Browsing by Author "Lopes, John"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    An investigation into the mechanisms whereby insulin protects the rat heart in a model of Low-Flow Ischemia
    (Stellenbosch : University of tellenbsoch, 2008-03) Lopes, John; Huisamen, B.; Van Rooyen, J.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences : Medical Physiology.
    ENGLISH ABSTRACT: BACKGROUND: Insulin has been shown to protect the heart against ischemia/reperfusion (I/R) damage by activating the reperfusion injury salvage kinase (RISK) pathway during reperfusion (Jonassen et al 2001 and 2004, Hausenloy and Yellon 2004). The main focus of investigation has since been on insulin-treatment during reperfusion as therapy for acute myocardial infarction. This is based on the premise that reperfusion is the only opportunity for therapy, which negates the possible therapeutic value of insulin during ischemia. The objective of this study was therefore to investigate if insulin-mediated protection during ischemia contributes to protection during reperfusion, and if so, to identify the mechanisms involved. AIMS: - To set up a model of low-flow ischemia (LFI) that could be used to investigate the mechanisms whereby insulin protects the rat heart against I/R. - Determine if insulin-mediated cardioprotection during ischemia contributes to cardioprotection during reperfusion. - Establish the effect of insulin signaling on cyclic AMP (cAMP) accumulation during LFI due to its association with ß-adrenergic receptor (ß-AR) induced ischemic damage. - Identify the role of the ß-AR and its downstream targets, adenylyl cyclase (AC), cAMP activated protein kinase (PKA) and phospholamban (PLN) in protection by insulin during LFI. - Determine the role of phosphoinositide 3-kinase (PI3K) and external glucose availability in cardioprotection elicited during ischemia by insulin. METHODS: Male wistar rats were perfused in Langendorff mode in the absence and presence of insulin (0.3 mIU/ml), which was added to the Krebs-Henseleit perfusion buffer after 10 min stabilization. The perfusion protocol was as follows: 30 min stabilization, 30-45 min LFI (0.2 ml/min) and 30 min reperfusion. Inhibitors for ß-AR (propranolol), AC (MDL-12,330A), PKA (Rp-8-CPT-cAMPS) and PI3K (wortmannin) were respectively administered 5 min before LFI and were present until the end of ischemia. To determine the role of glucose in protection, glucose was omitted during LFI in the insulin and non-insulin groups. RESULTS: Insulin protected the heart during ischemia by delaying and alleviating contracture development that was followed by reduced hypercontracture and improved function during reperfusion without insulin. Thus protection during ischemia contributes to protection during reperfusion. cAMP was unexpectedly higher in the insulin-protected hearts during LFI. AC inhibition prevented cAMP accumulation and abolished cardioprotection. Notably, the rate of contracture progression in non-insulin treated hearts was enhanced by AC inhibition. cAMP production by AC might therefore be cardioprotective during ischemia and is enhanced by insulin. Respective inhibition of the ß-AR and PKA protected the non-insulin treated hearts, but could not enhance insulin-induced protection. PLN phosphorylation was equally reduced in PKA-inhibited hearts and insulin treated hearts during LFI. Interestingly, ß-blockade did not alter the levels of cAMP accumulation regardless of insulin, yet PKA activation is cAMP-dependent. Finally, external glucose was found to be a prerequisite for insulin-mediated protection, but this not dependent on PI3K activation. CONCLUSION: We conclude that insulin protects the rat heart during LFI, which contributes to protection during reperfusion. This protection is dependent on AC activation and cAMP accumulation during ischemia, which may be an innate mechanism of protection that is enhanced by insulin. An additional mechanism of protection by insulin involves the inhibition of theß-AR/PKA pathway, which is however mediated by cAMP. We therefore propose a dual role for cAMP in protection and pathology during ischemia, which is possibly determined by the subcellular localization of cAMP in the ischemic cardiomyocyte. This proposes a possible role for the phosphodiesterases, which regulate compartmentalization of cAMP and should therefore be investigated during LFI protection by insulin. Insulin-induced protection during ischemia is largely dependent on glucose availability and therefore also anaerobic metabolism, but does not require PI3K.
