The Acute Care Undergraduate TEaching (ACUTE) initiative: consensus development of core competencies in acute care for undergraduates in the United Kingdom

Background: The care of the acutely ill patient in hospital is often sub-optimal. Poor recognition of critical illness combined with a lack of knowledge, failure to appreciate the clinical urgency of a situation, a lack of supervision, failure to seek advice and poor communication have been identified as contributory factors. At present the training of medical students in these important skills is fragmented. The aim of this study was to use consensus techniques to identify the core competencies in the care of acutely ill or arrested adult patients that medical students should possess at the point of graduation. Design: Healthcare professionals were invited to contribute suggestions for competencies to a website as part of a modified Delphi survey. The competency proposals were grouped into themes and rated by a nominal group comprised of physicians, nurses and students from the UK. The nominal group rated the importance of each competency using a 5-point Likert scale. Results: A total of 359 healthcare professionals contributed 2,629 competency suggestions during the Delphi survey. These were reduced to 88 representative themes covering: airway and oxygenation; breathing and ventilation; circulation; confusion and coma; drugs, therapeutics and protocols; clinical examination; monitoring and investigations; team-working, organisation and communication; patient and societal needs; trauma; equipment; pre-hospital care; infection and inflammation. The nominal group identified 71 essential and 16 optional competencies which students should possess at the point of graduation. Conclusions: We propose these competencies form a core set for undergraduate training in resuscitation and acute care.

Simple sequence repeats reveal uneven distribution of genetic diversity in chloroplast genomes of Brassica oleracea L. and (n=9) wild relatives

Diversity in the chloroplast genome of 171 accessions representing the Brassica 'C' (n = 9) genome, including domesticated and wild B. oleracea and nine inter-fertile related wild species, was investigated using six chloroplast SSR (microsatellite) markers. The lack of diversity detected among 105 cultivated and wild accessions of B. oleracea contrasted starkly with that found within its wild relatives. The vast majority of B. oleracea accessions shared a single haplotype, whereas as many as six haplotypes were detected in two wild species, B. villosa Biv. and B. cretica Lam.. The SSRs proved to be highly polymorphic across haplotypes, with calculated genetic diversity values (H) of 0.23-0.87. In total, 23 different haplotypes were detected in C genome species, with an additional five haplotypes detected in B. rapa L. (A genome n = 10) and another in B. nigra L. (B genome, n = 8). The low chloroplast diversity of B. oleracea is not suggestive of multiple domestication events. The predominant B. oleracea haplotype was also common in B. incana Ten. and present in low frequencies in B. villosa, B. macrocarpa Guss, B. rupestris Raf. and B. cretica. The chloroplast SSRs reveal a wealth of diversity within wild Brassica species that will facilitate further evolutionary and phylogeographic studies of this important crop genus.

Domain swapping in the human histamine H-1 receptor

G-protein-coupled receptors (GPCRs) represent the largest family of receptors involved in transmembrane signaling. Although these receptors were generally believed to be monomeric entities, accumulating evidence supports the presence of GPCRs in multimeric forms. Here, using immunoprecipitation as well as time-resolved fluorescence resonance energy transfer to assess protein-protein interactions in living cells, we unambiguously demonstrate the occurrence of dimerization of the human histamine H-1 receptor. We also show the presence of domain-swapped H-1 receptor dimers in which there is the reciprocal exchange of transmembrane domain TM domains 6 and 7 between the receptors present in the dimer. Mutation of aspartate(107) in transmembrane (TM) 3 or phenylalanine(432) in TM6 to alanine results in two radioligand-binding-deficient mutant H-1 receptors. Coexpression of H-1 D(107)A and H-1 F(432)A, however, results in a reconstituted radioligand binding site that exhibits a pharmacological profile that corresponds to the wildtype H-1 receptor. Interestingly, the H-1 receptor radioligands [H-3] mepyramine and [H-3]-(-)- trans-1-phenyl-3-N, N-dimethylamino-1,2,3,4-tetrahydronaphthalene show differential saturation binding values (B-max) for wild-type H-1 receptors but not for the radioligand binding site that is formed upon coexpression of H-1 D(107)A and H-1 F(432)A receptors, suggesting the presence of different H-1 receptor populations.

