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Biomedical subjects

J F Moorhead

Publications and source records attributed to J F Moorhead.

At least 37 records · Page 2Linked to original sources
PubMed1998

Cytokine regulation of low-density lipoprotein receptor gene transcription in human mesangial cells.

BACKGROUND: The intracellular transport of lipids through regulation of the LDL receptor (LDLr) may be important in the progression of renal dysfunction. The present study was undertaken to investigate whether cytokines have any major effects on LDLr regulation and lipid-mediated glomerular injury in human mesangial cells (HMC). METHODS: We explored the effects of 50 ng/ml of tumour necrosis factor alpha (TNF alpha), 5 ng/ml of transforming growth factor beta (TGF beta), platelet-derived growth factor (PDGF), and interleukin-1beta (IL-1beta) on the regulation of LDLr gene transcription in a human mesangial cell line (HMCL) using cell proliferation, LDL binding, northern blot and LDLr promoter activity assays. RESULTS: TNF alpha, TGF beta, PDGF or IL-1beta did not significantly stimulate HMCL proliferation at the concentrations given above, but maximally stimulated LDLr mRNA expression and increased LDLr promoter activity by 167.48+/-23.56%, 150.47+/-24.41%, 127.71+/-24.65% and 163.01+/-31.91% respectively, at 24 h. An increased LDL binding was observed in parallel with increased LDLr mRNA. The tyrosine kinase transduction pathway was involved in LDLr upregulation induced by all four cytokines. Additionally, TGF beta involved serine/threonine kinase and G-protein pathways, and IL-1beta involved calmodulin, serine/threonine kinase and PKC pathways in upregulating LDLr. A high concentration of LDL (250 microg/ml) inhibited promoter activity, but TNF alpha, TGF beta, PDGF and IL-1beta co-incubated with LDL could override transcriptional inhibition by LDL. CONCLUSION: TNF alpha, TGF beta, PDGF and IL-1beta increased LDLr gene expression by increasing sterol-independent and mitogenesis-independent gene transcription. This process may contribute to lipid deposition and foam cell formation in HMC.

Base Sequence↗
PubMed1997

Glomerular atherosclerosis.

This paper suggests a two-hit model for lipoprotein-mediated progressive renal disease, in which postsecretory modification of low-density lipoprotein may favour the transformation of mesangial cells, monocytes and macrophages to glomerular foam cells. Proteinuria and lipiduria would mediate tubulointerstitial damage. Based on this, careful treatment with lipid-lowering agents, lipopheresis and antioxidants may ameliorate the progression of glomerular and tubulointerstitial pathology.

Arteriosclerosis↗
PubMed1996

Do glomerular atherosclerosis and lipid-mediated tubulo-interstitial disease cause progressive renal failure in man?

The nephrotic syndrome presents the kidney with a new environment in which blood vessels, glomerular structures and tubules are exposed over substantial periods of time to lipoproteins. LDL has charge affinity with glomerular basement membrane glycosaminoglycans, so potentially increases or maintains albumin loss. This in turn stimulates LDL synthesis. HDL is small enough to be passed by the glomerular filter in substantial amounts and has been found to stimulate endothelin-1 production by human proximal tubular cells in culture. LDL also inhibits nitric oxide vasodilatory responses, an action which when added to that of endothelin-1 may result in decreased renal tissue oxygenation. Taken together, these aspects of the nephrotic syndrome broaden conventional definitions of atherosclerosis and offer a number of targets for therapy in progressive renal disease.

Arteriosclerosis↗
PubMed1995

Cost-effective rehabilitation: Part 1--Basic principles.

Patients may be referred for rehabilitation services with a variety of diagnoses, including stroke, spinal cord injury, brain injury, multiple trauma, orthopedic disorders, arthritis, multiple medical problems, and chronic pain. The goals and endpoints for treatment of these conditions are often unclear. The principles that are described in this article provide a structure for creating efficient and effective rehabilitation treatment plans. These principles can also focus the utilization and peer review processes and can assist in determining medical necessity of rehabilitation services. Part one of this two-part article discusses general principles of cost-effective rehabilitation. Part two, in the December 1995 issue, will focus on individual patient management issues.

