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Following the successful batch production of auxetic ultra high molecular weight polythylene, polypropylene and nylon, in the form of 10 mm diameter cylinders, a continuous melt extrusion route was adapted from conventional melt extrusion routes to produce fibres. Previous studies have shown that, once drawing has occured, the auxetic effect is lost and, consequently, the mechanical properties of these fibres range of applications. Research has therefore been undertaken into improving this matter by subjecting the auxetic fibres to a range of different thermal post-production processing conditions. The fibres then underwent mechanical testing. Differential Scanning Calorimetry and Video Extensometry. Results suggest that annealing enhances the mechanical properties of these fibres and may provide a further route to enhancing auxeticity in improving homogeneity by over 40%.

The low velocity impact resistance of auxetic carbon fibre laminates has been compared to that of laminates with matched throught-the-thickness modulus, but with Poisson's ratios of near zero and positive values. Four impact loads corresponding to major events in the static identation response were examined and damage was assessed by ultrasonic C-scans, detailed fractography and measurement of residual properties. It was found that enhancements were seen in resistance to low velocity for the auxetic laminates, but only at low energy levels, indicating some degree of rate dependency.

Excitotoxic lesions of posterior, but not anterior pedunculopontine tegmental nucleus (PPTg) change nicotine self-administration, consistent with the belief that the anterior PPTg (aPPTg) projects to substantia nigra pars compacta (SNC) and posterior PPTg (pPPTg) to the ventral tegmental area (VTA). The VTA is a likely site both of nicotine's reinforcing effect as well as its actions on locomotion. We hypothesized that pPPTg, but not aPPTg lesions, would alter locomotion in response to repeated nicotine administration by virtue of the fact that pPPTg appears to be more closely related to the VTA than is the aPPTg. Following excitotoxic lesions of aPPTg or pPPTg, rats were habituated to experimental procedures. Repeated (seven of each) nicotine (0.4 mg/kg) and saline injections were given following an on-off procedure. Measurement of spontaneous locomotion during habituation showed that aPPTg but not pPPTg lesioned rats were hypoactive relative to controls. Following nicotine, control rats showed locomotor depression for the first 2 days of treatment followed by enhanced locomotion relative to activity following saline treatment. Rats with aPPTg lesions showed a similar pattern, but the pPPTg lesioned rats showed no locomotor depression following nicotine treatment. These data confirm the role of the pPPTg in nicotine's behavioural effects-including the development of sensitization-and demonstrate for the first time that excitotoxic lesions of the aPPTg but not pPPTg generate a deficit in baseline activity. The finding that anterior but not posterior PPTg affects motor activity has significance for developing therapeutic strategies for Parkinsonism using deep brain stimulation aimed here. Publisher PDF

Myelin in the mammalian nervous system has a high concentration of galactolipids [galactosylceramide (GalCer) and sulfatide] with 2-hydroxy fatty acids. We recently reported that fatty acid 2-hydroxylase (FA2H), encoded by the FA2H gene, is the major fatty acid 2-hydroxylase in the mouse brain. In this report, we show that FA2H also plays a major role in the formation of 2-hydroxy galactolipids in the peripheral nervous system. FA2H mRNA and FA2H activity in the neonatal rat sciatic nerve increased rapidly during developmental myelination. The contents of 2-hydroxy fatty acids were approximately 5% of total galactolipid fatty acids at 4 days of age and increased to 60% in GalCer and to 35% in sulfatides at 60 days of age. The chain length of galactolipid fatty acids also increased significantly during myelination. FA2H expression in cultured rat Schwann cells was highly increased in response to dibutyryl cyclic AMP, which stimulates Schwann cell differentiation and upregulates myelin genes, such as UDP-galactose:ceramide galactosyltransferase and protein zero. These observations indicate that FA2H is a myelination-associated gene. FA2H-directed RNA interference (RNAi) by short-hairpin RNA expression resulted in a reduction of cellular 2-hydroxy fatty acids and 2-hydroxy GalCer in D6P2T Schwannoma cells, providing direct evidence that FA2H-dependent fatty acid 2-hydroxylation is required for the formation of 2-hydroxy galactolipids in peripheral nerve myelin. Interestingly, FA2H-directed RNAi enhanced the migration of D6P2T cells, suggesting that, in addition to their structural role in myelin, 2-hydroxy lipids may greatly influence the migratory properties of Schwann cells.

We look at the construction of constant composition codes (CCCs) from various types of partitions in finite projective spaces. In particular, we construct robust classes of codes using regular spreads of PG(2n−1,q) and Baer subgeometry partitions of PG(2n,q2). For each class of codes, we bound the minimum distance by considering how such partitions can intersect. As such, we prove results about the intersection of regular spreads and Baer subgeometry partitions, two of the classical partitions generated by subgroups of a Singer group. In addition, we examine other partitions of objects embedded in finite projective spaces and their associated codes. In each case, we compare our codes to a code of comparable parameters that meets the Plotkin bound.

Auxetic polymeric fibers have been produced using a melt-spinning technique. The effect of the processing parameters on the fibers has been examined. It was found that the auxetic effect occurs over a very tight temperature window with screw speed, take-off speed and die geometry affecting homogeneity and auxeticity. This is an important finding as it provides a method of producing more homogeneous auxetic fibers with tailored values of Poisson’s ratio.

Urotensin II is a neuropeptide first isolated from fish and later found in mammals: where it has potent cardiovascular, endocrine and behavioral effects. In rat brain the urotensin II receptor (UII-R) is predominately expressed in the cholinergic neurons of the pedunculopontine (PPTg) and laterodorsal tegmental nuclei. Typically, the function of the PPTg has been examined using excitotoxins, destroying both cholinergic and non-cholinergic neurons, which confounds interpretation. We took advantage of UII-R's unique expression profile, by combining UII with diphtheria toxin, to engineer a toxin specific for cholinergic neurons of the PPTg. In vitro, two different toxin constructs were shown to selectively activate UII-R (average EC50 approximately 30 nmol/L; calcium mobility assay) and to be 10,000-fold more toxic to UII-R expressing CHO cells, than wildtype cells (average LD50 approximately 2 nmol/L; cell viability). In vivo, pressure injection into the PPTg of rats, resulted in specific loss of choline transporter and NADPH diaphorase positive neurons known to express the UII-R. The lesions developed over time, resulting in the loss of over 80% of cholinergic neurons at 21 days, with little damage to surrounding neurons. This is the first highly selective molecular tool for the depletion of mesopontine cholinergic neurons. The toxin will help to functionally dissect the pedunculopontine and laterodorsal tegmental nuclei, and advance the understanding of the functions of these structures.

