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M Davies

Publications and source records attributed to M Davies.

At least 19 recordsLinked to original sources
PubMed1992

Involvement of extracellular-matrix-degrading metalloproteinases in rabbit aortic smooth-muscle cell proliferation.

We investigated the influence of two structurally unrelated inhibitors of matrix-degrading metalloproteinases, Ro 31-4724 and Ro 31-7467, on the primary proliferation of smooth-muscle cells from rabbit aortic explants. Both agents inhibited proliferation in a concentration-dependent manner, but did not affect cell viability. Smooth-muscle cells grown out from explants secreted 95 kDa and 72 kDa gelatinase enzymes that were also inhibited in a concentration-dependent manner by Ro 31-4724 and Ro 31-7467. Interstitial collagenase and stromelysin were not detected. We conclude that metalloproteinases are likely to be involved in the initiation of smooth-muscle proliferation.

Animals↗
PubMed1992

High-performance liquid chromatography of oligosaccharide alditols and glycopeptides on a graphitized carbon column.

The chromatographic behaviour of oligosaccharide alditols and glycopeptides containing neutral and acetamido sugars and sialic acid has been investigated on a HyperCarb porous graphitised carbon column. The alditols were substantially retained and could be eluted in 0-25% acetonitrile-0.05% trifluoroacetic acid in 0.05% aqueous trifluoroacetic acid between 3-30 min for mono- to hexasaccharides. Elution patterns were based on both size, charge and linkage such that isomeric compounds could be separated from each other.

Amino Acid Sequence↗
PubMed1992

Molecular characterization of a low-molecular-mass matrix metalloproteinase secreted by glomerular mesangial cells as PUMP-1.

A polymerase chain reaction (PCR)-based homology cloning strategy was used to define the spectrum of stromelysin-like matrix metalloproteinases (MMPs) synthesized by cultured glomerular mesangial cells (MC). Using this technique, cDNAs encoding an unusual, truncated member of the MMP family, punctuated (putative) metalloproteinase (PUMP-1), were exclusively isolated. Incubation with the cytokines interleukin 1 and tumour necrosis factor increased the abundance of PUMP-1 mRNA in mesangial cells. The mesangial PUMP-1 mRNA is processed in a tissue-specific manner, yielding a transcript containing repeated 3'-untranslated region ATTTA motifs commonly found in cytokines with limited mRNA stability. Polyclonal antibodies prepared against the C-terminal region of the PUMP-1 protein documented release of this enzyme by cultures of cytokine-stimulated MC and permitted identification of PUMP-1-expressing mesangial cells within clinical biopsy specimens of acute glomerulonephritis. These findings represent new molecular and clinical evidence that non-malignant cells process and secrete this unusual member of the MMP family in a cytokine-mediated, tissue-specific manner. Mesangial synthesis of PUMP-1 may contribute to the progression of injury during glomerular inflammatory states.

Amino Acid Sequence↗
PubMed1992

Proteinases and glomerular matrix turnover.

The mesangial cell MMPs and their inhibitor may represent proteins through which biological modifiers such as cytokines and growth factors can control and influence the organization of the glomerulus. At the present we can only speculate on their exact function in glomerular disease. They could conceivably play a role in glomerular conditions where mesangial hypercellularity and cytoplasmic interposition between the endothelium and the basement membrane are frequent occurrences, and in which cytokine-enhanced synthesis of matrix-degrading enzymes could result in severe structural damage. A number of glomerular diseases such as diabetic nephropathy are characterized by the accumulation of glomerular matrix proteins. This could be explained by the inappropriate expression of intrinsic mesangial cell MMPs or TIMP. Further investigation of these proteins in experimental models of glomerular disease or in situ hybridization studies using the available probes promises to be a rewarding area of research during the next few years. For these studies the availability of rTIMP and recent developments in the design of synthetic inhibitors of MMPs may allow more searching investigations into the role of MMP in the pathophysiology of glomerular disease.

