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W D Fraser

Publications and source records attributed to W D Fraser.

At least 73 records · Page 4Linked to original sources
PubMed1999

Immunohistochemical study of parathyroid hormone-related protein in vesical transitional epithelium of patients with spinal cord injury.

INTRODUCTION: Parathyroid hormone-related protein (PTHrP), in addition to the well-established role in endochrondral bone development, is believed to be an important mediator of cellular growth and differentiation in a number of non-bony tissues. OBJECTIVES: To compare the immunohistochemical staining of vesical transitional epithelium to antibodies raised to synthetic peptides of PTHrP composed of amino acid sequences 43 - 52 and 127 - 138 in patients with spinal cord injury (SCI) and neuropathic bladder (n=14), and control patients with intact neuraxis and no history of bladder cancer (n=10). SETTING: Male SCI patients registered with Regional Spinal Injuries Centre, Southport, England. INTERVENTION: Endoscopic cold cup biopsy from the trigone of the urinary bladder was taken from patients with SCI while they were undergoing a therapeutic procedure in the urinary bladder. The control samples of bladder biopsies were taken from the archives of the Department of Histopathology, District General Hospital, Southport. Immunohistochemistry was performed using rabbit antibodies raised against synthetic peptides of human PTHrP (43 - 52) and PTHrP (127 - 138). The biopsies were examined for immunostaining of transitional epithelium. RESULTS: Of the 14 biopsies of SCI patients, positive immunostaining using antibodies to both the PTHrP peptides was found in four cases; five biopsies showed positive immunostaining only to anti-PTHrP (43 - 52); and five biopsies showed no immunostaining with either of the PTHrP peptides. In contrast, transitional epithelium in the biopsy specimens of ten control subjects with no history of bladder cancer showed no immunostaining with either of the PTHrP peptides. CONCLUSION: This study revealed that the transitional epithelium of neuropathic urinary bladder exhibits increased predilection for positive immunohistochemical staining for PTHrP (43 - 52), and to a lesser extent, to PTHrP (127 - 138), as compared to the vesical transitional epithelium of able bodied individuals with no history of vesical malignancy. The possible role of PTHrP in the cellular differentiation of urothelium of neuropathic bladder, and thereby, in the pathogenesis of cystitis in SCI patients, needs to be explored.

Humans↗
PubMed1999

Urinary excretion of pyridinium crosslinks in healthy 4-10 year olds.

Urinary pyridinoline and deoxypyridinoline, pyridinium crosslinks released during breakdown of mature collagen, might serve as useful markers of bone resorption. Before their role can be identified, reference values must be established. In this study, free pyridinoline (f-Pyr), free deoxypyridinoline (f-DPyr), and creatinine (Cr) were measured in first morning void urine samples from 250 girls and 265 boys between the ages of 4 and 10 years. Overall, there was a decrease in f-Pyr:Cr and f-DPyr:Cr ratios with increasing age in both sexes, but there was a wide range of values for individuals of similar ages. Further studies are required to assess whether urinary pyridinium crosslink excretion is sufficiently deranged in conditions affecting bone metabolism for the measurement of these compounds to be of clinical value.

Age Factors↗
PubMed1999

Severe hypercalcaemia in B-cell lymphoma: combined effects of PTH-rP, IL-6 and TNF.

Hypercalcaemia as the only manifestation of B-cell lymphoma is seen very rarely. Its pathophysiology is heterogenous and not well understood. We report a 73-year-old man who presented with severe hypercalcaemia before any signs of malignancy became evident. He was diagnosed with a B-cell lymphoma on bone marrow trephine biopsy. The hypercalcaemia was associated with high plasma concentrations of parathyroid-hormone-related protein, interleukin-6 and tumour necrosis factor. Our patient had markedly increased osteoclast and osteoblast activity as a result of synergistic effects between these factors, with consequent severe hypercalcaemia. This is the first reported example of such combined effects of these factors in humans.

Aged↗
PubMed1998

Alteration of the circadian rhythm of intact parathyroid hormone and serum phosphate in women with established postmenopausal osteoporosis.

