Differences in the stability of intact osteocalcin in serum, lithium heparin plasma and EDTA plasma.
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Anticoagulants↗
Biomedical subjects
W D Fraser
Publications and source records attributed to W D Fraser.
Effect of glycoprotein and protein hormones on human meningioma cell proliferation in vitro.
Speculation that meningiomas are subject to female hormone influence is supported by their higher incidence in women and reports of exacerbation of symptoms during pregnancy and the luteal phase of the menstrual cycle. Previous reports have concentrated on the effects of the steroid hormones oestradiol and progesterone on meningioma proliferation. In this study we have investigated the roles of the glycoproteins LH, FSH and human chorionic gonadotrophin (hCG), and the protein hormones prolactin (PRL) and human placental lactogen (hPL) on the proliferation of human meningiomas in vitro. The three glycoproteins had an inhibitory effect on meningioma proliferation ranging from 5.0-50.0%, 10.0-63.0% and 2.4-34.0% at the highest concentrations of LH (25 mIU/ml), FSH (15 mIU/ml) and hCG (30 IU/ml) respectively. Cultures were also treated with PRL (100 and 200 ng/ml) and hPL (5 and 10 ng/ml) and the protein hormones had a stimulatory effect on cell proliferation of 12.0-55.5% and 11.4-73.6% when treated with 200 ng/ml PRL and 10 micrograms/ml hPL respectively. Our data suggest that increasing levels of the protein hormones PRL and hPL, falling levels of hCG and the absence of LH and FSH in the second and third trimesters of pregnancy may play a role in the acceleration of meningioma growth in these stages of pregnancy.
Adult↗
Interleukin-6 (IL-6) production and cell growth of cultured human ameningiomas:-interactions with interleukin-1 beta (IL-1 beta) and interleukin-4 (IL-4) in vitro.
We examined the production of interleukin (IL)-6 by human meningioma cells in vitro, and the effects of IL-1 beta and IL-4 on IL-6 production and meningioma cell growth. The histological classification of the tumours studied included transitional, syncytial, fibroblastic and atypical. All 10 meningiomas studied produced IL-6 (range 0.22-7.6 ng/ml/10(6) cells/24 h). Separate addition of IL-1 beta or IL-4 to cultures increased IL-6 production up to ten fold, and two to three fold, respectively. Growth studies with IL-6 indicated that this cytokine significantly increased terminal cell density at a concentration greater than 1 ng/ml in 60% of the meningioma cultures studied. IL-1 beta caused a significant decrease in the terminal cell density in 25% of the meningioma cultures studied whereas IL-4 had a tendency to significantly inhibit growth in 16.6% of the cultures. These data suggest that IL-6 production by meningiomas can be modified by other cytokines and secondly, that IL-6, IL-1 beta and IL-4 can modify growth in vitro and may act as autocrine factors in vivo. By further determining the cytokine profiles within meningiomas and their effects, a better understanding of meningioma growth characteristics may be obtained.
Cell Division↗
Absence of paramyxovirus RNA in cultures of pagetic bone cells and in pagetic bone.
It has been proposed that Paget's disease of bone is caused by the infection of bone cells with one or several paramyxoviruses. In this study we used the polymerase chain reaction (PCR), which allows the detection of very low levels of a target nucleic acid sequence, to study cultures of pagetic bone cells and samples of pagetic bone. Oligonucleotide primers were designed to flank a sequence of the nucleocapsid genome of measles virus and canine distemper virus (CDV). Within this fragment there were contrasting restriction endonuclease sites specific to measles or CDV that allowed identification of the original template. We were unable to detect paramyxovirus RNA in four strains of human bone cells outgrown from pagetic bone and one strain derived from an uninvolved site of a patient with Paget's disease. Furthermore, paramyxovirus sequences were not detected in cDNA prepared from six samples of pagetic bone biopsies. The work presented here further questions the role of measles and CDV in the abnormal remodeling observed in Paget's disease.
Aged↗
Primary cultures of human bone-derived cells produce parathyroid hormone-related protein: a study of 40 patients of varying age and pathology.
Parathyroid hormone-related protein (PTHrP), a mediator of hypercalcemia of malignancy, has been detected in many tumours and in some normal foetal and adult tissues. PTHrP has potent effects on bone turnover in vivo and in vitro. In this study we cultured cells derived from explants of bone obtained from 40 subjects (age range 2-88 years). Immunoreactive PTHrP (iPTHrP) was detected by immunoradiometric assay (IRMA) in conditioned medium from 25 of 40 cultures of bone-derived cells. PTHrP mRNA was detected in bone-derived cells by reverse transcriptase-linked polymerase chain reaction (RT-PCR). The identity of PCR products was confirmed by Southern blotting. Local production of PTHrP in vivo may be important in the regulation of bone growth and remodelling.
