bluuebunny/crossref_metadata_2025 huggingface dataset:
Moderate Exercise During Growth in Prepubertal Boys: Changes in Bone Mass, Size, Volumetric Density, and Bone Strength: A Controlled Prospective Study
Authors: Bradney M. , Pearce G. , Naughton G. , Sullivan C. , Bass S. , Beck T. , Carlson J. , Seeman E.
Published: April 2006

Cross-sectional studies of elite athletes suggest that growth is an opportune time for exercise to increase areal bone mineral density (BMD). However, as the exercise undertaken by athletes is beyond the reach of most individuals, these studies provide little basis for making recommendations regarding the role of exercise in musculoskeletal health in the community. To determine whether moderate exercise increases bone mass, size, areal, and volumetric BMD, two socioeconomically equivalent schools were randomly allocated to be the source of an exercise group or controls. Twenty boys (mean age 10.4 years, range 8.4–11.8) allocated to 8 months of 30-minute sessions of weight-bearing physical education lessons three times weekly were compared with 20 controls matched for age, standing and sitting height, weight, and baseline areal BMD. Areal BMD, measured using dual-energy X-ray absorptiometry, increased in both groups at all sites, except at the head and arms. The increase in areal BMD in the exercise group was twice that in controls; lumbar spine (0.61 ± 0.11 vs. 0.26 ± 0.09%/month), legs (0.76 ± 0.07 vs. 0.34 ± 0.08%/month), and total body (0.32 ± 0.04 vs. 0.17 ± 0.06%/month) (all p < 0.05). In the exercise group, femoral midshaft cortical thickness increased by 0.97 ± 0.32%/month due to a 0.93 ± 0.33%/month decrease in endocortical (medullary) diameter (both p < 0.05). There was no periosteal expansion so that volumetric BMD increased by 1.14 ± 0.33%/month, (p < 0.05). Cortical thickness and volumetric BMD did not change in controls. Femoral midshaft section modulus increased by 2.34 ± 2.35 cm3 in the exercise group, and 3.04 ± 1.14 cm3 in controls (p < 0.05). The growing skeleton is sensitive to exercise. Moderate and readily accessible weight-bearing exercise undertaken before puberty may increase femoral volumetric BMD by increasing cortical thickness. Although endocortical apposition may be a less effective means of increasing bone strength than periosteal apposition, both mechanisms will result in higher cortical thickness that is likely to offset bone fragility conferred by menopause-related and age-related endocortical bone resorption.
Genetic and Environmental Contributions to the Association Between Quantitative Ultrasound and Bone Mineral Density Measurements: A Twin Study
Authors: Howard Gabrielle M. , Nguyen Tuan V. , Harris Mark , Kelly Paul J. , Eisman John A.
Published: April 2006

This study was designed to assess the relative contributions of genetic and environmental factors to the variation and covariation of quantitative ultrasound (QUS) measurements and their relationships to bone mineral density (BMD). Forty-nine monozygotic (MZ) and 44 dizygotic (DZ) female twins between 20 and 83 years of age (53 ± 13 years, mean ± SD) were studied. Digital (phalangeal) QUS (speed of sound [SOS]) and calcaneal QUS (broadband ultrasound attenuation [BUA] and velocity of sound [VOS]) were measured using a DBM Sonic 1200 ultrasound densitometer and a CUBA ultrasound densitometer, respectively. Femoral neck (FN), lumbar spine (LS), and total body (TB) BMD were measured using dual-energy X-ray absorptiometry. Familial resemblance and hence heritability (proportion of variance of a trait attributable to genetic factors) were assessed by analysis of variance, univariate, and multivariate model-fitting genetic analyses. In both QUS and BMD parameters, MZ twins were more alike than DZ pairs. Estimates of heritability for age- and weight-adjusted BUA, VOS, and SOS were 0.74, 0.55, and 0.82, respectively. Corresponding indices of heritability for LS, FN, and TB BMD were 0.79, 0.77, and 0.82, respectively. In cross-sectional analysis, both BUA and SOS, but not VOS, were independently associated with BMD measurements. However, analysis based on intrapair differences suggested that only BUA was related to BMD. Bivariate genetic analysis indicated that the genetic correlations between BUA and BMD ranged between 0.43 and 0.51 (p < 0.001), whereas the environmental correlations ranged between 0.20 and 0.28 (p < 0.01). While the genetic correlations within QUS and BMD measurements were significant, factor analysis indicates that common genes affect BMD at different sites. Also, individual QUS measurements appear to be influenced by some common sets of genes rather than by environmental factors. Significant environmental correlations were only found for BMD measurements and ranged between 0.50 and 0.65 (p < 0.001). These data suggest that QUS and BMD measurements are highly heritable traits. While it appears that there is a common set of genes influencing both QUS and BMD measurements, specific genes yet to be identified appear to have greater effects than that of shared genes in each trait.
The Material Basis for Reduced Mechanical Properties in oim Mice Bones
Authors: Camacho Nancy P. , Hou Lindy , Toledano Talya R. , Ilg W. Alex , Brayton Cory F. , Raggio Cathleen L. , Root Leon , Boskey Adele L.
Published: April 2006

