bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Geometric Factors and Failure Load Level With the Distribution of Cervical vs. Trochanteric Hip Fractures
Authors: Pulkkinen Pasi , Eckstein Felix , Lochmüller Eva-Maria , Kuhn Volker , Jämsä Timo 
Published: June 2006

Abstract
We experimentally studied the distribution of hip fracture types at different structural mechanical strength. Femoral neck fractures were dominant at the lowest structural strength levels, whereas trochanteric fractures were more common at high failure loads. The best predictor of fracture type across all failure loads and in both sexes was the neck-shaft angle.
Introduction: Bone geometry has been shown to be a potential risk factor for osteoporotic fractures. Risk factors have been shown to differ between cervical and trochanteric hip fractures. However, the determinants of cervical and trochanteric fractures at different levels of structural mechanical strength are currently unknown. In addition, it is not known if the distribution of fracture types differs between sexes. The aim of this experimental study on excised femora was to investigate whether there exist differences in the distribution of cervical and trochanteric fractures between different structural mechanical strength levels and different sexes and to identify the geometric determinants that predict a fracture type.
Materials and Methods: The sample was comprised of 140 cadavers (77 females: mean age, 81.7 years; 63 males: mean age, 79.1 years) from whom the left femora were excised for analysis. The bones were radiographed, and geometrical parameters were determined from the digitized X-rays. The femora were mechanically tested in a side impact configuration, simulating a sideways fall. After the mechanical test, the fracture patterns were classified into cervical and trochanteric.
Results: The overall proportion of cervical fractures was higher in females (74%) than in males (49%) (p = 0.002). The fracture type distribution differed significantly across load quartiles in females (p = 0.025), but not in males (p = 0.205). At the lowest load quartiles, 94.7% of fractures in female and 62.5% in males were femoral neck fractures. At the highest quartiles, in contrast, only 52.6% of fractures in females and 33.3% in males were cervical fractures. Among geometric variables, the neck-shaft angle was the best predictor of fracture type, with higher values in subjects with cervical fractures. This finding was made in females (p &lt; 0.001) and males (p = 0.02) and was consistent across all failure load quartiles.
Conclusions: Femoral neck fractures predominate at the lowest structural mechanical strength levels, whereas trochanteric fractures are more common at high failure loads. Females are more susceptible to femoral neck fractures than males. The best predictor of fracture type across all structural strength levels and both sexes was the neck-shaft angle.
Vitamin D–Resistant Rickets and Type 1 Diabetes in a Child With Compound Heterozygous Mutations of the Vitamin D Receptor (L263R and R391S): Dissociated Responses of the CYP-24 and rel-B Promoters to 1,25-Dihydroxyvitamin D3
Authors: Nguyen Minh , d'Alesio Arnold , Pascussi Jean Marc , Kumar Rajiv , Griffin Matthew D , Dong Xiangyang , Guillozo Huguette , Rizk-Rabin Marthe , Sinding Christiane , Bougnères Pierre , Jehan Frédéric , Garabédian Michèle 
Published: June 2006

Abstract
We report here the first association between vitamin D–resistant rickets, alopecia, and type 1 diabetes in a child with compound heterozygous mutations in the VDR gene. Transfection studies suggest dissociated effects of VDR gene mutations on the regulation of genes involved in vitamin D metabolism and dendritic cell maturation.
Introduction: Whereas vitamin D may play a role in the immune tolerance process, no patient has been reported to associate hereditary vitamin D–resistant rickets (HVDRR) and an autoimmune disease, and no attempt has been made to delineate the outcome of mutations of the vitamin D receptor (VDR) on the transcription of genes controlling immune tolerance.
Materials and Methods: The VDR gene was analyzed in a child with vitamin D–resistant rickets, total alopecia, and early childhood–onset type 1 diabetes. Patient's fibroblasts and COS-7 cells transfected with wildtype or mutant VDRs were studied for ligand-binding capacity, transactivation activity using two gene promoters [CYP-24, a classical 1,25(OH)2D3-responsive gene, and relB, a critical NF-κB component for regulation of dendritic cell differentiation], VDR-RXR heterodimers association to CYP 24 VDREs by gel mobility shift assays, and co-activator binding by Glutathione-S-transferase pull-down assays.
Results: Two novel compound heterozygous mutations (L263R and R391S) were identified in the VDR ligand-binding domain in this child. Both mutations significantly impaired VDR ligand-binding capacity but had dissociated effects on CYP-24 and RelB promoter responses to vitamin D. CYP 24 response binding to SRC-1 and RXR-heterodimer binding to CYP24 VDREs were abolished in L263R mutants but normal or partially altered in R391S mutants. In the opposite, RelB responses to vitamin D were close to normal in L263R mutants but abolished in R391S mutants.
Conclusions: We report the first clinical association between HVDRR, total alopecia, and early childhood–onset type 1 diabetes. Mutations in the VDR ligand-binding domain may hamper the 1,25(OH)2D3–mediated relB responses, an effect that depends on the site of the VDR mutation and cannot be anticipated from VDR ligand-binding ability or CYP-24 response. Based on these results, we propose to survey the immune function in patients with HVDRR, including those with moderate features of rickets.
RANKL-Induced Expression of Tetraspanin CD9 in Lipid Raft Membrane Microdomain Is Essential for Cell Fusion During Osteoclastogenesis
Authors: Ishii Masaru , Iwai Kaori , Koike Masato , Ohshima Shiro , Kudo-Tanaka Eriko , Ishii Taeko , Mima Toru , Katada Yoshinori , Miyatake Kunio , Uchiyama Yasuo , Saeki Yukihiko 
Published: June 2006

