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We studied the effect of calcium deprivation and loading in 17 healthy subjects and 76 patients with renal calculi. Five had primary hyperparathyroidism with an elevated plasma ionised calcium and detectable plasma parathyroid hormone. Forty-nine had idiopathic hypercalciuria, defined by a urine calcium greater than 7 mmol/day on a free diet. Twenty-two were normocalciuric. Fasting plasma calcium, corrected for albumin, was higher in the patients with idiopathic hypercalciuria (2.40 +/- 0.10 mmol/l) than in controls (2.28 +/- 0.05 mmol/l, p less than 0.005). Plasma calcium was intermediate in the normocalciuric stone formers (2.35 +/- 0.08 mmol/l) and elevated in the patients with primary hyperparathyroidism (2.62 +/- 0.07 mmol/l). Nephrogenous cyclic adenosine monophosphate (cAMP) and parathyroid hormone levels were highest in the primary hyperparathyroid group and did not differ significantly within the other groups. Nephrogenous cAMP correlated positively with plasma calcium in the patients with primary hyperparathyroidism and negatively in controls; there was no correlation in the idiopathic hypercalciuria group. Following an oral calcium load, plasma calcium rose and nephrogenous cAMP fell similarly in all groups. Fasting urinary calcium and its increase after load were greatest in the idiopathic hypercalciuria and primary hyperparathyroid groups, with intermediate results in the normocalciuric patients. Neither the initial metabolic patterns nor the response to thiazide fitted with the previously described patterns of absorptive and renal hypercalciuria. Increased parathyroid gland activity is the most probable cause of idiopathic hypercalciuria.

We studied the effects of vitamin D metabolites in 29 patients established on chronic hemodialysis. The patients were divided into four groups; one was treated with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] 0.5 microgram/day, one with 24R,25-dihydroxyvitamin D3 [24,25-(OH)2D3] 10 micrograms/day, and one with both metabolites. The control group was not given vitamin D. Plasma levels of both metabolites were low before treatment. 1,25-(OH)2D3 levels became normal, and 24,25-(OH)2D3 increased to supranormal levels after administration of the corresponding metabolite. Combined treatment produced still higher plasma levels of 24,25-(OH)2D3, suggesting an interaction between the two metabolites. Patients receiving 1,25-(OH)2D3 alone had a greater increase in plasma calcium than those receiving both metabolites. In control patients, hyperparathyroid bone disease worsened over the 10-month observation period. 1,25-(OH)2D3 improved hyperparathyroid bone disease in most patients, as reflected by a reduction in osteoclast and osteoblast numbers, but had no demonstrable effect on mild osteomalacia. 24,25-(OH)2D3 had no significant effect on plasma biochemistry or bone histology, and the effect of combined treatment on histology was similar to that of 1,25-(OH)2D3 alone. Stainable bone aluminum increased slightly in patients given 1,25-(OH)2D3, but aluminum did not affect the response to treatment. We conclude that 1,25-(OH)2D3 is a useful agent in the treatment of renal bone disease, but no therapeutic role is apparent for 24,25-(OH)2D3.

The effects of intraperitoneal aluminum chloride (1.5 mg aluminum/kg/day for 9 weeks) were studied in normal and uremic rats. Parameters measured included tissue aluminum, serum vitamin D metabolites, and quantitative bone histology. Aluminum administration increased tissue concentrations of this metal in uremic and nonuremic animals. Bone aluminum concentrations were higher in uremic rats (121 +/- 27 mg/kg compared to 47 +/- 4), whereas liver values were higher in the nonuremic group (175 +/- 47 mg/kg compared to 100 +/- 36). Serum concentrations of 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D were reduced in uremia, but aluminum was without apparent effect on any vitamin D metabolite. Aluminum, in the doses administered, caused no skeletal changes in nonuremic animals. Some uremic, non-aluminum-treated rats developed osteomalacia and marrow fibrosis. However, osteomalacia was more severe and the osteoclast count was higher in the uremic, aluminum-treated rats. In this group of animals the mineral apposition rate was reduced at the metaphyseal endosteum but increased at the periosteum, indicating different control mechanisms at the two sites.

