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Activated Protein C (APC) is an endogenous anticoagulant that regulates thrombin generation. Its physiological importance is reflected by the thrombotic phenotype of PC deficient individuals and those with APC resistance due to mutation at the Factor V cleavage site. At a molecular level, thrombin binding to the receptor thrombomodulin (TM) converts endothelial protein C receptor (EPCR) bound PC into APC. APC has a negative feedback role in curbing thrombin generation by inactivating coagulation factors V and VIII. Clinically, acquired PC deficiency occurs in conditions such as severe sepsis as a result of mechanisms involving consumption, increased degradation by proteolytic enzymes and reduced hepatic synthesis. The initial success of APC in sepsis (PROWESS Trial) over other anticoagulants is thought to relate to anti-inflammatory and cyto-protective properties The interaction of EPCR-APC with protease activated receptor-1(PAR-1}, the prototypical thrombin receptor appears to be relevant in vivo. Intravenous injection of APC into mice leads to PAR-1-dependent gene induction and interestingly gene expression profiling of cytokine-stimulated endothelial cells demonstrates marked differences between APC and thrombin signaling. Cardiovascular dysfunction occurs frequently in patients with sepsis, increasing the mortality rate significantly from 20% to 70-90%. Key observations from the PROWESS Trial highlighted a possible link between APC and cardiovascular recovery. For those with cardiovascular dysfunction at baseline, APC treatment led to a significantly greater likelihood of organ resolution. Furthermore, in the most critically ill patients with multiple organ dysfunction, time to resolution of cardiac dysfunction was significantly shorter for APC treated patients with improvements linked to overall mortality reduction. The precise cause of cardiac dysfunction in sepsis remains unclear. Endothelial activation has been implicated as has decreased contractility and impaired myocardial compliance. Postulated mechanisms include cardiac myofibrillar dysfunction with altered calcium sensitivity and the influence of myocardial depressant factors such as pro-inflammatory cytokines and nitric oxide. The potential effects of APC on the cardiovascular system could be multifactorial. This thesis sets out to examine if the anti-inflammatory and cytoprotective properties of APC may be involved. In the first experimental chapter, the effect of APC in free or microparticulate form on human coronary artery endothelial cells was examined. An anti-inflammatory and cytoprotective profile is induced although evidence of reversing the pro-inflammatory effect of tumour necrosis factor alpha (TNFo) was inconclusive. In the second experimental chapter the effect of APC on cardiomyocyte contraction was studied using rat ventricular cardiomyocytes and this showed the potential role of EPCR and PAR-1. In view of the high efficiency of PAR-1 activation by thrombin, the third experimental chapter looked at whether any APC effect would continue to be relevant in the presence of thrombin. The APC response was observed at clinically relevant concentrations, without significant modification of calcium handling and despite the presence of thrombin. This led to the final experimental chapter where PAR-1 mediated effects appear to be regulated by downstream protein kinase C alpha (PKCa) providing mechanistic insight in to the findings This thesis concludes that APC has functional relevance with respect to cardiac cells both at the endothelial and contractile level. The results offer a framework to delineate distinct pathways for improved therapeutic manipulation in the treatment of myocardial sepsis and depression.

A research report submitted to the Faculty of Health Sciences at the University of the Witwatersrand in partial fulfillment of the requirements for the qualifications of MMed (Urology) 2017 / Background: Erectile dysfunction is one of the most important sequelae of pelvic fractures and may be transient or permanent. It can range from weak erections to severe sexual dysfunctions. Importantly, erectile dysfunction is more prevalent when the pelvic fracture is associated with urethral injury. Methods:  This was a retrospective study of patient records, with a prospective questionnaire arm for patients admitted to the hospitals with a pelvic fracture between 01/07/2011 to 30/04/2015.  The electronic databases of the Orthopedic Department at Helen Joseph Hospital and the Male Sexual Dysfunction Clinic at Charlotte Maxeke Johannesburg Academic Hospital were accessed for patients' contact details, by using the name and hospital number of each patient.  Each patient was contacted telephonically with an open speaker in a presence of a witness/translator. The information sheet was read to the patient before the telephonic consent was obtained.  After consent was obtained, patients were asked to verbally complete the International Index of Erectile Function score questionnaire. Results A total of 53 patients participated in the study, of which (43.4%) reported erectile dysfunction. The majority of patients indicated a recovery of erectile function between 2 8 | P a g e to 8 months after the injury. Most were found to still suffer from other forms of sexual impairment like orgasmic dysfunction and sexual satisfaction. However, sexual desire seemed to be preserved. Patients with sexual dysfunction were more likely to have had a urethral injury as well as a more severe fracture. Conclusions In our sample of 53 patients almost half reported sexual dysfunction after a pelvic fracture. Importantly, patients with urethral damage and a severe pelvic fracture should be followed up, as the risk of sexual dysfunction is high in these particular patients. / MT2017

