The cellular components of the blood, which become associated with fibrin through specific cellular adhesive processes, play a significant role in the breakdown of fibrin. Fibrinolysis by elastase and cathepsin G, enzymes present within the azurophilic granules of the neutrophil, has previously been shown. Recent studies have demonstrated neutrophil-mediated fibrinogenolysis by a membrane-associated protease which suggests that proteases connected with the neutrophil membrane might also be capable of clot dissolution. Investigations showed that neutrophil-mediated clot lysis was effected by a membrane-associated serine protease that can be dissociated by SDS-PAGE to bands that migrate to apparent molecular weights of 501 kDa, 398 kDa, 316 kDa, 245 kDa and 209 kDa. This degradation was distinct from that produced by plasmin, neutrophil lysosomal enzymes and purified human neutrophil elastase and enhanced the action of plasmin in clot solubilization. Preincubation of neutrophils with monoclonal antibodies directed against the CD 11 c/CD 18 integrin was able to significantly inhibit neutrophil membrane-dependent fibrinolytic activity. Upregulation of enzyme activity occurred following association of fibrin substrate with the cell membrane and was dependent on the activation of cellular kinases, in particular protein kinase C. Fibrin products generated by neutrophil membrane proteolytic activity were found to possess biological activity. The low molecular weight peptides effected substantial inhibition of thrombin-induced platelet aggregation while the presence of the higher molecular weight material could partially overcome platelet-induced resistance to plasmic lysis. No modulation of platelet-mediated fibrin clot retraction was observed using these same fibrin products. Neutrophil lysosomal enzyme activity was shown to further degrade the end products of plasmic fibrin degradation into low molecular weight material, followed by reassembly of higher molecular weight products in a process dependent on calcium and factor XIII. The reformed products have a similar molecular weight to those produced by plasmic lysis of fibrin, as well as a putative crosslinked site. However, the isoelectric point of these reformed products indicates they are distinctly different from plasmin-derived fibrin products. These reassembled products were recognized by a monoclonal antibody raised against D-dimer. Processing by neutrophils of the end products of plasmic fibrin degradation may have the potential for modulating the immune response as well as compromising the predictive value of tests measuring D-dimer, used as a laboratory marker of a number of thromboembolic disorders encountered in clinical practice.

Acute heart failure is a potentially lethal clinical emergency without any effective therapy. Using an isolated rat heart model, we established and validated a model of de novo acute heart failure to study novel putative cardio protective therapies against acute heart failure, including glucose, insulin and the molecular agent sphingosine-1-phosphate(component of high density lipoprotein) for recovery. In isolated rat hearts, the protocol consisted of three phases: stabilization at normotensive perfusion pressure, hypotensive acute heart failure and recovery by restoring normotension. Low glucose (2.5mM) and high albumin-bound free fatty acids (1.3mM) (±adrenaline 10-M) were added in theperfusate. Molecular and metabolic agents were administered either alone or in combination in the acute heart failure or recovery phases. Effects of glucose, insulin and sphingosine-1-phosphatewere observed on heart function, cell death and mitochondrial respiration. In the absence of adrenaline, combination of glucose andsphingosine-1-phosphateduring acute heart failure improved functional recovery by increasing the heart rate. In the presence of adrenaline, glucose and sphingosine-1-phosphate administered separately were cardioprotective in the recovery phase by improving heart rate. The combination of glucose+insulin and glucose+sphingosine-1-phosphate in the recovery phase also increased heart rate. Glucos9+sphingosine-1-phosphate+insulin increased heart rate and left ventricular developed pressure.Sphingosine-1-phosphate reduced expression of cytochrome C, but metabolic agents had no effect.AG490 (inhibitor of signal transducer and activator of transcription 3) attenuated the cardio protective effect of sphingosine-1-phosphatewithincreased expression of the phosphorylated inactive form of this transcription factor protein. Conclusion: We have established and validated an ex-vivo model of de novoacute heart failure. The combination of metabolic and molecular treatments improved heart function by increasingsinus node activity_ Sphingosine-1-phosphate not only improved heart rate, but also reduced cell death, an effect mediated via activation of signal transducer and activator of transcription 3. Our data provide novel principles and approaches for the treatment of acute heart failure.