Weaning, male rats were given ethane-1-hydroxy 1,1-diphosphonate (EHDP) or dichloromethylene diphosphonate (Cl2MDP) 0.5 mgP/kg/day for 140 days. Samples prepared after sacrifice were: (1) thin ground (30 micrometers) transverse tibial sections, (2) methacrylate-embedded 5 micrometers sections of the proximal tibial metaphysis, and (3) ultrathin calcified metaphyseal sections for electron microscopy. Cl2MDP reduced the diaphyseal medullary cavity, and EHDP increased the osteoid width. Both drugs increased endosteal bone apposition (possible secondarily to the impaired resorption) and, perhaps as a result, periosteal apposition was increased. Consequently, diaphyseal bone area was unchanged. Metaphyseal bone area was increased and osteoclast numbers reduced, in contrast to the increased osteoclast numbers reported previously in animal experiments with diphosphonates. Acid phosphatase activity within osteoclasts was markedly reduced with EDHP and unchanged with Cl2MDP. The ultrastructural changes in osteoclasts, i.e., a deficiency of ruffled borders, reduced numbers of cytoplasmic vacuoles and the presence of crystals between bone and the osteoclastic plasmalemma, were more marked with EHDP than Cl2MDP.

We have investigated and treated 176 patients who were suffering from renal calculi. The stones contained calcium in 87% of patients, predominantly urate in 11%, and rarely contained magnesium ammonium phosphate or cystine. Of the patients with calcium stones, hypercalciuria was present in 75% and was identified in 57% by the measurement of the 24-hour urinary calcium excretion, and in a further 18% by a standardization calcium "fast-and-load" test. Nine patients were found to have primary hyperparathyroidism and were treated surgically. A further 21% were suspected to have normocalcaemic hyperparathyroidism, and metabolic studies are being developed to clarify this. The treatment of hypercalciuria included a low-calcium diet, and various combinations of a thiazide diuretic, phosphate supplements and sodium cellulose phosphate. Hypercalciuria was controlled in all compliant patients, and only two developed further stones. Hyperuricosuria was rarely the sole metabolic abnormality in patients with calcium stones, though this might reflect the referral pattern of the Unit. Uric acid stones were frequently, but not invariably, associated with hyperuricosuria and acid urine, and even large uric acid calculi dissolved with a combined therapy of high fluid intake, allopurinol and an alkalinizing agent. Surgical treatment was rarely required in these patients. A stone in the renal pelvis of one patient was removed percutaneously and did not require ultrasonic fragmentation. Modern methods of investigation and treatment have greatly improved the outlook for patients with recurrent renal calculi.

Quantitative bone histology (on undecalcified sections following double tetracycline labeling), radiographs, and biochemistry were studied in 47 children, ages 1 to 17 years, with glomerular filtration rates (GFR) below 80 ml/min/1.73m2. The earliest histologic change was an increased osteoid surface accompanied by increased osteoblast and tetracycline surfaces. However, significant bone disease (increased osteoclastic surface, fibrosis, increased osteoid area, increased mineralization lag time, and reduced tetracycline uptake at osteoid surfaces) occurred only at GFR below 30 ml/min/1.73m2. Radiographs and alkaline phosphatase were normal in 25% of children with significant bone disease; parathyroid hormone was increased in 48% of children without bone disease. Thus, these noninvasive investigations were poor predictors of disease presence. GFR was the most sensitive indicator because bone disease occurred only at GFR below 30 ml/min/1.73m2 and was present in all children with GFR below 20 ml/min/1.73m2. It was concluded that bone histology is required for early detection of bone disease and is an essential tool in experimental studies of renal osteodystrophy. However, because the level of GFR will indicate the presence or absence of bone disease in most children, bone biopsy can be avoided generally in clinical practice.