Adolescent↗
Alteration of the circadian rhythm of intact parathyroid hormone following a 96-hour fast.
OBJECTIVE: PTH(1-84) secretion in normal male subjects follows a circadian rhythm. The control of this rhythm is multifactorial with both neuroendocrine and chemical influences. The aim of this study was to assess the effect of a 96-hour fast on the circadian rhythm of PTH(1-84), serum calcium, phosphate and nephrogenous cAMP (NcAMP), an index of PTH(1-84) bioactivity. DESIGN: Blood samples for estimation of all analytes were obtained over a 24-hour period at 30-minute intervals. Urine samples were obtained 4 hourly during the daytime and overnight. Each subject was studied on two occasions after being randomized to either (a) normal hospital diet or (b) a 96-hour fast with water freely available. SUBJECTS: Six healthy adult males aged between 28 and 40 years, mean 32 years. MEASUREMENTS: PTH(1-84) was measured by an in-house immunoradiometric assay. Serum calcium, phosphate, albumin, creatinine and urinary creatinine were measured by standard automated techniques. Calcium was adjusted for albumin. Plasma cAMP was estimated by a commercial method and urine cAMP by in-house radioimmunoassay and NcAMP obtained by calculation. Rhythm parameters were analysed by cosinor techniques. RESULTS: There were alterations in the circadian rhythms of serum phosphate, PTH(1-84) and NcAMP following a 96-hour fast. Fasting abolished the nocturnal rise in phosphate, PTH(1-84) and NcAMP but had little effect on the pattern of adjusted calcium over a 24-hour period. The mean concentrations of serum phosphate, adjusted calcium and NcAMP decreased significantly following the fast and mean PTH(1-84) increased during day time. CONCLUSIONS: Fasting for 96 hours significantly alters the circadian rhythm of PTH(1-84) secretion by lowering the mean calcium concentration and attenuating the circadian rhythm of serum phosphate.
Adult↗
Osteopenia in cerebral palsy.
The bone mineral density of the lumbar spine was assessed in nine non-ambulant children with cerebral palsy combined with measurements of serum 25-hydroxyvitamin D, parathyroid hormone, and urinary calcium excretion. Three children with recurrent fractures received treatment with bisphosphonates for periods ranging from 12-18 months. All the children demonstrated a severe reduction in bone mineral density even when allowance was made for their body weight. There were no consistent abnormalities of vitamin D or parathyroid hormone status. Three children had gross hypercalciuria. Each of the children treated with bisphosphonates demonstrated an increment in bone density ranging from 20-40% with no apparent adverse effects.
25-Hydroxyvitamin D 2↗
Parental origin of Gs alpha gene mutations in Albright's hereditary osteodystrophy.
Heterozygous mutations of the Gs alpha gene leading to reduced Gs alpha activity have been identified in patients with Albright's hereditary osteodystrophy (AHO). However, AHO may be associated with hormone resistance (pseudohypoparathyroidism type Ia, PHPIa) or a normal response (pseudo-pseudohypoparathyroidism, PPHP). As both disorders may occur within the same family, the relationship between Gs alpha genotype and phenotype remains unresolved. The AHO phenotype may be dependent upon the sex of the parent transmitting the Gs alpha mutation, perhaps through a gene imprinting mechanism. We have used an intragenic Gs alpha FokI polymorphism to determine the parental origin of Gs alpha gene mutations in sporadic and familial AHO. We now show that a de novo G-->A substitution at the exon 5 donor splice junction in a child with PPHP was paternally derived. Furthermore, in a female with PPHP, the Gs alpha abnormality was shown to be of paternal origin, while subsequent maternal processing and transmission resulted in PHPIa in two offspring. As transmission of PPHP has rarely been reported, determining parental origin of the disease allele in sporadic cases may provide insight into the mechanism of hormone resistance in AHO.
Adult↗
Acute effects of intravenous 1 alpha-hydroxycholecalciferol on parathyroid hormone, osteocalcin and calcitriol in man.