A 2D ‘Rough Particle’ model consisting of interlocking hexagons is reported. Analytical expressions for the in-plane Poisson’s ratios and Young’s moduli due to particle translation along the geometrically matched male and female interlocks are derived for the model. The dependency of the mechanical properties on each of the model (geometrical and stiffness) parameters is provided, and it is shown that the assembly of interlocking hexagons deforming by particle translation along the interlocks displays auxetic (negative Poisson’s ratio) behaviour. The model predictions are compared with experimental mechanical properties for auxetic polypropylene (PP) films and fibres. The model predicts the experimental Poisson’s ratio values very well (model: νxy = −1.30, νyx = −0.77; experiment (PP films): ν|| = −1.12, \(\nu_{\bot} = -0.77\)). The model generally overestimates the Young’s moduli of the films, but is in reasonable agreement with the axial Young’s modulus of the fibres.

The current status of research into auxetic (negative Poisson's ratio) materials is reviewed, with particular focus on those aspects of relevance to aerospace engineering. Developments in the modelling, design, manufacturing, testing, and potential applications of auxetic cellular solids, polymers, composites, and sensor/actuator devices are presented. Auxetic cellular solids in the forms of honeycombs and foams are reviewed in terms of their potential in a diverse range of applications, including as core materials in curved sandwich panel composite components, radome applications, directional pass band filters, adaptive and deployable structures, MEMS devices, filters and sieves, seat cushion material, energy absorption components, viscoelastic damping materials, and fastening devices. The review of auxetic polymers includes the fabrication and characterization of microporous polymer solid rods, fibres, and films, as well as progress towards the first synthetic molecular-level auxetic polymer. Potential auxetic polymer applications include self-locking reinforcing fibres in composites, controlled release media, and self-healing films. Auxetic composite laminates and composites containing auxetic constituents are reviewed and enhancements in fracture toughness, and static and low velocity impact performance are presented to demonstrate potential in energy absorber components. Finally, the potential of auxetics as strain amplifiers, piezoelectric devices, and structural health monitoring components is presented.

Microstructural formation in auxetic microporous UHMWPE has been studied in detail using extensive mapping of the microstructure during its processing. To ease sectioning for microstructural examination, a sintering and extrusion route was used. The fibrillar microstructure was found to occur in both the radial and longitudinal directions. Fibril generation was also seen to occur prior to extrusion with enough fibrils of sufficient size to lead to auxetic behaviour. A mechanism for fibril generation is proposed which is based on surface melting of the particles and drawing out of the interparticle contact points by particle movement, which is not necessarily the result of extrusion through a die. These findings will aid in the understanding of processing of auxetic microporous polymers and in the drive to extending the range available to include other polymeric materials and different processing routes.

Protective cell-mediated immune responses in cancer are critically dependent on T-helper type 1 (T(H)1) cytokines such as interferon-gamma (IFN-gamma). We have previously shown that the combination of CD40 stimulation and interleukin-2 (IL-2) leads to synergistic antitumor responses in several models of advanced metastatic disease. We now report that after this treatment and other immunotherapy regimens, the CD4+ T-cell population, in contrast to CD8+ T cells, did not significantly increase but rather exhibited a substantial level of apoptosis that was dependent on IFN-gamma. Mice immunized with tumor cells and treated with an immunotherapy regimen that was initially protective were later unable to mount effective memory responses compared with immunized mice not receiving immunotherapy. Immunotherapy given to tumor-bearing Ifngr-/- mice resulted in restoration of secondary responses. Thus, although immunotherapeutic regimens inducing strong IFN-gamma responses can lead to successful early antitumor efficacy, they may also impair the development of durable antitumor responses.

The variation of through-thickness Poisson's ratio with fibre type and orientation has been investigated using a specially developed Fortran program. Glass fibre/epoxy resin composites were always found to be conventional, but negative Poisson's ratio values of up to v 13 = -0.746 were produced over certain orientation angles for Kevlar and carbon reinforcements. This underlines the need for anisotropic pre-preg material. A range of [±β/±θ] s , angles were investigated for carbon fibre laminates and it was found that auxetic behaviour could be generated for β up to 45°. All the findings of this work have extended the range of laminates which can be engineered to be auxetic either by material (i.e. Kevlar as well as carbon) or by orientation (i.e. by introducing further β layers other than the 0° and 90° previously investigated).

Enabling warfighters to efficiently and safely execute dangerous missions, unmanned systems have been an increasingly valuable component in modern warfare. The evolving use of unmanned systems leads to vast amounts of data collected from sensors placed on the remote vehicles. As a result, many command and control (C2) systems have been developed to provide the necessary tools to perform one of the following functions: controlling the unmanned vehicle or analyzing and processing the sensory data from unmanned vehicles. These C2 systems are often disparate from one another, limiting the ability to optimally distribute data among different users. The Space and Naval Warfare Systems Center Pacific (SSC Pacific) seeks to address this technology gap through the UxV to the Cloud via Widgets project. The overarching intent of this three year effort is to provide three major capabilities: 1) unmanned vehicle control using an open service oriented architecture; 2) data distribution utilizing cloud technologies; 3) a collection of web-based tools enabling analysts to better view and process data. This paper focuses on how the UxV to the Cloud via Widgets system is designed and implemented by leveraging the following technologies: Data Distribution Service (DDS), Accumulo, Hadoop, and Ozone Widget Framework (OWF).

We propose a definition of infrastructure resilience that is tied to the operation (or function) of an infrastructure as a system of interacting components and that can be objectively evaluated using quantitative models. Specifically, for any particular system, we use quantitative models of system operation to represent the decisions of an infrastructure operator who guides the behavior of the system as a whole, even in the presence of disruptions. Modeling infrastructure operation in this way makes it possible to systematically evaluate the consequences associated with the loss of infrastructure components, and leads to a precise notion of "operational resilience" that facilitates model verification, validation, and reproducible results. Using a simple example of a notional infrastructure, we demonstrate how to use these models for (1) assessing the operational resilience of an infrastructure system, (2) identifying critical vulnerabilities that threaten its continued function, and (3) advising policymakers on investments to improve resilience.

