bluuebunny/crossref_metadata_2025 huggingface dataset:
Measurement and analysis of grip force during a golf shot
Authors: Komi E R , Roberts J R , Rothberg S J
Published: September 2008

In this study, grip force was measured during a standard golf tee shot using two different measurement techniques. The first utilized a matrix-type thin-film sensor applied to a golf grip, from which total grip force could be readily determined. The second method involved 31 individual thin-film force sensors strategically placed on two golf gloves, allowing the force output of specific regions of the hands to be measured. Twenty golfers of varying ability participated in each test. The discovery of a unique grip force ‘signature’ for each golfer emerged from these data. That is, each golfer had a very repeatable total grip force trace, but these traces varied considerably between golfers. High-speed video was also recorded for many of the golfers tested so that key phases in the swing could be identified on the force traces.
Optimal Stopping of Linear Diffusions with Random Discounting
Authors: Dayanik Savas
Published: September 2008

We propose a new solution method for optimal stopping problems with random discounting for linear diffusions whose state space has a combination of natural, absorbing, or reflecting boundaries. The method uses a concave characterization of excessive functions for linear diffusions killed at a rate determined by a Markov additive functional and reduces the original problem to an undiscounted optimal stopping problem for a standard Brownian motion. The latter can be solved essentially by inspection. The necessary and sufficient conditions for the existence of an optimal stopping rule are proved when the reward function is continuous. The results are illustrated on examples.
Queues with Many Servers: The Virtual Waiting-Time Process in the QED Regime
Authors: Mandelbaum Avishai , Momčilović Petar
Published: September 2008

We consider a first-come first-served multiserver queue in the Quality- and Efficiency-Driven (QED) regime. In this regime, which was first formalized by Halfin and Whitt, the number of servers N is not small, servers' utilization is [Formula: see text] (Efficiency-Driven) while waiting time is [Formula: see text] (Quality-Driven). This is equivalent to having the number of servers N being approximately equal to [Formula: see text], where R is the offered load and β is a positive constant.

For the G/DK/N queue in the QED regime, we analyze the virtual waiting time VN(t), as N increases indefinitely. Assuming that the service-time distribution has a finite support (hence the DK in G/DK/N), it is shown that, in the limit, the scaled virtual waiting time [Formula: see text] is representable as a supremum over a random weighted tree (S denotes a service time). Informally, it is then argued that, for large N, [Formula: see text]here [Formula: see text] is the averaging of [Formula: see text] over S, and the process [Formula: see text] is zero-mean Gaussian that summarizes all relevant information about arrivals and service times ([Formula: see text] arises as a limit of an infinite-server (G/DK/∞) process, appropriately scaled). The results are obtained by using both combinatorial and probabilistic arguments. Possible applications of our approximations include fast simulation of queues and estimation/prediction of customer waiting times in the QED regime.
Risk Tuning with Generalized Linear Regression
Authors: Rockafellar R. Tyrrell , Uryasev Stan , Zabarankin Michael
Published: September 2008

A framework is set up in which linear regression, as a way of approximating a random variable by other random variables, can be carried out in a variety of ways, which, moreover, can be tuned to the needs of a particular model in finance, or operations research more broadly. Although the idea of adapting the form of regression to the circumstances at hand has already found advocates in promoting quantile regression as an alternative to classical least-squares approaches, it is carried here much farther than that. Axiomatic concepts of error measure, deviation measure, and risk measure are coordinated with certain “statistics” that likewise say something about a random variable. Problems of regression utilizing these concepts are analyzed and the character of their solutions is explored in a range of examples. Special attention is paid to parametric forms of regression which arise in connection with factor models. It is argued that when different aspects of risk enter an optimization problem, different forms of regression ought to be invoked for each of those aspects.
The Flow Set with Partial Order
Authors: Atamtürk Alper , Zhang Muhong
Published: September 2008

The flow set with partial order is a mixed-integer set described by a budget on total flow and a partial order on the arcs that may carry positive flow. This set is a common substructure of resource allocation and scheduling problems with precedence constraints and robust network flow problems under demand/capacity uncertainty.

We give a polyhedral analysis of the convex hull of the flow set with partial order. Unlike for the flow set without partial order, cover-type inequalities based on partial order structure are a function of a lifting sequence. We study the lifting sequences and describe structural results on the lifting coefficients for general and simpler special cases. We show that all lifting coefficients can be computed in polynomial time by solving maximum weight closure problems in general. For the special case of induced-minimal covers, we give a sequence-dependent characterization of the lifting coefficients. We prove, however, if the partial order is defined by an arborescence, then lifting is sequence-independent and all lifting coefficients can be computed in linear time. Moreover, if the partial order is defined by a path (total order), then the coefficients can be expressed explicitly. We also give a complete polyhedral description of the flow set with partial order for the polynomially-solvable total order case. We show that finding an optimal lifting order for a given induced-minimal cover and a given fractional solution is a submodular optimization problem, which is solved greedily. Finally, we present preliminary computational results with a cutting-plane algorithm based on the lifting and separation results.
Approximate Minimization of the Regularized Expected Error over Kernel Models
Authors: Kůrková Věra , Sanguineti Marcello
Published: September 2008

