bluuebunny/crossref_metadata_2025 huggingface dataset:
Lack of association between the CALM1 core promoter polymorphism (-16C/T) and susceptibility to knee osteoarthritis in a Chinese Han population
Authors: Shi Dongquan , Ni Haijian , Dai Jin , Qin Jianghui , Xu Yong , Zhu Lunqing , Yao Chen , Shao Zhenxing , Chen Dongyang , Xu Zhihong , Yi Long , Ikegawa Shiro , Jiang Qing
Published: October 2008

Background

CALM1 gene encodes calmodulin (CaM), an important and ubiquitous eukaryotic Ca2+-binding protein. Several studies have indicated that a deficient CaM function is likely to be involved in the pathogenesis of osteoarthritis (OA). Using a convincing genome-wide association study, a Japanese group has recently demonstrated a genetic association between the CALM1 core promoter polymorphism (-16C/T transition SNP, rs12885713) and OA susceptibility. However, the subsequent association studies failed to provide consistent results in OA patients of differently selected populations. The present study is to evaluate the association of the -16C/T polymorphism with knee OA in a Chinese Han population.

Methods

A case-control association study was conducted. The polymorphism was genotyped in 183 patients who had primary symptomatic knee OA with radiographic confirmation and in 210 matched controls. Allelic and genotypic frequencies were compared between patients and control subjects.

Results

No significant difference was detected in genotype or allele distribution between knee OA and control groups (all P > 0.05). The association was also negative even after stratification by sex. Furthermore, no association between the -16C/T SNP genotype and the clinical variables age, sex, BMI (body mass index) and K/L (Kellgren/Lawrence) score was observed in OA patients.

Conclusion

The present study suggests that the CALM1 core promoter polymorphism -16C/T is not a risk factor for knee OA susceptibility in the Chinese Han population. Further studies are needed to give a global view of this polymorphism in pathogenesis of OA.
Reduced expression of N-Myc downstream-regulated gene 2 in human thyroid cancer
Authors: Zhao Huadong , Zhang Jian , Lu Jianguo , He Xianli , Chen Changsheng , Li Xiaojun , Gong Li , Bao Guoqiang , Fu Qiang , Chen Suning , Lin Wei , Shi Hai , Ma Jianjun , Liu Xinping , Ma Qingjiu , Yao Libo
Published: October 2008

Background

NDRG2 (N-Myc downstream-regulated gene 2) was initially cloned in our laboratory. Previous results have shown that NDRG2 expressed differentially in normal and cancer tissues. Specifically, NDRG2 mRNA was down-regulated or undetectable in several human cancers, and over-expression of NDRG2 inhibited the proliferation of cancer cells. NDRG2 also exerts important functions in cell differentiation and tumor suppression. However, it remains unclear whether NDRG2 participates in carcinogenesis of the thyroid.

Methods

In this study, we investigated the expression profile of human NDRG2 in thyroid adenomas and carcinomas, by examining tissues from individuals with thyroid adenomas (n = 40) and carcinomas (n = 35), along with corresponding normal tissues. Immunohistochemistry, quantitative RT-PCR and western blot methods were utilized to determine both the protein and mRNA expression status of Ndrg2 and c-Myc.

Results

The immunostaining analysis revealed a decrease of Ndrg2 expression in thyroid carcinomas. When comparing adenomas or carcinomas with adjacent normal tissue from the same individual, the mRNA expression level of NDRG2 was significantly decreased in thyroid carcinoma tissues, while there was little difference in adenoma tissues. This differential expression was confirmed at the protein level by western blotting. However, there were no significant correlations of NDRG2 expression with gender, age, different histotypes of thyroid cancers or distant metastases.

Conclusion

Our data indicates that NDRG2 may participate in thyroid carcinogenesis. This finding provides novel insight into the important role of NDRG2 in the development of thyroid carcinomas. Future studies are needed to address whether the down-regulation of NDRG2 is a cause or a consequence of the progression from a normal thyroid to a carcinoma.
Leptin/HER2 crosstalk in breast cancer: in vitro study and preliminary in vivoanalysis
Authors: Fiorio Elena , Mercanti Anna , Terrasi Marianna , Micciolo Rocco , Remo Andrea , Auriemma Alessandra , Molino Annamaria , Parolin Veronica , Di Stefano Bruno , Bonetti Franco , Giordano Antonio , Cetto Gian Luigi , Surmacz Eva
Published: October 2008

Background

Obesity in postmenopausal women is associated with increased breast cancer risk, development of more aggressive tumors and resistance to certain anti-breast cancer treatments. Some of these effects might be mediated by obesity hormone leptin, acting independently or modulating other signaling pathways. Here we focused on the link between leptin and HER2. We tested if HER2 and the leptin receptor (ObR) can be coexpressed in breast cancer cell models, whether these two receptors can physically interact, and whether leptin can transactivate HER2. Next, we studied if leptin/ObR can coexist with HER2 in breast cancer tissues, and if presence of these two systems correlates with specific clinicopathological features.

Methods

Expression of ObR, HER2, phospo-HER2 was assessed by immonoblotting. Physical interactions between ObR and HER2 were probed by immunoprecipitation and fluorescent immunostaining. Expression of leptin and ObR in breast cancer tissues was detected by immunohistochemistry (IHC). Associations among markers studied by IHC were evaluated using Fisher's exact test for count data.

