Medicine, Dentistry & Health Sciences Collected Works - Research Publications
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ItemMicrocytosis and possible early iron deficiency in paediatric inpatients: a retrospective audit.(Springer Science and Business Media LLC, 2009-05-29)BACKGROUND: Iron deficiency anaemia is a common paediatric problem worldwide, with significant neurodevelopmental morbidity if left untreated. A decrease in the mean corpuscular volume (MCV) can be used as a surrogate marker for detecting early iron deficiency prior to definitive investigation and treatment. An audit cycle was therefore undertaken to evaluate and improve the identification, follow-up and treatment of abnormally low MCV results amongst the paediatric inpatients in an English district general hospital. METHODS: The audit cycle was performed retrospectively over two three-month periods (February to April 2006; September to November 2006), amongst patients aged between one month and 16 years that had full blood counts performed whilst admitted on the paediatric ward. Patients with at least one abnormally low MCV result were identified, and their notes reviewed. We looked for any underlying explanation for the result, adequate documentation of the result as abnormal, and instigation of follow-up or treatment. In-between the two audit periods, the results of the first audit period were presented to the medical staff and suggestions were made for improvements in documentation and follow-up of abnormal results. The z-test was used to test for equality of proportions between the two audit samples. RESULTS: Out of 701 inpatients across both audit periods that had full blood counts, 61 (8.7%) had a low MCV result. Only 15% of patients in each audit period had an identifiable explanation for their low MCV values. Amongst the remaining 85% with either potentially explicable or inexplicable results, there was a significant increase in documentation of results as abnormal from 25% to 91% of cases between the first and second audit periods (p = 0.00 using z-test). However, there was no accompanying increase in the proportion of patients who received follow-up or treatment for their abnormal results. CONCLUSION: Abnormal red cell indices that may indicate iron deficiency are frequently missed amongst paediatric inpatients. Medical staff education and the use of appropriate protocols or pathways could further improve detection and treatment rates in this setting.
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ItemTemporal and mechanistic dissociation of ATP and adenosine release during ischaemia in the mammalian hippocampus(BLACKWELL PUBLISHING, 2007-06)Adenosine is well known to be released during cerebral metabolic stress and is believed to be neuroprotective. ATP release under similar circumstances has been much less studied. We have now used biosensors to measure and compare in real time the release of ATP and adenosine during in vitro ischaemia in hippocampal slices. ATP release only occurred following the anoxic depolarisation, whereas adenosine release was apparent almost immediately after the onset of ischaemia. ATP release required extracellular Ca2+. By contrast adenosine release was enhanced by removal of extracellular Ca2+, whilst TTX had no effect on either ATP release or adenosine release. Blockade of ionotropic glutamate receptors substantially enhanced ATP release, but had only a modest effect on adenosine release. Carbenoxolone, an inhibitor of gap junction hemichannels, also greatly enhanced ischaemic ATP release, but had little effect on adenosine release. The ecto-ATPase inhibitor ARL 67156, whilst modestly enhancing the ATP signal detected during ischaemia, had no effect on adenosine release. Adenosine release during ischaemia was reduced by pretreatment with homosysteine thiolactone suggesting an intracellular origin. Adenosine transport inhibitors did not inhibit adenosine release, but instead they caused a twofold increase of release. Our data suggest that ATP and adenosine release during ischaemia are for the most part independent processes with distinct underlying mechanisms. These two purines will consequently confer temporally distinct influences on neuronal and glial function in the ischaemic brain.
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ItemA Supplementary Description of Cypridina mariae and Rediagnosis of the Genus Cylindroleberis (Ostracoda: Myodocopa: Cylindroleberididae)(PUBLIC LIBRARY SCIENCE, 2008-04-16)The ostracod family Cylindroleberididae is based on the genus Cylindroleberis Brady, 1868, and has a complicated nomenclatural history. The type species of Cylindroleberis is Cypridina mariae Baird, 1850. Baird described only the carapace, which had been considered lost. Thus, there was no reference point for the concept C. mariae or the genus Cylindroleberis. Baird's material has now been found in the Natural History Museum, London, U.K., and is illustrated here. To clarify the taxonomic status of C. mariae and Cylindroleberis, specimens were obtained from near the type locality, and a supplementary description is presented. This includes description of appendages, particularly the first antenna and mandible, which contain important diagnostic characters. This supplementary description provides important information about C. mariae, allowing a revision of the genus Cylindroleberis, and establishing a framework for future biological research on this ostracod group.
