bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Genetic and Nongenetic Factors for Fluorouracil Treatment-Related Severe Toxicity: A Prospective Clinical Trial by the German 5-FU Toxicity Study Group
Authors: Schwab Matthias , Zanger Ulrich M. , Marx Claudia , Schaeffeler Elke , Klein Kathrin , Dippon Jürgen , Kerb Reinhold , Blievernicht Julia , Fischer Joachim , Hofmann Ute , Bokemeyer Carsten , Eichelbaum Michel 
Published: February 2008

Purpose To assess the predictive value of polymorphisms in dihydropyrimidine dehydrogenase (DPYD ), thymidylate synthase (TYMS ), and methylene tetrahydrofolate reductase (MTHFR ) and of nongenetic factors for severe leukopenia, diarrhea, and mucositis related to fluorouracil (FU) treatment. Patients and Methods A multicenter prospective clinical trial included 683 patients with cancer treated with FU monotherapy. Toxicity was documented according to World Health Organization grades. DPYD, TYMS, and MTHFR genotypes were determined, and DPYD was resequenced in patients with severe toxicity. Results Grade 3 to 4 toxicity occurred in 16.1% of patients. The sensitivity of DPYD*2A genotyping for overall toxicity was 5.5% (95%CI, 0.02 to 0.11), with a positive predictive value of 0.46 (95% CI, 0.19 to 0.75; P = .01). Inclusion of additional DPYD variants improved prediction only marginally. Analysis according to toxicity type revealed significant association of DPYD with mucositis and leukopenia, whereas TYMS was associated with diarrhea. Genotype, female sex, mode of FU administration, and modulation by folinic acid were identified as independent risk factors by multivariable analysis. A previously unrecognized significant interaction was found between sex and DPYD, which resulted in an odds ratio for toxicity of 41.8 for male patients (95% CI, 9.2 to 190; P < .0001) but only 1.33 (95% CI, 0.34 to 5.2) in female patients. Homozygosity for the TYMS enhancer region double repeat allele increased risk for toxicity 1.6-fold (95% CI, 1.08 to 2.22; P = .02). Conclusion DPYD, TYMS, and MTHFR play a limited role for FU related toxicity but a pronounced DPYD gene/sex-interaction increases prediction rate for male patients. Toxicity risk assessment should include sex, mode of administration, and folinic acid as additional predictive factors.
Getting a peace of the action: measures of post traumatic stress in UK military peacekeepers
Authors: Greenberg Neil , Iversen Amy , Hull Lisa , Bland Duncan , Wessely Simon 
Published: February 2008

Objectives This study aimed to measure prevalence of post traumatic stress disorder (PTSD) in a sample of UK Armed Forces peacekeepers. The study also aimed to explore the influence of deploying without an established peer group (deployment status) upon health outcomes using an accepted diagnostic tool for PTSD (PCL-M) and an alternative measure of post-traumatic distress. Design Using a sub-sample of the King's military cohort we surveyed personnel that deployed on peacekeeping operations between 1991 and 2000 ( n=1198). Setting Respondents' mean age was 36 years (min, 23 to max, 60) and 81% ( n=964) were serving in the Armed Forces at the time of participation. Main outcome measures PTSD prevalence was determined in British military peacekeepers using the PLC-M (cut-offs 44 and 50), the General Health Questionnaire (GHQ-12) and a composite brief measure of potential post traumatic symptomology, ‘PostTraumatic Stress Reaction’ (PTSR) for comparison. Results PTSD prevalence varied from 3.6 to 5.5%. Officers and married personnel were less likely to be cases. Neither gender, age or deployment status influenced PTSD prevalence. Conclusions PTSD was an uncommon disorder in this sample of British military peacekeepers, with prevalence rates being lower than those reported by other nations. Deploying without an established peer group was not associated with developing PTSD. We postulate that differences in culture and operational practices may account for the lower rates of PTSD.
Prostaglandin D2 Receptors Control Osteoclastogenesis and the Activity of Human Osteoclasts
Authors: Durand Marianne , Gallant Maxime A , de Brum-Fernandes Artur J 
Published: February 2008

