National Health and Medical Research Council (NHMRC)

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This is a collection of NHMRC-funded research publications authored by Flinders academics.

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    5-HT3 and 5-HT4 antagonists inhibit peristaltic contractions in guinea-pig distal colon by mechanisms independent of endogenous 5-HT
    (Frontiers, 2013-08) Sia, TC ; Whiting, Malcolm John ; Kyloh, Melinda ; Nicholas, Sarah J ; Oliver, John Reginald ; Brookes, Simon Jonathan ; Dinning, Phillip ; Wattchow, David Anthony ; Spencer, Nicholas John
    Recent studies have shown that endogenous serotonin is not required for colonic peristalsis in vitro, nor gastrointestinal (GI) transit in vivo. However, antagonists of 5-Hydroxytryptamine (5-HT) receptors can inhibit peristalsis and GI-transit in mammals, including humans. This raises the question of how these antagonists inhibit GI-motility and transit, if depletion of endogenous 5-HT does not cause any significant inhibitory changes to either GI-motility or transit? We investigated the mechanism by which 5-HT3 and 5-HT4 antagonists inhibit distension-evoked peristaltic contractions in guinea-pig distal colon. In control animals, repetitive peristaltic contractions of the circular muscle were evoked in response to fixed fecal pellet distension. Distension-evoked peristaltic contractions were unaffected in animals with mucosa and submucosal plexus removed, that were also treated with reserpine (to deplete neuronal 5-HT). In control animals, peristaltic contractions were blocked temporarily by ondansetron (1–10 μM) and SDZ-205–557 (1–10 μM) in many animals. Interestingly, after this temporary blockade, and whilst in the continued presence of these antagonists, peristaltic contractions recovered, with characteristics no different from controls. Surprisingly, similar effects were seen in mucosa-free preparations, which had no detectable 5-HT, as detected by mass spectrometry. In summary, distension-evoked peristaltic reflex contractions of the circular muscle layer of the guinea-pig colon can be inhibited temporarily, or permanently, in the same preparation by selective 5-HT3 and 5-HT4 antagonists, depending on the concentration of the antagonists applied. These effects also occur in preparations that lack any detectable 5-HT. We suggest caution should be exercised when interpreting the effects of 5-HT3 and 5-HT4 antagonists; and the role of endogenous 5-HT, in the generation of distension-evoked colonic peristalsis.
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    Ablation of Barrett's oesophagus: towards improved outcomes for oesophageal cancer?
    (John Wiley and Sons, 2012-09) Mayne, George C B ; Bright, Tim Flaxman ; Hussey, Damian James ; Watson, David Ian
    Barrett's oesophagus is the major risk factor for oesophageal adenocarcinoma. The management of Barrett’s oesophagus entails treating reflux symptoms with acid-suppressing medication or surgery (fundoplication). However neither form of anti-reflux therapy produces predictable regression, or prevents cancer development. Patients with Barrett’s oesophagus usually undergo endoscopic surveillance which aims to identify dysplastic changes or cancer at its earliest stage, when treatment outcomes should be better. Alternative endoscopic interventions are now available and are suggested for the treatment of early cancer, and prevention of progression of Barrett’s oesophagus to cancer. Such treatments could minimize the risks associated with oesophagectomy. The current status of these interventions is reviewed. Various endoscopic interventions have been described, but with long term outcomes uncertain, they remain somewhat controversial. Radiofrequency ablation (RFA) of dysplastic Barrett’s oesophagus might reduce the risk of cancer progression, although cancer development has been reported after this treatment. Endoscopic mucosal resection (EMR) allows a 1.5 to 2 cm diameter piece of oesophageal mucosa to be removed. This provides better pathology for diagnosis and staging, and if the lesion is confined to the mucosa and fully excised, EMR can be curative. The combination of EMR and RFA has been used for multifocal lesions, but long term outcomes are unknown. The new endoscopic interventions for Barrett’s oesophagus and early oesophageal cancer have potential to improve clinical outcomes, although evidence which confirms superiority over oesphagectomy is limited. Longer term outcome data and data from larger cohorts is required to confirm the appropriateness of these procedures
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    Aboriginal Australians' experience of social capital and its relevance to health and wellbeing in urban settings.
