Geophysics and the search of freshwater bodies

Geophysics may assist scent dogs and divers in the search of water bodies for human and animal remains, contraband, weapons and explosives by surveying large areas rapidly and identifying targets or environmental hazards. The most commonly applied methods are described and evaluated for forensic searches. Seismic reflection or refraction and CHIRPS are useful for deep, openwater bodies and identifying large targets, yet limited in streams and ponds. The use of ground penetrating radar (GPR) onwater(WPR) is of limited use in deepwaters (over 20 m) but is advantageous in the search for non-metallic targets in small ditches and ponds. Largemetal or metal-bearing targets can be successfully imaged in deep waters by using towfish magnetometers: in shallow waters such a towfish cannot be used, so a non-metalliferous boat can carry a terrestrial magnetometer. Each device has its uses, depending on the target and location: unknown target make-up (e.g. a homicide victimwith or without a metal object) may be best located using a range ofmethods (the multi-proxy approach), depending on water depth. Geophysics may not definitively find the target, but can provide areas for elimination and detailed search by dogs and divers, saving time and effort.

More-than-human histories and the failure of grand state schemes: sylviculture in the New Forest, England

As James Scott’s Seeing Like a State attests, forests played a central role in the rise of the modern state, specifically as test spaces for evolving methods of managing state resources at a distance, and as the location for grand state schemes. Together, such ambitions necessitated both the elimination of local understandings of forest management – to be replaced by centrally controlled scientific precision – and a narrowing of state vision. Forests thus began to be conflated with trees (and their timber) alone. All other aspects of the forest, both human and non-human, were ignored. Through the lens of the 18th and early 19th century New Forest in southern England, this paper examines the impact of government attempts to shift the focus of state forests from being remnant medieval hunting spaces to spaces of income generation through the creation of vast sylvicultural plantations. This state scheme not only reworked the relationship between the metropole and the provinces – something effected through systematic surveys and novel bureaucratic procedures – but also dramatically impacted upon the biophysical and cultural geographies of the forest. By equating forest space with trees alone, the British state failed to legislate for the actions of both local commoners and non-human others in resisting their schemes. Indeed, subsequent oppositions proved not only the tenacity of commoners in protecting their livelihoods but also the destructive power of non-human actants, specifically rabbits and mice. The paper concludes that grand state schemes necessarily fail due to their own internal illogic: the narrowing of state vision creates blind spots in which human and non-human lives assert their own visions.

Freedom of Expression and Hate Speech

This is a study of free speech and hate speech with reference to the international standards and to the United States jurisprudence. The study, in a comparative and critical fashion, depicts the historical evolution and the application of the concept of ‘free speech,’ within the context of ‘hate speech.’ The main question of this article is how free speech can be discerned from hate speech, and whether the latter should be restricted. To this end, it examines the regulation of free speech under the First Amendment to the United States Constitution, and in light of the international standards, particularly under the International Convention on the Elimination of All Forms of Racial Discrimination, International Covenant on Civil and Political Rights, and the European Convention on Human Rights and Fundamental Freedoms. The study not only illustrates how elusive the endeavour of striking a balance between free speech and other vital interests could be, but also discusses whether and how hate speech should be eliminated within the ‘marketplace of ideas.’

Sequential C-H and C-Ru bond formation and cleavage during the thermally induced rearrangement of aryl ruthenium(II) complexes with [C6H3(CH2NMe2)(2)-2,6](-) as a bidentate eta(2)-C,N coordinated ligand. The crystal structures of the isomeric pairs [RuCl{eta(6)-C10H14}{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,n}] (n = 4 or 6) and [Ru(eta(5)-C5H5){(eta(2)-C,N-C6H3(CH2NMe2)(2)-2,n} (PPH3)] (n = 4 or 6)

