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M Davies

Publications and source records attributed to M Davies.

At least 253 records · Page 14Linked to original sources
PubMed1994

Glomerular mesangial cells in vitro synthesize an aggregating proteoglycan immunologically related to versican.

Recent studies have shown that mesangial cells derived from human adult glomeruli synthesize a number of 35S-labelled proteoglycans including a large chondroitin sulphate proteoglycan (CSPG), two dermatan sulphate proteoglycans (biglycan and decorin) and two heparan sulphate proteoglycans [Thomas, Mason and Davies (1991) Biochem. J. 277, 81-88]. In the present study we have examined the interaction of these proteoglycans with hyaluronan (HA) using associative gel chromatography. Only the large CSPG bound to HA, with 60% of those molecules in the medium and 80% of those in the cell layer being able to interact. Reduction and alkylation, or treatment of the monomer CSPG with proteinases, prevented the formation of aggregates, suggesting that the core protein was involved. The aggregates formed between purified CSPG and HA could be dissociated in the presence of HA-oligosaccharides of at least 10 monosaccharides in length. The inclusion of link protein with CSPG and HA promoted the formation of aggregates. Experiments with 3H-labelled mesangial-cell proteoglycans confirmed that only the large CSPG, with core protein molecular masses of 400 kDa and 500 kDa, interacted with HA. After chondroitin ABC lyase treatment of CSPG isolated from conditioned culture medium, several bands similar to those observed with 3H-labelled core proteins were identified using a polyclonal antiserum that recognizes versican. A monoclonal antibody recognizing the 1-C-6 epitope in the G1 and G2 globular regions of aggrecan did not recognize either mesangial-cell CSPG or bovine aortic versican. Northern-blot analysis confirmed that human mesangial cells express versican. Thus human mesangial large CSPG is a member of the versican family of proteoglycans. The interaction of CSPG and HA within the glomerulus may be important in glomerular cell migration and proliferation.

Adult↗
PubMed1994

IVIC/Vetstream.

Explore the source record for details and available documents.

Humans↗
PubMed1994

Effect of angiotensin converting enzyme inhibition on plasma endothelin in congestive heart failure.

The influence of angiotensin converting enzyme inhibitor therapy on elevated plasma endothelin concentrations in chronic heart failure was investigated by measuring plasma endothelin immunoreactivity in 22 patients with severe but stable chronic heart failure before and after 16 weeks of therapy with quinapril (n = 12) or captopril (n = 10). Plasma endothelin immunoreactivity in the patients (10.2 +/- 34 pg/ml) was significantly higher than a control group (5.9 +/- 1.8 pg/ml). Quinapril improved symptoms and haemodynamics but did not affect plasma endothelin immunoreactivity (11.9 +/- 2.9 pg/ml at baseline and 12.3 +/- 3.4 pg/ml after 16 weeks of quinapril). Captopril also had no effect on endothelin levels (8.1 +/- 2.9 at baseline and 8.1 +/- 3.8 pg/ml after 16 weeks of captopril). The vasodilatory effects of angiotensin converting enzyme inhibitors in heart failure are not mediated by, or associated with, changes in plasma endothelin immunoreactivity.

Adult↗
PubMed1994

Extracellular matrix degrading metalloproteinases in the pathogenesis of arteriosclerosis.

We review the importance of extracellular matrix remodelling to the processes of vascular smooth muscle cell migration and proliferation that contribute to morphogenesis of the atherosclerotic plaque. In particular, the role of the matrix degrading metalloproteinase (MMP) family is discussed. This family of neutral, ZN(2+)-requiring enzymes are capable, in principle, of degrading all matrix proteins. Their activity is tightly controlled, however, at the level of synthesis of the inactive zymogens, activation by limited proteolysis and binding to endogenous inhibitor proteins (TIMPs). Direct evidence is presented for the involvement of MMPs in proliferation and outgrowth of vascular smooth muscle cells from explants of rabbit aorta in vitro. This was obtained using two structurally-unrelated inhibitors of MMPs, Ro 31-4724 and Ro 31-7467, both of which inhibited proliferation of cells in a concentration-dependent manner, Ro 31-4724 also inhibited outgrowth. Rabbit aortic smooth muscle cells were further shown to release MMPs, namely a 95 and a 72 kDa gelatinases that were inhibited by Ro 31-4724 and Ro 31-7467. The evidence suggests that degradation of basement membrane by gelatinase is required for proliferation and outgrowth of these cells. The implications of these findings for the pathogenesis and treatment of atherosclerosis are also discussed.

