased responsiveness to catecholamines and the impaired cardiac performance in adrenal crisis.

Adolescent↗
PubMed1994

Identification of serum-inducible genes: different patterns of gene regulation during G0-->S and G1-->S progression.

We have identified, by differential cDNA library screening, 15 serum inducible genes in the human diploid fibroblast cell line WI-38. The genes fall into two classes that are distinguished by their dependence on protein synthesis for the induction by serum, i.e., primary and secondary genes. While 11 of these genes encode known proteins, 4 other genes have not been described to date. The former genes encode proteins of diverse functions, including the monocyte-derived neutrophil chemotactic factor (MONAP), calmodulin, tropomyosin, tenascin, collagenase, plasminogen activator inhibitor-2a, the 'sperm-specific' cleavage signal-1 protein, metallothionein IIa and the mitochondrial chaperonin hsp-60. Interestingly, one of the unknown genes contains a large open reading frame for a polypeptide that is highly homologous to a previously unidentified long open reading frame in the opposite strand of the gene coding for the transcription factor HTF-4. We also studied the regulation of these serum-induced genes during cell cycle progression in normally cycling WI-38 and HL-60 cells separated by counterflow elutriation as well as in serum-stimulated HL-60 cells. Our results clearly show that, in contrast to the prevailing opinion, the expression of most genes induced after mitogen stimulation is not subject to a significant regulation in normally proliferating cells. This supports the hypothesis that the progression into S from either G0 or G1 are distinct processes with specific patterns of gene expression.

Amino Acid Sequence↗
PubMed1994

Differential induction of 'metabolic genes' after mitogen stimulation and during normal cell cycle progression.

Mitogenic stimulation of quiescent cells not only triggers the cell division cycle but also induces an increase in cell volume, associated with an activation of cellular metabolism. It is therefore likely that genes encoding enzymes and other proteins involved in energy metabolism and biosynthetic pathways represent a major class of mitogen-induced genes. In the present study, we investigated in the non-established human fibroblast line WI-38 the induction by mitogens of 17 genes whose products play a role in different metabolic processes. We show that these genes fall into 4 different categories, i.e. non-induced genes, immediate early (IE) primary genes, delayed early (DE) secondary genes and late genes reaching peak levels in S-phase. In addition, we have analysed the regulation of these genes during normal cell cycle progression, using HL-60 cells separated by counterflow elutriation. A clear cell cycle regulation was seen with those genes that are induced in S-phase, i.e. thymidine kinase, thymidylate synthase and dihydrofolate reductase. In addition, two DE genes showed a cell cycle dependent expression. Ornithine decarboxylase mRNA increased around mid-G1, reaching maximum levels in S/G2, while hexokinase mRNA expression was highest in early G1. In contrast, the expression of other DE and IE genes did not fluctuate during the cell cycle, a result that was confirmed with elutriated WI-38 and serum-stimulated HL-60 cells. These observations suggest that G0-->S and G1-->S transition are distinct processes, exhibiting characteristic programmes of gene regulation, and merging around S-phase entry.

Base Sequence↗
PubMed1994

Alternative splicing of human cyclin E.

Cyclin E is a regulatory subunit of the cdc2-related protein kinase cdk2, which is activated shortly before S-phase entry, thus defining it as a G1 cyclin. We report here the existence of a 43 kDa splice variant of human cyclin E, termed cyclin Es, which lacks 49 amino acids within the cyclin box compared to the known 48 kDa cyclin E. Cyclin Es is expressed at approximately 1/10 of the level of full-length cyclin E in several cell lines analysed. The two cyclin E forms differ functionally in that cyclin E, but not cyclin Es, is able to complex with cdk2, to activate the histone H1, pRb and p107 in vitro kinase activity of cdk2 and to rescue a triple CLN mutation in S. cerevisiae. Cyclin Es is the first splice variant of a cell cycle regulatory protein to be described. Our findings also indicate that the cyclin box in cyclin E mediates the interaction with cdk2.

Alternative Splicing↗
PubMed1994

Lineage-specific regulation of cell cycle gene expression in differentiating myeloid cells.

We have analysed the expression of 7 cyclin and cyclin-associated kinase (cdk) genes in the human myeloid cell line HL-60 at different stages of the cell cycle in non-synchronised cells and during terminal differentiation. A clear cell cycle-dependent expression was found with cyclins A (S+G2), B (G2) and E (late G1 and S), while other cell cycle genes showed only very weak (cdk2) or no periodic expression (cyclin D1, cyclin D2 and cdk4). Induction of macrophage-like differentiation by TPA or granulocytic differentiation by retinoic acid or DMSO was accompanied by a block in G1 and resulted in distinct patterns of gene expression that were lineage- and inducer-specific. These included: (i) a dramatic decrease in the expression of cyclin A, cyclin B and cdk2, and surprisingly an up-regulation of cyclin D1 in TPA-induced macrophage-like cells; (ii) a down-regulation of cyclin E in retinoic acid-induced granulocytic cells; and (iii) a decreased abundance of cyclin D1 and D2, but high levels of cyclin A, B and E RNA in DMSO-induced granulocytic cells. These observations suggest that the mechanisms leading to a differentiation-associated cell cycle arrest are lineage-specific, and that the sustained expression of cyclin and cdk genes does not interfere with the induction of terminal differentiation.