Cost-Benefit Analysis↗
PubMed1995

Cost-effective rehabilitation: Part 2--Approaches to patient management problems.

Part one of this two-part series discussed general principles of cost-effective rehabilitation: Patients in rehabilitation programs should be working toward achievement of real-world functional goals. Goals should be realistic, and reachable in a reasonable amount of time. Rehabilitation services should be provided at the lowest safe and effective level of care appropriate to the patient's needs. Patients should be participating to their full potential in an active therapy program. Therapy intended to maintain a patient's current condition should be carried out by nonprofessionals who have had training sessions with rehabilitation professionals as needed. Discharge planning begins on the day of admission to the inpatient or outpatient rehabilitation program. This second of the two-part series will focus on individual patient management issues. It discusses circumstances in which the principles of cost-effective rehabilitation may need to be modified. It also discusses approaches to remedy patient management problems that may lead to excessive or ineffective utilization of rehabilitation services.

Case Management↗
PubMed1994

Tubular lipidosis: epiphenomenon or pathogenetic lesion in human renal disease?

Tubular lipidosis is a commonly observed histological lesion in proteinuric renal diseases. We have studied the interaction between native and modified human lipoproteins and human renal proximal tubular cells to investigate whether lipoproteins could be injurious to tubular cells in culture. Human renal proximal tubular cells were cultured and characterized by established methods. Preliminary studies showed that these cells could take up and degrade normal human lipoproteins by high affinity (HDL) and low affinity (LDL) pathways. In subconfluent culture, native lipoproteins, that is, LDL, HDL2 and HDL3, had markedly different effects on cell growth as measured by 3H-thymidine uptake and total cell protein as compared to modified lipoproteins such as minimally modified and oxidized LDL. In addition, we found that renal tubular cells could oxidized native LDL in the presence of copper largely by a superoxide-mediated mechanism. Finally, cellular accumulation of lipid was demonstrated in vitro by incubating cultured cells with varying lipoprotein concentrations for up to 48 hours. Notably, cell detachment was observed only with high concentrations of modified LDL especially with minimally modified LDL. We speculate that uptake and oxidation of filtered LDL by tubular cells may lead to tubular injury in nephrotic states.

Cell Division↗
PubMed1994

Human high density lipoproteins stimulate endothelin-1 release by cultured human renal proximal tubular cells.

The vasoconstrictive and mitogenic actions of endothelins have been implicated in the pathogenesis of progressive renal disease. In the present study, we have assessed whether plasma high density lipoproteins (HDL), the major filtered urinary lipoprotein in nephrotic states, can influence endothelin-1 (ET-1) production by cultured human renal proximal tubular cells. Human HDL was found to stimulate ET-1 secretion up to fourfold in a dose- and time-dependent manner; the effect was greater in subconfluent cultures than in confluent ones. There was little difference between the stimulatory effect of HDL2 and the major HDL subclass, HDL3. Preincubation of the cells with albumin did not abolish the HDL effect, while partially- or fully-delipidated HDL3 largely reproduced the effect of whole HDL3. These findings suggest that stimulation of ET-1 secretion was not simply due to protein or lipid repletion of the cells. Rather, the effect was mediated by HDL apolipoproteins, although binding to the HDL receptors involved in cellular cholesterol homeostasis was not required as tetranitromethane-modified HDL3 was an equally effective agonist of ET-1 release. Apolipoprotein (apo) A-I was indirectly implicated in the process since modified HDL3 in which apoA-II largely replaced apoA-I was less potent than HDL3. A one hour exposure of the cells to HDL3 was sufficient to activate ET-1 production for the following 12 hours, although maximum activation required six hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
PubMed1993

Simvastatin therapy for hypercholesterolemic patients with nephrotic syndrome or significant proteinuria.