Several studies have established that the circulating concentration of intact parathyroid hormone, PTH (1-84), over 24 h follows a circadian rhythm. The importance of this circadian rhythm is not known although some authors have detected alterations in the rhythm in metabolic bone disease and following dietary manipulation. We have studied the circadian rhythm of PTH (1-84) in 8 premenopausal women, 8 postmenopausal women with established osteoporosis and 8 postmenopausal women with no evidence of osteoporosis. Blood samples were obtained at 30-min intervals over a 24-h period and significant differences were found in the profiles of PTH (1-84) and serum phosphate in the three groups studied. Premenopausal women possessed a nocturnal/early morning increase in PTH (1-84) and phosphate (between 2200 and 0700 hours), as did postmenopausal women without osteoporosis. In postmenopausal women with osteoporosis the nocturnal increase in PTH (1-84) and serum phosphate was absent and PTH (1-84) decreased during the period 2200-0700 hours. A shift in acrophase is observed between premenopausal and postmenopausal women without osteoporosis. No acrophase was found in postmenopausal women with osteoporosis for either PTH (1-84) or serum phosphate. No circadian rhythm, acrophase or significant amplitude was observed in serum adjusted calcium or ionized calcium in any group studied. Alterations in the circadian rhythms for PTH (1-84) and serum phosphate occur in patients with postmenopausal osteoporosis that suggest that normal dynamics of PTH (1-84) secretion may play a role in both calcium and phosphate metabolism and the bone remodelling process. Whether these changes are causative or a response to the pathology will require further investigation.

Adult↗
PubMed1998

Prediction of preterm delivery by fetal fibronectin: a meta-analysis.

OBJECTIVE: To assess the cervicovaginal fetal fibronectin test to predict preterm delivery. DATA SOURCES: We searched MEDLINE, Current Contents, Index Medicus, and proceedings of meetings for studies published between 1991 and June 1997. METHODS OF STUDY SELECTION: Inclusion criteria were prospective cohort study; test performed between 20 and 36 weeks' gestation; fetal fibronectin measured by a previously described assay, with a cutoff level set at 50 ng/mL; test results not disclosed to women or physicians; and fewer than 20% of study participants excluded from the analysis. TABULATION, INTEGRATION, AND RESULTS: Twenty-nine relevant studies were stratified according to the prevalence of preterm delivery, the number of tests performed, and delivery before 34, 35, or 37 weeks. Sensitivities, specificities, and likelihood ratios were calculated in each study. The summary estimates of the likelihood ratio for tests yielding positive results or tests yielding negative results along with their 95% confidence intervals (CIs) were computed in each stratum according to a random-effects model. All summary likelihood ratios for a test yielding positive results indicated a significant association with preterm delivery. The strongest association was found between a single test with positive results and delivery before 37 weeks in a low-risk population (likelihood ratio 7.5; 95% CI 4.6, 12.3). This association also was found in high-risk women (likelihood ratio 3.5; 95% CI 2.6, 4.6). In high-risk women, a test yielding negative results was associated with a reduction in risk of preterm delivery (likelihood ratio 0.4; 95% CI 0.3, 0.5). CONCLUSION: Fetal fibronectin in cervicovaginal secretions is associated with preterm delivery in both high-risk and low-risk women.

Cervix Uteri↗
PubMed1998

Human keratinocytes express transcripts for three isoforms of parathyroid hormone-related protein (PTHrP), but not for the parathyroid hormone/PTHrP receptor: effects of 1,25(OH)2 vitamin D3.

