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Biomedical subjects

W D Fraser

Publications and source records attributed to W D Fraser.

At least 19 recordsLinked to original sources
PubMed2000

Amniotomy for shortening spontaneous labour.

BACKGROUND: Early amniotomy has been advocated as a component of the active management of labour. Several randomised trials comparing routine amniotomy to an attempt to conserve the membranes have been published. Their limited sample sizes limit their ability to address the effects of amniotomy on indicators of maternal and neonatal morbidity. OBJECTIVES: To study the effects of amniotomy on the rate of Cesarean delivery and on other indicators of maternal and neonatal morbidity (Apgar less than 7 at 5 minutes, admission to NICU). SEARCH STRATEGY: The register of clinical trials maintained and updated by the Cochrane Pregnancy and Childbirth Group. SELECTION CRITERIA: All acceptably controlled trials of amniotomy during first stage of labour were eligible. DATA COLLECTION AND ANALYSIS: Data were extracted by two trained reviewers from published reports. Trials were assigned methodological quality scores based on a standardized rating system. Typical odds ratios (ORs) were calculated using Peto's method. MAIN RESULTS: Amniotomy was associated with a reduction in labour duration of between 60 and 120 minutes. There was a marked trend toward an increase in the risk of Cesarean delivery: OR = 1.26; 95% Confidence Interval (CI)=0.96-1. 66. The likelihood of a 5 minute Apgar score less than 7 was reduced in association with early amniotomy (OR = 0.54; 95% CI = 0.30-0.96). Groups were similar with respect to other indicators of neonatal status (arterial cord pH, NICU admissions). There was a statistically significant association of amniotomy with a decrease in the use of oxytocin: OR = 0.79; 95% CI = 0.67-0.92. REVIEWER'S CONCLUSIONS: Routine early amniotomy is associated with both benefits and risks. Benefits include a reduction in labour duration and a possible reduction in abnormal 5-minute Apgar scores. The meta-analysis provides no support for the hypothesis that routine early amniotomy reduces the risk of Cesarean delivery. Indeed there is a trend toward an increase in Cesarean section. An association between early amniotomy and Cesarean delivery for fetal distress is noted in one large trial. This suggests that amniotomy should be reserved for women with abnormal labour progress.

Amnion↗
PubMed2000

Is high-dose estrogen-induced osteogenesis in the mouse mediated by an estrogen receptor?

Although estrogen is known to induce new bone formation in the long bones of female mice, this response is only thought to occur following administration of high doses, suggesting that it may not be mediated by a conventional estrogen receptor. To address this question further, we first examined the stereospecificity of this response by comparing the potency of 17beta-estradiol (E(2)) in stimulating cancellous bone formation at the proximal tibial metaphysis of intact female mice with that of the relatively inactive stereoisomer, 17alpha-estradiol (alphaE(2)). We found that E(2) was significantly more potent than alphaE(2), as assessed by histomorphometry. To provide further evidence for an estrogen-receptor-mediated process, we examined whether E(2)-induced osteogenesis in intact female mice could be inhibited by the estrogen receptor antagonist, ICI 182,780 (ICI). Although ICI itself had no effect on histomorphometric indices of the proximal tibial metaphysis when given alone, it significantly inhibited the osteogenic response to E(2). Finally, we examined the dose dependency of E(2)-induced osteogenesis at the proximal tibial metaphysis in intact mice. We found that E(2) stimulated cancellous bone formation in a dose-dependent manner over a wide dose range (i. e., 1-4000 microg/kg per day), with significant increases observed at doses of 4 microg/kg per day and beyond. Our results raise the possibility that estrogen-induced osteogenesis in the mouse represents an estrogen-receptor-mediated response that is not confined solely to supraphysiological estrogen levels.

Animals↗
PubMed2000

Cytokine expression by cultured osteoblasts from patients with osteoporotic fractures.

Human osteoblasts were derived in culture from explants of bone from patients who had recently suffered osteoporotic fractures and from patients with no evidence of osteoporosis. The expression of cytokine mRNA in these osteoblasts was subsequently determined by reverse transcriptase-linked polymerase chain reaction (RT-PCR). We have detected mRNA for IL-1beta, IL-3, IL-6, IL-8, TNF-alpha and -beta, and the three TGF-beta isoforms in the cells. The profile of cytokines expressed by osteoblasts derived from patients with osteoporotic fractures was consistent with profiles observed in osteoblasts derived from patients with no evidence of reduced bone mass--the latter included children undergoing corrective surgery and adult subjects ranging from 31 to 80 years undergoing elective surgery for osteoarthritis and other bone pathologies.