Animals↗
PubMed1994

Synthesis and anti-HIV activity of some novel diaryl phosphate derivatives of AZT.

Novel diaryl phosphate triester derivatives of the anti-HIV nucleoside analogue AZT have been prepared by phosphorochloridate chemistry. These materials were designed to act as membrane-soluble pro-drugs of the bio-active free nucleotides. In particular, novel parasubstituted diaryl phosphate derivatives were prepared. In vitro evaluation revealed the compounds to have a pronounced and selective antiviral effect, the magnitude of which varied considerably with the nature of the aryl substituent. In particular, strongly electron-withdrawing aryl substituents correlate with high anti-HIV potency in C8166 cells. Along with AZT, the compounds are poorly effective in JM cells, which appear to lack thymidine kinase, indicating the phosphates to act as pro-drugs of the nucleoside rather than of the free phosphate.

Animals↗
PubMed1994

Relative roles of elastase and reactive oxygen species in the degradation of human glomerular basement membrane by intact human neutrophils.

Glomerular basement membrane (GBM) damage and proteinuria occurring during the early phase of acute glomerulonephritis are often neutrophil (PMN) dependent. The present study sought to identify the potential roles of PMN derived elastase and reactive oxygen species (ROS) in the pathogenesis of glomerular basement damage in an homologous in vitro model of anti-GBM nephritis using intact PMN. Human PMN (5 x 10(6)), incubated with human GBM (0.5 mg) pretreated with human anti-GBM IgG, degraded 10.3 +/- 1.1% of the GBM type IV collagen in six hours (8 micrograms/hr), and underwent a two-hour respiratory burst. The same number of sonically disrupted PMN solubulized 22.4 +/- 5.1% of GBM under the same incubation conditions. The inclusion of the elastase inhibitors alpha 1 proteinase inhibitor (alpha 1Pi), and a smaller highly-specific synthetic compound (L658,758), reduced degradation by PMN homogenates by 84.8% and 85.7%, respectively, whereas they were only able to inhibit intact PMN mediated degradation by a maximum of 49.2% and 50.9%, respectively. The inclusion of EDTA (10 mM), an inhibitor of metalloproteinases, reduced GBM degradation by APMA activated and disrupted PMN by only 7.5%. Incubation of PMN with diphenylene iodonium (DPI) abolished PMN reactive oxygen species generation by > 95% but preserved elastase release. This compound did not directly affect GBM degradation. It did, however, abolish the inhibitory effect of ROS on alpha 1Pi activity and thus indirectly reduced GBM damage by up to 20%.

Basement Membrane↗
PubMed1994

Oxidation of low density lipoprotein by mesangial cells may promote glomerular injury.

Low density lipoprotein (LDL) deposition and local oxidation play a key role in the pathogenesis of atherosclerosis and may likewise contribute to glomerular injury. These studies were designed to determine whether cultured human mesangial cells oxidize homologous LDL and to compare the effects of unmodified and oxidized lipoprotein on cell proliferation, viability and eicosanoid production. Cell-mediated lipoprotein oxidation was demonstrated and could be suppressed by oxygen free radical scavengers and inhibitors of arachidonic acid metabolism. When incubated with cells, oxidized LDL (Ox-LDL) at concentrations up to and including 100 micrograms/ml reduced 3H-thymidine incorporation without causing cytotoxicity as assessed by lactate dehydrogenase release. Under the same conditions there was a concentration-dependent increase in the synthesis of prostaglandins E2,6-keto-PGF1 alpha and thromboxane B2. In contrast, unmodified LDL enhanced DNA synthesis at concentrations less than 40 micrograms/ml and had little effect on eicosanoid production. These results demonstrate that exogenous oxidized LDL inhibits mesangial cell proliferation and increases eicosanoid synthesis. Unmodified lipoprotein can be directly oxidized by these cells through mechanisms that involve generation of oxygen free radicals.

Cell Division↗
PubMed1994

The source and possible significance of hyaluronan in the peritoneal cavity.