Abstract
We showed that CD9, a member of tetraspanin superfamily proteins, is expressed in a specific membrane microdomain, called “lipid raft,” and is crucial for cell fusion during osteoclastogenesis after activation of the RANK/RANKL system.
Introduction: Osteoclasts are bone-resorbing multinuclear polykaryons that are essential for bone remodeling and are formed through cell fusion of mononuclear macrophage/monocyte lineage precursors. Although osteoclastogenesis has been shown to be critically regulated by the RANK/RANKL system, the mechanism how precursor cells fuse with each other remains unclear. We examined the function of CD9, a member of tetraspanin superfamily, which has previously been shown to form macromolecular membrane microdomains and to regulate cell–cell fusion in various cell types.
Materials and Methods: We used RAW264.7, a macrophage/monocyte lineage cell line, which can differentiate into osteoclast-like polykaryons on the application of RANKL. Expression and distribution of CD9 was assessed by Western blotting, fluorescence-assorted cell sorting (FACS) and immunohistochemistry with light and electron microscopy. A specific neutralizing antibody and RNA interference were used to inhibit the function of CD9, and green fluorescent protein (GFP)-CD9 was exogenously expressed to enhance the effect of CD9. The distribution of CD9 in lipid microdomain was examined by biochemical (sucrose density gradient) isolation and imaging technique.
Results: CD9 is expressed on cell surfaces of RAW264.7, which is enhanced by RANKL. Targeted inhibition of CD9 decreases the number of osteoclast-like cells. On the other hand, overexpression of CD9 promotes spontaneous cell fusion even in the absence of RANKL. CD9 is localized in detergent-insoluble “lipid raft” microdomain in RANKL stimulation, and disruption of lipid rafts markedly reduces the formation of osteoclast-like polykaryons. Immunohistochemical studies of bone tissues revealed the expression of CD9 in osteoclasts in vivo.
Conclusions: These data suggest that function of tetraspanin CD9 and its expression in lipid rafts are crucial for cell fusion during osteoclastogenesis.
Deletion of a Single Allele of the Dkk1 Gene Leads to an Increase in Bone Formation and Bone Mass
Authors: Morvan Frederic , Boulukos Kim , Clément-Lacroix Philippe , Roman Sergio Roman , Suc-Royer Isabelle , Vayssière Béatrice , Ammann Patrick , Martin Patrick , Pinho Sonia , Pognonec Philippe , Mollat Patrick , Niehrs Christof , Baron Roland , Rawadi Georges 
Published: June 2006

