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Biomedical subjects

A J Yates

Publications and source records attributed to A J Yates.

At least 127 records · Page 7Linked to original sources
PubMed1988

Regulation of protein kinase C activity by various lipids.

Protein kinase C has recently attracted considerable attention because of its importance in the control of cell division, cell differentiation, and signal transduction across the cell membrane. The activity of this enzyme is altered by several lipids such as diacylglycerol, free fatty acids, lipoxins, gangliosides, and sulfatides. These lipids may interact with protein kinase C either directly or through calcium ions and produce their regulatory effect (activation or inhibition) on the activities of the enzymes phosphorylated by this kinase. These processes widen our perspective of the regulation of intercellular and intracellular communication.

Animals↗
PubMed1988

Sialyltransferase-1 in a human malignant glioma cell line. Kinetic characteristics and effect of human interferon-beta.

Sialyltransferase-1 activity was studied in cultured 12-18 human glioma cells. The apparent Km and Vmax with variable LacCer concentrations were 32 microM and 197 pmoles/mg protein/hr and with variable CMP-NeuAc concentrations were 172 microM and 877 pmoles/mg protein/hr., respectively. The pH optimum towards exogenous LacCer was 6.0 and towards endogenous acceptors was 6.2. The optimum protein:detergent ratio was 1:1. Human beta interferon (1000 units/ml medium) increased sialyltransferase-1 activity only slightly on a protein basis but increased it 47% on a per cell basis. These results demonstrate that one of the biochemical effects of beta-interferon on 12-18 human glioma cells is to stimulate ganglioside synthesis.

Cell Line↗
PubMed1988

Paget's disease of bone.

Paget's disease is a common disorder of bone of presumed viral aetiology which, in a minority of patients, may cause severe symptoms. Both calcitonin and the diphosphonates have specific anti-pagetic effects. Newer diphosphonates, unlike etidronate, do not impair mineralization, and when they become available these will be the drugs of choice. Until that time, both calcitonin and etidronate continue to have a useful place in the management of this disorder.

Calcitonin↗
PubMed1988

Contrasting effects of intravenous and oral etidronate on vitamin D metabolism in man.

1. We have studied the early effects of intravenously and orally administered etidronate on vitamin D metabolism and indirect indices of calcium and skeletal metabolism in 17 patients with Paget's disease of bone. 2. Administration of etidronate by mouth (700-1400 mg daily for 1 month) or its intravenous infusion (300 mg daily for 5 days) decreased bone resorption as judged by urinary excretion of hydroxyproline and significantly increased renal tubular reabsorption of phosphate. No significant change in serum activity of alkaline phosphatase was noted with either regimen. 3. When etidronate was given by mouth there was a progressive decrease in fasting urinary calcium excretion and a rise in serum 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. In contrast, intravenous etidronate decreased serum values of 1,25-(OH)2D3 and was associated with a progressive increase in fasting calcium excretion, suggesting a decrease in the net influx of calcium from the extracellular compartment to bone. Significant inverse correlations were noted between the change induced in 1,25-(OH)2D3 values at 2 weeks and the changes in serum calcium, phosphate and fasting urinary excretion of calcium. 4. These observations suggest that the different effects of intravenous and oral etidronate on 1,25-(OH)2D3 values are a consequence of different doses of etidronate used and the different effects of these regimens on the accretion of calcium into bone.

Administration, Oral↗
PubMed1988

Diphosphonates and phosphate homoeostasis in man.

1. The effects of three intravenous diphosphonates (etidronate, clodronate and aminohexane diphosphonate) on phosphate homoeostasis were studied in 30 patients with Paget's disease of bone and in three patients with hypoparathyroidism. 2. In Paget's disease, all three diphosphonates induced significant increases in serum phosphate and renal tubular reabsorption of phosphate. This effect was most marked and persistent after etidronate, whereas in the clodronate- and aminohexane diphosphonate-treated patients the increases were less, of shorter duration and followed thereafter by significant decreases in serum phosphate and renal tubular reabsorption of phosphate. Unlike etidronate, both clodronate and aminohexane diphosphonate caused a significant reduction in serum and urinary calcium, with appropriate homoeostatic increases in immunoassayable parathyroid hormone. 3. Phosphaturic responses to infused parathyroid hormone were observed in two patients with etidronate-induced hyperphosphataemia. 4. In three hypoparathyroid patients, clodronate induced a more marked increase in serum phosphate and renal tubular reabsorption of phosphate than in Paget's disease, which was of comparable degree but of shorter duration than that after etidronate in Paget's disease. 5. These findings suggest that all three diphosphonates increase renal tubular reabsorption of phosphate, but that this effect is attenuated with those diphosphonates which induce secondary hyperparathyroidism.