    (Elsevier, 2013-11) Browne-Yung, Kathryn ; Ziersch, Anna Marie ; Baum, Fran ; Gallaher, Gilbert
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    Accumulation of promutagenic DNA adducts in the mouse distal colon after consumption of heme does not induce colonic neoplasms in the western diet model of spontaneous colorectal cancer
    (Wiley-Blackwell, 2013-10-01) Winter, Jean ; Young, Graeme Paul ; Hu, Ying ; Gratz, Silvia W ; Conlon, Michael A ; Le Leu, Richard Kevin
    Scope: Red meat is considered a risk factor for colorectal cancer (CRC). Heme is considered to promote colonic hyperproliferation and cell damage. Resistant starch (RS) is a food that ferments in the colon with studies demonstrating protective effects against CRC. By utilizing the western diet model of spontaneous CRC, we determined if feeding heme (as hemin chloride) equivalent to a high red meat diet would increase colonic DNA adducts and CRC and whether RS could abrogate such effects. Methods and results: Four groups of mice: control, heme, RS and heme + RS were fed diets for 1 or 18 months. Colons were analyzed for apoptosis, proliferation, DNA adducts “8-hydroxy-2-deoxyguanosine” and “O6-methyl-2-deoxyguanosine” (O6MeG), and neoplasms. In the short term, heme increased cell proliferation (p < 0.05). Changes from 1 to 18 months showed increased cell proliferation (p<0.01) and 8-hydroxy-2-deoxyguanosine adducts (p < 0.05) in all groups, but only heme-fed mice showed reduced apoptosis (p < 0.01) and increasedO6MeGadducts (p<0.01). The incidence of colon neoplasms was not different between any interventions. Conclusion: We identified heme to increase proliferation in the short term, inhibit apoptosis over the long term, and increase O6MeG adducts in the colon over time although these changes did not affect colonic neoplasms within this mouse model.
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    Accurate Imputation-Based Screening of Gln368Ter Myocilin Variant in Primary Open-Angle Glaucoma
    (Association for Research in Vision and Ophthalmology, 2015-08) Gharahkhani, Puya ; Burdon, Kathryn Penelope ; Hewitt, Alex W ; Law, Matthew H ; Souzeau, Emmanuelle ; Montgomery, Grant W ; Radford-Smith, Graham ; Mackey, David A ; Craig, Jamie E ; MacGregor, Stuart
    PURPOSE: Myocilin (MYOC) is a well-established primary open-angle glaucoma (POAG) risk gene, with rare variants known to have high penetrance. The most common clinically relevant risk variant, Gln368Ter, has an allele frequency of 0.1% to 0.3% in populations of European ancestry. Detection of rare MYOC variants has traditionally been conducted using Sanger sequencing. Here we report the use of genotyping arrays and imputation to assess whether rare variants including Gln368Ter can be reliably detected. METHODS: A total of 1155 cases with advanced POAG and 1992 unscreened controls genotyped on common variant arrays participated in this study. Accuracy of imputation of Gln368Ter variants was compared with direct sequencing. A genome-wide association study was performed using additive model adjusted for sex and the first six principal components. RESULTS: We found that although the arrays we used were designed to tag common variants, we could reliably impute the Gln368Ter variant (rs74315329). When tested in 1155 POAG cases and 1992 controls, rs74315329 was strongly associated with risk (odds ratio = 15.53, P = 1.07 × 10-9). All POAG samples underwent full sequencing of the MYOC gene, and we found a sensitivity of 100%, specificity of 99.91%, positive predictive value of 95.65%, and negative predictive value of 100% between imputation and sequencing. Gln368Ter was also accurately imputed in a further set of 1801 individuals without POAG. Among the total set of 3793 (1992 + 1801) individuals without POAG, six were predicted (probability > 95%) to carry the risk variant. CONCLUSIONS: We demonstrate that some clinically important rare variants can be reliably detected using arrays and imputation. These results have important implications for the detection of clinically relevant incidental findings in ongoing and future studies using arrays.
