Drawing the hoarding line: balancing the spatial requirements of customer and contractor in occupied refurbishment of railway stations

In planning an occupied refurbishment the spatial needs of the contractor and of theongoing business have to be balanced. For the refurbishment of railway stations, aparticular concern to retailers and train operators is the disruptive effect ofconstruction works upon pedestrian movement. RaCMIT (Refurbishment andCustomer Movement Integration Tool) is a research project aimed at investigatingthis problem through concentration on decision criteria/processes of the client andmodels/observations of pedestrian movement. The objective of the research is todevelop a decision protocol and decision support tools, which assist both the clientand the construction planner in addressing these problems and which allows overalloptimisation of project value to the client?s business. The practice of spatial decisionmakingin station refurbishment projects has been investigated in two case studies.This paper concentrates on one case study where pedestrian movement was observedbefore and during the refurbishment. Research observations as well as currentliterature suggest that a) for overall decision-making, opportunities may be lost(under current practice) for minimising joint project cost/revenue (or other)disruption and b) for spatial decision-making, temporary station configuration duringconstruction may be a significant variable. In planning an occupied refurbishment the spatial needs of the contractor and of theongoing business have to be balanced. For the refurbishment of railway stations, aparticular concern to retailers and train operators is the disruptive effect ofconstruction works upon pedestrian movement. RaCMIT (Refurbishment andCustomer Movement Integration Tool) is a research project aimed at investigatingthis problem through concentration on decision criteria/processes of the client andmodels/observations of pedestrian movement. The objective of the research is todevelop a decision protocol and decision support tools, which assist both the clientand the construction planner in addressing these problems and which allows overalloptimisation of project value to the client?s business. The practice of spatial decisionmakingin station refurbishment projects has been investigated in two case studies.This paper concentrates on one case study where pedestrian movement was observedbefore and during the refurbishment. Research observations as well as currentliterature suggest that a) for overall decision-making, opportunities may be lost(under current practice) for minimising joint project cost/revenue (or other)disruption and b) for spatial decision-making, temporary station configuration duringconstruction may be a significant variable

Drawing the line: balancing the spatial requirements of customer and contractor in occupied refurbishment

In planning the refurbishment of railway stations the spatial needs of the contractor and ofthe ongoing business stakeholders have to be balanced. A particular concern is thedisruptive effect of construction works upon pedestrian movement.RaCMIT (Refurbishment and Customer Movement Integration Tool) is a research projectaimed at addressing this problem through combining the knowledge of the client projectmanager, the construction planner and the pedestrian modelling expert.The objective of the research is to develop a decision protocol (based on problemsencountered in two case studies) facilitating optimisation of overall project value to theclient?s business.Research observations as well as current literature suggest that:? for overall decision-making, opportunities may be lost (under current practice) forminimising joint project cost/revenue disruption and? for spatial decision-making, temporary station configuration during construction(and not just overall pedestrian capacity) is a significant variable for both businessand safety outcomes. In planning the refurbishment of railway stations the spatial needs of the contractor and ofthe ongoing business stakeholders have to be balanced. A particular concern is thedisruptive effect of construction works upon pedestrian movement.RaCMIT (Refurbishment and Customer Movement Integration Tool) is a research projectaimed at addressing this problem through combining the knowledge of the client projectmanager, the construction planner and the pedestrian modelling expert.The objective of the research is to develop a decision protocol (based on problemsencountered in two case studies) facilitating optimisation of overall project value to theclient?s business.Research observations as well as current literature suggest that:? for overall decision-making, opportunities may be lost (under current practice) forminimising joint project cost/revenue disruption and? for spatial decision-making, temporary station configuration during construction(and not just overall pedestrian capacity) is a significant variable for both businessand safety outcomes

Endo180 (MRC2) antibody-drug conjugate for the treatment of sarcoma.