Experimental evidence suggests that lipid lowering therapy could slow the progression of renal disease in humans. We have conducted a double-blind, placebo controlled trial of the HMG CoA reductase inhibitor simvastatin in patients with the nephrotic syndrome or significant proteinuria (> 1 g/day) and hypercholesterolemia (> or = 6.5 mmol/liter). Patients were placed on a lipid lowering diet for at least 10 weeks before randomization. After a four-week placebo run-in, 30 adults were randomized to simvastatin or placebo therapy (10 mg/day, increasing to 20 to 40 mg/day as required) for 24 weeks. There were seven dropouts, none of whom were "definitely" related to drug therapy. Total and LDL cholesterol levels fell by a mean of 33 and 31%, respectively, in simvastatin treated patients, compared with only 5 and 1% in patients on placebo (P < 0.001, P = 0.002, respectively). Apolipoprotein B100 levels fell by a mean of 31% in the simvastatin group but rose 0.3% in the placebo group (P = 0.014). There were no significant changes in HDL levels. There were no significant differences between the groups in their urine protein levels, their rise in plasma creatinine, or decline in plasma inulin clearance. Simvastatin is a safe, effective therapy for hypercholesterolemia in proteinuric states. A much larger trial is needed to show if potent lipid-lowering therapy slows progression of hypercholesterolemic proteinuric diseases.

Adolescent↗
PubMed1993

Lipiduria in renal disease.

This article reviews the published data on lipiduria in both health and disease. Small amounts of lipid appear in the urine under normal circumstances but, in the nephrotic syndrome in humans, there is also a considerable amount of high-density lipoprotein in the urine as well as smaller amounts of other lipoproteins. Potential tubular re-uptake mechanisms for lipoproteins have been demonstrated in both animal and cell-culture models. In humans, there is no direct evidence for these specific re-uptake mechanisms--it is only through specific staining of renal biopsies for apolipoproteins that the presence of such mechanisms in intracellular vesicular structures is suggested. It is possible that lipoprotein filtration and re-uptake by the tubule are important mechanisms in tubular injury.

Animals↗
PubMed1993

Oxidation of low-density lipoproteins by rat mesangial cells and the interaction of oxidized low-density lipoproteins with rat mesangial cells in vitro.

Glomerulosclerosis and atherosclerosis share common pathobiological mechanisms. Experiments carried out in vitro over the past decade using cells thought to be involved in the atherosclerotic process such as endothelial cells, smooth muscle cells, and monocyte/macrophages have shown that postsecretory modifications such as oxidation increase the atherogenicity of LDL. Animal experiments employing antioxidant therapy have also been shown to slow the progression of atherosclerotic lesions. We set out to investigate the interactions between oxidized LDL (oxLDL) and rat mesangial cells (RMC) that might be of importance in the glomerulosclerotic process. Our results show that RMC have the ability to oxidize LDL, that oxLDL binding was 2-3-fold greater than native LDL (nLDL), and that oxLDL was more cytotoxic to these cells than nLDL. We speculate that cell-mediated oxidation of LDL in vivo may play a role in the progression of the glomerulosclerotic process.

Animals↗
PubMed1993

Effect of cyclosporin A on endothelin synthesis by cultured human renal cortical epithelial cells.