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    Activation of intestinal spinal afferent endings by changes in intra‐mesenteric arterial pressure
    (John Wiley & Sons, inc., 2015-06-25) Humenick, A ; Chen, B N ; Wiklendt, Lukasz ; Spencer, Nicholas John ; Zagorodnyuk, Vladimir Petrovich ; Dinning, Phillip ; Costa, Marcello ; Brookes, Simon Jonathan
    KEY POINTS: A major class of mechano-nociceptors to the intestine have mechanotransduction sites on extramural and intramural arteries and arterioles ('vascular afferents'). These sensory neurons can be activated by compression or axial stretch of vessels. Using isolated preparations we showed that increasing intra-arterial pressure, within the physiological range, activated mechano-nociceptors on vessels in intact mesenteric arcades, but not in isolated arteries. This suggests that distortion of the branching vascular tree is the mechanical adequate stimulus for these sensory neurons, rather than simple distension. The same rises in pressure also activated intestinal peristalsis in a partially capsaicin-sensitive manner indicating that pressure-sensitive vascular afferents influence enteric circuits. The results identify the mechanical adequate stimulus for a major class of mechano-nociceptors with endings on blood vessels supplying the gut wall; these afferents have similar endings to ones supplying other viscera, striated muscle and dural vessels. ABSTRACT: Spinal sensory neurons innervate many large blood vessels throughout the body. Their activation causes the hallmarks of neurogenic inflammation: vasodilatation through the release of the neuropeptide calcitonin gene-related peptide and plasma extravasation via tachykinins. The same vasodilator afferent neurons show mechanical sensitivity, responding to crushing, compression or axial stretch of blood vessels - responses which activate pain pathways and which can be modified by cell damage and inflammation. In the present study, we tested whether spinal afferent axons ending on branching mesenteric arteries ('vascular afferents') are sensitive to increased intravascular pressure. From a holding pressure of 5 mmHg, distension to 20, 40, 60 or 80 mmHg caused graded, slowly adapting increases in firing of vascular afferents. Many of the same afferent units showed responses to axial stretch, which summed with responses evoked by raised pressure. Many vascular afferents were also sensitive to raised temperature, capsaicin and/or local compression with von Frey hairs. However, responses to raised pressure in single, isolated vessels were negligible, suggesting that the adequate stimulus is distortion of the arterial arcade rather than distension per se. Increasing arterial pressure often triggered peristaltic contractions in the neighbouring segment of intestine, an effect that was mimicked by acute exposure to capsaicin (1 μm) and which was reduced after desensitisation to capsaicin. These results indicate that sensory fibres with perivascular endings are sensitive to pressure-induced distortion of branched arteries, in addition to compression and axial stretch, and that they contribute functional inputs to enteric motor circuits.
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    Active Foot Synovitis in Patients With Rheumatoid Arthritis: Unstable Remission Status, Radiographic Progression, and Worse Functional Outcomes in Patients With Foot Synovitis in Apparent Remission
    (John Wiley & Sons Ltd, 2016-10-26) Wechalekar, Mihir ; Lester, Susan ; Hill, Catherine L ; Lee, Anita ; Rischmueller, Maureen ; Smith, Malcolm Douglas ; Walker, Jennifer ; Proudman, Susanna
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    Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study
    (Elsevier, 2014-12-02) Pathak, Rajeev K ; Middeldorp, Melissa E ; Lau, Dennis H ; Mehta, Abhinav B ; Mahajan, Rajiv ; Twomey, Darragh J ; Alasady, Muayad ; Hanley, Lorraine ; Antic, Nicholas Alexander ; McEvoy, Ronald Douglas ; Kalman, Jonathan M ; Abhayaratna, Walter P ; Sanders, Prashanthan
