The fragmentation pathways of protonated Amiton in the gas phase : towards the structural characterisation of organophosphorus chemical warfare agents by electrospray ionisation tandem mass spectrometry

Amiton (O,O-diethyl-S-[2-(diethylamino)ethyl]phosphorothiolate), otherwise known as VG, is listed in schedule 2 of the Chemical Weapons Convention (CWC) and has a structure closely related to VX (O-ethyl-S-(2-diisopropylamino)ethylmethylphosphonothiolate). Fragmentation of protonated VG in the gas phase was performed using electrospray ionisation ion trap mass spectrometry (ESI-ITMS) and revealed several characteristic product ions. Quantum chemical calculations provide the most probable structures for these ions as well as the likely unimolecular mechanisms by which they are formed. The decomposition pathways predicted by computation are consistent with deuterium-labeling studies. The combination of experimental and theoretical data suggests that the fragmentation pathways of VG and analogous organophosphorus nerve agents, such as VX and Russian VX, are predictable and thus ESI tandem mass spectrometry is a powerful tool for the verification of unknown compounds listed in the CWC. Copyright (c) 2006 Commonwealth of Australia. Published by John Wiley & Sons, Ltd.

Interacting motile agents : taking a mean-field approach beyond monomers and nearest-neighbor steps

We consider a discrete agent-based model on a one-dimensional lattice, where each agent occupies L sites and attempts movements over a distance of d lattice sites. Agents obey a strict simple exclusion rule. A discrete-time master equation is derived using a mean-field approximation and careful probability arguments. In the continuum limit, nonlinear diffusion equations that describe the average agent occupancy are obtained. Averaged discrete simulation data are generated and shown to compare very well with the solution to the derived nonlinear diffusion equations. This framework allows us to approach a lattice-free result using all the advantages of lattice methods. Since different cell types have different shapes and speeds of movement, this work offers insight into population-level behavior of collective cellular motion.

New regime for property agents and residential property sales in Queensland : Property Occupations Act 2014

This article examines the new Property Occupations Act 2014 (POA) and relevant provisions of the Agents Financial Administration Act 2014 (AFAA) and the impacts for property practitioners. The Acts are due to commence later in 2014 once regulations and relevant forms are drafted. Coinciding with the commencement of the Acts further versions of the REIQ Houses and Land Contract and REIQ Community Title Contract will also be released. The POA introduces changes for licencing of real estate agents, property developers and resident letting agents as well as significant changes for the contract formation process. The AFAA includes the trust account and claim fund provisions of PAMDA, which avoids duplication of these provisions across each of the industry-specific Bills. The most significant change is to the process for making a claim against the fund for the conduct of property agents.

Enhancement of bacterial mutagenicity of bifunctional alkylating agents by expression of mammalian glutathione s-transferase

Recently, we inserted the plasmid vector pKK233-2 containing rat GSH S-transferase (GST) 5-5 cDNA into Salmonella typhimurium TA1535 and found that these bacteria [GST 5-5(+)] expressed the protein and produced mutations when ethylene or methylene dihalides were added [Thier, R., Taylor, J. B., Pemble, S. E., Ketterer, B., Persmark, M., Humphreys, W. G., and Guengerich, F. P. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 8576-8580]. After exposure to the known GST 5-5 substrate 1,2-epoxy-3-(4′-nitrophenoxy)propane, the GST 5-5(+) strain showed fewer mutants than the bacteria transfected with the cDNA clone in a reverse orientation [GST 5-5(-)], suggesting a protective role of GST 5-5. However, mutations were considerably enhanced in the GST 5-5(+) strain [as compared to GST 5-5(-)] when 1,2,3,4-diepoxybutane (butadiene diepoxide) or 1,2-epoxy-4-bromobutane was added. The GST 5-5(+) and GST 5-5(-) bacterial stains showed similar responses to 1,2-epoxypropane, 3,4-epoxy-1-butene, and 1,4-dibromobutane. The results suggest that some bifunctional activated butanes are transformed to mutagenic products through GSH conjugation. We also found that the GST 5-5(+) strain showed enhanced mutagenicity with 1,4-dibromo-2,3-epoxybutane, 1,2-epoxy-3-bromopropane (epibromohydrin), and (±)-1,4-dibromo-2,3-dihydroxybutane. The possibility was considered that a 5-membered thialonium ion may be involved in the mutagenicity. Model thialonium compounds were rather stable to hydrolysis in aqueous solution at pH 7.4 and slowly alkylated 4-(4-nitrobenzyl)pyridine. The presence of a hydroxyl group β to the sulfur did not enhance reactivity. Mechanisms involving episulfonium ions are considered more likely. Potential oxidation products of the toxic pesticide 1,2-dibromo-3-chloropropane (DBCP) were also considered in this system. DBCP itself gave rather similar results in the two strains. Others have reported that oxidation of DBCP is required for mutagenicity, along with GST-catalyzed GSH conjugation [Simula, T. P., Glancey, M. J., Söderlund, E. J., Dybing, E., and Wolf, C. R. (1993) Carcinogenesis 14, 2303-2307]. The putative oxidation product 1,2-dibromopropional did not show a difference between the two strains. However, 1,3-dichloroacetone, a model for the putative oxidation product 1-bromo-3-chloroacetone, was considerably more mutagenic in the GST 5-5(+) strain.