Generation of anti-complement "prodrugs": cleavable reagents for specific delivery of complement regulators to disease sites

Expression of biologically active molecules as fusion proteins with antibody Fc can substantially extend the plasma half-life of the active agent but may also influence function. We have previously generated a number of fusion proteins comprising a complement regulator coupled to Fc and shown that the hybrid molecule has a long plasma half-life and retains biological activity. However, several of the fusion proteins generated had substantially reduced biological activity when compared with the native regulator or regulator released from the Fc following papain cleavage. We have taken advantage of this finding to engineer a prodrug with low complement regulatory activity that is cleaved at sites of inflammation to release active regulator. Two model prodrugs, comprising, respectively, the four short consensus repeats of human decay accelerating factor (CD55) linked to IgG4 Fc and the three NH2-terminal short consensus repeats of human decay accelerating factor linked to IgG2 Fc have been developed. In each, specific cleavage sites for matrix metalloproteinases and/or aggrecanases have been incorporated between the complement regulator and the Fc. These prodrugs have markedly decreased complement inhibitory activity when compared with the parent regulator in vitro. Exposure of the prodrugs to the relevant enzymes, either purified, or in supernatants of cytokine-stimulated chondrocytes or in synovial fluid, efficiently cleaved the prodrug, releasing active regulator. Such agents, having negligible systemic effects but active at sites of inflammation, represent a paradigm for the next generation of anti-C therapeutics.

Simulating the formation of secondary organic aerosol from the photooxidation of aromatic hydrocarbons

The formation and composition of secondary organic aerosol (SOA) from the photooxidation of benzene, p-xylene, and 1,3,5-trimethylbenzene has been simulated using the Master Chemical Mechanism version 3.1 (MCM v3.1) coupled to a representation of the transfer of organic material from the gas to particle phase. The combined mechanism was tested against data obtained from a series of experiments conducted at the European Photoreactor (EUPHORE) outdoor smog chamber in Valencia, Spain. Simulated aerosol mass concentrations compared reasonably well with the measured SOA data only after absorptive partitioning coefficients were increased by a factor of between 5 and 30. The requirement of such scaling was interpreted in terms of the occurrence of unaccounted-for association reactions in the condensed organic phase leading to the production of relatively more nonvolatile species. Comparisons were made between the relative aerosol forming efficiencies of benzene, toluene, p-xylene, and 1,3,5-trimethylbenzene, and differences in the OH-initiated degradation mechanisms of these aromatic hydrocarbons. A strong, nonlinear relationship was observed between measured (reference) yields of SOA and (proportional) yields of unsaturated dicarbonyl aldehyde species resulting from ring-fragmenting pathways. This observation, and the results of the simulations, is strongly suggestive of the involvement of reactive aldehyde species in association reactions occurring in the aerosol phase, thus promoting SOA formation and growth. The effect of NO, concentrations on SOA formation efficiencies (and formation mechanisms) is discussed.

Clinical trial: the effects of a trans-galactooligosaccharide prebiotic on faecal microbiota and symptoms in irritable bowel syndrome

Gut microflora-mucosal interactions may be involved in the pathogenesis of irritable bowel syndrome (IBS). To investigate the efficacy of a novel prebiotic trans-galactooligosaccharide in changing the colonic microflora and improve the symptoms in IBS sufferers. In all, 44 patients with Rome II positive IBS completed a 12-week single centre parallel crossover controlled clinical trial. Patients were randomized to receive either 3.5 g/d prebiotic, 7 g/d prebiotic or 7 g/d placebo. IBS symptoms were monitored weekly and scored according to a 7-point Likert scale. Changes in faecal microflora, stool frequency and form (Bristol stool scale) subjective global assessment (SGA), anxiety and depression and QOL scores were also monitored. The prebiotic significantly enhanced faecal bifidobacteria (3.5 g/d P < 0.005; 7 g/d P < 0.001). Placebo was without effect on the clinical parameters monitored, while the prebiotic at 3.5 g/d significantly changed stool consistency (P < 0.05), improved flatulence (P < 0.05) bloating (P < 0.05), composite score of symptoms (P < 0.05) and SGA (P < 0.05). The prebiotic at 7 g/d significantly improved SGA (P < 0.05) and anxiety scores (P < 0.05). The galactooligosaccharide acted as a prebiotic in specifically stimulating gut bifidobacteria in IBS patients and is effective in alleviating symptoms. These findings suggest that the prebiotic has potential as a therapeutic agent in IBS.