2-Hydroxy fatty acids are relatively minor species of membrane lipids found almost exclusively as N-acyl chains of sphingolipids. In mammals, 2-hydroxy sphingolipids are uniquely abundant in myelin galactosylceramide and sulfatide. Despite the well-documented abundance of 2-hydroxy galactolipids in the nervous system, the enzymatic process of the 2-hydroxylation is not fully understood. To fill this gap, we have identified a human fatty acid 2-hydroxylase gene (FA2H) that is highly expressed in brain. In this report, we test the hypothesis that FA2H is the major fatty acid 2-hydroxylase in mouse brain and that free 2-hydroxy fatty acids are formed as precursors of myelin 2-hydroxy galactolipids. The fatty acid compositions of galactolipids in neonatal mouse brain gradually changed during the course of myelination. The relative ratio of 2-hydroxy versus nonhydroxy galactolipids was very low at 2 days of age ( approximately 8% of total galactolipids) and increased 6- to 8-fold by 30 days of age. During this period, free 2-hydroxy fatty acid levels in mouse brain increased 5- to 9-fold, and their composition was reflected in the fatty acids in galactolipids, consistent with a precursor-product relationship. The changes in free 2-hydroxy fatty acid levels coincided with fatty acid 2-hydroxylase activity and with the upregulation of FA2H expression. Furthermore, mouse brain fatty acid 2-hydroxylase activity was inhibited by anti-FA2H antibodies. Together, these data provide evidence that FA2H is the major fatty acid 2-hydroxylase in brain and that 2-hydroxylation of free fatty acids is the first step in the synthesis of 2-hydroxy galactolipids.

Auxetic materials are referred to as those having negative Poisson’s ratio (ν). Initial work at Bolton successfully fabricated auxetic polypropylene fiber using a novel thermal melt-spinning technique. This paper reports in detail both the methods and principles involved in screening polyester powder and also the manufacturing method for successful production of auxetic polyester fibers. Videoextensometry along with micro-tensile testing were used to measure the Poisson’s ratio of the fiber. The Poisson’s ratio of the polyester fiber was found to vary between -0.65 and -0.75.

The use of DNA markers to evaluate genetic diversity is an important component of the management of animal genetic resources. The Food and Agriculture Organisation of the United Nations (FAO) has published a list of recommended microsatellite markers for such studies; however, other markers are potential alternatives. This paper describes results obtained with a set of amplified fragment length polymorphism (AFLP) markers as part of a genetic diversity study of European pig breeds that also utilized microsatellite markers. Data from 148 AFLP markers genotyped across samples from 58 European and one Chinese breed were analysed. The results were compared with previous analyses of data from 50 microsatellite markers genotyped on the same animals. The AFLP markers had an average within-breed heterozygosity of 0.124 but there was wide variation, with individual markers being monomorphic in 3-98% of the populations. The biallelic and dominant nature of AFLP markers creates a challenge for their use in genetic diversity studies as each individual marker contains limited information and AFLPs only provide indirect estimates of the allelic frequencies that are needed to estimate genetic distances. Nonetheless, AFLP marker-based characterization of genetic distances was consistent with expectations based on breed and regional distributions and produced a similar pattern to that obtained with microsatellites. Thus, data from AFLP markers can be combined with microsatellite data for measuring genetic diversity.

Primary objective: To investigate the relationship between performance on the Useful Field of View Test (UFOV) and driving performance following traumatic brain injury (TBI).Participants: Sixty people with TBI referred for driving evaluation.Measures: Useful Field of View Test, Global Rating Scale and Driver Assessment Scale.Results: Subject performance diminished as the complexity of the UFOV sub-tests increased. There was a significant relationship between UFOV performance, particularly on the second sub-test, and on-road driving performance. Subject age and Trail Making Test, Part B were also predictive of driving performance.Conclusions: The UFOV can be used as a screening measure to determine readiness to participate in an on-road driving assessment.

Force field based simulations have been employed to model the structure, and mechanical and mass transport properties of the all-silica zeolite MFI (ZSM5—Si96O192). Undeformed and deformed MFI subject to uniaxial loading in each of the three principal directions were investigated. The mechanical properties are predicted to include negative on-axis Poisson's ratios (auxetic behaviour) in the x 1–x 3 plane of the undeformed structure, and are strain-dependent. Transformation from positive-to-negative Poisson's ratio behaviour, and vice versa, is predicted for most on-axis Poisson's ratios at critical loading strains. Simulations of the simultaneous sorption of neopentane and benzene guest molecules onto the undeformed host MFI framework indicate a low neopentane-to-benzene loading ratio, consistent with experimental observation. The sorption of these two molecular species onto deformed MFI is Poisson's ratio- and strain-dependent. Uniaxial tensile loading along a direction containing a negative on-axis Pois...

Force field-based simulations have been employed to model the mechanical properties of a range of undeformed molecular polymeric honeycombs having conventional and re-entrant hexagon pores. The conventional and re-entrant hexagon honeycombs are predicted to display positive and negative in-plane Poisson's ratios, respectively, confirming previous simulations. The structure, and mechanical and mass transport properties of a layered re-entrant honeycomb ((2,8)-reflexyne) were studied in detail for a uniaxial load applied along the x 2 direction. The mechanical properties are predicted to be stress- (strain-) dependent and the trends can be interpreted using analytical expressions from honeycomb theory. Transformation from negative to positive Poisson's ratio behaviour is predicted at an applied stress of σ2 = 2 GPa. Simulations of the loading of C60 and C70 guest molecules into the deformed layered (2,8)-reflexyne host framework demonstrate the potential for tunable size selectivity within the host framewor...

A novel route for production of auxetic fibres has been adapted from conventional melt extrusion techniques. These fibres were reproduced, characterised and tested, for the first time, to assess the potential of auxetic fibres as reinforcements in composite materials. Initial experimental work has included the embedding of single fibres in modified epoxy resin. Auxetic fibre specimens were then compared with conventional fibre specimens through a specially designed fibre pullout testing procedure. The auxetic specimens displayed superior anchoring properties. The average maximum force at de-bonding of the auxetic fibres (0.95 N) was observed to be over 100% higher than that for conventional ones (0.44 N) and the average energy required to fully extract the auxetic fibre from the modified resin was 8.3 mJ while the conventional fibre required only 2.5 mJ on average. The results indicate that composites employing auxetic fibres as the reinforcement phase will exhibit enhanced resistance to failure due to fibre pullout.

