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Biomedical subjects

C R Paterson

Publications and source records attributed to C R Paterson.

At least 37 records · Page 2Linked to original sources
PubMed1997

Osteogenesis imperfecta and other heritable disorders of bone.

This chapter summarizes the many recent advances in our understanding of the principal heritable disorders of bone. In the course of little more than a decade many diseases that were recognizable only by their clinical and radiological features have become explicable in molecular terms. Large numbers of mutations of the genes coding for collagen, for alkaline phosphatase, for the cell surface receptors for parathyroid hormone and for calcium, and for a number of other proteins, are recognized. The chapter covers the many variants of osteogenesis imperfecta, the most common heritable cause of fractures. It also covers osteopetrosis, hypophosphatasia, pseudohypoparathyroidism (with Albright's hereditary osteodystrophy), familial benign hypercalcaemia, autosomal dominant hypocalcaemia and the molecular causes of some chondrodysplasias.

Bone Diseases↗
PubMed1996

Causes of death in osteogenesis imperfecta.

AIMS: To determine the causes of death in patients with osteogenesis imperfecta, excluding infants with the perinatal lethal form (type II). METHODS: Seventy nine patients with known osteogenesis imperfecta were identified, 37 of whom had been seen clinically in life. Causes of death were identified from death certificates, postmortem reports, medical records, hospital consultants, relatives, and the Brittle Bone Society's records. RESULTS: Patients with the milder types of osteogenesis imperfecta, I and IV, often had a normal lifespan and died of unrelated illnesses such as myocardial infarction and malignancy. In some of these patients and in many patients with the more severe type III disease, it was clear that osteogenesis imperfecta contributed significantly to death, almost certainly to many of the respiratory deaths and to deaths from cardiac failure due to kyphoscoliosis. Osteogenesis imperfecta also caused six deaths, directly or indirectly, due to basilar invagination of the skull. Osteogenesis imperfecta may have contributed to deaths from intracranial bleeding. Apparently minor traumatic incidents may have disastrous consequences in patients with this disorder. CONCLUSIONS: Prompt care for respiratory infections and prevention of trauma in patients with osteogenesis imperfecta is essential.

Adolescent↗
PubMed1995

Is previous hyperthyroidism still a risk factor for osteoporosis in post-menopausal women?

OBJECTIVE: Hyperthyroidism is a risk factor for osteoporosis, but the relative contributions of the episode of hyperthyroidism and thyroxine replacement for subsequent hyperthyroidism remain uncertain. In this study we have measured bone mineral density (BMD) in post-menopausal women with a previous history of hyperthyroidism, comparing those requiring thyroxine therapy with those remaining euthyroid and with an historical local control population. DESIGN: Cross-sectional study. PATIENTS: One hundred and six post-menopausal women with a previous history of hyperthyroidism. These were divided into four groups: treated with radioiodine, remaining euthyroid (group RU, n = 15); treated with radioiodine, receiving thyroxine for at least 5 years (group RT, n = 46); treated with surgery, remaining euthyroid (group SU, n = 21); treated with surgery, receiving thyroxine for at least 5 years (group ST, n = 24). There were 102 control subjects. MEASUREMENT: Forearm bone mineral density at distal and ultradistal sites as measured by single-photon absorptiometry. RESULTS: Results were expressed as 'Z-scores' i.e. number of standard deviations from the mean of a 5-year age-band from the local control population. Mean Z-scores at distal and ultradistal sites were as follows: -0.61 and -0.81 in group RU; -0.58 and -0.56 in group RT; -0.27 and -0.30 in group SU; -0.81 and -0.57 in group ST. Patients in groups RU, RT and ST but not SU had significantly lower BMD than controls. CONCLUSION: Post-menopausal women with previous hyperthyroidism treated with radioiodine have reduced BMD, whether or not receiving thyroxine. They should be targeted for densitometry and protective therapy with oestrogen should be considered. Those treated with surgery appear to be at less risk; this may be because most are diagnosed and treated whilst premenopausal. Thyroxine may have a deleterious effect in this group; longitudinal studies would provide further clarification.