Dietary vitamin E modulates differential gene expression in the rat hippocampus: potential implications for its neuroprotective properties

A wide range of cell culture, animal and human epidemiological studies are suggestive of a role of vitamin E (VE) in brain function and in the prevention of neurodegeneration. However, the underlying molecular mechanisms remain largely unknown. In the current investigation Affymetrix gene chip technology was utilised to establish the impact of chronic VE deficiency on hippocampal genes expression. Male albino rats were fed either a VE deficient or standard diet (60 mg/kg feed) for a period of 9 months. Rats were sacrificed, the hippocampus removed and genes expression established in individual animals. VE deficiency showed to have a strong impact on genes expression in the hippocampus. An important number of genes found to be regulated by VE was associated with hormones and hormone metabolism, nerve growth factor, apoptosis, dopaminergic neurotransmission, and clearance of amyloid-beta and advanced glycated endproducts. In particular, VE strongly affected the expression of an array of genes encoding for proteins directly or indirectly involved in the clearance of amyloid beta, changes which are consistent with a protective effect of VE on Alzheimer's disease progression.

Nutrient gene interactions in lipid metabolism

Purpose of review To summarize recent findings relating to the impact of dietary fat composition on whole body lipid metabolism, and common gene variants on the blood lipid response to dietary fat change. Recent findings In recent years a more comprehensive understanding of the impact of polyunsaturated fat (PUFA) intake on the regulation of transcription factors involved in lipogenesis and fatty acid and lipoprotein metabolism has emerged. The evidence is suggestive of a greater potency of the long chain n-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and in particular their oxidative products, relative to n-6 Pi In the area of nutrigenetics a number of common gene variants have been identified which may be important determinants of the blood lipid response to altered dietary fat composition. However, confirmation of associations in independent cohorts, and an understanding of the size effect of individual or combinations of genotypes, is often lacking. Summary Although in the future, genotyping holds the potential as a public health tool to target and personalize dietary advice, nutrigenetics is a relatively new science, and further research is needed to address the existing inconsistencies and knowledge gaps.

Wheat glutenin proteins assemble into a nanostructure with unusual structural features

The proteins of wheat have a known propensity to aggregate into a variety of forms. We report here a novel nanostructure from wheat proteins, derived from a crude extract of high molecular weight glutenins. The structure was characterised by a significant thioflavin T (ThT) fluorescence and a fibrillar morphology by transmission electron microscopy (TEM). The ThT fluorescence and TEM data are suggestive of an amyloid structure, but the X-ray fibre diffraction data show a reflection pattern (4.02, 4.2-4.3, 4.6, 12.9,19.3 and 38.7 angstrom) inconsistent with both the classic amyloid form and the previously described beta-helix structure. The 4.6 angstrom reflection is consistent with that predicted for the amyloid inter-beta-strand, and the absence of the inter-beta-sheet distance at approximate to 10-11 angstrom is not unprecedented in amyloid-like structures. However, our observed X-ray reflection pattern has not been previously reported and suggests a novel wheat glutenin nanostructure. (C) 2008 Elsevier Ltd. All rights reserved.

Impact of saturated, polyunsaturated and monounsaturated fatty acid-rich micelles on lipoprotein synthesis and secretion in Caco-2 cells