A q-ary (n, k)-MDS code, linear or not, satisfies n ≤ q + k − 1. A code meeting this bound is said to have maximum length. Using purely combinatorial methods we show that an MDS code with n = q + k − 2 can be uniquely extended to a maximum length code if and only if q is even. This result is best possible in the sense that there is, for example, a non-extendable 4-ary (5, 4)-MDS code. It may be that the proof of our result is as interesting as the result itself. We provide a simple necessary and sufficient condition $$\left( {{\text{property }}\mathcal{P}} \right)$$ for code extendability. In future work, this condition might be suitably modified to give an extendability condition for arbitrary (shorter) MDS codes.

Chemical modification of proteins by advanced glycation and lipoxidation end products is implicated in the pathogenesis of macrovascular disease in aging and diabetes. To identify biomarkers of the lipoxidative modification of protein, we studied the oxidation of phospholipids in the presence of the model protein RNase A and compared protein-bound products formed in these reactions with those formed during oxidation of plasma proteins. Metal-catalyzed oxidation of 1-palmitoyl-2-arachidonoyl-phosphatidylcholine or 1-palmitoyl-2-linoleoyl-phosphatidylcholine in the presence of RNase led to the loss of amino groups in RNase and the incorporation of phosphate, hexanoate, pentanedioate, nonanedioate, and palmitate into protein. Protein-bound palmitate and phosphate correlated strongly with one another, and protein-bound pentanedioate and nonanedioate, derived from arachidonate and linoleate, respectively, accounted for approximately 20% of the cross-linking of lipid phosphorus to protein. Similar results were obtained on oxidation of total plasma or isolated LDL. We conclude that alkanedioic acids are quantitatively important linkers of oxidized phospholipids to proteins and that measurement of protein-bound phosphate and long-chain fatty acids may be useful for assessing long-term lipid peroxidative damage to proteins in vivo. Analyses of plasma proteins from control and diabetic patients indicated significant increases in lipoxidative modification of protein in diabetic compared with control subjects.

Analytical and Molecular Mechanics methods have been used to study the structure and deformation mechanisms acting at the molecular level in the auxetic polymorph of crystalline silica (a-cristobalite). The Molecular Mechanics simulations indicate a stress-induced phase transition from α-cristobalite to 'ordered' β-cristobalite occurs for uniaxial loading along the x 3 direction. This is in reasonable agreement with the previous prediction from an analytical model assuming deformation is by concurrent dilation and cooperative rotation (about axes in the x 1 -x 2 plane, passing through the midpoints of opposing edges - the a-axes) of the SiO 4 tetrahedral molecular sub-units, previously shown to predict the Poisson's ratio for loading in the x 3 direction. The analytical models have been extended to include cooperative rotation of each tetrahedron about its axis (the c-axis) mostly closely aligned with the principal unit-cell x 3 -axis. The new models enable significantly improved prediction of the Poisson's ratios of α-cristobalite when loaded in one of the transverse (x 1 or x 2 ) directions. Parametric fitting of the analytical models indicate that the deformation mechanism for transverse uniaxial loading of α-cristobalite is by concurrent dilation and cooperative rotation about the local a and c-axes of the SiO 4 tetrahedra.

One method for producing synthetic auxetic materials is starting with polymer powders and using a combination of compaction, sintering, and extrusion. This article presents a novel variation on this route, omitting the extrusion stage and generating the required microstructure by compaction followed by multiple sintering. The effects of single, double, and quadruple sintering on compacted cylinders are examined in terms of a detailed microstructural examination, study of density and dimensional variations, and measurement of Poisson's ratio. The best results were obtained by compaction followed by double sintering, resulting in a strain dependent Poisson's ratio as low as ν = −0.32. This new technique has great potential for increasing the range of geometries that can be fabricated and is very akin to ceramic sintering techniques. POLYM. ENG. SCI., 45:568–578, 2005. © 2005 Society of Plastics Engineers

Analytical and Molecular Mechanics methods have been used to study the deformation mechanisms acting at the molecular level in the auxetic polymorph of crystalline silica (a-cristobalite). The analytical models indicate that a-cristobalite deforms by concurrent tetrahedral dilation and cooperative rotation when stretched along the x3 axis, and that a second phase is predicted to exist for this loading scenario, having a geometry similar to that of ‘idealised’ b-cristobalite. This is supported by preliminary Molecular Mechanics simulations, which also indicate that the cooperative rotation predicted for loading along x3 is not sufficient to describe the deformation mechanism for loading along x1. A negative hydrostatic pressure offset is observed to lead to a change in the sign of the predicted Poisson’s ratio from positive to negative, leading to improved agreement of the Molecular Mechanics model with experiment.

Comprehensive experimental study on materials fabrication and characterisation with a detailed discussion of properties and underlying mechanisms.

Aims/hypothesis. The accumulation of AGE is thought to play a role in the pathogenesis of chronic complications of diabetes mellitus and renal failure. All current measurements of AGE accumulation require invasive sampling. We exploited the fact that several AGE exhibit autofluorescence to develop a non-invasive tool for measuring skin AGE accumulation, the Autofluorescence Reader (AFR). We validated its use by comparing the values obtained using the AFR with the AGE content measured in extracts from skin biopsies of diabetic and control subjects.Methods. Using the AFR with an excitation light source of 300-420 nm, fluorescence of the skin was measured at the arm and lower leg in 46 patients with diabetes (Type 1 and 2) and in 46 age- and sex-matched control subjects, the majority of whom were Caucasian. Autofluorescence was defined as the average fluorescence per nm over the entire emission spectrum (420-600 nm) as ratio of the average fluorescence per nm over the 300-420-nm range. Skin biopsies were obtained from the same site of the arm, and analysed for collagen-linked fluorescence (CLF) and specific AGE: pentosidine, N-epsilon-(carboxymethyl)lysine (CML) and N-epsilon-(carboxyethyl)lysine (CEL).Results. Autofluorescence correlated with CLF, pentosidine, CML, and CEL (r=0.47-0.62, pless than or equal to0.002). In 32 of 46 diabetic patients (70%), autofluorescence values were above the 95% CI of the mean value in control subjects, and correlated with age, diabetes duration, mean HbA(1)c of the previous year and creatinine levels.Conclusions/interpretation. The AFR offers a simple alternative to invasive measurement of AGE accumulation and, to date, has been validated in non-pigmented skin. The AFR may prove to be a useful clinical tool for rapid risk assessment of AGE-related long-term complications in diabetes mellitus and in other conditions associated with AGE accumulation.