Learning from data under constraints on model complexity is studied in terms of rates of approximate minimization of the regularized expected error functional. For kernel models with an increasing number n of kernel functions, upper bounds on such rates are derived. The bounds are of the form a/n+b/√n, where a and b depend on the regularization parameter and on properties of the kernel, and of the probability measure defining the expected error. As a special case, estimates of rates of approximate minimization of the regularized empirical error are derived.
What Matchings Can Be Stable? The Testable Implications of Matching Theory
Authors: Echenique Federico
Published: September 2008

This paper studies the falsifiability of two-sided matching theory when agents' preferences are unknown. A collection of matchings is rationalizable if there are preferences for the agents involved so that the matchings are stable. We show that there are nonrationalizable collections of matchings; hence, the theory is falsifiable. We also characterize the rationalizable collections of matchings, which leads to a test of matching theory in the spirit of revealed-preference tests of individual optimizing behavior.
An Analytic Center Cutting Plane Approach for Conic Programming
Authors: Basescu Vasile L. , Mitchell John E.
Published: September 2008

We analyze the problem of finding a point strictly interior to a bounded, convex, and fully dimensional set from a finite dimensional Hilbert space. We generalize the results obtained for the linear programming (LP), semidefinite programming (SDP), and second-order core programming (SOCP) cases. The cuts added by our algorithm are central and conic. In our analysis, we find an upper bound for the number of Newton steps required to compute an approximate analytic center. Also, we provide an upper bound for the total number of cuts added to solve the problem. This bound depends on the quality of the cuts, the dimensionality of the problem and the thickness of the set we are considering.
The effect of component size and orientation on the concentrations of metal ions after resurfacing arthroplasty of the hip
Authors: Langton D. J. , Jameson S. S. , Joyce T. J. , Webb J. , Nargol A. V. F.
Published: August 2008

Increased concentrations of metal ions after metal-on-metal resurfacing arthroplasty of the hip remain a concern. Although there has been no proven link to long-term health problems or early prosthetic failure, variables associated with high metal ion concentrations should be identified and, if possible, corrected. Our study provides data on metal ion levels from a series of 76 consecutive patients (76 hips) after resurfacing arthroplasty with the Articular Surface Replacement. Chromium and cobalt ion concentrations in the whole blood of patients with smaller (≤ 51 mm) femoral components were significantly higher than in those with the larger (≥ 53 mm) components (p < 0.01). Ion concentrations in the former group were significantly related to the inclination (p = 0.01) and anteversion (p = 0.01) of the acetabular component. The same relationships were not significant in the patients with larger femoral components (p = 0.61 and p = 0.49, respectively). Accurate positioning of the acetabular component intra-operatively is essential in order to reduce the concentration of metal ions in the blood after hip resurfacing arthroplasty with the Articular Surface Replacement implant.
Bevacizumab: A Treatment Option for Recurrent Glioblastoma Multiforme
Authors: Buie Larry W , Valgus John M
Published: September 2008

Objective:

To review the available literature evaluating the effect of bevacizumab on progression-free survival when used in combination with irinotecan for recurrent glioblastoma multiforme (GBM).

Data Sources:

Searches of MEDLINE (1966-June 2008), the Cochrane Library. and International Pharmaceutical Abstracts (1970-June 2008) were conducted using the terms bevacizumab. irinotecan, and glioblastoma multiforme.

Study Selection And Data Extraction:

The search was limited to studies conducted in humans. All articles identified trom the data sources were evaluated. All clinical trials evaluating the efficacy and safety of bevacizumab in the treatment of recurrent GBM were included in the review.

Data Synthesis:

Hypoxia, mutagenesis, and the secretion of various growth (actors can all lead to production of vascular endothelial growth factor (VEGF), a proangiogenic growth factor, and angiogenesis in GBM. Neoplastic progression is dependent on angiogenesis, and anti-VEGF therapy has been successful in multiple disease states. However, there are currently no available anti-VEGF therapies approved tor treatment of GBM. Bevacizumab is a humanized monoclonal antibody that binds to and inhibits the activity of VEGF. When compared with data from clinical trials that use single chemotherapeutic agents in recurrent GBM, the addition of bevacizumab to cytotoxic chemotherapy, such as irinotecan, appears to improve progression-Iree survival in patients progressing on the standard of care, with a 6-month progression-free survival rate of 46%. Bevacizumab is well tolerated by most patients, with modest risk (11% tn Phase 2 trials) of venous thromboembolism.

Conclusions:

Although the combination of bevacizumab and irinotecan is producing positive results in patients with recurrent GBM, larger, randomized clinical trials need to be performed to determine the magnitude of the benefit from bevacizumab. Bevacizumab administered biweekly at a dose of 10 mg/kg in combination with irinotecan may improve progression-free survival.
Bevacizumab Sterility in Multiple Doses from a Single-Use Vial
Authors: Örnek Kemal , Karahan Zeynep Ceren , Ergin Ahmet , Tekeli Alper , Tekeli Oya
Published: September 2008

Background:

Recent reports have demonstrated that refrigerated bevacizumab can be stored for up to 3 weeks at 4 °C without loss of efficacy. There have been no previous reports addressing bevacizumab's sterility when stored and used as multiple doses from a single-use vial.

Objective:

To evaluate the sterility of bevacizumab when used as multiple doses from a single-use vial.

Methods:

Four groups of vials were used to simulate the storage and use conditions for bevacizumab. Each group contained 11 doses of 0.2 mL of bevacizumab. One sample from each group was cultured once each day at 37 °C for 10 days; one sample from each group was left for 15 days. MacConkey agar, blood agar, thioglycollate broth, and Sabouraud medium were used to assess bacterial and fungal growth.