In order to determine the place of Technetium-99m-pyrophosphate bone scintigraphy in the assessment of renal osteodystrophy, 17 patients with chronic renal failure requiring hemodialysis underwent bone scans and these were compared to results of biochemical, radiological and histologic studies. Bone histology was abnormal in all patients with most having evidence of osteomalacia and hyperparathyroid bone disease. Using semi-quantitative scan scores and regional bone-standard ratios, isotope uptake was increased in 16 patients, while 15 had elevated alkaline phosphatase levels and 7 had X-ray changes. An osteoid-osteoclast index combining histological osteomalacia and hyperparathyroid disease was derived and was found to correlate more closely with alkaline phosphatase and parathyroid hormone levels than with scan parameters. It was concluded that bone scans did not provide therapeutically useful information that could not be obtained from biochemical and radiological studies. It appeared that only bone histology could differentiate osteomalacia and hyperparathyroid bone disease.

Bone histology was quantitated in 10 osteoporotic patients aged between 17 and 51 years and in six healthy subjects aged between 23 and 43 years. The osteoporosis was of varying aetiology and was clinically stable. All patients were given tetracycline before biopsy and double tetracycline labelling was used in seven patients. Bone forming and resorbing surfaces were defined by the presence of osteoblasts and osteoclasts, respectively, which were identified by histochemical techniques. The associations between bone forming and resorbing surfaces were similar in patients and controls, though the range of values was wider in the patients than in the controls. Mineral apposition rate was normal in the osteoporotic patients, but there was a reduction in mineralising (tetracycline) surface, whether related to osteoid surface or to osteoblast surface. This did not indicate osteomalacia as the directly and indirectly measured mineralisation lag times were normal. The osteoid seams were thinner in osteoporotic patients than in controls. The data suggest that osteoclast and osteoblast numbers were normal in this group of osteoporotic patients but that the metabolic activity of osteoblasts was impaired.

Quantitative bone histology, biochemistry and height velocities were studied in 18 children suffering from chronic renal failure. Eight received calcitriol, 7 ergocalciferol and 3, though alloted to a treatment group, failed to comply with therapy. A histochemical stain for aluminum showed heavy deposition at the calcification front in 3 patients; 2, in the calcitriol group had severe osteomalacia which worsened during treatment, and 1 in the ergocalciferol group had osteomalacia which did not improve. One had never undergone hemodialysis. Bone histology improved markedly in the remaining 12 patients, whichever vitamin D preparation was used; it was unchanged in 3 non-compliant children. Plasma calcium levels rose while parathyroid hormone and alkaline phosphatase levels fell following both treatments, and were unchanged in non-compliant children. Hypercalcemia occurred more frequently following calcitriol therapy (11 episodes) than following ergocalciferol therapy (3 episodes). Height velocities, studied in 11 children, increased in 5 (3 on ergocalciferol and 2 on calcitriol) and were unchanged in 6 (1 on ergocalciferol, 5 on calcitriol). Improved bone histology did not correlate with increase in height velocity. As ergocalciferol and calcitriol had similar therapeutic effects and as side-effects were more common with calcitriol, it is concluded that calcitriol provides no advantage over ergocalciferol in the treatment of renal bone disease in children.

Identification of low levels of a metabolite of unaltered skeletal structure, 1-chloro-3-ethynylpent-1-en-3,4-diol (VII), detected in biological specimens of both nonfatal and fatal poisonings with DL-1-chloro-3-ethylpent-1-en-4-yn-3-ol (ethchlorvynol, la), has been achieved by high-resolution GC/MS. Corroborative evidence for the assigned structure (VII) was provided by synthesis, the design of which included as a central objective, concurrent access to 1-chloro-3-ethynyl-3,4-epoxy-1-pentene (VI), the putative direct precursor of VII. The diastereomeric epoxide mixture (VI) is mutagenic toward Escherichia coli WP2 try-hcr-, a UV-deficient repair strain. By contrast, neither Ia, VI, nor VII proved to be mutagenic toward Salmonella typhimurium (TA98, TA100, TA1535, and TA1539) with or without a liver postmitochondrial fraction. However, the epoxides (VI) proved cytotoxic to, for example, TA100, which apparently overlies its potency as a mutagen. The cytotoxicity of VI was also apparent in an in vitro culture system.