The effect of topical adrenergic and anticholinergic agents on the choroidal thickness of young healthy adults

The human choroid is capable of rapidly changing its thickness in response to a variety of stimuli. However little is known about the role of the autonomic nervous system in the regulation of the thickness of the choroid. Therefore, we investigated the effect of topical parasympatholytic and sympathomimetic agents upon the choroidal thickness and ocular biometrics of young healthy adult subjects. Fourteen subjects (mean age 27.9 ± 4 years) participated in this randomized, single-masked, placebo-controlled study. Each subject had measurements of choroidal thickness (ChT) and ocular biometrics of their right eye taken before, and then 30 and 60 min following the administration of topical pharmacological agents. Three different drugs: 2% homatropine hydrobromide, 2.5% phenylephrine hydrochloride and a placebo (0.3% hydroxypropyl methylcellulose) were tested in all subjects; each on different days (at the same time of the day) in randomized order. Participants were masked to the pharmacological agent being used at each testing session. The instillation of 2% homatropine resulted in a small but significant increase in subfoveal ChT at 30 and 60 min after drug instillation (mean change 7 ± 3 μm and 14 ± 2 μm respectively; both p < 0.0001). The parafoveal choroid also exhibited a similar magnitude, significant increase in thickness with time after 2% homatropine (p < 0.001), with a mean change of 7 ± 0.3 μm and 13 ± 1 μm (in the region located 0.5 mm from the fovea center), 6 ± 1 μm and 12.5 ± 1 μm (1 mm from the fovea center) and 6 ± 2 μm and 12 ± 2 μm (1.5 mm from the fovea center) after 30 and 60 min respectively. Axial length decreased significantly 60 min after homatropine (p < 0.01). There were also significant changes in lens thickness (LT) and anterior chamber depth (ACD) (p < 0.05) associated with homatropine instillation. No significant changes in choroidal thickness, or ocular biometrics were found after 2.5% phenylephrine or placebo at any examination points (p > 0.05). In human subjects, significant increases in subfoveal and parafoveal choroidal thickness occurred after administration of 2% homatropine and this implies an involvement of the parasympathetic system in the control of choroidal thickness in humans.

Professional learning from the inside - teachers as agents of school improvement: a principal's case study

This study considered the relationship between professional learning, teacher agency and school improvement. Specifically, it explored the principal's role in supporting teacher agency in their professional learning. It found that, with appropriate pressure and support from principals, school improvement for the betterment of student learning is attainable through teacher professional learning that is based 'within' a school. Particularly, it ascertained that schools need to give greater attention to the allocation of time for teacher professional learning, specifically: time before, during and after professional learning activities. Privileging time efficiently and effectively, heightens teacher agency in their learning.

Paralog-specific kinase inhibition of FGFR4: Adding to the arsenal of anti-FGFR agents

In this issue of Cancer Discovery, Hagel and colleagues report the design and the in vitro and in vivo activity of a novel, irreversible, paralog-specific kinase inhibitor of FGFR4, BLU9931. This compound binds covalently to a cysteine residue in the hinge region of FGFR4 but not in FGFR1-3. BLU9931 induces tumor shrinkage in hepatocellular carcinoma models that express a functioning ligand/receptor complex consisting of FGF19/FGFR4/KLB and adds to a growing list of anti-FGFR4 agents.