New air-stable ruthenium(II) complexes that contain the aryldiamine ligand [C6H3(CH2-NMe2)(2)-2,6](-) (NCN) are described. These complexes are [RuCl{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,6}(eta(6)-C10H14)] (2; C10H14 = p-cymene = C6H4Me-Pr-i-4), [Ru{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,6}(eta(5)-C5H5)(PPh3)] (5), and their isomeric forms [RuCl{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,4}(eta(6)-C10H14)] (3) and [Ru{eta(2)-C,N-C6H3(CH2NMe2)(2)-2,4}(eta(5)-C5H5)(PPh3)] (6), respectively. Complex 2 has been prepared from the reaction of [Li(NCN)](2) with [RuCl2(eta(6)-C10H14)](2), whereas complex 5 has been prepared by the treatment of [RuCl{eta(3)-N,C,N-C6H3(CH2NMe2)(2)-2,6}(PPh3)] (4) with [Na(C5H5)](n). Both 2 and 5 are formally 18-electron ruthenium(II) complexes in which the monoanionic potentially tridentate coordinating ligand NCN is eta(2)-C,N-bonded, In solution (halocarbon solvent at room temperature or in aromatic solvents at elevated temperature), the intramolecular rearrangements of 2 and 5 afford complexes 3 and 6, respectively. This is a result of a shift of the metal-C-aryl bond from position-1 to position-3 on the aromatic ring of the NCN ligand. The mechanism of the isomerization is proposed to involve a sequence of intramolecular oxidative addition and reductive elimination reactions of both aromatic and aliphatic C-H bonds. This is based on results from deuterium labeling, spectroscopic studies, and some kinetic experiments. The mechanism is proposed to contain fully reversible steps in the case of 5, but a nonreversible step involving oxidative addition of a methyl NCH2-H bond in the case of 2. The solid-state structures of complexes 2, 3, 5, and 6 have been determined by single-crystal X-ray diffraction. A new dinuclear 1,4-phenylene-bridged bisruthenium(II) complex, [1,4-{RuCl(eta(6)-C10H14)}(2){C-6(CH2NMe2)(4)-2,3,5,6-C,N,C',N'}] (9) has also been prepared from the dianionic ligand [C-6(CH2NMe2)(4)-2,3,5,6](2-) (C2N4). The C2N4 ligand is in an eta(2)-C,N-eta(2)-C',N'-bis(bidentate) bonding mode. Compound 9 does not isomerize in solution (halocarbon solvent), presumably because of the absence of an accessible C-aryl-H bond. Complex 9 could not be isolated in an analytically pure form, probably because of its high sensitivity to air and very low solubility, which precludes recrystallization.

The first structural characterization of a [2.2]PHANEPHOS - Transition-metal complex: Structure of rac-[Pd(4,12-bis(diphenylphosphino)[2.2]paracyclophane)Cl-2]

The solid-state structure of the [2.2]PHANEPHOS-transition-metal complex rac-[Pd(4,12-bis(diphenylphosphino)[2.2]paracyclophane)Cl-2] has been established by single-crystal X-ray diffraction. The P-Pd-P bite angle is ideally suited to catalytic processes such as carbon-carbon cross-coupling reactions, which involve reductive elimination as the rate-determining step.

Population pharmacokinetic model of canrenone after intravenous administration of potassium canrenoate to paediatric patients

Objectives: To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate in paediatric patients. Patients and Methods: Data were collected prospectively from 23 paediatric patients (2 days to 10 years of age; median weight 4 kg, range 2.16-28.0 kg) who received intravenous potassium canrenoate (K-canrenoate) as part of their intensive care therapy for removal of retained fluids e.g. in pulmonary oedema due to chronic lung disease and for the management of congestive heart failure. Plasma samples were analysed by HPLC for determination of canrenone (the major metabolite and pharmacologically active moiety) and the data subjected to pharmacokinetic analysis using NONMEM. Results: A one-compartment model best described the data. The only significant covariate was weight (WT). The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) were CL/F (L/hr) = 11.4 × (WT /70.0)(0.75) and V/F (L) = 374.2 × (WT/70) where WT is in kg. The values of CL/F and V/F in a 4 kg child would be 1.33 L/hr and 21.4 L, respectively, resulting in an elimination half-life of 11.2 hr. Conclusions: The range of estimated CL/F in the study population was 0.67-7.38 L/hr. The data suggest that adjustment of K-canrenoate dosage according to body weight is appropriate in paediatric patients

RESIDUES OF THE BETA-AGONIST CLENBUTEROL IN TISSUES OF MEDICATED FARM-ANIMALS

Reports of the illegal use of clenbuterol as a growth promotant prompted the development of a competitive enzyme immunoassay for this drug. This procedure was utilized to study the elimination of clenbuterol from tissues in sheep medicated with both therapeutic and growth-promoting doses of the drug. The results indicated that prior to removal of medication clenbuterol was widely distributed throughout the animal tissues. However as the withdrawal periods increased fluid targets such as urine and bile became less effective at detecting clenbuterol usage. At both therapeutic and growth-enhancing concentrations of clenbuterol liver samples remained positive up to the maximum withdrawal time given in this experiment (15 days). Concentrations of clenbuterol likely to cause food poisoning (> 100 ng/g) were only detected in liver samples taken prior to the removal of medication. The highest recorded concentration of clenbuterol in muscle was 22.5 ng/g.

