Ex vivo transdermal delivery of 3H-labelled atovaquone solid drug nanoparticles: a comparison of topical, intradermal injection and microneedle assisted administration.

Inherent barrier properties of the skin impose significant challenges to the transdermal delivery of drugs to systemic circulation. Here, the ex vivo transdermal permeation and deposition of an anti-malarial prophylactic atovaquone solid drug nanoformulation is radiometrically evaluated following application of a solid microneedle format.

Dense sampling of ethnic groups within African countries reveals fine-scale genetic structure and extensive historical admixture.

Previous studies have highlighted how African genomes have been shaped by a complex series of historical events. Despite this, genome-wide data have only been obtained from a small proportion of present-day ethnolinguistic groups. By analyzing new autosomal genetic variation data of 1333 individuals from over 150 ethnic groups from Cameroon, Republic of the Congo, Ghana, Nigeria, and Sudan, we demonstrate a previously underappreciated fine-scale level of genetic structure within these countries, for example, correlating with historical polities in western Cameroon. By comparing genetic variation patterns among populations, we infer that many northern Cameroonian and Sudanese groups share genetic links with multiple geographically disparate populations, likely resulting from long-distance migrations. In Ghana and Nigeria, we infer signatures of intermixing dated to over 2000 years ago, corresponding to reports of environmental transformations possibly related to climate change. We also infer recent intermixing signals in multiple African populations, including Congolese, that likely relate to the expansions of Bantu language-speaking peoples.

Evidence of the interplay of genetics and culture in Ethiopia.

The rich linguistic, ethnic and cultural diversity of Ethiopia provides an unprecedented opportunity to understand the level to which cultural factors correlate with-and shape-genetic structure in human populations. Using primarily new genetic variation data covering 1,214 Ethiopians representing 68 different ethnic groups, together with information on individuals' birthplaces, linguistic/religious practices and 31 cultural practices, we disentangle the effects of geographic distance, elevation, and social factors on the genetic structure of Ethiopians today. We provide evidence of associations between social behaviours and genetic differences among present-day peoples. We show that genetic similarity is broadly associated with linguistic affiliation, but also identify pronounced genetic similarity among groups from disparate language classifications that may in part be attributable to recent intermixing. We also illustrate how groups reporting the same culture traits are more genetically similar on average and show evidence of recent intermixing, suggesting that shared cultural traits may promote admixture. In addition to providing insights into the genetic structure and history of Ethiopia, we identify the most important cultural and geographic predictors of genetic differentiation and provide a resource for designing sampling protocols for future genetic studies involving Ethiopians.

Structure and ancestry patterns of Ethiopians in genome-wide autosomal DNA.

We review some of the current insights derived from the analyses of new large-scale, genome-wide autosomal variation data studies incorporating Ethiopians. Consistent with their substantial degree of cultural and linguistic diversity, genetic diversity among Ethiopians is higher than that seen across much larger geographic regions worldwide. This genetic variation is associated in part with ethnic identity, geography and linguistic classification. Numerous and varied admixture events have been inferred in Ethiopian groups, for example, involving sources related to present-day groups in West Eurasia and North Africa, with inferred dates spanning a few hundred to more than 4500 years ago. These disparate inferred ancestry patterns are correlated in part with groups' broad linguistic classifications, though with some notable exceptions. While deciphering these complex genetic signals remains challenging with available data, these studies and other projects focused on resolving competing hypotheses on the origins of specific ethnolinguistic groups demonstrate how genetic analyses can complement findings from anthropological and linguistic studies on Ethiopians.

Core principles to reduce current variations that exist in grading of midwifery practice in the United Kingdom.

AIM: To reduce variations in grading of midwifery practice and enhance reliability of assessment. BACKGROUND: The first phase of a national project showed there to be widely ranging interpretation and application of professional educational standards in relation to grading of practice in midwifery. This raised concerns about reliability and equity of professional assessment. The second phase therefore sought to achieve consensus on a set of core principles. METHODS: A participatory action research process in two stages, using a Mini-Delphi approach. Educational leads from all 55 institutions delivering midwifery programmes nationally were invited to participate. Stage one: Questionnaire comprising 12 statements drawn from the findings of the initial phase of the project. Stage two: Face-to-face discussion. FINDINGS: Statements were categorised based on questionnaire responses: 1) Consensus, 2) Staged consensus, 2) Minor modifications, 4) Controversial. Consensus was achieved on 11 core principles through group discussion; only one was omitted from the final set. RECOMMENDATIONS: All midwifery programmes nationally to incorporate the agreed core principles. Findings should be disseminated to the regulatory body to help inform changes to midwifery and nursing educational standards. The core principles may also contribute to curriculum development in midwifery and other professions internationally.

A scoping study to explore the application and impact of grading practice in pre-registration midwifery programmes across the United Kingdom.

Grading of practice is a mandatory element of programmes leading to registration as a midwife in the United Kingdom, required by the Nursing and Midwifery Council. This validates the importance of practice by placing it on an equal level with academic work, contributing to degree classification. This paper discusses a scoping project undertaken by the Lead Midwives for Education group across the 55 Higher Education Institutions in the United Kingdom which deliver pre-registration midwifery programmes. A questionnaire was circulated and practice tools shared, enabling exploration of the application of the standards and collation of the views of the Lead Midwives. Timing and individuals involved in practice assessment varied as did the components and the credit weighting applied to practice modules. Sign-off mentor confidence in awarding a range of grades had increased over time, and mentors seemed positive about the value given to practice and their role as professional gatekeepers. Grading was generally felt to be more robust and meaningful than pass/refer. It also appeared that practice grading may contribute to an enhanced student academic profile. A set of guiding principles is being developed with the purpose of enhancing consistency of the application of the professional standards across the United Kingdom.

