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It is unfortunately true that clinicians lack the necessary evidence to know how to use medications properly in large sections of the population and do not have optimal treatments to use for many neglected tropical diseases (NTDs). NTDs often disproportionately affect neglected populations that are left out of research efforts, such as children and pregnant women. As reliable access to safe, effective preventives and treatments can break the cycle of poverty, illness, and ensuing debility that further perpetuates poverty, it is of paramount importance to investigate and develop new medicines for neglected populations suffering from NTDs. Furthermore, there is not only a need to develop and evaluate novel therapies, but also to ensure that these are affordable, available, and adapted to the communities who need them. The NIH has proposed a “4 C's” framework which is relevant for neglected diseases and populations and should be leveraged for the study of the Twice Neglected: Consider inclusion; Collect data from neglected populations with neglected conditions; Characterize differences through meaningful analysis; Communicate findings pertaining to neglected diseases and populations. With this editorial, the British Journal of Clinical Pharmacology hereby launches a call for high-quality articles focusing on NTDs in special populations, to facilitate and encourage the reversal of this dual neglect.

Genetic and pharmacological evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular and animal models of Huntington's disease (HD), suggesting that selective inhibition of ATM could provide a novel clinical intervention to treat HD. Here, we describe the development and characterization of ATM inhibitor molecules to enable in vivo proof-of-concept studies in HD animal models. Starting from previously reported ATM inhibitors, we aimed with few modifications to increase brain exposure by decreasing P-glycoprotein liability while maintaining potency and selectivity. Here, we report brain-penetrant ATM inhibitors that have robust pharmacodynamic (PD) effects consistent with ATM kinase inhibition in the mouse brain and an understandable pharmacokinetic/PD (PK/PD) relationship. Compound 17 engages ATM kinase and shows robust dose-dependent inhibition of X-ray irradiation-induced KAP1 phosphorylation in the mouse brain. Furthermore, compound 17 protects against mHTT (Q73)-induced cytotoxicity in a cortical-striatal cell model of HD.

New Organisation for Economic Co-operation and Development (OECD) research suggests that effective donor programming on gender in fragile contexts requires doing more and doing things differently. A critical step is to close financing gaps in key sectors through both dedicated funding and gender mainstreaming. Donors can also do more to improve quality of programming, notably through supporting women as active agents in reducing conflict and fragility; paying more attention to transforming root causes of inequality and fragility, such as gender norms and relations; adopting more politically smart and adaptive approaches; and strengthening donor co-ordination on gender. Donors should ask not only how fragility shapes or impacts on gender inequality, but also how gender ideologies and practices can contribute to fuelling fragility. Top-level leadership, matched by dedicated expertise and robust accountability systems, was found to be key in improving how gender is integrated into donor programmes in...

Both autism spectrum (ASD) and anxiety disorders are associated with atypical neural and attentional responses to emotional faces, differing in affective face processing from typically developing peers. Within a longitudinal study of children with ASD (23 male, 3 female), we hypothesized that early ERPs to emotional faces would predict concurrent and later ASD and anxiety symptoms. Greater response amplitude to fearful faces corresponded to greater social communication difficulties at age 3, and less improvement by age 14. Faster ERPs to neutral faces predicted greater ASD symptom improvement over time, lower ASD severity in adolescence, and lower anxiety in adolescence. Early individual differences in processing of emotional stimuli likely reflect a unique predictive contribution from social brain circuitry early in life.

ObjectivesThe aim of the study was to evaluate citation analysis as an approach to measuring core outcome set (COS) uptake, by assessing whether the number of citations for a COS report could be used as a surrogate measure of uptake of the COS by clinical trial lists.Study Design and SettingCitation data were obtained for COS reports published before 2010 in five disease areas (systemic sclerosis,rheumatoid arthritis, eczema, sepsis and critical care, and female sexual dysfunction). Those publications identified as a report of a clinical trial were examined to identify whether or not all outcomes in the COS were measured in the trial.ResultsClinical trials measuring the relevant COS made up a small proportion of the total number of citations for COS reports. Not all trials citing a COS report measured all the recommended outcomes. Some trials cited the COS reports for other reasons, including the definition of a condition or other trial design issues addressed by the COS report.Conclusion Although citation data can be readily accessed, it should not be assumed that the citing of a COS report indicates that atrial has measured the recommended COS. Alternative methods for assessing COS uptake are needed.

