Biomedicals from Bone

The realm of biomaterials, under which biomedical materials can be categorised, has a broad definition base and recognises materials that are synthesized or naturally sourced. Biomaterials are normally those that come into contact with live tissue and physiological fluids. They have applications as prostheses to replace lost function of joints or to replace bone tissue, for diagnosing medical conditions, as a form of therapy, or as a storage unit. The diversity and scope of biomaterials science research, and especially its application to the improvement of trauma, disease, and congenital defects in the human condition, are making this branch of science increasingly dominant and topical in many countries. An exciting aspect is that such research is interdisciplinary. The varied problems of the human condition that biomaterials research addresses occupy the efforts not only of medical doctors who act as the end users of such technology, but also those of chemists, physicists, engineers, and biologists in creating the technological advances. Chemistry, in particular, plays a major role in such research, after all it is the foundation stone on which biomaterials polymer science and biomedical scaffold materials are built

A Recurrent Cooperative/Competitive Field for Segmentation of Magnetic Resonance Brain Imagery

The Grey-White Decision Network is introduced as an application of an on-center, off-surround recurrent cooperative/competitive network for segmentation of magnetic resonance imaging (MRI) brain images. The three layer dynamical system relaxes into a solution where each pixel is labeled as either grey matter, white matter, or "other" matter by considering raw input intensity, edge information, and neighbor interactions. This network is presented as an example of applying a recurrent cooperative/competitive field (RCCF) to a problem with multiple conflicting constraints. Simulations of the network and its phase plane analysis are presented

Examining variation in counter-terrorism listing regimes

http://www.ester.ee/record=b4684467*es

Liquid Chromatography-Mass Spectrometry Analysis of Dysfunctional Mitochondrial Metabolism: Insights into Rotenone Toxicity and Friedreichâ\u27s Ataxia

Mitochondrial dysfunction plays a role in a wide range of diseases resulting in an enormous public health burden. The goal of this thesis is to identify metabolic pathways that are disrupted in response to mitochondrial insults. A large proportion of this work is based on the generation of stable isotope labelled metabolites to allow for the rigorous quantification of intracellular metabolites by liquid chromatography-mass spectrometry. Once developed, this methodology was employed in cell culture models initially to characterize an unidentified acyl-CoA thioester induced by propionate metabolism. This novel pathway was identified as the direct formation of 2-methyl-2-pentenoyl-CoA, and using isotopic labeling by metabolic precursors served as a critical component to this pathway elucidation. These same techniques were then applied to studying rotenone, a mitochondrial complex I inhibitor associated with Parkinsonâ??s disease. Previous work by our group has shown that rotenone inhibits components of glucose metabolism. As demonstrated in this thesis, lipid oxidation and glutamine anaplerosis serve as important compensatory mechanisms in this setting. Furthermore, chiral analysis of 2-hydroxyglutarate, a metabolite linked to glutamine metabolism, revealed stereospecific alterations in response to rotenone. These previously unknown metabolic adaptations induced by rotenone may contribute to neurological phenotypes resulting from diminished complex I activity. Finally, a collaborative effort was initiated to study metabolic defects in Friedreichâ??s ataxia, a genetic disease suspected to occur, in part, due to deficiencies in mitochondrial complex I. Utilizing isolated platelets in combination with isotopic labeling it was shown that Friedreichâ??s ataxia patients exhibit diminished glucose metabolism with a concomitant increase in lipid oxidation. Taken together these findings suggest adaptations to glucose and lipid metabolism are metabolic characteristics resulting from disrupted mitochondrial function across multiple models, and description of these disruptions gives insight into basic metabolic biotransformation, toxicology, and etiology of poorly understood diseases

Classification of Phthalates According to Their (Q)SAR Predicted Acute Toxicity to Fish: A Case Study.

This report presents the preliminary results from a (Q)SAR investigation of the acute toxicity to fish (fathead minnow) for a dataset of phthalate esters. A chemical set of 341 phthalates was compiled by using different searching engines. Their acute toxicity to fathead minnow was calculated with the ECOSAR and TOPKAT software. A good correlation between the predictions from the two programs was established (r2 = 0.81). The chemicals were classified initially into four groups on a basis of their predicted by ECOSAR LC50 values: 1) no reasons for concern (LC50 > 100 mg/L), 2) harmful (10 mg/L 5). The predictions from TOPKAT (only predictions within the optimum prediction space were considered) correlated relatively well with those from ECOSAR. There were many high molecular weight phthalate esters in the chemical series, which appeared clearly outside the applicability domain of the ECOSAR models. This fact, as well as the understanding that beyond certain limits of hydrophobicity the toxicity of the organic chemicals decreases as a result of reduced bioconcentration, motivated the development of an algorithm for refinement of acute toxicity predictions of the phthalate esters using the bilinear relationship with log Kow. In addition, water solubility limits were considered. Long-term toxicity studies were not considered in this study. Transformation (e.g. biodegradability) of the parent compounds was not considered either. This could potentially be important as, theoretically, the transformation of very hydrophobic chemicals (log Kow > 7) or extremely hydrophobic chemicals (log Kow > 8.0) into more hydrophilic degradation/transformation products may increase the acute toxicity to fish. This case study provides an illustration of how (Q)SAR methods can be used in the development of chemical categories and how (Q)SAR results can be used to perform an initial screening in support of classification and labelling. The results are discussed and interpreted with a view of what constitutes a category, how it can be defined and described, what are its boundaries, and the need to define subcategories that might be useful for deciding on the level of acute toxicological hazard associated with different structural modifications. Due to the preliminary nature of the (Q)SAR models, the results of this study should be regarded as an illustration of the applicability of (Q)SAR methods. The actual model results and rule-based classification scheme will need validation and refinement before they could be considered for regulatory use.JRC.I.3-Toxicology and chemical substance