Diphosphonates↗
PubMed1988

Growth inhibition of cultured human glioma cells by beta-interferon is not dependent on changes in ganglioside composition.

This investigation tested the hypothesis that the growth inhibiting effects of human beta-interferon on cultured human glioma cells involves changes in the ganglioside composition of these cells. Four cell lines derived from human malignant gliomas (12-18, U-251 MG, I29-A, 7-24) and two lines from human fetal brain (CHI, CHII) were cultured in the presence and in the absence of human beta-interferon (HuIFN-beta), 1,000 units per ml medium for three days before harvesting. Human beta-interferon had an inhibitory effect on growth of glioma but not fetal brain cells. Total ganglioside sialic acid for all cell lines ranged between 3.5 and 13.8 micrograms/10(7) cells (0.6-3.9 micrograms/mg protein). No distinct difference in the amount of total ganglioside per cell was observed between neoplastic and non-neoplastic cells, but the latter had more ganglioside per mg total protein. All cell lines displayed different patterns of gangliosides determined by high performance thin layer chromatography, but there was no distinct difference between glioma and fetal brain cells. Human beta-interferon increased the total amount of ganglioside per cell in one fetal brain and two glioma lines, but on a protein basis in only one glioma cell line (I29-A); HuIFN-beta had only minor effects on ganglioside patterns. There was a slight shift towards a greater proportion of structurally simpler gangliosides in both fetal brain and two glioma cell lines exposed to HuIFN-beta, but the reverse occurred in glioma U-251 MG. None of these changes strongly correlated with the degree of growth inhibition due to HuIFN-beta.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain Neoplasms↗
PubMed1988

Effect of crush lesion on radiolabelling of ganglioside in rat peripheral nerve.

Left sciatic nerves of adult male Sprague-Dawley rats were crushed and allowed to recover for 0, 1, 2, 4, 7, or 14 days. At each of these times both L-5 dorsal root ganglia were injected with 100 microCi of [3H]glucosamine. Two days later, dorsal root ganglia, lumbosacral trunks, and sciatic nerves were removed bilaterally. The amounts of radiolabelled ganglioside in crushed lumbosacral trunks were consistently higher than in the controls, with the largest difference occurring within 2 days from simultaneous crush and injection to killing (specimens labelled day 0). The largest difference in the amount of radiolabelled ganglioside between crushed and control sciatic nerve (4-9 days from crush to killing) occurred later than that of lumbosacral trunk, but no significant difference occurred within the first 3 days following crush. There was only a slightly higher radioactivity in gangliosides totalled from all three anatomical specimens of crushed than in control nerves. The neutral nonganglioside lipid and acid-precipitable fraction followed patterns of synthesis and accumulation similar to those of the gangliosides. These findings indicate that after nerve crush gangliosides, glucosamine-labelled neutral nonganglioside lipids, and glycoproteins accumulate close to the proximal end of the regenerating axon. This accumulation could serve as a reservoir to increase the ganglioside concentration in the growth cone membrane.

Animals↗
PubMed1988

Effects of a synthetic peptide of a parathyroid hormone-related protein on calcium homeostasis, renal tubular calcium reabsorption, and bone metabolism in vivo and in vitro in rodents.

A synthetic peptide corresponding to the first 34 amino acids of the parathyroid hormone-related protein (PTH-rP) produced by a human tumor associated with hypercalcemia was examined for skeletal and renal effects on calcium metabolism in vivo and in vitro. These effects were compared with those of human parathyroid hormone (1-34), hPTH (1-34). Equal doses of PTH-rP(1-34) and hPTH(1-34) produced equivalent stimulation of adenylate cyclase in vitro in bone cells and kidney cells and tubules. Subcutaneous injection of PTH-rP(1-34) in mice caused a significant dose-related increase in blood ionized calcium similar to that seen with hPTH(1-34) at equivalent doses. Repeated injections of equal doses of both peptides caused sustained hypercalcemia which was significantly greater in PTH-rP(1-34)-treated mice, although each induced comparable increases in histomorphometric indices of osteoclastic bone resorption. PTH-rP(1-34) and hPTH(1-34) also caused similar increases in bone resorption when incubated with fetal rat long bones in organ culture. Infusion of either peptide into thyroparathyroidectomized rats suppressed urinary calcium excretion and increased urinary excretion of cyclic AMP. PTH-rP appears to have similar effects to those of PTH on the skeleton, the kidney, and overall calcium homeostasis.

Adenylyl Cyclases↗
PubMed1988

Glycolipids and gliomas. A review.