The acute effects of a single intravenous injection of 2 micrograms of 1 alpha-hydroxycholecalciferol (alfacalcidol) were studied for a 24-h period in six normal males (mean age 33 years), six women with primary hyperparathyroidism (mean age 72 years) and six women with established osteoporosis (mean age 63 years). In all three groups, serum calcitriol levels rose to a peak 2-3 h after administration of alfacalcidol. Basal levels were highest in the primary hyperparathyroidism group at (mean +/- SEM) 81 +/- 2 vs 62 +/- 12 (normal males) (p < 0.05) and 56 +/- 5 pmol/l (osteoporosis) (p < 0.01). Highest peak levels were found also in the primary hyperparathyroidism group at 150 +/- 15 vs 114 +/- 15 (normal males) (p < 0.05) and 127 +/- 15 pmol/l (osteoporosis) (p < 0.01). The rise in calcitriol was higher in the primary hyperparathyroidism group than either the normal males or osteoporotic patients (p < 0.05). No significant differences were evident in basal serum calcidiol concentrations among the three treatment groups. As might be expected, highest basal concentrations of parathyroid hormone (PTH), serum calcium and serum osteocalcin were noted in the primary hyperparathyroid group (PTH: 17.1 +/- 7.7 vs 1.9 +/- 0.5 (normal males) (p < 0.01) and 2.1 +/- 0.3 pmol/l (osteoporosis) (p < 0.01); calcium: 3.06 +/- 0.08 vs 2.50 +/- 0.02 (normal males) (p < 0.01) and 2.43 +/- 0.02 mmol/l (osteoporosis) (p < 0.01); osteocalcin: 1.10 +/- 0.08 vs 0.56 +/- 0.16 (normal males) (p < 0.05) and 0.53 +/- 0.21 nmol/l (osteoporosis) (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Changes in calciotrophic hormones and biochemical markers of bone turnover in normal human pregnancy.
Plasma concentrations of parathyroid hormone-related protein (PTHrP), parathyroid hormone, alkaline phosphatase, osteocalcin and albumin-adjusted calcium were measured along with nephrogenous cyclic adenosine monophosphate (NcAMP) in 10 normal women longitudinally through pregnancy. In addition, an assessment of bone resorption was made in these same subjects by the measurement in true fasting urine specimens of the calcium/creatinine ratio (Ca/Cr), hydroxyproline/creatinine ratio (HP/Cr), pyridinoline/creatinine ratio (Pyr/Cr) and deoxypyridinoline/creatine ratio (Dpyr/Cr). The PTHrP level rose through pregnancy from (mean +/- SEM) 0.8 +/- 0.2 pmol/l in the first trimester to 2.7 +/- 0.2 pmol/l 6 weeks postpartum (p < 0.0001). Serum alkaline phosphatase rose from 94 +/- 8 U/l (first trimester) to 347 +/- 25 U/l at term (p < 0.0001). A significant positive correlation was evident between PTHrP and alkaline phosphatase up to term (r = 0.44, p < 0.005). Parathyroid hormone concentrations remained unchanged during pregnancy but rose significantly postpartum from 1.8 +/- 0.2 pmol/l (first trimester) to 3.1 +/- 0.5 pmol/l (p < 0.0001). Similarly, osteocalcin, a marker of bone formative activity, remained unchanged through pregnancy but rose significantly at 6 weeks after delivery to 0.38 +/- 0.05 nmol/l from 0.19 +/- 0.03 nmol/l (first trimester) (p = 0.019). No significant change was noted in serum-adjusted calcium or NcAMP, either through pregnancy or at the postpartum assessment. Fasting urinary Ca/Cr fell through pregnancy from 0.70 +/- 0.11 (first trimester) to a nadir of 0.19 +/- 0.04 6 weeks postpartum (p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Performance during mild acute hypoxia.
The controversy regarding the effects of mild hypoxia on learning performance needs to be resolved, since this may be affecting flight operations and safety. This study examined the ability to learn new tasks at low altitudes. Naive subjects (n = 144) performed spatial orientation (Manikin), serial choice reaction time (SCRT) and logical reasoning (Baddeley) tasks at ground level and at altitudes of 1,524 m (5,000 ft), 2,438 m (8,000 ft), 3,048 m (10,000 ft), and 3,658 m (12,000 ft), at rest or during exercise (VO2 = 600 ml O2.min-1) in a hypobaric chamber. Each task was performed over four serial repetitions (blocks) and presented at ground level or one of the four test altitudes in a first session, and in the reverse order in a second session. Performance for the Manikin and SCRT tasks improved significantly (p < 0.0001) over the 4 blocks. No significant difference was found between the corresponding 4 blocks of the first session in resting and exercising subjects tested at ground level before altitude compared to altitude before ground level. In general, RT for the 3 tasks were faster in resting than in exercising subjects. These results indicate that the ability to learn new tasks is not impaired by mild hypoxia at altitudes of up to 3,658 m. We detected a biphasic response to altitude in LRT and SCRT performance, but not for Manikin performance.