The levels of hyaluronan (HA) were determined in dialysate from patients receiving CAPD. The levels found after the four hour dwell were 0.162 +/- 0.08 micrograms/ml (N = 16) in non-infected fluid and 1.69 +/- 1.12 (N = 5) during peritonitis, P < 0.0025. Similarly concentrations in overnight (8 to 10 hours) dwell dialysate were 0.384 +/- 0.22 micrograms/ml (N = 13) when uninfected and 3.17 +/- 2.28 (N = 8) during peritonitis, P < 0.0002. Following de novo catheter insertion the initial peritoneal washout yielded HA levels of 0.0032 +/- 0.0018 micrograms/ml (N = 7). In vitro human peritoneal cells synthesized HA, 90% of which was secreted into the culture medium (CM). By dissociative gel permeation chromatography on Sephacryl 1000 there were no significant differences in the molecular size of HA extracted from (a) non-infected fluid, (b) infected fluid and (c), mesothelial cell culture medium. These results indicate that the process of CAPD results in an increase in HA levels in the peritoneal cavity. During episodes of peritonitis these functions are further augmented. The likely source of HA in the dialysate is the peritoneal mesothelial cells. This response may be an initial event in wound repair.

Adolescent↗
PubMed1994

Identification and independent regulation of human mesangial cell metalloproteinases.

Mesangial cells are known to secrete metalloproteinases that are capable of degrading the constituents of the GBM, and hence are potentially involved not only in the regular maintenance of the ECM components in the glomerulus, but also of contributing to any damage to these components that occurs in disease states. In this report we positively identify by Northern blotting the neutral proteinase that is constitutively secreted by the human mesangial cell (HMC) as gelatinase A (MMP2). Stimulation of HMC gelatinase by IL-1 beta or PMA causes an increase in the total amount of gelatinolytic activity secreted. On examination, however, this increased activity is shown, both by immunoreactivity and by PCR to be due to the induction of the higher molecular weight form of gelatinase, gelatinase B (MMP9), while the amount of gelatinase A remained unaffected. In addition antigen and messenger RNA have been identified for both the specific inhibitors of metalloproteinases TIMP-1 and TIMP-2. The appearance of the larger inducible gelatinase with similar substrate specificity implies that the regular turnover of matrix components may be due to the constitutively released gelatinase A while in pathological situations the inducible gelatinase B becomes predominant. The synthesis and secretion of TIMP-1 and TIMP-2 indicates that the mesangial cell is capable of controlling the activity of its own secreted enzymes.

Base Sequence↗
PubMed1994

Human peritoneal mesothelial cell prostaglandin synthesis: induction of cyclooxygenase mRNA by peritoneal macrophage-derived cytokines.

Increasing evidence suggests that the mesothelial cell contributes to the control of inflammation in both the normal and inflamed peritoneal cavity. The present study examines the regulation of prostaglandin production by human peritoneal mesothelial cells (HPMC) following stimulation with peritoneal macrophage-conditioned medium and the cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha). IL-1 beta and TNF-alpha stimulated significant release of prostaglandin above background levels in a time and dose dependent manner. Stimulation of HPMC with IL-1 beta (500 pg/ml) or TNF-alpha (100 pg/ml) for 24 hours resulted in the release of 24.5 +/- 4.3 (N = 11) (z = 3.40, P < 0.001 vs. control) and 19.4 +/- 4.5 (N = 10; z = 3.29, P < 0.001 vs. control) pg 6-keto-PGF1 a/micrograms cellular protein, respectively. Pretreatment of HPMC with dexamethasone (10(-6) to 10(-9) M) inhibited both constitutive and cytokine stimulated prostaglandin synthesis in a dose dependent manner. Both PMø-CM and PMø-S.epiCM stimulated 6-keto-PGF1 alpha and PGE2 synthesis by HPMC in a time and dose dependent manner (PMø-S.epiCM >> PMø-CM). Co-incubation of HPMC with PMø-S.epiCM in the presence of anti-IL-1 beta and/or anti-TNF-alpha antibody, interleukin-1 receptor antagonist or soluble TNF receptor (TNF p75) significantly reduced the capacity of these supernatants to stimulate prostaglandin synthesis. Exposure of HPMC to cytokines or PMø-S.epiCM resulted in the time dependent increase in the levels of both Cox-1 and Cox-2 mRNA as assessed by RT/PCR analysis with the greatest increase being seen for Cox-2. These data demonstrate specific stimulation of eicosanoid metabolism in HPMC by peritoneal macrophage derived cytokines, indicating the possible importance of these mediators in the activation of intraperitoneal prostaglandin synthesis. HPMC prostaglandins might act as important pro/anti-inflammatory mediators contributing to a cytokine network in the peritoneal cavity during CAPD peritonitis.