Levels of glycation (fructose-lysine, FL) and advanced glycoxidation and lipoxidation end-products (AGE/ALEs) were measured in total skeletal (gastrocnemius) muscle and myofibril protein and compared to levels of the same compounds in insoluble skin collagen of control and diabetic rats. Levels of FL in total muscle and myofibril protein were 3-5% the level of FL in skin collagen. The AGE/ALEs, N(epsilon)-(carboxymethyl)lysine (CML) and N(epsilon)-(carboxyethyl)lysine, were also significantly lower in total muscle and myofibril protein, approximately 25% of levels in skin collagen. The newly described sulfhydryl AGE/ALE, S-(carboxymethyl)cysteine (CMC), was also measured in muscle; levels of CMC were comparable to those of CML and increased similarly in response to diabetes. Although FL and AGE/ALEs increased in muscle protein in diabetes, the relative increase was less than that seen in skin collagen. These data indicate that muscle protein is partially protected against the increase in both glycation and AGE/ALE formation in diabetes.

Either an in-plane or out-of-plane negative Poisson’s ratio,, in continuous carbon fibre/epoxy resin composites can be achieved, providing the fibre volume fraction and anisotropy are high enough, by selecting suitable stacking sequences. This paper examines the use of specially designed software which allows the designer to match the mechanical properties of laminates with predicted negative to those with similar mechanical properties but positive. This has allowed auxetic and matched carbon fibre/epoxy resin laminates to be specifically designed. These laminates were then fabricated and tested, with good agreement found to theoretical predictions. This study, then, provides a route to evaluating the effect of a negative alone on properties such as fracture toughness and impact resistance.

The pedunculopontine tegmental nucleus (PPTg) has long been suggested to have a role in reward-related behaviour, and there is particular interest in its possible role in drug reward systems. Previous work found increased i.v. self-administration (IVSA) of d-amphetamine following PPTg lesions when training had included both operant pre-training and priming injections. The present study examined the effect of excitotoxin lesions of the PPTg on d-amphetamine IVSA under three training conditions. Naive: no previous experience of d-amphetamine or operant responding. Pre-trained: given operant training with food before lesion surgery took place. Primed: given single non-contingent d-amphetamine infusion (0.1 mg/0.l ml) at the start of each session. Rats in all conditions were given either ibotenate or phosphate buffer control lesions of the PPTg before d-amphetamine (0.1 mg/0.1 ml infusion) IVSA training took place. Rats received eight sessions of training under a fixed ratio (FR2) schedule of d-amphetamine IVSA, followed by four sessions under a progressive ratio (PR5) schedule. In the naive condition, PPTg-lesioned rats were attenuated in their responding under FR2, and took significantly fewer infusions under PR5 than the control group. Under FR2 in the pre-trained condition, there was no difference between PPTg excitotoxin and control lesioned rats; however, PPTg-lesioned rats took significantly fewer infusions under the PR5 schedule. In the primed condition, there were no differences between PPTg-lesioned and control rats under either FR2 or PR5 schedules. These data demonstrate that operant training prior to PPTg lesion surgery corrects some, but not all, of the deficits seen in the naive condition. PPTg-lesioned rats in both naive and pre-trained conditions showed reduced responding for d-amphetamine under a PR5 schedule. These deficits are overcome by priming with d-amphetamine. We suggest that alterations in striatal dopamine activity following PPTg lesions underlie these effects.

Hyperglycaemia is the major risk factor for the development of complications in both Type I and Type II diabetes; however, there is growing evidence from several clinical trials that dyslipidaemia, including hypertriglyceridaemia, is a significant and independent risk factor for diabetic complications. In this paper, we propose that chemical modification of proteins by lipids may be a underlying pathogenic mechanism linking dyslipidaemia to diabetic complications. Thus the major AGEs (advanced glycation end-products) in tissues, such as carboxymethyl-lysine, carboxyethyl-lysine and hydroimidazolones, may, in fact, be ALEs (advanced lipoxidation end-products), derived from lipids. Increased lipid peroxidation and accelerated ALE formation, possibly catalysed by hyperglycaemia and oxidative stress, may be the mechanistic link between dyslipidaemia and diabetic complications. If correct, this proposal would suggest that inhibition or reversal of glycation, which is a central theme of this symposium, may not be sufficient for protection against diabetic complications.

Pyridoxamine (PM), originally described as a post-Amadori inhibitor of formation of advanced glycation end-products (AGEs), also inhibits the formation of advanced lipoxidation end-products (ALEs) on protein during lipid peroxidation reactions. In addition to inhibition of AGE/ALE formation, PM has a strong lipid-lowering effect in streptozotocin (STZ)-induced diabetic and Zucker obese rats, and protects against the development of nephropathy in both animal models. PM also inhibits the development of retinopathy and neuropathy in the STZ-diabetic rat. Several products of reaction of PM with intermediates in lipid autoxidation have been identified in model reactions in vitro and in the urine of diabetic and obese rats, confirming the action of PM as an AGE/ ALE inhibitor. PM appears to act by a mechanism analogous to that of AGE-breakers, by reaction with dicarbonyl intermediates in AGE/ALE formation. This review summarizes current knowledge on the mechanism of formation of AGE/ALEs, proposes a mechanism of action of PM, and summarizes the results of animal model studies on the use of PM for inhibiting AGE/ALE formation and development of complications of diabetes and hyperlipidemia.