Results

HER2 and ObR were coexpressed in all studied breast cancer cell lines. In MCF-7 cells, HER2 physically interacted with ObR and leptin treatment increased HER2 phosphorylation on Tyr 1248. In 59 breast cancers, the presence of leptin was correlated with ObR (the overall association was about 93%). This result was confirmed both in HER2-positive and in HER2-negative subgroups. The expression of leptin or ObR was numerically more frequent in larger (> 10 mm) tumors.

Conclusion

Coexpression of HER2 and the leptin/ObR system might contribute to enhanced HER2 activity and reduced sensitivity to anti-HER2 treatments.
SELDI-TOF-MS determination of hepcidin in clinical samples using stable isotope labelled hepcidin as an internal standard
Authors: Ward Douglas G , Roberts Keith , Stonelake Paul , Goon Patrick , Zampronio Cleidiane G , Martin Ashley , Johnson Philip J , Iqbal Tariq , Tselepis Chris
Published: October 2008

Background

Hepcidin is a 25-residue peptide hormone crucial to iron homeostasis. It is essential to measure the concentration of hepcidin in cells, tissues and body fluids to understand its mechanisms and roles in physiology and pathophysiology. With a mass of 2791 Da hepcidin is readily detectable by mass spectrometry and LC-ESI, MALDI and SELDI have been used to estimate systemic hepcidin concentrations by analysing serum or urine. However, peak heights in mass spectra may not always reflect concentrations in samples due to competition during binding steps and variations in ionisation efficiency. Thus the purpose of this study was to develop a robust assay for measuring hepcidin using a stable isotope labelled hepcidin spiking approach in conjunction with SELDI-TOF-MS.

Results

We synthesised and re-folded hepcidin labelled with 13C/15N phenylalanine at position 9 to generate an internal standard for mass spectrometry experiments. This labelled hepcidin is 10 Daltons heavier than the endogenous peptides and does not overlap with the isotopic envelope of the endogenous hepcidin or other common peaks in human serum or urine mass spectra and can be distinguished in low resolution mass spectrometers. We report the validation of adding labelled hepcidin into serum followed by SELDI analysis to generate an improved assay for hepcidin.

Conclusion

We demonstrate that without utilising a spiking approach the hepcidin peak height in SELDI spectra gives a good indication of hepcidin concentration. However, a stable isotope labelled hepcidin spiking approach provides a more robust assay, measures the absolute concentration of hepcidin and should facilitate inter-laboratory hepcidin comparisons.
Rescaling quality of life values from discrete choice experiments for use as QALYs: a cautionary tale
Authors: Flynn Terry N , Louviere Jordan J , Marley Anthony AJ , Coast Joanna , Peters Tim J
Published: October 2008

Background

Researchers are increasingly investigating the potential for ordinal tasks such as ranking and discrete choice experiments to estimate QALY health state values. However, the assumptions of random utility theory, which underpin the statistical models used to provide these estimates, have received insufficient attention. In particular, the assumptions made about the decisions between living states and the death state are not satisfied, at least for some people. Estimated values are likely to be incorrectly anchored with respect to death (zero) in such circumstances.

Methods

Data from the Investigating Choice Experiments for the preferences of older people CAPability instrument (ICECAP) valuation exercise were analysed. The values (previously anchored to the worst possible state) were rescaled using an ordinal model proposed previously to estimate QALY-like values. Bootstrapping was conducted to vary artificially the proportion of people who conformed to the conventional random utility model underpinning the analyses.

Results

Only 26% of respondents conformed unequivocally to the assumptions of conventional random utility theory. At least 14% of respondents unequivocally violated the assumptions. Varying the relative proportions of conforming respondents in sensitivity analyses led to large changes in the estimated QALY values, particularly for lower-valued states. As a result these values could be either positive (considered to be better than death) or negative (considered to be worse than death).

Conclusion

Use of a statistical model such as conditional (multinomial) regression to anchor quality of life values from ordinal data to death is inappropriate in the presence of respondents who do not conform to the assumptions of conventional random utility theory. This is clearest when estimating values for that group of respondents observed in valuation samples who refuse to consider any living state to be worse than death: in such circumstances the model cannot be estimated. Only a valuation task requiring respondents to make choices in which both length and quality of life vary can produce estimates that properly reflect the preferences of all respondents.
Outcome in patients with enthesitis related arthritis (ERA): juvenile arthritis damage index (JADI) and functional status
Authors: Sarma Pradip Kumar , Misra Ramnath , Aggarwal Amita
Published: October 2008

Background

Data on outcome of ERA is scarce and there is lack of well-accepted tools. JADI is a newly described outcome measure in JIA that has not been evaluated in ERA. We studied outcome in ERA using JADI and correlated it with traditional outcome measures.

Methods

We studied 49 consecutive patients of ERA with age ≥ 5 years and duration ≥ 1 year. Along with JADI, we recorded enthesitis, lumbar spinal anterior flexion by modified Schober's method, presence of inflammatory backache, loss of school years, HAQ-S, growth and pubertal delay. Parent's/patient's and physician's global assessments on 100 mm visual analogue scale.

