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S H Ralston

Publications and source records attributed to S H Ralston.

At least 19 recordsLinked to original sources
PubMed1995

Nitric oxide: a cytokine-induced regulator of bone resorption.

Nitric oxide (NO) has been reported to inhibit osteoclastic bone resorption, yet potent stimulators of bone resorption, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), are known to stimulate NO production. This paradox prompted us to reinvestigate the relationship between NO production and bone resorption in mouse calvarial organ cultures. Control cultures and those stimulated with calciotropic hormones and individual cytokines produced little NO, and under these conditions the NO synthase inhibitor, L-NG-monomethyl arginine (LMMA), had no significant effect on bone resorption. Cytokine combinations were much more potent stimulators of NO production than individual cytokines. Dramatic stimulation of NO production and inhibition of bone resorption resulted when gamma-interferon (IFN) was combined with IL-1 or TNF and these effects were reversed by LMMA. IFN had no effect on bone resorption and little effect on NO production when used alone or in combination with calciotropic hormones, however, suggesting that IFN selectively inhibits cytokine-induced bone resorption by generating large amounts of NO. IL-1 and TNF acted together to stimulate NO production but to a lesser degree than when combined with IFN. LMMA inhibited bone resorption induced by IL-1 and TNF, suggesting that lower concentrations of NO stimulate bone resorption. Experiments with the pharmacological NO donor S-nitroso-acetyl-penicillamine (SNAP) supported this view in showing generalized suppression of bone resorption at high SNAP concentrations, but potentiation of IL-1 induced bone resorption at lower SNAP concentrations. We conclude that cytokines are potent inducers of NO in bone and that cytokine-induced NO production has biphasic effects on bone resorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Origin of a negative calcium response element in an ALU-repeat: implications for regulation of gene expression by extracellular calcium.

The negative calcium response element type 2 (nCARE) is a regulatory DNA sequence consisting of a palindromic core sequence and several upstream T residues, which was originally described in the 5' flank of the human PTH gene. The nCARE functions in an orientation-specific manner to inhibit PTH transcription in response to raised extracellular calcium levels. Here we report that the PTH nCARE lies within a hitherto unrecognized ALU-like element situated approximately 3.6 kB upstream of the human PTH gene transcriptional start site. Since ALU elements are repetitive DNA sequences, which are widely distributed throughout the human genome, we hypothesized that other nCARE elements might also exist. A search of the GenBank/EMBL databases with the nCARE core sequence confirmed this to be the case showing the presence of 111 copies of the nCARE in human/primate sequences. Analysis of the 7SL RNA sequence from which ALU elements derive also showed the presence of an nCARE "core" sequence immediately upstream of the poly-A+ tail. These data suggest that the nCARE is derived from retrotransposition of 7SL RNA and forms an integral part of many ALU elements; reverse transcription of the poly-A+ tail of 7SL RNA adds T residues, which on retrotransposition into genomic DNA with the core sequence, forms an ALU element containing a functional nCARE. Some of the genes associated with nCARE elements express products which are affected by extracellular calcium concentrations and work is in progress to determine the functional effects of nCARE at these sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1995

Effect of oral clodronate on metastatic bone pain: a double-blind, placebo-controlled study.

PURPOSE: To study the effects of oral clodronate on bone pain in patients with advanced metastatic bone disease. PATIENTS AND METHODS: Fifty-five patients with progressing bone metastases were randomized to receive oral clodronate 1,600 mg/d (n = 27) or matching placebo (n = 28). The main outcome measures were bone pain (visual analog score), analgesic use, and compliance with therapy. RESULTS: Visual analog pain score (median [interquartile range]) decreased from the pretreatment value in the clodronate group (-0.9 [-2.6 to -0.4]), but increased in the placebo group (+0.4 [-1.0 to +4.0]) (P = .03 between groups). Analgesic use increased with disease progression to a similar extent in both groups (59% increased use in the clodronate group v 64% of placebo group; difference not significant). Ten patients (37%) in the clodronate group and 12 (46%) in the placebo group withdrew from the study prematurely, most often because of difficulty with swallowing the capsules. CONCLUSION: Clodronate improved control of bone pain to a modest degree in patients with advanced metastatic cancer, but did not reduce analgesic requirement significantly. Perhaps as a result of these factors, it proved difficult to maintain patients on therapy. Further studies will be needed to define the role of bisphosphonates such as clodronate in this situation, in comparison with established treatments such as radiotherapy and analgesics.