Bone aluminum, quantitative bone histology, and plasma parathyroid hormone (PTH) were compared in 29 patients undergoing chronic hemodialysis. Histologic techniques included double tetracycline labeling and histochemical identification of osteoclasts and osteoblasts. Bone aluminum was measured chemically by flameless atomic absorption spectrophotometry, and histochemically. When measured chemically, the bone aluminum was 67 +/- 46 (SD) mg/kg dry weight (normal 2.4 +/- 1.2 mg/kg); histochemically, aluminum was present at 2.9 +/- 4.4% of trabecular surface. The biochemical and histochemical results agreed well (r = 0.80, P less than 0.001). No double tetracycline labels were seen at the mineralization front where aluminum was deposited, indicating cessation of mineralization at these sites. The osteoblast surface correlated positively with plasma PTH (r = 0.67, P less than 0.001) and negatively with bone aluminum level (r = -0.42, P less than 0.05). Multiple linear regression showed a correlation of aluminum with osteoblasts additional to that of PTH, consistent with a direct effect of aluminum in depressing osteoblast numbers. Though a relationship between PTH and chemically determined bone aluminum level could not be demonstrated, there was a negative correlation between osteoclast count and aluminum, and the nine patients with severe hyperparathyroid bone disease had lower chemically determined aluminum levels than the other patients. These results suggest that aluminum (a) directly inhibits mineralization, (b) is associated with decreased PTH activity and hence osteoblast numbers, and (c) directly reduces osteoblast numbers. In addition to inducing severe, resistant osteomalacia, aluminum appears to contribute to the mild osteomalacia commonly seen in renal failure, characterized by extensive thin osteoid and low tetracycline and osteoblast surfaces.

Human papillomavirus (HPV) infections of the genital tract frequently involve cervical epithelium and produce a macroscopically flat lesion that the authors have called noncondylomatous cervical wart virus infection (NCWVI). Over a 6-month period, 92 of 7281 routine cervical smears (1.3%) and 46 of 183 colposcopically directed punch biopsies (25%) showed morphologic evidence of wart virus infection. The etiologic role of HPV was confirmed by the demonstration of virus particles in 24 of 53 cases (45%) examined by electron microscopy. The colposcopic features of NCWVI consist principally of epithelial opacity and vascular atypia, leading to frequent confusion with cervical intraepithelial neoplasia. Differences in surface contour, color, vascular patterns, and topography generally permit colposcopic differentiation. These 2 conditions sometimes coexist; whether the association is causal or casual in not presently known.

The clinicopathologic features are described of two patients whose cervical cytology smears showed features which were thought initially to indicate dysplasia, but which were later considered to be those of condylomata acuminata. One patient was an immunosuppressed renal transplant recipient, the other was a routine gynecologic clinic patient. No condylomas were recognizable clinically, and colposcopy showed only a flat but atypical transformation zone. Biopsy in each case showed a noncondylomatous warty lesion and wart virus particles were demonstrated by electron microscopy. These cases highlight the clinical, colposcopic, cytologic and histologic diagnostic difficulties which are encountered with cervical transformation zone wart virus infections, which are commoner than formerly realized. The possible relationship of wart virus infection to cancer of the cervix is also discussed.

A routine cervical smear from a 56-year-old postmenopausal woman showed appearances indicative of papilloma virus infection with atypia. In an attempt to prove the diagnosis, the smear was reprocessed for electron microscopic examination. The reprocessing technique is described. Ultrastructural preservation was poor, and significant shrinkage was observed. In spite of these technical difficulties it was possible to prove that the selected cells in the smear contained papilloma virus particles. The virus particles seen were intranuclear in location and spherical in shape with a diameter of 40 to 50 nm. As was demonstrated in this case, the technique described will prove useful in evaluating the reliability of various diagnostic criteria for identifying viral infections in routine smears. This will apply particularly in cases where cultural confirmation of a reported viral infection is not possible.