Results

The median age was 18.0 (10–27) years and the median duration of disease was 6.0 (1–17) years. All the patients were male and half (53.1%) were HLA B 27 positive. Fourteen had decreased anterior lumbar flexion movement and 32 had inflammatory backache. Active enthesitis was present in 63.3%. Functionally, mild, moderate and severe disability was seen in 18.4%, 34.7% & 14.3% respectively. Sixty five percent of patients lost education years. Twenty-eight patients had damaged joints with median of 2.0 joints (0–9). Seventeen patients (34.7%) had damaged joints in JADI-A score with a median of 1.0 (0–12). Growth failure was the commonest extra articular damage (8.2%) in JADI-E. JADI correlated with HAQ-S, parent's or patient's & physician's global assessment (p < 0.01). Limitation of spinal mobility had high correlation with HAQ-S; correlation with JADI-A was low.

Conclusion

Three fourth of the ERA patients had functional limitations. Half of the patients had damaged joints. Even though JADI correlated well with traditional outcome measures, it underestimates joint damage, and does not assess enthesitis and spinal limitation which affect functional status in ERA. Inclusion of these may make it more useful for ERA.
Morphology and head morphometric characters of sperm in Thai native crossbred stallions
Authors: Phetudomsinsuk Kanittha , Sirinarumitr Kaitkanoke , Laikul Aree , Pinyopummin Anuchai
Published: October 2008

Background

One of the semen quality parameters use to determine fertility is the percentage of sperm that express normal morphology. Sperm head morphometry is also correlated with fertility. The objectives of this study were 1) to investigate the sperm morphology and normal sperm head morphometry of Thai native crossbred stallions, and 2) to compare our results with the characteristics of proven fertile sperm from purebred stallions.

Methods

Semen samples were collected monthly from nine stallions, of which five were Thai native crossbred (T) and four were purebred of proven fertility (F: F1 was a Standard-bred; F2 was a Warm-blood; F3 and F4 were Thoroughbreds). All the animals were aged between 5 and 12 years. Sperm morphological examination was performed using formaldehyde-fixed samples under phase-contrast microscopy (1000×). Normal sperm head morphometry characteristics were measured by Computer-Assisted Semen Analysis (Hamilton Thorne, USA.) after applying the Harris' haematoxylin staining technique.

Results

The percentages of morphologically normal and abnormal sperm varied among individual stallions in both the T and F groups. The mean percentage of morphologically normal sperm was not significantly different (P > 0.05) between T and F stallions (mean ± SE, 49.7 ± 1.3 and 48.1 ± 2.8, respectively). A comparison between the T and F sperm heads revealed that all the dimensional parameters were significantly different (P < 0.05). The coefficients of within-animal variation (CVs) ranged from 2.6 (shape factor 1) to 7.5 (elongation) and 2.9 (shape factor 1) to 8.1 (elongation) in T and F, respectively. In the case of the T group, those sperm head parameters that featured a low within-animal CV and a high between-animal CV were perimeter (2.9, 19.1), shape factor 1 (2.6, 25.8) and shape factor 3 (3.8, 32.0). In the case of the F group, only shape factor 1 (2.9, 26.1) featured such characteristics.

Conclusion

We found variability in the percentage of morphologically normal and abnormal sperm, as well as in sperm head dimensions among Thai native crossbred stallions, and these results were similar to those of purebred stallions. Our findings demonstrate that the heads of the T sperm specimens were larger and rounder than that of the F sperm. Perimeter, shape factor 1 and shape factor 3 could be used as parameters for the identification of individual T stallions based on a sperm sample.
Analysis of saccharification in Brachypodium distachyon stems under mild conditions of hydrolysis
Authors: Gomez Leonardo D , Bristow Jennifer K , Statham Emily R , McQueen-Mason Simon J
Published: October 2008

Background

Brachypodium distachyon constitutes an excellent model species for grasses. It is a small, easily propagated, temperate grass with a rapid life cycle and a small genome. It is a self-fertile plant that can be transformed with high efficiency using Agrobacteria and callus derived from immature embryos. In addition, considerable genetic and genomic resources are becoming available for this species in the form of mapping populations, large expressed sequence tag collections, T-DNA insertion lines and, in the near future, the complete genome sequence. The development of Brachypodium as a model species is of particular value in the areas of cell wall and biomass research, where differences between dicots and grasses are greatest. Here we explore the effect of mild conditions of pretreatment and hydrolysis in Brachypodium stem segments as a contribution for the establishment of sensitive screening of the saccharification properties in different genetic materials.

Results

The non-cellulosic monosaccharide composition of Brachypodium is closely related to grasses of agricultural importance and significantly different from the dicot model Arabidopsis thaliana. Diluted acid pretreatment of stem segments produced significant release of sugars and negatively affected the amount of sugars obtained by enzymatic hydrolysis. Monosaccharide and oligosaccharide analysis showed that the hemicellulose fraction is the main target of the enzymatic activity under the modest hydrolytic conditions used in our assays. Scanning electron microscopy analysis of the treated materials showed progressive exposure of fibrils in the stem segments.