    BACKGROUND: The long-term outcome of atrial fibrillation (AF) ablation demonstrates attrition. This outcome may be due to failure to attenuate the progressive substrate promoted by cardiovascular risk factors. OBJECTIVES: The goal of this study was to evaluate the impact of risk factor and weight management on AF ablation outcomes. METHODS: Of 281 consecutive patients undergoing AF ablation, 149 with a body mass index ≥27 kg/m(2) and ≥1 cardiac risk factor were offered risk factor management (RFM) according to American Heart Association/American College of Cardiology guidelines. After AF ablation, all 61 patients who opted for RFM and 88 control subjects were assessed every 3 to 6 months by clinic review and 7-day Holter monitoring. Changes in the Atrial Fibrillation Severity Scale scores were determined. RESULTS: There were no differences in baseline characteristics, number of procedures, or follow-up duration between the groups (p = NS). RFM resulted in greater reductions in weight (p = 0.002) and blood pressure (p = 0.006), and better glycemic control (p = 0.001) and lipid profiles (p = 0.01). At follow-up, AF frequency, duration, symptoms, and symptom severity decreased more in the RFM group compared with the control group (all p < 0.001). Single-procedure drug-unassisted arrhythmia-free survival was greater in RFM patients compared with control subjects (p < 0.001). Multiple-procedure arrhythmia-free survival was markedly better in RFM patients compared with control subjects (p < 0.001), with 16% and 42.4%, respectively, using antiarrhythmic drugs (p = 0.004). On multivariate analysis, type of AF (p < 0.001) and RFM (hazard ratio 4.8 [95% confidence interval: 2.04 to 11.4]; p < 0.001) were independent predictors of arrhythmia-free survival. CONCLUSIONS: Aggressive RFM improved the long-term success of AF ablation. This study underscores the importance of therapy directed at the primary promoters of the AF substrate to facilitate rhythm control strategies.
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    Alteration of the function of the UDP-glucuronosyltransferase 1A subfamily by cytochrome P450 3A4: different susceptibility for UGT isoforms and UGT1A1/7 variants.
    (American Society for Pharmacology and Experimental Therapeutics (ASPET), 2014-02) Ishii, Y ; Koba, H ; Kinoshita, K ; Oizaki, T ; Iwamoto, Y ; Takeda, S ; Miyauchi, Y ; Nishimura, Y ; Egoshi, N ; Taura, F ; Morimoto, S ; Ikushiro, S ; Nagata, K ; Yamazoe, Y ; Mackenzie, Peter Ian ; Yamada, H
    Functional protein-protein interactions between UDP-glucuronosyltransferase (UGT)1A isoforms and cytochrome P450 (CYP)3A4 were studied. To this end, UGT1A-catalyzed glucuronidation was assayed in Sf-9 cells that simultaneously expressed UGT and CYP3A4. In the kinetics of UGT1A6-catalyzed glucuronidation of serotonin, both Michaelis constant (Km) and maximal velocity (Vmax) were increased by CYP3A4. When CYP3A4 was coexpressed with either UGT1A1 or 1A7, the Vmax for the glucuronidation of the irinotecan metabolite (SN-38) was significantly increased. S50 and Km both which are the substrate concentration giving 0.5 Vmax were little affected by simultaneous expression of CYP3A4. This study also examined the catalytic properties of the allelic variants of UGT1A1 and 1A7 and their effects on the interaction with CYP3A4. Although the UGT1A1-catalyzing activity of 4-methylumbelliferone glucuronidation was reduced in its variant, UGT1A1*6, the coexpression of CYP3A4 restored the impaired function to a level comparable with the wild type. Similarly, simultaneous expression of CYP3A4 increased the Vmax of UGT1A7*1 (wild type) and *2 (N129K and R131K), whereas the same was not observed in UGT1A7*3 (N129K, R131K, and W208R). In the kinetics involving different concentrations of UDP-glucuronic acid (UDP-GlcUA), the Km for UDP-GlcUA was significantly higher for UGT1A7*2 and *3 than *1. The Km of UGT1A7*1 and *3 was increased by CYP3A4, whereas *2 did not exhibit any such change. These results suggest that (1) CYP3A4 changes the catalytic function of the UGT1A subfamily in a UGT isoform-specific manner and (2) nonsynonymous mutations in UGT1A7*3 reduce not only the ability of UGT to use UDP-GlcUA but also CYP3A4-mediated enhancement of catalytic activity, whereas CYP3A4 is able to restore the UGT1A1*6 function.
