Superoxide dismutase mimics: chemistry, pharmacology, and therapeutic potential.

Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia-reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO(3)(*-), peroxyl radical, and less efficiently H(2)O(2). By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and/or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds.

Diet-induced obesity alters the differentiation potential of stem cells isolated from bone marrow, adipose tissue and infrapatellar fat pad: the effects of free fatty acids.

INTRODUCTION: Obesity is a major risk factor for several musculoskeletal conditions that are characterized by an imbalance of tissue remodeling. Adult stem cells are closely associated with the remodeling and potential repair of several mesodermally derived tissues such as fat, bone and cartilage. We hypothesized that obesity would alter the frequency, proliferation, multipotency and immunophenotype of adult stem cells from a variety of tissues. MATERIALS AND METHODS: Bone marrow-derived mesenchymal stem cells (MSCs), subcutaneous adipose-derived stem cells (sqASCs) and infrapatellar fat pad-derived stem cells (IFP cells) were isolated from lean and high-fat diet-induced obese mice, and their cellular properties were examined. To test the hypothesis that changes in stem cell properties were due to the increased systemic levels of free fatty acids (FFAs), we further investigated the effects of FFAs on lean stem cells in vitro. RESULTS: Obese mice showed a trend toward increased prevalence of MSCs and sqASCs in the stromal tissues. While no significant differences in cell proliferation were observed in vitro, the differentiation potential of all types of stem cells was altered by obesity. MSCs from obese mice demonstrated decreased adipogenic, osteogenic and chondrogenic potential. Obese sqASCs and IFP cells showed increased adipogenic and osteogenic differentiation, but decreased chondrogenic ability. Obese MSCs also showed decreased CD105 and increased platelet-derived growth factor receptor α expression, consistent with decreased chondrogenic potential. FFA treatment of lean stem cells significantly altered their multipotency but did not completely recapitulate the properties of obese stem cells. CONCLUSIONS: These findings support the hypothesis that obesity alters the properties of adult stem cells in a manner that depends on the cell source. These effects may be regulated in part by increased levels of FFAs, but may involve other obesity-associated cytokines. These findings contribute to our understanding of mesenchymal tissue remodeling with obesity, as well as the development of autologous stem cell therapies for obese patients.

Molecular engineering of mechanophore activity for stress-responsive polymeric materials

© The Royal Society of Chemistry.Force reactive functional groups, or mechanophores, have emerged as the basis of a potential strategy for sensing and countering stress-induced material failure. The general utility of this strategy is limited, however, because the levels of mechanophore activation in the bulk are typically low and observed only under large, typically irreversible strains. Strategies that enhance activation are therefore quite useful. Molecular-level design principles by which to engineer enhanced mechanophore activity are reviewed, with an emphasis on quantitative structure-activity studies determined for a family of gem-dihalocyclopropane mechanophores. This journal is

Computational issues in the modelling of materials-based manufacturing processes

The manufacture of materials products involves the control of a range of interacting physical phenomena. The material to be used is synthesised and then manipulated into some component form. The structure and properties of the final component are influenced by both interactions of continuum-scale phenomena and those at an atomistic-scale level. Moreover, during the processing phase there are some properties that cannot be measured (typically the liquid-solid phase change). However, it seems there is a potential to derive properties and other features from atomistic-scale simulations that are of key importance at the continuum scale. Some of the issues that need to be resolved in this context focus upon computational techniques and software tools facilitating: (i) the multiphysics modeling at continuum scale; (ii) the interaction and appropriate degrees of coupling between the atomistic through microstructure to continuum scale; and (iii) the exploitation of high-performance parallel computing power delivering simulation results in a practical time period. This paper discusses some of the attempts to address each of the above issues, particularly in the context of materials processing for manufacture.

Microwave curing of thermosetting polymer materials in microelectronics applications

Thermosetting polymer materials are widely utilised in modern microelectronics packaging technology. These materials are used for a number of functions, such as for device bonding, for structural support applications and for physical protection of semiconductor dies. Typically, convection heating systems are used to raise the temperature of the materials to expedite the polymerisation process. The convection cure process has a number of drawbacks including process durations generally in excess of 1 hour and the requirement to heat the entire printed circuit board assembly, inducing thermomechanical stresses which effect device reliability. Microwave energy is able to raise the temperature of materials in a rapid, controlled manner. As the microwave energy penetrates into the polymer materials, the heating can be considered volumetric – i.e. the rate of heating is approximately constant throughout the material. This enables a maximal heating rate far greater than is available with convection oven systems which only raise the surface temperature of the polymer material and rely on thermal conductivity to transfer heat energy into the bulk. The high heating rate, combined with the ability to vary the operating power of the microwave system, enables the extremely rapid cure processes. Microwave curing of a commercially available encapsulation material has been studied experimentally and through use of numerical modelling techniques. The material assessed is Henkel EO-1080, a single component thermosetting epoxy. The producer has suggested three typical convection oven cure options for EO1080: 20 min at 150C or 90 min at 140C or 120 min at 110C. Rapid curing of materials of this type using advanced microwave systems, such as the FAMOBS system [1], is of great interest to microelectronics system manufacturers as it has the potential to reduce manufacturing costs, increase device reliability and enables new device designs. Experimental analysis has demonstrated that, in a realistic chip-on-board encapsulation scenario, the polymer material can be fully cured in approximately one minute. This corresponds to a reduction in cure time of approximately 95 percent relative to the convection oven process. Numerical assessment of the process [2] also suggests that cure times of approximately 70 seconds are feasible whilst indicating that the decrease in process duration comes at the expense of variation in degree of cure within the polymer.