Conclusion

Results presented here indicate that under mild conditions cellulose and hemicellulose are hydrolysed to differing extents, with hemicellulose hydrolysis predominating. We anticipate that the sub-optimal conditions for hydrolysis identified here will provide a sensitive assay to detect variations in saccharification among Brachypodium plants, providing a useful analytical tool for identifying plants with alterations in this trait.
Gene expression analysis of glioblastomas identifies the major molecular basis for the prognostic benefit of younger age
Authors: Lee Yohan , Scheck Adrienne C , Cloughesy Timothy F , Lai Albert , Dong Jun , Farooqi Haumith K , Liau Linda M , Horvath Steve , Mischel Paul S , Nelson Stanley F
Published: October 2008

Background

Glioblastomas are the most common primary brain tumour in adults. While the prognosis for patients is poor, gene expression profiling has detected signatures that can sub-classify GBMs relative to histopathology and clinical variables. One category of GBM defined by a gene expression signature is termed ProNeural (PN), and has substantially longer patient survival relative to other gene expression-based subtypes of GBMs. Age of onset is a major predictor of the length of patient survival where younger patients survive longer than older patients. The reason for this survival advantage has not been clear.

Methods

We collected 267 GBM CEL files and normalized them relative to other microarrays of the same Affymetrix platform. 377 probesets on U133A and U133 Plus 2.0 arrays were used in a gene voting strategy with 177 probesets of matching genes on older U95Av2 arrays. Kaplan-Meier curves and Cox proportional hazard analyses were applied in distinguishing survival differences between expression subtypes and age.

Results

This meta-analysis of published data in addition to new data confirms the existence of four distinct GBM expression-signatures. Further, patients with PN subtype GBMs had longer survival, as expected. However, the age of the patient at diagnosis is not predictive of survival time when controlled for the PN subtype.

Conclusion

The survival benefit of younger age is nullified when patients are stratified by gene expression group. Thus, the main cause of the age effect in GBMs is the more frequent occurrence of PN GBMs in younger patients relative to older patients.
Effect of the rs997509 Polymorphism on the Association between Ectonucleotide Pyrophosphatase Phosphodiesterase 1 and Metabolic Syndrome and Impaired Glucose Tolerance in Childhood Obesity
Authors: Santoro Nicola , Cirillo Grazia , Lepore Maria Grazia , Palma Alfonsina , Amato Alessandra , Savarese Piera , Marzuillo Pierluigi , Grandone Anna , Perrone Laura , del Giudice Emanuele Miraglia
Published: October 2008

Context: Variants on the nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP-1) gene have been associated with obesity and insulin resistance. Because insulin resistance is a pivotal factor in the development of metabolic syndrome (MS) and impaired glucose tolerance (IGT), we aimed to test the association between the K121Q and rs997509 ENPP-1 variants with obesity, MS and IGT in obese children and adolescents.

Methods: We screened 809 children, 409 obese and 400 lean controls. Obese subjects underwent a standard oral glucose tolerance test, whole body insulin sensitivity index (WBISI) and homeostasis model assessment (HOMA) were calculated.

Results: No difference in prevalence for K121Q and rs997509 polymorphisms between obese and controls (P > 0.05) were observed. Obese children carrying the rs997509 rare allele showed higher insulin (P = 0.001), HOMA (P < .001) and lower WBISI values (P = 0.04) compared with common allele homozygous. A similar observation was done for K121Q variant, with 121Q allele carriers showing higher insulin (P = 0.03) and HOMA (P = 0.04) values than 121K homozygotes. Moreover, subjects carrying the rs997509 rare allele had higher risk of MS (odds ratio 2.4, 95% confidence interval: 1.3–4.3) and IGT (odds ratio 4.7, 95% confidence interval: 1.9–11.4) than common allele homozygotes. Evaluating combined effects of both polymorphisms, which are in strong linkage disequilibrium, we showed that the effect on insulin sensitivity was due to the rs997509 T variant.

Conclusion: We conclude that the ENPP1 rs997509T allele can predispose obese children to MS and IGT and that this variant might drive the association between the ENPP1 121Q allele and insulin resistance.
PAK1-mediated activation of ERK1/2 regulates lamellipodial dynamics
Authors: Smith Stephen D. , Jaffer Zahara M. , Chernoff Jonathan , Ridley Anne J.
Published: October 2008

PAK1 is a member of the p21-activated kinase (PAK) family of serine/threonine kinases that are activated by the Rho GTPases Rac and Cdc42, and are implicated in regulating morphological polarity, cell migration and adhesion. Here we investigate the function of PAK1 in cell motility using macrophages derived from PAK1-null mice. We show that CSF1, a macrophage chemoattractant, transiently stimulates PAK1 and MAPK activation, and that MAPK activation is reduced in PAK1–/– macrophages. PAK1 regulates the dynamics of lamellipodium extension as cells spread in response to adhesion but is not essential for macrophage migration or chemotaxis towards CSF1. Following adhesion, PAK1–/– macrophages spread more rapidly and have more lamellipodia than wild-type cells; however, these lamellipodia were less stable than those in wild-type macrophages. ERK1/2 activity was reduced in PAK1–/– macrophages during adhesion, and inhibition of ERK1/2 activation in wild-type macrophages was sufficient to increase the spread area and mimic the lamellipodial dynamics of PAK1–/– macrophages. Together, these data indicate that PAK1 signals via ERK1/2 to regulate lamellipodial stability.
Overexpressed cyclophilin B suppresses apoptosis associated with ROS and Ca2+ homeostasis after ER stress
Authors: Kim Jinhwan , Choi Tae Gyu , Ding Yan , Kim Yeonghwan , Ha Kwon Soo , Lee Kyung Ho , Kang Insug , Ha Joohun , Kaufman Randal J. , Lee Jinhwa , Choe Wonchae , Kim Sung Soo
Published: October 2008