Administration, Oral↗
PubMed1994

Nitric oxide production by human proximal tubular cells: a novel immunomodulatory mechanism?

It is believed that human proximal tubular cells may possess immunological function and play an important role in a variety of renal disease states such as interstitial nephritis, allograft rejection and drug induced nephrotoxicity. The role of cytokines and nitric oxide in the human forms of these disease states is not clear. In this study we examined the effect of stimulation with the cytokines IL-1 beta. TNF-alpha and IFN-gamma, individually and in combination, upon primary cultures of human proximal tubular cells. Nitric oxide production increased significantly within 24 hours following cytokine stimulation. This response was inhibited, in a dose dependent manner, by L-NMMA. PCR amplification of mRNA extracted from control and cytokine stimulated human proximal tubular cells revealed a NOS product with a > 97% homology with human hepatocyte inducible nitric oxide synthase. The results of this study clearly show that human proximal tubular cells, in primary culture, are capable of producing nitric oxide in response to an immune challenge secondary to the induction of nitric oxide synthase.

Amino Acid Oxidoreductases↗
PubMed1994

Human osteoblast-like cells produce nitric oxide and express inducible nitric oxide synthase.

Nitric oxide (NO) is a short-lived free radical that plays an important regulatory role in several biological processes. Cytokines such as interleukin-1, tumor necrosis factor, and interferon-gamma have been shown to stimulate NO production in many cells types. Although these cytokines are known to have potent effects on bone remodeling and osteoblast function, the role of NO as an effector molecule in bone has been little studied. Here we investigate the effects of cytokines and calciotropic hormones on NO production by human osteoblast-like cells (hOB) and the role of NO as a modulator of osteoblast growth. Unstimulated hOB produced little NO, as reflected by measurement of nitrite concentrations in hOB-conditioned medium. NO production was not significantly altered by PTH and 1,25-dihydroxyvitamin D or human recombinant interleukin-1 beta (10 U/ml), tumor necrosis factor-alpha (25 ng/ml), and interferon-gamma (100 U/ml) individually. Combinations of all three cytokines at these concentrations, however, dramatically increased both NO generation and cGMP production. The stimulatory effect of cytokines on NO production began 12 h after exposure and was inhibited by cycloheximide, actinomycin-D, dexamethasone, and the competitive inhibitor of NO synthase L-NG-monomethylarginine. Reverse transcription/polymerase chain reaction analysis of hOB RNA, followed by direct sequencing of the amplified products, showed that hOB express the inducible, rather than the endothelial or neuronal, forms of NO synthase. Cytokine-induced increases in NO production were associated with a marked inhibition of [3H]thymidine uptake to less than 10% of that observed in control cultures. Abrogation of NO synthesis with L-NG-monomethylarginine under these conditions significantly increased [3H]thymidine uptake to approximately 20% of the control value, suggesting that NO may partly be responsible for the inhibition of osteoblast proliferation induced by these cytokines. Our data indicate that proinflammatory cytokines induce NO production in osteoblast-like cells and show and that this mediator plays a role in regulating cell growth. These findings may have important implications for the pathogenesis and management of bone loss in diseases associated with cytokine activation, such as rheumatoid arthritis.

Amino Acid Oxidoreductases↗
PubMed1994

Pharmacological management of back pain syndromes.