Osteogenesis imperfecta (OI), a heritable disease caused by molecular defects in type I collagen, is characterized by skeletal deformities and brittle bones. The heterozygous and homozygous oim mice (oim/+ and oim/oim) exhibit mild and severe OI phenotypes, respectively, serving as controlled animal models of this disease. In the current study, bone geometry, mechanics, and material properties of 1-year-old mice were evaluated to determine factors that influence the severity of phenotype in OI. The oim/oim mice exhibited significantly smaller body size, femur length, and moment of area compared with oim/+ and wild-type (+/+) controls. The oim/oim femur mechanical properties of failure torque and stiffness were 40% and 30%, respectively, of the +/+ values, and 53% and 36% of the oim/+ values. Collagen content was reduced by 20% in the oim/oim compared with +/+ bone and tended to be intermediate to these values for the oim/+. Mineral content was not significantly different between the oim/oim and +/+ bones. However, the oim/oim ash content was significantly reduced compared with that of the oim/+. Mineral carbonate content was reduced by 23% in the oim/oim bone compared with controls. Mineral crystallinity was reduced in the oim/oim and oim/+ bone compared with controls. Overall, for the majority of parameters examined (geometrical, mechanical, and material), the oim/+ values were intermediate to those of the oim/oim and +/+, a finding that parallels the phenotypes of the mice. This provides evidence that specific material properties, such as mineral crystallinity and collagen content, are indicative and possibly predictive of bone fragility in this mouse model, and by analogy in human OI.
Novel Serum Markers of Bone Resorption: Clinical Assessment and Comparison with Established Urinary Indices
Authors: Woitge Henning W. , Pecherstorfer Martin , Li Yuming , Keck Andrea-V. , Horn Eva , Ziegler Reinhard , Seibel Markus J.
Published: April 2006

Although urinary measurements of collagen degradation provide valid estimates of bone resorption, their clinical application is hampered by pronounced analytical and biological variability. Therefore, immunoassays for the determination of such parameters in serum have been developed. In this study, we assessed the performance of three new serum markers of bone turnover, i.e., C-terminal and N-terminal telopeptides of type I collagen (S-CTX and S-NTX) and bone sialoprotein. Results were compared with urinary total pyridinoline, total deoxypyridinoline, and urinary C-terminal telopeptides of type I collagen (U-CTX) and urinary N-terminal telopeptides of type I collagen (U-NTX). The study population included healthy men (n = 27), premenopausal (n = 30) and postmenopausal (n = 31) women, patients with hepatic dysfunction (HF, n = 24), renal failure (RF, n = 30), breast cancer without (BC–, n = 24) and with (BC+, n = 30) bone metastases, primary vertebral osteoporosis (OPO, n = 27), primary hyperparathyroidism (PHPT, n = 16), active Paget's disease of bone (n = 18), multiple myeloma (MM, n = 18), and patients with hypercalcemia of malignancy before and after treatment with pamidronate (HOM, n = 28). Changes in urinary and serum markers were similar in most metabolic bone diseases. However, differentiation between healthy controls and OPO, or PHPT, was improved by the serum markers. In MM, all serum and urinary markers were elevated (p < 0.05 vs. controls). In BC+, skeletal involvement was reflected by significant increments in all indices (p < 0.01 vs. BC–), except U-CTX and S-CTX. In HOM, pamidronate-induced changes in biomarkers were most pronounced for U-CTX and S-CTX and S-NTX. HF and RF were associated with elevated levels of all serum markers (p < 0.05 vs. controls). In conclusion, measurements in serum reflect bone resorption to the same extent as the urinary indices. Since serum markers circumvent some of the limitations of urinary measurements, their use potentially improves the assessment of skeletal disorders.
Biochemical Markers of Bone Turnover and Prediction of Hip Bone Loss in Older Women: The Study of Osteoporotic Fractures
Authors: Bauer Douglas C. , Sklarin Peter M. , Stone Katie L. , Black Dennis M. , Nevitt Michael C. , Ensrud Kristine E. , Arnaud Claude D. , Genant Harry K. , Garnero Patrick , Delmas Pierre D. , Lawaetz Henrik , Cummings Steven R.
Published: April 2006

To examine the ability of commercially available biochemical markers of bone formation and resorption to predict hip bone loss, we prospectively obtained serum and timed 2-h urine specimens from 295 women age 67 years or older who were not receiving estrogen replacement therapy. Serum was assayed for two markers of bone formation: osteocalcin (OC) and bone-specific alkaline phosphatase (BALP). Urine specimens were assayed for four markers of bone resorption: N-telopeptides (NTX), free pyridinolines (Pyr), free deoxypyridinoline (Dpyr), and C-telopeptides (CTX). Measurements of hip bone mineral density were made at the time the samples were collected and then repeated an average of 3.8 years later. Higher levels of all four resorption markers were, on average, significantly associated with faster rates of bone loss at the total hip, but not at the femoral neck. Women with OC levels above the median had a significantly faster rate of bone loss than women with levels below the median, but there was no significant association between levels of BALP and hip bone loss. The sensitivity and specificity of higher marker levels for predicting rapid hip bone loss was limited, and there was considerable overlap in bone loss rates between women with high and low marker levels. We conclude that higher levels of urine NTX, CTX, Pyr, Dpyr, and serum OC are associated with faster bone loss at the hip in this population of elderly women not receiving estrogen replacement therapy, but these biochemical markers have limited value for predicting rapid hip bone loss in individuals.
Bone Mineral in Prepubertal Children: Gender and Ethnicity
Authors: Horlick Mary , Thornton John , Wang Jack , Levine Lenore S. , Fedun Barbara , Pierson Richard N.
Published: April 2006

Previous reports of gender and ethnic differences in bone mineral in prepubertal children have been inconsistent due to different methodologies, the problematic nature of bone density by dual-energy X-ray absorptiometry (DXA) calculated as the ratio of bone mineral mass to projected bone area (BA), and the generally small study populations. The aim of this study was to test the hypothesis that gender and ethnic differences in bone mineral by DXA are present in prepubertal children. The subjects were 336 healthy Asian, black, and white prepubertal children (172 females and 164 males). Total body bone mineral content (TBBMC) was adjusted for total body BA (TBBA), age, height, and weight. Adjusted mean TBBMC was greater in males than in females (p = 0.01). The gender difference was independent of ethnicity. Adjusted mean TBBMC was different for black compared with nonblack children (p = 0.001). The ethnic difference was a function of TBBA and weight. This study in a multiethnic population of prepubertal children shows (1) a gender difference in TBBMC and (2) an ethnic difference in TBBMC.
Effects of Loading Frequency on Mechanically Induced Bone Formation
Authors: Hsieh Yeou-Fang , Turner Charles H.
Published: April 2006

