http://hdl.handle.net/2440/9785 2013-05-19T21:13:58Z http://hdl.handle.net/2440/69326 Title: Apical localization of zinc transporter ZnT4 in human airway epithelial cells and its loss in a murine model of allergic airway inflammation Author: Murgia, Chiara Maria; Grosser, Dion Craig; Truong-Tran, Ai Quynh; Roscioli, Eugene; Michalczyk, Agnes; Ackland, Margaret Leigh; Stoltenberg, Meredin; Danscher, Gorm; Lang, Carol Jane; Knight, Darryl Andrew; Perozzi, Giuditta; Ruffin, Richard Ernest; Zalewski, Peter David Abstract: The apical cytoplasm of airway epithelium (AE) contains abundant labile zinc (Zn) ions that are involved in the protection of AE from oxidants and inhaled noxious substances. A major question is how dietary Zn traffics to this compartment. In rat airways, in vivo selenite autometallographic (Se-AMG)-electron microscopy revealed labile Zn-selenium nanocrystals in structures resembling secretory vesicles in the apical cytoplasm. This observation was consistent with the starry-sky Zinquin fluorescence staining of labile Zn ions confined to the same region. The vesicular Zn transporter ZnT4 was likewise prominent in both the apical and basal parts of the epithelium both in rodent and human AE, although the apical pools were more obvious. Expression of ZnT4 mRNA was unaffected by changes in the extracellular Zn concentration. However, levels increased 3-fold during growth of cells in air liquid interface cultures and decreased sharply in the presence of retinoic acid. When comparing nasal versus bronchial human AE cells, there were significant positive correlations between levels of ZnT4 from the same subject, suggesting that nasal brushings may allow monitoring of airway Zn transporter expression. Finally, there were marked losses of both basally-located ZnT4 protein and labile Zn in the bronchial epithelium of mice with allergic airway inflammation. This study is the first to describe co-localization of zinc vesicles with the specific zinc transporter ZnT4 in airway epithelium and loss of ZnT4 protein in inflamed airways. Direct evidence that ZnT4 regulates Zn levels in the epithelium still needs to be provided. We speculate that ZnT4 is an important regulator of zinc ion accumulation in secretory apical vesicles and that the loss of labile Zn and ZnT4 in airway inflammation contributes to AE vulnerability in diseases such as asthma. 2010-12-31T13:30:00Z http://hdl.handle.net/2440/69238 Title: Diagnostic accuracy of adenosine stress cardiovascular magnetic resonance following acute ST-segment elevation myocardial infarction post primary angioplasty Author: Wong, Dennis T. L.; Leung, Michael C.; Das, Rajiv; Liew, Gary Yin Hoe; Williams, Kerry F.; Dundon, Benjamin Kane; Molaee, Payman; Teo, Karen Shao Lin; Meredith, Ian Thomas; Worthley, Matthew Ian; Worthley, Stephen Grant Abstract: Background: Adenosine stress cardiovascular magnetic resonance (CMR) has been proven an effective tool in detection of reversible ischemia. Limited evidence is available regarding its accuracy in the setting of acute coronary syndromes, particularly in evaluating the significance of non-culprit vessel ischaemia. Adenosine stress CMR and recent advances in semi-quantitative image analysis may prove effective in this area. We sought to determine the diagnostic accuracy of semi-quantitative versus visual assessment of adenosine stress CMR in detecting ischemia in non-culprit territory vessels early after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). Methods: Patients were prospectively enrolled in a CMR imaging protocol with rest and adenosine stress perfusion, viability and cardiac functional assessment 3 days after successful primary-PCI for STEMI. Three short axis slices each divided into 6 segments on first pass adenosine perfusion were visually and semi-quantitatively analysed. Diagnostic accuracy of both methods was compared with non-culprit territory vessels utilising quantitative coronary angiography (QCA) with significant stenosis defined as ≥70%. Results: Fifty patients (age 59 ± 12 years) admitted with STEMI were evaluated. All subjects tolerated the adenosine stress CMR imaging protocol with no significant complications. The cohort consisted of 41% anterior and 59% non anterior infarctions. There were a total of 100 non-culprit territory vessels, identified on QCA. The diagnostic accuracy of semi-quantitative analysis was 96% with sensitivity of 99%, specificity of 67%, positive predictive value (PPV) of 97% and negative predictive value (NPV) of 86%. Visual analysis had a diagnostic accuracy of 93% with sensitivity of 96%, specificity of 50%, PPV of 97% and NPV of 43%. Conclusion: Adenosine stress CMR allows accurate detection of non-culprit territory stenosis in patients successfully treated with primary-PCI post STEMI. Semi-quantitative analysis may be required for improved accuracy. Larger studies are however required to demonstrate that early detection of non-culprit vessel ischemia in the post STEMI setting provides a meaningful test to guide clinical decision making and ultimately improved patient outcomes. Description: Extent: 8p. 2010-12-31T13:30:00Z http://hdl.handle.net/2440/64550 Title: Beneficial effects of perhexiline in cardiovascular disease states Author: Chirkov, Yuliy Y.; Sverdlov, Aaron Leonid; Horowitz, John David Abstract: Perhexiline, 2-(2,2-dicyclohexylethyl)piperidine, was originally developed as a prophylactic anti-anginal drug in the late 1960s. It was initially a popular and effective treatment for angina, having the almost unique property compared to other agents available at that time, of not inducing reductions in blood pressure or heart rate. Despite the initial success, its use diminished markedly due to the occurrence during long-term therapy of poorly understood side effects (neurotoxicity and hepatotoxicity), which later were shown to be associated with high plasma concentrations of perhexiline, occurring in patients with relatively slow hepatic metabolism of the drug. However, therapeutic plasma monitoring and associated dose adjustments have led to perhexiline's reintroduction into clinical practice. This new book discusses the benefits of perhexiline in the treatment of cardiovascular disease. 2009-12-31T13:30:00Z http://hdl.handle.net/2440/64549 Title: Beneficial clinical effects of perhexiline in cardiac patients: Multiple biochemical mechanisms Author: Chirkov, Yuliy Y.; Sverdlov, Aaron Leonid; Horowitz, John David Abstract: Perhexiline, 2-(2,2-dicyclohexylethyl)piperidine, was originally developed as a prophylactic anti-anginal drug in the late 1960s. It was initially a popular and effective treatment for angina, having the almost unique property compared to other agents available at that time, of not inducing reductions in blood pressure or heart rate. Despite the initial success, its use diminished markedly due to the occurrence during long-term therapy of poorly understood side effects (neurotoxicity and hepatotoxicity), which later were shown to be associated with high plasma concentrations of perhexiline, occurring in patients with relatively slow hepatic metabolism of the drug. However, therapeutic plasma monitoring and associated dose adjustments have led to perhexiline's reintroduction into clinical practice. Recent clinical data have proved its safety and maintained efficacy. Perhexiline reduced anginal frequency in patients with refractory angina. In patients with chronic heart failure, perhexiline improved peak exercise oxygen consumption, left ventricular ejection fraction, symptoms, resting and peak stress myocardial function. Perhexiline also appears to be effective in suppressing symptoms in patients with acute coronary syndromes or with advanced and inoperable aortic valvular stenosis. Herein we discuss perhexiline's pharmacology with particular emphasis on its mechanism(s) of action. 2009-12-31T13:30:00Z