The problem of latency in the development of tumors following exposure to nickel compounds.

Six previously published animal studies of tumor production have been reviewed, in order to relate time interval between exposure to nickel and development of tumor formation. Biopsies at intervals before final tumor formation, in some of these experiments, were reviewed to define interim changes between exposure and tumor diagnosis. Correlation between rat and human life span was used to suggest a latency of human tumor expectancy following exposure to nickel.

The role of 1,25-dihydroxyvitamin D in the mechanism of acquired vitamin D deficiency.

OBJECTIVE: We wished to assess the effect of changes in the plasma concentration of 1,25-dihydroxyvitamin D on the plasma elimination half-time for 25-hydroxyvitamin D in man. DESIGN: The turnover of 25-hydroxyvitamin D in plasma was investigated after intravenous doses of the radioactively labelled metabolite had been given to a group of patients (n = 17) with disorders of bone and mineral metabolism before and after oral treatment with calcium or 1,25-dihydroxyvitamin D. PATIENTS: Seven patients with post-menopausal osteoporosis, five with hypoparathyroidism, three with hypophosphataemic osteomalacia, one with renal osteodystrophy and one patient with coeliac disease were studied. MEASUREMENTS: Intravenous injections of 3H-labelled 25-hydroxyvitamin D were given and plasma elimination half-time assessed over periods of 4-14 days during which frequent measurements of plasma calcium, phosphate, parathyroid hormone, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were made. Changes in the plasma elimination half-time for 3H-25-hydroxyvitamin D before and after treatment with calcium and 1,25-dihydroxyvitamin D were evaluated by non-parametric statistical analysis. RESULTS: The elimination half-time for 3H-25-hydroxyvitamin D in plasma was significantly shortened by raising the circulating concentration of 1,25-dihydroxyvitamin D. Conversely, in a patient with intestinal malabsorption of calcium, the metabolic clearance of 3H-25-hydroxyvitamin D was prolonged when the concentration of 1,25-dihydroxyvitamin D in plasma was decreased by suppressing secondary hyperparathyroidism with large calcium supplements. In the longer-term studies (n = 10) there was a highly significant inverse relation (r = -0.88, P < 0.001) between the change in the plasma concentration of 1,25-dihydroxyvitamin D and the induced change in the elimination half-time of 3H-25-hydroxyvitamin D. There was also a significant correlation (r = 0.66, p < 0.0025) between the observed fall in the plasma concentration of unlabelled 25-hydroxyvitamin D and the predicted fall calculated from the measured value for the half-time of the 3H-labelled metabolite. In acute studies in patients with post-menopausal osteoporosis (n = 7), enhanced metabolic inactivation of 3H-25-hydroxyvitamin D was detectable within 24 hours of oral administration of 1,25-dihydroxyvitamin D. CONCLUSIONS: The effect of 1,25-dihydroxyvitamin D on the catabolism of 25-hydroxyvitamin D can contribute to the development of vitamin D deficiency in many clinical disorders. When the natural supply of vitamin D is limited by sunlight deprivation, a sustained increase in the plasma concentration of 1,25-dihydroxyvitamin D due to primary or secondary hyperparathyroidism will lead to accelerated depletion of vitamin D stores.

The problems of water pollution: an overview.

Most potentially toxic chemicals eventually find their way into waterways. The most common source of this pollution is from the air. More than 50 percent of the chemical pollution of the Great Lakes is believed to come from airborne pollutants, and the main sources of this pollution are smokestacks (energy plants, nuclear or conventional; trash-to-steam incinerators; industrial factories, chemical and wood pulp) and road traffic exhaust. Chemicals may reach waterways directly through partially filtered or untreated sewage and waterway traffic, both industrial and pleasure; or they may be deposited into the soil and reach rivers and estuaries through leakage (PCBs on cables, landfills, and regular or low-level nuclear waste) or locally from fields (fertilizers, herbicides, phosphates, and other chemicals.

Serum parathyroid hormone and calcitonin levels following ovariectomy in the adult rat.

