bluuebunny/crossref_metadata_2025_split huggingface dataset:
PLCL1 rs7595412 variation is not associated with hip bone size variation in postmenopausal Danish women
Authors: Cauchi Stéphane , Byrjalsen Inger , Durand Emmanuelle , Karsdal Morten A , Froguel Philippe 
Published: December 2009

Abstract

Background
Bone size (BS) variation is under strong genetic control and plays an important role in determining bone strength and fracture risk. Recently, a genome-wide association study identified polymorphisms associated with hip BS variation in the PLCL1 (phospholipase c-like 1) locus. Carriers of the major A allele of the most significant polymorphism, rs7595412, have around 17% larger hip BS than non-carriers. We therefore hypothesized that this polymorphism may also influence postmenopausal complications.

Methods
The effects of rs7595412 on hip BS, bone mineral density (BMD), vertebral fractures, serum Crosslaps and osteocalcin levels were analyzed in 1,191 postmenopausal Danish women.

Results
This polymorphism had no influence on hip and spine BS as well as on femur and spine BMD. Women carrying at least one copy of the A allele had lower levels of serum osteocalcin as compared with those homozygous for the G allele (p = 0.03) whereas no effect on serum Crosslaps was detected. Furthermore, women homozygous for the A allele were more affected by vertebral fractures than those carrying at least one copy of the G allele (p = 0.04).

Conclusions
In postmenopausal women, our results suggest that the PLCL1 rs7595412 polymorphism has no obvious effect on hip BS or BMD but may be nominally associated with increased proportion of vertebral fracture and increased levels of osteocalcin.
Lipogenesis in arterial wall and vascular smooth muscular cells: regulation and abnormalities in insulin-resistance
Authors: Hamlat Nadjiba , Forcheron Fabien , Negazzi Samia , del Carmine Peggy , Feugier Patrick , Bricca Giampiero , Aouichat-Bouguerra Souhila , Beylot Michel 
Published: December 2009

Abstract

Background
Vascular smooth muscular cells (VSMC) express lipogenic genes. Therefore in situ lipogenesis could provide fatty acids for triglycerides synthesis and cholesterol esterification and contribute to lipid accumulation in arterial wall with aging and during atheroma.

Methods
We investigated expression of lipogenic genes in human and rat arterial walls, its regulation in cultured VSMC and determined if it is modified during insulin-resistance and diabetes, situations with increased risk for atheroma.

Results
Zucker obese (ZO) and diabetic (ZDF) rats accumulated more triglycerides in their aortas than their respective control rats, and this triglycerides content increased with age in ZDF and control rats. However the expression in aortas of lipogenic genes, or of genes involved in fatty acids uptake, was not higher in ZDF and ZO rats and did not increase with age. Expression of lipogenesis-related genes was not increased in human arterial wall (carotid endarterectomy) of diabetic compared to non-diabetic patients. In vitro, glucose and adipogenic medium (ADM) stimulated moderately the expression and activity of lipogenesis in VSMC from control rats. LXR agonists, but not PXR agonist, stimulated also lipogenesis in VSMC but not in arterial wall in vivo. Lipogenic genes expression was lower in VSMC from ZO rats and not stimulated by glucose or ADM.

Conclusion
Lipogenic genes are expressed in arterial wall and VSMC; this expression is stimulated (VSMC) by glucose, ADM and LXR agonists. During insulin-resistance and diabetes, this expression is not increased and resists to the actions of glucose and ADM. It is unlikely that this metabolic pathway contribute to lipid accumulation of arterial wall during insulin-resistance and diabetes and thus to the increased risk of atheroma observed in these situations.
Effectiveness of adjuvant radiotherapy in patients with oropharyngeal and floor of mouth squamous cell carcinoma and concomitant histological verification of singular ipsilateral cervical lymph node metastasis (pN1-state) - A prospective multicenter randomized controlled clinical trial using a comprehensive cohort design
Authors: Moergel Maximilian , Jahn-Eimermacher Antje , Krummenauer Frank , Reichert Torsten E , Wagner Wilfried , Wendt Thomas G , Werner Jochen A , Al-Nawas Bilal 
Published: December 2009

Abstract

Background
Modern radiotherapy plays an important role in therapy of advanced head and neck carcinomas. However, no clinical studies have been published addressing the effectiveness of postoperative radiotherapy in patients with small tumor (pT1, pT2) and concomitant ipsilateral metastasis of a single lymph node (pN1), which would provide a basis for a general treatment recommendation.