Results:

A total of 44 samples of bevacizumab were included in this study. Each sample was placed on 4 growth media for microbial readings. All samples were found to be negative for microbial growth. No significant differences were observed among the groups. Possible limitations of this study included the number of samples for each group and in vitro design of the study, which might have affected the growth of bacterial organisms.

Conclusions:

Storage and multiple use of bevacizumab from single-use vials does not seem to result in microbial contamination.
The Sentimental Satire of Sophia Baddeley
Authors: Culley Amy
Published: August 2008

The article explores the literary significance of Elizabeth Steele’s The Memoirs of Mrs. Sophia Baddeley (1787) and considers the relationship between satire and sentiment in the self-representations of late-eighteenth-century courtesans. The Memoirs establishes the courtesan Baddeley as a sentimental heroine and translates her experience of domestic violence and sexual double standards into a satire of fashionable society. Steele’s narrative therefore anticipates the sentimental self-portraits of nineteenthcentury women writers and looks back to an earlier tradition of the referential scandal chronicle. In addition, it reveals the impact of the commercial exchanges of the literary marketplace on female self-representations.
Activation of β-Catenin Signaling in Articular Chondrocytes Leads to Osteoarthritis-Like Phenotype in Adult β-Catenin Conditional Activation Mice
Authors: Zhu Mei , Tang Dezhi , Wu Qiuqian , Hao Suyang , Chen Mo , Xie Chao , Rosier Randy N , O'Keefe Regis J , Zuscik Michael , Chen Di
Published: September 2008

Osteoarthritis (OA) is a degenerative joint disease, and the mechanism of its pathogenesis is poorly understood. Recent human genetic association studies showed that mutations in the Frzb gene predispose patients to OA, suggesting that the Wnt/β-catenin signaling may be the key pathway to the development of OA. However, direct genetic evidence for β-catenin in this disease has not been reported. Because tissue-specific activation of the β-catenin gene (targeted by Col2a1-Cre) is embryonic lethal, we specifically activated the β-catenin gene in articular chondrocytes in adult mice by generating β-catenin conditional activation (cAct) mice through breeding of β-cateninfx(Ex3)/fx(Ex3) mice with Col2a1-CreERT2 transgenic mice. Deletion of exon 3 of the β-catenin gene results in the production of a stabilized fusion β-catenin protein that is resistant to phosphorylation by GSK-3β. In this study, tamoxifen was administered to the 3- and 6-mo-old Col2a1-CreERT2;β-cateninfx(Ex3)/wt mice, and tissues were harvested for histologic analysis 2 mo after tamoxifen induction. Overexpression of β-catenin protein was detected by immunostaining in articular cartilage tissues of β-catenin cAct mice. In 5-mo-old β-catenin cAct mice, reduction of Safranin O and Alcian blue staining in articular cartilage tissue and reduced articular cartilage area were observed. In 8-mo-old β-catenin cAct mice, cell cloning, surface fibrillation, vertical clefting, and chondrophyte/osteophyte formation were observed. Complete loss of articular cartilage layers and the formation of new woven bone in the subchondral bone area were also found in β-catenin cAct mice. Expression of chondrocyte marker genes, such as aggrecan, Mmp-9, Mmp-13, Alp, Oc, and colX, was significantly increased (3- to 6-fold) in articular chondrocytes derived from β-catenin cAct mice. Bmp2 but not Bmp4 expression was also significantly upregulated (6-fold increase) in these cells. In addition, we also observed overexpression of β-catenin protein in the knee joint samples from patients with OA. These findings indicate that activation of β-catenin signaling in articular chondrocytes in adult mice leads to the premature chondrocyte differentiation and the development of an OA-like phenotype. This study provides direct and definitive evidence about the role of β-catenin in the development of OA.
Inhibition of Lamin A/C Attenuates Osteoblast Differentiation and Enhances RANKL-Dependent Osteoclastogenesis
Authors: Rauner Martina , Sipos Wolfgang , Goettsch Claudia , Wutzl Arno , Foisner Roland , Pietschmann Peter , Hofbauer Lorenz C
Published: September 2008

Age-related osteoporosis is characterized by low bone mass, poor bone quality, and impaired osteoblastogenesis. Recently, the Hutchinson-Gilford progeria syndrome (HGPS), a disease of accelerated aging and premature osteoporosis, has been linked to mutations in the gene encoding for the nuclear lamina protein lamin A/C. Here, we tested the hypothesis that inhibition of lamin A/C in osteoblastic lineage cells impairs osteoblastogenesis and accelerates osteoclastogenesis. Lamin A/C was knocked-down with small interfering (si)RNA molecules in human bone marrow stromal cells (BMSCs) differentiating toward osteoblasts. Lamin A/C knockdown led to an inhibition of osteoblast proliferation by 26% and impaired osteoblast differentiation by 48% based on the formation of mineralized matrix. In mature osteoblasts, expression levels of runx2 and osteocalcin mRNA were decreased by lamin A/C knockdown by 44% and 78%, respectively. Furthermore, protein analysis showed that osteoblasts with diminished levels of lamin A/C also secreted less osteocalcin and expressed a lower alkaline phosphatase activity (−50%). Lamin A/C inhibition increased RANKL mRNA and protein levels, whereas osteoprotegerin (OPG) expression was decreased, resulting in an increased RANKL/OPG ratio and an enhanced ability to support osteoclastogenesis, as reflected by a 34% increase of TRACP+ multinucleated cells. Our data indicate that lamin A/C is essential for proper osteoblastogenesis. Moreover, lack of lamin A/C favors an osteoclastogenic milieu and contributes to enhanced osteoclastogenesis.
Analysis of CYP27B1, Encoding 25-Hydroxyvitamin D-1α-Hydroxylase, as a Candidate Tumor Suppressor Gene in Primary and Severe Secondary/Tertiary Hyperparathyroidism
Authors: Lauter Kelly , Arnold Andrew
Published: September 2008

