Recent developments in compounds acting in the DNA minor groove.

The macromolecule that carries genetic information, DNA, is considered as an exceptional target for diseases depending on cellular division of malignant cells (i.e. cancer), microbes (i.e. bacteria) or parasites (i.e. protozoa). To aim for a comprehensive review to cover all aspects related to DNA targeting would be an impossible task and, hence, the objective of the present review is to present, from a medicinal chemistry point of view, recent developments of compounds targeting the minor groove of DNA. Accordingly, we discuss the medicinal chemistry aspects of heterocyclic small-molecules binding the DNA minor groove, as novel anticancer, antibacterial and antiparasitic agents.

Societal constraints related to environmental remediation and decommissioning programmes.

The decisions related to decommissioning or environmental remediation projects (D/ER) cannot be isolated from the socio-political and cultural environment. Experiences of the IAEA Member States point out the importance of giving due attention to the societal aspects in project planning and implementation. The purpose of this paper is threefold: i) to systematically review societal constraints that some organisations in different IAEA Member States encounter when implementing D/ER programmes, ii) to identify different approaches to overcome these constraints and iii) to collect examples of existing practices related to the integration of societal aspects in D/ER programmes worldwide. The research was conducted in the context of the IAEA project Constraints to Decommissioning and Environmental Remediation (CIDER). The research results show that societal constraints arise mostly as a result of the different perceptions, attitudes, opinions and concerns of stakeholders towards the risks and benefits of D/ER programmes and due to the lack of stakeholder involvement in planning. There are different approaches to address these constraints, however all approaches have common points: early involvement, respect for different views, mutual understanding and learning. These results are relevant for all on-going and planned D/ER programmes.

Updating irradiated graphite disposal: Project 'GRAPA' and the international decommissioning network.

Demonstrating competence in planning and executing the disposal of radioactive wastes is a key factor in the public perception of the nuclear power industry and must be demonstrated when making the case for new nuclear build. This work addresses the particular waste stream of irradiated graphite, mostly derived from reactor moderators and amounting to more than 250,000 tonnes world-wide. Use may be made of its unique chemical and physical properties to consider possible processing and disposal options outside the normal simple classifications and repository options for mixed low or intermediate-level wastes. The IAEA has an obvious involvement in radioactive waste disposal and has established a new project 'GRAPA' - Irradiated Graphite Processing Approaches - to encourage an international debate and collaborative work aimed at optimising and facilitating the treatment of irradiated graphite.

Assessing the uptake and effectiveness of a quick reference guide to antibiotic prescribing in Australian general practice.

Prescribing guidelines are an essential component of antimicrobial stewardship programs in Australian hospitals. Nonetheless, the majority of antibiotic prescribing occurs in the community and the effectiveness of guidelines developed specifically to meet the needs of Australian general practice is unknown. This study aims to assess the uptake and effectiveness of a quick reference guide to antibiotic prescribing among primary care prescribers. A quick reference guide to antibiotic prescribing was developed and prescribers in five Tasmanian practices were surveyed regarding use of this guide. Thirty-three surveys were returned and, of those answering specific sections, 75% were aware of the guide and 71% had used it within the last month. The guide affected the antibiotic prescribing practice of 74% of responding prescribers; most often on choice of antibiotic; but also on duration of treatment, dose and dosing frequency. A quick reference guide to antibiotic prescribing was well received by prescribers and may usefully support efforts to improve antimicrobial stewardship in the community.

Understanding the guanidine-like cationic moiety for optimal binding into the DNA minor groove.

Based on our previous positive results with bis-guanidine-like diaromatic compounds as DNA minor groove binders, we propose a new family: bis-2-amino-1,4,5,6-tetrahydropyrimidines. According to calculated parameters, these dicationic systems would have a more suitable size and lipophilicity for binding into the minor groove than previous series. Moreover, their DFT-optimised structures and docking into an AT oligomer model show that they would bind in the minor groove with good strength and without energy penalty. Hence, we prepared compounds 4 a-c and evaluated their binding to ssDNA and poly(dA-dT)2 by thermal denaturation experiments. The results showed that 4 a (CO) and 4 d (NH) were the best DNA binders. Compared to the previous series, 4 a-d are better binders than bis-guanidiniums but poorer than bis-2-aminoimidazolinium derivatives. Moreover, circular dichroism experiments using ssDNA and poly(dA-dT)2 confirmed binding into the minor groove. Based on our computational design as well as biophysical studies, we have been able to determine that the optimal interaction of guanidine-like dications in the minor grove occurs with bis-2-aminoimidazolinium systems.

