ABCB1 (MDR1) rs1045642 is associated with increased overall survival in plasma cell myeloma

Multi-drug resistance (MDR) may compromise the successful management of haematological malignancies, impairing the effectiveness of chemotherapy. The P-glycoprotein (P-gp) drug efflux pump, encoded by the gene ABCB1 (MDR1), is the most widely studied component in MDR. A single nucleotide polymorphism (SNP) has been identified within ABCB1, rs1045642 (C3435T), which may alter P-gp substrate specificity and have an impact on the effectiveness of treatment, and hence overall survival (OS). We estimated the frequency of this SNP in the Northern Irish population and investigated its impact on the OS of patients with plasma cell myeloma (PCM). There was no significant difference in the frequency of rs1045642 between the PCM cohort and an age- and gender-matched control population. Findings within the PCM cohort suggest that rs1045642 genotype influences OS (p = 2 x 10(-2)). If confirmed in larger studies, these results suggest that genotyping rs1045642 may be a useful predictor of outcome in PCM and could indicate modified treatment modalities in certain individuals.

Gamma ray-induced bystander effect in tumour glioblastoma cells: a specific study on cell survival, cytokine release and cytokine receptors.

Recent experimental evidence has challenged the paradigm according to which radiation traversal through the nucleus of a cell is a prerequisite for producing genetic changes or biological responses. Thus, unexposed cells in the vicinity of directly irradiated cells or recipient cells of medium from irradiated cultures can also be affected. The aim of the present study was to evaluate, by means of the medium transfer technique, whether interleukin-8 and its receptor (CXCR1) may play a role in the bystander effect after gamma irradiation of T98G cells in vitro. In fact the cell specificity in inducing the bystander effect and in receiving the secreted signals that has been described suggests that not only the ability to release the cytokines but also the receptor profiles are likely to modulate the cell responses and the final outcome. The dose and time dependence of the cytokine release into the medium, quantified using an enzyme linked immunosorbent assay, showed that radiation causes alteration in the release of interleukin-8 from exposed cells in a dose-independent but time-dependent manner. The relative receptor expression was also affected in exposed and bystander cells.

Uncertainty and Sensitivity Analysis in Aircraft Operating Costs in Structural Design Optimization

The paper focuses on the development of an aircraft design optimization methodology that models uncertainty and sensitivity analysis in the tradeoff between manufacturing cost, structural requirements, andaircraft direct operating cost.Specifically,ratherthanonlylooking atmanufacturingcost, direct operatingcost is also consideredintermsof the impact of weight on fuel burn, in addition to the acquisition cost to be borne by the operator. Ultimately, there is a tradeoff between driving design according to minimal weight and driving it according to reduced manufacturing cost. Theanalysis of cost is facilitated withagenetic-causal cost-modeling methodology,andthe structural analysis is driven by numerical expressions of appropriate failure modes that use ESDU International reference data. However, a key contribution of the paper is to investigate the modeling of uncertainty and to perform a sensitivity analysis to investigate the robustness of the optimization methodology. Stochastic distributions are used to characterize manufacturing cost distributions, andMonteCarlo analysis is performed in modeling the impact of uncertainty on the cost modeling. The results are then used in a sensitivity analysis that incorporates the optimization methodology. In addition to investigating manufacturing cost variance, the sensitivity of the optimization to fuel burn cost and structural loading are also investigated. It is found that the consideration of manufacturing cost does make an impact and results in a different optimal design configuration from that delivered by the minimal-weight method. However, it was shown that at lower applied loads there is a threshold fuel burn cost at which the optimization process needs to reduce weight, and this threshold decreases with increasing load. The new optimal solution results in lower direct operating cost with a predicted savings of 640=m2 of fuselage skin over the life, relating to a rough order-of-magnitude direct operating cost savings of $500,000 for the fuselage alone of a small regional jet. Moreover, it was found through the uncertainty analysis that the principle was not sensitive to cost variance, although the margins do change.

A Census-based longitudinal study of variations in survival amongst residents of nursing and residential homes in Northern Ireland

Background: despite the intensive services provided to residents of care homes, information on death rates is not routinely available for this population in the UK. Objective: to quantify mortality rates across the care home population of Northern Ireland, and assess variation by type of care home and resident characteristics. Design: a prospective, Census-based cohort study, with 5-year follow-up. Participants: all 9,072 residents of care homes for people aged 65 and over at the time of the 2001 census with a special emphasis on the 2,112 residents admitted during the year preceding census day. Measurements: age, sex, self-reported health, marital status, residence (not in care home, residential home, dual registered home, nursing home), elderly mentally infirm care provision. Results: the median survival among nursing home residents was 2.33 years (95% CI 2.25–2.59), for dual registered homes 2.75 (95% CI 2.42–3.17) and for residential homes 4.51 (95% CI 3.92–4.92) years. Age, sex and self-reported health showed weaker associations in the sicker populations in nursing homes compared to those in residential care or among the non-institutionalised. Conclusions: the high mortality in care homes indicates that places in care homes are reserved for the most severely ill and dependent. Death rates may not be an appropriate care quality measure for this population, but may serve as a useful adjunct for clinical staff and the planning of care home provision.

High density mangrove plantation enhances surface accretion, surface elevation change, and tree survival in coastal areas susceptible to sea-level rise

Survival, growth, above ground biomass accumulation, soil surface elevation dynamics and nitrogen accumulation in accreted sediments were studied in experimental treatments planted with four different densities (6.96, 3.26, 1.93 and 0.95 seedlings m-2) of the mangrove Rhizophora mucronata in Puttalam Lagoon, Sri Lanka. Measurements were taken over a period of 1171 days and were compared with those from unplanted controls. Trees at the lowest density showed significantly reduced survival, whilst measures of individual tree growth did not differ significantly among treatments. Rates of surface sediment accretion (means ± S.E.) were 13.0 (±1.3), 10.5 (±0.9), 8.4 (±0.3), 6.9 (±0.5) and 5.7 (±0.3) mm yr-1 at planting densities of 6.96, 3.26, 1.93, 0.95, and 0 (unplanted control) seedlings m-2, respectively, showing highly significant differences among treatments. Mean (± S.E.) rates of surface elevation change were much lower than rates of accretion at 2.8 (±0.2), 1.6 (±0.1), 1.1 (±0.2), 0.6 (±0.2) and -0.3 (±0.1) mm yr-1 for 6.96, 3.26, 1.93, 0.95, and 0 seedlings m-2, respectively. All planted treatments appeared to accumulate greater nitrogen concentrations in the sediment compared to the unplanted control, and suggests one potential causal mechanism for the facilitatory effects observed; high densities of plants potentially contribute to the accretion of greater amounts of nutrient rich sediment. While this potential process needs further study, this study demonstrated how higher densities of mangroves enhance rates of sediment accretion and surface elevation, processes that may be crucial in mangrove ecosystem adaptation to sea level rise. There was no evidence that increasing plant density evoked a trade-off with growth and survival of the planted trees. Rather facilitatory effects enhanced survival at high densities, suggesting that local land managers may be able to take advantage of plantation densities to help mitigate sea-level rise effects by encouraging positive soil surface elevation increment, and perhaps even greater nutrient retention to promote mangrove growth and ameliorate nearshore eutrophication in tropical island environments.