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ItemMucin 1 (MUC1) is a novel partner for MAL2 in breast carcinoma cells(BMC, 2009-01-28)BACKGROUND: The MAL2 gene, encoding a four-transmembrane protein of the MAL family, is amplified and overexpressed in breast and other cancers, yet the significance of this is unknown. MAL-like proteins have trafficking functions, but their molecular roles are largely obscure, partly due to a lack of known binding partners. METHODS: Yeast two-hybrid screening of a breast carcinoma cDNA expression library was performed using a full-length MAL2 bait, and subsequent deletion mapping experiments were performed. MAL2 interactions were confirmed by co-immunoprecipitation analyses and confocal microscopy was employed to compare protein sub-cellular distributions. Sucrose density gradient centrifugation of membranes extracted in cold Triton X-100 was employed to compare protein distributions between Triton X-100-soluble and -insoluble fractions. RESULTS: The tumor-associated protein mucin 1 (MUC1) was identified as a potential MAL2 partner, with MAL2/MUC1 interactions being confirmed in myc-tagged MAL2-expressing MCF-10A cells using co-immunoprecipitation assays. Deletion mapping experiments demonstrated a requirement for the first MAL2 transmembrane domain for MUC1 binding, whereas the MAL2 N-terminal domain was required to bind D52-like proteins. Confocal microscopy identified cytoplasmic co-localisation of MUC1 and MAL2 in breast cell lines, and centrifugation of cell lysates to equilibrium in sucrose density gradients demonstrated that MAL2 and MUC1 proteins were co-distributed between Triton X-100-soluble and -insoluble fractions. However co-immunoprecipitation analyses detected MAL2/MUC1 interactions in Triton X-100-soluble fractions only. Myc-MAL2 expression in MCF-10A cells was associated with both increased MUC1 detection within Triton X-100-soluble and -insoluble fractions, and increased MUC1 detection at the cell surface. CONCLUSION: These results identify MUC1 as a novel MAL2 partner, and suggest a role for MAL2 in regulating MUC1 expression and/or localisation.
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ItemNumerical and functional defects of blood dendritic cells in early- and late-stage breast cancer(NATURE PUBLISHING GROUP, 2007-10-30)The generation of antitumour immunity depends on the nature of dendritic cell (DC)-tumour interactions. These have been studied mostly by using in vitro-derived DC which may not reflect the natural biology of DC in vivo. In breast cancer, only one report has compared blood DC at different stages and no longitudinal evaluation has been performed. Here we conducted three cross-sectional and one one-year longitudinal assessments of blood DC in patients with early (stage I/II, n=137) and advanced (stage IV, n=36) disease compared to healthy controls (n=66). Patients with advanced disease exhibit markedly reduced blood DC counts at diagnosis. Patients with early disease show minimally reduced counts at diagnosis but a prolonged period (1 year) of marked DC suppression after tumour resection. While differing in frequency, DC from both patients with early and advanced disease exhibit reduced expression of CD86 and HLA-DR and decreased immunostimulatory capacities. Finally, by comparing a range of clinically available maturation stimuli, we demonstrate that conditioning with soluble CD40L induces the highest level of maturation and improved T-cell priming. We conclude that although circulating DC are compromised by loco-regional and systemic breast cancer, they respond vigorously to ex vivo conditioning, thus enhancing their immunostimulatory capacity and potential for immunotherapy.
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ItemNo Preview AvailableAnaesthesia in septic patients: good preparation and making the right choice?(BIOMED CENTRAL LTD, 2009)Septic patients may require anaesthesia for surgery or to facilitate endotracheal intubation for respiratory failure. These patients frequently start with a deranged haemodynamic state, including vasodilation with hypotension, and cardiomyopathy, making induction of anaesthesia a potentially hazardous task. Anaesthetic agents are well known to decrease contractility and to cause vasodilation - in part from direct effect of the drugs, and in part due to the state of anaesthesia, that causes reduced sympathetic tone. Before induction, the physician should understand the haemodynamic state (especially using echocardiography), should restore cardiovascular reserve with inotropes and vasopressors, and should induce anaesthesia with the smallest dose of the safest drug. In the previous issue of Critical Care, Zausig and colleagues show that propofol may not be the safest choice of induction agent in septic patients.
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ItemNo Preview AvailableThe MACPF/CDC family of pore-forming toxins(WILEY, 2008-09)Pore-forming toxins (PFTs) are commonly associated with bacterial pathogenesis. In eukaryotes, however, PFTs operate in the immune system or are deployed for attacking prey (e.g. venoms). This review focuses upon two families of globular protein PFTs: the cholesterol-dependent cytolysins (CDCs) and the membrane attack complex/perforin superfamily (MACPF). CDCs are produced by Gram-positive bacteria and lyse or permeabilize host cells or intracellular organelles during infection. In eukaryotes, MACPF proteins have both lytic and non-lytic roles and function in immunity, invasion and development. The structure and molecular mechanism of several CDCs are relatively well characterized. Pore formation involves oligomerization and assembly of soluble monomers into a ring-shaped pre-pore which undergoes conformational change to insert into membranes, forming a large amphipathic transmembrane beta-barrel. In contrast, the structure and mechanism of MACPF proteins has remained obscure. Recent crystallographic studies now reveal that although MACPF and CDCs are extremely divergent at the sequence level, they share a common fold. Together with biochemical studies, these structural data suggest that lytic MACPF proteins use a CDC-like mechanism of membrane disruption, and will help understand the roles these proteins play in immunity and development.