Maillard or browning reactions between reducing sugars and protein lead to formation of advanced glycation end products (AGEs) and are thought to contribute to the pathogenesis of diabetic complications. AGE inhibitors such as aminoguanidine and pyridoxamine (PM) inhibit both the formation of AGEs and development of complications in animal models of diabetes. PM also inhibits the chemical modification of protein by advanced lipoxidation end products (ALEs) during lipid peroxidation reactions in vitro. We show here that several PM adducts, formed in incubations of PM with linoleate and arachidonate in vitro, are also excreted in the urine of PM-treated animals. The PM adducts N-nonanedioyl-PM (derived from linoleate), N-pentanedioyl-PM, N-pyrrolo-PM, and N-(2-formyl)-pyrrolo-PM (derived from arachidonate), and N-formyl-PM and N-hexanoyl-PM (derived from both fatty acids) were quantified by liquid chromatography-mass spectrometry analysis of rat urine. Levels of these adducts were increased 5-10-fold in the urine of PM-treated diabetic and hyperlipidemic rats, compared with control animals. We conclude that the PM functions, at least in part, by trapping intermediates in AGE/ALE formation and propose a mechanism for PM inhibition of AGE/ALE formation involving cleavage of alpha-dicarbonyl intermediates in glycoxidation and lipoxidation reactions. We also conclude that ALEs derived from polyunsaturated fatty acids are increased in diabetes and hyperlipidemia and may contribute to development of long term renal and vascular pathology in these diseases.

The AGE inhibitor pyridoxamine inhibits lipemia and development of vascular and renal disease in Zucker obese rats. Background In previous studies, pyridoxamine (PM) limited the formation of advanced glycation end products (AGEs) and development of nephropathy in streptozotocin-diabetic rats without affecting glycemic control. However, the lipid-lowering effects of PM and the correlation of plasma cholesterol and triglycerides with AGEs in skin collagen suggested that lipids might be an important source of AGEs in the diabetic rat. This study addresses the effects of hyperlipidemia on formation of advanced glycation and lipoxidation end products (AGE/ALEs) and the effects of PM on hyperlipidemia, hypertension, AGE/ALE formation, and development of nephropathy in the nondiabetic, Zucker obese rat. Methods Three groups of Zucker rats were studied: lean (Fa/ fa ), untreated fatty ( fa/fa ), and fa/fa treated with PM (2 g/L drinking water). Blood pressure, plasma lipids and creatinine, and urinary albumin were measured monthly. AGE/ALEs were measured in skin collagen by high-performance liquid chromatography (HPLC) and gas chromatography/mass spectrometry (GC/MS). Changes in wall thickness of the aorta and renal arterioles were evaluated by light microscopy. Results AGE/ALEs formation was increased two- to threefold in skin collagen of obese versus lean rats. PM inhibited the increases in AGE/ALEs in collagen, and significantly decreased the rise in plasma triglycerides, cholesterol, and creatinine, corrected hypertension and thickening of the vascular wall, and nearly normalized urinary protein and albumin excretion in Zucker fa/fa rats. Conclusion Lipids are an important source of chemical modification of tissue proteins, even in the absence of hyperglycemia. PM inhibited AGE/ALE formation and hyperlipidemia and protected against renal and vascular pathology in a nondiabetic model.

Alderson AL, Novack TA. Reliable serial measurement of cognitive processes in rehabilitation: the Cognitive Log. Arch Phys Med Rehabil 2003;84:668-72. Objective: To evaluate the reliability and utility of a brief quantitative measure of cognitive recovery, the Cognitive Log (Cog-Log), developed for daily use with rehabilitation inpatients to provide information about the recovery of higher neurocognitive processes including verbal recall, attention, working memory, motor sequencing, and response inhibition. Design: Descriptive study of the Cog-Log's normative scores, reliability (interrater, internal consistency), and validity as shown by its relationship to standard neuropsychologic measures. Setting: Inpatient rehabilitation hospital affiliated with a large university medical center. Participants: One hundred fifty neurorehabilitation inpatients with acquired brain injury; 83 young adults without acquired brain injury were included to provide normative data. Interventions: Not applicable. Main Outcome Measures: The Cog-Log; standardized neuropsychologic measures of memory (Wechsler Memory Scale-Revised, Rey Auditory Verbal Learning Test), language, attention (Wechsler Adult Intelligence Scale-Revised), and reasoning (Trail Making Test). Results: Reliability analysis showed strong interrater reliability across items (Spearman r , .749–1.00) and high internal consistency (Cronbach α=.778). Factor analysis of the Cog-Log using principal components extraction revealed a unitary factor (eigenvalue=3.48). Cog-Log items designed to measure working memory and immediate and delayed verbal memory were most strongly predictive of performance on similar standardized neuropsychologic measures administered on the same day. Conclusion: The Cog-Log appears to be a reliable and efficient tool for measuring ongoing neurocognitive recovery during inpatient rehabilitation.

The pedunculopontine tegmental nucleus (PPTg) interacts with anatomical systems thought to be involved in mediating sensitisation of the locomotor response to repeated d-amphetamine. The PPTg has direct and indirect connections with the nucleus accumbens and prefrontal cortex, and also influences midbrain dopamine activity through direct projections to substantia nigra and ventral tegmental area. In this experiment, the development of behavioural sensitisation to the locomotor stimulant effects of repeated d-amphetamine was examined in rats bearing excitotoxic lesions of the PPTg, and sham-lesioned controls. Rats were given repeated d-amphetamine (1.5 mg/kg i.p.) treatment in an on–off procedure, with saline and d-amphetamine given on alternate days, such that rats received a total of seven d-amphetamine and seven saline treatments. Locomotor responses were measured in photocell cages. On the first day of d-amphetamine treatment, there was no difference between excitotoxin and sham-lesioned rats. Development of sensitisation to the locomotor stimulant effects of d-amphetamine was delayed in PPTg-lesioned rats, relative to the sham-lesioned control rats. However, there was no difference between lesion and control groups in the locomotion seen on saline-treatment days. These data suggest that the PPTg is involved in the development of behavioural sensitisation to the locomotor stimulant effects of repeated d-amphetamine, and indicate that traditional striatal circuitry models of the mechanisms underlying sensitisation should be extended to include the PPTg.

Advanced glycosylation end-products (AGEs) are believed to play a significant role in the development of vascular complications in diabetic patients. One such product, AGE-LDL, has been shown to be immunogenic. In this report, we describe the isolation and characterization of human AGE-LDL antibodies from the sera of seven patients with Type 1 diabetes by affinity chromatography using an immobilized AGE-LDL preparation that contained primarily the AGE N epsilon (carboxymethyl)lysine (CML, 14.6 mmol/mol lysine), and smaller amounts of N epsilon (carboxyethyl)lysine (CEL, 2.7 mmol/mol lysine). The isolated antibodies were predominantly IgG of subclasses 1 and 3, and considered proinflammatory because of their ability to promote Fc gamma R-mediated phagocytosis and to activate complement. We determined dissociation constants (Kd) for the purified antibodies. The average Kd values (4.76 +/- 2.52 x 10(-9) mol/l) indicated that AGE-LDL antibodies are of higher avidity than oxidized LDL antibodies measured previously (Kd = 1.53 +/- 07 x 10(-8) ml/l), but of lower avidity than rabbit polyclonal LDL antibodies (Kd = 9.34 x 10(-11)). Analysis of the apolipoprotein B-rich lipoproteins isolated with polyethylene glycol-precipitated antigen-antibody complexes from the same patients showed the presence of both CML and CEL, thus confirming that these two modifications are recognized by human autoantibodies. A comparative study of the reactivity of purified AGE-LDL antibodies with CML-LDL and CML-serum albumin showed no cross-reactivity.