Several aspects of the relationships between glycolipids, gliomas, and problems involved in studying these are reviewed. Major problems that currently must be addressed include developing a classification scheme that more accurately predicts the biological behavior of these tumors, obtaining samples representative of the patient's glioma, and identifying appropriate control specimens. Results of analytical studies indicate that the patterns of gangliosides in human glioma tissues generally correlate with the degree of histological malignancy. Some gliomas contain unusual, and perhaps unique, glycolipids. Exogenous glycosphingolipids can alter cell shape and growth, which may involve modulation of growth factor receptors and protein kinases. Tumor glycolipids may also modulate immune functions in patients harboring gliomas. Transfection of nonneural cells with some oncogenes can alter glycolipid metabolism, which may be part of the mechanism through which these oncogenes exert their effects.

Animals↗
PubMed1987

Aminohexane diphosphonate in the treatment of Paget's disease of bone.

We studied the effects of the intravenous or oral administration of aminohexane diphosphonate (AHDP) in 42 patients with active Paget's disease of bone. Treatment of mouth (400 mg daily for 1 month) or intravenously (25 mg or 50 mg daily for 5 days) induced marked suppression of biochemical indices of disease activity. Urinary excretion of hydroxyproline fell to 39 and 42% of pretreatment values (oral and IV treatments respectively), and was followed by a similar decrease in the serum activity of alkaline phosphatase. In both groups of patients, disease activity remained suppressed for the 6 months of followup, and pain improved in 34 out of 37 patients who had bone pain attributed to Paget's disease. Both biopsies indicated that osteoblast and osteoclast numbers decreased with no adverse effects on mineralization. Neither regime was associated with significant side effects. We conclude that short courses of AHDP provide a promising treatment for the long-term control of Paget's disease.

Administration, Oral↗
PubMed1987

Gangliosides suppress the proliferation of autoreactive cells in experimental allergic encephalomyelitis: ganglioside effects on IL-2 activity.

Gangliosides have been shown to suppress human and murine lymphocyte proliferative responses in vitro. We tested the suppressive effects of gangliosides on the proliferation of autoreactive lymphoid cells obtained from Lewis rats with experimental allergic encephalomyelitis (EAE). Exogenous rat brain gangliosides inhibited both antigen- and mitogen-induced proliferation by as much as 79 and 93%, respectively. Gangliosides similarly inhibited the antigen-induced proliferation of a myelin basic protein (MBP)-reactive T-cell line which is able to passively induce EAE. Suppression was greatest when gangliosides were added at the initiation of culture, and was not abrogated by supraoptimal antigen concentration. Interleukin 2 (IL-2) activity in culture supernatants was not diminished by the addition of gangliosides. Gangliosides did not inhibit the IL-2-induced proliferation of a murine IL-2-dependent cell line, CTLL-20, unless the IL-2 was first preincubated with gangliosides before the addition of CTLL-20. Preincubation of CTLL-20 with gangliosides resulted in no inhibition of the subsequent responses to IL-2. Exogenous gangliosides did not decrease the binding of a monoclonal antibody directed against the rat cell surface IL-2 receptor. Addition of exogenous IL-2 to ganglioside-suppressed cultures had no effect or only partially restored the proliferative responses. Therefore, gangliosides were shown to inhibit the proliferation of autoreactive lymphoid cells without affecting IL-2 production or IL-2 receptor expression.

Animals↗
PubMed1987

A comparison of single and multiple intravenous infusions of 3-amino-1-hydroxypropylidene-1, 1-bisphosphonate (APD) in the treatment of hypercalcemia of malignancy.

Following rehydration with intravenous saline, 27 patients with hypercalcemia of malignancy were treated with a total of 32 courses of 3-amino-1-hydroxypropylidene-1, 1-bisphosphonate (APD) given by slow intravenous infusion. Twelve treatments consisted of daily infusions of APD for between two and six days whereas single-dose APD was used in 20 treatments. Mean albumin-adjusted serum calcium fell to the upper end of the reference range at seven days from the start of treatment, both in multiple-dose and in single-dose treatment groups. No relationship between total dose of APD and hypocalcemic response was observed. However, second treatments with APD following recurrence of hypercalcemia in five patients were significantly less effective than the original therapy, suggesting that resistance to APD may develop. Multiple-dose and single-dose intravenous APD treatments appear to be equally effective in the acute management of hypercalcemia of malignancy.

Bone Neoplasms↗
PubMed1987

Control of cyclic adenosine 3',5'-monophosphate production in osteoclasts: calcitonin-induced persistent activation and homologous desensitization of adenylate cyclase.