Background: Risky decision-making is strongly implicated in adverse real-world risk-taking behaviour, and is associated with Substance Use Disorder, including Methamphetamine Use Disorder. Laboratory neurocognitive tasks typically utilized to assess risky decision-making have been able to distinguish participants with Substance Use Disorder from controls, although considerable heterogeneity is still evident within substance-using populations, which remains largely unexplained. Preliminary evidence has also tied risky decision-making to treatment outcomes, although no research has investigated risk-decision-making within Methamphetamine Use Disorder in the context of Contingency Management treatment. Methods: This study aimed to investigate decision-making on the Iowa Gambling Task and the Balloon Analogue Risk at baseline as both a function and predictor of treatment response on an 8-week treatment of Contingency Management. Of 26 participants with Methamphetamine Use Disorder, 17 responded to Contingency Management treatment, whilst 9 were non-responders. Using various mixed-effect modelling techniques and ANCOVA, performance by nonresponders were compared to responders, as well as a group of 19 healthy, nonsubstance-using control participants. Results: Group differences between non-responders, responders and controls were exclusively obtained on the Iowa Gambling Task. A trend-level (p=.051), large effect size (g=-0.98) was observed in the effect of reward magnitude between non-responders and healthy controls. More specifically, non-responders tended to seek-out large short-term rewards in spite of long-term losses relative to controls, however, groups did not also differ in effect of short-term loss magnitude. Non-responders also appeared to demonstrate poorer learning than healthy controls, although this finding was also at trend-level (p=.081) with a medium effect size (g =-0.63). In addition, results showed that responders and non-responders were differentially influenced by the frequency of outcomes, where responders demonstrated a greater preference for frequent rewards and infrequent losses relative to non-responders. This difference was at trend-level (p=.053) and the effect was moderately sized (g =-0.74). Impulsivity did not moderate group differences in decision-making, but did positively predict a greater likelihood of relapse at least once during Contingency Management (p =.035), although this effect was small (OR=1.10). Poor overall performance on the IGT appeared to predict a greater likelihood of prolonged relapse on Contingency Management following initial relapse, although this was at trend-level (p =.071) with a small effect size (OR=1.80). Conclusion: Findings provide evidence for individual differences in risky decision-making within Methamphetamine User Disorder, suggesting that risky decision-making is unlikely to be a homogeneous characteristic of substance-using populations, as is typically treated in the literature. Risky decision-making may also act as a risk factor for poor treatment success on Contingency Management, which in turn suggests that assessing risky decision-making of individuals with Methamphetamine Use disorder prior to commencing Contingency Management treatment might assist in identifying those at high risk.

Introduction: Little is known about the molecular genetics of cardiomyopathy in Africans. Aims: to (I) determine the prevalence of desmosomal gene mutations in arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM) in desmosomal protein genes (i.e., plakophilin 2, desmocollin 2, desmoglein 2, and plakoglobin), (2) establish the presence of a founder effect in families with a recurrent mutation in the plakophilin 2 (PKP2) gene, (3) investigate whether single nucleotide polymorphisms found in desmosomal genes affect gene expression, and (4) search for new candidate genes for ARVC in families where no causal mutation was found in desmosomal protein genes. Methods: 177 participants with cardiomyopathy were screened for desmosomal gene mutations which were confumed by Sanger sequencing. The following methods were used: in the founder effect study we used haplotyping with microsatellite markers; for total gene expression we used real time polymerase chain reaction and allelic expression imbalance and exome sequencing was used for mutation screening in two siblings with severe early onset ARVC. To all novel variants identified prediction tools were used to predict the pathogenicity of the variant in uestion. Results: 21.5% of ARVC pro bands had a disease-causing mutation in one of four desmosomal genes; no disease-causing mutation was found in the 112 OCM index cases. A recurrent PKP2 mutation occurred on a common haplotype background in four white South African probands with cardiomyopathy. Investigation of a common PKP2 polymorphism had no effect on total gene expression nor was there evidence of allelic expression imbalance. Finally, rare mutations were found in PARVA and HMGXB3 by exome sequencing of two siblings.