Adolescent↗
PubMed2000

Short-term changes in growth and urinary growth hormone, insulin-like growth factor-I and markers of bone turnover excretion in healthy prepubertal children.

Childhood growth is a non-linear process. To assess whether there is a biochemical correlate of non-linear growth, we have measured free pyridinoline (fPYR) and deoxypyridinoline (fDPYR) excretion in seven healthy prepubertal children, aged 6.1-7.7 years. To examine the link between short-term growth and hormone output, urinary growth hormone (uGH) and insulin-like growth factor-I (uIGF-I) were also measured. Height and weight were measured and a timed overnight urine was collected three times per week from September to July, with results expressed as a weekly change in height (Dheight(w)) or weight (Dweight(w)), and as weekly average hormone or bone marker excretion (uGH(w), uIGF-I(w), fPYR(w), fDPYR(w)). Subject specific SD scores (SDS) were derived for each variable.Dheight(w)and Dweight(w)did not correlate to uGH(w), uIGF-I(w), fPYR(w)or fDPYR(w). Dheight(w)SDS was weakly but significantly correlated to fPYR(w)SDS (r = +0.16;P<0.05) and fDPYR(w)SDS (r = +0.15;P<0.05). The percentage of high frequency (2-4 weeks) variation in uGH(w)excretion, as defined by time series analysis, was correlated with the mean uIGF-I(w)(r = +0.81;P<0.05), which in turn was significantly reduced (92 +/- 38 vs 120 +/- 47 ng;P<0.001) during periods of slow growth (Dheight(w)< 0.05 cm/week). We conclude that in normal children the amount of urinary fPYR, fDPYR, GH and IGF-I does not provide a direct biochemical correlate of growth from week to week. However good growth is associated with a relative increase in fPYR and fDPYR excretion, while poor growth is associated with reduced IGF-I excretion, which in turn is influenced by the temporal secretory pattern of GH over 2-4 weeks.

Amino Acids↗
PubMed2000

Cost-effectiveness of a delayed pushing policy for patients with epidural anesthesia. The PEOPLE (Pushing Early or Pushing Late with Epidural) Study Group.

OBJECTIVE: The purpose of this study was to estimate the economic efficiency of a policy of delayed pushing for nulliparous women who have full dilatation while they are under epidural anesthesia. STUDY DESIGN: A cost-effectiveness evaluation was based on a randomized controlled trial. Resource use and clinical effectiveness data were collected for 1862 women who were randomly allocated to either a delayed pushing group (n = 936) or an early pushing group (n = 926). Costs (in 1997 Canadian dollars) were collected for each item of resource use. Sensitivity analysis was used to examine the robustness of the main results. RESULTS: Delayed pushing was effective at reducing the number of difficult deliveries (relative risk, 0.79; 95% confidence interval, 0.66 to 0.95). The mean cost of intrapartum care was significantly higher in the delayed pushing group ($625.86 vs $557.64; P <.0005). There were no significant differences in mean costs of postnatal care ($2146.67 vs $2133.54; P =.871) or total hospital care ($2772.53 vs $2691.18; P =.324). The incremental cost per difficult delivery prevented was estimated at $1743.06. The incremental cost-effectiveness ratio remained fairly robust with variations in the values of key parameters incorporated into the sensitivity analysis. CONCLUSIONS: The results of this economic evaluation should inform decision makers determining whether to advocate a policy of delayed pushing for nulliparous women who have full dilatation while they are under epidural anesthesia.

Anesthesia, Epidural↗
PubMed2000

Multicenter, randomized, controlled trial of delayed pushing for nulliparous women in the second stage of labor with continuous epidural analgesia. The PEOPLE (Pushing Early or Pushing Late with Epidural) Study Group.