Characterisation of protein stability in rod-insert vaginal rings

A major goal in vaccine development is elimination of the ‘cold chain’, the transport and storage system for maintenance and distribution of the vaccine product. This is particularly pertinent to liquid formulation of vaccines. We have previously described the rod-insert vaginal ring (RiR) device, comprising an elastomeric body into which are inserted lyophilised, rod-shaped, solid drug dosage forms, and having potential for sustained mucosal delivery of biomacromolecules, such as HIV envelope protein-based vaccine candidates. Given the solid, lyophilised nature of these insert dosage forms, we hypothesised that antigen stability may be significantly increased compared with more conventional solubilised vaginal gel format. In this study, we prepared and tested vaginal ring devices fitted with lyophilised rod inserts containing the model antigen bovine serum albumin (BSA). Both the RiRs and the gels that were freeze-dried to prepare the inserts were evaluated for BSA stability using PAGE, turbidimetry, microbial load, MALDI-TOF and qualitative precipitate solubility measurements. When stored at 4 oC, but not when stored at 40 oC / 75% RH, the RiR formulation offered protection against structural and conformational changes to BSA. The insert also retained matrix integrity and release characteristics. The results demonstrate that lypophilised gels can provide relative protection against degradation at lower temperatures compared to semi-solid gels. The major mechanism of degradation at 40 oC / 75% RH was shown to be protein aggregation. Finally, in a preliminary study, we found that addition of trehalose to the formulation significantly reduces the rate of BSA degradation as compared to the original formulation when stored at 40 oC /75% RH. Establishing the mechanism of degradation, and finding that degradation is decelerated in the presence of trehalose, will help inform further development of RiRs specifically and polymer based freeze-dried systems in general.

Surface localisation of photosensitisers on intraocular lens biomaterials for prevention of infectious endophthalmitis and retinal protection

Cataract surgery is one of the most commonly-practiced surgical procedures in Western medicine, and, while complications are rare, the most serious is infectious postoperative endophthalmitis. Bacteria may adhere to the implanted intraocular lens (IOL) and subsequent biofilm formation can lead to a chronic, difficult to treat infection. To date, no method to reduce the incidence of infectious endophthalmitis through bacterial elimination, while retaining optical transparency, has been reported. In this study we report a method to optimise the localisation of a cationic porphyrin at the surface of suitable acrylate copolymers, which is the first point of contact with potential pathogens. The porphyrin catalytically generates short-lived singlet oxygen, in the presence of visible light, which kills adherent bacteria indiscriminately. By restricting the photosensitiser to the surface of the biomaterial, reduction in optical transparency is minimised without affecting efficacy of singlet oxygen production. Hydrogel IOL biomaterials incorporating either methacrylic acid (MAA) or methyl methacrylate (MMA) co-monomers allow tuning of the hydrophobic and anionic properties to optimise the localisation of porphyrin. Physiochemical and antimicrobial properties of the materials have been characterised, giving candidate materials with self-generating, persistent anti-infective character against Gram-positive and Gram-negative organisms. Importantly, incorporation of porphyrin can also serve to protect the retina by filtering damaging shortwave visible light, due to the Soret absorption (?max) 430 nm). © 2012 Elsevier Ltd. All rights reserved.

The effect of hypoxia on propranolol clearance during antegrade and retrograde flow in the isolated perfused rat liver preparation

We investigated, using the single-pass isolated perfused rat liver preparation, whether the centrilobular location of hepatic oxidative drug metabolism could be a contributing factor to the marked sensitivity of drug oxidation to hypoxia. Livers (N = 7) were each perfused for 130 min with 2 micrograms/mL (+)-propranolol, a drug metabolized almost entirely by oxidation in the rat. The direction of flow was reversed after 60 min, the order of flow direction being randomized. Normal oxygenation was used during the first 30 min of antegrade and of retrograde perfusion, but in the second 30 min perfusate was equilibrated with a N2/O2 mixture designed to reduce hepatic oxygen delivery by half. During normal oxygenation there was no significant difference between antegrade and retrograde perfusion in hepatic oxygen delivery and physiological parameters such as oxygen consumption and extraction, perfusion pressure and bile flow. During hypoxia, mean oxygen delivery was slightly lower with retrograde perfusion (retrograde: mean = 2.37 mumol/min/g liver, range = 1.56-3.17; antegrade: mean = 2.90 mumol/min/g liver, range = 1.96-4.08; P = 0.04), but there was no significant difference in physiological parameters within each liver (P > 0.05). Propranolol clearance during normal oxygenation was similar to the perfusion rate (10 mL/min) and was the same for both directions of perfusion (antegrade 9.88 +/- 0.07 mL/min, retrograde 9.88 +/- 0.13 mL/min, P > 0.05). Hypoxia reduced propranolol clearance substantially, but the decrease was significantly greater with antegrade perfusion (5.65 +/- 1.89 mL/min) than with retrograde perfusion (6.76 +/- 1.95 mL/min, P = 0.014). Oxidative drug metabolism is located primarily in the centrilobular zone and sinusoidal oxygen concentration is lowest in the "downstream" zone with both antegrade and retrograde perfusion. These findings suggest that the centrilobular location of propranolol metabolism may influence the effect of hypoxia on propranolol elimination, but is not a major contributor to the marked sensitivity of propranolol elimination to hypoxia antegrade perfusion.