The anabolic effect of mechanical loading on bone tissue is modulated by loading frequency. The objective of this study was to characterize the new bone formation on the periosteal and endocortical surfaces of the ulnar diaphysis in adult, female rats in response to controlled dynamic loading and to examine the interactions between strain magnitude, loading frequency, and bone formation rate (BFR/BS) for frequencies ranging from 1 to 10 Hz. Cyclic, compressive loading was applied to the ulnas of 60 adult, female rats divided into 12 loading groups. Loading was applied for 360 cycles/day with peak loads ranging from 4.3 to 18N at frequencies of 1, 5, and 10 Hz. After 2 weeks of loading, bone formation on the periosteal and endocortical surfaces of the ulna was quantified using double-label histomorphometry on transverse sections obtained at the middiaphysis. Periosteal bone formation increased in a dose-response manner with peak load at each of the three loading frequencies tested. Loading frequency significantly affected the x intercepts and slopes of the peak strain versus BFR/BS (p < 0.001) and peak strain versus mineralizing surface (MS/BS; p < 0.001) curves. Periosteal osteogenesis was best predicted by a mathematical model that assumed: (1) bone cells are activated by fluid shear stresses and (2) that stiffness of the bone cells and the extracellular matrix near the cells increases at higher loading frequencies because of viscoelasticity. Consequently, mechanotransduction appears to involve a complex interaction between extracellular fluid forces and cellular mechanics.
Tumor Necrosis Factor α-Induced Osteoclastogenesis Requires Tumor Necrosis Factor Receptor-Associated Factor 6
Authors: Kaji Keisuke , Katogi Rei , Azuma Yoshiaki , Naito Asuka , Inoue Jun-Ichiro , Kudo Akira
Published: April 2006

Although tumor necrosis factor receptor-associated factor 6 (TRAF6) is required in receptor activator of NF-κB-receptor activator of NF-κB ligand (RANK-RANKL) signaling for osteoclastogenesis, it has remained unclear whether TRAF6 is crucial in tumor necrosis factor α (TNF-α)-induced osteoclastogenesis. We examined TRAF6 function in the TNF-α-induced osteoclastogenesis by using osteoclast progenitor cells from TRAF6-deficient mice. The results indicated that TNF-α did not effectively induce osteoclast differentiation from osteoclast progenitor cells derived from these mice into mature multinucleated osteoclasts, although c-jun N-terminal kinase (JNK) and TNF-α activation was observed in osteoclast progenitor cells. Thus, we have provided the first evidence showing that TRAF6 is involved in TNF-α-induced osteoclastogenesis.
Pathophysiology and Recent Advances in the Management of Renal Osteodystrophy
Authors: Elder Grahame
Published: April 2006

Bone disease is observed in 75–100% of patients with chronic renal failure as the glomerular filtration rate (GFR) falls below 60 ml/minute. Hyperparathyroid (high turnover) bone disease is found most frequently followed by mixed osteodystrophy, low-turnover bone disease, and osteomalacia. With advancing renal impairment, “skeletal resistance” to parathyroid hormone (PTH) occurs. To maintain bone turnover, intact PTH (iPTH) targets from two to four times the upper normal range have been suggested, but whole PTH(1–84) assays indicate that amino-terminally truncated fragments, which accumulate in end-stage renal disease (ESRD), account for up to one-half of the measured iPTH. PTH levels and bone-specific alkaline phosphatase (BSAP) provide some information on bone involvement but bone biopsy and histomorphometry remains the gold standard. Calcitriol and calcium salts can be used to suppress PTH and improve osteomalacia but there is growing concern that these agents predispose to the development of vascular calcification, cardiovascular morbidity, low-turnover bone disease and fracture. Newer therapeutic options include less calcemic vitamin D analogues, calcimimetics and bisphosphonates for hyperparathyroidism, and sevelamer for phosphate control. Calcitriol and hormone-replacement therapy (HRT) have been shown to maintain bone mineral density (BMD) in certain patients with end-stage renal disease (ESRD). After renal transplantation, renal osteodystrophy generally improves but BMD often worsens. Bisphosphonate therapy may be appropriate for some patients at risk of fracture. When renal bone disease is assessed using a combination of biochemical markers, histology and bone densitometry, early intervention and the careful use of an increasing number of effective therapies can reduce the morbidity associated with this common problem.
Vitamin D Analogue-Specific Recruitment of Vitamin D Receptor Coactivators
Authors: Issa Laura L. , Leong Gary M. , Sutherland Robert L. , Eisman John A.
Published: April 2006