The symptom of back pain may be the result of many different pathologies. As such, patients with back pain require careful assessment to determine whether the cause is from the spine or other systems. For acute mechanical back pain, treatment is often symptomatic. Symptomatic treatment may include analgesics, anti-inflammatories and/or muscle relaxants. Patients may also need hypnotics in the short term to help them sleep at night. However, drug therapy should be reduced and stopped as soon as possible. Furthermore, too much bedrest may be counterproductive. Paracetamol (acetaminophen) is the standard treatment for transient back pain. More severe pain may require the addition of an opioid, such as codeine or dextropropoxyphene. Morphine and pethidine (meperidine) may be necessary in patients with back pain due to neoplastic disease or osteoporotic fracture. However, the opioid analgesics are associated with dependence, tolerance and adverse effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) have analgesic efficacy comparable with paracetamol. Individual patients respond differently to different NSAIDs, and several agents may have to be tried. Long term therapy with NSAIDs is necessary in diseases with an inflammatory component such as ankylosing spondylitis. Calcitonin reduces bone resorption and bone blood flow, and has been suggested to have central analgesic effects. As such, it has been used successfully in patients with Paget's disease, osteolytic bone disease and osteoporosis. Bisphosphonates also inhibit osteoclastic bone resorption and may be useful in Paget's disease, osteolytic metastases and osteoporotic fractures. Other drugs which may be useful in relieving back pain associated with specific circumstances include the tricyclic antidepressants, anxiolytics, antiepileptic agents, corticosteroids, colchicine and chymopapain.

Adrenal Cortex Hormones↗
PubMed1992

Factors predicting the acute effect of pamidronate on serum calcium in hypercalcemia of malignancy.

In this study we retrospectively reviewed results of the first 9 days of treatment with pamidronate at doses of 30 mg (n = 13), 45 mg (n = 9), and 90 mg (n = 13) in an attempt to see what factors influenced the response of serum calcium to pamidronate. The nadir of serum calcium obtained post treatment was correlated with pretreatment levels of nephrogenous cyclic adenosine monophosphate (NcAMP), the renal tubular threshold for phosphate reabsorption (TmPO4), and the renal tubular threshold for calcium reabsorption (TmCa). Using the post treatment serum calcium levels, patients were divided into "good" and "poor" responders depending on whether a normal serum calcium was obtained. Pretreatment NcAMP was significantly correlated with the magnitude of the response of serum calcium (r = 0.45, P = 0.0001). Pretreatment NcAMP was significantly higher in the poor responders (mean +/- SEM): 65.0 +/- 9.4 nmol/liter GF (poor responders) versus 29.6 +/- 6.3 (good responders), P = 0.004. NcAMP as a predictor of the acute response of serum calcium showed a sensitivity of 93% and a specificity of 72%. Pretreatment TmPO4 was negatively correlated with the serum calcium response post treatment (r = -0.41, P = 0.003). However, though TmPO4 tended to be lower in the poor responders, this was not statistically significant [0.65 mmol/liter GF +/- 0.09 (poor responders) versus 0.76 mmol/liter GF +/- 0.06 (good responders)]. As a predictor of the acute response of serum calcium, TmPO4 was less good with a sensitivity of 70% and specificity of 58%. No significant correlation was present between TmCa and the serum calcium response.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1992

Medical management of hypercalcaemia.

1. Hypercalcaemia is a common disorder, which frequently requires specific treatment either to control symptoms, or to prevent the development of irreversible organ damage or death. Although the best and most effective way of controlling hypercalcaemia in the long-term is to treat the underlying cause, medical antihypercalcaemic therapy is often required in clinical practice, either as a holding measure, or because the primary disease cannot itself be treated. 2. The mainstays of medical antihypercalcaemic therapy are firstly, to promote calcium excretion by the kidney by restoring extracellular volume with intravenous saline and secondly, to administer pharmacological agents which inhibit bone resorption. Measures which seek to reduce intestinal calcium absorption are seldom effective. 3. Intravenous bisphosphonates are the treatment of first choice for the initial management of hypercalcaemia, followed by continued oral, or repeated intravenous bisphosphonates to prevent relapse. These drugs have a relatively slow onset of action (1-3 days) but have potent and sustained inhibitory effects on bone resorption, resulting in a long duration of action (12-30 days). 4. Of the other agents available, calcitonin has an important place in the management of severe hypercalcaemia where a rapid effect is desirable; calcitonin is best used in conjunction with a bisphosphonate however, because of its short duration of action. Intravenous phosphate also has a place in the emergency management of severe hypercalcaemia, but is probably best reserved for patients in whom other less toxic therapies have failed. Corticosteroids are generally ineffective except in certain specific instances and are best avoided in the routine treatment of undiagnosed hypercalcaemia.

