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. Singlestranded 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 relation-

These results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.

Aims-To determine the causes of death in patients with osteogenesis imperfecta, excluding infants with the perinatal lethal form (type II).

Analyses of the urinary concentration relative to creatinine of the collagen crosslinks, pyridinoline (Pyd) and deoxy-pyridinoline (Dpd) were made in 47 patients with metabolic bone diseases to assess the validity of these assays as indicators of bone resorption. The mean values for patients with Paget's disease of bone, primary hyperparathyroidism and osteomalacia were significantly higher (P less than 0.001) than those for age-matched healthy individuals. During treatment of Paget's disease with bisphosphonates, there was a steady decline in the urinary concentration of the crosslinks to the normal range; this change occurred earlier than for serum alkaline phosphatase. There were significant correlations (P less than 0.01) between the concentrations of both crosslinks and the corresponding values for hydroxyproline. At lower crosslink concentrations, however, these relationships were less marked due to large variations in hydroxyproline values. The results show that measurements of urinary Pyd and Dpd provide clinically applicable indices of bone resorption that are more specific than other markers.

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.

Seasonal variations in vitamin D nutrition were assessed by measurements of serum 25-hydroxycholecalciferol levels in outdoor workers, indoor workers and long-term hospital inpatients. All three groups showed seasonal changes and the outdoor workers had, as might be expected, the highest levels at all seasons. However, the highest levels of 25-hydroxycholecalciferol were found in October in the indoor workers and in November for the outdoor workers whereas the peak in ultraviolet exposure was in July. The possible reasons for this long lag are discussed; the most likely explanation is that vitamin D continues to be formed and stored during the autumn especially in outdoor workers.

Objective: To investigate the effect of socioeconomic group (with reference to age and sex) on the rate of, course of, and survival after coronary events. Design: Community coronary event register from 1985 to 1991. Setting: City of Glasgow north of the River Clyde, population 196 000. Subjects: 3991 men and 1551 women aged 25-64 years on the Glasgow MONICA coronary event register with definite or fatal possible or unclassifiable events according to the criteria of the World Health Organisation's MONICA project (monitoring trends and determinants in cardiovascular disease). Main outcome measures: Rate of coronary events; proportion of subjects reaching hospital alive; case fatality in admitted patients and in community overall. Results: Event rates increased with age for both sexes and were greater in men than women at all ages. The rate increased 1.7-fold in men and 2.4-fold in women from the least (Q1) to the most (Q4) deprived socioeconomic quarter. The socioeconomic gradient decreased with age and was steeper for women than men. The proportion treated in hospital (66%) decreased with age, was greater in women than men, and decreased in both sexes with increasing deprivation (age standardised odds ratio 0.82 for Q4 v Q1) Case fatality in hospital (20%) increased with age, was greater for women than men when age was standardised, and showed no strong socioeconomic pattern. Overall case fatality in the community (50%) increased with age, was similar between the sexes, and increased from Q1 to Q4 (age standardised odds ratio 1.12 in men, 1.18 in women). Conclusions: Socioeconomic group affects not only death rates from myocardial infarction but also event rates and chance of admission. This should be taken into account when different groups of patients are compared. Because social deprivation is associated with so many more deaths outside hospital, primary and secondary prevention are more likely than acute hospital care to reduce the socioeconomic variation in mortality.

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.