A young man developed acute renal failure and hypercalcaemia following severe burns. The hypercalcaemia was initially controlled by haemodialysis, but it persisted after return of renal function. Plasma PTH was inappropriately elevated, but the nephrogenous cyclic adenosine monophosphate level was low; thus the PTH was probably not biologically active, and may have been artefactually elevated by the moderate renal impairment. Bone histology, showed a normal resorbing surface, but a zero forming surface, implying that the bone dissolution leading to hypercalcaemia resulted from a failure of bone formation. Because of widespread infection and impaired renal function, the hypercalcaemia could not be treated by corticosteroid drugs, mithramycin or phosphate, and there was no response to salmon calcitonin. He was therefore treated with intravenous sodium sulphate, which increased urinary calcium excretion and reduced the plasma calcium. Sodium sulphate still has a role in the treatment of patients with hypercalcaemia.

A women suffering from the candidiasis-endocrinopathy syndrome, developed severe myopathy in her fourth decade and died from it at the age of 37 years. Associated conditions were hypoparathyroidism, vitiligo, chronic mucocutaneous candidiasis, short stature, intellectual disability, ovarian failure and alopecia totalis. Muscle biopsy findings were non-specific with focal atrophy of type 2 fibres. Serum immunoglobulin levels were normal. The only demonstrable abnormalities of her immune system were impaired T-cell function and antibody production by B-cells (detectable to smooth muscle, mitochondria and gastric parietal cells). The T-cell abnormality may have been part of a more generalized cell defect, resulting from an unidentified genetic abnormality, whilst the circulating antibodies could have been a response to tissue damage. There was no convincing evidence of primary autoimmune damage.

Quantitative bone histology was studied in 23 patients with malignant hypercalcemia (MH) due to carcinoma (16) or immunoproliferative disease (7). Plasma calcium was 3.37 +/- 0.47 (mean +/- SD) mmol/liter. Bone resorbing surface (RS) was measured using a sensitive histochemical stain to identify osteoclasts. In the MH patients with carcinoma, the RS was 3.1 +/- 2.6% compared to 1.0 +/- 0.3% in controls (P less than 0.02). In the myeloma patients it was 2.3 +/- 1.7%, and in normocalcemic patients with malignant disease 0.8 +/- 1.1%. RS did not correlate with serum PTH, and several high RS values were associated with undetectable PTH. RS correlated with forming surface (FS) in MH patients (r = 0.44, P less than 0.05) and controls (r = 0.68, P less than 0.005), but there was a greater RS relative to FS in MH patients than in controls (P less than 0.005). "Excess" RS in the MH patients was calculated by subtracting the RS accounted for by the measured FS, using the relationship defined by the controls. Bone loss, as reflected in urinary calcium excretion, correlated weakly with excess RS (r = 0.44, P less than 0.05) but was high even when excess RS was zero. Thus, the histological findings do not account for the bone loss, and additional resorption around bone metastases is likely; the results of this study are consistent with a humoral substance produced by the malignant tissue causing generalized bone resorption in addition to bone dissolution around metastases.