OBJECTIVE: This study was undertaken to determine whether a policy of delayed pushing for nulliparous women with continuous-infusion epidural analgesia reduces the risk of difficult delivery (cesarean delivery, operative delivery from a midpelvic position, low-pelvic procedures with rotation >45 degrees ). STUDY DESIGN: In this multicenter, randomized, controlled trial women in the delayed pushing group (n = 936) were advised to wait > or =2 hours after full dilatation before commencement of pushing. Women in the early pushing group (n = 926) were advised to commence pushing as soon as they had been randomly assigned. RESULTS: Difficult delivery was reduced with delayed pushing (relative risk, 0.79; 95% confidence interval, 0.66-0.95). The greatest effect was on midpelvic procedures (relative risk, 0.72; 95% confidence interval, 0.55-0.93). Although there was little evidence for an effect on low-pelvic procedures, spontaneous delivery was more frequent among women who practiced delayed pushing (relative risk, 1.09; 95% confidence interval, 1.00-1.18). Abnormal umbilical cord blood pH (<7.15 venous value or <7.10 arterial value) was more frequent in the delayed pushing group (relative risk, 2.45, 95% confidence interval, 1.35-4. 43). However, scores for a summary indicator, the Neonatal Morbidity Index, were similarly distributed in the 2 groups. CONCLUSION: Delayed pushing is an effective strategy to reduce difficult deliveries among nulliparous women.

Analgesia, Epidural↗
PubMed2000

A detailed assessment of alterations in bone turnover, calcium homeostasis, and bone density in normal pregnancy.

The effects of pregnancy on bone turnover and the potential risk of developing an osteoporotic fracture in pregnancy are controversial. Utilizing biochemical markers of bone formation and resorption and dual-energy X-ray absorptiometry (DEXA), bone turnover before, during, and after pregnancy was studied in detail. Ten women (mean age 30 years; range 23-40) were recruited. Prepregnancy data were obtained and then a review was performed at 2-week intervals , once pregnancy was confirmed, until 14 weeks of gestation and thereafter monthly until term. Bone mineral density (BMD) was estimated by DEXA scanning of hip, spine, and forearm preconception and postpartum. In addition, BMD of the forearm at 14 weeks and 28 weeks gestation was obtained. All pregnancies had a successful outcome. Urinary free pyridinium cross-links, free pyridinoline (fPyr) and free deoxypyridinoline (fDPyr), were normal prepregnancy (mean [+/-SD]) 14.6 nmol/mmol (1.8) and 5.0 nmol/mmol (1.0) creat, respectively. By 14 weeks, they had increased to 20.8 nmol/mmol (4.3) and 6.1 nmol mmol (1.4) (both p < 0.02) and by 28 weeks to 26.3 nmol/mmol (5.6) and 7.4 nmol/mmol (1.6) (both p < 0.01). The ratio of fPyr to fDPyr remained constant. A similar significant increase was observed in N-telopeptide (NTx). Bone formation was assessed by measurement of carboxyterminal propeptide of type 1 collagen (P1CP) and bone-specific alkaline phosphatase (BSAP). Neither were altered significantly before 28 weeks, but subsequently mean P1CP increased from 110 microg/liter (23) to 235 microg/liter (84) at 38 weeks and mean BSAP increased from 11.1 U/liter (5.0) to 28.6 U/liter (11.1) (p < 0.01 for both variables). Lumbar spine (L1-L4) BMD decreased from a prepregnancy mean of 1.075 g/cm (0.115) to 1.054 g/cm2 (0.150) postpartum (p < 0.05). Total hip BMD decreased from a prepregnancy mean of 0.976 g/cm2 (0.089) to 0.941 g/cm2 (0.097) (p < 0.05). Forearm BMD at midradius, one-third distal and ultradistal decreased but did not reach statistical significance. As assessed by these bone markers, in the first 2 trimesters of pregnancy, bone remodeling is uncoupled with a marked increase in bone resorption. A corresponding increase in formation markers is not observed until the third trimester. Spinal BMD exhibits a significant decrease from prepregnancy to the immediate postpartum period with a mean reduction in BMD of 3.5 % in 9 months.

Absorptiometry, Photon↗
PubMed2000

A mathematical model of cerebral perfusion subjected to Gz acceleration.