Although the 5-year survival rates for sarcoma patients have improved, the proportion of patients relapsing after first line treatment remains high and survival of patients with metastatic disease is dismal. Moreover, the extensive molecular heterogeneity of the multiple different sarcoma subtypes poses a substantial challenge to developing more personalized treatment strategies. From immunohistochemical staining of a large set of 625 human soft tissue sarcomas we demonstrate strong tumor cell staining of the Endo180 (MRC2) receptor in a high proportion of samples, findings echoed in gene expression datasets showing a significantly increased expression in both soft tissue and bone sarcomas compared to normal tissue. Endo180 is a constitutively recycling transmembrane receptor and therefore an ideal target for an antibody-drug conjugate (ADC). An anti-Endo180 monoclonal antibody conjugated to the anti-mitotic agent, MMAE via a cleavable linker, is rapidly internalized into target cells and trafficked to the lysosome for degradation, causing cell death specifically in Endo180 expressing sarcoma cell lines. In a sarcoma tumor xenograft model, the Endo180-vc-MMAE ADC, but not an Isotype-vc-MMAE control or the unconjugated Endo180 antibody, drives on target cytotoxicity resulting in tumor regression and a significant impairment of metastatic colonization of the lungs, liver and lymph nodes. These data, together with the lack of a phenotype in mice with an Mrc2 genetic deletion, provide pre-clinical proof-of-principle evidence for the future development of an Endo180-ADC as a therapeutic strategy in a broad range of sarcoma subtypes and, importantly, with potential impact both on the primary tumor and in metastatic disease

Highly consistent genetic alterations in childhood adrenocortical tumours detected by comparative genomic hybridization

We have examined 11 cases of childhood adrenocortical tumours for copy number changes using comparative genomic hybridization (CGH). The changes seen are highly consistent between cases, and are independent of tumour type (carcinoma versus adenoma) or the presence of a germline TP53 mutation. The regions of chromosomal gain and loss identified in this study indicate the location of genes that are potentially important in the development and progression of childhood adrenocortical tumours. Finally, the copy number changes identified in childhood tumours are distinctly different to those seen in adult cases (Kjellman et al (1996) Cancer Res56: 4219–4223), and we propose that this indicates that childhood tumours are of embryonal origin. © 1999 Cancer Research Campaig

Anti-müllerian hormone is not associated with cardiometabolic risk factors in adolescent females

<p>Objectives: Epidemiological evidence for associations of Anti-Müllerian hormone (AMH) with cardiometabolic risk factors is lacking. Existing evidence comes from small studies in select adult populations, and findings are conflicting. We aimed to assess whether AMH is associated with cardiometabolic risk factors in a general population of adolescent females.</p> <p>Methods: AMH, fasting insulin, glucose, HDLc, LDLc, triglycerides and C-reactive protein (CRP) were measured at a mean age 15.5 years in 1,308 female participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Multivariable linear regression was used to examine associations of AMH with these cardiometabolic outcomes.</p> <p>Results: AMH values ranged from 0.16–35.84 ng/ml and median AMH was 3.57 ng/ml (IQR: 2.41, 5.49). For females classified as post-pubertal (n = 848) at the time of assessment median (IQR) AMH was 3.81 ng/ml (2.55, 5.82) compared with 3.25 ng/ml (2.23, 5.05) in those classed as early pubertal (n = 460, P≤0.001). After adjusting for birth weight, gestational age, pubertal stage, age, ethnicity, socioeconomic position, adiposity and use of hormonal contraceptives, there were no associations with any of the cardiometabolic outcomes. For example fasting insulin changed by 0% per doubling of AMH (95%CI: −3%,+2%) p = 0.70, with identical results if HOMA-IR was used. Results were similar after additional adjustment for smoking, physical activity and age at menarche, after exclusion of 3% of females with the highest AMH values, after excluding those that had not started menarche and after excluding those using hormonal contraceptives.</p> <p>Conclusion: Our results suggest that in healthy adolescent females, AMH is not associated with cardiometabolic risk factors.</p&gt

An infectious aetiology for childhood brain tumours? Evidence from space–time clustering and seasonality analyses

