Nephrotoxicity and nephrocarcinogenicity of dinitrotoluene : new aspects to be considered

Technical dinitrotoluene (DNT) is a mixture of 2,4- and 2,6-DNT. In humans, industrial or environmental exposure can occur orally, by inhalation, or by skin contact. The classification of DNT as an 'animal carcinogen' is based on the formation of malignant tumors in kidneys, liver, and mammary glands of rats and mice. Clear signs of toxic nephropathy were found in rats dosed with DNT, and the concept was derived of an interrelation between renal toxicity and carcinogenicity. Recent data point to the carcinogenicity of DNT on the urinary tract of exposed humans. Between 1984 and 1997, 6 cases of urothelial cancer and 14 cases of renal cell cancer were diagnosed in a group of 500 underground mining workers in the copper mining industry of the former GDR and having high exposures to explosives containing technical DNT. The incidences of both urothelial and renal cell tumors in this group were 4.5 and 14.3 times higher, respectively, than anticipated on the basis of the cancer registers of the GDR. The genotyping of all identified tumor patients for the polymorphic enzymes NAT2, GSTM1, and GSTT1 identified the urothelial tumor cases as exclusively 'slow acetylates'. A group of 161 miners highly exposed to DNT was investigated for signs of subclinical renal damage. The exposures were categorized semi-quantitatively into 'low', 'medium', 'high', and 'very high'. A straight dose-dependence of the excretion of urinary biomarker proteins with the ranking of exposure was seen. Biomarker excretion (alpha1-microglobulin, glutathione S-transferases alpha and pi) indicated that DNT-induced damage was directed toward the tubular system. New data on DNT-exposed humans appear consistent with the concept of cancer initiation by DNT isomers and the subsequent promotion of renal carcinogenesis by selective damage to the proximal tubule. The differential pathways of metabolic activation of DNT appear to apply to the proximal tubule of the kidney and to the urothelium of the renal pelvis and lower urinary tract as target tissues of carcinogenicity.

Serum levels of soluble receptor for advanced glycation end products and of S100 proteins are associated with inflammatory, autoantibody, and classical risk markers of joint and vascular damage in rheumatoid arthritis

Introduction: The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptor molecules. High concentrations of three of its putative proinflammatory ligands, S100A8/A9 complex (calprotectin), S100A8, and S100A12, are found in rheumatoid arthritis (RA) serum and synovial fluid. In contrast, soluble RAGE (sRAGE) may prevent proinflammatory effects by acting as a decoy. This study evaluated the serum levels of S100A9, S100A8, S100A12 and sRAGE in RA patients, to determine their relationship to inflammation and joint and vascular damage. Methods: Serum sRAGE, S100A9, S100A8 and S100A12 levels from 138 patients with established RA and 44 healthy controls were measured by ELISA and compared by unpaired t test. In RA patients, associations with disease activity and severity variables were analyzed by simple and multiple linear regressions. Results: Serum S100A9, S100A8 and S100A12 levels were correlated in RA patients. S100A9 levels were associated with body mass index (BMI), and with serum levels of S100A8 and S100A12. S100A8 levels were associated with serum levels of S100A9, presence of anti-citrullinated peptide antibodies (ACPA), and rheumatoid factor (RF). S100A12 levels were associated with presence of ACPA, history of diabetes, and serum S100A9 levels. sRAGE levels were negatively associated with serum levels of C-reactive protein (CRP) and high-density lipoprotein (HDL), history of vasculitis, and the presence of the RAGE 82Ser polymorphism. Conclusions: sRAGE and S100 proteins were associated not just with RA inflammation and autoantibody production, but also with classical vascular risk factors for end-organ damage. Consistent with its role as a RAGE decoy molecule, sRAGE had the opposite effects to S100 proteins in that S100 proteins were associated with autoantibodies and vascular risk, whereas sRAGE was associated with protection against joint and vascular damage. These data suggest that RAGE activity influences co-development of joint and vascular disease in rheumatoid arthritis patients.

