Biomedical subjects
Publications and source records attributed to M P Whyte.
Five of 6 patients with lytic Paget bone disease treated with daily doses of synthetic human calcitonin for more than six months showed radiologic evidence of healing and arrest of the lytic front.
To examine the effect of estrogens on circulating levels of calcium-regulating hormones, total serum calcium, ionized calcium, inorganic phosphate, immunoreactive parathyroid hormone, calcitonin, 1,25-dihydroxyvitamin D, and estradiol (E2) levels were assayed on menstrual cycle days 3 and 13 in 12 healthy young women. Despite a 3-fold increase in serum E2 levels by midcycle, no differences in the other factors were observed. Furthermore, iv infusion of calcium (3 mg/kg over a 10-min period) produced similar changes in the serum levels of immunoreactive parathyroid hormone and calcitonin on days 3 and 13 in 8 women. Our findings suggest that in normal menstruating women, endogenous increases in E2 neither directly nor indirectly stimulate 1,25-dihydroxyvitamin D production, nor do they affect circulating levels of the hormones known to influence calcium homeostasis in man.
To clarify the role of alkaline phosphatase (ALP) and ATPase in skeletal mineralization, we studied the effect of the anthelmintic drug, l-tetramisole (levamisole), a stereospecific inhibitor of ALP activity, and its inactive isomer, d-tetramisole (dexamisole), on in vitro calcification of rachitic rat cartilage. ALP activity in homogenized rachitic rat proximal tibiae was inhibited by l-tetramisole in a dose-dependent manner. Histochemical and electron microscopic cytochemical analysis of intact epiphyseal plate rachitic rat cartilage showed that 5 x 10(-2) M and greater concentrations of l-tetramisole (1) virtually abolished ALP activity, (2) moderately reduced ATPase activity, and (3) prevented in vitro cartilage calcification, while preserving the structural integrity of the matrix vesicles. Concentrations of d-tetramisole as high as 1 x 10(-1) M failed to inhibit ALP activity in tibial homogenates by more than 10 per cent and did not alter histochemical staining of enzyme activity or calcification in intact cartilage slices. Heating the cartilage slices destroyed ALP activity, prevented calcification, and disrupted matrix vesicle integrity. These data show that there is a close association between ALP activity and in vitro calcification of rachitic rat cartilage. In the absence of ALP activity, intact matrix vesicles do not promote calcification. Our data also suggest that some ATPase activity of rachitic rat cartilage may be distinct from ALP activity.
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We used heat inactivation, L-phenylalanine inhibition, and electrophoresis on polyacrylamide gel and cellulose acetate membranes--with and without use of specific antisera against the liver-bone, intestinal, and placental isoenzymes--to distinguish and quantitate the different alkaline phosphatase isoenzymes in sera from 23 adult members of a kindred affected by the adult form of hypophosphatasia. Nine subjects had values for total activity more than two standard deviations below the mean values for age- and sex-matched normal persons. Bone isoenzyme was diminished in all nine, whereas liver isoenzyme was subnormal in only four. Phosphoethanolamine and phosphoserine in the urine of eight hypophosphatasemic individuals correlated inversely with both total and liver alkaline phosphatase activity in their serum, but not with the activity of the bone isoenzyme. Total activity in the serum of adult kindred members correlated best with the circulating liver isoenzyme activity. The findings suggest that altered hepatic metabolism is responsible for the increased urinary excretion of phosphoethanolamine, and perhaps phosphoserine, in hypophosphatasia.