Acute Disease↗
Cardiovascular responses with standard and extended bladder coverage G-suits during rapid decompression.
This study compared the cardiovascular responses of subjects exposed to 60,000 ft. rapid decompressions while wearing the Combined Advanced Technology Enhanced Design "G" Ensemble (COMBAT EDGE or CE) and the Tactical Life Support System (TLSS). Eight subjects were rapidly decompressed from 22,500 ft (6,858 m) to 60,000 ft (18,288 m), once wearing the CE ensemble and once wearing the TLSS ensemble. There were significant differences in heart rate, stroke volume, cardiac index, and mean arterial pressure (p < 0.0001), due to garment type, with TLSS providing better cardiovascular support. Oxygen saturation did not decrease to the same degree with CE as with TLSS (p < 0.0001). Both TLSS and CE provided sufficient physiological support to maintain oxygen saturations above 65% during the 3-min exposures to 60,000 ft altitude. Short-term physiological support at higher altitudes with greater PPB levels or longer duration excursions at 60,000 ft may not be possible without the greater G-suit bladder coverage and cardiovascular support provided by TLSS-type garments.
Adult↗
Association of severe haemophilia A with osteoporosis: a densitometric and biochemical study.
Following a femoral neck fracture and vertebral compression fractures in two patients with severe haemophilia A, bone density and turnover were measured in 19 males with severe haemophilia A (all HIV negative, 18/19 hepatitis C antibody positive) and in 19 age/sex matched controls. Bone density at the lumbar spine (L2-4), measured by dual energy X-ray absorptiometry, was significantly lower in the haemophiliac patients (HPs) at (mean +/- SEM) 1.109 +/- 0.042 g/cm2 vs. 1.234 +/- 0.027 in controls; p = 0.018. Femoral neck density was also lower at 0.877 +/- 0.034 g/cm2 (HPs) vs. 1.067 +/- 0.032; p < 0.0005. No significant differences were evident between the groups for serum calcium, parathyroid hormone, luteinizing hormone, follicle-stimulating hormone or 1,25 dihydroxyvitamin D3, nor for fasting urinary hydroxyproline, pyridinoline or deoxypyridinoline excretion. Serum total alkaline phosphatases was elevated in HPs at 200 +/- 10 U/l vs. 158 +/- 8; p = 0.004. Similarly, gamma-glutamyl transferase was elevated at 42 +/- 7 U/l (HPs) vs. 20 +/- 2; p = 0.007. Serum total testosterone and sex-hormone-binding globulin (SHBG) were higher in HPs at 26 +/- 2.5 nmol/l vs. 17.4 +/- 1.6 (p = 0.009) and 56 +/- 6 nmol/l vs. 27 +/- 3 (p = 0.0005), respectively. Free androgen index, however, was lower in HPs at 44 +/- 5 vs 69 +/- 7; p = 0.008. These results suggest significant osteopenia associated with haemophilia A. This may be partly due to liver dysfunction in HPs, but other factors, e.g. relative immobilization, may also be relevant.
Absorptiometry, Photon↗
Improved sensitivity and precision of thyroid-stimulating hormone measurements by standardizing signal reagent addition in the Amerlite TSH 30 assay.
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Humans↗
Effect of early amniotomy on the risk of dystocia in nulliparous women. The Canadian Early Amniotomy Study Group.
BACKGROUND: Early amniotomy has been advocated as a means of preventing dystocia, but its efficacy has not been studied prospectively. The purpose of this multicenter study was to determine whether routine early amniotomy reduces the risk of dystocia for nulliparous women in spontaneous labor. METHODS: We studied 925 nulliparous women in labor, who were stratified according to the degree of cervical dilatation (< 3 cm vs. > or = 3 cm) and randomly assigned to either early rupture of the membranes (amniotomy group) or conservative management of labor (conservative-management group). Dystocia was defined as a period of at least four hours after dilatation of the cervix to 3 cm had been reached during which the mean rate of cervical dilatation was less than 0.5 cm per hour. RESULTS: Dystocia was significantly less frequent in the amniotomy group than in the conservative-management group (34 percent vs. 45 percent; relative risk, 0.8; 95 percent confidence interval, 0.6 to 0.9). The median length of time from randomization to full dilatation was 136 minutes shorter in the amniotomy group, and there was a trend toward less frequent use of oxytocin among the women assigned to amniotomy (36 percent vs. 41 percent; relative risk, 0.9; 95 percent confidence interval, 0.8 to 1.0). In a stratified analysis, the frequency of dystocia associated with amniotomy was reduced only among women with > or = 3 cm initial dilatation. The cesarean-section rate was similar in the two groups (amniotomy, 12 percent; conservative management, 11 percent). There were no statistically significant differences in outcome between the infants delivered by the women in the two groups; the measures of an adverse outcome included admission to a neonatal intensive care unit, five-minute Apgar score below 7, and arterial cord-blood pH below 7.2. CONCLUSIONS: Early amniotomy is an effective method of shortening the duration of labor and reducing the frequency of dystocia among nulliparous women in labor, but it does not lower the rate of cesarean section.