Bone Resorption↗
PubMed1992

A new method for the radiological assessment of vertebral squaring in ankylosing spondylitis.

A method has been developed for the objective assessment of vertebral 'squaring' based on quantitative morphometric analysis of vertebral 'concavity' in lateral radiographs of the lumbar spine. The reference range for vertebral concavity was defined as greater than 1.0-4.0 mm from measurements of 255 radiologically normal lumbar vertebrae in 51 patients with non-specific back pain. Evidence of vertebral squaring, as defined by concavity measurements of 1 mm or less, was found in 28% of vertebrae from 103 patients with ankylosing spondylitis and 8% of vertebrae from 10 patients with Reiter's syndrome. Assessment of vertebral squaring by the concavity measurement was more reproducible than subjective analysis in the diagnosis of vertebral squaring; in a subgroup of 30 patients with seronegative spondyloarthropathy, the interobserver agreement on the presence or absence of vertebral squaring as assessed by two independent clinicians was 84%, compared with 94% using the concavity measurement. Corresponding values for intraobserver agreement were 79% for subjective analysis and 84% for the concavity measurement. The vertebral concavity measurement is performed simply, rapidly (about three minutes for five lumbar vertebrae), and requires no special experience or equipment. As a result of this, the technique may be of value in the radiological diagnosis of ankylosing spondylitis and in assessing changes in vertebral squaring in individual patients with time.

Adult↗
PubMed1991

Interleukin-6 does not stimulate bone resorption in neonatal mouse calvariae.

Recombinant human interleukin-6 (IL-6) was assessed for its ability to stimulate bone resorption in prelabeled mouse calvariae in vitro. IL-6 had no effect on bone resorption at concentrations ranging from 300 to 10,000 U/ml (3-1000 pg/ml). Neither the presence of indomethacin nor prolonged incubation periods (96 h) affected this result. IL-6 did not affect resorption stimulated by human recombinant IL-1 alpha (rIL-1 alpha) but inhibited resorption stimulated by parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. rIL-1 alpha, PTH, and 1,25-(OH)2D3 induced IL-6 release by calvariae. We conclude from these studies that IL-6 does not stimulate bone resorption in neonatal mouse calvariae. However, it may act as a locally produced inhibitor and therefore a paracrine regulator of bone resorption induced by osteotropic hormones. IL-6 could also function as a long-range stimulator of systemic reactions and acute-phase responses to local inflammatory and neoplastic lesions in bone.

Animals↗
PubMed1991

Failure to detect paramyxovirus sequences in Paget's disease of bone using the polymerase chain reaction.

It is widely believed that Paget's disease of bone is due to a "slow virus" infection of osteoclasts with one of the paramyxovirus group. Controversy continues to surround the identity of the virus involved, however, since at different times evidence has been presented implicating measles virus (MV), respiratory syncytial virus (RSV), and canine distemper virus (CDV) as putative infective agents. In this study we used the technique of reverse transcription and polymerase chain reaction (PCR) to screen for paramyxovirus sequences in ribonucleic acid (RNA) extracted from pagetic bone. We were able to detect viral amplification products of the appropriate size in RNA extracted from as few as 50 cells experimentally infected with a wide range of paramyxoviruses, including measles, canine distemper, parainfluenza 3, and respiratory syncytial virus, but we found no evidence of viral products in RNA extracts of affected bone from 10 consecutive patients with Paget's disease. This study fails to support the hypothesis that active infection with one of these or a related paramyxovirus is involved in the pathogenesis of Paget's disease.