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Bioavailability of vitamin D (D) was assessed by competitive protein-binding assay of serum 25-hydroxyvitamin D (25OHD) levels in normal adult volunteers after a single oral, sc, or im dose of commercially available D pharmaceuticals or after a single iv injection of ethanol-propylene glycol solution containing D. Similar increases in serum 25OHD levels were noted after either iv D2 or D3 (100 micrograms/kg), suggesting that the 25-hydroxylation of D2 and D3 is comparable in man. Absolute increases in serum 25OHD levels were similar in subjects receiving D in iv doses of 100 and 250 micrograms/kg; however, subjects receiving the larger dose had higher basal 25OHD levels. This finding suggests an inverse relationship in man between basal serum 25OHD concentrations and relative serum 25OHD increments after administration of pharmacological doses of D. Oil depot sc and im injection of D (200 micrograms/kg) resulted in delayed serum 25OHD increases compared to oral and iv dosing (100 micrograms/kg). Studies after im oil depot injection of [3H]D3 into rats showed that D administered in this manner had delayed bioavailability but remained unaltered in situ. Differences in D pharmaceutical bioavailability should be considered in treatment or prophylaxis with this sterol.
Investigation of the kindred of a 58-year-old woman with all of the features of "adult" hypophosphatasia revealed 12 individuals in 3 generations with subnormal circulating total alkaline phosphatase (AP) activity. The pattern of inheritance suggested autosomal dominant transmission, with incomplete penetrance of the trait particularly in the young males. Hypophosphatasic individuals other than the proposita were clinically well but had loss of permanent teeth, showing that dental abnormalities could be the only clinical manifestation of the disorder. Radiographic investigation of the proposita revealed that completion of stress fractures was necessary for healing; maturation of incomplete fractures resulted in stable Looser zones. Skeletal survey and radionuclide bone imaging were unremarkable in hypophosphatasic individuals without fracture. Subclinical osteopenia was found in several affected women by metacarpal cortical width and bone densitometric measurements. Laboratory studies showed increased plasma and urinary phosphoethanolamine levels in affected individuals. Phosphoethanolamine and phosphoserine appeared to be natural subtrates for AP since a negative correlation existed between each substrate and circulating total AP activity. Phosphoethanolamine and phosphoserine levels were greatest in the clinically affected proposita; furthermore, only she showed absence of leukocyte AP activity. Heat fractionation of her total circulating AP activity suggested severe reduction in the bone isoenzyme. Hypophosphatasic children had higher levels of total circulating AP than affected adults; the increase was apparently secondary to increased bone isoenzyme. Iliac crest bone biopsies showed greater abnormality in affected women. Osteoidosis was particularly pronounced in the proposita's younger affected sister and hypophosphatasic daughter. Histomorphometric analyses of the biopsies revealed a paucity of osteoblasts despite increased quantities of unmineralized matrix. The finding that hypophosphatasic children in this kindred had higher circulating total AP activity than adults and were able to model their skeleton normally, together with observations that the bone biopsy in adults had a paucity of osteoblasts, suggests that some factor(s) during growth is able to induce both AP activity and osteoblast function, or, that this disorder is an "abiotrophy" with deficient osteoblastic formation and/or accelerated destruction in adult life.
A 22-year-old woman had polyostotic fibrous dysplasia (POFD) and idiopathic hypothalamic hypogonadotropic hypogonadism (isolated gonadotropin deficiency). Recurrent fracture of dysplastic bone during childhood was associated with primary amenorrhea, clinical and laboratory evidence of estrogen deficiency, and subnormal circulating and urinary gonadotropin levels during adolescence. Gonadorelin (luteinizing hormone-releasing hormone) stimulation initially showed a luteinizing hormone (LH) response but absent follicle-stimulating hormone (FSH) response. After three months without estrogen and progesterone and after four days of gonadorelin "priming," a subsequent gonadorelin infusion produced an enhanced LH and FSH response. All other tests of peripheral and trophic hormone levels and pituitary trophic hormone reserves were normal. Whereas POFD is known to occur with sexual precocity and other endocrinopathies, to our knowledge this is the first report of its association with isolated gonadotropin deficiency.
Genetic, rheumatologic, immunologic, metabolic, and renal studies of a father and son with idiopathic multicentric osteolysis are reported. The disorder appeared through mutation. The father developed symptoms as an infant, his son at age 4 years and 9 months. Both have micrognathia and hypotelorism and were exceptionally tall during the symptomatic phase of their disease. Biopsies of the son's wrist showed normal synovium, encroachment on cartilage by fibrocellular tissue, and both osteoclastic resorption and repair of affected bone. Hydroxyproline in his urine was increased. No immunologic, renal, or other metabolic abnormalities were identified.