Aged↗
PubMed1995

Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism.

Familial benign hypercalcemia (FBH) and neonatal hyperparathyroidism (NHPT) are disorders of calcium homeostasis that are associated with missense mutations of the calcium-sensing receptor (CaR). We have undertaken studies to characterize such CaR mutations in FBH and NHPT and to explore methods for their more rapid detection. Nine unrelated kindreds (39 affected, 32 unaffected members) with FBH and three unrelated children with sporadic NHPT were investigated for mutations in the 3,234-bp coding region of the CaR gene by DNA sequencing. Six novel heterozygous (one nonsense and five missense) mutations were identified in six of the nine FBH kindreds, and two de novo heterozygous missense mutations and one homozygous frame-shift mutation were identified in the three children with NHPT. Our results expand the phenotypes associated with CaR mutations to include sporadic NHPT. Single-stranded conformational polymorphism analysis was found to be a sensitive and specific mutational screening method that detected > 85% of these CaR gene mutations. The single-stranded conformational polymorphism identification of CaR mutations may help in the distinction of FBH from mild primary hyperparathyroidism which can be clinically difficult. Thus, the results of our study will help to supplement the clinical evaluation of some hypercalcemic patients and to elucidate further the structure-function relationships of the CaR.

Amino Acid Sequence↗
PubMed1994

Energy expenditure and body composition in growth hormone deficient adults on exogenous growth hormone.

OBJECTIVES: We assessed whether the obesity observed in growth hormone deficient adults is maintained by a reduction in energy expenditure. We studied the effects of exogenous growth hormone on energy expenditure and body composition. DESIGN: We performed an open study with growth hormone administered at 0.5 units per kilogram ideal body weight per week for 3 months. PATIENTS: Seven growth hormone deficient adults were studied. Thirty-eight healthy volunteers had their resting metabolic rate measured, with seven of them proceeding to have their total energy expenditure assessed. MEASUREMENTS: Total energy expenditure was measured by the doubly labelled water method (D2O18), resting metabolic rate by ventilated hood indirect calorimetry, and fat free mass from the dilution volume of oxygen-18. Body composition and components of energy expenditure were assessed before, at 2 weeks and at the end of the 3-month treatment period on exogenous growth hormone. RESULTS: Growth hormone deficient adults did not have a low total energy expenditure compared to healthy controls (13.12 vs 12.75 MJ/24 h) with only one patient expending less than 10 MJ/24 h. None had a resting metabolic rate lower than the 95% confidence limits of normality. The amount of energy expended on physical activity and thermogenesis was significant (6.54 MJ/24 h) and was similar to healthy controls (6.47 MJ/24 h). Resting metabolic rate increased by 15.9% after 14 days on exogenous growth hormone and was elevated 12.1% after 3 months treatment but the ratio to fat-free mass remained unaltered. Total energy expenditure increased by 13.4% after 14 days therapy. Fat-free mass increased significantly after 3 months treatment by (mean) 4.5 kg with no change in fat mass and no loss in body weight. CONCLUSIONS: Obesity maintenance in growth hormone deficient adults is not a consequence of reduced total energy expenditure or a reduced exercise energy output. There was also no evidence for an energy sparing mechanism. Energy expenditure was increased by exogenous growth hormone but was not associated with a loss in fat mass or body weight suggesting the need for dietetic advice for those already obese at the outset of therapy.

Adult↗
PubMed1994

Bone density in osteogenesis imperfecta may well be normal.

