bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of Bazedoxifene in Reducing New Vertebral Fracture Risk in Postmenopausal Women With Osteoporosis: Results From a 3-Year, Randomized, Placebo-, and Active-Controlled Clinical Trial
Authors: Silverman Stuart L , Christiansen Claus , Genant Harry K , Vukicevic Slobodan , Zanchetta José R , de Villiers Tobie J , Constantine Ginger D , Chines Arkadi A 
Published: July 2008

Abstract
In this 3-yr, randomized, double-blind, placebo- and active-controlled study, healthy postmenopausal women with osteoporosis (55–85 yr of age) were treated with bazedoxifene 20 or 40 mg/d, raloxifene 60 mg/d, or placebo. The primary endpoint was incidence of new vertebral fractures after 36 mo; secondary endpoints included nonvertebral fractures, BMD, and bone turnover markers. Among 6847 subjects in the intent-to-treat population, the incidence of new vertebral fractures was significantly lower (p &lt; 0.05) with bazedoxifene 20 mg (2.3%), bazedoxifene 40 mg (2.5%), and raloxifene 60 mg (2.3%) compared with placebo (4.1%), with relative risk reductions of 42%, 37%, and 42%, respectively. The treatment effect was similar among subjects with or without prevalent vertebral fracture (p = 0.89 for treatment by baseline fracture status interaction). The incidence of nonvertebral fractures with bazedoxifene or raloxifene was not significantly different from placebo. In a posthoc analysis of a subgroup of women at higher fracture risk (femoral neck T-score ≤ –3.0 and/or ≥1 moderate or severe vertebral fracture or multiple mild vertebral fractures; n = 1772), bazedoxifene 20 mg showed a 50% and 44% reduction in nonvertebral fracture risk relative to placebo (p = 0.02) and raloxifene 60 mg (p = 0.05), respectively. Bazedoxifene significantly improved BMD and reduced bone marker levels (p &lt; 0.001 versus placebo). The incidence of vasodilatation, leg cramps, and venous thromboembolic events was higher with bazedoxifene and raloxifene compared with placebo. In conclusion, bazedoxifene significantly reduced the risk of new vertebral fracture in postmenopausal women with osteoporosis and decreased the risk of nonvertebral fracture in subjects at higher fracture risk.
Effect of Temporal Changes in Bone Turnover on the Bone Mineralization Density Distribution: A Computer Simulation Study
Authors: Ruffoni Davide , Fratzl Peter , Roschger Paul , Phipps Roger , Klaushofer Klaus , Weinkamer Richard 
Published: July 2008

Abstract
The heterogeneous distribution of mineral content in trabecular bone reflects the continuous renewal of bone material in bone remodeling and the subsequent increase in mineral content in the newly formed bone packets. The bone mineralization density distribution (BMDD) is typically used to describe this nonuniform mineral content of the bone matrix. Our mathematical model describes changes of the BMDD of trabecular bone as a function of bone resorption and deposition rates and the mineralization kinetics in a newly formed bone packet. Input parameters used in the simulations were taken from experimental studies. The simulations of the time evolution of the BMDD after increase in bone turnover (perimenopausal period) resulted in a shift of the BMDD toward lower values of the mineral content. Transiently, there was a broadening of the BMDD configuration partly showing two peaks, which points to a strongly heterogeneous distribution of the mineral. Conversely, when the remodeling rate was reduced (antiresorptive therapy), the BMDD shifted toward higher values of the mineral content. There was a transient narrowing of the distribution before broadening again to reach the new steady state. Results from this latter simulation are in good agreement with measurements of the BMDD of patients after 3 and 5 yr of treatment with risedronate. Based on available experimental data on bone remodeling, this model gives reliable predictions of changes in BMDD, an important factor of bone material quality. With the availability of medications with a known effect on bone turnover, this knowledge opens the possibility for therapeutic manipulation of the BMDD.
Unraveling Ambiguous NAT2 Genotyping Data
Authors: Agúndez José A G , Golka Klaus , Martínez Carmen , Selinski Silvia , Blaszkewicz Meinolf , García-Martín Elena 
Published: July 2008

