Source of Previous Treatment for Re-Treatment TB Cases Registered under the National TB Control Programme, India, 2010

BACKGROUND: In 2009, nearly half (289,756) of global re-treatment TB notifications are from India; no nationally-representative data on the source of previous treatment was available to inform strategies for improvement of initial TB treatment outcome. OBJECTIVES: To assess the source of previous treatment for re-treatment TB patients registered under India's Revised National TB control Programme (RNTCP). METHODOLOGY: A nationally-representative cross sectional study was conducted in a sample of 36 randomly-selected districts. All consecutively registered retreatment TB patients during a defined 15-day period in these 36 districts were contacted and the information on the source of previous treatment sought. RESULTS: Data was collected from all 1712 retreatment TB patients registered in the identified districts during the study period. The data includes information on 595 'relapse' cases, 105 'failure' cases, 437 'treatment after default (TAD)' cases and 575 're-treatment others' cases. The source of most recent previous anti-tuberculosis therapy for 754 [44% (95% CI, 38.2%-49.9%)] of the re-treatment TB patients was from providers outside the TB control programme. A higher proportion of patients registered as TAD (64%) and 'retreatment others' (59%) were likely to be treated outside the National Programme, when compared to the proportion among 'relapse' (22%) or 'failure' (6%). Extrapolated to national registration, of the 292,972 re-treatment registrations in 2010, 128,907 patients would have been most recently treated outside the national programme. CONCLUSIONS: Nearly half of the re-treatment cases registered with the national programme were most recently treated outside the programme setting. Enhanced efforts towards extending treatment support and supervision to patients treated by private sector treatment providers are urgently required to improve the quality of treatment and reduce the numbers of patients with recurrent disease. In addition, reasons for the large number of recurrent TB cases from those already treated by the national programme require urgent detailed investigation

Application of Permutation Genetic Algorithm for Sequential Model Building–Model Validation Design of Experiments

YesThe work presented in this paper is motivated by a complex multivariate engineering problem associated with engine mapping experiments, which require efficient Design of Experiment (DoE) strategies to minimise expensive testing. The paper describes the development and evaluation of a Permutation Genetic Algorithm (PermGA) to support an exploration-based sequential DoE strategy for complex real-life engineering problems. A known PermGA was implemented to generate uniform OLH DoEs, and substantially extended to support generation of Model Building–Model Validation (MB-MV) sequences, by generating optimal infill sets of test points as OLH DoEs, that preserve good space filling and projection properties for the merged MB + MV test plan. The algorithm was further extended to address issues with non-orthogonal design spaces, which is a common problem in engineering applications. The effectiveness of the PermGA algorithm for the MB-MV OLH DoE sequence was evaluated through a theoretical benchmark problem based on the Six-Hump-Camel-Back (SHCB) function, as well as the Gasoline Direct Injection (GDI) engine steady state engine mapping problem that motivated this research. The case studies show that the algorithm is effective at delivering quasi-orthogonal space-filling DoEs with good properties even after several MB-MV iterations, while the improvement in model adequacy and accuracy can be monitored by the engineering analyst. The practical importance of this work, demonstrated through the engine case study, also is that significant reduction in the effort and cost of testing can be achieved.The research work presented in this paper was funded by the UK Technology Strategy Board (TSB) through the Carbon Reduction through Engine Optimization (CREO) project

Neoplastic transformation of breast epithelial cells by genotoxic stress

<p>Abstract</p> <p>Background</p> <p>Exposure to genotoxic stresses such as radiation and tobacco smoke can cause increased cancer incidence rate as reflected in an in depth meta-analysis of data for women and breast cancer incidence. Published reports have indicated that exposures to low dose radiation and tobacco smoke are factors that contribute to the development of breast cancer. However, there is a scarcity of information on the combinatorial effects of low dose radiation and tobacco smoke on formation and progression of breast cancer. The combination of these two genotoxic insults can induce significant damage to the genetic material of the cells resulting in neoplastic transformation.</p> <p>Methods</p> <p>To study the effects of low dose ionizing radiation and tobacco smoke on breast cells, MCF 10A cells were treated either with radiation (Rad - 0.1 Gray) or cigarette smoke condensate (Csc - 10 microgram/ml of medium) or a combination of Rad + Csc. Following treatments, cells were analyzed for cell cycle distribution patterns and the ability to extrude the Hoechst 33342 dye. In addition, <it>in vitro </it>invasion and migration as well as mammosphere formation assays were performed. Finally, differential gene expression profiles were generated from the individual and combination treatment.</p> <p>Results</p> <p>Exposure of MCF 10A cells to the combination of radiation plus cigarette smoke condensate generated a neoplastic phenotype. The transformed phenotype promoted increased mammosphere numbers, altered cell cycle phases with a doubling of the population in S phase, and increased invasion and motility. Also, exclusion of Hoechst 33342 dye, a surrogate marker for increased ABC transporters, was observed, which indicates a possible increase in drug resistance. In addition, changes in gene expression include the up regulation of genes encoding proteins involved in metabolic pathways and inflammation.</p> <p>Conclusions</p> <p>The results indicate that when normal breast cells are exposed to low dose radiation in combination with cigarette smoke condensate a phenotype is generated that exhibits traits indicative of neoplastic transformation. More importantly, this is the first study to provide a new insight into a possible etiology for breast cancer formation in individuals exposed to low dose radiation and tobacco smoke.</p