Base Sequence↗
PubMed1994

Cyclosporin A and vitamin D metabolism: studies in patients with psoriasis and in rats.

1. Cyclosporin A, an immunosuppressive drug used to treat psoriasis, stimulates renal synthesis of 1,25-dihydroxyvitamin D in rats. 1,25-Dihydroxyvitamin D can also reduce the activity of psoriasis, and in the present study we have examined the possibility that cyclosporin A mediates some of its actions in psoriasis by renal or extra-renal production of 1,25-dihydroxyvitamin D. 2. Treatment of 12 psoriatic patients with cyclosporin A (5 mg day-1 kg-1) for 3 months significantly improved the psoriasis activity and severity index and reduced glomerular filtration rate, but serum 1,25-dihydroxyvitamin D levels were not changed. However, 1-3 months after stopping cyclosporin A treatment, an increase in the psoriasis activity and severity index score was accompanied by a small, but significant, increase in serum 1,25-dihydroxyvitamin D concentration. Plasma 1,25-dihydroxyvitamin D levels in rats gavaged with cyclosporin A (15 mg day-1 kg-1 for 2 weeks) were significantly increased compared with controls, but a lower dose of cyclosporin A (2.4 mg day-1 kg-1) had no effect. Renal 25-hydroxyvitamin D-24-hydroxylase activity in rat kidney homogenates was not different between control and cyclosporin A-treated rats. Renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity was not detectable in these homogenates. Extra-renal production of 1,25-dihydroxyvitamin D by activated macrophages isolated from the synovial fluid of patients with inflammatory arthritis was reduced after incubation with cyclosporin A (0.1-10 mumol/l) for 30 h or 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The information handling techniques of research (laboratory and clinical) scientists: preliminary indications of current practice.

This paper arises from a longitudinal study concerning the impact of information technology developments on the information handling techniques of research (laboratory and clinical) scientists from the perspective of perceived value or benefit based on subjective evaluation by users. The project's main method of data collection is the semi-structured interview utilizing samples from various categories of Imperial Cancer Research Fund (ICRF) staff plus a composite external comparison group. This method is complemented by analyses of Library and Information Services Department's (LIS's) records (particularly statistics of database usage and requests relating to document supply) and, where possible, indications of other software usage (to provide further background to the degree of electronic activity of users). This paper focuses on the ICRF staff sample only and reports selected results obtained from interviews during the first phase of the project, October 1992-September 1993, which give preliminary indications of the information handling techniques of research scientists at that time.

Attitude of Health Personnel↗
PubMed1994

Impaired glucose tolerance and insulin insensitivity in primary hyperparathyroidism.