CYP27B1, encoding 25-hydroxyvitamin D-1α-hydroxylase, converts 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D, and is expressed primarily in the kidney but also in nontraditional sites including the parathyroid glands. Whereas the role of locally produced 1,25-dihydroxyvitamin D is not yet clear, it is possible that it contributes importantly to vitamin D–mediated inhibition of parathyroid cell growth, so CYP27B1 can be considered a candidate parathyroid tumor suppressor gene in that its acquired inactivation in a parathyroid cell could confer a tumorigenic growth advantage. Expression of CYP27B1 has also been reported to be altered in parathyroid neoplasms. Because detection of inactivating mutations is the central criterion for validating a candidate tumor suppressor, we directly sequenced the coding region and all splice sites of CYP27B1 in 31 sporadic parathyroid adenomas and 31 parathyroid tumors from patients with refractory secondary/tertiary hyperparathyroidism. No nonsense, frameshift, or other inactivating mutations were found, and there was no sign of homozygous deletion. Our findings indicate that CYP27B1 does not commonly serve as a classical tumor suppressor gene in the development of sporadic parathyroid adenomas or of refractory secondary/tertiary hyperparathyroidism.
CD33+ CD14− Phenotype Is Characteristic of Multinuclear Osteoclast-Like Cells in Giant Cell Tumor of Bone
Authors: Forsyth Ramses G , De Boeck Gitte , Baelde Johannes J , Taminiau Anthonie HM , Uyttendaele Dirk , Roels Hendrik , Praet Marleen M , Hogendoorn Pancras CW
Published: September 2008

Giant cell tumor of bone (GCTB) is a benign bone tumor with a shown clinical behavior of local recurrences and rare distant metastases. GCTB is composed of uniformly distributed osteoclastic giant cells, thought to originate from the fusion of monocyte–macrophage lineage cells, in a background consisting of mononuclear rounded cells and spindle-shaped cells. Several reports showed the specific expression of markers, such as CD14 on the mononuclear rounded cell population, however, lacking osteoclastic giant cells. Blood monocytes that were CD14+, CD33+, or CD14+/CD33+ have also been shown to be programmed as pre-osteoclasts. The macrophage marker CD33 is expressed earlier than CD14 in macrophage maturation, whereas CD14 is expressed longer than CD33. The aim of this study was to investigate CD14/CD33 expression profiles in GCTB. Nineteen GCTB tumor samples of 19 patients were studied. Immunofluorescent analyses were performed with monoclonal antibodies against CD14, CD33, RANK, and CD51. To unambiguously further prove the expression of these molecules, quantitative RT-PCR was used with subsequent sequencing of its products. All samples showed similar immunoreactivity profiles. The mononuclear rounded cell population was positive for RANK, CD51, CD14, and CD33. The osteoclastic giant cell population expressed RANK and CD51, as well as CD33, but was consistently negative for CD14 expression. The CD14 and CD33 profiles were confirmed by quantitative RT-PCR. These RT-PCR products were sequence verified. Osteoclasts in GCTB are the result of fusion of CD33-expressing pre-osteoclasts that further fuse with CD14+ mononuclear cells. Although these results reflect a static rather than a dynamic spectrum, we strongly believe that osteoclastogenesis seems not to be the exclusive result of fusion of intratumoral CD14+ mononuclear cells. Moreover, CD33-modulated osteoclastogenesis opens up the possibility for novel therapeutic directions.
Paget's Disease of Bone: Histologic Analysis of 754 Patients
Authors: Seitz Sebastian , Priemel Matthias , Zustin Jozef , Beil F Timo , Semler Jutta , Minne Helmut , Schinke Thorsten , Amling Michael
Published: September 2008

Although Paget's disease of bone (PDB) is the second most common metabolic bone disease, to our knowledge, there is only one quantitative analysis on the histological and especially on the histomorphometric level. Therefore, the aim of this study was to analyze, on the basis of the Hamburg Bone Register, PBD in terms of incidence, skeletal distribution, malignant transformation, and histological and histomorphometric characteristics. Bone biopsies and patient files of 754 cases with histologically proven PDB were reviewed in a retrospective study. Quantitative static histomorphometry was performed on a representative subgroup of 247 biopsies derived from patients with manifestation of PDB at the iliac crest and compared with an age- and sex-matched control group. The peak incidence of PDB was between 70 and 80 yr of age. The majority of monostotic skeletal manifestation was localized at the os ilium, followed by the spine and femur. Histomorphometric results showed a high bone turnover with a significant increase in bone resorption and bone formation indices leading to an increased bone volume. Paget sarcoma was diagnosed in 6 of 754 patients, indicating a malignant transformation in 0.8% of the affected patients. Taken together, our study characterizes PDB in Germany on the basis of one of the largest cohorts of patients with histologically proven PDB. Moreover, for the first time, a quantitative histomorphometric approach was taken for >200 cases, where we could show local high bone mass lesions as a result of an increase of both osteoclast and osteoblast indices.
An Integrative Genetics Approach to Identify Candidate Genes Regulating BMD: Combining Linkage, Gene Expression, and Association
Authors: Farber Charles R , van Nas Atila , Ghazalpour Anatole , Aten Jason E , Doss Sudheer , Sos Brandon , Schadt Eric E , Ingram-Drake Leslie , Davis Richard C , Horvath Steve , Smith Desmond J , Drake Thomas A , Lusis Aldons J
Published: September 2008

