Changes in standard of candidates taking the MRCP(UK) Part 1 examination, 1985 to 2002: Analysis of marker questions

The maintenance of standards is a problem for postgraduate medical examinations, particularly if they use norm-referencing as the sole method of standard setting. In each of its diets, the MRCP(UK) Part 1 Examination includes a number of marker questions, which are unchanged from their use in a previous diet. This paper describes two complementary studies of marker questions for 52 diets of the MRCP(UK) Part 1 Examination over the years 1985 to 2001 to assess whether standards have changed

Quantifying the effect of testate amoeba decomposition on peat-based water-table reconstructions

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.Testate amoebae are a widely-used tool for palaeohydrological reconstruction from peatlands. However, it has been observed that weak idiosomic siliceous tests (WISTs) are common in uppermost peats, but very rarely found as subfossils deeper in the peat profile. This taphonomic problem has been noted widely and it has been established that WISTs disaggregate and/or dissolve in the low pH condition of ombrotrophic peatlands. Here we investigate the effect of this taphonomic problem on water-table reconstructions from thirty European peatlands through the comparison of reconstructions based on all taxa and those with WISTs removed. In almost all cases the decomposition of WISTs does not introduce discernible bias to peatland water-table reconstructions. However, some discrepancy is apparent when large abundances of Corythion-Trinema type are present (9−12 cm deviation with 50–60% abundance of this particular taxon). We recommend that WISTs should be removed before carrying out water-table reconstructions, and that the minimum count of testate amoebae per sample should exclude WISTs to ensure the development of robust reconstructions

Paternally expressed imprinted genes under positive Darwinian selection in Arabidopsis thaliana

Genomic imprinting is an epigenetic phenomenon where autosomal genes display uniparental expression depending on whether they are maternally or paternally inherited. Genomic imprinting can arise from parental conflicts over resource allocation to the offspring, which could drive imprinted loci to evolve by positive selection. We investigate whether positive selection is associated with genomic imprinting in the inbreeding species Arabidopsis thaliana. Our analysis of 140 genes regulated by genomic imprinting in the A. thaliana seed endosperm demonstrates they are evolving more rapidly than expected. To investigate whether positive selection drives this evolutionary acceleration, we identified orthologs of each imprinted gene across 34 plant species and elucidated their evolutionary trajectories. Increased positive selection was sought by comparing its incidence among imprinted genes with non-imprinted controls. Strikingly, we find a statistically significant enrichment of imprinted paternally expressed genes (iPEGs) evolving under positive selection, 50.6% of the total, but no such enrichment for positive selection among imprinted maternally expressed genes (iMEGs). This suggests that maternally- and paternally-expressed imprinted genes are subject to different selective pressures. Almost all positively selected amino acids were fixed across 80 sequenced A. thaliana accessions, suggestive of selective sweeps in the A. thaliana lineage. The imprinted genes under positive selection are involved in processes important for seed development including auxin biosynthesis and epigenetic regulation. Our findings support a genomic imprinting model for plants where positive selection can affect paternally-expressed genes due to continued conflict with maternal sporophyte tissues, even when parental conflict is reduced in predominantly inbreeding species

Investigating human audio-visual object perception with a combination of hypothesis-generating and hypothesis-testing fMRI analysis tools

Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A < AV > V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis

Picomolar, selective, and subtype-specific small-molecule inhibition of TRPC1/4/5 channels

The concentration of free cytosolic Ca(2+) and the voltage across the plasma membrane are major determinants of cell function. Ca(2+)-permeable non-selective cationic channels are known to regulate these parameters but understanding of these channels remains inadequate. Here we focus on Transient Receptor Potential Canonical 4 and 5 proteins (TRPC4 and TRPC5) which assemble as homomers or heteromerize with TRPC1 to form Ca(2+)-permeable non-selective cationic channels in many mammalian cell types. Multiple roles have been suggested including in epilepsy, innate fear, pain and cardiac remodeling but limitations in tools to probe these channels have restricted progress. A key question is whether we can overcome these limitations and develop tools which are high-quality, reliable, easy to use and readily accessible for all investigators. Here, through chemical synthesis and studies of native and over-expressed channels by Ca(2+) and patch-clamp assays, we describe compound 31 (C31), a remarkable small-molecule inhibitor of TRPC1/4/5 channels. Its potency ranged from 9 to 1300 pM, depending on the TRPC1/4/5 subtype and activation mechanism. Other channel types investigated were unaffected, including TRPC3, TRPC6, TRPV1, TRPV4, TRPA1, TRPM2, TRPM8 and store-operated Ca(2+) entry mediated by Orai1. These findings suggest identification of an important experimental tool compound which has much higher potency for inhibiting TRPC1/4/5 channels than previously reported agents, impressive specificity, and graded subtype selectivity within the TRPC1/4/5 channel family. The compound should greatly facilitate future studies of these ion channels. We suggest naming this TRPC1/4/5-inhibitory compound Pico145