Prolonged accumulation of misfolded proteins in the endoplasmic reticulum (ER) results in ER stress-mediated apoptosis. Cyclophilins are protein chaperones that accelerate the rate of protein folding through their peptidyl-prolyl cis-trans isomerase (PPIase) activity. In this study, we demonstrated that ER stress activates the expression of the ER-localized cyclophilin B (CypB) gene through a novel ER stress response element. Overexpression of wild-type CypB attenuated ER stress-induced cell death, whereas overexpression of an isomerase activity-defective mutant, CypB/R62A, not only increased Ca2+ leakage from the ER and ROS generation, but also decreased mitochondrial membrane potential, resulting in cell death following exposure to ER stress-inducing agents. siRNA-mediated inhibition of CypB expression rendered cells more vulnerable to ER stress. Finally, CypB interacted with the ER stress-related chaperones, Bip and Grp94. Taken together, we concluded that CypB performs a crucial function in protecting cells against ER stress via its PPIase activity.
Signaling through urokinase and urokinase receptor in lung cancer cells requires interactions with β1 integrins
Authors: Tang Chi-Hui , Hill Marla L. , Brumwell Alexis N. , Chapman Harold A. , Wei Ying
Published: October 2008

The urokinase receptor (uPAR) is upregulated upon tumor cell invasion and correlates with poor lung cancer survival. Although a cis-interaction with integrins has been ascribed to uPAR, whether this interaction alone is critical to urokinase (uPA)- and uPAR-dependent signaling and tumor promotion is unclear. Here we report the functional consequences of point mutations of uPAR (H249A-D262A) that eliminate β1 integrin interactions but maintain uPA binding, vitronectin attachment and association with αV integrins, caveolin and epidermal growth factor receptor. Disruption of uPAR interactions with β1 integrins recapitulated previously reported findings with β1-integrin-derived peptides that attenuated matrix-dependent ERK activation, MMP expression and in vitro migration by human lung adenocarcinoma cell lines. The uPAR mutant cells acquired enhanced capacity to adhere to vitronectin via uPAR–αVβ5-integrin, rather than through the uPAR–α3β1-integrin complex and they were unable to initiate uPA signaling to activate ERK, Akt or Stat1. In an orthotopic lung cancer model, uPAR mutant cells exhibited reduced tumor size compared with cells expressing wild-type uPAR. Taken together, the results indicate that uPAR–β1-integrin interactions are essential to signals induced by integrin matrix ligands or uPA that support lung cancer cell invasion in vitro and progression in vivo.
Fusion-pore expansion during syncytium formation is restricted by an actin network
Authors: Chen Andrew , Leikina Eugenia , Melikov Kamran , Podbilewicz Benjamin , Kozlov Michael M. , Chernomordik Leonid V.
Published: October 2008

Cell-cell fusion in animal development and in pathophysiology involves expansion of nascent fusion pores formed by protein fusogens to yield an open lumen of cell-size diameter. Here we explored the enlargement of micron-scale pores in syncytium formation, which was initiated by a well-characterized fusogen baculovirus gp64. Radial expansion of a single or, more often, of multiple fusion pores proceeds without loss of membrane material in the tight contact zone. Pore growth requires cell metabolism and is accompanied by a local disassembly of the actin cortex under the pores. Effects of actin-modifying agents indicate that the actin cortex slows down pore expansion. We propose that the growth of the strongly bent fusion-pore rim is restricted by a dynamic resistance of the actin network and driven by membrane-bending proteins that are involved in the generation of highly curved intracellular membrane compartments.
Identification of a developmentally regulated pathway of membrane retrieval in neuronal growth cones
Authors: Bonanomi Dario , Fornasiero Eugenio F. , Valdez Gregorio , Halegoua Simon , Benfenati Fabio , Menegon Andrea , Valtorta Flavia
Published: October 2008