Amino Acid Sequence↗
PubMed1992

The role of 1,25-dihydroxyvitamin D in the mechanism of acquired vitamin D deficiency.

OBJECTIVE: We wished to assess the effect of changes in the plasma concentration of 1,25-dihydroxyvitamin D on the plasma elimination half-time for 25-hydroxyvitamin D in man. DESIGN: The turnover of 25-hydroxyvitamin D in plasma was investigated after intravenous doses of the radioactively labelled metabolite had been given to a group of patients (n = 17) with disorders of bone and mineral metabolism before and after oral treatment with calcium or 1,25-dihydroxyvitamin D. PATIENTS: Seven patients with post-menopausal osteoporosis, five with hypoparathyroidism, three with hypophosphataemic osteomalacia, one with renal osteodystrophy and one patient with coeliac disease were studied. MEASUREMENTS: Intravenous injections of 3H-labelled 25-hydroxyvitamin D were given and plasma elimination half-time assessed over periods of 4-14 days during which frequent measurements of plasma calcium, phosphate, parathyroid hormone, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were made. Changes in the plasma elimination half-time for 3H-25-hydroxyvitamin D before and after treatment with calcium and 1,25-dihydroxyvitamin D were evaluated by non-parametric statistical analysis. RESULTS: The elimination half-time for 3H-25-hydroxyvitamin D in plasma was significantly shortened by raising the circulating concentration of 1,25-dihydroxyvitamin D. Conversely, in a patient with intestinal malabsorption of calcium, the metabolic clearance of 3H-25-hydroxyvitamin D was prolonged when the concentration of 1,25-dihydroxyvitamin D in plasma was decreased by suppressing secondary hyperparathyroidism with large calcium supplements. In the longer-term studies (n = 10) there was a highly significant inverse relation (r = -0.88, P < 0.001) between the change in the plasma concentration of 1,25-dihydroxyvitamin D and the induced change in the elimination half-time of 3H-25-hydroxyvitamin D. There was also a significant correlation (r = 0.66, p < 0.0025) between the observed fall in the plasma concentration of unlabelled 25-hydroxyvitamin D and the predicted fall calculated from the measured value for the half-time of the 3H-labelled metabolite. In acute studies in patients with post-menopausal osteoporosis (n = 7), enhanced metabolic inactivation of 3H-25-hydroxyvitamin D was detectable within 24 hours of oral administration of 1,25-dihydroxyvitamin D. CONCLUSIONS: The effect of 1,25-dihydroxyvitamin D on the catabolism of 25-hydroxyvitamin D can contribute to the development of vitamin D deficiency in many clinical disorders. When the natural supply of vitamin D is limited by sunlight deprivation, a sustained increase in the plasma concentration of 1,25-dihydroxyvitamin D due to primary or secondary hyperparathyroidism will lead to accelerated depletion of vitamin D stores.

Aged↗
PubMed1992

Estimation of erythropoietin secretion rate in normal and uremic subjects.

We have developed a method for directly estimating the secretion rate of endogenous erythropoietin (EPO) in human subjects. Carrier-free recombinant human EPO was labeled with 125I by the chloramine T method. Human serum albumin was then added prior to removal of free iodide. Seven normal subjects and nine patients with chronic uremia and anemia were studied. Each subject received a bolus of 125I-EPO according to body size and then a constant infusion for 5 h. Secretion rate was calculated as the rate of infusion divided by serum EPO specific activity given by the protein-bound counts divided by the EPO concentration. Serum EPO concentration was significantly higher in the patients than the controls (mean 30.9 pg/ml vs. 11.1 pg/ml, P < 0.05), although all values were within the normal range. Mean EPO secretion rate was 255 in the patients (range 68-1,101) and 190 pg.kg-1 x h-1 in the normal group (range 52-382). This difference was not significant. As the subjects were in a steady state, EPO disappearance/degradation was the same in patients compared with controls despite a relatively hypoplastic marrow.