We report here for the first time that human renal proximal tubular cells secrete endothelin, clear evidence of de-novo endothelin synthesis by these cells and the effect of cyclosporin A (CsA) on endothelin synthesis both in short-term (24 h) and medium-term (5-day) culture. Human renal cortical epithelial cells were cultured and shown to possess proximal tubular characteristics. These cells produced endothelin in culture in a time-dependent manner, as measured by radioimmunoassay (291.6 +/- 51.4 pg/well/24 h). Furthermore, endothelin production by these cells was significantly decreased by up to 80% by cycloheximide (1051.8 +/- 54.9 pg/mg cell protein/24 h versus 253.2 +/- 12.6 pg/mg cell protein/24 h), showing that these cells actively synthesize endothelin. In short-term culture (24 h), CsA significantly inhibited endothelin synthesis at a medium concentration of 10,000 micrograms/l. No change in endothelin synthesis was seen at lower CsA concentrations. In contrast, over a 5-day period, a non-significant increase in endothelin synthesis was observed at CsA concentrations of 2000 micrograms/l (152.5 +/- 20.4%); however, cell growth was significantly decreased at this concentration (71.33 +/- 6.39%). Using a newly developed two-site immunoradiometric assay specific for endothelin-1 (ET-1), we demonstrate that ET-1 is the major endothelin isoform produced by human renal proximal tubular cells.

Animals↗
PubMed1993

Serum cholesterol falls spontaneously in nephrotic patients with progressive renal disease.

Total cholesterol (TC) levels were lower than expected in some patients with advanced renal disease and nephrotic-range proteinuria. Studies of 35 clinically stable nonuremic patients and of 12 nephrotic patients with advancing renal failure were therefore performed. Analysis of pooled biochemical data from 35 patients who were hypercholesterolemic on entry to the clinic revealed a positive correlation between TC and reciprocal creatinine (l/Cr) while serum albumin (ALB) was negatively correlated with l/Cr and TC. In the 12 nephrotic patients with negative reciprocal creatinine slopes there was a strong correlation between the slopes of l/Cr and TC. These data suggest that plasma cholesterol falls in the nephrotic hypercholesterolemic patients in whom renal disease progresses, and that the slopes of plasma cholesterol and reciprocal creatinine are closely related.

Cholesterol↗
PubMed1993

Low-dose simvastatin is safe in hyperlipidaemic renal transplant patients.

Hyperlipidaemia is common after renal transplantation, and because of its association with atherosclerosis, interest has increased in the use of lipid-lowering drugs in transplant patients. Dietary approaches have not been consistently successful, and multiple pharmacotherapy and drug interactions have led to difficulties in establishing lipid-lowering drug regimes. The statins reduce plasma cholesterol by inhibiting the rate-limiting step in cholesterol synthesis, and although some side-effects have been reported in their use after transplantation, the efficacy and safety of low doses has not been formally established. A randomized single-blind placebo crossover study designed to determine the safety and effectiveness of simvastatin in a single daily 5-mg evening dose was therefore conducted in 26 stable renal transplant patients, 14 of whom were receiving cyclosporin A. The results demonstrated no difference between total cholesterol levels in the baseline simvastatin and placebo periods: 7.97 +/- 1.2 and 7.59 +/- 1.5 mmol/l respectively. After 8 weeks of simvastatin, the total cholesterol declined significantly to 6.72 +/- 0.87 mmol/l (P < 0.001). A significant difference was found when the placebo and simvastatin cholesterol levels were compared at 4 and 8 weeks (P < 0.01). LDL cholesterol decreased from 4.74 +/- 0.87 to 3.78 +/- 0.78 mmol/l after 8 weeks on simvastatin (P < 0.001), and apo B fell from 142 +/- 31 to 112 +/- 22 mg/dl (P < 0.001). The difference in LDL cholesterol and apo B after 8 weeks of simvastatin when compared with the corresponding values on placebo was also significant (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Cervical myelopathy presenting as a genu recurvatum gait disorder.

A 49-year-old man presenting with a genu recurvatum gait disorder was found to have a cervical myelopathy, probably on the basis of cervical spondylosis and a cervical disc herniation compromising a congenitally narrow cervical spinal canal. Satisfactory resolution of abnormal hyperextension of the knee was achieved through the use of an ankle-foot orthosis. A genu recurvatum gait disorder as the presenting sign of cervical myelopathy does not appear to have been reported previously.

Cervical Vertebrae↗