BACKGROUND: When the human body is exposed to a high gravitational load, the blood supply to the brain is reduced and loss of consciousness may occur. Our goal is to identify the principal mechanical causes of reduced blood supply to the brain during high +Gz. METHODS: We have developed a mathematical model to investigate the influence of Gz on the cerebral circulation. Blood flow is modeled using a one-dimensional flow approximation, in which the cross-sectional area of elastic vessels is determined as a non-linear function of the transmural (blood minus external) pressure. The intracranial vessels are subjected to cerebrospinal fluid pressure (PCSF) which is determined from the condition that the cranial volume is conserved. RESULTS: For a constant pressure difference of 100 mm Hg applied to the arterial and venous ends of the model, blood flow is diminished for +Gz. At approximately +5 G, the blood flow predicted by the model is insufficient to maintain normal functioning of the brain. PCSF is approximately equal to the blood pressure in the large intracranial veins for all values of Gz. Extracranial arteries and the intracranial vessels do not collapse, even when Gz is substantially higher than normal. However, the extracranial veins are collapsed even for moderate +Gz. CONCLUSIONS: Even if cardiac output is maintained at normal levels, cerebral perfusion will fall because of the increasing resistance of the cerebral flow circuit. This increase is largely due to the collapse of the extracranial veins, which begins at moderate Gz and becomes dominant at a Gz of approximately 4.5.

Adaptation, Physiological↗
PubMed1999

Signaling in human osteoblasts by extracellular nucleotides. Their weak induction of the c-fos proto-oncogene via Ca2+ mobilization is strongly potentiated by a parathyroid hormone/cAMP-dependent protein kinase pathway independently of mitogen-activated protein kinase.

Extracellular nucleotides acting through specific P2 receptors activate intracellular signaling cascades. Consistent with the expression of G protein-coupled P2Y receptors in skeletal tissue, the human osteosarcoma cell line SaOS-2 and primary osteoblasts express P2Y1 and P2Y2 receptors, respectively. Their activation by nucleotide agonists (ADP and ATP for P2Y1; ATP and UTP for P2Y2) elevates [Ca2+]i and moderately induces expression of the c-fos proto-oncogene. A synergistic effect on c-fos induction is observed by combining ATP and parathyroid hormone, a key bone cell regulator. Parathyroid hormone elevates intracellular cAMP levels and correspondingly activates a stably integrated reporter gene driven by the Ca2+/cAMP-responsive element of the human c-fos promoter. Nucleotides have little effect on either cAMP levels or this reporter, instead activating luciferase controlled by the full c-fos promoter. This induction is reproduced by a stably integrated serum response element reporter independently of mitogen-activated protein kinase activation and ternary complex factor phosphorylation. This novel example of synergy between the cAMP-dependent protein kinase/CaCRE signaling module and a non-mitogen-activated protein kinase/ternary complex factor pathway that targets the serum response element shows that extracellular ATP, via P2Y receptors, can potentiate strong responses to ubiquitous growth and differentiative factors.

Adenosine Triphosphate↗
PubMed1999

Human serum beta2-microglobulin levels: correlation with total serum IgG and placental IgG transfer in HIV-infected and non-HIV infected individuals.

The acquisition of maternal immunoglobulin G (IgG) is fundamental to the immune defence of the neonate. The receptor responsible for IgG transfer across the human placenta has also been implicated in the maintenance of IgG levels in the circulation. beta2-microglobulin is part of the Fc receptor (FcR) that has recently been purified from the human placenta. In HIV infection, increasing serum levels of total IgG and beta2-microglobulin are observed as the disease progresses. Herein, we have investigated the correlation between beta2-microglobulin and total serum IgG levels in HIV-seropositive mothers and their term neonates (HIV group, n = 37), as well as in HIV-seronegative mothers and their term neonates (control group, n = 50). Serum maternal beta2-microglobulin was directly correlated with total serum IgG levels in HIV-infected mothers (r = 0.58; P = 0.0002), but not in healthy HIV-seronegative mothers (r = -0.20; P = 0.16). Maternal serum beta2-microglobulin was also inversely correlated with placental antibody transfer of total IgG in mother-newborn pairs from the HIV group (r = 0.38; P = 0.02), but not from the control group (r = 0.15. P = 0.31). These results seem to indicate that, in HIV infection, elevated serum beta2-microglobulin levels could be involved in maintenance of abnormally high total serum IgG concentrations; by interfering with the binding of IgG to Fc receptors at the maternal-fetal interface, they might also reduce IgG transfer. By contrast, in normal non-HIV infected individuals, serum beta2-microglobulin levels do not appear implicated in regulation of these two phenomena.

Adult↗
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↗