Bibliography: leaves 183-238. / There exists but one local detailed, documented study by Bergensen (1989) that focused on the effects of pet facilitated therapy on the self-esteem and socialisation of primary school children. In addition, a handful of articles have been published in South African journals. It is rather perturbing to note that a proven, highly effective adjunct to conventional therapeutic intervention is lacking in the South African therapeutic milieu. The marked ignorance and defence behind practitioners scorn for this form of therapy is rather perplexing, especially in light of its official existence for over thirty years. This dissertation probes the concept of pet-facilitated therapy by referring to extensive studies, focusing on various sub-populations, and concludes with a study investigating local opposition to pet therapy.

Includes bibliographical references (leaves 68-75) / Objectives: To investigate whether or not OSAS patients from the South African population showed any cognitive impairment relative to healthy individuals from the same population, and to assess whether or not untreated OSAS patients and patients on CPAP treatment differed in their cognitive functioning.

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No description available.

Children with fetal alcohol spectrum disorders (FASD) are frequently reported by caregivers and teachers to have difficulties in socio-emotional functioning. It has been suggested that deficits in emotion regulation underlie these deficits in socio-emotional functioning. Children with prenatal alcohol exposure (PAE) have also been found to demonstrate higher rates of insecure attachment, as well as disorganised attachment. Previous research proposes that the attachment relationship serves as a foundation for the development of emotion regulation. However, while this association has been examined in typically developing samples, the relation between attachment and emotion regulation has yet to be examined in individuals with FASD. Previous research has also suggested that a portion of individuals who are considered heavily exposed but are non-syndromal (HE) who do not present with the full phenotype characteristic of FAS or PFAS may nevertheless present with subtle facial dysmorphism only detectable using dense surface modelling and signature analyses of 3D facial images. Furthermore, it has been shown that HE children with this subtle facial dysmorphism perform more poorly on cognitive assessments than HE children who do not present with this subtle facial dysmorphism. These findings therefore suggest that presence of even subtle dysmorphism (i.e. only detectable on signature analyses of 3D facial images) consistent with FAS can be a good indicator of cognitive performance. Given this, the aims of the current study were to examine the association between FAS-dysmorphism and insecure as well as disorganised attachment. Furthermore, the study aimed to examine the extent to which FAS-dysmorphism was associated with emotion regulation difficulties in adolescence after controlling for the effects of attachment security in infancy. Participants included 77 adolescents (M age = 17.66, SD = .7): 13 with fetal alcohol syndrome (FAS), 12 with partial FAS (PFAS), 7 HE-dysmorphic (HE+), 18 HE-nondysmorphic (HE-) and 27 non- or minimally exposed controls. At the 13-month infant assessment, the mother-infant attachment relationship was assessed using the Ainsworth Strange Situation Paradigm (Hay, Jacobson, Molteno, Viljoen, & Jacobson, 2004; Jacobson & Jacobson, 2013). At the adolescent follow-up assessment, emotion regulation was assessed using two caregiver-report measures – the Emotion Regulation Checklist (ERC; Shields & Cicchetti, 1997) and the Affect Regulation Checklist (ARC; Moretti, 2003). Results showed that infants with FASdysmorphism+ did not demonstrate significantly higher levels of insecure and disorganised attachment than those in the FAS-dysmorphism- group. In terms of emotion regulation, FASdysmorphism+ did not significantly predict any of the adaptive or maladaptive emotion regulation subscales. However, insecure attachment predicted maladaptive emotion regulation, but not adaptive emotion regulation. These results suggest that while individuals with FASD are often reported to exhibit difficulties with emotion regulation, other variables, including IQ and attachment security in infancy, may explain some of the variation in the emotion regulation difficulties observed for individuals with FASD.

No description available.