Abstract
We recently showed that human osteoblasts synthesize prostaglandin D2 (PGD2) and express both DP and CRTH2 receptors. Activation of the DP receptor decreased osteoprotegerin production, whereas activation of the CRTH2 receptor induced osteoblast chemotaxis and decreased RANKL expression. Our objectives in this study were to determine the presence, distribution, and action of these receptors in the functions of human osteoclasts and in osteoclastogenesis. Immunohistochemistry was used to detect the presence of DP and CRTH2 in in vitro–differentiated human osteoclasts in culture and in osteoclasts in situ. The effects of the activation of PGD2 receptors on the cytoskeleton were determined by fluorescence microscopy. Specific agonists and antagonists allowed the study of the roles of these receptors on bone resorption and osteoclast differentiation. Our results show that in vitro–differentiated human osteoclasts and authentic fetal osteoclasts express both DP and CRTH2 receptors, as shown by immunocytochemistry. Similar results were obtained in osteoclasts from normal, osteoporotic, pagetic, and osteoarthritic adult bone tissues. Stimulation of osteoclasts with PGD2 induced a robust reorganization of the cytoskeleton with a decrease in the number of cells presenting actin rings and an increase of lamellipodia, effects mediated by the DP and CRTH2 receptors, respectively. PGD2 showed an inhibitory effect on bone resorption activity acting through the DP receptor. In vitro osteoclastogenesis from peripheral blood mononuclear cells cultured in the presence of RANKL and macrophage-colony stimulating factor was decreased by activation of either DP or CRTH2 receptors. These results suggest that PGD2 receptors could be useful targets in certain bone diseases because their specific activation/inhibition leads to a decrease in osteoclastogenesis and to inhibition of bone resorption by osteoclasts.
Assessment of the 10-Year Probability of Osteoporotic Hip Fracture Combining Clinical Risk Factors and Heel Bone Ultrasound: The EPISEM Prospective Cohort of 12,958 Elderly Women
Authors: Hans Didier , Durosier Claire , Kanis John A , Johansson Helena , Schott-Pethelaz Anne-Marie , Krieg Marc-Antoine 
Published: February 2008

Abstract
This study aimed to develop a hip screening tool that combines relevant clinical risk factors (CRFs) and quantitative ultrasound (QUS) at the heel to determine the 10-yr probability of hip fractures in elderly women. The EPISEM database, comprised of ∼13,000 women ≥70 yr of age, was derived from two population-based white European cohorts in France and Switzerland. All women had baseline data on CRFs and a baseline measurement of the stiffness index (SI) derived from QUS at the heel. Women were followed prospectively to identify incident fractures. Multivariate analysis was performed to determine the CRFs that contributed significantly to hip fracture risk, and these were used to generate a CRF score. Gradients of risk (GR; RR/SD change) and areas under receiver operating characteristic curves (AUC) were calculated for the CRF score, SI, and a score combining both. The 10-yr probability of hip fracture was computed for the combined model. Three hundred seven hip fractures were observed over a mean follow-up of 3.2 yr. In addition to SI, significant CRFs for hip fracture were body mass index (BMI), history of fracture, an impaired chair test, history of a recent fall, current cigarette smoking, and diabetes mellitus. The average GR for hip fracture was 2.10 per SD with the combined SI + CRF score compared with a GR of 1.77 with SI alone and of 1.52 with the CRF score alone. Thus, the use of CRFs enhanced the predictive value of SI alone. For example, in a woman 80 yr of age, the presence of two to four CRFs increased the probability of hip fracture from 16.9% to 26.6% and from 52.6% to 70.5% for SI Z-scores of +2 and −3, respectively. The combined use of CRFs and QUS SI is a promising tool to assess hip fracture probability in elderly women, especially when access to DXA is limited.
Vitamin D Insufficiency: Disease or No Disease?
Authors: Hansen Karen E , Jones Andrea N , Lindstrom Mary J , Davis Lisa A , Engelke Jean A , Shafer Martin M 
Published: February 2008