Characterization of the interaction of staphylococcal enterotoxin B with CD1d expressed in human renal proximal tubule epithelial cells.

BACKGROUND: Participation of renal cells in the pathogenesis of staphylococcal enterotoxin B (SEB) is critical for late cleansing and sequestration of the antigens facilitated by CD1d mediated antigen sensing and recognition. This is a noted deviation from the typical antigen recognition process that recruits the major histocompatibility complex class II (MHC II) molecules. The immunological importance of CD1d is underscored by its influences on the performances of natural killer T-cells and thereby mediates the innate and adaptive immune systems. RESULTS: Using diffraction-based dotReady™ immunoassays, the present study showed that SEB directly and specifically conjugated to CD1d. The specificity of the conjugation between SEB and CD1d expressed on human renal proximal tubule epithelial cells (RPTEC) was further established by selective inhibition of CD1d prior to its exposure to SEB. We found that SEB induced the expression of CD1d on the cell surface prompting a rapid conjugation between them. The mRNA transcripts encoding CD1d remained elevated potentially after completing the antigen cleansing process. CONCLUSION: Molecular targets associated with the delayed pathogenic response have essential therapeutic values. Particularly in the event of bioterrorism, the caregivers are typically able to intervene much later than the toxic exposures. Given circumstances mandate a paradigm shift from the conventional therapeutic strategy that counts on targeting the host markers responding to the early assault of pathogens. We demonstrated the role of CD1d in the late stage of pathogen recognition and cleansing, and thereby underscored its clinical potential in treating bioweaponizable antigens, such as Staphylococcal enterotoxin B (SEB).

Presenting qualitative data through the co-construction of a model.

Research skills are developed in pre-registration midwifery curricula to enhance student midwives' appreciation and appropriate application of evidence within their midwifery practice. A spontaneous, innovative session was facilitated based on student experiences of non-midwifery placements, which helped demonstrate how qualitative data are analysed and can then be presented. By listening to each other's varied experiences, the students were able to relate their research knowledge to date with their collective 'empirical data' to enhance their understanding of presenting qualitative research. The paper reports on the learning process. It is an evaluation of the session, with student permission for publication gained; it is not research.

Exploring the value of the tripartite assessment of students in pre-registration midwifery education: a review of the evidence.

Many universities use a tripartite assessment within the pre-registration midwifery curriculum to grade student practice; we consider what the purpose and value are from an educational, formal and social perspective. By utilising research, policy documents and reflections from our experiences we explore the principles which underpin this judgement of student performance. After deliberation, we consider the increased presence in practice to have many benefits, but have evidence that it is not required educationally, to assess student practice, or to formalise the assessment process, since sign-off mentors are now better prepared to undertake this role. Thus, to support our increased partnership with practice, afforded by tripartite assessments, we offer an alternative.

The transcriptional repressor TupA in Aspergillus niger is involved in controlling gene expression related to cell wall biosynthesis, development, and nitrogen source availability.

The Tup1-Cyc8 (Ssn6) complex is a well characterized and conserved general transcriptional repressor complex in eukaryotic cells. Here, we report the identification of the Tup1 (TupA) homolog in the filamentous fungus Aspergillus niger in a genetic screen for mutants with a constitutive expression of the agsA gene. The agsA gene encodes a putative alpha-glucan synthase, which is induced in response to cell wall stress in A. niger. Apart from the constitutive expression of agsA, the selected mutant was also found to produce an unknown pigment at high temperatures. Complementation analysis with a genomic library showed that the tupA gene could complement the phenotypes of the mutant. Screening of a collection of 240 mutants with constitutive expression of agsA identified sixteen additional pigment-secreting mutants, which were all mutated in the tupA gene. The phenotypes of the tupA mutants were very similar to the phenotypes of a tupA deletion strain. Further analysis of the tupA-17 mutant and the ΔtupA mutant revealed that TupA is also required for normal growth and morphogenesis. The production of the pigment at 37°C is nitrogen source-dependent and repressed by ammonium. Genome-wide expression analysis of the tupA mutant during exponential growth revealed derepression of a large group of diverse genes, including genes related to development and cell wall biosynthesis, and also protease-encoding genes that are normally repressed by ammonium. Comparison of the transcriptome of up-regulated genes in the tupA mutant showed limited overlap with the transcriptome of caspofungin-induced cell wall stress-related genes, suggesting that TupA is not a general suppressor of cell wall stress-induced genes. We propose that TupA is an important repressor of genes related to development and nitrogen metabolism.

Professional education must remain rigorous and thorough.

I was dismayed by David Cameron's speech at the RCN congress in Harrogate (news May 13), even more so when he received a standing ovation.

Methylmercury, fish consumption, and the precautionary principle.

This paper considers several broad issues in the context of probabilistic assessment of the benefits of curtailing mercury (Hg) emissions from U.S. coal-fired power plants, based on information developed from recent literature and epidemiology studies of health effects of methylmercury. Exposure of the U.S. population is considered on the national scale, in large part because of recent questions arising from survey and experimental data about the relative importance of local deposition of airborne Hg. Although epidemiological studies have provided useful information, safe levels of Hg exposure remain uncertain, in part because of other dietary considerations in the populations that were studied. For example, much of the seafood consumed in one of the major studies was also contaminated with polychlorinated biphenyls, as are fish taken from some U.S. fresh waters. The primary epidemiological approach involves cross-study comparisons in relation to mean exposures, rather than detailed critiques of individual effects reported in each study. U.S. exposures are seen to be well below the levels at which adverse health effects are reported. This analysis supports the conclusion that unilateral reduction of Hg emissions from U.S. coal-fired power plants alone is unlikely to realize significant public health benefits.