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S H Ralston

Publications and source records attributed to S H Ralston.

At least 19 recordsLinked to original sources
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↗
PubMed1990

Prevalence of vertebral compression fractures due to osteoporosis in ankylosing spondylitis.

OBJECTIVE: To determine the prevalence of vertebral compression fractures due to osteoporosis in patients with ankylosing spondylitis. DESIGN: Prospective study of 111 consecutive patients; patients with vertebral compression fractures were entered into a case-control study. SETTING: Outpatient clinic at the centre for rheumatic diseases, Glasgow. PATIENTS: 111 Consecutive patients with ankylosing spondylitis. Patients with compression fractures were matched for age and sex with two controls selected from the rest of the group. Patients with biconcave vertebral fractures were also studied. MAIN OUTCOME MEASURES: Assessments of spinal deformity and mobility and analysis of lateral radiographs of spines for presence of syndesmophytes. RESULTS: Fifteen patients with compression fractures and five with biconcave fractures were studied. Compared with the controls the patients with compression fractures had increased formation of syndesmophytes in the lumbar spine, whereas those with biconcave fractures had increased formation throughout the spine. Patients with compression fractures also had a greater degree of spinal deformity (distance from wall to tragus 24.5 cm v 12.7 cm in controls), less spinal mobility (20 v 45.6 degrees of flexion), and reduced chest expansion (2 cm v 3cm). CONCLUSION: Vertebral compression fractures due to osteoporosis are a common but frequently unrecognised complication of ankylosing spondylitis and may contribute to the pathogenesis of spinal deformity and back pain.

Adolescent↗
PubMed1990

Estrogen inhibits release of tumor necrosis factor from peripheral blood mononuclear cells in postmenopausal women.

Cytokines, such as interleukin-1 (IL-1) and tumor necrosis factors (TNF), produced by cells of the monocyte-macrophage lineage in the local bone microenvironment, are potentially important local regulators of bone turnover. To investigate whether the protective effects of estrogen against postmenopausal bone loss may be mediated by inhibition of cytokine release, we studied the effects of 17 beta-estradiol, dihydrotestosterone, and hydrocortisone on TNF release from human peripheral blood mononuclear cells (PBMC) in vitro. In unstimulated cells derived from eight postmenopausal women, seven of whom had osteoporotic vertebral fractures, 17 beta-estradiol inhibited TNF release in a dose-dependent manner between 10(-6) and 10(-12) M but had no consistent effect on cells derived from men or premenopausal women. Dihydrotestosterone in concentrations of up to 10(-6) M had no effect on TNF release in any patient group, whereas hydrocortisone at 10(-6) M was a potent inhibitor of TNF release in all groups. Since TNF is a potent stimulator of bone resorption, the inhibitory effect of estrogen on TNF release may be part of the mechanism by which it exerts a protective effect on the skeleton in postmenopausal women. These observations may also be relevant in other inflammatory diseases of connective tissue, such as rheumatoid arthritis, in which disease activity may fluctuate as estrogen levels change--during the menstrual cycle, in pregnancy, and after the menopause.

Adult↗
PubMed1990

Hypercalcaemia in rheumatoid arthritis revisited.

The prevalence and mechanisms of hypercalcaemia were studied in a series of patients attending a regional referral centre for rheumatic diseases. In a prospective study one case of hypercalcaemia due to primary hyperparathyroidism was found in 251 consecutive patients who were screened over a three month period. In a retrospective study of 39 patients who had been discovered to be hypercalcaemic during the preceding 12 months known cases of hypercalcaemia were found in 38 (97%) cases. Primary hyperparathyroidism was the most common cause (n = 24; 62%), followed by thiazide treatment in five (13%), cancer in three (8%), immobility in three (8%), vitamin D toxicity in two (5%), and chronic liver disease in one (3%). In one case the diagnosis remained unclear after full investigation. This study shows that the causes of hypercalcaemia in rheumatological patients are similar to those in the general population. These observations contrast with previous reports, which suggested that hypercalcaemia may be a complication of rheumatoid arthritis itself.

Adult↗
PubMed1990

An unusual case of pustulotic arthro-osteitis affecting the leg, and erosive polyarthritis.

Pustulotic arthro-osteitis is a syndrome, originally described in Japan, in which a sterile inflammatory osteitis of the sternoclavicular region occurs in combination with a non-erosive arthritis, sacroiliitis, and a pustulotic rash on the palms and soles. Although the disease has been reported in white populations, it is rarely seen by rheumatologists in the United Kingdom. The case of a Scottish woman is described in whom the diagnosis of pustulotic arthro-osteitis was overlooked because of an atypical site of the disease--the fibula, an erosive arthritis, and absence of a pustular rash at the time of her presentation with musculoskeletal symptoms. This case shows that the syndrome may easily by missed unless clinical suspicion is high and should be considered in any patient with culture negative osteitis, even outside the sternoclavicular region.

Arthritis↗
PubMed1990

Immobilization-related hypercalcaemia--a possible novel mechanism and response to pamidronate.

Immobilization-related hypercalcaemia is an uncommon but important condition being associated not infrequently with both urolithiasis and osteoporosis. In this study 5 patients who had been immobilized for a mean of 3 months and had a mean adjusted serum calcium of 3.15 mmol/l were treated with doses of intravenous pamidronate ranging between 10 mg and 45 mg. All patients became normocalcaemic by day 3. Patients 1-3 mobilized shortly after treatment and remained normocalcaemic. In those patients who continued to be immobile hypercalcaemia recurred after an interval of several weeks. Retreatment with pamidronate again resulted in normocalcaemia. No side effects were noted with treatment. All of the patients studied had increased rates of bone resorption as shown by elevated urinary hydroxyproline/creatinine ratios (median:range) of 0.101:0.045-0.180 (normal less than 0.033) and elevated calcium/creatinine ratios of 2.50:0.69-3.63 (normal less than 0.50). None of the patients in this study had any of the usual risk factors for developing immobilization-related hypercalcaemia though all 5 patients had problems with significant sepsis which we postulate may have lead to cytokine release which in turn contributed to the development of hypercalcaemia. We conclude that pamidronate (at doses as low as 10 mg) is safe and effective in immobilization-related hypercalcaemia and suggest that sepsis should be added to the list of risk factors for development of this syndrome.

Adult↗
PubMed1990

Breast cancer-associated hypercalcaemia: a reassessment of renal calcium and phosphate handling.

The mechanisms of hypercalcaemia were assessed in 20 hypercalcaemic patients with breast cancer. Abnormalities suggestive of a PTH-related peptide (PTHrP) mechanism were observed in up to 60% of cases; urinary cyclic adenosine monophosphate (UcAMP) was elevated in nine patients (45%), renal tubular reabsorption of calcium (RTRCa) was elevated in nine (45%) and the renal tubular threshold for phosphate reabsorption (TmPO4) depressed in 12 (60%). While TmPO4 was lower in patients with high UcAMP, there was no consistent relationship between RTRCa and UcAMP or UcAMP and the extent of bone metastases. In a control group of nine normocalcaemic breast cancer patients, bone resorption as assessed by urinary calcium/creatinine ratio was slightly increased but UcAMP, RTRCa and TmPO4 were generally normal. These observations indicate that a PTHrP-mediated mechanism of hypercalcaemia may be operative in up to 60% of patients with breast cancer, irrespective of the presence or extent of bone metastases.

Biomarkers↗