A revised classification for direct tooth-colored restorative materials

Composite resins and glass-ionomer cements were introduced to dentistry in the 1960s and 1970s, respectively. Since then, there has been a series of modifications to both materials as well as the development other groups claiming intermediate characteristics between the two. The result is a confusion of materials leading to selection problems. While both materials are tooth-colored, there is a considerable difference in their properties, and it is important that each is used in the appropriate situation. Composite resin materials are esthetic and now show acceptable physical strength and wear resistance. However, they are hydrophobic, and therefore more difficult to handle in the oral environment, and cannot support ion migration. Also, the problems of gaining long-term adhesion to dentin have yet to be overcome. On the other hand, glass ionomers are water-based and therefore have the potential for ion migration, both inward and outward from the restoration, leading to a number of advantages. However, they lack the physical properties required for use in load-bearing areas. A logical classification designed to differentiate the materials was first published by McLean et al in 1994, but in the last 15 years, both types of material have undergone further research and modification. This paper is designed to bring the classification up to date so that the operator can make a suitable, evidence-based, choice when selecting a material for any given situation.

Thermographic investigation of contemporary resin-containing dental materials

This is the sixth paper that I have published involving thermography. In this research we were using thermogrphy to measure the temperature increases generated during photocuring of a range of clinical materials. The materials investigated were all commonly used products. The work also investigated the insulation potential of various thicknesses of human dentine when placed between the curing materials and the thermal imaging camera. From a clinical perspective this work may be used to influence the methods used to place restorative dental materials

Physicochemical characterization of bioactive polyacrylic acid organogels as potential antimicrobial implants for the buccal cavity

This study describes the formulation and physicochemical characterization of poly(acrylic acid) (PAA) organogels, designed as bioactive implants for improved treatment of infectious diseases of the oral cavity. Organogels were formulated containing a range of concentrations of PAA (3-10% w/w) and metronidazole (2 or 5% w/w, representing a model antimicrobial agent) in different nonaqueous solvents, namely, glycerol (Gly), polyethylene glycol (PEG 400), or propylene glycol (PG). Characterization of the organogels was performed using flow rheometry, compressional analysis, oscillatory rheometry, in vitro mucoadhesion, moisture uptake, and drug release, methods that provide information pertaining to the nonclinical and clinical use of these systems. Increasing the concentration of PAA significantly increased the consistency, compressibility, storage modulus, loss modulus, dynamic viscosity, mucoadhesion, and the rate of drug release. These observations may be accredited to enhanced molecular polymer entanglement. In addition, the choice of solvent directly affected the physicochemical parameters of the organogels, with noticeable differences observed between the three solvents examined. These differences were accredited to the nature of the interaction of PAA with each solvent and, importantly, the density of the resultant physical cross-links. Good correlation was observed between the viscoelastic properties and drug release, with the exception of glycerol-based formulations containing 5 and 10% w/w PAA. This disparity was due to excessive swelling during the dissolution analysis. Ideally, formulations should exhibit controlled drug release, high viscoelasticity, and mucoadhesion, but should flow under minimal stresses. Based on these criteria, PEG 400-based organogels composed of 5% or 10% w/w PAA exhibited suitable physicochemical properties and are suggested to be a potentially interesting strategy for use as bioactive implants designed for use in the oral cavity. © 2008 American Chemical Society.

Mineralogy of selected geological deposits from the United Kingdom and the Republic of Ireland as possible capping materials for low-level radioactive waste disposal facilities