We studied the effect of age on bone composition and osteocyte viability in femoral heads from fifty-one subjects. The assessment included determination of: bone volume, ash weight, calcium, and phosphorus content; osteocyte viability in fresh sections stained for lactate dehydrogenase activity; microfractures in fresh sections after removal of marrow elements; bone area, the presence of metabolic bone disease, and the histology of microfractures in embedded calcified sections; and the extent of trabecular microfractures. Bone area and numbers of microfractures were also assessed in eight elderly hip-fracture patients. Bone volume decreased with age, but there was considerable variation in each age group, and no significant difference between men and women. Ash weight and the bone content of calcium and phosphorus also decreased with age, but were constant if corrected for bone volume. Almost all osteocytes were viable in subjects who were younger than twenty-five years, and thereafter viability progressively decreased to a mean of 74 per cent in the eighth decade of life. There was a significant negative correlation between osteocyte viability and age. There was no evidence of metabolic bone disease in any patient. The numbers of microfractures increased with age and correlated negatively with bone viability (r = -0.31, p less than 0.05); in simple linear correlation a relationship between bone area and microfractures could not be demonstrated but in multiple linear correlation, after the inclusion of bone viability, there was an additional negative correlation between numbers of microfractures and bone area (p less than 0.005). Bone area and numbers of microfractures in hip-fracture patients were similar to those in age-matched controls.

75 patients with Paget's disease of bone were treated with a drug combination intended to increase the production of endogenous calcitonin and decrease that of parathyroid hormone. The first regimen of oral calcium, thiazide diuretic, aluminum hydroxide and low-phosphorus diet was given to 41 patients for a mean of 800 days. A simpler regimen of oral calcium and thiazide diuretic was given to 34 patients for a mean of 750 days. There was a similar fall in mean plasma alkaline phosphatase to 71 +/- 24 (SD)% of initial with the first regimen and 72 +/- 17% with the second at 150 days, with a gradual rise after 500 days. Urinary hydroxyproline fell from 165 +/- 111 to 112 +/- 93 mg/day. Plasma calcium rose slightly with both regimens and plasma inorganic phosphorus fell with the first. Serum parathyroid hormone and calcitonin levels were unchanged. Urinary calcium was not changed by the first regimen and rose by 40 +/- 54 mg/24 h with the second. Clinical improvement approximately paralleled biochemical improvement. It is suggested that, in view of its low cost and convenience, this treatment has a place in the management of Paget's disease of bone.

Biochemical data and bone histology from 44 haemodialysis patients was compared using an histologic technique capable of evaluating separately the individual components of osteodystrophy. Hyperparathyroid bone disease was diagnosed by an elevated osteoclast count, and in advanced disease there was also fibrosis and woven bone. Osteomalacia, defined as an impairment in the rate of bone mineralisation, was present in two distinct forms: osteomalacia type I, characterised by wide osteoid seams, and osteomalacia type II, characterised by extensive thin, inactive osteoid. The histologic diagnoses were hyperparathyroid bone disease (15), osteomalacia type I (3), osteomalacia type II (6), hyperparathyroid bone disease and osteomalacia type I (12), hyperparathyroid bone disease and osteomalacia type II (6), normal (2). Aluminium was evident histochemically in 17 biopsies. Vitamin D metabolite levels were low in most patients and did not correlate with any biochemical or histological parameter. Parathyroid hormone levels were highly correlated with histological features of hyperparathyroid bone disease, and also correlated with plasma calcium, suggesting a degree of autonomy of parathyroid hormone secretion. Urea and creatinine were higher in the hyperparathyroid bone disease than the osteomalacia groups suggesting that poor dialysis contributes to the former. Statistical analysis showed that osteomalacia type I was associated with relatively low plasma calcium and phosphorus levels; osteomalacia type II was associated with increased bone aluminium and with the uraemic process itself, as reflected in the plasma creatinine level. This study shows relationships between renal osteodystrophy and plasma calcium and phosphorus levels, but no relationship with vitamin D metabolites. Aluminium appears to impair mineralisation even at relatively low levels of accumulation. However there are other unidentified factors associated with the uraemic process, contributing to all three components of renal osteodystrophy.

Calcium levels in blood are maintained within narrow limits by parathyroid hormone, acting on kidney, bone and gut. Our understanding of the mechanisms of these actions has increased greatly in recent years, for example by identification of new hormones (eg 1,25 dihydroxy vitamin D) and by the study of isolated bone cells. Though most clinical disorders of calcium metabolism are now readily diagnosed and many are effectively treated, some serious problems still remain. Foremost amongst these are the early diagnosis of osteoporosis and the treatment of osteoporosis after fractures have occurred. Most disorders of calcium metabolism have ophthalmologic manifestations, sometimes troublesome to the patient, and sometimes diagnostically helpful.