Synthetic ligands for the vitamin D receptor (VDR) are potential therapeutic agents for metabolic, neoplastic, and autoimmune disorders. Some of these ligands have similar or more potent antiproliferative, yet reduced hypercalcemic actions, than calcitriol. However, the mechanisms for these differential actions have not been clearly defined. We hypothesized that these gene- and tissue-specific effects may relate to ligand-directed selective recruitment of transcriptional coactivators. To identify key elements in ligand structure that facilitate VDR-coactivator interactions, the current studies assessed the ability of the VDR to recruit the coactivators GRIP1 and RAC3 following activation by a series of 20-R- and 20-S (20-epi)-modified analogues. The strength of VDR-coactivator interactions was ligand-specific and did not always correlate with ligand-receptor binding affinity. In general, the 20-epi analogues enhanced these interactions, whereas the 20-R-modified analogues were less effective than calcitriol. The 16-ene,23-yne modification and fluorinated substituents to the side-chain attenuated interaction with coactivators. The enhanced ability of the VDR to recruit GRIP1 following activation by the 20-epi analogues was consistent with potentiation of 20-epi analogue-induced transactivation of the osteocalcin gene promoter by GRIP1. Overall, the structure of the ligand side-chain as well as its orientation seemed to affect the avidity of coactivator binding. These results suggest that selective recruitment of coactivators may contribute to gene- and tissue-specific effects of vitamin D analogues.
Overexpression of Dlx5 in Chicken Calvarial Cells Accelerates Osteoblastic Differentiation
Authors: Tadic Tade , Dodig Milan , Erceg Ivana , Marijanovic Inga , Mina Mina , Kalajzic Zana , Velonis Dimitrios , Kronenberg Mark S. , Kosher Robert A. , Ferrari Deborah , Lichtler Alexander C.
Published: April 2006

Our laboratory and others have shown that a homeodomain protein binding site plays an important role in transcription of the Col1a1 gene in osteoblasts. This suggests that homeodomain proteins have an important role in osteoblast differentiation. We have investigated the role of Dlx5 in osteoblastic differentiation. In situ hybridization studies indicated that Dlx5 is expressed in chick calvarial osteoblasts (cCOB) in vivo. Northern blot analysis indicated that Dlx5 expression in cultured cCOBs is induced concurrently with osteoblastic markers. To study the effect of overexpression of Dlx5 on osteoblast differentiation, we infected primary osteoblast cultures from 15-day-old embryonal chicken calvaria with replication competent retroviral vectors [RCASBP(A)] expressing Dlx5 or control replication competent avian splice acceptor brianhightiter polymerase subtype A [RCASBP(A)]. Expression of Col1a1, osteopontin, alkaline phosphatase, and osteocalcin messenger RNA (mRNA) occurred sooner and at higher levels in cultures infected with RCASBP(A)DLX5 than in RCASBP(A)-infected cultures. Mineralization of Dlx5-expressing cultures was evident by days 12-14, and RCAS-infected control osteoblasts did not begin to mineralize until day 17. Dlx5 also stimulated osteoblastic differentiation of calvarial cells that do not normally undergo osteoblastic differentiation in vitro. Our results suggest that Dlx5 plays an important role in inducing calvarial osteoblast differentiation.
Role of Inducible Nitric Oxide Synthase in Skeletal Adaptation to Acute Increases in Mechanical Loading
Authors: Watanuki Makoto , Sakai Akinori , Sakata Takeshi , Tsurukami Hiroshi , Miwa Masao , Uchida Yasuo , Watanabe Ken , Ikeda Kyoji , Nakamura Toshitaka
Published: April 2006

To clarify the role of nitric oxide (NO) in regulation of bone metabolism in response to skeletal loading, we examined inducible NO synthase (iNOS) gene knockout mice in the tail-suspension model. Histomorphometric analyses of proximal tibias revealed that 7 days of tail suspension decreased the bone volume (BV/TV) and bone formation rate (BFR/BS) and increased the osteoclast surface (Oc.S/BS) in mice with all iNOS genotypes. Both iNOS+/+ and iNOS+/− mice responded to subsequent 14-day reloading, with increases in BV/TV and BFR/BS and a decrease in Oc.S/BS, whereas these responses were abolished in iNOS−/− mice. The osteoblasts flattened after tail suspension appeared cuboidal during subsequent reloading. Immunoreactivity for iNOS was detected in these osteoblasts and osteocytes by immunohistochemistry. These defective responses after reloading were rescued in iNOS−/− mice by treatment with an NO donor nitroglycerine (NG). Conversely, the responses in iNOS+/+ mice were inhibited by treatment with an NOS inhibitor aminoguanidine (AG). In bone marrow cell cultures, mineralized nodules derived from iNOS−/− mice after reloading were significantly reduced. Taken together, our results suggest that NO generated by iNOS in osteoblasts plays a critical role in adjusting bone turnover and increasing osteogenic activity in response to the acute increase in mechanical loading after tail suspension.
Male Sex and Low Physical Activity Are Associated With Reduced Spine Bone Mineral Density in Survivors of Childhood Acute Lymphoblastic Leukemia
Authors: Tillmann V. , Darlington A. S. E. , Eiser C. , Bishop N. J. , Davies H. A.
Published: April 2006