The ovariectomized rat is a reasonably good and often utilized model of human post-menopausal osteoporosis (Devlin and Ferguson, 1989). Mature rats were either ovariectomized or underwent a sham operation, killed at intervals following operation and the serum concentration of parathyroid hormone and calcitonin at death related to the histomorphometry of the cancellous bone of the proximal ilium. The mean serum calcitonin concentration for all ovariectomized rats was 66.4 pg/ml (SD = 18) and for the control rats was 76.42 pg/ml (SD = 20). The serum calcitonin concentration in the ovariectomized rats was significantly negatively correlated with the extent of erosion cavities of the cancellous bone (r = -0.598, t = -2.36, p = 0.039). No significant correlation was observed for the control rats (r = -0.107, t = -0.357, p = 0.727). The mean extent of erosion cavities in the ovariectomized group was 6.81% (SD = 1.94) and in the control group was 6.47% (SD = 2.21), with no significant differences between the two groups (t = 0.41, p = 0.69). No significant correlations were observed in serum parathyroid hormone (PTH) concentration with the bone resorption parameters. From this study it was concluded that calcitonin may be of aetiological importance in bone loss in the ovariectomized rat.

Evidence for nonrenal synthesis of 1,25-dihydroxyvitamin D in patients with inflammatory arthritis.

The extrarenal synthesis of 1,25-dihydroxyvitamin D [1,25-(OH)2D] is a characteristic of activated macrophages and has been demonstrated to occur in vitro in synovial fluid macrophages from patients with inflammatory arthritis. To examine whether such synthesis occurs in vivo, 19 patients with rheumatoid arthritis, 5 patient controls, and 5 healthy controls received a challenge oral dose of 250 micrograms 25-hydroxyvitamin D3 (25-OHD3) and the serum 1,25-(OH)2D3 response was measured. The median rise in serum 1,25-(OH)2D3 was significantly greater (22 pg/ml) in the rheumatoid patients compared to either of the control groups (8 pg/ml), although the increase in precursor 25-OHD3 was similar in all groups. The serum 1,25-(OH)2D concentration did not rise above the normal upper limit in any of the control subjects but exceeded the normal range in 8 of the rheumatoid patients. Extrarenal 1,25-(OH)2D synthesis is substrate dependent, unlike renal 1 alpha-hydroxylation, which is homeostatically controlled. Excessive 1,25-(OH)2D3 synthesis in the rheumatoid group on raising the 25-OHD3 concentration is indicative of nonrenal production of the hormonal metabolite. Further evidence for substrate-dependent extrarenal synthesis came from measurements of 25-OHD and 1,25-(OH)2D in paired serum and synovial fluid samples from 19 patients with inflammatory arthritis, including 15 with rheumatoid arthritis. Synovial fluid 1,25-(OH)2D was usually present at a lower concentration than serum 1,25(OH)2D, with which it was strongly correlated (Kendall's R = 0.46, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Renal osteodystrophy in CAPD.

At start of dialysis most patients have histological bone abnormalities. These can be divided into two groups--high turnover and low turnover bone disease. Low turnover aplastic disease was previously attributed to aluminum accumulation but is now known to occur even in patients with less than 5% surface stainable aluminium. It is characterised by a mineralisation defect, thin osteoid seams, decreased numbers of osteoclasts and osteoblasts and absent aluminium staining. We have avoided aluminium containing phosphate binders (ACPBs) completely, with a combination of oral calcium carbonate and "low calcium" (1.25 mMol/l) dialysis fluid. Phosphate control has been good (mean less than 1.6 mMol/l) and over the first twelve months serum PTH levels have fallen significantly. Transient asymptomatic episodes of hypercalcaemia have occurred but no patient required ACPBs. Bone biopsies at the start of CAPD in 34 patients showed over 50% to have osteitis fibrosa (OF) but in five cases (15.6%) the aplastic lesion was found without aluminium staining. In seven follow-up biopsies OF improved in 3 cases, osteomalacia improved in 1, became aplastic in 1, while aplastic bone worsened in 1 and changed to mild OF in 1. We conclude that the predominant bone lesion in our patients at start of CAPD is OF, but 15% already have aplastic bone. "Low calcium" dialysis fluid enables ACPBs to be avoided in the majority of CAPD patients.

A modified Brown and Hopps stain for identification of gram-positive and gram-negative microorganisms in glycol methacrylate-embedded tissues.

Plastic embedding is a recently developed technique that has been shown to be superior to conventional paraffin embedding in the histopathologic identification of microorganisms in tissue specimens. This report describes a modification of the Brown and Hopps stain for the differentiation of gram-positive and gram-negative microorganisms in 3-micron-thick plastic sections. This technique is easily performed and has a rapid turnaround time. This staining method permits a more precise histopathologic diagnosis of infectious agents than is possible in paraffin-embedded tissues.