A comparative pharmacokinetic study of conventional propranolol and long acting preparation of propranolol in patients with cirrhosis and normal controls

1 Six male patients with alcoholic cirrhosis and seven normal control subjects were each given 80 mg twice daily of conventional propranolol for 1 week and 160 mg once daily of a long acting preparation (LA) of propranolol for 1 week. 2 Plasma propranolol levels were measured at regular intervals on the first and seventh days of both weeks and also following an acute intravenous infusion of 10 mg propranolol on a separate occasion. 3 After the single intravenous dose the elimination half-life tended to be prolonged in the cirrhotic group (median 7.15 h) compared with controls (median 2.92 h) (P = 0.055). 4 After multiple oral dosing with 80 mg twice daily of conventional propranolol the steady-state plasma concentration (Css), area under the curve (AUC tau), peak concentration (Cmax) and trough concentration (Cmin) were significantly higher in cirrhotic patients and the peak: trough ratio (Cmax/Cmin) was significantly lower than controls. 5 After multiple oral dosing with 160 mg LA once daily Cmin was significantly higher than Cmax/min significantly lower in cirrhotic patients; Css, AUC and Cmax were higher than controls but not statistically different. 6 Within both subject groups the bioavailability of 80 mg twice daily of conventional propranolol tended to be greater than 160 mg LA once daily. Cmax was significantly higher in both groups and Css higher in the cirrhotic group with conventional propranolol. 7 In the cirrhotic group the mean reduction in supine heart rate in the steady state was 31.8% with conventional 80 mg twice daily propranolol and 23.75% with 160 mg LA once daily.(ABSTRACT TRUNCATED AT 250 WORDS)

Prophylactic ranitidine treatment in critically ill children - a population pharmacokinetic study

Aims: To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. Methods: Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. Results: A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (-12.618; P <0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1lh for total clearance and 285l for volume of distribution, both allometrically modelled for a 70kg adult. Final estimates for absorption rate constant and bioavailability were 1.31h and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. Conclusions: Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary.

Morbillivirus cross-species infection:is there a risk for humans?

The World Health Organisation (WHO) has set regional elimination goals for Measles (MV) eradication to be achieved by 2020 or earlier. A major question is whether an opportunity for veterinary virus infection of humans may arise when MV is eradicated and if vaccination is discontinued. Lessons have been learned from animal to human virus transmission i.e. human immunodeficiency virus (HIV) and more recently from severe acute respiratory syndrome (SARS) and avian influenza virus infections. We are therefore alerted to the risk of zoonosis from the veterinary morbilliviruses. In this review the evidence from viral genomics, animal studies and cell culture experiments will be explored to evaluate the possibility of cross infection of humans with these viruses.

How pathogen-derived cysteine proteases modulate host immune responses

In mammals, cysteine proteases are essential for the induction and development of both innate and adaptive immune responses. These proteases play a role in antigen-and pathogen-recognition and elimination, signal processing and cell homeostasis. Many pathogens also secrete cysteine proteases that often act on the same target proteins as the mammalian proteases and thereby can modulate host immunity from initial recognition to effector mechanisms. Pathogen-derived proteases range from nonspecific proteases that degrade multiple proteins involved in the immune response to enzymes that are very specific in their mode of action. Here, we overview current knowledge of pathogen-derived cysteine proteases that modulate immune responses by altering the normal function of key receptors or pathways in the mammalian immune system.

Accumulation or production of arsenobetaine in humans?

Arsenobetaine has always been referred to as a non-toxic but readily bioavailable compound and the available data would suggest that it is neither metabolised by nor accumulated in humans. Here this study investigates the urine of five volunteers on an arsenobetaine exclusive diet for twelve days and shows that arsenobetaine was consistently excreted by three of the five volunteers. From the expected elimination pattern of arsenobetaine in rodents, no significant amount of arsenobetaine should have been detectable after 5 days of the trial period. The arsenobetaine concentration found in the urine was constant after 5 days and varied between 0.2 and 12.2 microg As per L for three of the volunteers. Contrary to the established belief that arsenobetaine is neither accumulated nor generated by humans, the presented results would suggest that either accumulated arsenobetaine in the tissues is slowly released over time or that arsenobetaine is a human metabolite of dimethylarsinic acid or inorganic arsenic from the trial food, or both. Either possibility is intriguing and raises fundamental questions about human arsenic metabolism and the toxicological and environmental inertness of arsenobetaine.