Microtubulin binding sites as target for developing anticancer agents

Microtubules (MTs) play important and diverse roles in eukaryotic cells. Their function and biophysical properties have made α−and β−tubulin, the main components of MTs, the subject of intense study. Interfering with normal MT dynamics, for example, by the addition of tubulin ligands, can cause the cell great distress and affect MT stability and functions, including mitosis, cell motion and intracellular organelle transport. It has been shown in the literature that tubulin is an important target molecule for developing anticancer drugs. Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. This mode of action is also shared with other natural agents eg colchicine and podophyllotoxin. However various tubulin isotypes have shown resistance to taxanes and other MT agents. Therefore, there is a strong need to design and develop new natural analogs as antimitotic agents to interact with tubulin at sites different from those of vinca alkaloids and taxanes. This minireview provides SAR on several classes of antimitotic agents reported in the literature. The structures and data given are essential to the scientists who are involved in drug design and development in the field of anticancer drugs.

SERS-barcoded colloidal gold NP assemblies as imaging agents for use in biodiagnostics

There is a growing need for new biodiagnostics that combine high throughput with enhanced spatial resolution and sensitivity. Gold nanoparticle (NP) assemblies with sub-10 nm particle spacing have the benefits of improving detection sensitivity via Surface enhanced Raman scattering (SERS) and being of potential use in biomedicine due to their colloidal stability. A promising and versatile approach to form solution-stable NP assemblies involves the use of multi-branched molecular linkers which allows tailoring of the assembly size, hot-spot density and interparticle distance. We have shown that linkers with multiple anchoring end-groups can be successfully employed as a linker to assemble gold NPs into dimers, linear NP chains and clustered NP assemblies. These NP assemblies with diameters of 30-120 nm are stable in solution and perform better as SERS substrates compared with single gold NPs, due to an increased hot-spot density. Thus, tailored gold NP assemblies are potential candidates for use as biomedical imaging agents. We observed that the hot-spot density and in-turn the SERS enhancement is a function of the linker polymer concentration and polymer architecture. New deep Raman techniques like Spatially Offset Raman Spectroscopy (SORS) have emerged that allow detection from beneath diffusely scattering opaque materials, including biological media such as animal tissue. We have been able to demonstrate that the gold NP assemblies could be detected from within both proteinaceous and high lipid containing animal tissue by employing a SORS technique with a backscattered geometry.

Randomised clinical trial of a family-based lifestyle intervention for childhood obesity involving parents as the exclusive agents of change

Parent-centred interventions for childhood obesity aim to improve parents' skills and confidence in managing children's dietary and activity patterns, and in promoting a healthy lifestyle in their family. However, few studies assess changes in parenting over the course of treatment. This study describes the evaluation of a lifestyle-specific parenting program (Group Lifestyle Triple P) on multiple child and parent outcomes. One-hundred-and-one families with overweight and obese 4- to 11-year-old children participated in an intervention or waitlist control condition. The 12-week intervention was associated with significant reductions in child BMI z score and weight-related problem behaviour. At the end of the intervention, parents reported increased confidence in managing children's weight-related behaviour, and less frequent use of inconsistent or coercive parenting practices. All short-term intervention effects were maintained at one-year follow-up assessment, with additional improvements in child body size. The results support the efficacy of Group Lifestyle Triple P and suggest that parenting influences treatment outcomes. Further research is needed to evaluate the long-term effectiveness of the intervention and to elucidate the mechanisms of change. © 2010 Elsevier Ltd.