The purpose of this study was to examine the effect of prolonged exercise on plasma lipid and lipoprotein concentrations and to identify caloric time-points where changes occurred. Eleven active male subjects ran on a treadmill at 70% of maximal fitness (VO2max) and expended 6278.7 kilojoules (Kj) energy (1500 kcal). Blood samples were obtained at the 4185.8 Kj (1000 kcal) timepoint during exercise and at each additional 418.6 Kj (100 kcal) expenditure until 6278.7 Kj was expended. After correcting for plasma volume changes, decreases in low-density lipoprotein cholesterol (LDL-C) were observed during exercise at time-points corresponding to 4604.4 and 5441.5 Kj (1100 and 1300 kcal) of energy expenditure, and immediately after exercise. Total cholesterol concentrations decreased significantly at exercise kilojoule expenditures of 4604.4, 5441.5 and 5860.1 (1100, 1300 and 1400 kcal). There were also exercise induced increases in high-density lipoprotein cholesterol (HDL-C) and HDL2-C concentrations immediately after exercise. Although acute lipid and lipoprotein changes are typically reported in the days following exercise, the current data indicate that some lipoprotein concentrations change during acute exercise. Our data suggest that a threshold of exercise may be necessary to change lipoproteins during exercise. Future work should identify potential mechanisms (lipoprotein lipase, cholesterol ester transport protein, LDL uptake) that alter lipoprotein concentrations during prolonged exercise.

Wireless mesh networks (WMNs) are interconnected systems of wireless access points (APs) that provide untethered network connectivity for a group of users who require data, voice, and/or video communication. The wireless access medium of a WMN makes it particularly vulnerable to attack and exploitation. We seek a method for quickly designing WMN physical topologies (i.e., the placement of APs) that are robust to the effects of electromagnetic jamming. The conflicting interests of a network designer and attacker in respectively maximizing and minimizing network performance make this problem a natural candidate for the use of game theory. We apply the game theoretic defender-attacker-defender (DAD) methodology to the simultaneous routing, resource allocation, and coverage (SRRA+C) model of WMN performance to simulate the design, attack, and operation of a WMN. Our algorithm and associated decision-support tool can quickly prescribe jamming-robust WMN topologies that minimize the worst possible damage that an adversary can inflict. Our approach considers radio-operating characteristics, the relative importance of client coverage and network flow, and the effects of radio propagation over terrain. To our knowledge, we are the first to use an algorithm with proven global convergence to design jamming-robust WMNs, and the first to apply the DAD framework to the problem of WMN design.

Developing robust, quantitative methods to optimize resource allocations in response to epidemics has the potential to save lives and minimize health care costs. In this paper, we develop and apply a computationally efficient algorithm that enables us to calculate the complete probability distribution for the final epidemic size in a stochastic Susceptible-Infected-Recovered (SIR) model. Based on these results, we determine the optimal allocations of a limited quantity of vaccine between two non-interacting populations. We compare the stochastic solution to results obtained for the traditional, deterministic SIR model. For intermediate quantities of vaccine, the deterministic model is a poor estimate of the optimal strategy for the more realistic, stochastic case., Comment: 21 pages, 7 figures

Total pressure measurements are reported for the binary mixtures of 2-ethoxyethanol with methyl acetate, ethyl acetate, propyl acetate, and ethyl propionate at 313.15 K and for 2-ethoxyethanol with methyl formate at 308.15 K. The data were obtained using a Van Ness type apparatus and were fitted to the modified Margules equation (or one of its simplified cases) using Barker's method. All mixtures show positive deviations from ideality and are represented by the model to within an average absolute deviation of approximately 0.06 kPa.

We hypothesized that the beneficial effects of a variety of pharmacological agents on the progression of diabetic complications were mediated by a common pathway limiting the formation of advanced glycation and advanced lipoxidation end products (AGEs/ALEs) on protein. We studied the effects of the AGE/ALE inhibitor pyridoxamine (PM), the antioxidant vitamin E (VE) and the ACE inhibitor enalapril (EP) on the development of nephropathy and retinopathy in STZ-induced diabetic rats over 29 weeks. Blood glucose and glycohemoglobin were similar in all diabetic groups. Plasma lipids rose continuously in diabetic animals and only PM significantly attenuated this increase. Early nephropathy was indicated by increased plasma creatinine, and urinary albumin, protein and TGF-β excretion in untreated rats. While all interventions limited renal damage to some extent, PM was the most effective, although the increased expression of renal laminin β1 and fibronectin mRNA was normalized by all therapies. Measurement of retinal damage (acellular capillaries, vascular basement membrane-associated laminin) showed that only PM significantly limited signs of early retinopathy in diabetic rats. Only PM limited the increases in the AGE/ALEs in renal and retinal tissue, and in skin collagen, of diabetic rats. Our results suggest that limiting both dyslipidemia and AGE/ALE formation is required for maximum protection of renal and retinal function in the STZ-diabetic rat.

The term 'auxetic' is applied to materials that possess a negative Poisson's ratio ν. The use of auxetic polymers has been limited because of problems with deploying them in their fabricated forms, i.e. as 10 mm diameter cylinders. This paper reports the successful development of a processing route to produce a more useful and usable form of auxetic polymeric material, namely fibres. A conventional polymer processing technique (melt spinning) is the basis of this technique, with novel modifications. Video extensometry was used to measure the Poisson's ratio and a value of ν = -0.60±0.05 was obtained.