Osteogenesis imperfecta (OI) is often regarded as a form of osteoporosis. However, the bone fragility is the result of defective collagen and earlier work has demonstrated that cortical thickness, in bones not previously fractured, is usually normal. We have now measured the bone mineral content of the distal forearm in 61 adult patients with well characterized OI. Three patients with the Silence type III disorder had bone mass values well below the reference interval. For the 47 type I patients and 11 type IV patients, the bone mass was significantly lower than normal (P < 0.001). However 70% of patients had values within the reference interval. One cannot therefore exclude the diagnosis of OI by finding normal values with densitometry. Diagnostic difficulties do not occur in type III patients and our main objective was to recruit as many individuals as possible with OI types I and IV. In the type IV disease, the diagnosis can be particularly difficult without a positive family history. Since the evaluation of bone density by subjective examination of radiographs is a much less precise procedure, most patients with type I and IV OI would be expected to have 'normal' appearances with this assessment. Osteogenesis imperfecta cannot be excluded on the basis of apparently normal bone density or cortical thickness with routine radiographs.

Absorptiometry, Photon↗
PubMed1993

Osteogenesis imperfecta: the distinction from child abuse and the recognition of a variant form.

Unexplained fractures are characteristic of both osteogenesis imperfecta (OI) and non-accidental injury (NAI) but in most cases the diagnosis is straightforward. However, in a few OI patients an initial diagnosis of NAI is made. Factors contributing to such difficulties include failure to recognise that OI can occur without a family history, without blue sclerae, without osteopenia, without an excess of Wormian bones, or with metaphyseal fractures. In addition we report on 39 patients with an unusual history in that fractures only occurred in the first year of life. Rib fractures, metaphyseal abnormalities and periosteal reactions were common. The initial diagnosis was usually OI if the fractures occurred in hospital, but NAI if they appeared to have been sustained at home. Additional findings such as anaemia, vomiting, hepatomegaly, and apnoeic attacks were often found in these patients. The disorder has some similarities to the syndrome of infantile copper deficiency. Like the latter it is particularly common in preterm infants and in twins. Therefore, we are attempting to examine the incidence of significant hypocupraemia in unselected preterm infants. We suggest that the likely cause of this "temporary brittle bone disease" is a temporary deficiency of an enzyme, perhaps a metalloenzyme, involved in the post-translational processing of collagen.

Child Abuse↗
PubMed1993

Factors associated with variation in plasma copper levels in preterm infants of very low birth weight.

At 2-weekly intervals from age 4-14 weeks, the possible effects on plasma copper concentration of gestation, multiple birth, fractional weight change from birth (W/BW) and, up to 10 weeks, average daily total copper intake from birth were explored in 43 preterm infants of very low birth weight. There was no significant association between the logarithm of the plasma copper concentration (ln Cu) and multiple birth at any time and no significant association between ln Cu and gestation was found from 4-12 weeks. From age 4-10 weeks, there was a significant negative correlation between ln Cu and W/BW and at 4, 6 and 10 weeks there was also a significant negative correlation between ln Cu and copper intake. W/BW and copper intake were correlated throughout. At 14 weeks, ln Cu correlated positively with gestation and negatively with W/BW but, at this age, gestation and W/BW were correlated. The maximum total variation (R2) in ln Cu explained by its regression on gestation, multiple birth, W/BW and/or copper intake combined was only about 31% (at 10 weeks). The potential for copper depletion may be greater in rapidly growing infants.

Birth Weight↗
PubMed1993

A technique for the tensile testing of demineralised bone.

The purpose of this study was to devise a method for the tensile testing of the organic component of demineralised bone. It was hoped that the method could be applied to determine whether an observed reduction in the strength of bone in copper-deficient rats could be attributed to a reduction in the cross-linking of collagen. Tensile testing of a fully demineralised specimen proved impossible to perform because of the difficulty in gripping the material, which tended to slide out of its holding clamps. The technique devised involved the demineralisation of only the diaphysis of the bone, leaving the bone ends intact. This enabled the bone to be gripped firmly at both ends in an Instron tensile testing machine. Elongation under loading of the demineralised diaphysis was measured by the Instron and a video recording was made of the elongation of the central portion. The strain was found to be uniform. Tensile strength was found to correlate with copper levels in the liver (r = 0.54, p < 0.05), although no significant differences were found between the strength, the stiffness, or the strain to failure for bone from the copper-deficient animals and bone from the normal controls. The test method itself should be useful in other studies in which the tensile properties of the organic phase of bone need to be measured.

