Biomedical subjects

W D Fraser

Publications and source records attributed to W D Fraser.

At least 55 records · Page 3Linked to original sources

PubMed2000

Biochemical markers of bone turnover following high-dose chemotherapy and autografting in multiple myeloma.

The effect of high-dose chemotherapy and autografting on bone turnover in myeloma is not known. A study of 32 myeloma patients undergoing blood or marrow transplant (BMT), conditioned with high-dose melphalan, was done. Bone resorption was assessed by urinary free pyridinoline (fPyr) and deoxypyridinoline (fDPyr), expressed as a ratio of the urinary creatinine concentration. Bone formation was assessed by serum concentration of procollagen 1 extension peptide (P1CP) and bone-specific alkaline phosphatase (BSAP). Eighteen cases had normal fPyr and fDPyr at transplant, and in all but one of these cases the level remained normal throughout subsequent follow-up. In contrast, in 14 cases urinary fPyr and fDPyr levels were increased at transplant. In these cases, both fPyr and fDPyr fell to normal levels over the next few months (P = .0009 and.0019, respectively). fPyr and fDPyr levels at transplant and their trends post-BMT were unrelated to the use of pre-BMT or post-BMT bisphosphonate or post-BMT interferon. Nine cases had elevated P1CP or BSAP at transplant, which rapidly normalized. In most patients there was an increase in P1CP and/or BSAP several months post-transplant. In conclusion, increased osteoclast activity may be present even in apparent plateau phase of myeloma. High-dose chemotherapy with autografting may normalize abnormal bone resorption, although the effect may take several weeks to emerge and may be paralleled by increased osteoblast activity. The findings provide biochemical evidence that autografting may help normalize the abnormal bone turnover characteristic of myeloma. (Blood. 2000;96:2697-2702)

Adult↗

PubMed2000

Rapid detection of group B streptococci in pregnant women at delivery.

BACKGROUND: Group B streptococcal infections are an important cause of neonatal morbidity and mortality. A rapid method for the detection of this organism in pregnant women at the time of delivery is needed to allow early treatment of neonates. METHODS: We studied the efficacy of two polymerase-chain-reaction (PCR) assays for routine screening of pregnant women for group B streptococci at the time of delivery. We obtained anal, vaginal, and combined vaginal and anal specimens from 112 pregnant women; in 57 women, specimens were obtained before and after the rupture of the amniotic membranes. The specimens were tested for group B streptococci by culture in a standard selective broth medium, with a conventional PCR assay, and with a new fluorogenic PCR assay. RESULTS: Among the 112 women, the results of the culture of the combined vaginal and anal specimens were positive for group B streptococci in 33 women (29.5 percent). The two PCR assays detected group B streptococcal colonization in specimens from 32 of these 33 women: the one negative PCR result was in a sample obtained after the rupture of membranes. As compared with the culture results, the sensitivity of both PCR assays was 97.0 percent and the negative predictive value was 98.8 percent. Both the specificity and the positive predictive value of the two PCR assays were 100 percent. The length of time required to obtain results was 30 to 45 minutes for the new PCR assay, 100 minutes for the conventional PCR assay, and at least 36 hours for culture. CONCLUSIONS: Colonization with group B streptococci can be identified rapidly and reliably by a PCR assay in pregnant women in labor both before and after the rupture of membranes.

Anal Canal↗

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

Absence of measles virus and canine distemper virus transcripts in long-term bone marrow cultures from patients with Paget's disease of bone.

The presence of intranuclear inclusions in pagetic osteoclasts with similar characteristics to those seen in some slow viral diseases has lead to the hypothesis that Paget's disease is caused by a similar infection. Bone marrow aspirates from seven patients with hemipelvic Paget's disease were taken from both sides of the pelvis and cultured under identical conditions. RNA was extracted after approximately 2 weeks of culture and reverse transcriptase-linked polymerase chain reaction used to investigate the expression of measles and canine distemper virus RNA. We were unable to detect the presence of measles virus (MV) or canine distemper virus (CDV) transcripts in bone marrow cultures from either affected or unaffected sites in any of our patients. The results of this study do not support a role for MV or CDV in the pathogenesis of Paget's disease of bone.

Animals↗

PubMed2000

Expression and functional consequences of 11beta-hydroxysteroid dehydrogenase activity in human bone.

