Medicine, Dentistry & Health Sciences Collected Works - Research Publications

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    Fat depot-specific characteristics are retained in strains derived from single human preadipocytes
    Tchkonia, T ; Giorgadze, N ; Pirtskhalava, T ; Thomou, T ; DePonte, M ; Koo, A ; Forse, RA ; Chinnappan, D ; Martin-Ruiz, C ; von Zglinicki, T ; Kirkland, JL (AMER DIABETES ASSOC, 2006-09)
    Fat depots vary in size, function, and potential contribution to disease. Since fat tissue turns over throughout life, preadipocyte characteristics could contribute to this regional variation. To address whether preadipocytes from different depots are distinct, we produced preadipocyte strains from single abdominal subcutaneous, mesenteric, and omental human preadipocytes by stably expressing human telomere reverse transcriptase (hTERT). These strains could be subcultured repeatedly and retained capacity for differentiation, while primary preadipocyte adipogenesis and replication declined with subculturing. Primary omental preadipocytes, in which telomeres were longest, replicated more slowly than mesenteric or abdominal subcutaneous preadipocytes. Even after 40 population doublings, replication, abundance of the rapidly replicating preadipocyte subtype, and resistance to tumor necrosis factor alpha-induced apoptosis were highest in subcutaneous, intermediate in mesenteric, and lowest in omental hTERT-expressing strains, as in primary preadipocytes. Subcutaneous hTERT-expressing strains accumulated more lipid and expressed more adipocyte fatty acid-binding protein (aP2), peroxisome proliferator-activated receptor gamma2, and CCAAT/enhancer-binding protein alpha than omental cells, as in primary preadipocytes, while hTERT abundance was similar. Thus, despite dividing 40 population doublings, hTERT strains derived from single preadipocytes retained fat depot-specific cell dynamic characteristics, consistent with heritable processes contributing to regional variation in fat tissue function.
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    Microcytosis and possible early iron deficiency in paediatric inpatients: a retrospective audit.
    Subramanian, DN ; Kitson, S ; Bhaniani, A (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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    Temporal and mechanistic dissociation of ATP and adenosine release during ischaemia in the mammalian hippocampus
    Frenguelli, BG ; Wigmore, G ; Llaudet, E ; Dale, N (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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    A Supplementary Description of Cypridina mariae and Rediagnosis of the Genus Cylindroleberis (Ostracoda: Myodocopa: Cylindroleberididae)
    Syme, AE ; Poore, GCB ; Stepanova, A (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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    Mucin 1 (MUC1) is a novel partner for MAL2 in breast carcinoma cells
    Fanayan, S ; Shehata, M ; Agterof, AP ; McGuckin, MA ; Alonso, MA ; Byrne, JA (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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    Aiming to increase birth weight: a randomised trial of pre-pregnancy information, advice and counselling in inner-urban Melbourne.
    Lumley, J ; Donohue, L (Springer Science and Business Media LLC, 2006-12-10)
    BACKGROUND: In the 1980s there was substantial interest in early pregnancy and pre-pregnancy interventions to increase birth weight and reduce preterm birth. We developed an inter-pregnancy intervention, implemented in a randomised controlled trial, to be provided by midwives at home soon after women's first birth. METHODS: MCH nurses invited women to take part during their home visit to new mothers. Women's contact details, with their permission, were passed to the study midwife. She had a randomisation schedule to which women's names were added before she met the women or their partners. All women recruited had a home visit from the study midwife with a discussion of their first pregnancy, labour and birth and the postpartum experience. Women in the intervention arm received in addition a pre-pregnancy intervention with discussion of social, health or lifestyle problems, preparation and timing for pregnancy, family history, rubella immunisation, referrals for health problems, and a reminder card. The primary outcome was defined as a birth weight difference in the second birth of 100 g (one-sided) in favour of the intervention. Additional data collected were gestational age, perinatal deaths and birth defects. Analyses used EPI-INFO and STATA. RESULTS: Intervention and comparison groups were comparable on socioeconomic factors, prior reproductive history and first birth outcomes. Infant birth weight in the second birth was lower (-97.4 g,)) among infants in the intervention arm. There were no significant differences between intervention and comparison arms in the proportion of women having a preterm birth, an infant with low birthweight, or an infant with a birth weight <10th percentile. There were more adverse outcomes in the intervention arm: ten births <32 weeks), compared with one in standard care, and more infants with a birth weight <2000 g, 16 compared with two in standard care CONCLUSION: As the primary outcome was envisaged to be either improved birth weight or no effect, the study was not designed to identify the alternative outcome with confidence. Despite widespread support for pre-pregnancy interventions to improve maternal and perinatal health, this first randomised controlled trial of a multi-component intervention provided at home, did not have a beneficial outcome.