Parathyroid hormone-related protein (PTHrP) is strongly expressed in the epidermis and has been implicated in the regulation of growth and differentiation of keratinocytes. PTHrP has N-terminal sequence homology with parathyroid hormone (PTH) and binds to the type I PTH/PTHrP receptor, but earlier reports suggest that keratinocytes do not possess this cell surface receptor. In order to determine which PTHrP mRNA isoforms are expressed by keratinocytes and whether the type I receptor mRNA is present, we designed specific primers for reverse transcriptase-polymerase chain reaction. The interaction of PTHrP with other promoters of keratinocyte differentiation is unclear. In particular, 1,25(OH)2D3 is also fundamental in calcium homeostasis and induces changes in intracellular calcium. We therefore investigated the effect of 1,25(OH)2D3 on PTHrP mRNA expression and protein production in cultured human keratinocytes. Cells were incubated for 3 days at concentrations of 1.25(OH)2D3 of 10(-10)-10(-6) mol/L. PTHrP in culture supernatant, measured by two site immunoradiometric assay, was 915 +/- 98 PTHrP fmol/mg of cell layer protein in untreated cultures decreasing to 570 +/- 113 with 10(-8) mol/L and 402 +/- 24 with 10(-6) mol/L 1,25(OH)2D3 (mean +/- SEM, P < 0.01, n = 6). Transcripts for all three PTHrP isoforms (139, 141 and 173 amino acids) were detectable in keratinocyte mRNA. Corresponding to the decrease in PTHrP protein we demonstrated a reduction in all three PTHrP mRNA transcripts after 3 days' incubation with 1,25(OH)2D3 over a concentration range 10(-10)-10(-6) mol/L. Repeated studies failed to detect type I PTH/PTHrP receptor mRNA in human keratinocytes, either in control cultures or in the presence of 1,25(OH)2D3. We have shown that keratinocytes produce abundant PTHrP and that this is modulated by 1,25(OH)2D3, suggesting a physiological role. Further studies are required to investigate the relative expression of PTHrP isoforms, their role in keratinocyte signalling and the receptors involved.

Calcifediol↗
PubMed1998

Gonadal status is an important determinant of bone density in acromegaly.

OBJECTIVE: To measure bone mineral density (BMD) in patients with acromegaly and to look for clinical features which may explain previously reported discrepant results. DESIGN: Prospective case controlled observational study. PATIENTS: 18 patients with acromegaly (seven women, 11 men; mean age 53.2 +/- 3.5 years). Eight patients had active disease and 10 had controlled acromegaly. Growth hormone and insulin-like growth factor-1 (IGF-1) concentrations were measured to assess disease activity. MEASUREMENTS: BMD was measured at four sites on the lumbar spine, three at the femoral neck and at Ward's triangle using a Hologic dexa scanner. Results were compared to a locally determined control population (n = 1800). In eight patients with active acromegaly, urinary free pyridinoline and deoxypyridinoline, and serum osteocalcin, propeptide of type 1 procollagen, vitamin D, 1000 h parathyroid hormone, bone specific alkaline phosphatase, calcium and phosphate concentrations were measured before and after 6 months treatment with octreotide. RESULTS: The mean BMD for all acromegalic patients was not significantly different from the control population except at the femoral neck where it was increased (P = 0.05). At all sites, the BMD of patients who had been hypogonadal (n = 12/18) was significantly lower (P < 0.05-0.01) than that of patients who had been eugonadal (n = 6/18). BMD for hypogonadal patients was lower than the control population at Ward's triangle (P = 0.03). Eugonadal acromegalic patients had BMD greater than non-acromegalic controls at all sites. Patients with controlled acromegaly had a higher BMD than non-acromegalic controls, but there were no differences in BMD between patients with active and controlled acromegaly. Serum IGF-1 concentrations decreased from 64.5 +/- 5.1 nmol/l to 37.5 +/- 6.9 nmol/l (P = 0.02) after 6 months treatment with octreotide, but there was no change in any of the biochemical markers of bone turnover. CONCLUSIONS: Eugonadal acromegalic patients have increased lumbar spine and femoral neck BMD compared to hypogonodal acromegalic patients and the general population, but it is reduced if patients have been hypogonadal.

Acromegaly↗
PubMed1998

Does sweeping of the membranes reduce the need for formal induction of labour? A randomised controlled trial.