AbstractBackground: Arylamine N-acetyltransferase 2 (CoASAc; NAT2, EC 2.3.1.5) is a drug-metabolizing enzyme that displays common polymorphisms leading to impaired drug metabolism and adverse drug effects. Determination of the N-acetyltransferase 2 (arylamine N-acetyltransferase) (NAT2) genotype in clinical practice is hampered by the occurrence of ambiguous haplotype combinations that may lead to patient misclassification. We determined the frequencies for ambiguous NAT2 haplotypes and diplotypes in a white population and investigated the use of PHASE v2.1.1, a statistical program for haplotype reconstruction, to clarify this ambiguity and classify individuals according to their acetylation status.Methods: By means of allele-specific haplotype mapping and sequencing, we determined the haplotypes for 7 common single-nucleotide polymorphisms in the NAT2 gene (n = 2624 haplotypes). To test the performance of PHASE, actual genotypes were deconstructed and then reconstructed by haplotype prediction.Results: We identified 21 NAT2 allelic variants, including a new variant allele that combines the single-nucleotide polymorphisms rs1801279, rs1799929, and rs1208. In contrast, the previously described variant alleles *5G, *5J, *6E, *7A, *11A, *11B, and *14B were not identified in the study population. Ambiguous haplotypes were observed in 98 alleles (3.7%), and ambiguous diplotypes were observed in 64 individuals (4.9%). Eleven individuals (0.8%) were misclassified by the use of haplotype prediction.Conclusions: Ambiguous NAT2 genotyping data are common. Actual NAT2 genotypes cannot be fully determined by haplotype prediction techniques. This study provides real haplotype data that can be used as a guide to convert NAT2 haplotypes and diplotypes into actual genotypes in white individuals.
Frequency-Dependent Selection and the Evolution of Assortative Mating
Authors: Otto Sarah P , Servedio Maria R , Nuismer Scott L 
Published: July 2008

Abstract
A long-standing goal in evolutionary biology is to identify the conditions that promote the evolution of reproductive isolation and speciation. The factors promoting sympatric speciation have been of particular interest, both because it is notoriously difficult to prove empirically and because theoretical models have generated conflicting results, depending on the assumptions made. Here, we analyze the conditions under which selection favors the evolution of assortative mating, thereby reducing gene flow between sympatric groups, using a general model of selection, which allows fitness to be frequency dependent. Our analytical results are based on a two-locus diploid model, with one locus altering the trait under selection and the other locus controlling the strength of assortment (a “one-allele” model). Examining both equilibrium and nonequilibrium scenarios, we demonstrate that whenever heterozygotes are less fit, on average, than homozygotes at the trait locus, indirect selection for assortative mating is generated. While costs of assortative mating hinder the evolution of reproductive isolation, they do not prevent it unless they are sufficiently great. Assortative mating that arises because individuals mate within groups (formed in time or space) is most conducive to the evolution of complete assortative mating from random mating. Assortative mating based on female preferences is more restrictive, because the resulting sexual selection can lead to loss of the trait polymorphism and cause the relative fitness of heterozygotes to rise above homozygotes, eliminating the force favoring assortment. When assortative mating is already prevalent, however, sexual selection can itself cause low heterozygous fitness, promoting the evolution of complete reproductive isolation (akin to “reinforcement”) regardless of the form of natural selection.
Dissection of Darkener of Apricot Kinase Isoform Functions in Drosophila
Authors: Kpebe Arlette , Rabinow Leonard 
Published: July 2008