We examined the ability of pyridoxamine (PM), an inhibitor of formation of advanced glycation end products (AGEs) and lipoxidation end products (ALEs), to protect against diabetes-induced retinal vascular lesions. The effects of PM were compared with the antioxidants vitamin E (VE) and R-alpha-lipoic acid (LA) in streptozotocin-induced diabetic rats. Animals were given either PM (1 g/l drinking water), VE (2,000 IU/kg diet), or LA (0.05%/kg diet). After 29 weeks of diabetes, retinas were examined for pathogenic changes, alterations in extracellular matrix (ECM) gene expression, and accumulation of the immunoreactive AGE/ALE N( epsilon )-(carboxymethyl)lysine (CML). Acellular capillaries were increased more than threefold, accompanied by significant upregulation of laminin immunoreactivity in the retinal microvasculature. Diabetes also increased mRNA expression for fibronectin (2-fold), collagen IV (1.6-fold), and laminin beta chain (2.6-fold) in untreated diabetic rats compared with nondiabetic rats. PM treatment protected against capillary drop-out and limited laminin protein upregulation and ECM mRNA expression and the increase in CML in the retinal vasculature. VE and LA failed to protect against retinal capillary closure and had inconsistent effects on diabetes-related upregulation of ECM mRNAs. These results indicate that the AGE/ALE inhibitor PM protected against a range of pathological changes in the diabetic retina and may be useful for treating diabetic retinopathy.

Purpose: Most studies that use either a single exercise session, exercise training, or a cross-sectional design have failed to find a relationship between exercise and plasma lipoprotein(a) [Lp(a)] concentrations. However, a few studies investigating the effects of longer and/or more strenuous exercise have shown elevated Lp(a) concentrations, possibly as an acute-phase reactant to muscle damage. Based on the assumption that greater muscle damage would occur with exercise of longer duration, the purpose of the present study was to determine whether exercise of longer duration would increase Lp(a) concentration and creatine kinase. (CK) activity more than exercise of shorter duration. Methods: Ten endurance-trained men (mean +/- SD: age, 27 +/- 6 yr; maximal oxygen consumption [(V)over dotO(2max)], 57 +/- 7 mL(.)kg(-1) min(-1)) completed two separate exercise sessions at 70% (V)over dotO(2max). One session required 900 kcal of energy expenditure (60 +/- 6 min), and the other required 1500 kcal (112 +/- 12 min). Fasted blood samples were taken immediately before (0-pre), immediately after (0-post), 1 d after (1-post), and 2 d after (2-post) each exercise session. Results: CK activity increased after both exercise sessions (mean +/- SE; 800 kcal: 0-pre 55 +/- 11, 1-post 168 +/- 64 U(.)L(-1.)min(-1); 1500 kcal: 0-pre 51 +/- 5, 1-post 187 +/- 30, 2-post 123 +/- 19 U(.)L(-1.)min(-1); P < 0.05). However, median Lp(a) concentrations were not altered by either exercise session (800 kcal: 0-pre 5.0 mg(.)dL(-1), 0-post 3.2 mg(.)dL(-1), 1-post 4.0 mg(.)dL(-1), 2-post 3.4 mg(.)dL(-1); 1500 kcal: 0-pre 5.8 mg(.)dL(-1), 0-post 4.3 mg(.)dL(-1), 1-post 3.2 mg(.)dL(-1), 2-post 5.3 mg(.)dL(-1)). In addition, no relationship existed between exercise-induced changes in CK activity and Lp(a) concentration (800 kcal: r = -0.26; 1500 kcal: r = -0.02). Conclusion: These results suggest that plasma Lp(a) concentration will not increase in response to minor exercise-induced muscle damage in endurance-trained runners.

SummaryRare Breeds International (RBI) is the global non-governmental organization (NGO) concerned with the conservation of animal genetic resources (AnGR). It works in conjunction with FAO and with other organizations associated with livestock production. RBI members form a grassroots network that is rich in experience and knowledge of native breeds and affiliated national organizations maintain a valuable database of AnGR. Information is disseminated through major international conferences which are held at intervals of three years and through annual regional meetings. The cumulative expertise of the RBI membership facilitates a wide variety of projects, which range from policy interaction with governmental agencies to emergency rescue action and breeding programmes for relic breeds. RBI communicates mainly through publication of proceedings of major conferences and also by dedicated and linked websites.

Rationale: Second-order schedules of heroin self-administration provide a method of measuring heroin-seeking behaviour independently of the effects of the drug on motor behaviour and of investigating the role of heroin-associated stimuli in such heroin-seeking behaviour. Objectives: These experiments aimed to establish a second-order schedule of heroin self-administration in rats, similar to that already established in this laboratory for cocaine self-administration and to investigate the role of discrete heroin-associated stimuli in the maintenance of heroin-seeking behaviour under a second-order schedule of reinforcement. Methods: Heroin i.v. self-administration (0.04 mg/infusion) was initially contingent upon a lever press, and each infusion was paired with presentation of a 20-s light-conditioned stimulus (CS). Following acquisition of heroin self-administration, the response requirement was progressively increased so that, ultimately, responding was maintained under a fixed interval (FI) 15 min [fixed ratio (FR)5:S] second-order schedule. The effects of varying the dose of heroin (0.01 mg and 0.08 mg/infusion) and pre-treatment with the µ-opiate receptor antagonist, naloxone, on responding under a FI15(FR5:S) schedule were investigated. In addition, the role of the heroin-associated CS on responding was assessed by measuring the effects of omitting the CS during heroin-seeking behaviour and during extinction of responding, as well as the effect of CS presentation on the reinstatement of heroin-seeking behaviour following extinction. Results: A second-order schedule of heroin self-administration was established. There were no clear effects on heroin-seeking behaviour of increasing or decreasing the dose of heroin. Although no effect of naloxone pre-treatment was seen on heroin-seeking behaviour during the first, drug-free interval of responding, an extinction-like pattern of responding was seen in that interval during subsequent sessions. Omission of the light CS resulted in a reduction in levels of responding for i.v. heroin, indicating its role in maintaining heroin-seeking behaviour. However, under extinction conditions, response-contingent CS presentations did not affect the rate of extinction, nor did non-contingent presentations of the CS following extinction reinstate heroin-seeking behaviour. Conclusions: These experiments have established a method of measuring heroin-seeking behaviour in rats by adopting a second-order schedule of i.v. heroin self-administration. The results indicate a relatively weak impact of discrete, heroin-associated cues on heroin-seeking behaviour relative to cocaine-seeking behaviour studied under similar conditions.