MMed (Urology), Faculty of Health Sciences, University of the Witwatersrand / The metabolic syndrome has recently become one of the major public health challenges and results from the increasing prevalence of obesity. Erectile dysfunction (ED) affects up to half of men over the age of forty. Men with co-morbid disease and risk factors including cardiovascular disease, hypertension, dyslipidaemia and depression all report a higher prevalence of ED. The current study investigated the prevalence of the metabolic syndrome in one hundred men with (ED) presenting to the Male Sexual Dysfunction Clinic at the Johannesburg Hospital. Participants underwent a thorough history taking and examination session which included the International Index of Erectile Function Score. Several fasting biochemistry and hormonal tests were performed. Participants were divided by race into three groups. Data was recorded in EXCEL and reported as mean±std or as a number (frequency). Where applicable, correlation between variables was determined. The prevalence of the metabolic syndrome was 39%, with the highest prevalence (54%) in the group comprising Asian, Coloured and Chinese participants. Eighty percent of participants had moderate-severe (ED), with a mean duration of 3,8 years. Glucose and HbA1c were strong predictors of ED duration. Severity of ED was not influenced by the presence of the metabolic syndrome. Men presenting with ED may represent an ideal patient group to screen for the metabolic syndrome, and therefore for cardiovascular disease, especially for those men within the asymptomatic period.

Introduction: Adverse childhood experiences (ACEs) have been linked with negative physical and mental health outcomes in adulthood. A limited amount of literature has discussed the impact of individual ACEs on HIV risk behaviors using nationally representative data. Objective: This study investigated how ACEs impact HIV risk behaviors using cross-sectional data from the 2011 and 2012 Behavioral Risk Factor Surveillance System (BRFSS). Methods: Data were obtained from BRFSS for 2011 and 2012. Only states that answered the optional ACE questionnaire were included in the study. All ten ACEs were categorized into abuse (parents physically hurt you in any way or parents swore, insulted or put you down), household dysfunction (lived with anyone mentally ill, lived with parental alcoholic, lived with parental drug abuser, had a parent incarcerated, parents beat each other, or parents were divorced or separated) and childhood sexual abuse (forced to have sex, forced to touch sexually, or forced to be touched sexually). The number of individuals in each category were then categorized based on if they said yes to HIV risk behaviors: used intravenous drugs in the past year, been treated for a sexually transmitted or venereal disease in the past year, and/or given or received anal sex without a condom in the past year. Sociodemographic factors were assessed including race (White, Black, Hispanic, or Other), sex, income (<$15,000, $15,000-<$25,000, $25,000-<$35,000, $35,000-<$50,000, and >$50,000), education (high school education or less and some college or more), age (18-34, 35-54, and 55+) and marital status (currently married or widowed and never married, divorced or separated). Weighted multiple logistic regression analyses were used to examine the association between ACEs and HIV risk behaviors controlling for sociodemographic characteristics. Results: The unweighted sample size was 151,289. The final adjusted sample size was 58,622. Majority of those who said yes to HIV risk behaviors were among the ages of 18-34 (7.92%) compared to other age categories. Adults with an income of <$15,000 had a higher prevalence of saying yes to HIV risk behaviors compared to all other income categories (6.30% vs. 4.85% vs. 3.87% vs. 3.12% vs 2.33%). Adults who experienced growing up with a parent in jail or had a parent who abused drugs had a higher prevalence of saying yes to HIV risk behaviors (11.18% and 11.14% respectively). Of the 4.34% of adults who were forced to have sex as a child, 12.17% said yes to HIV risk behaviors. All ACEs were significantly associated with HIV risk behaviors (P<0.0001). Multiple logistic regression analysis show that adults who grew up with parents who abused drugs (Odds Ratio (OR)= 1.74, 95% Confidence Interval (CI)= 1.72-1.74) or were forced to have sex as a child (OR=1.70, 95% CI=1.68-1.72) were more likely to have HIV risk behaviors. Not being currently married or widowed increased the odds of HIV risk behaviors by 2.31 times (OR= 2.31, 95% CI= 2.30-2.33). Conclusions: ACEs were positively associated with HIV risk behaviors. Longitudinal studies are warranted to confirm the causal relationship. Educational and prevention measures may be considered to address this public health problem.

Sustained nitroglycerin (GTN) therapy impairs endothelial function in healthy volunteers and patients with cardiovascular disease, caused by an increase in vascular oxidative stress. This study aims to estimate the effect of rosiglitazone on vascular endothelial function in healthy volunteers continuously dosed to transdermal GTN (0.6mg/hr) for 7 days. To assess endothelial function, forearm blood flow was measured by venous occlusion strain-gauge plethysmography in response to intra-brachial infusions of acetylcholine. GTN-treated subjects experienced significant attenuation of endothelium-dependent responses to acetylcholine (p<0.05; compared to placebo), but was reversed with vitamin C (p=ns; compared to placebo). Endothelium-dependent responses to acetylcholine were blunted in groups randomized to rosiglitazone alone (p<0.05; compared to placebo) and rosiglitazone + GTN (p<0.05 compared to placebo). Interestingly, this effect was not modified by vitamin C. In conclusion, rosiglitazone impairs endothelial function and concurrent therapy with rosiglitazone does not attenuate the adverse effects of transdermal GTN on the vasculature.