Numerous quantitative trait loci (QTLs) affecting bone traits have been identified in the mouse; however, few of the underlying genes have been discovered. To improve the process of transitioning from QTL to gene, we describe an integrative genetics approach, which combines linkage analysis, expression QTL (eQTL) mapping, causality modeling, and genetic association in outbred mice. In C57BL/6J × C3H/HeJ (BXH) F2 mice, nine QTLs regulating femoral BMD were identified. To select candidate genes from within each QTL region, microarray gene expression profiles from individual F2 mice were used to identify 148 genes whose expression was correlated with BMD and regulated by local eQTLs. Many of the genes that were the most highly correlated with BMD have been previously shown to modulate bone mass or skeletal development. Candidates were further prioritized by determining whether their expression was predicted to underlie variation in BMD. Using network edge orienting (NEO), a causality modeling algorithm, 18 of the 148 candidates were predicted to be causally related to differences in BMD. To fine-map QTLs, markers in outbred MF1 mice were tested for association with BMD. Three chromosome 11 SNPs were identified that were associated with BMD within the Bmd11 QTL. Finally, our approach provides strong support for Wnt9a, Rasd1, or both underlying Bmd11. Integration of multiple genetic and genomic data sets can substantially improve the efficiency of QTL fine-mapping and candidate gene identification.
Subpixel Enhancement of Nonuniform Tissue (SPENT): A Novel MRI Technique for Quantifying BMD
Authors: Yiannakas Marios C , Carmichael David W , Farquharson Michael J , Ordidge Roger J
Published: September 2008

BMD is commonly obtained with DXA, but this is confounded by the length and composition of tissues that the X-ray must traverse. Subpixel enhancement of nonuniform tissue (SPENT) is a novel MRI technique that can provide (direction specific) information based on the subvoxel structural uniformity of a sample. We hypothesized that the SPENT signal would be related to BMD. This hypothesis was tested using (1) 2D computer simulation of a simplified bone structure and (2) in vitro experiments. Simulation results suggested that a resolution of 610–800 μm was required for SPENT to be correlated well with the simulated bone volume fraction (BVF) and, at this resolution, a modest signal-to-noise ratio (SNR > 5) was required for reasonable data quality. For the experiments, 15-mm3 human trabecular bone samples were used (1) to quantify BMD (through both physical measurement and DXA) and (2) to perform MRI on a 7T system. Standard and SPENT images were obtained. Normalized SPENT (NSPENT) images were calculated by pixel-by-pixel division of the SPENT images by the standard proton density images to remove any dependence on proton density and coil uniformity from the SPENT images. The average NSPENT values were determined over the sample volume and compared with the reference BMD measurements. Each of the individual NSPENT directions was highly correlated with BMD (x-NSPENT, R2 = 0.73, p < 0.001; y-NSPENT, R2 = 0.76, p < 0.001; z-NSPENT, R2 = 0.89, p < 0.001). With all three individual NSPENT directions combined, the correlation with BMD was found to be the highest (xyz-NSPENT, R2 = 0.95, p < 0.001). The results suggest that the SPENT technique can provide a noninvasive measure of BMD at resolution and SNR levels achievable in vivo.
Genetic Variation in Sex Hormone Genes Influences Heel Ultrasound Parameters in Middle-Aged and Elderly Men: Results From the European Male Aging Study (EMAS)
Authors: Limer Kate L , Pye Stephen R , Thomson Wendy , Boonen Steven , Borghs Herman , Vanderschueren Dirk , Huhtaniemi Ilpo T , Adams Judith E , Ward Kate A , Platt Hazel , Payne Debbie , John Sally L , Bartfai Gyorgy , Casanueva Felipe , Finn Joseph D , Forti Gianni , Giwercman Aleksander , Han Thang S , Kula Krzysztof , Lean Michael E , Pendleton Neil , Punab Margus , Silman Alan J , Wu Frederick C , O'Neill Terence W
Published: September 2008