OBJECTIVE: 1. To evaluate the effectiveness of sweeping of the membranes to reduce the need for a formal induction of labour; 2. to evaluate the side effects of this intervention. DESIGN: A randomised controlled clinical trial. SETTING: Three tertiary care hospitals of the province of Quebec, Canada. POPULATION: Two hundred women for whom non-urgent induction of labour was medically indicated. METHODS: Women were randomly allocated to sweeping of membranes, or vaginal examination for Bishop scoring only. MAIN OUTCOME MEASURES: 1. Cumulative incidence and relative risk of induction of labour by either oxytocin, prostaglandins or amniotomy; 2. women's discomfort and side effects attributable to sweeping of the membranes. RESULTS: Women allocated to sweeping of the membranes required formal induction of labour less frequently than women in the control group, but this difference was not statistically significant (49% vs 60%, RR 0.83, 95% CI 0.64-1.07). Pain during vaginal examination and other side effects were more frequently reported by women allocated to the sweeping group. CONCLUSIONS: The observed reduction in the need for formal induction of labour is smaller than in previous studies. Side effects and discomfort associated with sweeping of the membranes must be taken into account when counselling women who require induction of labour.

Adult↗
PubMed1998

Evidence for carbimazole as an antioxidant?

There is evidence in the literature to support the view that antioxidants are involved in the pathogenesis of Graves disease and that antioxidants may act as free radical scavengers. This study has compared the effects of a 12 month course of conventional Carbimazole therapy on peripheral blood antioxidant levels with those of a 12 month course of a higher dose treatment regime. Fifty seven patients were enrolled into the study. Those in Group 1 (n = 23) received a 12 month course of 60 mg/day Carbimazole. Those in Group 2 (n = 34) received 45 mg/day for the first month, 30 mg/day for the second and 20 mg/day for the remaining 10 months of treatment. T3 was added in both groups after 2-4 months to maintain patients euthyroid. Baseline samples were also obtained from 30 control subjects. Blood samples were taken for the measurement of plasma thiol (PSH), lysate thiol (LSH), superoxide dismutase (SOD) and caeruloplasmin (CP) and for routine thyroid function tests (TT4, TT3 and TSH). In untreated Graves' patients, serum levels of PSH and SOD were reduced and levels of LSH increased compared to controls. Following 2 months high dose Carbimazole therapy there was a significant increase in PSH levels and a significant reduction in CP levels compared to presentation levels. In the more conventional dose Group 2 patients PSH levels also rose significantly during the first 2 months of treatment. Levels for both groups were still significantly lower than the control group. After 12 months high dose Carbimazole therapy PSH levels had decreased so that they no longer differed from untreated levels. LSH and SOD levels still remained abnormal. CP levels continued to fall. Similar findings were obtained in those patients receiving the more conventional course of treatment. At no point was their any significant difference in antioxidant levels between the two treatment groups. The abnormal levels of antioxidants in the serum of untreated Graves' patients confirm their involvement in the pathogenesis of Graves' disease. Carbimazole therapy appeared to have only short term effects on the peripheral blood levels of the antioxidants measured. Carbimazole appeared to act only on the extra cellular markers of antioxidant activity (PSH, CP) although the disease itself had marked intracellular effects (LSH, SOD). These findings suggest that Carbimazole does not act as a free radical scavenger.

Adult↗
PubMed1998

Osteoporosis in pregnancy: more than postural backache.

Though uncommon, osteoporosis can occur in pregnancy or shortly after delivery. The most common feature is back pain, often severely disabling. Suspect osteoporosis if pain of sudden onset in the upper lumbar or thoracic spine is not relieved by simple analgesia, or if there is a noticeable loss of height. X-rays reveal low bone density and fractures of the vertebrae. 70% of cases occur in first pregnancies. Recurrence is unusual. Most cases resolve spontaneously; a minority cause disability lasting months or years. If osteoporosis is diagnosed, breast feeding should be discouraged because of its effect on bone mineral density. Anyone who has had osteoporosis of pregnancy is at risk of postmenopausal osteoporosis and should take medical advice.

Bone Density↗
PubMed1997

Effects of PTH on PTHrP gene expression in human osteoblasts: up-regulation with the kinetics of an immediate early gene.