Survivors of acute lymphoblastic leukemia (ALL) are at risk of osteoporosis and obesity. We studied bone mineral density (BMD), percent of fat mass (%FM), and activity levels in survivors of ALL treated without radiotherapy. Lumbar and total areal BMD (g/cm2) and %FM were measured in 28 survivors (aged 5.7-14.7 years) of childhood ALL by dual-energy X-ray absorptiometry (DXA) scan (GE Lunar, Prodigy) an average of 5 years after completion of chemotherapy (UK Medical Research Council randomized trial protocol XI [UKALL XI]). One boy fractured his arm during treatment. Apparent volumetric lumbar BMD (BMD vol; g/cm3) was calculated and %FM was adjusted for sex and age (%FM adj). Physical activity was measured by accelerometer and questionnaire. The results were compared with 28 sex- and age-matched healthy controls. Total body and lumbar areal BMD (g/cm2) were not different between the ALL group and the control group. However, mean lumbar BMD vol in survivors of ALL was significantly lower than in controls (0.303 ± 0.036 g/cm3 vs. 0.323 ± 0.03 g/cm3; p < 0.01), which mostly was caused by the difference in boys (0.287 ± 0.032 g/cm3 vs. 0.312 ± 0.027 g/cm3; p < 0.05). Weekly activity score by questionnaire was significantly lower in the ALL group than in the control group (geometric mean 50 vs. geometric mean 74; p < 0.05). Male gender, low activity levels and an intravenous (iv) high dose of methotrexate were associated with low lumbar BMD vol. Patients who received an iv high dose of methotrexate (n = 18) had significantly higher %FM adj than those with intrathecal methotrexate only (n = 10; 141 ± 70% vs. 98 ± 37%; p < 0.05). In conclusion, male survivors of childhood ALL have reduced lumbar BMD vol, whereas no such difference was seen in girls. Overall, survivors of ALL were physically less active than their healthy controls and lower activity correlated with lower lumbar BMD vol and higher %FM adj.
Association Between Bone Mineral Density and the Use of Nonsteroidal Anti-Inflammatory Drugs and Aspirin: Impact of Cyclooxygenase Selectivity
Authors: Carbone Laura D , Tylavsky Frances A , Cauley Jane A , Harris Tamara B , Lang Thomas F , Bauer Douglas C , Barrow Karen D , Kritchevsky Stephen B
Published: April 2006

BMD was examined in users of NSAIDs (by COX selectivity) and aspirin in the Health ABC cohort (n = 2853). Significantly higher BMD was found in users of relative COX-2 selective NSAIDs with aspirin (COX-2/ASA) compared with nonusers. This suggests a role for COX-2/ASA in osteoporosis.

Introduction: The purpose of this study was to determine the relationship of nonsteroidal anti-inflammatory drug (NSAID) use, by cyclo-oxygenase selectivity (COX), and aspirin use on bone mineral density (BMD) in participants from the Health, Aging, and Body Composition (Health ABC) population-based cohort. It is known that NSAIDs inhibit the COX enzyme and decrease production of prostaglandins, which are involved in regulation of bone turnover. COX has two isoforms, COX-1 and COX-2. Production of prostaglandins associated with bone loss is primarily mediated through the COX-2 pathway. In addition, aspirin may have effects on bone independent of the prostaglandin pathway.

Materials and Methods: NSAID (by COX selectivity) and aspirin use and BMD were assessed in 2853 adults (49.5% women, 50.5% men; 43.1% black, 56.9% white; mean age: 73.6 years) from the Health ABC cohort. For the purposes of this analysis, relative COX-1 selective NSAIDs were defined as having a ratio of COX-1 IC50 to COX-2 IC50 of >1 in whole blood, and relative COX-2 selective NSAIDs were defined as having a ratio of COX-1 IC50 to COX-2 IC50 of <1 in whole blood. Analysis of covariance was used to compare BMD across each NSAID use and aspirin use category adjusting for age, race, gender, weight, height, study site, calcium and vitamin D supplementation, Womac score, history of rheumatoid arthritis, history of arthritis other than rheumatoid, and smoking status.

Results: After adjustment for possible confounders, current use of relative COX-2 selective NSAIDs with aspirin was associated with higher BMD at the whole body (4.2%, 1.2–7.3 CI) and total hip (4.6%, 0.5–8.8 CI) by DXA and at both trabecular (34.1%, 15.4–52.7 CI) and cortical spine (12.8%, 2.3–23.3 CI) by quantitative computed tomography.

Conclusions: Our data suggest that the combination of relative COX-2 selective NSAIDs and aspirin is associated with higher BMD at multiple skeletal sites in men and women.
Paracrine Overexpression of IGFBP-4 in Osteoblasts of Transgenic Mice Decreases Bone Turnover and Causes Global Growth Retardation
Authors: Zhang Mei , Faugere Marie-Claude , Malluche Hartmut , Rosen Clifford J , Chernausek Steven D , Clemens Thomas L
Published: April 2006

Insulin-like growth factor binding protein 4 (IGFBP-4) is abundantly expressed in bone and is generally believed to function as an inhibitor of IGF action. To investigate the function of locally produced IGFBP-4 in bone in vivo, we targeted expression of IGFBP-4 to osteoblasts using a human osteocalcin promoter to direct transgene expression. IGFBP-4 protein levels in calvaria of transgenic (OC-BP4) mice as measured by Western ligand blot were increased 25-fold over the endogenous level. Interestingly, levels of IGFBP-5 were decreased in the OC-BP4 mice, possibly because of a compensatory alteration in IGF-1 action. Morphometric measurements showed a decrease in femoral length and total bone volume in transgenic animals compared with the controls. Quantitative histomorphometry at the distal femur disclosed a striking reduction in bone turnover in the OC-BP4 mice. Osteoblast number/bone length and bone formation rate/bone surface in OC-BP4 mice were approximately one-half that seen in control mice. At birth, OC-BP4 mice were of normal size and weight but exhibited striking postnatal growth retardation. Organ allometry (mg/g body weight) analysis revealed that, whereas most organs exhibited a proportional reduction in weight, calvarial and femoral wet weights were disproportionally small (∼70% and 80% of control, respectively). In conclusion, paracrine overexpression of IGFBP-4 in the bone microenvironment markedly reduced cancellous bone formation and turnover and severely impaired overall postnatal skeletal and somatic growth. We attribute these effects to the sequestration of IGF-1 by IGFBP-4 and consequent impairment of IGF-1 action in skeletal tissue.
Is the Use of Placebo Controls Ethically Permissible in Clinical Trials of Agents Intended to Reduce Fractures in Osteoporosis?
Authors: Brody Baruch A , Dickey Nancy , Ellenberg Susan S , Heaney Robert P , Levine Robert J , O'brien Richard L , Purtilo Ruth B , Weijer Charles
Published: April 2006