Glucocorticoids have an essential role in skeletal development and function but are detrimental in excess. In several tissues, glucocorticoid action is dependent upon the expression of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) isozymes, which interconvert active cortisol (F) and inactive cortisone (E). We previously demonstrated the expression of 11beta-HSD isozymes in human osteosarcoma cell lines, osteoblast cultures, and fetal bone. We now characterize 11beta-HSD expression in adult human bone using specific antihuman 11beta-HSD antibodies, riboprobes, and enzyme activity studies. In addition, the effect of 11beta-HSD on bone metabolism in vivo was assessed using the 11beta-HSD inhibitor carbenoxolone in eight normal male volunteers. In fresh normal human bone tissue, both 11beta-dehydrogenase (cortisol-to-cortisone conversion) and reductase (cortisone-to-cortisol conversion) activities were demonstrated. There was considerable interindividual variation in the dehydrogenase, but not reductase, activity. In bone homogenates, activity was NADP-dependent with a K(m) for F of 4.8 +/- 1.2 micromol/L, suggesting the presence of 11beta-HSD1. This was confirmed by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Immunohistochemistry and in situ hybridization studies demonstrated 11beta-HSD1 isozyme expression in cells of the osteoblast lineage and in osteoclasts. The 11beta-HSD2 isozyme was expressed, but only in osteoblasts and at a low level. Ingestion of 300 mg of carbenoxolone by eight normal volunteers for 7 days resulted in a significant decrease in the bone resorption markers, pyridinoline (Pyr) and deoxypyridinoline (DPyr) (change in urinary Pyr/creatinine -1.55 +/- 0.55 [mean +/- SE], for DPyr/creatinine -0. 4 +/- 0.14 nmol/mmol; p < 0.05 for both), with no overall change in the bone formation markers C- and N-terminal propeptides of type I collagen (PICP and PINP). These data suggest that local tissue metabolism of glucocorticoids is likely to be important in determining the sensitivity of both osteoblasts and osteoclasts to glucocorticoids. In particular, variation in 11beta-HSD isozyme expression and activity may explain individual variation in susceptibility to glucocorticoid-induced osteoporosis.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed2000

Parathyroid hormone-related protein (1-34) and urothelial redifferentiation in the neuropathic urinary bladder.

STUDY DESIGN: A comparative study of immunostaining for parathyroid hormone-related protein (1-34) (PTHrP (1-34)) in the vesical epithelium of biopsies obtained from patients with non-neuropathic bladder and those with neuropathic bladder. OBJECTIVES: To investigate the immunostaining for PTHrP (1-34) in the control cases and in neuropathic bladders showing (1) normal transitional epithelium, (2) hyperplastic transitional epithelium, and (3) squamous metaplasia. SETTING: Regional Spinal Injuries Centre, and Department of Cellular Pathology, Southport & Ormskirk Hospitals NHS Trust, Southport, Department of Pathology, Royal Liverpool University Hospital and the Departments of Clinical Chemistry and Cell Biology, The University of Liverpool, Liverpool, England. METHODS: Cold cup biopsies of bladder mucosa were taken from patients suffering from neuropathic urinary bladder when they were undergoing a therapeutic procedure in the urinary tract. Immunohistochemistry was performed on these biopsy specimens using a rabbit polyclonal antibody raised to a synthetic peptide corresponding to human PTHrP (1-34). Control group (n=10) consisted of archival biopsies taken from non-neuropathic bladders. RESULTS: In the control group, the transitional epithelium showed no immunostaining, or at the most, very faint positive staining was seen in the transitional epithelium of non-neuropathic bladder. Positive immunostaining to PTHrP (1-34) was seen in the normal transitional epithelium of neuropathic bladder in nine of 13 cases. Hyperplastic transitional epithelium showed positive immunostaining for PTHrP (1-34) in 11 of 13 biopsies from patients with neuropathic bladder. Immunostaining for PTHrP (1-34) was observed in the metaplastic squamous epithelium in 14 of 17 cases with neuropathic bladder. CONCLUSION: The transitional epithelium of non-neuropathic bladder showed no immunostaining, or at the most, very faint positive staining for PTHrP (1-34). In contrast to this, positive immunostaining for PTHrP (1-34) was observed more frequently in the vesical epithelium of neuropathic bladder. This observation opens up avenues for innovative therapy with PTHrP or its analogues for possible modulation of urothelial differentiation in the neuropathic bladder.

Adult↗

PubMed2000

Parathyroid hormone-related protein in the aetiology of fibrous dysplasia of bone in the McCune Albright syndrome.