Abstract
Vitamin D insufficiency (VDI) is widely reported. In patients with normal PTH, the diagnosis rests on increases in fractional calcium absorption (FCA) when 25(OH)D increases above 30 ng/ml. However, estimates of increased FCA after correction of VDI vary dramatically, depending on study methods. We used a dual stable calcium isotope to clarify the impact of vitamin D repletion on FCA in postmenopausal women with VDI. We hypothesized that FCA would increase with vitamin D repletion. We studied postmenopausal women with VDI [25(OH)D = 16–24 ng/ml] and an estimated calcium intake ≤1100 mg daily. Exclusion criteria included hypercalcemia, hypercalciuria, renal insufficiency, nephrolithiasis, gastrointestinal disorders, osteomalacia, prior adult fragility fracture, baseline T-score &lt; −3.0, and use of medications known to interfere with vitamin D or calcium metabolism. Each woman underwent inpatient FCA studies before and after correction of VDI. We used ergocalciferol 50,000 IU/d for 15 days to achieve vitamin D repletion. During each study, women consumed their typical diet. They ingested 44Ca orally with breakfast and received 42Ca intravenously. We collected urine for 24 h and measured its calcium isotope content by mass spectrometry. Eighteen women completed the study; all but two had normal PTH. During the first and second FCA studies, their mean 25(OH)D level was 22 ± 4 and 64 ± 21 ng/ml, respectively (p &lt; 0.001). Subjects' average FCA was 24 ± 7% initially and 27 ± 6% after vitamin D repletion (p = 0.04). Thus, FCA increased by 3 ± 1% with correction of VDI. Postmenopausal women with VDI experience small FCA increments with vitamin D therapy. In existing literature, this small change in FCA does not associate with lower fracture rates or consistently higher bone mass. Future studies should ascertain whether small FCA increments favorably affect the skeleton.
Mechanisms of the Anabolic Effects of Teriparatide on Bone: Insight From the Treatment of a Patient With Pycnodysostosis
Authors: Chavassieux Pascale , Karsdal Morten Asser , Segovia-Silvestre Toni , Neutzsky-Wulff Anita V , Chapurlat Roland , Boivin Georges , Delmas Pierre D 
Published: February 2008

Abstract
Pycnodysostosis is an extremely rare genetic osteosclerosis caused by cathepsin K deficiency. We hypothesized that teriparatide, a potent anabolic agent used in the treatment of osteoporosis, might reduce skeletal fragility by activating bone turnover. We studied a typical case of pycnodysostosis in a 37-yr-old woman who exhibited short stature, skull and thorax deformities, and a history of severe fragility fractures. Cathepsin K gene sequencing was performed. Before and after 6 mo of 20 μg/d teriparatide, biochemical markers of bone turnover were measured, and 3D bone structure and microarchitecture was assessed in vivo by HR-pQCT. Qualitative and quantitative analysis of transiliac bone biopsies were performed, and the degree of mineralization was evaluated by quantitative microradiography. In vitro assessment of bone resorption was performed after separation and differentiation of CD14+ monocytes from peripheral blood. Bone structure assessed by HR-pQCT on the radius and tibia showed augmentation of cortical and trabecular density. Transiliac bone biopsy showed highly increased bone mass (+63% versus age- and sex-matched controls), a decrease in bone remodeling without evidence of active osteoblasts, and a severe decrease in the dynamic parameters of bone formation (mineralizing surfaces, −90% and bone formation rate, −93% versus age- and sex-matched controls). This depressed bone turnover probably explained the increased degree of mineralization. The presence of a novel missense mutation leading to an A141V amino acid substitution confirmed a genetic defect of cathepsin K as the cause of the disease. The deficiency of active osteoclasts was confirmed by an in vitro study that showed a decreased concentration of CD14+ monocytes (the precursor of osteoclasts) in blood. These osteoclasts had low resorptive activity when incubated on bone slices. After 6 mo of teriparatide, the structure, microarchitecture, and turnover of bone—assessed by HR-pQCT, histology, and bone turnover markers—remained unchanged. Our data strongly suggest that some features of the osteoclastic phenotype—that are absent in pycnodysostosis—are a prerequisite for the anabolic effect of PTH on osteoblasts.
Compromised Bone Marrow Perfusion in Osteoporosis
Authors: Griffith James F , Yeung David KW , Tsang Polly H , Choi Kai C , Kwok Timothy CY , Ahuja Anil T , Leung Kwok S , Leung Ping C 
Published: February 2008