Fifty melamine-ware articles were tested for the migration of formaldehyde - with hexamethylenetetramine (HMTA) expressed as formaldehyde - to see whether the total specific migration limit (SML(T)) was being observed. The SML(T), given in European Commission Directive 2002/72/EC as amended, is 15 mg kg(-1). Fourier transform-infrared (FT-IR) spectroscopy was carried out on the articles to confirm the plastic type. Articles were exposed to the food simulant 3% (w/v) aqueous acetic acid under conditions representing their worst foreseeable use. Formaldehyde and HMTA in food simulants were determined by a spectrophotometric derivatization procedure. Positive samples were confirmed by a second spectrophotometric procedure using an alternative derivatization agent. As all products purchased were intended for repeat use, three sequential exposures to the simulant were carried out. Formaldehyde was detected in the simulant exposed to 43 samples. Most of the levels found were well below the limits set in law such that 84% of the samples tested were compliant. However, eight samples had formaldehyde levels that were clearly above the legal maximum at six to 65 times the SML(T).

Methods for attaching lipophilic side-chains to an amino-modified uracil base in oligonucleotides via orthogonal amide and disulphide linkages are described. The oligonucleotide conjugates are characterised in terms of their distinctive chromatographic and spectroscopic properties.

The employment relationship is redefined with each new communication. If all communication presents a consistent vision, that vision can infuse the organization.

We report the overproduction of the non-specific endonuclease domain of the bacterial toxin colicin E9 and its preliminary characterisation in vitro. The enzymatic colicins (61 kDa) are normally released from producing cells in a complex with their cognate inhibitors, known as the immunity proteins (9.5 kDa). Tryptic digestion of the purified ColE9 complex was found to generate two major components, a monomer derived from the N-terminal and central regions of the toxin and a heterodimer comprising the catalytically active C-terminal domain of the colicin bound to its intact immunity protein, Im9. N-terminal amino acid sequencing, in conjunction with electrospray mass spectrometry, shows that preparations of the DNase domain isolated by this method are heterogeneous, thus making subsequent mechanistic and structural analysis difficult. This problem was circumvented by selectively overexpressing the C-terminal 15-kDa nuclease domain of colicin E9 in tandem with its cognate inhibitor in Escherichia coli. This tandem overexpression strategy allowed high-level production of a 25-kDa protein complex comprising the C-terminal DNase domain of colicin E9 tightly bound to its specific inhibitor Im9, thus masking the anticipated toxicity of the nuclease. The DNase domain was then separated from Im9 under denaturing conditions, refolded by removal of the denaturant and the renatured protein shown to possess both endonuclease and Im9 binding activity. These results describe a novel method for the overproduction of a nuclease in bacteria by co-expressing its specific inhibitor and lay the foundations for a full mechanistic, biophysical and structural characterization of the isolated DNase domain of the colicin E9 toxin.

This study explored young people's attitudes towards, and knowledge of, the UK criminal justice system and their human rights. Knowledge and attitudes were measured using a 120-item questionnaire that was administered to 141 young offenders who were incarcerated for the first time (Offenders Inexperienced with Incarceration), young offenders who were incarcerated more than once (Offenders Experienced with Incarceration); and a Control group (of nonincarcerated young people). The results found that Offenders Experienced with Incarceration did not possess a greater knowledge of the criminal justice system, despite their increased experience. However, their attitude was significantly more negative than that of either the Offenders Inexperienced with Incarceration or the Control group. The Control group demonstrated a better understanding and a significantly more positive attitude towards their human rights than either of the offender groups. In conclusion, the current level of understanding and attitudes of young offenders about the criminal justice system and their human rights suggest that they may be limited in their capacity to make informed decisions regarding active participation.

To evaluate treatment-seeking behaviour, financial impact and time lost due to malaria events, in southern Mozambique and eastern South Africa.In-depth household surveys (828 in Mozambique and 827 in South Africa) were analysed. An asset index was calculated using principal component analysis to allow comparison across socio-economic groups. Direct costs of seeking care and the time lost due to malaria were determined. The extent of catastrophic payments was assessed using as thresholds the traditional 10% of household income and 40% of non-food income, as recently recommended by WHO.Poverty was highly prevalent: 70% of the South African and 95% of Mozambican households studied lived on less than $1 per capita per day. Around 97% of those with recent malaria sought healthcare, mainly in public facilities. Out-of-pocket household expenditure per malaria episode averaged $2.30 in South Africa and $6.50 in Mozambique. Analysis at the individual household level found that 32-34% of households in Mozambique, compared with 9-13% of households in South Africa, incurred catastrophic payments for malaria episodes. Results based on mean values underestimated the prevalence of catastrophic payments. Days off work/school were higher in Mozambique.The high rate of health seeking in public health facilities seems unusual in the African context, which bodes well for high coverage with artemisinin-based combinations, even if only deployed within the public sector. However, despite no or modest charges for public sector primary healthcare, households frequently incur catastrophic expenditure on a single malaria episode.