Substantial progress has been made in developing treatments that reduce the risk of fractures in osteoporosis. However, available treatments are only partially effective, they are not widely used, and there is need to search for more effective means of fracture prevention. Currently known effective means of reducing fractures were found using randomized placebo-controlled trials. The use of placebo controls in clinical trials has been a subject of significant controversy in recent years. The Declaration of Helsinki revision of October 2000 caused great concern among clinical investigators about the future use of placebo controls if known effective therapeutic agents are available. A working group of ethicists, clinical trial design experts, and clinical investigators examined the current state of knowledge of osteoporosis treatment and trials. They concluded that if placebo controls put subjects at substantial risk of serious outcomes, they are not ethically permissible. Placebo controls in osteoporosis trials with fracture as the measured outcome are permissible only under narrowly defined conditions. Placebo controls may be used if competent, well-informed patients refuse approved therapies for sound reasons, there is a reasonable basis for substantial disagreement or lack of consensus among professionals about whether approved treatments are better than placebos, or subjects are refractory to known effective agents. Active control trials are permissible and desirable if they can be designed and conducted in ways that overcome the interpretive difficulties often associated with such trials.
Increased Bone Formation in Mice Lacking Plasminogen Activators
Authors: Daci E , Everts V , Torrekens S , Van Herck E , Tigchelaar-Gutterr W , Bouillon R , Carmeliet G
Published: April 2006

Plasminogen activators tPA and uPA are involved in tissue remodeling, but their role in bone growth is undefined. Mice lacking tPA and uPA show increased bone formation and bone mass. The noncollagenous components of bone matrix are also increased, probably from defective degradation. This study underlines the importance of controlled bone matrix remodeling for normal endochondral ossification.

Introduction: Proteolytic pathways are suggested to play a role in endochondral ossification. To elucidate the involvement of the plasminogen activators tPA and uPA in this process, we characterized the long bone phenotype in mice deficient in both tPA and uPA (tPA−/−:uPA−/−).

Materials and Methods: Bones of 2- to 7-day-old tPA−/−:uPA−/− and wild-type (WT) mice were studied using bone histomorphometry, electron microscopy analysis, and biochemical assessment of bone matrix components. Cell-mediated degradation of metabolically labeled bone matrix, osteoblast proliferation, and osteoblast differentiation, both at the gene and protein level, were studied in vitro using cells derived from both genotypes.

Results: Deficiency of the plasminogen activators led to elongation of the bones and to increased bone mass (25% more trabecular bone in the proximal tibial metaphysis), without altering the morphology of the growth plate. In addition, the composition of bone matrix was modified in plasminogen activator deficient mice, because an increased amount of proteoglycans (2×), osteocalcin (+45%), and fibronectin (+36%) was detected. Matrix degradation assays showed that plasminogen activators, by generating plasmin, participate in osteoblast-mediated degradation of the noncollagenous components of bone matrix. In addition, proliferation of primary osteoblasts derived from plasminogen activator-deficient mice was increased by 35%. Finally, osteoblast differentiation and formation of a mineralized bone matrix were enhanced in osteoblast cultures derived from tPA−/−:uPA−/− mice.

Conclusions: The data presented indicate the importance of the plasminogen system in degradation of the noncollagenous components of bone matrix and suggest that the accumulation of these proteins in bone matrix—as occurs during plasminogen activator deficiency—may in turn stimulate osteoblast function, resulting in increased bone formation.
Metabolic Acidosis Stimulates RANKL RNA Expression in Bone Through a Cyclo-oxygenase-Dependent Mechanism
Authors: Frick Kevin K , Bushinsky David A
Published: April 2006

Metabolic acidosis inhibits osteoblastic bone formation and stimulates osteoclastic resorption. To determine whether acidosis alters expression of RNA for the osteoclastic differentiation factor RANKL, mouse calvariae were incubated in neutral or physiologically acidic media. Acidosis resulted in a significant cyclo-oxygenase-dependent increase in RANKL RNA levels, which would be expected to induce the associated increase in bone resorption.

Introduction: Metabolic acidosis increases net calcium efflux from bone, initially through physicochemical mechanisms and later through predominantly cell-mediated mechanisms. Acidosis decreases osteoblastic bone formation and increases osteoclastic resorption. The growth and maturation of osteoclasts, derived from hematopoietic precursors in the monocyte/macrophage lineage, are dependent on the interplay of a number of factors. Commitment of pre-osteoclasts to osteoclasts is induced by the interaction of the osteoclastic cell-surface receptor RANK with a ligand expressed by osteoblasts, RANKL. The RANK/RANKL interaction not only initiates a differentiation cascade that culminates in mature bone-resorbing osteoclasts but also increases osteoclastic resorptive capacity and survival.

Methods: To test the hypothesis that metabolic acidosis increases expression of RANKL, we cultured neonatal mouse calvariae in acidic (initial medium pH ∼7.1 and [HCO3−] ∼11 mM) or neutral (initial medium pH ∼7.5 and [HCO3−] ∼25 mM) medium for 24 and 48 h. We determined the relative expression of RANKL RNA by reverse transcriptase-polymerase chain reaction (RT-PCR) and quantitated the expression by Northern analysis.

Results: In this model of metabolic acidosis, there was significantly increased expression of RANKL RNA at both 24 (2-fold) and 48 h (5-fold) compared with respective controls. Net calcium efflux from bone was also increased in acidic medium compared with control medium. At 48 h, net calcium efflux correlated directly with RANKL expression (r = 0.77, n = 15, p < 0.001). Inhibition of prostaglandin synthesis with indomethacin blocked the acid-induced increase in RANKL RNA as well as the increased calcium efflux.