Abstract
A link between bone blood flow and osteoporosis may exist. Outside of the spine, the proximal femur is the most common site of osteoporotic fracture and is also an area prone to avascular necrosis and fracture nonunion. This study of the proximal femur investigates the relationship between BMD, bone marrow fat content, bone perfusion, and muscle perfusion. One hundred twenty healthy female subjects (mean age, 74 yr; age range, 67–89 yr) underwent DXA examination of the hip, proton MR spectroscopy, and dynamic contrast-enhanced MR imaging of the right proximal femur, acetabulum, and adductor thigh muscle. In all bone areas examined (femoral head, femoral neck, femoral shaft, acetabulum), perfusion indices (maximum enhancement, enhancement slope) were significantly reduced in subjects with osteoporosis compared with subjects with osteopenia or normal BMD. Adductor muscle perfusion was not affected by change in BMD. As marrow perfusion decreased in the proximal femur, marrow fat increased (r = 0.827). This increase in fat content seemed to account for the decrease in marrow perfusion more than a reduction in BMD. For normal BMD subjects, perfusion parameters in the femoral head were one third of those in the femoral neck or shaft and one fifth of those in the acetabulum. Perfusion throughout the proximal femur is reduced in osteoporotic subjects compared with osteopenic and normal subjects. This reduction in perfusion only affects bone and not those tissues outside of bone with the same blood supply. As bone perfusion decreased, there was a corresponding increase in marrow fat.
HMGB1 Regulates RANKL-Induced Osteoclastogenesis in a Manner Dependent on RAGE
Authors: Zhou Zheng , Han Jun-Yan , Xi Cai-Xia , Xie Jian-Xin , Feng Xu , Wang Cong-Yi , Mei Lin , Xiong Wen-Cheng 
Published: February 2008

Abstract
High-mobility group box 1 (HMGB1), a nonhistone nuclear protein, is released by macrophages into the extracellular milieu consequent to cellular activation. Extracellular HMGB1 has properties of a pro-inflammatory cytokine through its interaction with receptor for advanced glycation endproducts (RAGE) and/or toll-like receptors (TLR2 and TLR4). Although HMGB1 is highly expressed in macrophages and differentiating osteoclasts, its role in osteoclastogenesis remains largely unknown. In this report, we present evidence for a function of HMGB1 in this event. HMGB1 is released from macrophages in response to RANKL stimulation and is required for RANKL-induced osteoclastogenesis in vitro and in vivo. In addition, HMGB1, like other osteoclastogenic cytokines (e.g., TNFα), enhances RANKL-induced osteoclastogenesis in vivo and in vitro at subthreshold concentrations of RANKL, which alone would be insufficient. The role of HMGB1 in osteoclastogenesis is mediated, in large part, by its interaction with RAGE, an immunoglobin domain containing family receptor that plays an important role in osteoclast terminal differentiation and activation. HMGB1-RAGE signaling seems to be important in regulating actin cytoskeleton reorganization, thereby participating in RANKL-induced and integrin-dependent osteoclastogenesis. Taken together, these observations show a novel function of HMGB1 in osteoclastogenesis and provide a new link between inflammatory mechanisms and bone resorption.
Serum Biomarker Profile Associated With High Bone Turnover and BMD in Postmenopausal Women
Authors: Bhattacharyya Sudeepa , Siegel Eric R , Achenbach Sara J , Khosla Sundeep , Suva Larry J 
Published: February 2008

Abstract
Early diagnosis of the onset of osteoporosis is key to the delivery of effective therapy. Biochemical markers of bone turnover provide a means of evaluating skeletal dynamics that complements static measurements of BMD by DXA. Conventional clinical measurements of bone turnover, primarily the estimation of collagen and its breakdown products in the blood or urine, lack both sensitivity and specificity as a reliable diagnostic tool. As a result, improved tests are needed to augment the use of BMD measurements as the principle diagnostic modality. In this study, the serum proteome of 58 postmenopausal women with high or low/normal bone turnover (training set) was analyzed by surface enhanced laser-desorption/ionization time-of-flight mass spectrometry, and a diagnostic fingerprint was identified using a variety of statistical and machine learning tools. The diagnostic fingerprint was validated in a separate distinct test set, consisting of serum samples from an additional 59 postmenopausal women obtained from the same Mayo cohort, with a gap of 2 yr. Specific protein peaks that discriminate between postmenopausal patients with high or low/normal bone turnover were identified and validated. Multiple supervised learning approaches were able to classify the level of bone turnover in the training set with 80% sensitivity and 100% specificity. In addition, the individual protein peaks were also significantly correlated with BMD measurements in these patients. Four of the major discriminatory peaks in the diagnostic profile were identified as fragments of interalpha-trypsin-inhibitor heavy chain H4 precursor (ITIH4), a plasma kallikrein-sensitive glycoprotein that is a component of the host response system. These data suggest that these serum protein fragments are the serum-borne reflection of the increased osteoclast activity, leading to the increased bone turnover that is associated with decreasing BMD and presumably an increased risk of fracture. In conjunction with the identification of the individual proteins, this protein fingerprint may provide a novel approach to evaluate high bone turnover states.
Semantics as lexicography
Authors: Geurts Bart 
Published: February 2008