Methods/Design
The present study is a non-blinded, prospective, multi-center randomized controlled trial (RCT). As the primary clinical endpoint, overall-survival in patients receiving postoperative radiation therapy vs. patients without adjuvant therapy following curative intended surgery is compared. The aim of the study is to enroll 560 adult males and females for 1:1 randomization to one of the two treatment arms (irradiation/no irradiation). Since patients with small tumor (T1/T2) but singular lymph node metastasis are rare and the amount of patients consenting to randomization is not predictable in advance, all patients rejecting randomization will be treated as preferred and enrolled in a prospective observational study (comprehensive cohort design) after giving informed consent. This observational part of the trial will be performed with maximum consistency to the treatment and observation protocol of the RCT. Because the impact of patient preference for a certain treatment option is not calculable, parallel design of RCT and observational study may provide a maximum of evidence and efficacy for evaluation of treatment outcome. Secondary clinical endpoints are as follows: incidence and time to tumor relapse (locoregional relapse, lymph node involvement and distant metastatic spread), Quality of life as reported by EORTC (QLQ-C30 with H&N 35 module), and time from operation to orofacial rehabilitation. All tumors represent a homogeneous clinical state and therefore additional investigation of protein expression levels within resection specimen may serve for establishment of surrogate parameters of patient outcome.

Conclusion
The inherent challenges of a rare clinical condition (pN1) and two substantially different therapy arms would limit the practicality of a classical randomized study. The concept of a Comprehensive Cohort Design combines the preference of a randomized study, with the option of careful data interpretation within an observational study.

Trial registration
ClinicalTrials.gov: NCT00964977
SP-D counteracts GM-CSF-mediated increase of granuloma formation by alveolar macrophages in lysinuric protein intolerance
Authors: Douda David N , Farmakovski Nicole , Dell Sharon , Grasemann Hartmut , Palaniyar Nades 
Published: December 2009

AbstractBackgroundPulmonary alveolar proteinosis (PAP) is a syndrome with multiple etiologies and is often deadly in lysinuric protein intolerance (LPI). At present, PAP is treated by whole lung lavage or with granulocyte/monocyte colony stimulating factor (GM-CSF); however, the effectiveness of GM-CSF in treating LPI associated PAP is uncertain. We hypothesized that GM-CSF and surfactant protein D (SP-D) would enhance the clearance of proteins and dying cells that are typically present in the airways of PAP lungs.MethodsCells and cell-free supernatant of therapeutic bronchoalveolar lavage fluid (BALF) of a two-year-old patient with LPI were isolated on multiple occasions. Diagnostic BALF samples from an age-matched patient with bronchitis or adult PAP patients were used as controls. SP-D and total protein content of the supernatants were determined by BCA assays and Western blots, respectively. Cholesterol content was determined by a calorimetic assay or Oil Red O staining of cytospin preparations. The cells and surfactant lipids were also analyzed by transmission electron microscopy. Uptake of Alexa-647 conjugated BSA and DiI-labelled apoptotic Jurkat T-cells by BAL cells were studied separately in the presence or absence of SP-D (1 μg/ml) and/or GM-CSF (10 ng/ml),ex vivo. Specimens were analyzed by light and fluorescence microscopy.ResultsHere we show that large amounts of cholesterol, and large numbers of cholesterol crystals, dying cells, and lipid-laden foamy alveolar macrophages were present in the airways of the LPI patient. Although SP-D is present, its bioavailability is low in the airways. SP-D was partially degraded and entrapped in the unusual surfactant lipid tubules with circular lattice,in vivo. We also show that supplementing SP-D and GM-CSF increases the uptake of protein and dying cells by healthy LPI alveolar macrophages,ex vivo. Serendipitously, we found that these cells spontaneously generated granulomas,ex vivo, and GM-CSF treatment drastically increased the number of granulomas whereas SP-D treatment counteracted the adverse effect of GM-CSF.ConclusionsWe propose that increased GM-CSF and decreased bioavailability of SP-D may promote granuloma formation in LPI, and GM-CSF may not be suitable for treating PAP in LPI. To improve the lung condition of LPI patients with PAP, it would be useful to explore alternative therapies for increasing dead cell clearance while decreasing cholesterol content in the airways.
Computational modeling of the EGFR network elucidates control mechanisms regulating signal dynamics
Authors: Wang Dennis YQ , Cardelli Luca , Phillips Andrew , Piterman Nir , Fisher Jasmin 
Published: December 2009