Abstract
The Darkener of apricot (Doa) locus of Drosophila encodes a LAMMER protein kinase affecting alterative splicing, and hence sex determination, via the phosphorylation of SR and SR-like proteins. Doa encodes 6 different kinases via alternative promoter usage. To provide further insight into the roles of the multiple isoforms, we mapped polymorphisms, deletions, and P-element insertions in the locus, identifying several that are largely, if not completely, isoform specific in their effects. These tests, along with the use of lines permitting overexpression and interfering RNA expression, demonstrate that the major isoforms of 55 and 105 kDa perform separate functions. The 105-kDa and a minor 138-kDa isoform are both vital but do not apparently perform functions essential for sex determination. Curiously, male-specific lethality induced by overexpression of the 55-kDa kinase in the larval fat body is rescued by coexpression of TRA, suggesting a sex-specific physiological role for this isoform. Maternal effects in which the survival of heteroallelic adults depends upon the direction of the cross are consistent with a role for a 105-kDa cytoplasmic kinase in oogenesis or early larval development.
Within-Generation Mutation Variance for Litter Size in Inbred Mice
Authors: Casellas Joaquim , Medrano Juan F 
Published: July 2008

Abstract
The mutational input of genetic variance per generation ($\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\sigma}}_{\mathrm{m}}^{2}\) \end{document}$) is the lower limit of the genetic variability in inbred strains of mice, although greater values could be expected due to the accumulation of new mutations in successive generations. A mixed-model analysis using Bayesian methods was applied to estimate $\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\sigma}}_{\mathrm{m}}^{2}\) \end{document}$ and the across-generation accumulated genetic variability on litter size in 46 generations of a C57BL/6J inbred strain. This allowed for a separate inference on $\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\sigma}}_{\mathrm{m}}^{2}\) \end{document}$ and on the additive genetic variance in the base population ($\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\sigma}}_{\mathrm{a}}^{2}\) \end{document}$). The additive genetic variance in the base generation was 0.151 and quickly decreased to almost null estimates in generation 10. On the other hand, $\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\sigma}}_{\mathrm{m}}^{2}\) \end{document}$ was moderate (0.035) and the within-generation mutational variance increased up to generation 14, then oscillating between 0.102 and 0.234 in remaining generations. This pattern suggested the existence of a continuous uploading of genetic variability for litter size ($\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(h^{2}{=}0.045\) \end{document}$). Relevant genetic drift was not detected in this population. In conclusion, our approach allowed for separate estimation of $\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\sigma}}_{\mathrm{a}}^{2}\) \end{document}$ and $\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\sigma}}_{\mathrm{m}}^{2}\) \end{document}$ within the mixed-model framework, and the heritability obtained highlighted the significant and continuous influence of new genetic variability affecting the genetic stability of inbred strains.
A Theory of Age-Dependent Mutation and Senescence
Authors: Moorad Jacob A , Promislow Daniel E L 
Published: July 2008

Abstract
Laboratory experiments show us that the deleterious character of accumulated novel age-specific mutations is reduced and made less variable with increased age. While theories of aging predict that the frequency of deleterious mutations at mutation–selection equilibrium will increase with the mutation's age of effect, they do not account for these age-related changes in the distribution of de novo mutational effects. Furthermore, no model predicts why this dependence of mutational effects upon age exists. Because the nature of mutational distributions plays a critical role in shaping patterns of senescence, we need to develop aging theory that explains and incorporates these effects. Here we propose a model that explains the age dependency of mutational effects by extending Fisher's geometrical model of adaptation to include a temporal dimension. Using a combination of simple analytical arguments and simulations, we show that our model predicts age-specific mutational distributions that are consistent with observations from mutation-accumulation experiments. Simulations show us that these age-specific mutational effects may generate patterns of senescence at mutation–selection equilibrium that are consistent with observed demographic patterns that are otherwise difficult to explain.
Functional Conservation of β-Hairpin DNA Binding Domains in the Mcm Protein of Methanobacterium thermoautotrophicum and the Mcm5 protein of Saccharomyces cerevisiae
Authors: Leon Ronald P , Tecklenburg Marianne , Sclafani Robert A 
Published: July 2008