Abstract
Wnt/β-catenin signaling has been proven to play a central role in bone biology. Unexpectedly, the Wnt antagonist Dkk2 is required for terminal osteoblast differentiation and mineralized matrix formation. We show that Dkk1, unlike Dkk2, negatively regulates osteoblast differentiation and bone formation.
Introduction: The Wnt co-receptor LRP5 is a critical regulator of bone mass. Dickkopf (Dkk) proteins act as natural Wnt antagonists by bridging LRP5/6 and Kremen, inducing the internalization of the complex. Wnt antagonists are thus expected to negatively regulation bone formation. However, Dkk2 deficiency results in increased bone, questioning the precise role of Dkks in bone metabolism.
Materials and Methods: In this study, we investigated specifically the role of Dkk1 in bone in vitro and in vivo. Using rat primary calvaria cells, we studied the effect of retroviral expression of Dkk1 on osteoblast differentiation. In addition, the effect of Dkk1 osteoblast was studied in MC3T3-E1 cells by means of recombinant protein. Finally, to address the role of Dkk1 in vivo, we analyzed the bone phenotype of Dkk1+/− animals.
Results: Retroviral expression of Dkk1 in rat primary calvaria cells resulted in a complete inhibition of osteoblast differentiation and formation of mineralized nodules, with a marked decrease in the expression of alkaline phosphatase. Dkk1 expression also increased adipocyte differentiation in these cell cultures. Recombinant murine Dkk1 (rmDkk1) inhibited spontaneous and induced osteoblast differentiation of MC3T3-E1 cells. To determine the role of Dkk1 in vivo and overcome the embryonic lethality of homozygous deletion, we studied the bone phenotype in heterozygous Dkk1-deficient mice. Structural, dynamic, and cellular analysis of bone remodeling in Dkk1+/− mice showed an increase in all bone formation parameters, with no change in bone resorption, leading to a marked increase in bone mass. Importantly, the number of osteoblasts, mineral apposition, and bone formation rate were all increased several fold.
Conclusions: We conclude that Dkk1 protein is a potent negative regulator of osteoblasts in vitro and in vivo. Given that a heterozygous decrease in Dkk1 expression is sufficient to induce a significant increase in bone mass, antagonizing Dkk1 should result in a potent anabolic effect.
Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women's Health Initiative Randomized Trial
Authors: Jackson Rebecca D , Wactawski-Wende Jean , LaCroix Andrea Z , Pettinger Mary , Yood Robert A , Watts Nelson B , Robbins John A , Lewis Cora E , Beresford Shirley AA , Ko Marcia G , Naughton Michelle J , Satterfield Suzanne , Bassford Tamsen 
Published: June 2006

Abstract
Further analyses from the Women's Health Initiative estrogen trial shows that CEE reduced fracture risk. The fracture reduction at the hip did not differ appreciably among risk strata. These data do not support overall benefit over risk, even in women at highest risk for fracture.
Introduction: The Women's Health Initiative provided evidence that conjugated equine estrogen (CEE) can significantly reduce fracture risk in postmenopausal women. Additional analysis of the effects of CEE on BMD and fracture are presented.
Materials and Methods: Postmenopausal women 50–79 years of age with hysterectomy were randomized to CEE 0.625 mg daily (n = 5310) or placebo (n = 5429) and followed for an average 7.1 years. Fracture incidence was assessed by semiannual questionnaire and verified by adjudication of radiology reports. BMD was measured in a subset of women (N = 938) at baseline and years 1, 3, and 6. A global index was used to examine whether the balance of risks and benefits differed by baseline fracture risk.
Results: CEE reduced the risk of hip (hazard ratio [HR], 0.65; 95% CI, 0.45–0.94), clinical vertebral (HR, 0.64; 95% CI, 0.44–0.93), wrist/lower arm (HR, 0.58; 95% CI, 0.47–0.72), and total fracture (HR, 0.71; 95% CI, 0.64–0.80). This effect did not differ among strata according to age, oophorectomy status, past hormone use, race/ethnicity, fall frequency, physical activity, or fracture history. Total fracture reduction was less in women at the lowest predicted fracture risk in both absolute and relative terms (HR, 0.86; 95% CI, 0.68–1.08). CEE also provided modest but consistent positive effects on BMD. The HRs of the global index for CEE were relatively balanced across tertiles of summary fracture risk (lowest risk: HR, 0.81; 95% CI, 0.62–1.05; mid risk: HR, 1.09; 95% CI, 0.92–1.30; highest risk: HR, 1.04; 95% CI, 0.88–1.23; interaction, p = 0.42).
Conclusions: CEE reduces the risk of fracture and increases BMD in hysterectomized postmenopausal women. Even among the women with the highest risk for fractures, when considering the effects of estrogen on other important health outcomes, a summary of the burden of monitored effects does not indicate a significant net benefit.
Mice Lacking Cathepsin K Maintain Bone Remodeling but Develop Bone Fragility Despite High Bone Mass
Authors: Li Chao Yang , Jepsen Karl J , Majeska Robert J , Zhang Jian , Ni Rujing , Gelb Bruce D , Schaffler Mitchell B 
Published: June 2006