Hormonal control of cAMP production in the osteoclast has not been investigated in detail because this bone-resorbing cell has been difficult to isolate. We have used osteoclasts freshly isolated by disaggregation from neonatal rat long bones and settled onto coverslips (100-150 cells per coverslip) to examine the effects of calcitonin and prostaglandin E2 on osteoclast cAMP levels and cytoplasmic spreading. Salmon, eel, and human calcitonin (CT), and various analogs, stimulated cAMP production in a dose-dependent manner with relative potencies as seen in other response systems. Forskolin (10(-7) M) increased the sensitivity and amplitude of the response. Pretreatment with pertussis toxin (200 ng/ml for 3 h) had no effect suggesting that CT does not act through Ni, the inhibitory guanine nucleotide regulatory unit of adenylate cyclase. CT treatment was associated with rapid and dose-dependent induction of a persistent activated state of adenylate cyclase and homologous desensitization, the former being a particular feature of CT action previously observed in nonosteoclastic cells. Quantitative histomorphometry demonstrated a sensitive, dose dependent, and prolonged (greater than 2 h) reduction in osteoclast plan area after exposure to salmon CT. Although prostaglandin E2 also stimulated cAMP production and resulted in cell contraction in osteoclasts this was not associated with persistent activation of adenylate cyclase nor with prolonged contraction. Persistent activation of adenylate cyclase may be an important mechanism in CT inhibition of osteoclast function.

Adenylate Cyclase Toxin↗
PubMed1987

Comparative effects of intravenous diphosphonates on calcium and skeletal metabolism in man.

We have assessed the early effects of three diphosphonates on calcium and skeletal homeostasis in 68 patients with Paget's disease of bone treated with daily intravenous infusions for five consecutive days. Both clodronate (300 mg/day) and aminohexane diphosphonate (AHDP; 50 mg/day) induced a fall in serum and urine calcium, and secondary hyperparathyroidism. In contrast, these changes were not observed with etidronate (300-700 mg/day) despite similar effects on bone resorption, as judged by urinary excretion of hydroxyproline with each of the three disphosphonates. Histological studies during the early phase of treatment indicated that etidronate, but not clodronate or AHDP, acutely impaired the accretion of calcium into bone, thereby offsetting a hypocalcaemic response. All three diphosphonates induced significant increases in plasma phosphate and tubular reabsorption of phosphate (TmP/GFR). The increase induced by etidronate remained significantly higher than pretreatment values for one month, whereas those induced by clodronate and AHDP were less marked and ill-sustained, and followed by significant decreases in both measurements. These data indicate that the effects of different diphosphonates on serum calcium homeostasis are heterogeneous, depending not only on the prevailing rate of bone resorption, but also on the rate of bone formation, and the effect of each diphosphonate on bone and mineral accretion.

Alkaline Phosphatase↗
PubMed1987

Treatment of the hypercalcaemia of malignancy with intravenous clodronate.

We studied the effects of intravenous clodronate (100-300 mg daily for 3-10 days) in 27 episodes of hypercalcaemia due to malignancy. Comparisons were also made between responses in patients with haematological malignancies and those with solid tumours. Following extracellular volume expansion, clodronate induced a significant decrease in serum calcium within 2 days of the start of treatment which was maximal at 7 days. This was associated with a decrease in bone resorption as judged by decreases in urinary excretion of hydroxyproline and calcium. Hypercalcaemia recurred 5-7 days after stopping treatment. Patients with solid tumours had higher pretreatment serum calcium values than those with haematological malignancies despite comparable values for fasting urinary excretion of calcium suggesting that renal tubular reabsorption of calcium was more markedly increased in patients with solid tumours. No difference was observed in the final calcium values between patients with solid tumours and haematological malignancies except in those patients in whom renal tubular reabsorption of calcium was markedly increased before treatment. We conclude that intravenous clodronate provides a safe and effective treatment of hypercalcaemia due to a wide range of tumour types provided that increased bone resorption contributes significantly to the hypercalcaemia. When increased renal reabsorption of calcium is the predominant mechanism for the maintenance of hypercalcaemia, the response to clodronate is incomplete.

Adult↗
PubMed1987

Duration of effect of oral diphosphonate therapy in Paget's disease of bone.

The effects of the diphosphonates etidronate and clodronate were studied in 144 patients with Paget's disease. All five programmes of treatment tested induced a similar suppression of disease activity as judged by serum alkaline phosphatase concentrations, but the proportion of patients responding and the duration of responses differed significantly between programmes. The proportion responding to etidronate 5-10 mg/kg/day for six months was less than for other regimens, and the most sustained response was after treatment with clodronate 1600 mg daily for six months. More complete biochemical suppression was associated with the more prolonged responses irrespective of the regimen used.

Administration, Oral↗