Determinants of the serum concentration of 1,25-dihydroxyvitamin D in primary hyperparathyroidism.

1. The serum concentrations of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were measured in 44 patients with primary hyperparathyroidism. 2. In 14 patients the serum concentration of 1,25-dihydroxyvitamin D was greater than normal (142-337 pmol/l). One patient had a subnormal concentration of 1,25-dihydroxyvitamin D (36 pmol/l) but no other evidence of vitamin D deficiency. 3. The possible biological determinants of the serum concentration of 1,25-dihydroxyvitamin D were sought by multivariate analysis of relevant variables. The serum concentration of 1,25-dihydroxyvitamin D was found to be significantly and positively correlated with the serum concentrations of 25-hydroxyvitamin D (P less than 0.001) and parathyroid hormone (P less than 0.003), and with the glomerular filtration rate (P less than 0.03), and negatively correlated with the serum concentrations of calcium (P less than 0.02) and phosphate (P = 0.055) (multiple R = 0.638, P less than 0.002). 4. In primary hyperparathyroidism the major determinant of serum 1,25-dihydroxyvitamin D is the availability of precursor 25-hydroxyvitamin D. 5. The finding that serum 1,25-dihydroxyvitamin D is commonly normal in patients with primary hyperparathyroidism despite an adequate state of vitamin D nutrition, can be explained in terms of the constraining influences of hypercalcaemia and variable degrees of renal dysfunction on the biosynthesis of 1,25-dihydroxyvitamin D.

The mechanism of malignant tumor induction by nickel subsulfide.

Experiments were performed to study the earliest changes and their sequence in the development of malignant tumors following implantation of 10 mg of nickel subsulfide (Ni3S2) into the right quadriceps muscle of seven male Fischer rats. Biopsies were performed when nodules reached one to three mm, and, later, when they were five to seven mm, and, finally, at sacrifice, to confirm the fully developed tumor pattern. Light microscopy of the earliest samples showed groups of cells clumped and scattered among degenerating muscle fibers. Mitoses were seen and inflammatory cells were not a feature. Electron microscopy showed individual degenerating muscle fibers, but also cells with characteristic features of myofibroblasts. In many cells osmium, dense fragments suggestive of crystalline material, were seen in the cytoplasm and nuclei. In the second set of biopsy material, myofibroblasts with well defined and dilated rough endoplasmic reticulum, intracellular membrane-bound collagen, and microfilaments with focal "dense bodies" were numerous. Mitoses were frequent. Immunohistochemistry showed strongly positive reaction to Vimentin and muscle-specific Actin in the tumor cells. In the fully developed tumors, the previously described typical storiform cell pattern with spindle and spheroidal cells with frequent mitoses was seen. Vimentin and muscle-specific Actin stains were strongly positive. The long latent period, the evidence of cell degeneration, necrosis, foreign material (probably of nickel composition), cell invasion, and subsequent rapid myofibroblast-type cell development, proliferating to malignant tumors highly suggestive of malignant fibrous histiocytoma, seem to suggest an epigenetic form of carcinogenicity of cytotoxic variety. Whether the tumor cells derive from transformed myofibrils or from activated pluripotential mesenchymal cells, or from both, remains in doubt.

Antigen localization in immunoperoxidase-stained plastic-embedded soft tissues.

Immunoperoxidase stains were performed on normal and neoplastic tissue from prostate, colon, thyroid, lung, nerve, uterus, and placenta embedded in both plastic (glycolmethacrylate [GMA]) and paraffin. Positive results in plastic section were obtained for carcinoembryonic antigen (CEA), keratin, epithelial membrane antigen (EMA), thyroglobulins, S-100, prostate-specific antigen, human chorionic gonadotrophin (HCG), and beta-HCG. More delicate staining with more precise localization of antigens is noted. Superior (paraformaldehyde) fixation and cold processing followed by GMA polymerization (4 degrees C) allow for optimum antigen survival. After fixation, tissue processing involves a series of 0.1 mol/L phosphate buffer rinses with sucrose and ammonium chloride in a conventional dip-and-dunk processor placed in a 4 degrees C cold room. Acetone dehydrations are used before GMA infiltration, cold polymerization, and sectioning. Before immunoperoxidase staining, the plastic section is digested in .25% bovine trypsin for ten minutes. The immunoperoxidase methods described can be useful when small biopsies are routinely embedded in plastic to obtain improved histologic (hematoxylin-eosin) sections. There may also be research applications in quantifying antigen expression in benign, dysplastic, and neoplastic tissues by examining the stains under high power.