Abstract
Over the past few decades, the interpretation of language has gradually come to be accepted as a subject deserving its own academic regalia, such as conferences, journals, and university chairs. The definition of the emerging field of inquiry is, as yet, very moot. It is not even decided that it is a single field, rather than several related ones, and whether it (or they) should be subsumed under linguistics, psychology, or somewhere else. But there is a measure of consensus about the kind of topics the fledgling discipline is supposed to address. Here are a few examples:
NSM and the meaning of color words
Authors: Kay Paul 
Published: February 2008

Abstract
Uwe Durst (D) is to be commended for a clear exposition of the Natural Semantic Metalanguage (NSM) theory of Anna Wierzbicka (W) and her associates. In addition to laying out clearly the assumptions of the NSM theory, D states that
The …NSM model… has turned out to be a most useful theoretical and methodological framework for semantic analysis in various linguistic… domains.
NSM: Theoretical, methodological and applicational problems
Authors: Koptjevskaja-Tamm Maria , Ahlgren Inger 
Published: February 2008

Abstract

0. Introduction

Durst's paper is a well-written and clear survey of the Natural Semantic Metalanguage (NSM) model. However, it strikes us as somewhat over-enthusiastic and slightly simplistic: alternative positions and voices are not present, there is often no deep argumentation for or against a certain position, problems and complications are very seldom mentioned.
Servant of two masters? NSM and semantic explanation
Authors: Riemer Nick 
Published: February 2008

Abstract

1. Introduction

Uwe Durst opens his helpful précis with the claims that NSM ‘has turned out to be a most useful theoretical and methodological framework for semantic analysis’, and that it ‘is free from various shortcomings of other semantic frameworks.’ Since the insights of NSM scholars into the details of many semantic domains have frequently been acknowledged, the theory's usefulness for semantic description need scarcely be doubted. I would like to suggest, however, that Durst's second claim is more questionable. Not only is NSM subject to shortcomings of its own distinctive stripe, but it inherits others from the approach to semantic analysis characteristic of linguistics generally, of which, in the last analysis, it is only a particularly forthright exemplar. NSM's most significant problems, then, are just the problems of semantics in general, seen as part of the would-be scientific project of linguistics. These problems are not always obvious from Durst's survey, and in this commentary I will indicate some of the most interesting. Given the space available, I will not discuss the universality of NSM's proposed primitives, perhaps the issue which has most often stimulated discussion. I will also only address the lexical semantics aspects of NSM. These are, in any case, at the theory's core, and since analogous issues arise in its treatment of other topics, the omission from this commentary of any discussion of the NSM approach to morphology, cultural scripts, pragmatics, and the like is, I trust, appropriate.
Listen: Sequenzielle und prosodische Struktur einer kommunikativen Praktik – eine Untersuchung im Rahmen der Interaktionalen Linguistik
Authors: Selting Margret 
Published: February 2008

Abstract
I describe the construction of lists in my corpus of conversations in, mostly, Northern Standard German. With respect to the general structure of listing and lists, I will show the following points:

(i) Listing is always an embedded practice; lists are normally middle parts of a larger three-component structure that consists of

(a) the projection component, projecting more-to-come, i. e. a multiunit turn to be constructed, either a pre-detailing and/or a general formulation;

(b) the list itself, preferably three-parted, suggesting the items as part of either a closed or an open number of list items, as a practice of detailing;

(c) the gestalt closure, i. e. a post-detailing component, completing the structure around the list.

(ii) We should distinguish between (a) closed lists that suggest a closed number of items, and (b) open lists that suggest an open number of items. These classes of lists are produced with different kinds of practices. It seems to be the prosody that is used to suggest the intended kind of list, irrespective of its syntactic embedding.

(iii) Lists may be produced with different kinds of, albeit similar, intonation contours. But it is not so much the particular intonation contour that is constitutive of lists, but a variety of similar contours plus the repetition of the chosen contour for at least some or even all of the list items. Furthermore, intonation is deployed to suggest the interpretation of a potential final list item as either a list completer or as another item of the list with some kind of gestalt closure still to come.

I will show that intonation is indeed one of the methodically used constitutive cues that makes the production and structuring of lists recognizable for recipients.