Abstract

Background
The epidermal growth factor receptor (EGFR) signaling pathway plays a key role in regulation of cellular growth and development. While highly studied, it is still not fully understood how the signal is orchestrated. One of the reasons for the complexity of this pathway is the extensive network of inter-connected components involved in the signaling. In the aim of identifying critical mechanisms controlling signal transduction we have performed extensive analysis of an executable model of the EGFR pathway using the stochastic pi-calculus as a modeling language.

Results
Our analysis, done through simulation of various perturbations, suggests that the EGFR pathway contains regions of functional redundancy in the upstream parts; in the event of low EGF stimulus or partial system failure, this redundancy helps to maintain functional robustness. Downstream parts, like the parts controlling Ras and ERK, have fewer redundancies, and more than 50% inhibition of specific reactions in those parts greatly attenuates signal response. In addition, we suggest an abstract model that captures the main control mechanisms in the pathway. Simulation of this abstract model suggests that without redundancies in the upstream modules, signal transduction through the entire pathway could be attenuated. In terms of specific control mechanisms, we have identified positive feedback loops whose role is to prolong the active state of key components (e.g., MEK-PP, Ras-GTP), and negative feedback loops that help promote signal adaptation and stabilization.

Conclusions
The insights gained from simulating this executable model facilitate the formulation of specific hypotheses regarding the control mechanisms of the EGFR signaling, and further substantiate the benefit to construct abstract executable models of large complex biological networks.
The use of multi-variate models for the prediction of heat transfer in vehicle exhaust systems
Authors: Bannister C D , Brace C J , Taylor J , Brooks T , Fraser N 
Published: December 2009

This paper describes the development of an exhaust system model based on the characterization of heat transfer in a series of 11 test sections designed to represent a range of configurations seen in production exhaust systems. These sections include variations in the wall thickness, diameter, bend angle, and radius. This work is part of a larger activity aimed at the accurate modelling of heat transfer and subsequent catalyst light-off in production exhaust systems consisting of similar geometries. For each section a range of steady state tests was performed on a dynamic test cell using a port injected gasoline engine. In each case a correlation between the observed Reynolds number Re and the Nusselt number Nu was developed. A model of the system was implemented in MATLAB—Simulink in which each pipe element was split into 25 subelements by dividing the pipe into five, both axially and radially. After each individual section had been characterized, a generic model was built that was capable of determining the relationship between the Nusselt number and the Reynolds number for previously unseen pipe geometries. Complex exhaust systems can be constructed from smaller elements of defined geometry. The modelling approach was validated using experimental data gathered from vehicle testing on a chassis dynamometer. The steady state relationship between Re and Nu allows heat transfer in the test section to be predicted over transient test cycles and demonstrates good agreement with relationships in the literature.
Effect of a Pharmacy-Based Health Literacy Intervention and Patient Characteristics on Medication Refill Adherence in an Urban Health System
Authors: Gazmararian Julie , Jacobson Kara L , Pan Yi , Schmotzer Brian , Kripalani Sunil 
Published: December 2009

BACKGROUND Limited health literacy is associated with poor understanding of medication instructions and may be related to medication adherence. OBJECTIVE To evaluate a 3-part intervention (automated telephone reminder calls to refill prescriptions, picture prescription card, and clear health communication training for pharmacists) intended to increase refill adherence through attention to health literacy. METHODS Three pharmacies that serve a primarily indigent, minority population served as the intervention sites, and one pharmacy served as the control site. To evaluate the impact of the 6-month intervention on medication adherence, pharmacy refill data were used to calculate the cumulative medication gap (CMG), in which values close to zero indicate better adherence. The primary measure of treatment effect was a comparison of the change in refill adherence within each group, from baseline to follow-up. RESULTS A total of 173 patients were enrolled in the intervention group and 102 patients in the control group. Medication adherence was significantly different between intervention (CMG = 0.25) and control (CMG = 0.18) groups at baseline (p = 0.004). Refill adherence in the intervention group improved slightly during follow-up (CMG = 0.23), while it worsened slightly in the control group (CMG = 0.21), but the change in adherence between intervention and control groups was not significantly different (p = 0.4). Between 80% and 90% of intervention participants indicated that receiving the picture prescription and phone call interventions helped them remember when and how to take their medications and refill their prescriptions. No patient characteristics, including health literacy, were consistently associated with adherence. CONCLUSIONS Implementation of a 3-part intervention—automated telephone reminders, picture prescription card, and pharmacist communication skills training—did not significantly improve refill adherence among inner-city patients. Further study should explore whether other aspects of medication management, such as dosing or adverse events, can be improved through these types of interventions, implemented either alone or in combination.
Candida Meningitis Post Gliadel Wafer Placement Successfully Treated with Intrathecal and Intravenous Amphotericin B
Authors: Glick Jorie A , Graham Robert S , Voils Stacy A 
Published: December 2009