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    Ambivalence and its influence on participation and non-participation in screening for colorectal cancer
    (SAGE, 2013-09) Oster, Candice ; Zajac, Ian ; Flight, Ingrid ; Hart, Elizabeth ; Turnbull, Deborah ; Wilson, Carlene J ; Young, Graeme Paul
    Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, and an ideal target for early detection and prevention through cancer screening. Unfortunately, rates of participation in screening are less than adequate. In this article we explore why people who were offered a fecal immunochemical test for CRC decided to participate or not, and for those who did participate, what influenced them to take action and complete the test. We conducted four focus groups and 30 telephone interviews with 63 people. The main reason people decided to screen was “wanting to know” their CRC status, which operated on a continuum ranging from wanting to know, through varying degrees of ambivalence, to not wanting to know. The majority of participants expressed ambivalence about CRC screening, and the main cue to action was the opportunity to screen without being too inconvenienced.
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    Ambulatory models of care for obstructive sleep apnea: diagnosis and management
    (Wiley-Blackwell, 2013-04-25) Chai-Coetzer, Ching Li ; Antic, Nicholas Alexander ; McEvoy, Ronald Douglas
    The high prevalence of obstructive sleep apnoea (OSA) and increasing awareness of its potential health consequences has placed significant pressure on laboratory-based sleep services leading to growing waiting lists and delays in diagnosis and treatment. Consequently, there has been increasing interest in the use of simplified, ambulatory models of care involving clinical prediction tools, portable sleep monitoring and home autotitrating continuous positive airway pressure. Researchers are also exploring the potential role for a wider range of health-care providers, including trained nurses and general practitioners, in the primary management of OSA. Recent randomized, controlled studies evaluating the clinical effectiveness of ambulatory management strategies versus traditional laboratory-based care for patients with OSA have consistently demonstrated that comparable patient outcomes can be achieved. The cost-effectiveness of these strategies is currently being debated, and further research examining the long-term economic implications of ambulatory models of care is needed.
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    Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma
    (Nature Publishing Group, 2018-02-18) Gharahkhani, Puya ; Burdon, Kathryn Penelope ; Cooke-Bailey, Jessica N ; Hewitt, Alex W ; Law, Matthew H ; Pasquale, Louis R ; Kang, Jae Hee ; Haines, Jonathan L ; Souzeau, Emmanuelle ; Zhou, Tiger ; Siggs, Owen M ; Landers, John ; Awadalla, Mona S ; Sharma, Shiwani ; Mills, Richard Arthur ; Ridge, Bronwyn ; Lynn, David J ; Casson, Robert J ; Graham, Stuart L ; Goldberg, Ivan ; White, Andrew J ; Healey, Paul R ; Grigg, John RB ; Lawlor, Mitchell ; Mitchell, Paul ; Ruddle, Jonathan B ; Coote, Michael A ; Walland, Mark ; Best, Stephen ; Vincent, Andrea ; Gale, Jesse ; Radford-Smith, Graham ; Whiteman, David C ; Montgomery, Grant W ; Martin, Nicholas G ; Mackey, David A ; Wiggs, Janey L ; MacGregor, Stuart ; Craig, Jamie E ; Neighborhood Consortium
    Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - “response to fluid shear stress” and “abnormal retina morphology” - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.