Parathyroid hormone-related peptide (PTHrP) is a local regulator of human bone turnover, which shares some sequence homology with the systemic hormone parathyroid hormone (PTH). The two proteins exert cellular effects through interaction with a common G protein-coupled PTH/PTHrP receptor on target cells. Whilst the PTH gene has a relatively simple structure the PTHrP gene is complex, alternative splicing of which can generate multiple mRNA species encoding PTHrP of 139, 141 and 173 amino acids. To date little is known regarding the extent to which PTH and PTHrP interact to modulate bone cell function. In this study we have used the quantitative technique of Real-Time polymerase chain reaction (PCR) to investigate the ability of PTH to induce PTHrP expression in SaOS-2 cells and in primary human osteoblasts. In addition, we have used the semi-quantitative techniques of PCR followed by Southern analysis and scanning densitometry to investigate the effects of PTH(1-34) on expression of mRNA species encoding the three PTHrP isoforms. We report a 50 fold increase in PTHrP mRNA expression 30 min after treatment with 100 ng/ml human recombinant PTH (1-34) in SaOS-2 cells, and a 38 fold rise in human osteoblasts 45-90 min post-PTH treatment. mRNA species encoding for PTHrP 1-139, 1-141 and 1-173 were all induced in human osteoblasts 45 min after exposure to PTH. Whilst the 1-139 mRNA species exhibited a sustained expression, both the 1-141 and 1-173 isoforms showed a biphasic induction with a second peak 6 hr post PTH treatment. These data demonstrate that PTH induces expression of the PTHrP gene in both SaOS-2 and primary human osteoblasts with the kinetics of an immediate early gene. Up-regulation of the PTHrP gene in response to PTH may be an important physiological mechanism by which this systemic factor effects a localised response in bone.

Cyclic AMP Response Element-Binding Protein↗
PubMed1997

Constitutive co-expression of estrogen and progesterone receptor mRNA in human meningiomas by RT-PCR and response of in vitro cell cultures to steroid hormones.

Although it is well recognised that human meningiomas are rich in progesterone receptor (PgR), controversy has existed about the presence of the estrogen receptor (ER) in these tumours. We have investigated the presence of both ER and PgR in a series of 20 human meningiomas, spanning the main histological groups, using reverse transcription linked PCR (RT-PCR). Total RNA was extracted from whole tissues and reverse transcribed to yield cDNA. This was amplified using primers specifically designed to detect ER and PgR. All samples co-expressed ER and PgR mRNA, irrespective of tumour classification, patient age or sex. In general, transcripts for PgR appeared considerably stronger than those for ER, and although this was a purely qualitative study, it suggests increased expression of PgR. Addition of exogenous 17beta-estradiol or progesterone to meningioma cell cultures showed that 2/4 cultures responded to these steroids. Our results confirm that human meningiomas do express gene transcripts for ER, and that previous failures to detect ER in these tumours may be due to the lack of sensitivity of the techniques employed. However, these receptors may not be functional in all tumours.

Adult↗
PubMed1997

Multivariate analysis of risk factors for operative delivery in nulliparous women. Canadian Early Amniotomy Study Group.

OBJECTIVE: Our purpose was to develop predictive models of operative delivery in nulliparous women on the basis of sociodemographic, anthropometric, and obstetric risk factors. STUDY DESIGN: Data were obtained prospectively on 925 nulliparous women in spontaneous term labor with a single fetus in cephalic presentation. Operative delivery was defined as either a midforceps or a cesarean delivery. Variables were grouped into two categories: those that could be assessed at admission and those appearing during labor. Multiple logistic regression was used to identify variables predictive of operative delivery. RESULTS: Among variables that can be documented at admission, independent predictors of operative delivery were maternal age and height, pregnancy weight gain, smoking status, gestational age, and admission cervical dilatation. Of these, maternal age > or = 35 years was the most strongly related to operative delivery. When variables documented later during labor were added to this first model, variables retained in the second model were age and height, smoking status, presence of dystocia, epidural analgesia, and fetal heart rate tracing abnormalities. The adjusted odds ratio of operative delivery in the presence of epidural anesthesia was 3.4 (95% confidence interval 2.0 to 5.8). This association was similar in the presence or absence of dystocia. When the specificity was in the range of 85%, the first and second models have sensitivities of 34% and 48%, respectively, and positive predictive values of 39% and 46%, respectively, which is higher than the a priori risk of operative delivery in the study population (21%). CONCLUSIONS: The models, based on data easily available, may help to predict the need for midforceps or cesarean section in low-risk nulliparous women. Before application in a clinical setting, these statistical models require validation in a separate cohort. The observed association between epidural anesthesia and operative delivery deserves interest but clinical trials are required to determine whether this relation is causal.

