Benzothiazole bipyridine complexes of ruthenium(II) with cytotoxic activity

A series of benzothiazole-substituted trisbipyridine ruthenium(II) analogues {[Ru(bpy)(2)(4,5'-bbtb)](2+), [Ru(bpy)(2)(5,5'-bbtb)](2+) and [Ru(bpy)(2)(5-mbtb)](2+) [bpy is 2,2'-bipyridine, bbtb is bis(benzothiazol-2-yl)-2,2'-bipyridine, 5-mbtb is 5-(benzothiazol-2-yl),5'-methyl-2,2'-bipyridine]} have been prepared and compared with the complex [Ru(bpy)(2)(4,4'-bbtb)](2+) reported previously. From the UV-vis spectral studies, substitution at the 5-position of the bpy causes the ligand-centred transitions to occur at considerably lower energy than for those with the functionality at the 4-position, while at the same time causing the emission to be effectively quenched. However, substitution at the 4-position causes the metal-to-ligand charge transfer to occur at lower energies. Fluorescent intercalator displacement studies indicate that the doubly substituted complexes displace ethidium bromide from a range of oligonucleotides, with the greater preference shown for bulge and hairpin sequences by the Lambda enantiomer. Since the complexes only show small variation in the UV-vis spectra on the introduction of calf thymus DNA and a small increase in fluorescence they do not appear to be intercalators, but appear to associate within one of the grooves. All of the reported bisbenzothiazole complexes show reasonable cytotoxicity against a range of human cancer cell lines.

‘Risk, Politics and the ‘Scientification’ of Political Judgement: Prisoner Release and Conflict Transformation in Northern Ireland’

Drawing on research in Northern Ireland into the process of release under the Belfast/Good Friday Agreement, this article explores the identification and classification of risk in relation to prisoners released early under the Sentences (NI) Act. The main argument is that conflict, post-conflict and transitional conditions expose more starkly the political underpinnings of risk-management strategy and the article demonstrates the particular variant of Politicized Risk Assessment (PRA) recently used in the release of prisoners in Northern Ireland

A Robust Curve-Fitting Procedure for the Analysis of Plasmid DNA Strand Break Data from Gel Electrophoresis

A robust method for fitting to the results of gel electrophoresis assays of damage to plasmid DNA caused by radiation is presented. This method makes use of nonlinear regression to fit analytically derived dose response curves to observations of the supercoiled, open circular and linear plasmid forms simultaneously, allowing for more accurate results than fitting to individual forms. Comparisons with a commonly used analysis method show that while there is a relatively small benefit between the methods for data sets with small errors, the parameters generated by this method remain much more closely distributed around the true value in the face of increasing measurement uncertainties. This allows for parameters to be specified with greater confidence, reflected in a reduction of errors on fitted parameters. On test data sets, fitted uncertainties were reduced by 30%, similar to the improvement that would be offered by moving from triplicate to fivefold repeats (assuming standard errors). This method has been implemented in a popular spreadsheet package and made available online to improve its accessibility. (C) 2011 by Radiation Research Society

C∗-Segal algebras with order unit

We introduce the notion of a (noncommutative) C *-Segal algebra as a Banach algebra (A, {norm of matrix}{dot operator}{norm of matrix} A) which is a dense ideal in a C *-algebra (C, {norm of matrix}{dot operator}{norm of matrix} C), where {norm of matrix}{dot operator}{norm of matrix} A is strictly stronger than {norm of matrix}{dot operator}{norm of matrix} C onA. Several basic properties are investigated and, with the aid of the theory of multiplier modules, the structure of C *-Segal algebras with order unit is determined.

Hot-melt extrusion technology and pharmaceutical application

The use of hot-melt extrusion (HME) within the pharmaceutical industry is steadily increasing, due to its proven ability to efficiently manufacture novel products. The process has been utilized readily in the plastics industry for over a century and has been used to manufacture medical devices for several decades. The development of novel drugs with poor solubility and bioavailability brought the application of HME into the realm of drug-delivery systems. This has specifically been shown in the development of drug-delivery systems of both solid dosage forms and transdermal patches. HME involves the application of heat, pressure and agitation through an extrusion channel to mix materials together, and subsequently forcing them out through a die. Twin-screw extruders are most popular in solid dosage form development as it imparts both dispersive and distributive mixing. It blends materials while also imparting high shear to break-up particles and disperse them. HME extrusion has been shown to molecularly disperse poorly soluble drugs in a polymer carrier, increasing dissolution rates and bioavailability. The most common difficulty encountered in producing such dispersions is stabilization of amorphous drugs, which prevents them from recrystallization during storage. Pharmaceutical industrial suppliers, of both materials and equipment, have increased their development of equipment and chemicals for specific use with HME. Clearly, HME has been identified as an important and significant process to further enhance drug solubility and solid-dispersion production. © 2012 Future Science Ltd.

Polysaccharide co-polymerases:the enigmatic conductors of the O-antigen assembly orchestra

The O-antigen lipopolysaccharides on bacterial surface contain variable number of oligosaccharide repeat units with their length having a modal distribution specific to the bacterial strain. The polysaccharide length distribution is controlled by the proteins called polysaccharide co-polymerases (PCPs), which are embedded in the inner membrane in Gram-negative bacteria and form homo oligomers. The 3D structures of periplasmic domains of several PCPs have been determined and provided the first insights into the possible mechanism of polysaccharide length determination mechanism. Here we review the current knowledge of structure and function of these polysaccharide length regulators.