The growth-cone plasma membrane constantly reconfigures during axon navigation and upon target recognition. The identity and regulation of the membrane pathway(s) participating in remodeling of the growth-cone surface remain elusive. Here, we identify a constitutive, high-capacity plasma-membrane-recycling activity in the axonal growth cones, which is mediated by a novel bulk endocytic pathway that is mechanistically related to macropinocytosis. This pathway generates large compartments at sites of intense actin-based membrane ruffling through the actions of phosphatidylinositol 3-kinase, the small GTPase Rac1 and the pinocytic chaperone Pincher. At early developmental stages, bulk endocytosis is the primary endocytic pathway for rapid retrieval of the growth-cone plasma membrane. At later stages, during the onset of synaptogenesis, an intrinsic program of maturation leads to downregulation of basal bulk endocytosis and the emergence of depolarization-induced synaptic-vesicle exo-endocytosis. We propose that the control of bulk membrane retrieval contributes to the homeostatic regulation of the axonal plasma membrane and to growth-cone remodeling during axonal outgrowth. In addition, we suggest that the downregulation of bulk endocytosis during synaptogenesis might contribute to the preservation of synaptic-vesicle specificity.
An in-service dynamic model of a diesel railcar from operational modal analysis and finite-element model updating
Authors: Hanson D , Winton M , Randall R B , Ford R A J , Thompson D J , Waters T P , Antoni J
Published: October 2008

Builders of passenger rail vehicles need methods for predicting vibrational behaviour so that they can meet ride quality specifications. Conventional finite-element (FE) models used for stress analysis may not be accurate enough for this because of imponderables such as the stiffness of spot-welded joints. One solution is to adjust FE models based on vibration measurements. This model updating is now possible using commercially available software. Usually, the updating is based on vibration tests carried out under laboratory conditions, which may produce different results from normal operation. In this paper, two simple FE models of a railcar are updated using vibration data obtained from a newly designed railcar under in-service conditions. Measurements were made on a railcar loaded to represent crush-loaded conditions and running down track, with the only excitation that naturally occurring due to track roughness, engine excitation, aerodynamic loading etc. Unlike standard laboratory vibration testing, this input excitation could not be measured, so advanced forms of output-only analysis were required. By using these data as input to a commercial updating package, the simple FE models have been updated and the effectiveness of the technique assessed.
Convective heat dissipation from a wheel-hub-mounted railway brake disc
Authors: Tirovic M , Galindo-Lopez C H
Published: October 2008

Air flow and convective heat dissipation from a wheel-hub-mounted railway brake disc were studied using computational fluid dynamics (CFD). The analyses enabled detailed insight into air flow, temperature, speed, pressure, and convective heat transfer coefficient distributions, never before available to a brake designer. Such results are practically impossible to experimentally obtain at reasonable cost. Particularly interesting finding is the existence of relatively considerable secondary flow — circumferential flow behind the vanes. Although this effect may reduce air pumping, and therefore radial air speed, it increases turbulence by promoting airflow between channels.

Average values of the convective heat transfer coefficients obtained using CFD are practically identical to the experimental values derived from cooling tests performed on dynamometer and spin rig. Compared with other railway disc designs, this disc demonstrates exceptionally good convective cooling characteristics, in particular considering its size and investigated operating condition (rotation in still air).

The computational studies of air flow and heat dissipation characteristics are an excellent base for development work in improving existing and generating new disc designs with high heat dissipation characteristics. Future work is concentrated on conducting additional analyses of the current disc design, in order to investigate the most effective ways of maximizing convective cooling.
An overview of some high-speed train derailments: Means of minimizing consequences based on empirical observations
Authors: Brabie D , Andersson E
Published: October 2008

Studies published on rail vehicles— post-derailment behaviour as a means of minimizing consequences are surprisingly scarce. This paper sets a first step to reduce this lack of knowledge by analysing a collection of incident/accident case studies, with the main focus on the course of events immediately after derailments. This is mainly with respect to whether the train stays upright and close to the track centre-line and is ‘safe’ or deviates laterally with a probable serious consequence. Accordingly, an empirical database is established containing as much relevant information as possible of past incidents and accidents occurring at speeds over 70 km/h due to mechanical failure close to the running gear/track interface, as well as other causes that ultimately brought the train into a derailed situation. Although two derailments are never the same, certain patterns appeared to emerge based on the descriptions available in each incident or accident report. Mechanical restrictions between axles and bogie frames appear to minimize the risk of derailments after an axle failure on the outside of the wheel. Once derailed, evidence suggests that certain low-reaching parts on the wheelset or the bogie frame may act as substitute guidance mechanisms, thereby minimizing large lateral train deviations. However, for a large number of events, the available information does not allow conclusions based on observations only. This paper is the first in a forthcoming series dealing with the possibilities of minimizing devastating consequences of high-speed derailments by appropriate measures and features in the train design including the running gear.
Prediction of low-speed aerodynamic load and aeroacoustic noise around simplified panhead section model
Authors: Lee J , Cho W
Published: October 2008

This paper deals with a low-speed aerodynamic and aeroacoustic analysis of the two-dimensional panhead section model that is a simplification of the pantograph used in high-speed railway (HSR). As a preliminary study of HSR whose actual operating speed is over 300 km/h, the present study considers the low-speed aerodynamics and aeroacoustics in which the speed range is between 120 and 180 km/h. The computational fluid dynamics-based analysis is performed using FLUENT and the low-speed wind tunnel test is conducted to verify the flow simulation as well. The aerodynamic noise is predicted using Ffowcs Williams—Hawkings equation without the quadrupole term. The present study suggests the use of a thin plate (i.e. lift generator) to generate the positive up-lift force that can provide the stable aerodynamic contact between the panhead strips and the catenary system. For a number of panhead section models, acoustic pressure fluctuations and sound pressure levels are analysed to identify the optimum plate length of the lift generator in terms of aerodynamic stability and aeroacoustic noise reduction.
A system and stakeholder approach for the identification of condition information: A case study for the Swedish railway
Authors: Granström R
Published: October 2008