Genes involved in sex hormone pathways are candidates for influencing bone strength. Polymorphisms in these genes were tested for association with heel quantitative ultrasound (QUS) parameters in middle-aged and elderly European men. Men 40–79 yr of age were recruited from population registers in eight European centers for the European Male Aging Study (EMAS). Polymorphisms were genotyped in AR, ESR1, ESR2, CYP19A1, CYP17A1, SHBG, SRD5A2, LHB, and LHCGR. QUS parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured in the heel and used to derive BMD. The relationships between QUS parameters and polymorphisms were assessed using linear regression adjusting for age and center. A total of 2693 men, with a mean age of 60.1 ± 11.1 (SD) yr were included in the analysis. Their mean BUA was 80.0 ± 18.9 dB/Mhz, SOS was 1550.2 ± 34.1 m/s, and BMD was 0.542 ± 0.141 g/cm2. Significant associations were observed between multiple SNPs in a linkage disequilibrium (LD) block within CYP19A1, peaking at the TCT indel with the deletion allele associating with reduced ultrasound BMD in heterozygotes (β =−0.016, p = −0.005) and homozygotes (β = −0.029, p = 0.001). The results for BUA and SOS were similar. Significant associations with QUS parameters were also observed for the CAG repeat in AR and SNPs in CYP17A1, LHCGR, and ESR1. Our data confirm evidence of association between bone QUS parameters and polymorphisms in CYP19A1, as well as modest associations with polymorphisms in CYP17A1, ESR1, LHCGR, and AR in a population sample of European men; this supports a role for genetically determined sex hormone actions in influencing male bone health.
Does Immunohistochemistry Allow Easy Detection of Lymphatics in the Optic Nerve Sheath?
Authors: Killer Hanspeter E. , Jaggi Gregor P. , Miller Neil R. , Flammer Josef , Meyer Peter
Published: September 2008

We evaluated the validity of anti-D2-40 and anti-LYVE-1 (antibodies against lymphatic endothelium) for IHC diagnosis and semiquantification of lymphatic vessels in the dura mater of the intraorbital portion of the human optic nerve (ON). Fourteen specimens were analyzed using light microscopy within 12 hr postmortem. We found in all specimens that both D2-40 and LYVE-1 stained lymphatic vessels as well as venules and arterioles. Our findings show lymphatic vessels in the meninges of the intraorbital portion of the human ON. Anti-D2-40 and anti-LYVE-1 antibodies, however, are not found to be exclusively specific to the endothelial layer of lymphatics because they also stain the endothelial layer of venules and arterioles. For the unequivocal identification of lymphatics, additional morphological criteria are necessary. Nevertheless, D2-40 and LYVE-1 staining allows rapid identification of endothelial layers.
Capacity of Dental Pulp Differentiation in Mouse Molars as Demonstrated by Allogenic Tooth Transplantation
Authors: Takamori Yasuhiko , Suzuki Hironobu , Nakakura-Ohshima Kuniko , Cai Jinglei , Cho Sung-Won , Jung Han-Sung , Ohshima Hayato
Published: September 2008

Dental pulp elaborates both bone and dentin under pathological conditions such as tooth replantation/transplantation. This study aims to clarify the capability of dental pulp to elaborate bone tissue in addition to dentin by allogenic tooth transplantation using immunohistochemistry and histochemistry. After extraction of the molars of 3-week-old mice, the roots and pulp floor were resected and immediately allografted into the sublingual region in a littermate. In addition, we studied the contribution of donor and host cells to the regenerated pulp tissue using a combination of allogenic tooth transplantation and lacZ transgenic ROSA26 mice. On Days 5-7, tubular dentin formation started next to the preexisting dentin at the pulp horn where nestin-positive odontoblast-like cells were arranged. Until Day 14, bone-like tissue formation occurred in the pulp chamber, where intense tartrate-resistant acid phosphatase-positive cells appeared. Furthermore, allogenic transplantation using ROSA26 mice clearly showed that both donor and host cells differentiated into osteoblast-like cells with the assistance of osteoclast-lineage cells, whereas newly differentiated odontoblasts were exclusively derived from donor cells. These results suggest that the odontoblast and osteoblast lineage cells reside in the dental pulp and that both donor and host cells contribute to bone-like tissue formation in the regenerated pulp tissue.
Distribution of Tight Junction Proteins in Adult Human Salivary Glands
Authors: Maria Ola M. , Kim Jung-Wan Martin , Gerstenhaber Jonathan A. , Baum Bruce J. , Tran Simon D.
Published: September 2008

Tight junctions (TJs) are an essential structure of fluid-secreting cells, such as those in salivary glands. Three major families of integral membrane proteins have been identified as components of the TJ: claudins, occludin, and junctional adhesion molecules (JAMs), plus the cytosolic protein zonula occludens (ZO). We have been working to develop an orally implantable artificial salivary gland that would be suitable for treating patients lacking salivary parenchymal tissue. To date, little is known about the distribution of TJ proteins in adult human salivary cells and thus what key molecular components might be desirable for the cellular component of an artificial salivary gland device. Therefore, the aim of this study was to determine the distribution of TJ proteins in human salivary glands. Salivary gland samples were obtained from 10 patients. Frozen and formalin-fixed paraffin-embedded sections were stained using IHC methods. Claudin-1 was expressed in ductal, endothelial, and ∼25% of serous cells. Claudins-2, −3, and −4 and JAM-A were expressed in both ductal and acinar cells, whereas claudin-5 was expressed only in endothelial cells. Occludin and ZO-1 were expressed in acinar, ductal, and endothelial cells. These results provide new information on TJ proteins in two major human salivary glands and should serve as a reference for future studies to assess the presence of appropriate TJ proteins in a tissue-engineered human salivary gland.
Acetylcholine Release in the Mesocorticolimbic Dopamine System during Cocaine Seeking: Conditioned and Unconditioned Contributions to Reward and Motivation
Authors: You Zhi-Bing , Wang Bin , Zitzman Dawnya , Wise Roy A.
Published: September 2008