To investigate whether infections or other environmental exposures may be involved in the aetiology of childhood central nervous system tumours, we have analysed for space–time clustering and seasonality using population-based data from the North West of England for the period 1954 to 1998. Knox tests for space–time interactions between cases were applied with fixed thresholds of close in space, <5 km, and close in time, <1 year apart. Addresses at birth and diagnosis were used. Tests were repeated replacing geographical distance with distance to the Nth nearest neighbour. N was chosen such that the mean distance was 5 km. Data were also examined by a second order procedure based on K-functions. Tests for heterogeneity and Edwards' test for sinusoidal variation were applied to examine changes of incidence with month of birth or diagnosis. There was strong evidence of space–time clustering, particularly involving cases of astrocytoma and ependymoma. Analyses of seasonal variation showed excesses of cases born in the late Autumn or Winter. Results are consistent with a role for infections in a proportion of cases from these diagnostic groups. Further studies are needed to identify putative infectious agents

New mutations at the imprinted Gnas cluster show gene dosage effects of Gsα in postnatal growth and implicate XLαs in bone and fat metabolism, but not in suckling

The imprinted Gnas cluster is involved in obesity, energy metabolism, feeding behavior, and viability. Relative contribution of paternally expressed proteins XLαs, XLN1, and ALEX or a double dose of maternally expressed Gsα to phenotype has not been established. In this study, we have generated two new mutants (Ex1A-T-CON and Ex1A-T) at the Gnas cluster. Paternal inheritance of Ex1A-T-CON leads to loss of imprinting of Gsα, resulting in preweaning growth retardation followed by catch-up growth. Paternal inheritance of Ex1A-T leads to loss of imprinting of Gsα and loss of expression of XLαs and XLN1. These mice have severe preweaning growth retardation and incomplete catch-up growth. They are fully viable probably because suckling is unimpaired, unlike mutants in which the expression of all the known paternally expressed Gnasxl proteins (XLαs, XLN1 and ALEX) is compromised. We suggest that loss of ALEX is most likely responsible for the suckling defects previously observed. In adults, paternal inheritance of Ex1A-T results in an increased metabolic rate and reductions in fat mass, leptin, and bone mineral density attributable to loss of XLαs. This is, to our knowledge, the first report describing a role for XLαs in bone metabolism. We propose that XLαs is involved in the regulation of bone and adipocyte metabolism

Adenosine A2A receptor modulation of hippocampal CA3-CA1 synapse plasticity during associative learning in behaving mice

© 2009 Nature Publishing Group All rights reservedPrevious in vitro studies have characterized the electrophysiological and molecular signaling pathways of adenosine tonic modulation on long-lasting synaptic plasticity events, particularly for hippocampal long-term potentiation(LTP). However, it remains to be elucidated whether the long-term changes produced by endogenous adenosine in the efficiency of synapses are related to those required for learning and memory formation. Our goal was to understand how endogenous activation of adenosine excitatory A2A receptors modulates the associative learning evolution in conscious behaving mice. We have studied here the effects of the application of a highly selective A2A receptor antagonist, SCH58261, upon a well-known associative learning paradigm - classical eyeblink conditioning. We used a trace paradigm, with a tone as the conditioned stimulus (CS) and an electric shock presented to the supraorbital nerve as the unconditioned stimulus(US). A single electrical pulse was presented to the Schaffer collateral–commissural pathway to evoke field EPSPs (fEPSPs) in the pyramidal CA1 area during the CS–US interval. In vehicle-injected animals, there was a progressive increase in the percentage of conditioning responses (CRs) and in the slope of fEPSPs through conditioning sessions, an effect that was completely prevented (and lost) in SCH58261 (0.5 mg/kg, i.p.)-injected animals. Moreover, experimentally evoked LTP was impaired in SCH58261- injected mice. In conclusion, the endogenous activation of adenosine A2A receptors plays a pivotal effect on the associative learning process and its relevant hippocampal circuits, including activity-dependent changes at the CA3-CA1 synapse.This study was supported by grants from the Spanish Ministry of Education and Research (BFU2005-01024 and BFU2005-02512), Spanish Junta de Andalucía (BIO-122 and CVI-02487), and the Fundación Conocimiento y Cultura of the Pablo de Olavide University (Seville, Spain).B. Fontinha was in receipt of a studentship from a project grant (POCI/SAU-NEU/56332/2004) supported by Fundação para a Ciência e Tecnologia (FCT, Portugal), and of an STSM from Cost B30 concerted action of the EU