The purpose of this paper is to identify stakeholders— need for system condition information in order to improve railway punctuality. The paper provides a holistic formulation of maintenance-related punctuality problems within the interface between the contact wire and the pantograph. From the identified problem formulation, the information needed to support the maintenance of technical functions can be identified. The incorporated system and stakeholder perspective adds a dimension to the explanation of what information is needed and why it is needed. The system and stakeholder perspective on the assessment of the information need can serve as decision support when acquiring new condition monitoring technologies. On the basis of the problem formulation, this perspective can also serve as an illustration of how information is to be used to improve punctuality. In order to identify stakeholders— need for system condition information, a failure mode and effects analysis (FMEA) approach was used. The FMEA is complemented with information derived from informal interviews performed with a variety of experts working with issues related to contact wires and pantographs. The applied methodology can be useful for conducting further research studies on other stakeholder and engineering interfaces, such as the wheel—rail interface.
Calculation of dynamic impact loads for railway bridges using a direct integration method
Authors: Gu G , Kapoor A , Lilley D M
Published: October 2008

This paper introduces railway bridge assessment in the UK and the concept of dynamic impact loads. The dynamic impact loads demonstrated in the codes of practice in several other countries have been reviewed and have been found to be significantly different in the different codes. A technique for calculating dynamic impact load using a direct integration method has been developed. In many cases, the mass of the train may be similar to the mass of the bridge in heavy railway bridges but the mass of the vehicle is normally neglected in an analysis due to complexities in computation. Time-varying non-linear mass models are employed to reflect the effect of moving vehicle mass. An existing prototype bridge has been selected to compare results from the codes of practice and the technique developed in this study. The correlation between vehicle speed, axle load, and dynamic impact load has been investigated.
Modelling of the dynamic behaviour of in situ concrete railway sleepers
Authors: Dahlberg T
Published: October 2008

An analytical solution to the problem of a vibrating beam on an elastic foundation is presented. An application example of a concrete railway sleeper embedded in an elastic medium (the ballast) is provided. The sleeper is also elastically connected to the rails. The Rayleigh—Timoshenko (R—T) beam theory for a beam on an elastic foundation is used and eigenfrequencies are calculated. The beam (sleeper) is divided into three sections that have piecewise constant properties. The central portion of the beam is slightly thinner than the outer parts, and each one of the three parts may or may not be supported by the elastic foundation. The elastic connections to the rails are situated at the two joinings of the three sleeper sections.

Conclusions drawn are that the Euler—Bernoulli beam theory can be used to calculate two, or maximum three, eigenfrequencies of the sleeper. For higher frequencies, the R—T beam theory should be used. The foundation stiffness influences the lowest bending-mode eigenfrequency the most; higher eigenfrequencies are practically unaffected by the foundation stiffness. The influence of railpad (and rail) stiffness on the sleeper eigenfrequencies is negligible.
A review on non-destructive evaluation of rails: State-of-the-art and future development
Authors: Ph Papaelias M , Roberts C , Davis C L
Published: October 2008

Rails are systematically inspected for internal and surface defects using various non-destructive evaluation (NDE) techniques. During the manufacturing process, rails are inspected using automated optical cameras and eddy current sensing systems for any surface damage, while the presence of internal defects is assessed through ultrasonic inspection. Similarly, ultrasonic transducers and magnetic induction sensors have been extensively used by the rail industry for the inspection of rails in-service. More recently, automated vision techniques and hybrid systems based on the simultaneous use of pulsed eddy current probes and conventional ultrasonic probes have been introduced for the high-speed inspection of rail tracks. Other NDE techniques, such as electromagnetic acoustic transducers, laser ultrasonics, guided waves, and alternating current field measurement probes, are also under development for application in the rail industry.

This paper comprehensively reviews NDE methodologies in use around Europe and North America for rail defect detection. This includes a detailed overview of the background theory and the techniques used to incorporate condition data into maintenance procedures. It also presents a review of the current state-of-the-art in NDE of railways coupled with a discussion of future developments and novel inspection methodologies in the field.
Effects of payment for performance in primary care: Qualitative interview study
Authors: Maisey Susan , Steel Nick , Marsh Roy , Gillam Stephen , Fleetcroft Robert , Howe Amanda
Published: October 2008

Objectives

To understand the effects of a large scale ‘payment for performance’ scheme (the Quality and Outcomes Framework [QOF]) on professional roles and the delivery of primary care in the English National Health Service.

Methods

Qualitative semi-structured interview study. Twenty-four clinicians were interviewed during 2006: one general practitioner and one practice nurse in 12 general practices in eastern England with a broad range of sociodemographic and organizational characteristics.