Conclusions: Metabolic acidosis induces osteoblastic prostaglandin synthesis, followed by autocrine or paracrine induction of RANKL. This increase in RANKL would be expected to augment osteoclastic bone resorption and help explain the increase in cell-mediated net calcium efflux.
Characterization of a Soluble Ligand Binding Domain of the NMDA Receptor Regulatory Subunit NR3A
Authors: Yao Yongneng , Mayer Mark L.
Published: April 2006

NR3A is expressed widely in the developing CNS of mammals. Coassembly of NR3A with NR1 and NR2 modifies NMDA receptor-mediated responses, reducing calcium permeability and single-channel conductance. The ligand binding properties of NR3A are unknown but shape the role NR3A plays when incorporated into NMDA receptors. Here, a soluble NR3A ligand binding domain (NR3A S1S2) was constructed based on amino acid sequence alignments with other glutamate receptor ion channels and is expressed inEscherichia coli. After purification by affinity, gel filtration, and ion exchange chromatography, NR3A S1S2 behaves as a monomer even at a concentration of 20 mg/ml, as determined by size-exclusion chromatography and dynamic light scattering. NR3A S1S2 has very high affinity for glycine with an apparent dissociation constant (Kd) of 40 nm, 650-fold less than theKdfor NR1. Glutamate, which binds to NR2 subunits, also binds to NR3A, but with very low affinity (Kd= 9.6 mm); in contrast, binding of glutamate to NR1 was not detectable even at a 300 mmconcentration. The antagonist binding profiles of NR3A and NR1 also show striking differences. 6-Cyano-2,3-dihydroxy-7-nitro-quinoxaline (CNQX), and its analogCGP78608, bind to NR3A S1S2 with low micromolar affinity, whereas for NR1, the affinity ofCGP78608increases 1000-fold compared with CNQX. Other high-affinity NR1 antagonists also show very weak binding to NR3A. Proteolysis protection experiments reveal that CNQX andCGP78608bind to and stabilize domain 1 of NR3A S1S2 but increase proteolysis of domain 2, indicating that they produce conformational changes distinct from those induced by glycine andd-serine.
The Discursive Malleability of an Identity
Authors: LaDousa Chaise
Published: April 2006

This article employs a dialogic approach, in the parlance of Bakhtin, to explore the ways in which a school smedium,its primary language of instruction, has become a major category of identity in North India. Many people describe themselves and others by invoking attendance at either a Hindi‐ or English‐medium school. The first task of this article is to account for what Bakhtin callscentripetal forcesthat enable people at different positions in terms of class or school experience to use a common duality of Hindiversus English‐medium and its attendant social resonances. The second task is to account for the abilities of a teacher to question the inevitability of the medium divide and to radically reframe what is important about schooling. Her abilities derive, in part, from her experiences with schools, attesting to Bakhtin s insight that centripetal forces in language are never total, and that centrifugal forces arise from complex engagements with institutions.
Comparative Arawakan Histories: Rethinking Language Family and Culture Area in Amazonia
Authors: Aikhenvald Alexandra Y.
Published: April 2006

Comparative Arawakan Histories: Rethinking Language Family and Culture Area in Amazonia By Jonathan D. Hill Fernando Santos‐Granero. eds. Urbana. University of Illinois Press. 2002.
I Am My Language: Discourses of Women and Children in the Borderlands
Authors: De Fina Anna
Published: April 2006

I Am My Language: Discourses of Women and Children in the Borderlands By Norma González. Tucson. The University of Arizona Press. 2001.
Words and Phrases: Corpus Studies of Lexical Semantics
Authors: Goddard Cliff
Published: April 2006

Words and Phrases: Corpus Studies of Lexical Semantics By Michael Stubbs. Massachusetts. Blackwell Publishers. 2001.
Language Endangerment and Language Maintenance
Authors: Turin Mark
Published: April 2006

Language Endangerment and Language Maintenance: By David Bradley and Maya Bradley. eds. London. RoutledgeCurzon (Taylor and Francis Group). 2002.
Language Contact and Language Conflict in Arabic: Variations on Sociolinguistic Theme
Authors: Wagner Lauren
Published: April 2006

Language Contact and Language Conflict in Arabic: Variations on Sociolinguistic Theme By Aleya Rouchdy. ed. London. RoutledgeCurzon. 2002.
Scandalous Events: Metropolitan Culture and Moral Change in Post-Second World War London
Authors: MORT FRANK
Published: April 2006

ABSTRACT Historians of the sexual and cultural changes associated with the “permissive” moment of the 1960s have tended to emphasize a progressive narrative of reform focused on national policies and their social outcomes. This article explores a diffierent dynamic, highlighting the ways in which a series of scandalous and transgressive events, associated with particular networks of metropolitan culture in London, played a significant role in reshaping sexual beliefs and attitudes within English society during the postwar period.
Monstrous Acts: Problematizing Violence in Young Adult Literature
Authors: Franzak Judith , Noll Elizabeth
Published: April 2006

Despite a growing body of work that draws attention to the presence of violence in the mass media and its effects on youth, little critical attention has been paid to the role of violence in young adult literature. The authors believe that by bringing violence to the foreground in the study of texts, they can enrich and deepen what these stories offer readers. They suggest that the study of textual representations of violence is an important and underdeveloped aspect of literary analysis.