Abstract
Bone microstructural and biomechanical properties were analyzed in mice genetically lacking cathepsin K (CatK). CatK deficiency (CatK−/−) produced mild osteopetrosis, elevated numbers of osteoclasts, regions of disorganized bone microstructure, and increased bone fragility, showing how chronic alteration of enzyme activity during skeletal development dramatically affects bone organization and function.
Introduction: Mouse models of CatK deficiency recapitulate the osteopetrosis of human pyknodysostosis and allow study of clinically relevant issues: how inhibition of this enzyme activity affects bone integrity structurally and biomechanically. To address these questions, we generated CatK-deficient mice by targeted disruption of the Ctsk gene and compared their bone structural and mechanical properties with wildtype (WT) controls.
Materials and Methods: Standard histomorphometric and biomechanical analyses were performed on femora from C57BL/6J male and female CatK−/−, CatK+/−, and WT mice.
Results: CatK−/− femora exhibited the mild metaphyseal osteopetrosis, a greater cortical bone area and thickness, normal bone strength, but a high degree of brittleness (nearly 50–70% decrease in postyield displacement versus WT) and a 30–40% reduction in the work-to-failure. In cancellous bone, osteoclast numbers and resorption surface were increased markedly (∼150% and 50%, respectively), despite the overall decrease in net bone resorption for CatK-deficient mice. Bone formation indices were altered in CatK−/− mice as well, with significant increases in mineral appositional rate, but not in bone formation surface; these data suggest difference in osteoblast work but not in their recruitment in CatK deficiency. CatK-deficient cortical bones had large areas of woven bone and intracortical resorption spaces within the disorganized tissue. Bone phenotype in CatK−/− was similar in males and females.
Conclusions: Genetic CatK deficiency in mice results not only in the impairment of osteoclast function and osteopetrosis, but also altered osteoblast function, defective tissue organization, and very brittle bones. Whether this bone fragility in CatK deficiency results entirely from indirect effects of suppressed bone turnover because of impaired osteoclast function or perhaps represents a previously unappreciated more direct role for CatK in bone formation remains to be established.
Influence of Mom and Dad: Quantitative Genetic Models for Maternal Effects and Genomic Imprinting
Authors: Santure Anna W , Spencer Hamish G 
Published: June 2006

Abstract
The expression of an imprinted gene is dependent on the sex of the parent it was inherited from, and as a result reciprocal heterozygotes may display different phenotypes. In contrast, maternal genetic terms arise when the phenotype of an offspring is influenced by the phenotype of its mother beyond the direct inheritance of alleles. Both maternal effects and imprinting may contribute to resemblance between offspring of the same mother. We demonstrate that two standard quantitative genetic models for deriving breeding values, population variances and covariances between relatives, are not equivalent when maternal genetic effects and imprinting are acting. Maternal and imprinting effects introduce both sex-dependent and generation-dependent effects that result in differences in the way additive and dominance effects are defined for the two approaches. We use a simple example to demonstrate that both imprinting and maternal genetic effects add extra terms to covariances between relatives and that model misspecification may over- or underestimate true covariances or lead to extremely variable parameter estimation. Thus, an understanding of various forms of parental effects is essential in correctly estimating quantitative genetic variance components.
Unequal Sister Chromatid and Homolog Recombination at a Tandem Duplication of the a1 Locus in Maize
Authors: Yandeau-Nelson Marna D , Xia Yiji , Li Jin , Neuffer M Gerald , Schnable Patrick S 
Published: June 2006

Abstract
Tandemly arrayed duplicate genes are prevalent. The maize A1-b haplotype is a tandem duplication that consists of the components, α and β. The rate of meiotic unequal recombination at A1-b is ninefold higher when a homolog is present than when it is absent (i.e., hemizygote). When a sequence heterologous homolog is available, 94% of recombinants (264/281) are generated via recombination with the homolog rather than with the sister chromatid. In addition, 83% (220/264) of homolog recombination events involved α rather than β. These results indicate that: (1) the homolog is the preferred template for unequal recombination and (2) pairing of the duplicated segments with the homolog does not occur randomly but instead favors a particular configuration. The choice of recombination template (i.e., homolog vs. sister chromatid) affects the distribution of recombination breakpoints within a1. Rates of unequal recombination at A1-b are similar to the rate of recombination between nonduplicated a1 alleles. Unequal recombination is therefore common and is likely to be responsible for the generation of genetic variability, even within inbred lines.
A Bayesian Heterogeneous Analysis of Variance Approach to Inferring Recent Selective Sweeps
Authors: Marshall John M , Weiss Robert E 
Published: June 2006