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    Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity
    (American Society for Clinical Investigation, 2016) Souma, Tomokazu ; Tompson, Stuart W ; Thomson, Benjamin R ; Siggs, Owen M ; Kizhatil, Krishnakumar ; Yamaguchi, Shinji ; Feng, Liang ; Limviphuvadh, Vachiranee ; Whisenhunt, Kristina N ; Maurer-Stroh, Sebastian ; Yanovitch, Tammy L ; Kalaydijieva, Luba ; Azmanov, Dimitar N ; Finzi, Simone ; Mauri, Lucia ; Javadiyan, Shahrbanou ; Souzeau, Emmanuelle ; Zhou, Tiger ; Hewitt, Alex W ; Kloss, Bethany ; Burdon, Kathryn Penelope ; Mackey, David A ; Allen, Keri F ; Ruddle, Jonathan B ; Lim, Sing-Hui ; Rozen, Steve ; Tran-Viet, Khanh-Nhat ; Liu, Xiaorong ; John, Simon ; Wiggs, Janey L ; Pasutto, Francesca ; Craig, Jamie E ; Jin, Jing ; Quaggin, Susan ; Young, Terri L
    Primary congenital glaucoma (PCG) is a devastating eye disease and an important cause of childhood blindness worldwide. In PCG, defects in the anterior chamber aqueous humor outflow structures of the eye result in elevated intraocular pressure (IOP); however, the genes and molecular mechanisms involved in the etiology of these defects have not been fully characterized. Previously, we observed PCG-like phenotypes in transgenic mice that lack functional angiopoietin-TEK signaling. Herein, we identified rare TEK variants in 10 of 189 unrelated PCG families and demonstrated that each mutation results in haploinsufficiency due to protein loss of function. Multiple cellular mechanisms were responsible for the loss of protein function resulting from individual TEK variants, including an absence of normal protein production, protein aggregate formation, enhanced proteasomal degradation, altered subcellular localization, and reduced responsiveness to ligand stimulation. Further, in mice, hemizygosity for Tek led to the formation of severely hypomorphic Schlemm’s canal and trabecular meshwork, as well as elevated IOP, demonstrating that anterior chamber vascular development is sensitive to Tek gene dosage and the resulting decrease in angiopoietin-TEK signaling. Collectively, these results identify TEK mutations in patients with PCG that likely underlie disease and are transmitted in an autosomal dominant pattern with variable expressivity.
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    Anterior 90° partial vs Nissen fundoplication - 5 year follow-up of a single-centre randomised trial
    (Springer-Verlag, 2012-09) Watson, David Ian ; Devitt, Peter G ; Smith, Lorelle T ; Jamieson, Glyn G
    Introduction Nissen fundoplication can be followed by side effects, and this has driven modifications, including partial fundoplications. We previously reported early outcomes from a randomised trial of Nissen vs anterior 900 partial fundoplication. This paper reports 5 year follow-up outcomes to determine whether anterior 900 fundoplication achieves a satisfactory longer term outcome. Methods From February 1999 to August 2003, 79 patients were randomized to Nissen vs. Anterior 90o fundoplication. Patients were followed yearly using a standardized clinical questionnaire which included symptom scores to assess heartburn, dysphagia, other post-fundoplication side effects, and overall satisfaction with the outcome. Five year clinical outcomes were analysed. Results Seventy four patients were available for follow-up at 5 years. There were no significant differences for: heartburn or satisfaction, although more patients used antisecretory medication after anterior 900 fundoplication (29.7% vs 8.1%). Dysphagia was greater after Nissen fundoplication when measured by an analog score for solid food and a composite dysphagia score. Symptoms of bloating were more common following Nissen fundoplication (80.0% vs 32.4%), and less patients could eat a normal diet (78.4% vs. 94.6%). Re-operation was undertaken in 4 patients after Nissen fundoplication (dysphagia – 3, hiatus hernia -1) vs. 3 after anterior 900 fundoplication (recurrent reflux – 3). Conclusions At 5 years, Anterior 900 partial fundoplication was associated with less side effects, offset by greater use of antisecretory medication. Reflux symptoms and overall satisfaction were similar to Nissen fundoplication. Laparoscopic anterior 900 partial fundoplication is an effective treatment for gastro-esophageal reflux.
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    Argon plasma coagulation ablation versus endoscopic surveillance of Barrett’s oesophagus: late outcomes from two randomized trials.