Base Sequence↗
PubMed1994

Magnetic resonance angiography: methods and its applications to the coronary arteries.

The non-invasive visualisation of the coronary arteries with magnetic resonance imaging would be a highly useful tool for the diagnosis of coronary artery disease, with a potential to partly replace current invasive imaging modalities, and would be a step towards more patient comfort. While magnetic resonance (MR) angiography of most larger blood vessels can nowadays be performed routinely, current techniques are inadequate to image the coronary arteries. This paper provides a short overview of the principal techniques for MR angiography. The combination of a multiple-slice MR angiography technique with a simple and easily performed breathhold scheme is described, which allows to image the main branches of the coronary artery tree within one scan of 9 to 12 min duration. For display the coronary vessels are segmented semi-automatically and reconstructed as 3D-objects. Results of volunteer scans and examinations of patients with known coronary artery disease show the feasibility of the approach. However, due to the need for a breathhold scheme, patient cooperation is required.

Coronary Angiography↗
PubMed1994

Protein kinase A phosphorylates cyclin D1 at three distinct sites within the cyclin box and at the C-terminus.

Cyclin D1 is a nuclear phosphoprotein that is thought to play a major role in the control of G0/G1-->S progression. The fact that its expression is not tightly regulated during cell cycle progression suggests that its activity might be modulated by post-translational mechanisms. In the present study, we show that out of five serine-threonine kinases tested only protein kinase A (PKA) was able to phosphorylate cyclin D1 in vitro. In agreement with this observation, forskolin treatment, but not TPA stimulation, led to increased phosphorylation of cyclin D1 in vivo. Phosphoamino acid analysis and two-dimensional phosphopeptide mapping of wild-type and truncated cyclin D1 proteins showed that PKA phosphorylates three distinct serine residues in cyclin D1 at positions 90, 197 and 234. Serine-90 is located within the cyclin box, raising the possibility that phosphorylation of cyclin D1 might play a role in regulating the interaction with other proteins.

Cyclic AMP-Dependent Protein Kinases↗
PubMed1994

Plasma catecholamines and adrenoceptors in young hypertensive patients.

An elevated sympathoadrenal tone and an imbalance in postsynaptic alpha- and beta-adrenoceptor function are discussed as factors in the pathogenesis of essential hypertension. This study examined plasma catecholamines, thrombocyte alpha2-adrenoceptors and lymphocyte beta2-adrenoceptors in 16 young patients with newly detected essential hypertension and 26 normotensive age matched controls (27.1 +/- 4.5 vs. 24.8 +/- 2.8 years; NS). Plasma noradrenaline (276 +/- 34 vs. 216 +/- 18 pg/ml, P < 0.05) and plasma adrenaline (96 +/- 15 vs. 31 +/- 4 pg/ml, P < 0.0001) were significantly elevated in hypertensive patients. Thrombocyte alpha2-adrenoceptor density was only nonsignificantly decreased (230 +/- 37 vs. 311 +/- 36 fmol/mg protein, NS), whereas lymphocyte beta2-adrenoceptor density was markedly reduced (15.3 +/- 2.3 vs. 22.6 +/- 1.8 fmol/mg protein, P < 0.01) in hypertensive patients. Elevated plasma catecholamines are consistent with a pathophysiological role for increased sympathetic neural activity in young hypertensive patients. Assuming that results of adrenoceptor studies on blood elements are applicable on vascular receptors, our results are consistent with an imbalance of postsynaptic adrenoceptor functions which promotes the pressor effects of the sympathetic system.

Adult↗
PubMed1994

Inducible acceleration of G1 progression through tetracycline-regulated expression of human cyclin E.

Cyclin E is a cell cycle-regulated protein that activates the cdc2-related protein kinases cdk2 shortly before S-phase entry. In order to analyse the biological role of cyclin E, we have generated HeLa cells that allow the conditional expression of ectopic human cyclin E. In these cells, a cyclin E cDNA is under the control of a bacterial tetracycline repressor-VP16 activator hybrid protein. In the absence of tetracycline, the endogenous gene becomes activated and leads to the synthesis of elevated levels of cyclin E. Concomitant with this increase in cyclin E expression we show by a combined time-lapse video recording/5-bromo-deoxyuridine labelling procedure a significant acceleration of G1 transition by approximately 1.5 hours. This observation is consistent with the idea that cyclin E is a rate-limiting factor with respect to the control of G1-->S transition. The experimental system described here should also prove useful to address the function of cyclin E in further detail.

Cyclins↗