An evaluation of urologist-operated ultrasound and its use in the urological out-patient clinic.

The value of urologist-operated real time ultrasound scanning was assessed in the urological out-patient clinic. In terms of accuracy, the urologists' ultrasound scans of the genito-urinary tract proved comparable with those of the radiologists. The techniques were quickly learned and scanning added little to the consultation time. Scanning during clinic time was shown to be both time-saving and cost-effective by allowing more rapid assessment of the patient and a speedier diagnosis. In economic terms considerable savings could be made by reducing the need for formal ultrasound referrals, since patients scanned at the out-patient clinic would be spared two further trips to hospital, one for the formal examination and another for the out-patient clinic review. Clinic turnover thus becomes more efficient and inconvenience to the patient and transport costs are lessened.

Fat embolism to the cardiac conduction system associated with sudden death.

During a brief hospital stay, a patient under treatment with corticosteroids for lymphoma died suddenly and unexpectedly. At autopsy, fat emboli were identified in the lungs, myocardium, liver, and brain. Examination of the cardiac conduction system revealed fat emboli in the vessels of the bundle of His as well as those accompanying the bundle branches, a finding believed to have resulted in the sudden death. This report is the first of fat embolization to the cardiac conduction system and emphasizes the importance of examination of this system in cases of unexplained or sudden death.

Metabolic inactivation of vitamin D is enhanced in primary hyperparathyroidism.

1. The elimination half-time of 25-hydroxyvitamin D in plasma was estimated after intravenous injection of the radioactively labelled metabolite in seven patients with primary hyperparathyroidism before and after excision of a parathyroid adenoma. 2. The elimination half-time of 25-hydroxyvitamin D was significantly shortened in primary hyperparathyroidism and reverted towards normal after parathyroidectomy. 3. The increased metabolic clearance of 25-hydroxyvitamin D in primary hyperparathyroidism was accounted for by an increased excretion of vitamin D-derived inactivation products in the faeces. 4. Enhanced hepatic inactivation of 25-hydroxyvitamin D may be important in the development of vitamin D deficiency in primary hyperparathyroidism.

The problems of environmental hazardous substances: an overview.

It was decided to present an overview of problems of environmental hazardous substances by selecting three areas of concern which represent different aspects of the overall subject. All three are topics of great interest at the present time. They provide examples of different causes of the hazards and different approaches to their resolution or containment. Aerial and water contamination by radon gas are a natural hazard only recently recognized. Radon can be contained, but it will require cooperative action and expenditure. Herbicides are a continuing problem demanding increased research activity to establish risk-benefit decisions. Pollution of estuaries and oceans require new development of models for establishing safe levels of some pollutants and prohibition of others.

Histogenesis of subcutaneous malignant tumors resulting from nickel subsulfide implantation.

Tumors are described which have been produced by subcutaneous (s.c.) implantation of nickel subsulfide (Ni3S2) in 00 gelatin capsules in the left axillary region of Fischer 344 rats. This is in contradistinction to previous accounts where intramuscular (i.m.) or, in a few cases, subcapsular testicular implantation sites have been used. The advantages of the s.c. route are discussed, including the removal of the difficulties of distinguishing degenerating and regenerating striated muscle cells from tumor cells. The s.c. induced tumors were transplanted as far as the F6 generation, in some cases. Cells from tumor transplanted as far as the F3 generation were grown in tissue culture and then reimplanted s.c. Cytology of the tumors remained remarkably constant in all tumors, even after serial transplants and culture. A characteristic storiform pattern, with two major cell types -myofibroblasts and histiocyte-like cells, was seen. The question of pluripotential cell origin is discussed. The striking similarity of appearance to human malignant fibrous histiocytoma is noted; however, in view of the somewhat controversial origin of the human tumor, the simple designation, "nickel-induced malignant tumor of pluripotential origin", is preferred. The use of this model with its demonstrated ability to reproduce characteristic appearances seems to be valuable for the study of soft tissue sarcomas.