Abstract
The distribution of microsatellite allele sizes in populations aids in understanding the genetic diversity of species and the evolutionary history of recent selective sweeps. We propose a heterogeneous Bayesian analysis of variance model for inferring loci involved in recent selective sweeps by analyzing the distribution of allele sizes at multiple loci in multiple populations. Our model is shown to be consistent with a multilocus test statistic, ln RV, proposed for identifying microsatellite loci involved in recent selective sweeps. Our methodology differs in that it accepts original allele size data rather than summary statistics and allows the incorporation of prior knowledge about allele frequencies using a hierarchical prior distribution consisting of log normal and gamma probability distributions. Interesting features of the model are its ability to simultaneously analyze allele size data for any number of populations and to cope with the presence of any number of selected loci. The utility of the method is illustrated by application to two sets of microsatellite allele size data for a group of West African Anopheles gambiae populations. The results are consistent with the suppressed-recombination model of speciation, and additional candidate loci on chromosomes 2 (079 and 175) and 3 (088) are discovered that escaped former analysis.
Quantitative Trait Linkage Analysis Using Gaussian Copulas
Authors: Li Mingyao , Boehnke Michael , Abecasis Gonçalo R , Song Peter X-K 
Published: June 2006

Abstract
Mapping and identifying variants that influence quantitative traits is an important problem for genetic studies. Traditional QTL mapping relies on a variance-components (VC) approach with the key assumption that the trait values in a family follow a multivariate normal distribution. Violation of this assumption can lead to inflated type I error, reduced power, and biased parameter estimates. To accommodate nonnormally distributed data, we developed and implemented a modified VC method, which we call the “copula VC method,” that directly models the nonnormal distribution using Gaussian copulas. The copula VC method allows the analysis of continuous, discrete, and censored trait data, and the standard VC method is a special case when the data are distributed as multivariate normal. Through the use of link functions, the copula VC method can easily incorporate covariates. We use computer simulations to show that the proposed method yields unbiased parameter estimates, correct type I error rates, and improved power for testing linkage with a variety of nonnormal traits as compared with the standard VC and the regression-based methods.
An Integrated-Likelihood Method for Estimating Genetic Differentiation Between Populations
Authors: Kitakado Toshihide , Kitada Shuichi , Kishino Hirohisa , Skaug Hans Julius 
Published: June 2006

Abstract
The aim of this article is to develop an integrated-likelihood (IL) approach to estimate the genetic differentiation between populations. The conventional maximum-likelihood (ML) and pseudolikelihood (PL) methods that use sample counts of alleles may cause severe underestimations of FST, which means overestimations of θ = 4Nm, when the number of sampling localities is small. To reduce such bias in the estimation of genetic differentiation, we propose an IL method in which the mean allele frequencies over populations are regarded as nuisance parameters and are eliminated by integration. To maximize the IL function, we have developed two algorithms, a Monte Carlo EM algorithm and a Laplace approximation. Our simulation studies show that the method proposed here outperforms the conventional ML and PL methods in terms of unbiasedness and precision. The IL method was applied to real data for Pacific herring and African elephants.
Scan of Human Genome Reveals No New Loci Under Ancient Balancing Selection
Authors: Bubb K L , Bovee D , Buckley D , Haugen E , Kibukawa M , Paddock M , Palmieri A , Subramanian S , Zhou Y , Kaul R , Green P , Olson M V 
Published: June 2006

Abstract
There has been much speculation as to what role balancing selection has played in evolution. In an attempt to identify regions, such as HLA, at which polymorphism has been maintained in the human population for millions of years, we scanned the human genome for regions of high SNP density. We found 16 regions that, outside of HLA and ABO, are the most highly polymorphic regions yet described; however, evidence for balancing selection at these sites is notably lacking—indeed, whole-genome simulations indicate that our findings are expected under neutrality. We propose that (i) because it is rarely stable, long-term balancing selection is an evolutionary oddity, and (ii) when a balanced polymorphism is ancient in origin, the requirements for detection by means of SNP data alone will rarely be met.