Microdialysis was used to assess the contribution to cocaine seeking of cholinergic input to the mesocorticolimbic dopamine system in ventral tegmental area (VTA). VTA acetylcholine (ACh) was elevated in animals lever pressing for intravenous cocaine and in cocaine-experienced and cocaine-naive animals passively receiving similar “yoked” injections. In cocaine-trained animals, the elevations comprised an initial (first hour) peak to ∼160% of baseline and a subsequent plateau of 140% of baseline for the rest of the cocaine intake period. In cocaine-naive animals, yoked cocaine injections raised ACh levels to the 140% plateau but did not cause the initial 160% peak. In cocaine-trained animals that received unexpected saline (extinction conditions) rather than the expected cocaine, the initial peak was seen but the subsequent plateau was absent. VTA ACh levels played a causal role and were not just a correlate of cocaine seeking. Blocking muscarinic input to the VTA increased cocaine intake; the increase in intake offset the decrease in cholinergic input, resulting in the same VTA dopamine levels as were seen in the absence of the ACh antagonists. Increased VTA ACh levels (resulting from 10 μmVTA neostigmine infusion) increased VTA dopamine levels and reinstated cocaine seeking in cocaine-trained animals that had undergone extinction; these effects were strongly attenuated by local infusion of a muscarinic antagonist and weakly attenuated by a nicotinic antagonist. These findings identify two cholinergic responses to cocaine self-administration, an unconditioned response to cocaine itself and a conditioned response triggered by cocaine-predictive cues, and confirm that these cholinergic responses contribute to the control of cocaine seeking.
Endophilin B1 as a Novel Regulator of Nerve Growth Factor/ TrkA Trafficking and Neurite Outgrowth
Authors: Wan Jun , Cheung Anthony Y. , Fu Wing-Yu , Wu Chengbiao , Zhang Mingjie , Mobley William C. , Cheung Zelda H. , Ip Nancy Y.
Published: September 2008

Neurotrophins and their cognate receptors Trks are important regulators of neuronal survival and differentiation. Recent studies reveal that internalization and trafficking of Trks play a critical role in neurotrophin-mediated signaling. At present, little is known of the molecular events that mediate this process. In the current study, we show that endophilin B1 is a novel regulator of nerve growth factor (NGF) trafficking. We found that endophilin B1 interacts with both TrkA and early endosome marker EEA1. Interestingly, knockdown of endophilin B1 results in enlarged EEA1-positive vesicles in NGF-treated PC12 cells. This is accompanied by increased lysosomal targeting of NGF/TrkA and TrkA degradation, and reduced total TrkA levels. In addition, knockdown of endophilin B1 attenuates Erk1/2 activation in the endosomal fraction after NGF treatment. This is accompanied by a marked inhibition of NGF-induced gene transcription and neurite outgrowth in endophilin B1-knocked down cells. Our observations implicate endophilin B1 as a novel regulator of NGF trafficking, thereby affecting TrkA levels and downstream signaling on endosomes to mediate biological functions of NGF.
Retinal ON Bipolar Cells Express a New PCP2 Splice Variant That Accelerates the Light Response
Authors: Xu Ying , Sulaiman Pyroja , Feddersen Rod M. , Liu Jian , Smith Robert G. , Vardi Noga
Published: September 2008

PCP2, a member of the GoLoco domain-containing family, is present exclusively in cerebellar Purkinje cells and retinal ON bipolar cells. Its function in these tissues is unknown. Biochemical and expression system studies suggest that PCP2 is a guanine nucleotide dissociation inhibitor, although a guanine nucleotide exchange factor has also been suggested. Here, we studied the function of PCP2 in ON bipolar cells because their light response depends on Gαo1, which is known to interact with PCP2. We identified a new splice variant of PCP2 (Ret-PCP2) and localized it to rod bipolar and ON cone bipolar cells. Electroretinogram recordings from PCP2-null mice showed a normal a-wave but a slower falling phase of the b-wave (generated by the activity of ON bipolar cells) relative to the wild type. Whole-cell recordings from rod bipolar cells showed, both under Ames medium and after blocking GABAA/Cand glycine receptors, that PCP2-null rod bipolar cells were more depolarized than wild-type cells with greater inward current when clamped to −60 mV. Also under both conditions, the rise time of the response to intense light was slower by 28% (Ames) and 44% (inhibitory blockers) in the null cells. Under Ames medium, we also observed >30% longer decay time in the PCP2-null rod bipolar cells. We conclude that PCP2 facilitates cation channels closure in the dark, shortens the rise time of the light response directly, and accelerates the decay time indirectly via the inhibitory network. These data can most easily be explained if PCP2 serves as a guanine nucleotide exchange factor.
Sex-Specific Programming of Offspring Emotionality after Stress Early in Pregnancy
Authors: Mueller Bridget R. , Bale Tracy L.
Published: September 2008