OBJECTIVE: Fibrous dysplasia, observed in bone lesions in the McCune Albright syndrome (MAS), is thought to result from abnormalities in cells of the osteogenic lineage associated with over-activation of the cAMP signalling pathway in affected cells. The aim of this study was to investigate the role of parathyroid hormone-related protein (PTHrP) in the aetiology of MAS, and to determine a possible therapeutic role for 1,25-dihydroxy vitamin D(3) (1,25(OH)(2)D(3)). DESIGN: The effects of 1,25(OH)(2)D(3) on PTHrP production and mRNA expression were determined in vitro. 1,25(OH)(2)D(3) therapy was administered to three patients with MAS. PATIENTS: Clinical data from four MAS patients (MAS1, 2, 3 and 4), and in vitro studies using bone from three MAS patients (MAS1, 2, and 3), are presented. MEASUREMENTS: Immunoradiometric assay and low-cycle number reverse transcriptase-linked PCR were used to determine PTHrP production and mRNA expression in vitro. Standard clinical biochemistry was recorded pre and post commencement of 1,25(OH)(2)D(3) treatment. RESULTS: We report the elevated secretion of PTHrP, and a concomitant rise in PTHrP mRNA expression, in cultured osteoblasts from three MAS patients. Treatment with 1,25(OH)(2)D(3) produced a dose-dependent decrease in PTHrP protein secretion and mRNA expression. Marked improvement in bone biochemistry in MAS1, 2 and 3 post treatment with 1,25(OH)(2)D(3) is documented. CONCLUSION: This study provides the first evidence suggesting that PTHrP may contribute to the aetiology of fibrous dysplasia in MAS. In addition, the therapeutic administration of 1,25(OH)92)D(3) may provide clinicians with an important new regime for symptomatic relief of bone pain and fracture in some patients with MAS.

Adolescent↗

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

Hypocalcaemia in severe meningococcal infections.

AIM: To determine the incidence of hypocalcaemia in critically ill children with meningococcal disease. METHODS: In a prospective cohort study, 70 of 80 patients admitted consecutively with a clinical diagnosis of meningococcal disease to intensive care had measurements of total and ionised calcium on admission. Parathormone and calcitonin were measured in a proportion of the children. RESULTS: Total and ionised calcium concentrations were low in 70% of the children. There was a weak relation of calcium concentration to the volume of blood derived colloid which had been given, but a good relation to disease severity, where sicker children had lower calcium concentrations. Although the parathormone concentration was higher in children with lower calcium concentrations, some children had low ionised calcium concentrations, without an increase of parathormone concentration. Serum calcitonin concentration was not related to calcium concentrations. CONCLUSION: Hypocalcaemia is common in meningococcal disease.

Calcitonin↗

PubMed2000

A negative search for a paramyxoviral etiology of Paget's disease of bone: molecular, immunological, and ultrastructural studies in UK patients.

Paget's disease of bone is a common bone disease characterized by increased and disorganized bone remodeling at focal sites throughout the skeleton. The etiology of the disease is unresolved. A persistent viral infection has long been suggested to cause the disease. Antigen and/or nucleic acid sequences of paramyxoviruses (in particular measles virus [MV], canine distemper virus [CDV], and respiratory syncytial virus [RSV]) have been reported in pagetic bone by a number of groups; however, others have been unable to confirm this and so far no virus has been isolated from patients. Here, we reexamined the question of viral involvement in Paget's disease in a study involving 53 patients with established disease recruited from seven centers throughout the United Kingdom. Thirty-seven patients showed clear signs of active disease by bone scan and/or histological assessment of the bone biopsy specimens and 12 of these had not received any therapy before samples were taken. Presence of paramyxovirus nucleic acid sequences was sought in bone biopsy specimens, bone marrow, or peripheral blood mononuclear cells using reverse-transcription polymerase chain reaction (RT-PCR) with a total of 18 primer sets (7 of which were nested), including 10 primer sets (including 3 nested sets) specifically for MV or CDV. For each patient at least one sample was tested with all primer sets by RT-PCR and no evidence for the presence of paramyxovirus RNA was found in any patient. In 6 patients, bone biopsy specimens with clear histological evidence of active disease tested negative for presence of measles and CDV using immunocytochemistry (ICC) and in situ hybridization (ISH). Intranuclear inclusion bodies, similar to those described by others previously, were seen in pagetic osteoclasts. The pagetic inclusions were straight, smooth tubular structures packed tightly in parallel bundles and differed from nuclear inclusions, known to represent MV nucleocapsids, in a patient with subacute sclerosing panencephalitis (SSPE) in which undulating, diffuse structures were found, arranged loosely in a nonparallel fashion. In the absence of amplification of viral sequences from tissues that contain frequent nuclear inclusions and given that identical inclusions are found in other bone diseases with a proven genetic, rather than environmental, etiology, it is doubtful whether the inclusions in pagetic osteoclasts indeed represent viral nucleocapsids. Our findings in this large group of patients recruited from throughout the United Kingdom do not support a role for paramyxovirus in the etiology of Paget's disease.

Aged↗

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↗