Matrix Metalloproteinase-8 Mediates the Unfavorable Systemic Impact of Local Irradiation on Pharmacokinetics of Anti-Cancer Drug 5-Fluorouracil

Concurrent chemoradiation with 5-fluorouracil (5-FU) is widely accepted for cancer treatment. However, the interactions between radiation and 5-FU remain unclear. Here, we evaluated the influence of local irradiation on the pharmacokinetics of 5-FU in rats. The single-fraction radiation was delivered to the whole pelvic fields of Sprague-Dawley rats after computerized tomography-based planning. 5-FU at 100 mg/kg was prescribed 24 hours after radiation. A high-performance liquid chromatography system was used to measure 5-FU in the blood. Matrix metalloproteinase-8 (MMP-8) inhibitor I was administered to examine whether or not RT modulation of 5-FU pharmacokinetic parameters could be blocked. Compared with sham-irradiated controls, whole pelvic irradiation reduced the area under the concentration versus time curve (AUC) of 5-FU in plasma and, in contrast, increased in bile with a radiation dose-dependent manner. Based on protein array analysis, the amount of plasma MMP-8 was increased by whole pelvic irradiation (2.8-fold by 0.5 Gy and 5.3-fold by 2 Gy) in comparison with controls. Pretreatment with MMP-8 inhibitor reversed the effect of irradiation on AUC of 5-FU in plasma. Our findings first indicate that local irradiation modulate the systemic pharmacokinetics of 5-FU through stimulating the release of MMP-8. The pharmacokinetics of 5-FU during concurrent chemoradiaiton therapy should be rechecked and the optimal 5-FU dose should be reevaluated, and adjusted if necessary, during CCRT

Global gene expression analyses of bystander and alpha particle irradiated normal human lung fibroblasts: Synchronous and differential responses

<p>Abstract</p> <p>Background</p> <p>The existence of a radiation bystander effect, in which non-irradiated cells respond to signals from irradiated cells, is now well established. It raises concerns for the interpretation of risks arising from exposure to low doses of ionizing radiation. However, the regulatory mechanisms involved in the bystander response have not been well elucidated. To provide insight into the signaling pathways responding in bystanders, we have measured global gene expression four hours after bystander and direct alpha particle exposure of primary human lung fibroblasts.</p> <p>Results</p> <p>Although common p53-regulated radiation response genes like <it>CDKN1A </it>were expressed at elevated levels in the directly exposed cultures, they showed little or no change in the bystanders. In contrast, genes regulated by NFκB, such as <it>PTGS2 </it>(cyclooxygenase-2), <it>IL8 </it>and <it>BCL2A1</it>, responded nearly identically in bystander and irradiated cells. This trend was substantiated by gene ontology and pathway analyses of the microarray data, which suggest that bystander cells mount a full NFκB response, but a muted or partial p53 response. In time-course analyses, quantitative real-time PCR measurements of <it>CDKN1A </it>showed the expected 4-hour peak of expression in irradiated but not bystander cells. In contrast, <it>PTGS2, IL8 </it>and <it>BCL2A1 </it>responded with two waves of expression in both bystander and directly irradiated cells, one peaking at half an hour and the other between four and six hours after irradiation.</p> <p>Conclusion</p> <p>Two major transcriptional hubs that regulate the direct response to ionizing radiation are also implicated in regulation of the bystander response, but to dramatically different degrees. While activation of the p53 response pathway is minimal in bystander cells, the NFκB response is virtually identical in irradiated and bystander cells. This alteration in the balance of signaling is likely to lead to different outcomes in irradiated cells and their bystanders, perhaps leading to greater survival of bystanders and increased risk from any long-term damage they have sustained.</p