Postprocedural effects of gastrointestinal endoscopy performed as a day case procedure in children : implications for patient and family education

A prospective design that included a survey tool, nursing care records, and telephone interview was used to determine postprocedural effects experienced by children and families following gastrointestinal endoscopy performed as a day procedure. One hundred twenty-one children attending a pediatric gastroenterology unit for endoscopy under general anesthesia participated in the study. Physical symptoms, day care/school attendance, behavioral issues, and economic factors in the 72 hours post procedure were identified. Over half the children (n = 69, 57%) experienced pain in the hospital post procedure. Pain was reported by 73 children (60%) at home on the day of the procedure, by 55 children (45%) on Day 1 post procedure, and by 37 children (31%) on Day 2 post procedure. The throat was the most common site of pain. Nausea or vomiting was experienced by 37 children (31%) at some time following their procedure but was not associated with procedure type, age, or fasting time. Over half the children (n = 53, 51%) who usually attended day care or school did not attend the day following their procedure. Twenty-four parents (40%) who would normally have worked on the day after the procedure did not attend employment. These findings have been used to improve the preprocedural information and discharge management of patients treated in a pediatric gastroenterology ambulatory setting. © The Society of Gastroenterology Nurses & Associates 2007. All Rights Reserved.

Risedronate in adults with osteogenesis imperfecta type I: Increased bone mineral density and decreased bone turnover, but high fracture rate persists

Summary Bisphosphonates can increase bone mineral density (BMD) in children with osteogenesis imperfecta (OI). In this study of adults with OI type I, risedronate increased BMD at lumbar spine (but not total hip) and decreased bone turnover. However, the fracture rate in these patients remained high. Introduction Intravenous bisphosphonates given to children with OI can increase BMD and reduce fracture incidence. Oral and/or intravenous bisphosphonates may have similar effects in adults with OI. We completed an observational study of the effect of risedronate in adults with OI type I. Methods Thirty-two adults (mean age, 39 years) with OI type I were treated with risedronate (total dose, 35 mg weekly) for 24 months. Primary outcome measures were BMD changes at lumbar spine (LS) and total hip (TH). Secondary outcome measures were fracture incidence, bone pain, and change in bone turnover markers (serum procollagen type I aminopropeptide (P1NP) and bone ALP). A meta-analysis of published studies of oral bisphosphonates in adults and children with OI was performed. Results Twenty-seven participants (ten males and seventeen females) completed the study. BMD increased at LS by 3.9% (0.815 vs. 0.846 g/cm 2, p=0.007; mean Z-score, -1.93 vs. -1.58, p=0.002), with no significant change at TH. P1NP fell by 37% (p=0.00041), with no significant change in bone ALP (p=0.15). Bone pain did not change significantly (p=0.6). Fracture incidence remained high, with 25 clinical fractures and 10 major fractures in fourteen participants (0.18 major fractures per person per year), with historical data of 0.12 fractures per person per year. The meta-analysis did not demonstrate a significant difference in fracture incidence in patients with OI treated with oral bisphosphonates. Conclusions Risedronate in adults with OI type I results in modest but significant increases in BMD at LS, and decreased bone turnover. However, this may be insufficient to make a clinically significant difference to fracture incidence.

Perinatal nutrition and gastrointestinal disorders : Working Group Report of the Second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition

Metabolic programming during the perinatal period as a consequence of early nutrition is an emerging area of great interest. This concept is known as the "fetal origins of adult disease" theory (1). Numerous epidemiological studies published over the past 20 years or so have suggested that small body size at birth and during infancy and, more specifically, intrauterine growth retardation are associated later in life with lowered cognitive performance and increased rates of coronary heart disease and its major biological risk factors, ie, raised blood pressure, insulin resistance, coronary artery disease, and abnormalities in lipid metabolism. The molecular mechanisms that govern this phenomenon in humans, however, are unknown and need to be elucidated.

Cloning and gastrointestinal expression of rat hephaestin: Relationship to other iron transport proteins

The membrane-bound ceruloplasmin homolog hephaestin plays a critical role in intestinal iron absorption. The aims of this study were to clone the rat hephaestin gene and to examine its expression in the gastrointestinal tract in relation to other genes encoding iron transport proteins. The rat hephaestin gene was isolated from intestinal mRNA and was found to encode a protein 96% identical to mouse hephaestin. Analysis by ribonuclease protection assay and Western blotting showed that hephaestin was expressed at high levels throughout the small intestine and colon. Immunofluorescence localized the hephaestin protein to the mature villus enterocytes with little or no expression in the crypts. Variations in iron status had a small but nonsignificant effect on hephaestin expression in the duodenum. The high sequence conservation between rat and mouse hephaestin is consistent with this protein playing a central role in intestinal iron absorption, although its precise function remains to be determined.