Guanidine complexes of platinum: a theoretical study.

We have studied theoretically the complexes of model N-phenylguanidine/ium derivatives with PtCl3(-) and PtCl2 in different coordinating modes (mono- and bidentate) with different N atoms of the guanidine/ium moiety using the B3LYP/6-31+G** and LANL2DZ mixed basis set. This will aid the understanding of the complexation between platinum and the guanidine or guanidinium moiety in order to design dual anticancer agents that combine a guanidine-based DNA minor groove binder and a cisplatin-like moiety. Calculated interaction and relative energies, analysis of the electron density, and examination of the orbital interactions indicate that the most stable type of complex is that with a monodentate interaction between PtCl3(-) and guanidinium established through one of the NH2 groups. Next, we optimized the structure of three bis-guanidinium diaromatic systems developed in our group as DNA minor groove binders and their complexation with PtCl3(-), finding that the formation of Pt complexes of these minor groove binders is favorable and would produce stable monodentate coordinated systems.

Intravenous versus oral dexamethasone premedication in preventing Paclitaxel infusion hypersensitivity reactions in gynecological malignancies.

OBJECTIVE: Dexamethasone premedication is required with paclitaxel to prevent infusion-related hypersensitivity reactions (HSRs). Both oral dexamethasone (PO-D; 20 mg 12 and 6 hours before paclitaxel) and intravenous dexamethasone (IV-D; 20 mg 30 minutes before paclitaxel) regimens are used. The optimal premedication regimen and management of patients after HSR are unclear. METHODS: Data on HSRs in women receiving paclitaxel, 175 mg/m², every 3 weeks at Imperial College Healthcare Trust from May 2011 to February 2012 were obtained from the pharmacy database. During this period, dexamethasone premedication for paclitaxel was administered orally (PO-D; 20 mg 12 and 6 hours before paclitaxel) from May to August 2011, then changed to intravenous dexamethasone (IV-D; 20 mg 30 minutes before paclitaxel) for 3 months, and then reverted to PO-D from November 2011. There were 93 and 55 patients who received PO-D and IV-D before paclitaxel, respectively. Hypersensitivity reaction rates were pooled with those from published studies for analysis. Gynecologic oncology centers in the UK and Canada were surveyed regarding premedication and post-HSR management. A Markov Monte-Carlo simulation model compared costs and benefits of different strategies. RESULTS: Hypersensitivity reaction rates with PO-D and IV-D were 5.4% (5/93) versus 14.5% (8/55) (P = 0.07) in Imperial College Healthcare Trust patients, and 6.8% (20/290) versus 14.1% (30/212) (P = 0.009) on pooled analysis with data from 2 additional studies (502 patients), respectively. However, IV-D is the most common premedication regimen used in the UK and Canada (48.5% and 34.2% of centers). Post-HSR paclitaxel on a desensitization protocol is a cost-effective alternative to discontinuing paclitaxel altogether. CONCLUSION: Oral dexamethasone seems to be superior to IV-D in preventing HSRs. Post-HSR patients should be considered for desensitization.

Factors affecting wound leakage in 23-gauge sutureless pars plana vitrectomy.

PURPOSE: To evaluate risk factors for sclerotomy leakage in 23-gauge sutureless pars plana vitrectomy in 219 patients. METHODS: Nested case-control study involving 48 patients with wound leaks (visible on-table sclerotomy leakage requiring sutures) and 171 control subjects without wound leaks. Patients received either a conventional sclerotomy incision at 45°, which was then changed to 90° midincision, or an extremely oblique sclerotomy incision (OSI) at 10°, which was then changed to 30° midincision. Risk factors studied included age, gender, laterality, surgical duration, sclerotomy incision (OSI vs. conventional sclerotomy incision), preoperative diagnosis (macular vs. nonmacular), history of vitrectomy, and primary surgeon (attending vs. supervised resident). RESULTS: Multivariate logistic regression analysis found significant (P ≤ 0.05) protective factors for wound leakage including OSI, macular preoperative diagnosis, no previous vitrectomy, and female gender. Surgical duration at least 45 minutes was considered a borderline risk factor. CONCLUSION: Using an extremely OSI versus a conventional sclerotomy incision reduces the incidence of wound leakage postoperatively because of its self-sealing effect. Other factors that contribute to wound leakage, such as increased surgical duration and nonmacular diagnosis, may be indirect measurements of extensive trocar rotation, causing wound leakage despite the use of an OSI.