Epidermal growth factor receptors and cyclooxygenase-2 in the pathogenesis of non-small cell lung cancer : potential targets for chemoprevention and systemic therapy

The epidermal growth factor receptor (EGFR) is part of a family of plasma membrane receptor tyrosine kinases that control many important cellular functions, from growth and proliferation to cell death. Cyclooxygenase (COX)-2 is an enzyme which catalyses the conversion of arachidonic acid to prostagladins and thromboxane. It is induced by various inflammatory stimuli, including the pro-inflammatory cytokines, Interleukin (IL)-1β, Tumour Necrosis Factor (TNF)-α and IL-2. Both EGFR and COX-2 are over-expressed in non-small cell lung cancer (NSCLC) and have been implicated in the early stages of tumourigenesis. This paper considers their roles in the development and progression of lung cancer, their potential interactions, and reviews the recent progress in cancer therapies that are directed toward these targets. An increasing body of evidence suggests that selective inhibitors of both EGFR and COX-2 are potential therapeutic agents for the treatment of NSCLC, in the adjuvant, metastatic and chemopreventative settings. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

Damage propagation in reinforced concrete frames under external blast loading

Iconic and significant buildings are the common target of bombings by terrorists causing large numbers of casualties and extensive property damage. Recent incidents were external bomb attacks on multi-storey buildings with reinforced concrete frames. Under a blast load circumstance, crucial damage initiates at low level storeys in a building and may then lead to a progressive collapse of whole or part of the structure. It is therefore important to identify the critical initial influence regions along the height, width and depth of the building exposed to blast effects and the structure response in order to assess the vulnerability of the structure to disproportionate and progressive collapse. This paper discusses the blast response and the propagation of its effects on a two dimensional reinforced concrete (RC) frame, designed to withstand normal gravity loads. The explicit finite element code, LS DYNA is used for the analysis. A complete RC portal frame seven storeys by six bays is modelled with reinforcement details and appropriate materials to simulate strain rate effects. Explosion loads derived from standard manuals are applied as idealized triangular pressures on the column faces of the numerical models. The analysis reports the influence of blast propagation as displacements and material yielding of the structural elements in the RC frame. The effected regions are identified and classified according to the load cases. This information can be used to determine the vulnerability of multi-storey RC buildings to various external explosion scenarios and designing buildings to resist blast loads.

Vulnerability and damage analysis of reinforced concrete framed buildings subjected to near field blast events

Terrorists usually target high occupancy iconic and public buildings using vehicle borne incendiary devices in order to claim a maximum number of lives and cause extensive damage to public property. While initial casualties are due to direct shock by the explosion, collapse of structural elements may extensively increase the total figure. Most of these buildings have been or are built without consideration of their vulnerability to such events. Therefore, the vulnerability and residual capacity assessment of buildings to deliberately exploded bombs is important to provide mitigation strategies to protect the buildings' occupants and the property. Explosive loads and their effects on a building have therefore attracted significant attention in the recent past. Comprehensive and economical design strategies must be developed for future construction. This research investigates the response and damage of reinforced concrete (RC) framed buildings together with their load bearing key structural components to a near field blast event. Finite element method (FEM) based analysis was used to investigate the structural framing system and components for global stability, followed by a rigorous analysis of key structural components for damage evaluation using the codes SAP2000 and LS DYNA respectively. The research involved four important areas in structural engineering. They are blast load determination, numerical modelling with FEM techniques, material performance under high strain rate and non-linear dynamic structural analysis. The response and damage of a RC framed building for different blast load scenarios were investigated. The blast influence region for a two dimensional RC frame was investigated for different load conditions and identified the critical region for each loading case. Two types of design methods are recommended for RC columns to provide superior residual capacities. They are RC columns detailing with multi-layer steel reinforcement cages and a composite columns including a central structural steel core. These are to provide post blast gravity load resisting capacity compared to typical RC column against a catastrophic collapse. Overall, this research broadens the current knowledge of blast and residual capacity analysis of RC framed structures and recommends methods to evaluate and mitigate blast impact on key elements of multi-storey buildings.

Correlation between extent of osteolytic damage and metastatic burden of human breast cancer metastasis in nude mice : real-time PCR quantitation

Orthotopic or intracardiac injection of human breast cancer cell lines into immunocompromised mice allows study of the molecular basis of breast cancer metastasis. We have established a quantitative real-time PCR approach to analyze metastatic spread of human breast cancer cells inoculated into nude mice via these routes. We employed MDA-MB-231 human breast cancer cells genetically tagged with a bacterial β-galactosidase (Lac-Z) retroviral vector, enabling their detection by TaqMan® real-time PCR. PCR detection was linear, specific, more sensitive than conventional PCR, and could be used to directly quantitate metastatic burden in bone and soft organs. Attesting to the sensitivity and specificity of the PCR detection strategy, as few as several hundred metastatic MDA-MB-231 cells were detectable in 100 μm segments of paraffin-embedded lung tissue, and only in samples adjacent to sections that scored positive by histological detection. Moreover, the measured real-time PCR metastatic burden in the bone environment (mouse hind-limbs, n = 48) displayed a high correlation to the degree of osteolytic damage observed by high resolution X-ray analysis (r2 = 0.972). Such a direct linear relationship to tumor burden and bone damage substantiates the so-called 'vicious cycle' hypothesis in which metastatic tumor cells promote the release of factors from the bone which continue to stimulate the tumor cells. The technique provides a useful tool for molecular and cellular analysis of human breast cancer metastasis to bone and soft organs, can easily be extended to other cell/marker/organ systems, and should also find application in preclinical assessment of anti-metastatic modalities.