Using a conceptual model, the authors analyzed violence in contemporary young adult fiction on three levels: individual, institutional, and cultural‐structural. They present descriptive analyses of eight novels and offer ideas and resources for engaging students in critical inquiry of the violence portrayed.
Comprehension Strategy Use During Peer‐Led Discussions of Text: Ninth Graders Tackle “The Lottery”
Authors: Berne Jennifer I. , Clark Kathleen F.
Published: April 2006

This article reports and discusses the findings of an initial inquiry into secondary school students' comprehension strategy use during small‐group, peer‐led discussions of literary text. One classroom of ninth‐grade English students in the midwestern United States participated in the inquiry. Data consisted of the verbatim transcripts of four small groups of students in the class who engaged in discussions. Two research questions were explored:

Is there evidence of comprehension strategy use during students' small‐group, peer‐led discussions of text?

If so, what is the nature of students' comprehension strategy use?

The transcripts were coded with an instrument derived from research‐validated comprehension strategies cited in the literature. The data revealed evidence of students' use of multiple comprehension strategies.
Inheritance of Resistance to Sorghum Shoot Fly, Atherigona soccata
Authors: Dhillon M. K. , Sharma H. C. , Reddy B. V. S. , Singh Ram , Naresh J. S.
Published: April 2006

The sorghum shoot fly, Atherigona soccata Rond. (Diptera: Muscidae), is one of the most important pests of sorghum [Sorghum bicolor (L.) Moench], and host plant resistance is an important component for the management of this pest. Most of the sorghum hybrids currently under cultivation are based on cytoplasmic male‐sterility (CMS). To develop a strategy to develop sorghum hybrids with resistance to shoot fly, we studied the nature of gene action for resistance to this pest in F1 hybrids derived from shoot fly‐resistant and ‐susceptible CMS and restorer lines. The hybrids based on shoot fly‐resistant CMS and restorer lines were glossy and trichomed and had lower proportion of plants with eggs (78.5% vs. 88.4 to 93.3%) and deadhearts (40.8% vs. 60.8 to 75.3%) than the hybrids based on other cross combinations, suggesting that resistance is required in both CMS and restorer lines for obtaining shoot fly‐resistant hybrids. Proportional contributions of CMS lines for oviposition, deadhearts, leaf glossiness, and recovery resistance were greater than those of the restorer lines. The general (GCA) and specific combining ability (SCA) estimates suggested that inheritance for oviposition nonpreference, deadhearts, recovery resistance, and the morphological traits associated with resistance or susceptibility to A. soccata were governed by additive‐type of gene action. The SCA effects and heterosis estimates indicated that heterosis breeding would not be rewarding in breeding for resistance to shoot fly.
The Corpse and the Cargo: The Hegelian Past in Ibsen's Naturalistic Cycle
Authors: Johnston Brian
Published: April 2006

All the dead voices…They speak all at onceEach one to itself …To have lived is not enough for themThey have to talk about itTo be dead is not enough for them …Waiting for Godot

We are in for a sequentiality of improbable possibles…Finnegans Wake

Contrary to usual assumptions, Ibsen's cycle of 12 naturalistic plays, from Pillars of Society to When We Dead Awaken, is extremely learned work, closer to the writings of James Joyce or T. S. Eliot than to the typical drama of modern realism. The cycle is filled with the sense of history, the accumulations of the spirit of man. Its learning is deeply ingrained in its art, dictating form as well as content: it is unlike the learning of, say, Man and Superman, which is more or less on the surface for the audience's immediate comprehension and enjoyment.
Peter Brook's Tempest
Authors: Croyden Margaret
Published: April 2006

Peter Brook's “experiment,” as it became known, was originally launched by Jean-Louis Barrault in Paris in May, 1968, under the auspices of the Théâtre des Nations, and later performed in London. Barrault had invited Brook and the Royal Shakespeare Company to organize a company of international artists—actors, directors, scenic designers (including Joe Chaikin, Victor Garcia, and Geoffrey Reeves)—to examine and experiment with some fundamental questions in form: what is theatre, what is a play, what is the relationship of the actor to audience, and what are the conditions which serve all of them best? As a frame of reference for this research, Brook decided to work on ideas from The Tempest. The play appealed to Brook because, according to him, it had always appeared on the stage as something sentimental and pallid.
Notes on Political Street Theatre, Paris: 1968, 1969
Authors: Lebel Jean-Jacques
Published: April 2006

From the early twenties, when the Paris Dadaists enacted the Trial of Maurice Barrès in the St. Julien le Pauvre Park, to the recent theatrical events of a political nature performed in the streets, there is a long story of militant outsiders and antiartists for whom the cultural industry is just another aspect of capitalism and, as such, must be destroyed. On the other hand there are non-political Fluxus-type events, arty-farty happenings, and street shows such as those organized by the Groupe de Recherche de l'Art Visuel which claim to be “unintentional” and not aimed at the destruction of the existing social structure. These events are still concerned with the history of art, of theatre, or of culture in general and tend to be quickly absorbed into the art market, the “avant-garde” department of Madison Avenue, and wind up as the latest form of entertainment for Jackie Onassis. It is important not to confuse the art of revolution with its commercial and bourgeois imitation.
The New Cuban Theatre: A Report
Authors: Tunberg Karl A.
Published: April 2006

Cuba has had only ten years of revolution. It is a country still struggling to overcome a history of economic imperialism, social oppression, and hurricanes. Before 1959, Cuba was the world's leading supplier of dope and whores, and in Havana alone were the three most famous pornographic theatres in the world. By most standards, however, a Cuban culture, Cuban art, did not exist. (The one exception was the folk culture of the Afro-Cubans which is now flourishing and statesupported.) “Cuban theatre” consisted of a few professional groups in Havana who, by and large, did European imitations aimed at the tiny Cuban bourgeoisie.

Since 1959, the Cubans have developed an excellent professional theatre which is open to stylistic experiment; a large public which is much more honest than polite; and amateur theatre on all levels of society—in schools, factories, small towns, hospitals, cane-cutting brigades, youth brigades, the armed forces, etc.