Adult↗
PubMed1992

Mesangial cell proteoglycans: synthesis and metabolism.

In cultures of human adult glomerular mesangial cells, large chondroitin sulfate proteoglycans (CSPG) and small dermatan sulfate proteoglycans (DSPG) are synthesized. The large CSPG has a core protein, M(r) of 400,000 (major) and M(r) of 500,000 (minor), and binds to hyaluronic acid to form large aggregates. The two small DSPGs (Mr of approximately 350,000 and M(r) of approximately 200,000) were related to biglycan and decorin, respectively. The majority of these proteoglycans were located in the culture medium, but a hydrophobic form of the CSPG was extracted from the cell layer. Mesangial cells in the growing phase synthesized and secreted all three types of proteoglycans, but in cells arrested in G0 by serum deprivation the incorporation of (35S)sulfate in CSPG was drastically reduced. In the same cells stimulated to proliferate by replacing the medium with one containing serum, the synthesis of CSPG dramatically enhanced. The synthesis of CSPG and DSPG was also elevated in cells cocultured with cytokines but in contrast was significantly reduced when cultured in medium containing hyperglycemic levels of glucose. Finally, preliminary experiments are reported that indicate that CSPG and DSPG bind to low-density lipoproteins in vitro. These observations suggest a possible specialized function for proteoglycans in cellular processes characteristic of glomerular disease.

Animals↗
PubMed1992

Structural characterization of the mesangial cell type IV collagenase and enhanced expression in a model of immune complex-mediated glomerulonephritis.

Secretion of glomerular cell-derived matrix metalloproteinases (MMPs) and their specific inhibitors, TIMP-1,2, may play an important role in the turnover of the glomerular extracellular matrix under basal and pathologic conditions. A 66-68 kd MMP secreted by cultured mesangial cells (MC) with activity against Type IV collagen and gelatin was purified and shown by amino-acid sequence analysis to be identical with a Type IV collagenase/gelatinase secreted by certain transformed tumor cell lines. The expression of the mesangial MMP in vivo was limited within the kidney to a small subset of the intrinsic glomerular mesangial cell population. After induction of acute anti-Thy 1.1 glomerulonephritis, there was a large increment in the number of Type IV collagenase-secreting MC, temporally coincident with the development of mesangial hypercellularity. The expression of the MMP inhibitor protein, TIMP-1, was not changed over this period. Ultrastructural studies localized the mesangial MMP to areas of evolving mesangiolysis and at sites of glomerular basement membrane disruption. Enhanced expression of the mesangial cell-derived Type IV collagenase may contribute to the evolution of glomerular injury in this model of immune complex-mediated glomerulonephritis or may be involved in the extensive matrix remodeling process that accompanies this form of glomerular injury.

Amino Acid Sequence↗
PubMed1979

Clinical characteristics of imipramine-induced orthostatic hypotension.

The effects of imipramine hydrochloride on blood-pressure were examined in a prospective and a retrospective study. In a prospective study of 44 depressed patients given imipramine in doses to achieve antidepressant plasma-concentrations there was no effect of the drug on lying blood-pressure. When patients then stood up, the drug produced an average fall in systolic pressure of 26 mm Hg (t = 13.6, P less than 0.001) that was consistent over the four weeks of observation. Contrary to expectation, this fall was independent of patients' age, pre-existing heart-disease, or plasma-level of the drug. The best predictor of orthostatic hypotension during treatment was the degree of orthostatic drop in pressure before treatment (r = 0.695, P less than 0.001). In order to establish the clinical significance of this orthostatic drop in pressure, a retrospective study of 148 depressed patients treated with imipramine was conducted. These 148 patients, average age 59 years, received an average dose of 225 mg of imipramine. Almost 20% of them had symptoms usually associated with orthostatic hypotension that were severe enough to interfere with their treatment: over 4% sustained physical injuries. In our experience orthostatic hypotension is the commonest serious cardiovascular side-effect of imipramine.

Adult↗