    (Georg Thieme Verlag, 2013-11) Sie, Corina ; Bright, Tim Flaxman ; Schoeman, Mark ; Game, Philip A ; Tam, William ; Devitt, Peter G ; Watson, David Ian
    Introduction: Argon plasma coagulation (APC) has been used to ablate dysplastic and non-dysplastic Barrett’s esophagus. In this study we determined the longer term efficacy of APC ablation within two randomized controlled trials of APC versus surveillance for Barrett’s esophagus in patients in whom gastroesophageal reflux was controlled by either surgery (Surgical trial) or proton pump inhibitors (Medical trial). Methods: One hundred and twenty nine patients with Barrett’s esophagus (nondysplastic or low grade dysplasia) were randomized to undergo either ablation using APC or ongoing endoscopy surveillance. Outcomes were determined at 3 time points: short-term (12 months), mid-term (42-75 months) and long-term (>84 months). Results: Initial ablation of >95% of the Barrett’s esophagus was achieved in 61 of 63 patients randomized to. At short-term follow-up >95% ablation persisted in 47 of 56 patients. At mid-term follow-up this continued in 33 of 49 patients. 32 were followed long term, and >95% ablation of the Barrett’s esophagus was maintained in 21 of 32. In the control groups the length of Barrett’s esophagus reduced from a mean of 4.2 cm to 3.1 cm at long term follow-up. High grade dysplasia (HGD) developed in 1 patient in the APC group and 3 in the surveillance group. Low grade dysplasia developed in 1 in the APC group and 7 in the surveillance group. Conclusions: APC ablation reduced the extent of Barrett’s esophagus, and this was maintained in some patients at longer term follow-up. However, progression to HGD can still occur despite APC ablation, suggesting endoscopic surveillance is still required.
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    Ascending excitatory neural pathways modulate slow phasic myogenic contractions in the isolated human colon
    (Wiley-Blackwell, 2013-05-01) Carbone, Simona ; Dinning, Phillip ; Costa, Marcello ; Spencer, Nicholas John ; Brookes, Simon Jonathan ; Wattchow, David Anthony
    Background In animal models, enteric reflex pathways have potent effects on motor activity; their roles have been much less extensively studied in human gut. The aim of this study was to determine if ascending excitatory interneuronal pathways can modulate spontaneous phasic contractions in isolated preparations of human colonic circular muscle. Methods Human colonic preparations were cut into T shapes, with vertical bar of the ‘T’ pharmacologically isolated. Electrical stimulation and the nicotinic agonist, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), were applied to the isolated region and circular muscle contractile activity was measured from the cross-bar of the T, more than 10 mm orally from the region of stimulation. Key Results The predominant form of spontaneous muscle activity consisted of tetrodotoxin-resistant, large amplitude, slow phasic contractions (SPCs), occurring at average intervals of 124 ± 68 s. Addition of a high concentration of hexamethonium (1 mmol L-1) to the superfusing solution significantly increased the interval between SPCs to 278.1 ± 138.3 s (P < 0.005). Focal electrical stimulation more than 10 mm aboral to the muscle recording site advanced the onset of the next SPC, and this effect persisted in hexamethonium. However, the effect of electrical stimulation was blocked by tetrodotoxin (TTX, 1 µmol L-1). Application of the nicotinic agonist DMPP (1 mmol L-1) to the aboral chamber often stimulated a premature SPC (n = 4). Conclusions & Inferences The major form of spontaneous contractility in preparations of human colonic circular muscle is SPCs, which are myogenic in origin. Activation of ascending excitatory neural pathways, which involve nicotinic receptors, can modulate the timing of SPCs and thus influence human colonic motility.
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    Assessment of corneal thickness measurement using swept-source Fourier-domain anterior segment optical coherence tomography and Scheimpflug camera
    (Elsevier, 2012-07-01) Huang, Jinhai ; Feng, Yifan ; Wang, Qinmei ; Pesudovs, Konrad
    No abstract available
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    Assessment of polygenic effects links primary open-angle glaucoma and age-related macular degeneration
    (Nature Publishing Group, 2016) Cuellar-Partida, Gabriel ; Craig, Jamie E ; Burdon, Kathryn Penelope ; Wang, Jie Jin ; Vote, Brendan J ; Souzeau, Emmanuelle ; McAllister, Ian L ; Isaacs, Timothy ; Lake, Stewart ; Mackey, David A ; Constable, Ian J ; Mitchell, Paul ; Hewitt, Alex W ; MacGregor, Stuart
    Primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD) are leading causes of irreversible blindness. Several loci have been mapped using genome-wide association studies. Until very recently, there was no recognized overlap in the genetic contribution to AMD and POAG. At genome-wide significance level, only ABCA1 harbors associations to both diseases. Here, we investigated the genetic architecture of POAG and AMD using genome-wide array data. We estimated the heritability for POAG (h2 g = 0.42 ± 0.09) and AMD (h2 g = 0.71 ± 0.08). Removing known loci for POAG and AMD decreased the h2 g estimates to 0.36 and 0.24, respectively. There was evidence for a positive genetic correlation between POAG and AMD (rg = 0.47 ± 0.25) which remained after removing known loci (rg = 0.64 ± 0.31). We also found that the genetic correlation between sexes for POAG was likely to be less than 1 (rg = 0.33 ± 0.24), suggesting that differences of prevalence among genders may be partly due to heritable factors.