Adult↗
PubMed1997

PTHrP and the PTH/PTHrP receptor are co-expressed in human breast and colon tumours.

Using RNA extracted from human tumour samples removed during surgery, we have analysed expression of mRNA for parathyroid hormone-related protein (PTHrP) and for the PTH/PTHrP receptor by RT-PCR in a panel of human breast and colon tumours. All but 1 of 18 breast tumour samples expressed PTHrP, whereas receptor expression was detected in 11 of these. Expression of the PTH/PTHrP receptor was found in three out of four metastatic lesions, including one sample in which no receptor was detected in the primary tumour. PTHrP expression was also detected in five colon tumours, and receptor expression detected in two of these. These results demonstrate that PTHrP and the PTHrP receptor are also co-expressed in breast tumours in vivo and provide further evidence that PTHrP may be an important autocrine/paracrine growth factor in breast cancer.

Breast Neoplasms↗
PubMed1997

Biochemical markers of bone turnover in seronegative spondylarthropathy: relationship to disease activity.

To investigate bone turnover in patients with seronegative spondylarthropathy, a bone formation marker, type 1 procollagen carboxy-terminal propeptide (P1CP), and resorption markers, the pyridinium cross-links of collagen [urinary free (f) PYR and DPYR], were measured. The median f-PYR, f-DPYR and P1CP (+/-interquartile range) were 15.8 (6.00) nmol/mmol creatinine, 3.8 (2.2) nmol/mmol creatinine and 101.5 (38) micrograms/1, respectively. There was a positive correlation between resorption markers and acute-phase reactants such as C-reactive protein (r = 0.42 for PYR, r = 0.42 for DPYR, P < 0.05), and a negative correlation observed between P1CP and the erythrocyte sedimentation rate (r = -0.64, P < 0.05). In the subgroup of patients with an elevated CRP concentration, the concentration of PYR and DPYR was significantly increased (f-PYR 25.7 vs 15.8 and f-DPYR 6.6 vs 3.8, P < 0.01 for f-PYR, P < 0.05 for f-DPYR). This study suggests than an elevation in acute-phase response in patients with seronegative spondylarthropathy is associated with increased concentration of bone resorption markers with a tendency for reduction in bone formation markers. This may represent uncoupling of bone formation and resorption, leading to bone loss in such patients.

Acute-Phase Reaction↗
PubMed1997

Paget's disease of bone.

The highest incidence of Paget's disease is in the United Kingdom and is lower in other European countries. Worldwide the incidence appears to be decreasing. Some countries have observed a reduction in the severity at presentation, perhaps reflecting changes in migration of the UK population. Evidence of a genetic susceptibility to Paget's disease is accumulating, with chromosome 6 (the HLA locus) and 18q emerging as strong candidates. Use of molecular biology techniques has yielded evidence on the possible role of paramyxovirus infection in the etiology of Paget's disease. Altered measles virus nucleocapsid transcripts have been detected in bone marrow cell cultures and peripheral blood mononuclear cells from Paget's disease patients. Canine distemper virus may be the etiologic agent, and ownership of a mongrel dog or a dog not vaccinated against canine distemper virus is associated with an increased risk of Paget's disease. Familial Paget's disease is associated with more severe disease than is seen in sporadic cases. Quality of life may be reduced in patients with Paget's disease, and psychological problems are often present. New biochemical markers of resorption and formation appear to offer little advantage over urinary hydroxyproline and serum total alkaline phosphatase measurements in assessing Paget's disease activity or response to therapy. The best therapeutic responses are observed following treatment with the bisphosphonates, and oral etidronate is now being superseded by oral tiludronate, oral or intravenous alendronate, and clodronate or intravenous pamidronate.

Humans↗