Aged↗
PubMed1991

Direct and indirect assessment of the parathyroid hormone response to pamidronate therapy in Paget's disease of bone and hypercalcaemia of malignancy.

In patients with either Paget's disease or hypercalcaemia associated with malignancy (HCM) we have assessed the parathyroid response to pamidronate therapy, both by immunoassay of serum intact parathyroid hormone PTH (1-84) and by measurement of indirect parameters of PTH bioactivity, tubular maximum reabsorption of phosphate (TmPO4/GFR) and nephrogenous cyclic AMP (NcAMP). In 12 patients with Paget's disease, therapy with pamidronate produced a small but significant decrease in adjusted serum calcium within the reference interval which was accompanied by a progressive increase in PTH (1-84) secretion and a corresponding fall in TmPO4/GFR and increase in NcAMP. In 12 patients with HCM pretreatment, PTH (1-84) concentrations were suppressed, whilst mean TmPO4/GFR was reduced and NcAMP was increased, compatible in most patients, with parathyroid hormone-related peptide (PTHrP) driven hypercalcaemia. Therapy with pamidronate produced the expected fall in serum calcium but caused an increase in PTH (1-84) secretion in the presence of absolute hypercalcaemia. The initial subnormal TmPO4/GFR decreased further to a nadir on day 5, and there was a corresponding further increase in NcAMP. By day 7, however, when PTH (1-84) concentrations were maximal, there was a significant paradoxical rise in TmPO4/GFR and a corresponding decrease in NcAMP. These data are consistent with a variable trigger point for PTH (1-84) secretion, one consequence of which is a reduction in the risk of hypocalcaemia following pamidronate. The results have major clinical implications for the interpretation of PTH (1-84) measurements in patients who are being treated or about to be treated for bone disease or for hypercalcaemia of malignancy (HCM).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

A comparison of low versus high dose pamidronate in cancer-associated hypercalcaemia.

Pamidronate has been demonstrated to be an effective agent in the treatment of cancer-associated hypercalcaemia. The dose regime, however, remains controversial. In this study 16 patients with cancer-associated hypercalcaemia were given 30 mg pamidronate by intravenous infusion and 16 were given 90 mg also by infusion. Groups were well-matched in terms of tumour types, bone metastases, pre-treatment serum calcium and creatinine, fasting urinary calcium/creatinine ratio, nephrogenous cAMP and the renal tubular threshold for phosphate reabsorption (TmPO4). The calcium lowering effect was similar in both treatment groups with nadir at day 6 of mean (+/- SEM) 2.48 mmol/l (+/- 0.06) in the 30 mg group and at day 9 in the 90 mg group of 2.51 mmol/l (+/- 0.03) (P less than 0.01). 10 patients in the 30 mg group and 8 in the 90 mg group were normocalcaemic at this point. Similarly when those patients with more severe hypercalcaemia (greater than 3.30 mmol/l, n = 7 in each group) were analysed separately, no significant difference was evident between the two groups. Urinary calcium/creatinine ratios fell to a nadir at day 6 in both groups of 0.33 (+/- 0.05) (30 mg group) and 0.37 (+/- 0.10) (90 mg group) (P less than 0.01). Follow-up results after the initial 9 days showed the mean time to relapse to be 38 days (range 18-90) in the 30 mg group and 34 days (11-105) in the 90 mg group.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium↗
PubMed1991

Clinical experience with pamidronate in the treatment of Paget's disease of bone.