Results

Participants reported substantial improvements in teamwork and in the organization, consistency and recording of care for conditions incentivized in the scheme, but not for non-incentivized conditions. The need to carry out and record specific clinical activities was felt to have changed the emphasis from ‘patient led’ consultations and listening to patients’ concerns. Loss of continuity of care and of patient choice were described. Nurses experienced increased workload but enjoyed more autonomy and job satisfaction. Doctors acknowledged improved disease management and teamwork but expressed unease about ‘box-ticking’ and increased demands of team supervision, despite better terms and conditions. Doctors were less motivated to achieve performance indicators where they disputed the evidence on which they were based. Participants expressed little engagement with results of patient surveys or patient involvement initiatives. Some participants described data manipulation to maximize practice income. Many felt overwhelmed by the flow of policy initiatives.

Conclusions

Payment for performance is driving major changes in the roles and organization of English primary health care teams. Non-incentivized activities and patients’ concerns may receive less clinical attention. Practitioners would benefit from improved dissemination of the evidence justifying the inclusion of new performance indicators in the QOF.
What benefits will choice bring to patients? Literature review and assessment of implications
Authors: Fotaki Marianna , Roland Martin , Boyd Alan , Mcdonald Ruth , Scheaff Rod , Smith Liz
Published: October 2008

Objectives

To assess the demand for, and likely impact of, increasing patient choice in health care. The study examined whether patients would like to exercise choice of hospital, primary care provider and treatment, and investigated the likely impact of policies designed to increase choice on equity of access, and on the efficiency and quality of service delivery.

Method

Theory-based literature review including an analysis of the intended and unintended impact of choice-related policies in health care in the UK, European Union and USA. Selected papers focused not only on offering choice to individual patients but also evidence of the impact of choice by patients’ agents such as GPs, and on the impact of introducing choice in education and social services.

Results

Choosing between hospitals or primary care providers is not currently a high priority for the public, except where local services are poor, e.g. they have long waiting times and where individual patients’ circumstances do not limit their ability to travel. When patients become ill, they are increasingly likely to wish to rely on a trusted health practitioner to choose their treatment. Better educated populations make greater use of information and are more likely to exercise choice in health care. The increase in inequality which this could produce might be reduced by specific provision of information and help, enabling less advantaged populations to make choices about health care. There was little evidence in the literature that providing greater choice will in itself improve efficiency or quality of care.

Conclusion

Although patients may themselves make limited use of choices, the existence of choice may, in theory, stimulate providers to improve quality of care. Patients do, however, want to be more involved in individual decisions about their own treatment, and generally participate much less in these decisions than they would wish.
Improving the appropriateness of referrals and waiting times for endoscopic procedures
Authors: Mariotti Giuliano , Meggio Alberto , De Pretis Giovanni , Gentilini Maria
Published: October 2008

Objective

There is a lack of standard methods for determining the clinical priority of patients referred by general practitioners (GPs) for specialist outpatient consultations. We introduced a system of progressive involvement by general practitioners and specialists with 80 diagnostic procedures. The aim of this study was to evaluate this new method of prioritization of patients suffering from significant gastroenterological disorders needing rapid access to diagnostic procedures.

Methods

The study included 438 outpatients who were referred for and underwent a gastroscopy or colonoscopy. GPs used a ranking of waiting times for different levels of clinical priority, called ‘homogeneous waiting groups’. Specialists also assigned a priority level for each patient as well as evaluating the appropriateness of the referral and the presence of significant endoscopic disorders. Agreement between GPs’ and specialists’ priority assessments was evaluated by the kappa statistic.

Results

Most referrals (74.4%) were deemed low priority by GPs, with no maximum waiting time assigned. The level of agreement between GPs and specialists as regards patients’ priorities was poor or moderate: for gastroscopy the kappa was 0.31 (weighted kappa 0.47) and for colonoscopy 0.44 (weighted kappa 0.46). There was an association between the proportion of significant disorders identified with endoscopy and the priority assigned to the referral (x2 = 18.9, 1 df, p < 0.001). The overall proportion of referrals deemed inappropriate by specialists was 22.1%.

Conclusions

There is value in liaison between GPs and specialists for achieving timely referrals and avoiding delayed diagnosis though higher levels of agreement need to be achieved.
Impact of critical care outreach services on the delivery and organization of hospital care
Authors: Baker-Mcclearn Denise , Carmel Simon
Published: October 2008

Objectives

To evaluate the impact of critical care outreach services on the delivery and organization of hospital care from the perspective of staff working in acute hospitals.

Methods

One hundred semi-structured interviews were undertaken with hospital staff who were either members of, or who came into contact with, the outreach service in eight hospitals in England.

Results

Outreach services had two main impacts on the delivery and organization of hospital care, reflecting the organizational and educational aims of the policy. First, on the organization of patient care: it was suggested that care was more timely, there were fewer referrals to the intensive care unit (ICU) and ICUs felt more able to discharge patients to hospital wards. There were also perceived to be improved links between ward nurses and medical teams and improved morale among ICU nurses. Second, on the confidence and skills of ward staff (nurses and junior doctors): increased contact on the wards resulted in more opportunities to share critical care skills. However, there remained concerns about the sustainability of improved skills and some respondents felt that junior doctors were becoming de-skilled.

Conclusion

Critical care outreach services have had a positive impact on the delivery and organization of hospital care. In attempting to share critical care skills, however, these services can experience a tension between the aims of service delivery and education - a tension which is partly resolved by sharing skills in the clinical and organizational context of direct patient care.