Prenatal stress is associated with an increased vulnerability to neurodevelopmental disorders, including autism and schizophrenia. To determine the critical time window when fetal antecedents may induce a disease predisposition, we examined behavioral responses in offspring exposed to stress during early, mid, and late gestation. We found that male offspring exposed to stress early in gestation displayed maladaptive behavioral stress responsivity, anhedonia, and an increased sensitivity to selective serotonin reuptake inhibitor treatment. Long-term alterations in central corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR) expression, as well as increased hypothalamic–pituitary–adrenal (HPA) axis responsivity, were present in these mice and likely contributed to an elevated stress sensitivity. Changes in CRF and GR gene methylation correlated with altered gene expression, providing important evidence of epigenetic programming during early prenatal stress. In addition, we found the core mechanism underlying male vulnerability may involve sex-specific placenta responsivity, where stress early in pregnancy significantly increased expression of PPARα (peroxisome proliferator-activated receptor α), IGFBP-1 (insulin-like growth factor binding protein 1), HIF3α (hypoxia-inducible factor 3a), and GLUT4 (glucose transporter 4) in male placentas but not females. Examination of placental epigenetic machinery revealed basal sex differences, providing further evidence that sex-specific programming begins very early in pregnancy, and may contribute to the timing and vulnerability of the developing fetus to maternal perturbations. Overall, these results indicate that stress experience early in pregnancy may contribute to male neurodevelopmental disorders through impacts on placental function and fetal development.
Eye Position Representation in Human Anterior Parietal Cortex
Authors: Balslev Daniela , Miall R. Chris
Published: September 2008

Eye position helps locate visual targets relative to one's own body and modulates the distribution of attention in visual space. Whereas in the monkey, proprioceptive eye position signals have been recorded in the somatosensory cortex, in humans, no brain site has yet been associated with eye position. We aimed to disrupt the proprioceptive representation of the right eye in the left somatosensory cortex, presumably located near the representation of the right hand, using repetitive transcranial magnetic stimulation (rTMS). Head-fixed subjects reported their perceived visual straight-ahead position using both left and right eye monocular vision, before and after 15 min of 1 Hz rTMS. rTMS over left somatosensory but not over left motor cortex shifted the perceived visual straight ahead to the left, whereas nonvisual detection of body midline was unchanged for either brain area. These results can be explained by the underestimation of the angle of gaze of the right eye when fixating the target. To link this effect more tightly to an altered ocular proprioception, we applied a passive deviation to the right eye before the visual straight-ahead task. Passive eye displacement modulated the shift in the perceived straight ahead induced by somatosensory rTMS, without affecting the perceived straight ahead at baseline or after motor cortex rTMS. We conclude that the anterior parietal cortex in humans encodes eye position and that this signal has a proprioceptive component.
Nucleus Accumbens Adenosine A2AReceptors Regulate Exertion of Effort by Acting on the Ventral Striatopallidal Pathway
Authors: Mingote Susana , Font Laura , Farrar Andrew M. , Vontell Regina , Worden Lila T. , Stopper Colin M. , Port Russell G. , Sink Kelly S. , Bunce Jamie G. , Chrobak James J. , Salamone John D.
Published: September 2008

Goal-directed actions are sensitive to work-related response costs, and dopamine in nucleus accumbens is thought to modulate the exertion of effort in motivated behavior. Dopamine-rich striatal areas such as nucleus accumbens also contain high numbers of adenosine A2Areceptors, and, for that reason, the behavioral and neurochemical effects of the adenosine A2Areceptor agonist CGS 21680 [2-p-(2-carboxyethyl) phenethylamino-5′-N-ethylcarboxamidoadenosine] were investigated. Stimulation of accumbens adenosine A2Areceptors disrupted performance of an instrumental task with high work demands (i.e., an interval lever-pressing schedule with a ratio requirement attached) but had little effect on a task with a lower work requirement. Immunohistochemical studies revealed that accumbens neurons that project to the ventral pallidum showed adenosine A2Areceptors immunoreactivity. Moreover, activation of accumbens A2Areceptors by local injections of CGS 21680 increased extracellular GABA levels in the ventral pallidum. Combined contralateral injections of CGS 21680 into the accumbens and the GABAAagonist muscimol into ventral pallidum (i.e., “disconnection” methods) also impaired response output, indicating that these structures are part of a common neural circuitry regulating the exertion of effort. Thus, accumbens adenosine A2Areceptors appear to regulate behavioral activation and effort-related processes by modulating the activity of the ventral striatopallidal pathway. Research on the effort-related functions of these forebrain systems may lead to a greater understanding of pathological features of motivation, such as psychomotor slowing, anergia, and fatigue in depression.
Midbrain Dopamine Neurons: Projection Target Determines Action Potential Duration and Dopamine D2Receptor Inhibition
Authors: Margolis Elyssa B. , Mitchell Jennifer M. , Ishikawa Junko , Hjelmstad Gregory O. , Fields Howard L.
Published: September 2008

Broad action potentials (APs) and dopamine (DA) D2receptor (D2R)-mediated inhibition are widely used to identify midbrain DA neurons. However, when these measures are taken alone they do not predict DA content in ventral tegmental area (VTA) neurons. In fact, some VTA neuronal properties correlate better with projection target than neurotransmitter content. Here we report that amygdala (AMYG)-projecting VTA DA neurons have brief APs and lack D2R agonist (quinpirole; 1 μm) autoinhibition. However, they are hyperpolarized by both the GABABagonist baclofen (1 μm) and the κ-opioid receptor agonist U69593 [(+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide; 1 μm]. Furthermore, we show that accurate prediction of DA content in VTA neurons is possible when the projection target is known: in both nucleus accumbens- and AMYG-projecting neural populations, AP durations are significantly longer in DA than non-DA neurons. Among prefrontal cortex-projecting neurons, quinpirole sensitivity, but not AP duration, is a predictor of DA content. Therefore, in the VTA, AP duration and inhibition by D2R agonists may be valid markers of DA content in neurons of known projection target.