We conducted a retrospective study of AIDS-associated cerebral toxoplasmosis. Eighteen patients received pyrimethamine plus sulfadiazine and 25 co-trimoxazole, with comparable baseline characteristics. There were no differences in clinical outcomes, but co-trimoxazole was better tolerated (p = 0.066). There was also a trend towards more deaths among patients who received glucocorticoids.

When siblings were temporarily excluded from visiting their baby brother or sister in NICU and SCBU clinical areas, I noticed that great difficulties and misunderstandings started to arise in many families on the unit. Siblings were confused and parents reported they felt that their behaviour was the reason of them not being able to visit, which in time added to parents stress levels and copying strategies. To reduce this negative impact a way was sought to respond to their needs and their parent’s needs of ensuring attachment and communication links exist between older siblings at home and the baby they have yet to meet through daily progress diaries. Here is the poster I designed explaining the benefits to parents and why this is so important to consider all members of the family when the unthinkable happens. Through introducing this positive evaluated practice we have noticed many extra improvements in family centred care. Not only have the siblings enjoyed there special diaries and communication with the baby in hospital, the parents have also embraced this form of communication. It has also enhanced staff communication as it has raised their awareness of the families home experiences and difficulties. We plan to continue this practice even when siblings are again permitted into the neonatal setting as it also provides an excellent account of the early journey these young vulnerable children experience.

Topical application of the isoflavone equol immediately following solar-simulated UV (SSUV) radiation exposure has previously been demonstrated to have significant photoprotective effects. Equol reduced both the inflammatory edema and the systemic suppression of the contact hypersensitivity reaction in hairless mice. Furthermore, daily topical equol application immediately following irradiation during a 10-week chronic SSUV exposure regime also reduced photocarcinogenesis severity in the mouse. This study examines the potential for topical equol to prevent photoaging in response to chronic SSUV irradiation for up to 30 weeks. We did not find consistent expression of the characteristic markers of photoaging until 30 weeks, although moderate epidermal hyperplasia and a transient increase in dermal mast cell numbers were evident after 1 week. Daily application of 10 muM equol lotion significantly reduced these early changes. However after 30 weeks of SSUV exposure, photoaging was well developed, as shown histologically by markedly increased epidermal hyperplasia, increased dermal mast cell number, pronounced focal elastotic deposits, degraded dermal collagen and deposition of glycosaminoglycans in the lower dermis. Topical equol treatment protected significantly from each of these impairments, as demonstrated histologically and quantitatively. Additionally, equol was found to have strong antioxidant action against acute UVA (320-400 nm)-induced lipid peroxidation of mouse skin, this property accounting for its antiphotoaging mechanism. The evidence for equol's antiphotoaging activity, taken together with its anti-inflammatory, immunoprotective and anticarcinogenic efficacy against SSUV irradiation in the mouse, suggests that equol could be developed as a helpful topical photoprotective agent for daily use by humans.

Part 1: Introduction 1. Introduction Karen Barnes and 'Funmi Olonisakin 2. The Evolution and Implementation of United Nations Security Council Resolution 1325: An Overview Karen Barnes Part 2: Country Case Studies 3. Kosovo Gendered Violence and UNSCR 1325: Shifting paradigms on Women, Peace and Security Catherina H. Hall-Martin 4. Security Council Resolution 1325 Implementation in Liberia: Dilemmas and Challenges E. Njoki Wamai 5. Nepal and the Implementation of United Nations Security Council 1325 Lesley Abdela 6. Implementation of United Nations Security Council Resolution 1325 in Nigeria Eka Ikpe 7. Rwanda and the Implementation of United Nations Security Council Resolution 1325 Kiri-Ann E. Richardson Olney 8. Lost in Translation? UNAMSIL, Security Council Resolution 1325 and Women Building Peace in Sierra Leone Karen Barnes 9. The Impact of UN Security Council Resolution 1325 and Peacekeeping Operations in Sudan Gihan Eltahir 10. Women and Gender Issues in Peacebuilding: Lessons Learned from Timor-Leste Sumie Nakaya Part 3: Regional Case Studies 11. The African Union and Implementation of UNSCR 1325 Bineta Diop 12. The Gender Dimensions of the ECOWAS Peace and Security Architecture: a Regional Perspective on UN Security Council Resolution 1325 Awa Ceesay- Ebo 13. A look at Security Council Resolution 1325 in SADC Nyaradzo Machingambi-Pariola 14. Turning policies into action? The European Union and the Implementation of UNSCR 1325 Karen Barnes Part 4: Conclusion 15. Conclusion 'Funmi Olonisakin and Eka Ikpe