Adult↗
PCR detection of cytokines in normal human and pagetic osteoblast-like cells.
We investigated the expression of cytokine transcripts in osteoblast-like cells derived from explants of pagetic and normal bone. A reverse transcription-linked PCR was used that allowed the simultaneous analysis of a range of cytokines. Normal osteoblast-like cells were found to contain the transcripts for IL-1 beta, IL-6, and TGF-beta 1. For the first time we detected in bone cells the two other mammalian isoforms of TGF-beta, beta 2, and beta 3. Furthermore, we have also identified mRNA for IL-3 and the novel chemotactic factor, IL-8. Using this sensitive technique it was not possible to detect mRNA for IL-1 alpha, IL-2, IL-4, IL-5, IL-7, TNF-alpha, or interferon-gamma. The human osteosarcoma cell line Saos-2 also showed a similar pattern of expression of these cytokines to primary osteoblast-like cells, with the exception that TNF-alpha was also identified. Cells isolated from pagetic bone showed essentially the same profile of cytokine expression as normal bone except that TNF-alpha was also detected in two of four samples. The cytokine profile of successive populations of cells harvested from one explant culture at 9, 22, and 57 days showed a consistent pattern of cytokine expression, demonstrating the phenotypic stability of the osteoblast-like cells in long-term cultures.
Base Sequence↗
Coincidental occurrence of primary hyperparathyroidism and cancer-associated hypercalcaemia in a middle-aged man.
Primary hyperparathyroidism (PHPT) is found not uncommonly in patients with cancer. In this report, however, we describe a patient where both humoral hypercalcaemia of malignancy and PHPT were present coincidentally. A 47-year-old man was found to have PHPT due to parathyroid hyperplasia. Serum parathyroid hormone (PTH) levels, which were elevated before parathyroidectomy, were undetectable post-operatively; however, hypercalcaemia persisted. Nephrogenous cyclic adenosine monophosphate was elevated along with this undetectable PTH, indicative of the presence of a PTH-like factor in the serum. This was confirmed by the finding of an elevated level of PTH-related protein (PTHrP) in plasma (9.1 pmol/l, normal < 2.6 pmol/l). Secondary carcinoma was identified in a lesion in the region of the manubrium sternii. This stained positively for PTHrP by immunocytochemistry and PTHrP messenger RNA was detected by in-situ hybridization. This case illustrates the value of sensitive PTH assays in distinguishing PHPT from other causes of hypercalcaemia and also shows the importance of considering primary hyperparathyroidism in the differential diagnosis of the patient with cancer and hypercalcaemia.
Bone Neoplasms↗
Hypercalcaemia due to parathyroid hormone-related protein: long-term circulating levels may not reflect tumour activity.
Parathyroid hormone-related protein is responsible for the hypercalcaemia caused by many tumours. Measurement of parathyroid hormone-related protein is becoming more accessible with the introduction of commercial assays. We report a case of hypercalcaemia of malignancy secondary to parathyroid hormone-related protein in a woman with renal carcinoma. The parathyroid hormone-related protein was assayed using a new immunoradiometric assay. We demonstrated an initial fall in parathyroid hormone-related protein and calcium levels after surgery and a rise in both before clinical relapse. However, the clinical relapse was itself associated with a fall in serum parathyroid hormone-related protein, nephrogenous cAMP and calcium, suggesting that the tumour had stopped producing parathyroid hormone-related protein or perhaps that post-translational processing had occurred as the tumour advanced. The tumour was investigated for parathyroid hormone-related protein mRNA content using reverse transcriptase polymerase chain reaction, both at diagnosis in surgically removed material, and using post-mortem specimens. The level of parathyroid hormone-related protein mRNA, while present, was much reduced in the recurrent tumour suggesting that active parathyroid hormone-related protein production fell substantially as the tumour advanced. This case suggests that, although demonstration of parathyroid hormone-related protein in hypercalcaemia is useful for diagnosis, tumoral secretion of this product may alter.
Adenocarcinoma, Clear Cell↗