Sustained nitroglycerin (GTN) therapy impairs endothelial function in healthy volunteers and patients with cardiovascular disease, caused by an increase in vascular oxidative stress. This study aims to estimate the effect of rosiglitazone on vascular endothelial function in healthy volunteers continuously dosed to transdermal GTN (0.6mg/hr) for 7 days. To assess endothelial function, forearm blood flow was measured by venous occlusion strain-gauge plethysmography in response to intra-brachial infusions of acetylcholine. GTN-treated subjects experienced significant attenuation of endothelium-dependent responses to acetylcholine (p<0.05; compared to placebo), but was reversed with vitamin C (p=ns; compared to placebo). Endothelium-dependent responses to acetylcholine were blunted in groups randomized to rosiglitazone alone (p<0.05; compared to placebo) and rosiglitazone + GTN (p<0.05 compared to placebo). Interestingly, this effect was not modified by vitamin C. In conclusion, rosiglitazone impairs endothelial function and concurrent therapy with rosiglitazone does not attenuate the adverse effects of transdermal GTN on the vasculature.

Background and Purpose: The Massachusetts Male Aging Study found 52% of men aged 40 to 70 years suffered from erectile dysfunction (ED). Approximately two millions men in Taiwan were ED suffers, only 10% of them had taken Viagra&#x00AE;. The potential market is very attractive to pharmatheutical industry. By law, ED medicines are prescriptive drugs; in practice, more than 80% of ED drugs were sold without prescription in Taiwan. The launch of Levitra&#x00AE; and Cialis&#x00AE; has boosted the competition in the ED drug market. The purposes of this study are 1) to compare the marketing strategies of Viagra&#x00AE;, Levitra&#x00AE; and Cialis&#x00AE;, 2) to analyze factors influencing physicians¡¦ prescription, 3) to analyze factors affecting drug purchasers¡¦ decision, and 4) to survey the preference of drugstores owners on selling these drugs. Materials and Methods: The first step is face-to-face, in-depth interviews with product mangers to understand their marketing strategies. We will ask them to rate the significance of factors (e.g. efficacy, safety, price) affecting physicians¡¦ and patients¡¦ preference. Product mangers will be requested to rate the importance and relevance of the way product messages delivered to doctors¡¦ prescription behaviors. Questionnaires will be mailed to all urologists in Taiwan to survey factors they concerned when prescribing. We use mailing questionnaires and face-to-face interviews to assess the impact of drug efficacy, duration, safety, etc. on drug purchasers¡¦ decision. Drugstores owners will be interviewed to understand their favor in promoting certain drug. Comparative studies will be done to evaluate the difference between product mangers, physicians and patients. Results The marketing strategy of Pfizer is to emphasize the well-documented efficacy and long-term safety of Viagra&#x00AE; by seminars for physicians. Educational talks will be given to the public to explore the potential consumers. The goal of Bayer is to urge the silent ED suffers search for medical help, and to convince physicians that Levitra&#x00AE; is the drug of choice for ED patients. Eli-Lilly put almost all their marketing efforts and resources in drugstores. Drug efficacy and safety are most important factors influencing physicians¡¦ prescription. Approximately 85% of urologists surveyed favor Viagra&#x00AE;, 21% have safety concern on Cialis&#x00AE;. Most urologists considered Levitra&#x00AE; as alternative of Viagra&#x00AE; when failed. All product mangers overestimate the impact of key opinion leaders, literature, and seminars on physicians¡¦ prescription behaviors. Patients¡¦ survey disclosed that drug efficacy and safety are most important factors affecting drug purchasing. As compared to physicians, patients have more concern on the time of onset and duration. About 20% of drug purchasers are not ED suffers; 62% of purchasing is sporadic, one third of Viagra&#x00AE; users have the attempt to try other ED drugs. The drugstores owners have no specific preference for any drugs. Conclusions The extension of life expectancy and open discussion of male ED problem had resulted in tremendous growth of ED drug market. The launch of new drug may stimulate the selling amount in short run; the long-term market shares depend mainly on the drug efficacy and safety. In our study, we found that safety profile is the main concern for both physicians and drug purchasers. We believed that Viagra&#x00AE; may stay as the market leader, while Levitra&#x00AE; may have only small market share. Certain groups of drug purchasers, especially fake ED suffers and those who with multiple sex-partners will have high brand loyalty to Cialias&#x00AE;.

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