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ItemThe CHOICE (Choice of Health Options In prevention of Cardiovascular Events) replication trial: study protocol(BMC, 2008-10-06)BACKGROUND: Although morbidity and mortality from coronary heart disease (CHD) are high, only a minority of acute coronary syndrome (ACS) survivors accesses an effective secondary prevention program. We aim to determine whether the previously proven CHOICE program can be replicated at multiple sites and whether ongoing reinforcement further improves risk factor modification. METHODS/DESIGN: Participants eligible for but not accessing standard cardiac rehabilitation will be randomly allocated to either a previously tested 3-month CHOICE program or a 30-month CHOICE program (CHOICE-plus). Both groups will participate in individualised risk factor modules of differing duration that involve choice, goal setting and telephone follow-up for three months. CHOICE-plus will also receive additional face-to-face and telephone reinforcement between three and 30 months. At one site we will recruit a randomised control group, receiving conventional care. Primary outcomes are lipid levels, blood pressure, physical activity levels and smoking rates. Secondary outcomes include readmission rates, death, the number of risk factors, other modifiable risk factors, quality of life and process evaluation measures over three years. DISCUSSION: We present the rationale and design of a multi-centre, replication study testing a modular approach for the secondary prevention of CHD following an ACS. TRIAL REGISTRATION: [Clinical Trial Registration Number, ACTRN12608000182392].
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ItemMINT: the Molecular INTeraction database.(Oxford University Press (OUP), 2007-01)The Molecular INTeraction database (MINT, http://mint.bio.uniroma2.it/mint/) aims at storing, in a structured format, information about molecular interactions (MIs) by extracting experimental details from work published in peer-reviewed journals. At present the MINT team focuses the curation work on physical interactions between proteins. Genetic or computationally inferred interactions are not included in the database. Over the past four years MINT has undergone extensive revision. The new version of MINT is based on a completely remodeled database structure, which offers more efficient data exploration and analysis, and is characterized by entries with a richer annotation. Over the past few years the number of curated physical interactions has soared to over 95 000. The whole dataset can be freely accessed online in both interactive and batch modes through web-based interfaces and an FTP server. MINT now includes, as an integrated addition, HomoMINT, a database of interactions between human proteins inferred from experiments with ortholog proteins in model organisms (http://mint.bio.uniroma2.it/mint/).
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ItemThe male sex pheromone of the butterfly Bicyclus anynana: towards an evolutionary analysis.(Public Library of Science (PLoS), 2008-07-23)BACKGROUND: Female sex pheromones attracting mating partners over long distances are a major determinant of reproductive isolation and speciation in Lepidoptera. Males can also produce sex pheromones but their study, particularly in butterflies, has received little attention. A detailed comparison of sex pheromones in male butterflies with those of female moths would reveal patterns of conservation versus novelty in the associated behaviours, biosynthetic pathways, compounds, scent-releasing structures and receiving systems. Here we assess whether the African butterfly Bicyclus anynana, for which genetic, genomic, phylogenetic, ecological and ethological tools are available, represents a relevant model to contribute to such comparative studies. METHODOLOGY/PRINCIPAL FINDINGS: Using a multidisciplinary approach, we determined the chemical composition of the male sex pheromone (MSP) in the African butterfly B. anynana, and demonstrated its behavioural activity. First, we identified three compounds forming the presumptive MSP, namely (Z)-9-tetradecenol (Z9-14:OH), hexadecanal (16:Ald ) and 6,10,14-trimethylpentadecan-2-ol (6,10,14-trime-15-2-ol), and produced by the male secondary sexual structures, the androconia. Second, we described the male courtship sequence and found that males with artificially reduced amounts of MSP have a reduced mating success in semi-field conditions. Finally, we could restore the mating success of these males by perfuming them with the synthetic MSP. CONCLUSIONS/SIGNIFICANCE: This study provides one of the first integrative analyses of a MSP in butterflies. The toolkit it has developed will enable the investigation of the type of information about male quality that is conveyed by the MSP in intraspecific communication. Interestingly, the chemical structure of B. anynana MSP is similar to some sex pheromones of female moths making a direct comparison of pheromone biosynthesis between male butterflies and female moths relevant to future research. Such a comparison will in turn contribute to understanding the evolution of sex pheromone production and reception in butterflies.