Angiokeratoma, a vascular dermatosis, is currently recognized as having six clinical presentations. A woman with extensive skin lesions compatible with the clinical diagnosis of angioma serpiginosum was found to have biopsy changes consistent with angiokeratoma. Her case emphasizes the histologic similarities between these entities and suggests an additional clinical presentation for angiokeratoma--angiokeratoma serpiginosum.
Technetium-99m pyrophosphate bone images were contrasted with radiographic findings in two patients with osteopoikilosis, one with osteopathia striata, and one with melorheostosis. Despite the striking radiographic findings, scans were normal in osteopoikilosis and osteopathia striata. In melorheostosis, focal increased radiopharmaceutical accumulation appeared in each radiographically abnormal area. Technetium-99m pyrophosphate bone images should prove helpful when superimposed osseous disease must be differentiated from osteopoikilosis, osteopathia striata, or melorheostosis.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
Four members of a family with an autosomal dominant form of cerebellar degeneration all had slow eye-movements, i.e. slow pursuit with absence of both nystagmus and rapid saccadic movements. Three showed progressive mental deterioration. One patient had nevus of Ota (oculodermal melanocytosis) and a history of grand mal epilepsy. In these four patients the symptoms first occurred between the ages of 10 and 31 years--the onset apparently appearing earlier with successive generations. Current studies implicate a brain-stem lesion of the paramedian pontine reticular formation in the pathogenesis of the oculomotor abnormality. The possibility of a neurocutaneous syndrome, specifically a 'melanophakomatosis', in the patient with seizures and nevus of Ota is discussed; however, absence of these findings in other affected relatives makes a fortuitous association more probable. The literature on nevus of Ota associated with neurological disease is considered.
Osteoporosis is characterized by low bone density, and osteopenia is responsible for 1.5 million fractures in the United States annually. In order to identify regions of the genome which are likely to contain genes predisposing to osteopenia, we genotyped 149 members of seven large pedigrees having recurrence of low bone mineral density (BMD) with 330 DNA markers spread throughout the autosomal genome. Linkage analysis for this quantitative trait was carried out using spine and hip BMD values by the classical lod-score method using a genetic model with parameters estimated from the seven families. In addition, non-parametric analysis was performed using the traditional Haseman-Elston approach in 74 independent sib pairs from the same pedigrees. The maximum lod score obtained by parametric analysis in all families combined was +2.08 (theta = 0.05) for the marker CD3D on chromosome 11q. All other combined lod scores from the parametric analysis were less than +1.90, the threshold for suggestive linkage. Non-parametric analysis suggested linkage of low BMD to chromosomes 1p36 (Zmax = +3.51 for D1S450) and 2p23-24 (Zmax = +2.07 for D2S149). Maximum multi-point lod scores for these regions were +2.29 and +2.25, respectively. A third region with associated lod scores above the threshold of suggestive linkage in both single-point and multi-point non-parametric analysis was on chromosome 4qter (Zmax = +2.95 for D4S1539 and Zmax = +2.48 for D4S1554). Our data suggest the existence of multiple genes involved in controlling spine and hip BMD, and indicate several candidate regions for further screening in this and other independent samples.
Audiometric tests were conducted on 19 subjects with hypophosphatemic bone disease to investigate whether auditory impairment like that reported in affected adults occurs in young patients. No hearing loss or significant auditory findings were noted among the children or young adult patients. However, sensorineural hearing loss of cochlear origin was identified in the three oldest subjects (40 to 58 years), although a history of noise exposure in two of them could explain the observations. The results indicate that if an association exists between hypophosphatemic bone disease and hearing impairment, the auditory signs will not develop until adulthood in treated patients. Additional studies of large populations of affected adults are needed to identify the incidence and mechanism(s) of the auditory system abnormalities and to assess any effect of medical therapy for the metabolic bone disease.