Bisphosphonates have been shown to be effective in treating the increased bone turnover associated with Paget's disease of bone. In this study two groups of patients were treated with pamidronate by intravenous infusion. In group 1 (n = 15) 30 mg of pamidronate was given once a week for six weeks. A subgroup (group 1A, n = 6) of more severely affected patients (pretreatment serum alkaline phosphatase (ALP) greater than 1000 U/l, normal range 80-280 U/l) received a further 60 mg weekly for three weeks. Group 2 (n = 24) received 45 mg of pamidronate every three months for one year. In both groups the level of ALP in serum samples decreased steadily throughout the year. In group 1 the level decreased to a mean value of 230 U/l (95% confidence interval 188-281) and in group 2 to 297 U/l (227-389). Four of the six patients in group 1A achieved normal ALP, whereas ALP remained at an increased level in all of the 10 patients in group 2 whose pretreatment ALP was greater than 1000 U/l, suggesting that a dose-response effect exists. The lowest hydroxyproline to creatinine ratios (normal ratio less than 0.033) were observed at the end of treatment in group 1, with a mean ratio of 0.022 (range 0.015-0.033) and at three months after the start of treatment in group 2 with a mean ratio of 0.029 (range 0.022-0.037). There was a significant decrease in the turnover of bone, as measured by whole body retention of radiolabelled bisphosphonate, from a mean of 49.3 to 41.0% (p less than 0.01). These data confirm that pamidronate is effective in the management of Paget's disease of bone. For patients with levels of ALP in serum samples of up to four times above the upper limit of the normal reference range, an effective and convenient regimen is 45 mg every three months for one year. For patients with higher levels of ALP higher doses may be more effective.

Adult↗
PubMed1991

Parathyroid hormone-related protein of malignancy: immunohistochemical and biochemical studies in normocalcaemic and hypercalcaemic patients with cancer.

Immunohistochemical staining for parathyroid hormone-related protein was performed in 27 tumours from 19 normocalcaemic and eight hypercalcaemic patients with cancer. All the tumours from hypercalcaemic patients stained positively for the protein, as did 17 tumours from normocalcaemic patients. Only hypercalcaemic patients had biochemical evidence of increased bone resorption and abnormalities of renal tubular reabsorption of calcium and phosphate, consistent with the presence of parathyroid hormone-related protein. While tumour mass was higher in hypercalcaemic patients, only one of the initially normocalcaemic patients with positively staining tumours subsequently went on to develop hypercalcaemia and more advanced disease. These data confirm the importance of parathyroid hormone-related protein as a mediator of humoral hypercalcaemia in patients with solid tumours and suggest that low tumour mass may be one reason why serum calcium values are not increased in all patients with tumours containing parathyroid hormone-related protein. None the less normocalcaemia, despite tumour progression in patients whose tumours stained positively for parathyroid hormone-related protein, suggests that other factors may also be important, such as differences in the rate of secretion of the protein by different tumours, or the production of different forms of parathyroid hormone-related protein with varying biological effects.

Humans↗
PubMed1990

Cancer-associated hypercalcemia: morbidity and mortality. Clinical experience in 126 treated patients.

STUDY OBJECTIVE: To review the effects of antihypercalcemic treatment on morbidity and mortality in cancer-associated hypercalcemia. DESIGN: Retrospective study of 126 consecutive patients with cancer-associated hypercalcemia. SETTING: Inpatient referrals from a teaching hospital in the United Kingdom. INTERVENTION: Medical antihypercalcemic therapy supplemented by specific anticancer therapy where possible. MEASUREMENTS AND MAIN RESULTS: Median survival was 30 days. Survival did not differ in patients treated with different antihypercalcemic regimens but was longer (median, 135 days; P less than 0.001) in a subgroup of 26 patients for whom specific anticancer therapy was available. Polyuria and polydipsia improved after therapy in 83% of cases, central nervous system symptoms in 71%, constipation in 70%, nausea and vomiting in 56%, anorexia in 50%, and malaise and fatigue in 47% (all significant, P less than 0.001, pre-treatment compared with post-treatment). Pain control improved in only 23% of cases (not significant). Only 7% of patients with post-treatment serum calcium values above 3.50 mmol/L improved clinically compared with 80% whose calcium values fell below 2.80 mmol/L (P less than 0.001). Corresponding figures for the proportion of patients discharged from the hospital were 0% and 68% (P less than 0.001). CONCLUSIONS: Life expectancy is poor in cancer-associated hypercalcemia even in patients who are actively treated. Antihypercalcemic therapy has an important palliative role, however, because symptoms are usually improved and, in many cases, patients may be made well enough to be discharged from the hospital during the terminal stages of their illness.

Adolescent↗