Meal fatty acids have been shown to modulate the size and composition of triacylglycerol (TAG)-rich lipoproteins influencing the magnitude and duration of the postprandial plasma TAG response. As a result there is considerable interest in the origin of these meal fatty-acid induced differences in particle composition. Caco-2 cells were incubated over 4 days with fatty acid mixtures resembling the composition of saturated (SFA), monounsaturated (MUFA) and polyunsaturated fatty acid (PUFA)-rich meals fed in a previous postprandial study to determine their impact on lipoprotein synthesis and secretion. The MUFA- and PUFA-rich mixtures supported greater intracellular TAG, but not cholesterol accumulation compared with the SFA-rich mixture (P < 0.001). The MUFA-rich mixture promoted significantly greater TAG and cholesterol secretion than the other mixtures and significantly more apolipoprotein B-100 secretion than the PUFA-rich mixture (P < 0.05). Electron microscopy revealed the SFA-rich mixture had led to unfavourable effects on cellular morphology, compared with the unsaturated fatty acid-rich mixtures. Our findings suggest the MUFA-rich mixture, may support the formation of a greater number of TAG-rich lipoproteins, which is consistent with indirect observations from our human study. Our electron micrographs are suggestive that some endocytotic uptake of MUFA-rich taurocholate micelles may promote greater lipoprotein synthesis and secretion in Caco-2 cells.

Under-investigation of older people with abnormal chest radiographs

Background: Whilst many authors have previously suggested that older people are under-represented in the investigation and management of lung cancer, few data are available as to the effect of age on the subsequent investigation and management of a patient with an abnormal chest radiograph. Methods: During a 3-month period in a university teaching hospital, all abnormal chest radiographs suggestive of a possible diagnosis of lung cancer were identified, and patients subsequently followed to determine investigation, management and date of death over a 5-year period. Results: Thirty-seven younger (less than or equal to69 years, median age 62 years) and 43 older patients ( 670 years, median age 80 years) were identified. Of the 80 patients with a possible bronchial carcinoma only 59% had a further chest radiograph performed. Bronchoscopy was performed in 34% of patients, but a biopsy of the lesion was undertaken in only 24% of patients. Sixteen of the 80 patients, irrespective of what investigations had been undertaken, were referred for an oncological or surgical opinion. During the study period ( 3 months), 24% of the patients died. At 6, 24 and 60 months, respectively, the total deaths were 40, 78 and 88%. Conclusion: Older patients compared with those aged less than 70 years were less likely to be investigated, further, were more likely to be managed differently (i.e., less aggressively) and more likely to die within each time interval. In more of the older group a presumed death certificate diagnosis of pneumonia was made. When an abnormal chest radiograph raises the possibility of an underlying bronchial carcinoma, the finding of this study suggests that an ageist attitude influences the subsequent management of some patients. Copyright (C) 2005 S. Karger AG, Basel.

Polymer-drug conjugates: current status and future trends

Polymer conjugates are nano-sized, multicomponent constructs already in the clinic as anticancer compounds, both as single agents or as elements of combinations. They have the potential to improve pharmacological therapy of a variety of solid tumors. Polymer-drug conjugation promotes passive tumor targeting by the enhanced permeability and retention (EPR) effect and allows for lysosomotropic drug delivery following endocytic capture. In the first part of this review, we analyze the promising results arising from clinical trials of polymer-bound chemotherapy. The experience gained on these studies provides the basis for the development of a more sophisticated second-generation of polymer conjugates. However, many challenges still lay ahead providing scope to develop and refine this field. The "technology platform'' of polymer therapeutics allows the development of both new and exciting polymeric materials, the incorporation of novel bioactive agents and combinations thereof to address recent advances in drug therapy. The rational design of polymer drug conjugates is expected to realize the true potential of these "nanomedicines".

Understanding the relationship between repetition priming and mere exposure

Over the last two decades interest in implicit memory, most notably repetition priming, has grown considerably. During the same period, research has also focused on the mere exposure effect. Although the two areas have developed relatively independently, a number of studies has described the mere exposure effect as an example of implicit memory. Tacit in their comparisons is the assumption that the effect is more specifically a demonstration of repetition priming. Having noted that this assumption has attracted relatively little attention, this paper reviews current evidence and shows that it is by no means conclusive. Although some evidence is suggestive of a common underlying mechanism, even a modified repetition priming (perceptual fluency/attribution) framework cannot accommodate all of the differences between the two phenomena. Notwithstanding this, it seems likely that a version of this theoretical framework still offers the best hope of a comprehensive explanation for the mere exposure effect and its relationship to repetition priming. As such, the paper finishes by offering some initial guidance as to ways in which the perceptual fluency/attribution framework might be extended, as well as outlining important areas for future research.