Glomerulonephritis associated with antibodies to neutrophil cytoplasm and glomerular basement membrane

The prognosis for recovery of renal function of oligoanuric patients with anti-glomerular basement membrane disease is generally regarded as poor. Five patients are reported with dialysis-dependent renal failure in whom antibodies were present simultaneously both to neutrophil cytoplasm and glomerular basement membrane all of whom responded, at least initially, to immunosuppressive therapy and plasma exchange. Two of the 5 remain in clinical and immunological remission at 25 and 51 months of follow-up. We suggest that reversal of dialysis-dependent renal failure may be possible in some patients who display this dual antibody positivity.

Cause-specific mortality adjudication in the UPLIFT® COPD trial:findings and recommendations

Mortality is an important endpoint in chronic obstructive pulmonary disease (COPD) trials, although accurately determining cause of death is difficult. In the Understanding the Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial, a mortality adjudication committee (MAC) provided systematic, independent and blinded assessment of cause-specific mortality of all 981 reported deaths. Here we describe this process of mortality adjudication and methodological revisions introduced to help standardise the adjudication of two areas recognised to pose particular difficulty; firstly, the classification of fatal COPD exacerbations that occur in the setting of pneumonia and secondly, the categorisation of sudden death. In addition MAC determined cause of death was compared with that reported by site investigators (SIs). MAC-assigned causes of death were: respiratory, 35%; cancer, 25%; cardiovascular, 11%; sudden cardiac death, 4.4%; sudden death, 3.4%; other, 8.8%; unknown, 12.4%. Cancer/cardiac deaths were more common in Global Initiative for Chronic Obstructive Lung Disease stage II, respiratory deaths in stages III and IV. Agreement between MAC and SI regarding cause of death was complete (50.2%), incomplete (18.5%) or none (31.3%). The SI classified deaths as cardiac three-fold more frequently than MAC (incidence rate [IR]/100 patient-years 0.797 vs. 0.257), although IR ratios for cardiac deaths for tiotropium vs. control were similar between SI and MAC. Discrepancies between MAC- and SI-adjudicated causes of death are common, especially increased reporting of cardiac deaths by the SI. Future multicentre COPD trials should plan appropriate infrastructure before study initiation to ensure collection and interpretation of fatal events data.

Metasurfaces with interwoven conductor patterns on dielectric substrates

The properties of metasurfaces comprised of interwoven conductor patterns on dielectric substrates have been examined. The significant reduction of the fundamental resonance frequency fr and expanded fractional bandwidths (FBWs) offered by the intertwined spirals and Brigid’s crosses extended beyond a single unit cell has been achieved with the aid of thin dielectric substrates. A qualitative model has been proposed and proved to adequately predict the main properties of entwined spiral arrays on dielectric substrates.

High population prevalence of cardiac troponin I measured by a high-sensitivity assay and cardiovascular risk estimation: the MORGAM Biomarker Project Scottish Cohort

Aims
Our aim was to test the prediction and clinical applicability of high-sensitivity assayed troponin I for incident cardiovascular events in a general middle-aged European population.

Methods and results
High-sensitivity assayed troponin I was measured in the Scottish Heart Health Extended Cohort (n = 15 340) with 2171 cardiovascular events (including acute coronary heart disease and probable ischaemic strokes), 714 coronary deaths (25% of all deaths), 1980 myocardial infarctions, and 797 strokes of all kinds during an average of 20 years follow-up. Detection rate above the limit of detection (LoD) was 74.8% in the overall population and 82.6% in men and 67.0% in women. Troponin I assayed by the high-sensitivity method was associated with future cardiovascular risk after full adjustment such as that individuals in the fourth category had 2.5 times the risk compared with those without detectable troponin I (P < 0.0001). These associations remained significant even for those individuals in whom levels of contemporary-sensitivity troponin I measures were not detectable. Addition of troponin I levels to clinical variables led to significant increases in risk prediction with significant improvement of the c-statistic (P < 0.0001) and net reclassification (P < 0.0001). A threshold of 4.7 pg/mL in women and 7.0 pg/mL in men is suggested to detect individuals at high risk for future cardiovascular events.

Conclusion
Troponin I, measured with a high-sensitivity assay, is an independent predictor of cardiovascular events and might support selection of at risk individuals.

The Saccharomyces cerevisiae quinone oxidoreductase Lot6p: stability, inhibition and cooperativity

Lot6p (EC 1.5.1.39; Ylr011wp) is the sole quinone oxidoreductase in the budding yeast, Saccharomyces cerevisiae. Using hexahistidine tagged, recombinant Lot6p, we determined the steady-state enzyme kinetic parameters with both NADH and NADPH as electron donors; no cooperativity was observed with these substrates. The NQO1 inhibitor curcumin, the NQO2 inhibitor resveratrol, the bacterial nitroreductase inhibitor nicotinamide and the phosphate mimic vanadate all stabilise the enzyme towards thermal denaturation as judged by differential scanning fluorimetry. All except vanadate have no observable effect on the chemical cross-linking of the two subunits of the Lot6p dimer. These compounds all inhibit Lot6p's oxidoreductase activity, and all except nicotinamide exhibit negative cooperativity. Molecular modelling suggests that curcumin, resveratrol and nicotinamide all bind over the isoalloxazine ring of the FMN cofactor in Lot6p. Resveratrol was predicted to contact an α-helix that links the two active sites. Mutation of Gly-142 (which forms part of this helix) to serine does not greatly affect the thermal stability of the enzyme. However, this variant shows less cooperativity towards resveratrol than the wild type. This suggests a plausible hypothesis for the transmission of information between the subunits and, thus, the molecular mechanism of negative cooperativity in Lot6p.