Pedagogy as influencing nursing students' essentialized understanding of culture.

In this qualitative study, we explored how students understood "culture." Participants defined culture and wrote narratives regarding specific cultural encounters. The sample comprised both nursing (n=14) and non-nursing (n=8) students to allow for comparison groups. Content analysis of the narratives revealed two broad paradigms of cultural understanding: essentialist and constructivist. Essentialist narratives comprised four themes: determinism (culture defied individual resistance); relativism (the possibility of making value judgments disappeared); Othering (culture was equated to exotica, and emphasized difference); and, reductionism (personhood was eclipsed by culture). In contrast, the constructivist narratives were characterized by influence (non-determinism), dynamism (culture was dynamic and evolutionary); and, relationship-building. The unintended negative consequences of essentialist notions of culture were revealed in the nursing students' narratives. Pedagogy is implicated in nursing students' essentialized understanding of culture.

The use of agar as a novel filler for monolithic matrices produced using hot melt extrusion.

The use of filler materials in an extended release monolithic polymer matrix can lead to a vastly altered release profile for the active pharmaceutical ingredient. A range of excipients for use in monolithic matrices have been discussed in the literature. The body of work described in this research paper outlines the use of agar as a novel filler material in a hot melt extruded polymer matrix. Several batches of matrix material were prepared with Diclofenac sodium used as the active pharmaceutical ingredient (API). Agar and microcrystalline cellulose were used as the filler materials in varying ratios, to examine the effect of % filler content as well as filler type on the properties of the hot melt extruded matrix. The resultant extrudates were characterised using steady state parallel plate rheometry, differential scanning calorimetry (DSC) and dissolution testing. The rheometry analysis concluded that the fillers used resulted in an increase in the matrix viscosity. The DSC scans obtained showed negligible effects on the melting behavior of the matrix as a result of the filler inclusion. Dissolution analysis showed that the presence of the fillers resulted in a slower release rate of API than for the matrix alone. The results detailed within this paper indicate that agar is a viable filler for extended release hot melt produced dosage forms.

Hindcasting of nutrient loadings from its catchment on a highly valuable coastal lagoon: the example of the Fleet, Dorset, UK, 1866-2004.

BACKGROUND: Nutrient loadings from its catchment upon The Fleet, a highly valuable coastal lagoon in Southern England, were hindcast for the period AD 1866-2004, using a catchment model, export coefficients, and historical data on land use changes, livestock numbers, and human population. Agriculture was the main nutrient source throughout, other inputs representing minor contributions. Permanent pasture was historically the main land use, with temporary grassland and cereals increasing during the mid-20th century. Sheep, the main 19th century livestock, were replaced by cattle during the 1930s. RESULTS: Total nitrogen loadings rose from ca 41 t yr-1 during the late 19th century to 49-54 t yr-1 for the mid-20th, increasing to 98 t yr-1 by 1986. Current values are ca 77 t yr-1. Total phosphorus loads increased from ca 0.75 t yr-1 for the late 19th century to ca 1.6 t yr-1 for the mid-20th, reached ca 2.2 t yr-1 in 1986, and are now ca 1.5 t yr-1. Loadings rose most rapidly between 1946 and 1988, owing to increased use of inorganic fertilisers, and rising sheep and cattle numbers. Livestock were the main nutrient source throughout, but inputs from inorganic fertilisers increased after 1946, peaking in 1986. Sewage treatment works and other sources contribute little nitrogen, but ca 35% of total phosphorus. Abbotsbury Swannery, an ancient Mute Swan community, provides ca 0.5% of total nitrogen, and ca 5% of total phosphorus inputs. CONCLUSION: The Fleet has been grossly overloaded with nitrogen since 1866, climaxing during the 1980s. Total phosphorus inputs lay below 'permissible' limits until the 1980s, exceeding them in inner, less tidal parts of the lagoon, during the 1940s. Loadings on Abbotsbury Bay exceeded 'permissible' limits by the 1860s, becoming 'dangerous' during the mid-20th century. Phosphorus stripping at point sources will not significantly reduce loadings to all parts of the lagoon. Installation of 5 m buffer strips throughout the catchment and shoreline will marginally affect nitrogen loadings, but will reduce phosphorus inputs to the West Fleet below 'permissible' limits. Only a combination of measures will significantly affect Abbotsbury Bay, where, without effluent diversion, loadings will remain beyond 'permissible'.