A Compendium of Case Studies that Helped to Shape the REACH Guidance on Chemical Categories and Read Across

This document pulls together the compendium of case studies that were conducted as part of the REACH project charged with developing technical guidance on the use and formation of chemical grouping approaches (chemical categories/read-across). The lessons and insights from each of these case studies helped to shape the technical content captured in the resulting guidance. The case studies are presented in their original form. They are grouped into two themes for ease of reference: current and prospective experiences in the formation and/or use of category approaches.JRC.I.3-Toxicology and chemical substance

In Silico Prediction of Physicochemical Properties

This report provides a critical review of computational models, and in particular(quantitative) structure-property relationship (QSPR) models, that are available for the prediction of physicochemical properties. The emphasis of the review is on the usefulness of the models for the regulatory assessment of chemicals, particularly for the purposes of the new European legislation for the Registration, Evaluation, Authorisation and Restriction of CHemicals (REACH), which entered into force in the European Union (EU) on 1 June 2007. It is estimated that some 30,000 chemicals will need to be further assessed under REACH. Clearly, the cost of determining the toxicological and ecotoxicological effects, the distribution and fate of 30,000 chemicals would be enormous. However, the legislation makes it clear that testing need not be carried out if adequate data can be obtained through information exchange between manufacturers, from in vitro testing, and from in silico predictions. The effects of a chemical on a living organism or on its distribution in the environment is controlled by the physicochemical properties of the chemical. Important physicochemical properties in this respect are, for example, partition coefficient, aqueous solubility, vapour pressure and dissociation constant. Whilst all of these properties can be measured, it is much quicker and cheaper, and in many cases just as accurate, to calculate them by using dedicated software packages or by using (QSPRs). These in silico approaches are critically reviewed in this report.JRC.I.3-Toxicology and chemical substance

The Use of Chemical Reactivity Assays in Toxicity Prediction

The use of so-called “in chemico” methodology - abiotic assays that measure chemical reactivity - is gaining ground as relevant and reliable means of toxicity prediction. In this report we explain the basis of the in chemico approach to toxicity prediction and we review the studies that have developed the concept and its practical application since the 1930s, with special attention being paid to studies aimed at the development of Quantitative Structure-Activity Relationship (QSAR) models and read-across approaches. The studies covered in this review are limited to non-enzymatic experiments and to nucleophiles up to 50 amino acids. The main applications identified are related to the assessment of skin sensitisation, aquatic toxicity and hepatotoxicity. Various experimental measures of nucleophile depletion or adduct formation have been proposed as chemical reactivity descriptors, but no single protocol has emerged as the most generally useful. It is concluded that in chemico approaches provide a promising means of toxicity prediction within their applicability domains and should be further developed and investigated as alternative methods to animal testing, especially when used in the context of integrated testing strategies based on the use of multiple non-animal methods.JRC.DG.I.6-Systems toxicolog

Analysis of the Cramer classification scheme for oral systemic toxicity - implications for its implementation in Toxtree

In the application of the Threshold of Toxicological Concern (TTC) concept to non-cancer endpoints, the decision tree proposed by Cramer, Ford and Hall in 1978, commonly referred to as the Cramer scheme, is probably the most widely used approach for classifying and ranking chemicals according to their expected level of oral systemic toxicity. The decision tree categorises chemicals, mainly on the basis of chemical structure and reactivity, into three classes indicating a high (Class III), medium (Class II) or low (Class I) level of concern. Each Cramer class is associated with a specified human exposure level, below which chemicals are considered to present a negligible risk to human health. In the absence of experimental hazard data, these exposure threshold (TTC) values have formed the basis of priority setting in the risk assessment process. To facilitate the application of the TTC approach, the original Cramer scheme, and an extended version, have been implemented in Toxtree, a freely available software tool for predicting toxicological effects and mechanisms of action. Building on previous work by Patlewicz and coworkers, this report provides some suggestions for improving the Cramer scheme based on a review of the scientific literature, a survey of Toxtree users, and an analysis of lists of body and food components incorporated in Toxtree.JRC.DG.I.6-Systems toxicolog