Abstract
Mcm proteins are an important family of evolutionarily conserved helicases required for DNA replication in eukaryotes. The eukaryotic Mcm complex consists of six paralogs that form a heterohexameric ring. Because the intact Mcm2-7 hexamer is inactive in vitro, it has been difficult to determine the precise function of the different subunits. The solved atomic structure of an archaeal minichromosome maintenance (MCM) homolog provides insight into the function of eukaryotic Mcm proteins. The N-terminal positively charged central channel in the archaeal molecule consists of β-hairpin domains essential for DNA binding in vitro. Eukaryotic Mcm proteins also have β-hairpin domains, but their function is unknown. With the archaeal atomic structure as a guide, yeast molecular genetics was used to query the function of the β-hairpin domains in vivo. A yeast mcm5 mutant with β-hairpin mutations displays defects in the G1/S transition of the cell cycle, the initiation phase of DNA replication, and in the binding of the entire Mcm2-7 complex to replication origins. A similar mcm4 mutation is synthetically lethal with the mcm5 mutation. Therefore, in addition to its known regulatory role, Mcm5 protein has a positive role in origin binding, which requires coordination by all six Mcm2-7 subunits in the hexamer.
Differential Gene Expression of TRPM1, the Potential Cause of Congenital Stationary Night Blindness and Coat Spotting Patterns (LP) in the Appaloosa Horse (Equus caballus)
Authors: Bellone Rebecca R , Brooks Samantha A , Sandmeyer Lynne , Murphy Barbara A , Forsyth George , Archer Sheila , Bailey Ernest , Grahn Bruce 
Published: July 2008

Abstract
The appaloosa coat spotting pattern in horses is caused by a single incomplete dominant gene (LP). Homozygosity for LP (LP/LP) is directly associated with congenital stationary night blindness (CSNB) in Appaloosa horses. LP maps to a 6-cM region on ECA1. We investigated the relative expression of two functional candidate genes located in this LP candidate region (TRPM1 and OCA2), as well as three other linked loci (TJP1, MTMR10, and OTUD7A) by quantitative real-time RT–PCR. No large differences were found for expression levels of TJP1, MTMR10, OTUD7A, and OCA2. However, TRPM1 (Transient Receptor Potential Cation Channel, Subfamily M, Member 1) expression in the retina of homozygous appaloosa horses was 0.05% the level found in non-appaloosa horses (R = 0.0005). This constitutes a &gt;1800-fold change (FC) decrease in TRPM1 gene expression in the retina (FC = −1870.637, P = 0.001) of CSNB-affected (LP/LP) horses. TRPM1 was also downregulated in LP/LP pigmented skin (R = 0.005, FC = −193.963, P = 0.001) and in LP/LP unpigmented skin (R = 0.003, FC = −288.686, P = 0.001) and was downregulated to a lesser extent in LP/lp unpigmented skin (R = 0.027, FC = −36.583, P = 0.001). TRP proteins are thought to have a role in controlling intracellular Ca2+ concentration. Decreased expression of TRPM1 in the eye and the skin may alter bipolar cell signaling as well as melanocyte function, thus causing both CSNB and LP in horses.
Use of Complementary and Alternative Medicine by Pediatric Patients With Functional and Organic Gastrointestinal Diseases: Results From a Multicenter Survey
Authors: Vlieger Arine M. , Blink Marjolein , Tromp Ellen , Benninga Marc A. 
Published: July 2008