OBJECTIVE: A high prevalence of diabetes mellitus has been shown in patients with primary hyperparathyroidism (PHPT). However, it is unclear whether this is related to the metabolic abnormalities in PHPT or to the presence of other risk factors for glucose intolerance in these patients. The aim of our study was to determine whether glucose intolerance and insulin insensitivity occur in subjects with PHPT who do not have other risk factors for diabetes mellitus. DESIGN: Cross-sectional study of glucose metabolism in PHPT patients without other risk factors for diabetes mellitus, compared to age and body mass index (BMI) matched healthy subjects. SUBJECTS: Nineteen non-obese, non-diabetic, normotensive patients with PHPT and 11 age and BMI matched healthy subjects. MEASUREMENTS: The continuous infusion of glucose test was used to assess glucose tolerance. Plasma glucose and insulin were measured during a 1-hour continuous infusion of glucose (5 mg/kg ideal body weight/min); insulin sensitivity and beta-cell function were derived from the glucose and insulin data by mathematical modelling. Fasting serum concentrations of parathyroid hormone, ionized calcium and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured in all subjects. RESULTS: PHPT patients attained higher plasma glucose levels at the end of the glucose infusion (median 9.0 (interquartile range 8.1-9.8) mmol/l) than did controls (7.9 (7.1-8.9) mmol/l, P < 0.05), and 8 (42%) PHPT patients had impaired glucose tolerance. Insulin sensitivity was lower in PHPT (60.3% (49.8-85.4)) than in controls (113.7% (89.3-149.2), P < 0.001); beta-cell function was not different in PHPT subjects. PHPT subjects with impaired glucose tolerance had reduced beta-cell function compared to PHPT subjects with normal glucose tolerance (89.9% (70.5-106.4) vs 120% (98.8-156.6) respectively, P < 0.05). No significant correlations were found between insulin sensitivity and PTH (rs = -0.21), 1,25(OH)2D (rs = -0.14), ionized calcium (rs = -0.11) and inorganic phosphate (rs = 0.34). Beta-cell function did not correlate with PTH (rs = 0.15), 1,25(OH)2D (rs = 0.04), ionized calcium (rs = 0.23) or inorganic phosphate (rs = -0.35). CONCLUSION: Insulin insensitivity is present in PHPT even in the absence of hypertension and obesity, and may be the cause of glucose intolerance and diabetes. PHPT subjects with reduced beta-cell function are more likely to develop glucose intolerance.

Adult↗
PubMed1994

Improvement in glucose tolerance and beta-cell function in a patient with vitamin D deficiency during treatment with vitamin D.

Glucose metabolism was studied in a patient with vitamin D deficiency during its treatment with small doses of vitamin D. A continuous infusion of glucose test was performed to assess glucose tolerance and insulin sensitivity and beta-cell function were derived by mathematical modelling. Fasting glucose was 5.6 mmol/l and achieved glucose after the infusion was 10.4 mmol/l confirming diabetes. The test was repeated 0.5, 1, 3 and 5 months after starting treatment. Serum calcium increased glucose intolerance from 1.76 to 2.0, 2.08, 1.96 and 2.0 mmol/l, respectively; vitamin D reached supraphysiological levels initially and returned to normal levels, and parathyroid hormone levels were normalized. Her weight did not change during treatment. Glucose tolerance improved during treatment and achieved glucose was 9.4, 8.6, 9.2 and 9.0 mmol/l at 0.5, 1, 3 and 5 months, respectively; insulin sensitivity did not change. Beta-cell function improved from 101% at diagnosis to 126%, 147%, 173% and 198% at 0.5, 1, 3 and 5 months, respectively. Improvement in beta-cell function and consequently in glucose tolerance is likely to have been due to correction of hypocalcaemia, vitamin D deficiency and secondary hyperparathyroidism.

Aged↗
PubMed1994

Anxiety and congenital central hypoventilation syndrome.

OBJECTIVE: It has been hypothesized that individuals who cannot perceive elevations of CO2 will be less anxious than individuals with intact CO2 perception. To test this hypothesis, children with congenital central hypoventilation syndrome, who have a potentially lethal chronic illness associated with lack of CO2 perception and thus provide a natural experimental group, were studied. METHOD: Rates of anxiety symptoms and disorders in children with congenital central hypoventilation syndrome (N = 13) were compared with rates in an age-matched, nonreferred group of community subjects (N = 292) that included subgroups of children with asthma (N = 15) and other chronic medical illnesses (N = 66). Anxiety symptoms were assessed with information obtained from structured interviews of the parents, which provided both total symptom scores and DSM-III-R diagnoses. RESULTS: The children with congenital central hypoventilation syndrome exhibited significantly fewer anxiety symptoms than all other comparison subjects. Two of these children (15%) met criteria for anxiety disorders, a rate lower than that of the whole community group (24%) and of the chronically ill comparison subgroups (32%-47%). The largest difference in the prevalence of disorder emerged between the children with congenital central hypoventilation syndrome (15%) and those with asthma (47%). In the comparison of children with congenital central hypoventilation syndrome and children with other chronic illnesses, a priori analysis showed that the former had significantly lower rates of disorders that have been linked to panic in the literature. CONCLUSIONS: This study supports theories of anxiety that implicate CO2 perception in the pathophysiology of panic and related anxiety states.

Adolescent↗