OBJECTIVE To report a case of Candida meningitis post Gliadel wafer (polifeprosan 20 with carmustine implant) placement successfully treated with the combination of intrathecal and intravenous amphotericin B. CASE SUMMARY A 33-year-old white female with a history of recurrent oligodendroglioma was admitted to the neuroscience intensive care unit with acute mental status changes. Computed tomography of the head demonstrated a cystic dilation of the right frontoparietal tumor resection cavity with Gliadel wafers in place and the presence of a large fluid collection. The cavity was debrided surgically and a ventriculostomy catheter was left in place. Cerebrospinal fluid (CSF) cultures were positive for Candida albicans and methicillin-resistant coagulase-negative Staphylococcus spp. Antiinfective therapy with intrathecal and intravenous amphotericin B as well as flucytosine and vancomycin was started. The patient had subsequent improvement in clinical manifestations, resolution of CSF leukocytosis, and mycologic cure. DISCUSSION Candida meningitis occurs primarily in the setting of immunosuppression, intravenous drug abuse and following neurosurgical procedures. Secondary bacterial and fungal infections have been reported following Gliadel wafer placement in patients with brain tumor resection. Caniiia meningitis has traditionally been treated with intravenous amphotericin B with or without oral flucytosine. There have been reports of treatment with intrathecal amphotericin B with variable clinical outcomes. CONCLUSIONS This case demonstrates successful treatment of Candida meningitis post Gliadel wafer placement with the combination of intrathecal and intravenous amphotericin B. This treatment modality may provide an effective therapeutic option for other patients with Candida meningitis, especially those unresponsive to intravenous therapy.
Maternal Plasma DNA Analysis with Massively Parallel Sequencing by Ligation for Noninvasive Prenatal Diagnosis of Trisomy 21
Authors: Chiu Rossa WK , Sun Hao , Akolekar Ranjit , Clouser Christopher , Lee Clarence , McKernan Kevin , Zhou Daixing , Nicolaides Kypros H , Lo YM Dennis 
Published: December 2009

Abstract
Background: Noninvasive prenatal diagnosis of trisomy 21 (T21) has recently been shown to be achievable by massively parallel sequencing of maternal plasma on a sequencing-by-synthesis platform. The quantification of several other human chromosomes, including chromosomes 18 and 13, has been shown to be less precise, however, with quantitative biases related to the chromosomal GC content.
Methods: Maternal plasma DNA from 10 euploid and 5 T21 pregnancies was sequenced with a sequencing-by-ligation approach. We calculated the genomic representations (GRs) of sequenced reads from each chromosome and their associated measurement CVs and compared the GRs of chromosome 21 (chr21) for the euploid and T21 pregnancies.
Results: We obtained a median of 12 × 106 unique reads (21% of the total reads) per sample. The GRs deviated from those expected for some chromosomes but in a manner different from that previously reported for the sequencing-by-synthesis approach. Measurements of the GRs for chromosomes 18 and 13 were less precise than for chr21. z Scores of the GR of chr21 were increased in the T21 pregnancies, compared with the euploid pregnancies.
Conclusions: Massively parallel sequencing-by-ligation of maternal plasma DNA was effective in identifying T21 fetuses noninvasively. The quantitative biases observed among the GRs of certain chromosomes were more likely based on analytical factors than biological factors. Further research is needed to enhance the precision for measuring for the representations of chromosomes 18 and 13.
β-Catenin as a multilayer modulator of zonal cytochrome P450 expression in mouse liver
Authors: Braeuning Albert , Schwarz Michael 
Published: December 2009