Response and damage evaluation of reinforced concrete frames subjected to blast loading

Bomb attacks carried out by terrorists, targeting high occupancy buildings, have become increasingly common in recent times. Large numbers of casualties and property damage result from overpressure of the blast followed by failing of structural elements. Understanding the blast response of multi-storey buildings and evaluating their remaining life have therefore become important. Response and damage analysis of single structural components, such as columns or slabs, to explosive loads have been examined in the literature, but the studies on blast response and damage analysis of structural frames in multi-storey buildings is limited and this is necessary for assessing the vulnerability of them. This paper investigates the blast response and damage evaluation of reinforced concrete (RC) frames, designed for normal gravity loads, in order to evaluate their remaining life. Numerical modelling and analysis were carried out using the explicit finite element software, LS DYNA. The modelling and analysis takes into consideration reinforcement details together and material performance under higher strain rates. Damage indices for columns are calculated based on their residual and original capacities. Numerical results generated in the can be used to identify relationships between the blast load parameters and the column damage. Damage index curve will provide a simple means for assessing the damage to a typical multi-storey building RC frame under an external bomb circumstance.

Case studies on vibration based damage identification : multi-criteria approach

Vibration based damage identification methods examine the changes in primary modal parameters or quantities derived from modal parameters. As one method may have advantages over the other under some circumstances, a multi-criteria approach is proposed. Case studies are conducted separately on beam, plate and plate-on-beam structures. Using the numerically simulated modal data obtained through finite element analysis software, algorithms based on flexibility and strain energy changes before and after damage are obtained and used as the indices for the assessment of the state of structural health. Results show that the proposed multi-criteria method is effective in damage identification in these structures.

Review of vibration-based damage detection and condition assessment of bridge structures using structural health monitoring

As a part of vital infrastructure and transportation networks, bridge structures must function safely at all times. However, due to heavier and faster moving vehicular loads and function adjustment, such as Busway accommodation, many bridges are now operating at an overload beyond their design capacity. Additionally, the huge renovation and replacement costs always make the infrastructure owners difficult to undertake. Structural health monitoring (SHM) is set to assess condition and foresee probable failures of designated bridge(s), so as to monitor the structural health of the bridges. The SHM systems proposed recently are incorporated with Vibration-Based Damage Detection (VBDD) techniques, Statistical Methods and Signal processing techniques and have been regarded as efficient and economical ways to solve the problem. The recent development in damage detection and condition assessment techniques based on VBDD and statistical methods are reviewed. The VBDD methods based on changes in natural frequencies, curvature/strain modes, modal strain energy (MSE) dynamic flexibility, artificial neural networks (ANN) before and after damage and other signal processing methods like Wavelet techniques and empirical mode decomposition (EMD) / Hilbert spectrum methods are discussed here.

Damage assessment in multiple-girder composite bridge using vibration characteristics

This paper uses dynamic computer simulation techniques to apply a procedure using vibration-based methods for damage assessment in multiple-girder composite bridge. In addition to changes in natural frequencies, this multi-criteria procedure incorporates two methods, namely the modal flexibility and the modal strain energy method. Using the numerically simulated modal data obtained through finite element analysis software, algorithms based on modal flexibility and modal strain energy change before and after damage are obtained and used as the indices for the assessment of structural health state. The feasibility and capability of the approach is demonstrated through numerical studies of proposed structure with six damage scenarios. It is concluded that the modal strain energy method is competent for application on multiple-girder composite bridge, as evidenced through the example treated in this paper.

Improved maritime target tracker using colour fusion

Searching for humans lost in vast stretches of ocean has always been a difficult task. This paper investigates a machine vision system that addresses this problem by exploiting the useful properties of alternate colour spaces. In particular, the paper investigates the fusion of colour information from the HSV, RGB, YCbCr and YIQ colour spaces within the emission matrix of a Hidden Markov Model tracker to enhance video based maritime target detection. The system has shown promising results. The paper also identifies challenges still needing to be met.