Animals↗
PubMed1993

Suppressed TSH levels secondary to thyroxine replacement therapy are not associated with osteoporosis.

OBJECTIVE: Recent studies have suggested that patients receiving thyroxine are at increased risk of osteoporosis. We set out to measure bone mineral densities in two groups of post-menopausal women receiving thyroxine replacement therapy (those with serum TSH levels persistently suppressed or non-suppressed) and to compare the results in both groups with those of the local control population. DESIGN: Cross-sectional study. PATIENTS: Seventy-eight post-menopausal women who had been treated with thyroxine for primary autoimmune or idiopathic hypothyroidism for a minimum of 5 years, 44 with TSH persistently suppressed and 34 non-suppressed. One hundred and two control subjects. MEASUREMENTS: Forearm bone mineral density at proximal and distal sites as measured by single-photon absorptiometry. RESULTS: Results were expressed as Z-scores, i.e. number of standard deviations from the mean of a 5-year age-band from the local control population. Mean Z-scores at proximal and distal sites for the non-suppressed patients were -0.03 and -0.07 and for the suppressed patients were -0.20 and -0.25, representing a decrease in bone mineral density of at most 5% in the suppressed patients. The differences between the three groups were not statistically significant. CONCLUSION: In this patient population, the reduction in bone mineral density due to thyroxine is small. It is unlikely to be of clinical significance and should not on its own be an indication for reduction of thyroxine dose in patients who are clinically euthyroid.

Bone Density↗
PubMed1993

Osteoporosis and the Marfan syndrome.

Fourteen patients with Marfan syndrome, defined according to present criteria, had bone mineral content of the distal forearm measured by single photon absorptiometry. Patients were matched for age and sex with a large local group of healthy volunteers. While further work is needed with other methods of densitometry with measurements at other sites, our results provide no evidence that there is an increased incidence of osteoporosis in Marfan syndrome. Previous reports of an association were probably due to incorrect clinical diagnosis or confusion with clinically similar syndromes known to cause osteoporosis.

Absorptiometry, Photon↗
PubMed1993

Impaired mechanical strength of bone in experimental copper deficiency.

Copper, through its role as cofactor for lysyl oxidase, is essential for intra- and inter-molecular cross-links in collagen. Copper deficiency, in man and in animals, is associated with bone fragility ascribed to defective cross-links. To assess bone strength in copper-deficient animals, we designed a sensitive torsion-testing apparatus according to biomechanical considerations. Femora from 7 copper-deficient rats and from their pair-fed controls were tested in torsional loading until fracture. Significant decreases in the maximal sustained torque (t = 2.93, p < 0.05), in the ultimate angular deformation (t = 2.52, p < 0.05) and in the toughness (t = 2.88, p < 0.05) were demonstrated. In a complementary study, it was shown that the ash weight and the calcium content of the femora from the copper-deficient animals did not differ from those of the controls. It was likely, therefore, that the impaired mechanical strength was related to defects in the collagen component of bone.

Animals↗
PubMed1993

Effect of iron-folate supplementation on serum copper concentration in late pregnancy.

The effect of iron-folate supplementation on maternal serum copper concentration in late pregnancy (33 to 35 weeks gestation) was examined. In the 30 women who had taken daily iron-folate supplements since the start of the second trimester (11 to 15 weeks gestation), the median serum copper concentration was lower than that in the 27 women who had taken no supplements (p < 0.005). However, in the supplemented women the median values for serum iron concentration and blood hemoglobin concentration were higher, and the median value for serum transferrin concentration was lower, than the corresponding median values in the unsupplemented women (p < 0.001, p < 0.02 and p < 0.001, respectively). Further work is needed to determine whether the difference between the median values for serum copper concentration is due to a reduction in values in the women who took iron-folate, perhaps as a result of an interaction between iron and copper, or is due to an increase in values in the unsupplemented women secondary to their apparently reduced iron status.

Adolescent↗