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    Association of eNOS polymorphisms with primary angle-closure glaucoma
    (Association for Research in Vision and Ophthalmology, 2013-03) Awadalla, Mona S ; Thapa, Suman S ; Hewitt, Alex W ; Craig, Jamie E ; Burdon, Kathryn Penelope
    Purpose: Recently, several studies have investigated genetic associations between Cytochrome P450 (CYP1B1), Endothelial nitric oxide synthase (eNOS) and Neurotrophin-4 (NTF4) with primary angle-closure glaucoma (PACG) in various ethnic groups. Here we investigate the association of these candidate genes with PACG in samples from Australia and Nepal. Method: A total of 235 patients with PACG (106 Nepalese and 129 Australian) and 492 controls (204 Nepalese and 288 Australian) were included. Tag single nucleotide polymorphisms (SNPs) were selected to cover the majority of common variation within the candidate genes and genotyped in DNA extracted from peripheral whole blood. Allele and haplotype analyses were conducted in PLINK. Bonferroni correction was applied for the total number of SNPs in this study (p=0.05/15=0.003) Results: In the Australian cohort, one eNOS SNP rs3793342 shows significance association with PACG in the Australian cohort after Bonferroni correction (p-value 0.003, OR 0.5 95% CI 0.3-0.8). After adjusting the results for sex and age both SNPs rs3793342 and rs7830 showed significance after Bonferroni correction (p-value of 0.001 and 0.003, respectively). The eNOS haplotype of all 7 typed SNPs showed significant association with a global p-value of 0.019, with the CGCAATC haplotype giving a specific p-value of 0.008 and odds ratio of 1.5 (95% CI 0.9-2.4). In the Nepalese cohort, SNPs in CYP1B1 and NTF4 genes showed borderline association with PACG but did not survive Bonferroni correction. Conclusions: The present data support the involvement of common variations in eNOS with PACG pathogenesis. Differences were observed in the two populations studied, and additional replication studies in other populations are necessary to confirm these associations
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    Association of genetic variants with primary angle closure glaucoma in two different populations
    (Public Library of Science, 2013) Awadalla, Mona S ; Thapa, Suman S ; Hewitt, Alex W ; Burdon, Kathryn Penelope ; Craig, Jamie E
    PURPOSE: A recent large genome-wide association study (GWAS) identified multiple variants associated with primary angle-closure glaucoma (PACG). The present study investigated the role of these variants in two cohorts with PACG recruited from Australia and Nepal. METHOD: Patients with PACG and appropriate controls were recruited from eye clinics in Australia (n = 232 cases and n = 288 controls) and Nepal (n = 106 cases and 204 controls). Single nucleotide polymorphisms (SNPs) rs3753841 (COL11A1), rs1015213 (located between PCMTD1 and ST18), rs11024102 (PLEKHA7), and rs3788317 (TXNRD2) were selected and genotyped on the Sequenom. Analyses were conducted using PLINK and METAL. RESULTS: After adjustment for age and sex, SNP rs3753841 was found to be significantly associated with PACG in the Australian cohort (p = 0.017; OR = 1.34). SNPs rs1015213 (p = 0.014; OR 2.35) and rs11024102 (p = 0.039; OR 1.43) were significantly associated with the disease development in the Nepalese cohort. None of these SNPs survived Bonferroni correction (p = 0.05/4 = 0.013). However, in the combined analysis, of both cohorts, rs3753841 and rs1015213 showed significant association with p-values of 0.009 and 0.004, respectively both surviving Bonferroni correction. SNP rs11024102 showed suggestive association with PACG (p-value 0.035) and no association was found with rs3788317. CONCLUSION: The present results support the initial GWAS findings, and confirm the SNP's contribution to PACG. This is the first study to investigate these loci in both Australian Caucasian and Nepalese populations.