Abstract
The liver is the major organ for metabolism of drugs and other xenobiotics. Expression of many drug-metabolizing enzymes is not equally distributed throughout the liver: under normal conditions, many of them, including the most relevant members of the cytochrome P450 superfamily, are exclusively expressed in a hepatocyte subpopulation located near branches of the efferent central vein. Activation of different ligand-dependent transcription factors by exogenous compounds stimulates high expression of certain cytochrome P450 isoforms. This process also occurs preferentially in perivenous hepatocytes. The mechanisms, however, which determine the zone-specificity of basal and xenobiotic-induced expression of cytochrome P450 enzymes, have remained largely unknown for decades. Very recently, signaling through the Wnt/β-catenin pathway has been implicated in the regulation of zonal gene expression in mouse liver. In this review, current knowledge of cytochrome P450 regulation by β-catenin-dependent transcription is summarized and underlying molecular mechanisms are discussed.
The epimerase activity of anthocyanidin reductase from Vitis vinifera and its regiospecific hydride transfers
Authors: Gargouri Mahmoud , Chaudière Jean , Manigand Claude , Maugé Chloé , Bathany Katell , Schmitter Jean-Marie , Gallois Bernard 
Published: December 2009

Abstract
Anthocyanidin reductase (ANR) from Vitis vinifera catalyzes an NADPH-dependent double reduction of anthocyanidins producing a mixture of (2S,3R)- and (2S,3S)-flavan-3-ols. At pH 7.5 and 30°C, the first hydride transfer to anthocyanidin is irreversible, and no intermediate is released during catalysis. ANR reverse activity was assessed in the presence of excess NADP+. Analysis of products by reverse phase and chiral phase HPLC demonstrates that ANR acts as a flavan-3-ol C3-epimerase under such conditions, but this is only observed with 2R-flavan-3-ols, not with 2S-flavan-3-ols produced by the enzyme in the forward reaction. In the presence of deuterated coenzyme 4S-NADPD, ANR transforms anthocyanidins into dideuterated flavan-3-ols. The regiospecificity of deuterium incorporation into catechin and afzelechin – derived from cyanidin and pelargonidin, respectively – was analyzed by liquid chromatography coupled with electro- spray ionization-tandem mass spectrometry (LC/ESI-MS/MS), and it was found that deuterium was always incorporated at C2 and C4. We conclude that C3-epimerization should be achieved by tautomerization between the two hydride transfers and that this produces a quinone methide intermediate which serves as C4 target of the second hydride transfer, thereby avoiding any stereospecific modification of carbon 3. The inversion of C2 stereochemistry required for ‘reverse epimerization’ suggests that the 2S configuration induces an irreversible product dissociation.
Peptides from the Mycobacterium tuberculosis Rv1980c protein involved in human cell infection: insights into new synthetic subunit vaccine candidates
Authors: Rodríguez Diana , Vizcaíno Carolina , Ocampo Marisol , Curtidor Hernando , Pinto Marta , Elkin Patarroyo Manuel , Alfonso Patarroyo Manuel 
Published: December 2009

Abstract

Mycobacterium tuberculosis infection continues to be a major cause of morbidity and mortality throughout the world. The vast complexity of the intracellular pathogen M. tuberculosis and the diverse mechanisms by which it can invade host cells highlight the importance of developing a fully protective vaccine. Our vaccine development strategy consists of including fragments from multiple mycobacterial proteins involved in cell invasion. The aim of this study was to identify high activity binding peptides (HABPs) in the immunogenic protein Rv1980c from M. tuberculosis H37Rv with the ability to inhibit mycobacterial invasion into U937 monocyte-derived macrophages and A549 cells. The presence and transcription of the Rv1980c gene was assessed in members belonging to the M. tuberculosis complex and other nontuberculous mycobacteria by PCR and RT-PCR, respectively. Cell surface localization was confirmed by immuno-electron microscopy. Three peptides binding with high activity to U937 cells and one to A549 cells were identified. HABPs 31100, 31101, and 31107 inhibited invasion of M. tuberculosis into A549 and U937 cells and therefore could be promising candidates for the design of a subunit-based antituberculous vaccine.