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    Fever detection from free-text clinical records for biosurveillance
    Chapman, WW ; Dowling, JN ; Wagner, MM (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2004-04)
    Automatic detection of cases of febrile illness may have potential for early detection of outbreaks of infectious disease either by identification of anomalous numbers of febrile illness or in concert with other information in diagnosing specific syndromes, such as febrile respiratory syndrome. At most institutions, febrile information is contained only in free-text clinical records. We compared the sensitivity and specificity of three fever detection algorithms for detecting fever from free-text. Keyword CC and CoCo classified patients based on triage chief complaints; Keyword HP classified patients based on dictated emergency department reports. Keyword HP was the most sensitive (sensitivity 0.98, specificity 0.89), and Keyword CC was the most specific (sensitivity 0.61, specificity 1.0). Because chief complaints are available sooner than emergency department reports, we suggest a combined application that classifies patients based on their chief complaint followed by classification based on their emergency department report, once the report becomes available.
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    Numerical and functional defects of blood dendritic cells in early- and late-stage breast cancer
    Pinzon-Charry, A ; Ho, CSK ; Maxwell, T ; McGuckin, MA ; Schmidt, C ; Furnival, C ; Pyke, CM ; Lopez, JA (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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    Suppressor of cytokine signalling gene expression is elevated in breast carcinoma
    Raccurt, M ; Tam, SP ; Lau, P ; Mertani, HC ; Lambert, A ; Garcia-Caballero, T ; Li, H ; Brown, RJ ; McGuckin, MA ; Morel, G ; Waters, MJ (NATURE PUBLISHING GROUP, 2003-08-04)
    Cytokines are important for breast cell function, both as trophic hormones and as mediators of host defense mechanisms against breast cancer. Recently, inducible feedback suppressors of cytokine signalling (SOCS/JAB/SSI) have been identified, which decrease cell sensitivity to cytokines. We examined the expression of SOCS genes in 17 breast carcinomas and 10 breast cancer lines, in comparison with normal tissue and breast lines. We report elevated expression of SOCS-1-3 and CIS immunoreactive proteins within in situ ductal carcinomas and infiltrating ductal carcinomas relative to normal breast tissue. Significantly increased expression of SOCS-1-3 and CIS transcripts was also shown by quantitative in situ hybridisation within both tumour tissue and reactive stroma. CIS transcript expression was elevated in all 10 cancer lines, but not in control lines. However, there was no consistent elevation of other SOCS transcripts. CIS protein was shown by immunoblot to be present in all cancer lines at increased levels, mainly as the 47 kDa ubiquitinylated form. A potential proliferative role for CIS overexpression is supported by reports that CIS activates ERK kinases, and by strong induction in transient reporter assays with an ERK-responsive promoter. The in vivo elevation of SOCS gene expression may be part of the host/tumour response or a response to autocrine/paracrine GH and prolactin. However, increased CIS expression in breast cancer lines appears to be a specific lesion, and could simultaneously shut down STAT 5 signalling by trophic hormones, confer resistance to host cytokines and increase proliferation through ERK kinases.
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    The genome sequence of Xanthomonas oryzae pathovar oryzae KACC10331, the bacterial blight pathogen of rice.
    Lee, B-M ; Park, Y-J ; Park, D-S ; Kang, H-W ; Kim, J-G ; Song, E-S ; Park, I-C ; Yoon, U-H ; Hahn, J-H ; Koo, B-S ; Lee, G-B ; Kim, H ; Park, H-S ; Yoon, K-O ; Kim, J-H ; Jung, C-H ; Koh, N-H ; Seo, J-S ; Go, S-J (Oxford University Press (OUP), 2005)
    The nucleotide sequence was determined for the genome of Xanthomonas oryzae pathovar oryzae (Xoo) KACC10331, a bacterium that causes bacterial blight in rice (Oryza sativa L.). The genome is comprised of a single, 4 941 439 bp, circular chromosome that is G + C rich (63.7%). The genome includes 4637 open reading frames (ORFs) of which 3340 (72.0%) could be assigned putative function. Orthologs for 80% of the predicted Xoo genes were found in the previously reported X.axonopodis pv. citri (Xac) and X.campestris pv. campestris (Xcc) genomes, but 245 genes apparently specific to Xoo were identified. Xoo genes likely to be associated with pathogenesis include eight with similarity to Xanthomonas avirulence (avr) genes, a set of hypersensitive reaction and pathogenicity (hrp) genes, genes for exopolysaccharide production, and genes encoding extracellular plant cell wall-degrading enzymes. The presence of these genes provides insights into the interactions of this pathogen with its gramineous host.