Solid low-level radioactive waste (LLW) is currently being disposed at a number of facilities in the United Kingdom (UK). The safety of these facilities relies to some extent on the use of engineered barriers, such as a cap, to isolate the waste and protect the environment. Generally, the material used as the barrier layer within such a cap should be of low permeability and it should retain this property over long timescales (beyond a few decades normally required for facilities containing non-radioactive wastes). The objective of this research is to determine the mineralogy of selected geological deposits from the UK and Ireland as part of a larger project to examine their suitability as a capping material, particularly on LLW sites. Mineral transformations, as a result of future climate change, may impact on the long-term performance of the cap and even the disposal facility. X-ray diffraction (XRD) was carried-out on the sand, silt and clay fractions of the London Clay, Belfast Upper Boulder Clay, Irish Glacial Till, Belfast Sleech, and Ampthill Clay geological deposits. Minerals were present that could pose both positive and negative effects on the long-term performance of the cap. Smectite, which has a high shrink swell potential, may produce cracks in London Clay, Belfast Upper Boulder Clay and Ampthill Clay capping material during dry, hotter periods as a possible consequence of future climate change; thus, resulting in higher permeability. Ampthill Clay and Belfast Sleech had elevated amounts of organic matter (OM) at 5.93% and 5.88%, respectively, which may also contribute to cracking. Over time, this OM may decompose and result in increased permeability. Gypsum (CaSO4) in the silt and sand fractions of Ampthill Clay may reduce the impact of erosion during wetter periods if it is incorporated into the upper portion of the cap. There are potential negative effects from the acidity created by the weathering of pyrite (FeS2) present in the silt and sand fractions of Belfast Sleech and Ampthill Clay that could impede the growth of grasses used to stabilize the surface of the capping material if this material is used as part of the vegetative soil layer. Additionally, acidic waters generated from pyrite weathering could negatively impact the lower lying capping layers and the disposal facility in general. However, the calcium carbonate (CaCO3) present in the silt and sand fractions of these deposits, and dolomite (CaMg(CO3)2) in Belfast Sleech, may counter act the acidity.

KCNQ Currents and Their Contribution to Resting Membrane Potential and the Excitability of Interstitial Cells of Cajal From the Guinea Pig Bladder

PURPOSE: The presence of novel KCNQ currents was investigated in guinea pig bladder interstitial cells of Cajal and their contribution to the maintenance of the resting membrane potential was assessed. MATERIALS AND METHODS: Enzymatically dispersed interstitial cells of Cajal were patch clamped with K(+) filled pipettes in voltage clamp and current clamp modes. Pharmacological modulators of KCNQ channels were tested on membrane currents and the resting membrane potential. RESULTS: Cells were stepped from -60 to 40 mV to evoke voltage dependent currents using a modified K(+) pipette solution containing ethylene glycol tetraacetic acid (5 mM) and adenosine triphosphate (3 mM) to eliminate large conductance Ca activated K channel and K(adenosine triphosphate) currents. Application of the KCNQ blockers XE991, linopirdine (Tocris Bioscience, Ellisville, Missouri) and chromanol 293B (Sigma) decreased the outward current in concentration dependent fashion. The current-voltage relationship of XE991 sensitive current revealed a voltage dependent, outwardly rectifying current that activated positive to -60 mV and showed little inactivation. The KCNQ openers flupirtine and meclofenamic acid (Sigma) increased outward currents across the voltage range. In current clamp mode XE991 or chromanol 293B decreased interstitial cell of Cajal resting membrane potential and elicited the firing of spontaneous transient depolarizations in otherwise quiescent cells. Flupirtine or meclofenamic acid hyperpolarized interstitial cells of Cajal and inhibited any spontaneous electrical activity. CONCLUSIONS: This study provides electrophysiological evidence that bladder interstitial cells of Cajal have KCNQ currents with a role in the regulation of interstitial cell of Cajal resting membrane potential and excitability. These novel findings provide key information on the ion channels present in bladder interstitial cells of Cajal and they may indicate relevant targets for the development of new therapies for bladder instability.

Remote Detection and Identification of Organic Remains: An Assessment of Archaeological Potential

This paper reviews the various methods of using natural or induced light spectra as analytical tools in forensic archaeology. Chemical identi?cation can be made at long range and wide scale (tens of metres) down to short range and very small scale (nanometres). The identi?cation of organic gases and materials has used either chemical capture and chromatography, induced (laser or ultraviolet) light sources or laser Raman microscope spectroscopy. The remote gas detection method relies on the identi?cation of atmospheric gases by their characteristic light spectra. Modern spectroscopes can detect gases down to a few parts per million of an atmosphere. When the light source (wavelength) and direction is controlled, so laser-induced spectroscopy may be used to monitor the emission of gases such methane from buried organic remains. In order to identify the location of buried organic remains, a grid of sample points must be established using a base line or global
positioning system. When matched to base line or ground-positioning systems, such data can be manipulated by geographical information system packages. This would enable pinpointing of anomalies for excavation or avoidance. Microscope-based laser Raman spectroscopy can be used to directly analyse captured gases, swabs and surfaces without the problems of long-path detection. Copyright ? 2002 John Wiley & Sons, Ltd.

Application of the zero-range potential model to positron annihilation on molecules

In this paper we use a zero-range potential (ZRP) method to model positron interaction with molecules. This allows us to investigate the e?ect of molecular vibrations on positron–molecule annihilation using the van der Waals dimer Kr2 as an example. We also use the ZRP to explore positron binding to polyatomics and examine the dependence of the binding energy on the size of the molecule for alkanes. We ?nd that a second bound state appears for a molecule with ten carbons, similar to recent experimental evidence for such a state emerging in alkanes with twelve carbons.