Enhancement of the anti-tumour effect of cyclophosphamide by the bioreductive drugs AQ4N and tirapazamine

The ability of the bioreductive drugs AQ4N and tirapazamine to enhance the anti-tumour effect of cyclophosphamide was assessed in three murine tumour models. In male BDF mice implanted with the T50/80 mammary carcinoma, AQ4N (50–150 mg kg−1) in combination with cyclophosphamide (100 mg kg−1) produced an effect equivalent to a single 200 mg kg−1dose of cyclophosphamide. Tirapazamine (25 mg kg−1) in combination with cyclophosphamide (100 mg kg−1) produced an effect equivalent to a single 150 mg kg−1dose of cyclophosphamide. In C3H mice implanted with the SCCVII or RIF-1 tumours, enhancement of tumour cell killing was found with both drugs in combination with cyclophosphamide (50–200 mg kg−1); AQ4N (50–200 mg kg−1) produced a more effective combination than tirapazamine (12.5–50 mg kg−1). Unlike tirapazamine, which showed a significant increase in toxicity to bone marrow cells, the combination of AQ4N (100 mg kg−1) 6 h prior to cyclophosphamide (100 mg kg−1) resulted in no additional toxicity towards bone marrow cells compared to that caused by cyclophosphamide alone. In conclusion, AQ4N gave a superior anti-tumour effect compared to tirapazamine when administered with a single dose of cyclophosphamide (100 mg kg−1). © 2000 Cancer Research Campaig

Oxide Heterostructures from a Realistic Many-Body Perspective

Oxide heterostructures are a new class of materials by design, that open the possibility for engineering challenging electronic properties, in particular correlation effects beyond an effective single-particle description. This short review tries to highlight some of the demanding aspects and questions, motivated by the goal to describe the encountered physics from first principles. The state-of-the-art methodology to approach realistic many-body effects in strongly correlated oxides, the combination of density functional theory with dynamical mean-field theory, will be briefly introduced. Discussed examples deal with prominent Mott-band- and band-band-insulating type of oxide heterostructures, where different electronic characteristics may be stabilized within a single architectured oxide material.Comment: 19 pages, 9 figure

Treating latent TB in primary care: a survey of enablers and barriers among UK General Practitioners.

BACKGROUND: Treating latent tuberculosis infection (LTBI) is an important public health intervention. In the UK, LTBI treatment is delivered in secondary care. Treating LTBI in the community would move care closer to home and could increase uptake and treatment completion rates. However, healthcare providers' views about the feasibility of this in the UK are unknown. This is the first study to investigate perceived barriers and enablers to primary care-based LTBI treatment among UK general practitioners (GPs). METHODS: A national survey amongst 140 randomly sampled UK GPs practising in areas of high TB incidence was performed. GPs' experience and perceived confidence, barriers and enablers of primary care-based LTBI treatment were explored and multivariable logistic regression was used to determine whether these were associated with a GP's willingness to deliver LTBI treatment. RESULTS: One hundred and twelve (80 %) GPs responded. Ninety-three (83 %; 95 % CI 75 %-89 %) GPs said they would be willing to deliver LTBI treatment in primary care, if key perceived barriers were addressed during service development. The major perceived barriers to delivering primary care-based LTBI treatment were insufficient experience among GPs of screening and treating LTBI, lack of timely specialist support and lack of allied healthcare staff. In addition, GPs felt that appropriate resourcing was key to the successful and sustainable delivery of the service. GPs who reported previous experience of screening or treatment of patients with active or latent TB were almost ten times more likely to be willing to deliver LTBI treatment in primary care compared to GPs with no experience (OR: 9.98; 95 % CI 1.22-81.51). CONCLUSIONS: UK GPs support primary care-based LTBI treatment, provided they are given appropriate training, specialist support, staffing and financing