We have developed a technique for assessing bone viability by the histochemical demonstration of lactate dehydrogenase (LDH) activity in osteocytes. Fresh sawn and ground (75 microns) sections were prepared from femoral heads removed at operation from patients with osteoarthritis of the hip. The sections were decalcified overnight in cold 10% EDTA, pH 7.0. LDH activity was shown by the tetrazolium-formazan reaction with nitroblue tetrazolium as indicator and lithium lactate as substrate. Osteocytes were regarded as viable if their cytoplasm stained dark blue, indicating LDH activity; lacunae containing non-viable osteocytes could be identified by interference contrast illumination. Nearly all osteocytes were viable in the samples studied. Small trabecular fragments, such as could be obtained by needle biopsy, were also suitable for staining after grinding to approximately 50 microns. The method should have application both in research and in diagnosis of ischemic bone disease.

A GLC analysis for free ftorafur was developed to follow in drug disposition in body fluids of patients. The free drug was extracted from aqueous biological samples with chloroform, derivatized by methylation, and chromatographed on 1% HI-EFF 8BP using flame-ionization detection. The analysis is sensitive (0.25 microgram/ml of plasma) and specific for the intact molecule, and it does not interfere with subsequent fluorouracil analysis of the same sample.

Osteocyte viability was investigated in femoral head bone removed from 38 patients with chronic hip disease, with the use of a histochemical stain to demonstrate lactate dehydrogenase (LDH) activity in osteocytes. Where the osteocyte cytoplasm did not show LDH activity, the cell was considered dead; when several adjacent osteocytes were dead, the bone in that area was regarded as nonviable. The preoperative diagnoses were idiopathic osteoarthritis in 25, chondrocalcinosis in six, rheumatoid arthritis in two, Paget's disease in two, avascular necrosis in two, and congenital dislocation of the hip in one patient. In 16 of the patients with idiopathic osteoarthritis and the two with avascular necrosis, nonviable osteocytes were present in the central regions of many trabeculae, these areas usually being separated by cement lines from viable bone. The pattern suggested previous necrosis of part of the femoral head, with later new bone formation. The pattern was not observed in either control subjects, or patients with known articular disease, such as chondrocalcinosis. Bone collapse of variable severity was apparent radiographically in nine patients with histologic bone death, but not in other patients. Bone death is commonly present in idiopathic osteoarthritis and could be a cause rather than a result of the arthritis.

Bone mineral content (BMC) was measured in the os calcis of 232 normal subjects aged 17-82 years. The mean reproducibility (coefficient of variation) of the measurement was 1.8%. Substantial bone loss occurred between the ages of 20 and 50 years, and in females the menopause was associated with additional bone loss. There was no significant difference in the rate of bone loss in females and males, but the mean BMC was greater at all ages in males than in females. We also compared os calcis BMC with spinal bone mineral density (BMD), measured by quantitative computed tomographic (CT) scanning, in 85 subjects: 33 were normal controls, 19 had osteoporosis defined by the presence of one or more pathological fractures, and in the remainder the CT examination was performed at the patient's request. Os calcis BMC correlated with spinal BMD in both females (r = 0.69, p less than 0.001) and males (r = 0.84, p less than 0.001). However, the os calcis BMC did not reliably predict spine values around the CT "fracture threshold" of 90-100 mg/cm3 and did not correlate with osteoporotic fracture as well as did spinal BMD. It is concluded that measurement of the os calcis BMC is of limited clinical usefulness for the early diagnosis of osteoporosis.

A double-blind controlled study is reported of salmefamol 200 mug and salbutamol 200 mug administered by aerosol before exercise tests in asthmatic children. Both drugs prevented exercise-induced asthma. There was no significant difference between them.