  • Thumbnail Image
    Item
    Priority areas for cannabis and cannabinoid product research in South Africa
    (AOSIS, 2018-06) Augustine, Tanya N.; Cairns, Carel J.; Chetty, Sean; Dannatt, Lisa G.; Gravett, Nadine; Grey, Glenda; Grobler, Gerhard; Jafta, Zukiswa; Kamerman, Peter; Lopes, John; Matsabisa, Motlalepula G.; Mugabo, Pierre; Mulder, Michelle; Parry, Charles; Rataemane, Solomon; Siegfried, Nandi; Steenkamp, Vanessa; Thomas, Eileen; Van Zyl-Smit, Richard
    The legalisation of cannabis for medicinal use is a contentious space both politically and in the medical community. In 2014, the Medical Innovation Bill introduced by Mario Oriani-Ambrosini MP, aimed to shift the political and legal positions of cannabis as an illegal substance to one available for research and medical use. To date, progress on this has been slow. Cannabis and cannabinoid products are currently available for medicinal use in several countries, including the Netherlands and 29 states in the United States. Locally, anecdotal reports suggest that many of our patients with chronic medical conditions are using cannabis and cannabis-derived or cannabinoid products for symptom alleviation.
  • Thumbnail Image
    Item
    A secondary analysis using individual patient data of two pragmatic cluster-randomized control trials evaluating 3 monthly and 6 monthly community-based multimonth dispensing of antiretroviral treatment in Southern Africa
    (Stellenbosch : Stellenbosch University, 2021-03) Lopes, John; Fatti, Geoffrey; Lombard, Carl J.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Global Health. Epidemiology and Biostatistics.
    ENGLISH SUMMARY: Randomized evidence of the effectiveness of community-based multi-month dispensing (MMD) of antiretroviral treatment (ART) is lacking, particularly for 6 months MMD with only annual clinical consultations. Data from two cluster randomized trials (CRTs) were pooled to compare community-based MMD of ART versus non-inferior to standard-of-care facility-based MMD. Methods: Adult people living with HIV (PLHIV) stable on ART for ≥6 months with viral load suppression (VLS) at baseline was included. Community-based 3 monthly (3MC) and 6 monthly (6MC) ART refill dispensing were compared to control facility-based 3 monthly (3MF). Twelve months retention-in-care (primary outcome) was evaluated by intention-to-treat using individual-level regression analyses, with a prespecified non-inferiority margin of -3.25% risk difference (RD). Secondary outcomes evaluated after 12 months were; (1) retention within the study arm (2) VLS, (3) number of unscheduled facility visits, and after 18 months; (4) attrition in ART care. Results: Data pooling yielded a total of 10136 participants with relatively balanced characteristics across the arms, except for age and district. Retention after 12 months was noninferior in the adjusted analysis (3MC: RD=0.3, 95% CI: -0.8 to 1.4 vs 3MF, 6MC: RD=-0.2, 95 % CI: -1.4 to 1.0 vs 3MF). VLS was high (≥97.9%) with no differences between the arms, risk ratio (RR) of 1.0 for 3MC (95 % CI: 1.0 to 1.0, p=0.885) and 6MC (95 % CI: 1.0 to 1.0, p=0.186) compared to 3MF. The incidence rate ratio (IRR) for unscheduled visits showed no difference between 3MC (IRR=0.6, 95 % CI: 0.2 to 2.1, p=0.383) and 6MC (IRR=1.0, 95 % CI: 0.4 to 2.5, p=0.974) compared to 3MF. Participant attrition (0-18 months) for Zimbabwe showed no differences between the arms, facility location or healthcare level. Conclusion: Community-based MMD of ART at 3 and 6 monthly refills for PLHIV stable on ART is safe to scale-up, without increased unscheduled facility visits or compromise in VLS.