OBJECTIVES. Many pediatric patients use complementary and alternative medicine, especially when facing a chronic illness for which treatment options are limited. So far, research on the use of complementary and alternative medicine in patients with functional gastrointestinal disease has been scarce. This study was designed to assess complementary and alternative medicine use in children with different gastrointestinal diseases, including functional disorders, to determine which factors predicted complementary and alternative medicine use and to assess the willingness of parents to participate in future studies on complementary and alternative medicine efficacy and safety.
PATIENTS AND METHODS. The prevalence of complementary and alternative medicine use was assessed by using a questionnaire for 749 children visiting pediatric gastroenterology clinics of 9 hospitals in the Netherlands. The questionnaire consisted of 35 questions on the child's gastrointestinal disease, medication use, health status, past and future complementary and alternative medicine use, reasons for its use, and the necessity of complementary and alternative medicine research.
RESULTS. In this study population, the frequency of complementary and alternative medicine use was 37.6%. A total of 60.3% of this group had used complementary and alternative medicine specifically for their gastrointestinal disease. This specific complementary and alternative medicine use was higher in patients with functional disorders than organic disorders (25.3% vs 17.2%). Adverse effects of allopathic medication, school absenteeism, age ≤11 years, and a low effect of conventional treatment were predictors of specific complementary and alternative medicine use. Almost all (93%) of the parents considered it important that pediatricians initiate complementary and alternative medicine research, and 51% of parents were willing to participate in future complementary and alternative medicine trials.
CONCLUSIONS. Almost 40% of parents of pediatric gastroenterology patients are turning to complementary and alternative medicine for their child. Lack of effectiveness of conventional therapy, school absenteeism, and adverse effects of allopathic medication are more important predictors of complementary and alternative medicine use than the type of gastrointestinal disease. Because evidence on most complementary and alternative medicine modalities in children with gastrointestinal disorders is lacking, there is an urgent need for research in this field.
Diagnosis of process faults in chemical systems using a local partial least squares approach
Authors: Kruger Uwe , Dimitriadis Grigorios 
Published: July 2008

AbstractThis article discusses the application of partial least squares (PLS) for monitoring complex chemical systems. In relation to existing work, this article proposes the integration of the statistical local approach into the PLS framework to monitor changes in the underlying model rather than analyzing the recorded input/output data directly. As discussed in the literature, monitoring changes in model parameters addresses the problems of nonstationary behavior and presents an analogy to model‐based approaches. The benefits of the proposed technique are that (i) a detailed mechanistic plant model is not required, (ii) nonstationary process behavior does not produce false alarms, (iii) parameter changes can be non‐Gaussian, (iv) Gaussian monitoring statistics can be established to simplify the monitoring task, and (v) fault magnitude and signatures can be estimated. This is demonstrated by a simulation example and the analysis of recorded data from two chemical processes. © 2008 American Institute of Chemical Engineers AIChE J, 2008
Timed sequential induction chemotherapy and risk‐adapted postremission therapy for acute myelogenous leukemia
Authors: Kalaycio Matt , Advani Anjali , Pohlman Brad , Sekeres Mikkael , Tripp Barbara , Rybicki Lisa , Sobecks Ronald 
Published: July 2008

AbstractCytogenetic analysis at the time of diagnosis predicts outcome in patients with acute myelogenous leukemia (AML). For those patients with favorable risk cytogenetics, stem cell transplant can be delayed until the time of relapse. For those patients with nonfavorable cytogenetic risk profiles, stem cell transplant may be required for optimal survival benefit. We treated patients with de novo AML and age less than 60 years first with etoposide, mitoxantrone, cytarabine, and G‐CSF (EMA‐G) to induce remission. Patients in complete remission were assigned to treatment with chemotherapy alone if they had favorable risk cytogenetics defined as the identification of a core‐binding factor translocation. Patients with any other cytogenetic profile were assigned to treatment with either autologous or allogeneic stem cell transplant depending on the availability of an HLA‐matched donor. Following EMA‐G, 33 of 40 patients (83%) achieved CR. Of the 25 patients who actually were treated with postremission chemotherapy, 21 were treated with their assigned risk‐adapted therapy. Of the 33 patients in remission, 5 year relapse‐free survival (RFS) and overall survival (OS) was 46 and 38%, respectively. Our intensive and risk‐adapted, stem cell transplant approach to the treatment of patients with AML requires a better definition of risk and does not appear to substantially improve results compared with more standard approaches. Am. J. Hematol., 2008. © 2008 Wiley‐Liss, Inc.