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Dans cette thèse, nous cherchons à développer de nouvelles techniques pour écrire plus simplement des programmes formellement vérifiés. Nous procédons en étudiant l'utilisation de Coq en tant que langage de programmation dans différents environnements. Coq étant un langage purement fonctionnel, nous nous concentrons surtout sur la représentation et la spécification d'effets impurs, tel que les exceptions, les références mutables, les entrées-sorties et la concurrence.Nous travaillons premièrement sur deux projets préliminaires qui nous aident à comprendre les défis existants dans la programmation en Coq. Le premier projet, Cybele, est un plugin Coq pour écrire des preuves par réflexion efficaces avec effets. Nous compilons et nous exécutons les effets impurs en OCaml pour générer une prophétie, une forme de certificat, et interprétons les effets dans Coq en utilisant cette prophétie. Le second projet, le compilateur CoqOfOCaml, importe des programmes OCaml avec effets dans Coq en utilisant un système d'inférence d'effets.Puis nous décrivons différentes représentations génériques et composables d'effets impurs en Coq. Les calculs avec pause combinent les effets d'exceptions et de références mutables avec un mécanisme de pause. Ce mécanisme de pause permet de rendre explicite les étapes d'évaluation dans le but de représenter l'évaluation concurrente de deux termes. En implémentant le serveur web Pluto en Coq, nous réalisons que les entrées-sorties asynchrones sont l'effet le plus utile : cet effet est présent dans la plupart des programmes et ne peux être encodé de façon purement fonctionnelle. Nous concevons alors les "calculs asynchrones" comme moyen pour représenter et compiler des programmes avec événements en Coq.Finalement, nous étudions des techniques pour prouver des propriétés à propos de programmes avec effets. Nous commençons avec la vérification du système de blog ChickBlog écrit dans le langage des "calculs interactifs". Ce blog lance un fil d'exécution par client. Nous vérifions notre blog en utilisant une méthode de spécification par cas d'utilisation. Nous adaptons cette technique à la théorie des types en exprimant un cas d'utilisation comme un co-programme bien typé. Grâce à ce formalisme, nous pouvons présenter un cas d'utilisation comme un programme de test symbolique et le déboguer symboliquement, étape par étape, en utilisant le mode interactif de Coq. À notre connaissance, ceci représente la première telle adaptation de la spécification par cas d'utilisation en théorie des types. Nous pensons que la spécification formelle par cas d'utilisation est l'une des clés pour vérifier des programmes avec effets, sachant que la méthode des cas d'utilisation s'est avérée utile dans l'industrie pour exprimer des spécifications informelles. Nous étendons notre formalisme aux programmes concurrents et potentiellement non-terminants, avec le langage des "calculs concurrents". Nous concevons également un vérificateur de modèles pour vérifier l'absence d'interblocage dans un programme concurrent, en compilant la composition parallèle vers l'opérateur de choix non-déterministe. / In this thesis, we develop new techniques to conveniently write formally verified programs. To proceed, we study the use of Coq as a programming language in different settings. Coq being a purely functional language, we mainly focus on the representation and on the specification of impure effects, like exceptions, mutable references, inputs-outputs, and concurrency.First, we work on two preliminary projects helping us to understand the challenges of programming in Coq. The first project, Cybele, is a Coq plugin to write efficient proofs by reflection with effects. We compile and execute the impure effects in OCaml to generate a prophecy, a kind of certificate, and then interpret the effects in Coq using the prophecy. The second project, the compiler CoqOfOCaml, imports OCaml programs with effects into Coq, using an effect inference system.Next, we describe different generic and composable representations of impure effects in Coq. The breakable computations combine the standard exceptions and mutable references effects, with a pause mechanism to make explicit the evaluation steps in order to represent the concurrent evaluation of two terms. By implementing the Pluto web server in Coq, we realize that the most important effects to program are the asynchronous inputs-outputs. Indeed, these effects are ubiquitous and cannot be encoded in a purely functional manner. Thus, we design the asynchronous computations as a first way to represent and compile programs with events and handlers in Coq.Then, we study techniques to prove properties about programs with effects. We start with the verification of the blog system ChickBlog written in the language of the interactive computations. This blog runs one worker with synchronous inputs-outputs per client. We verify our blog using the method of specification by use cases. We adapt this technique to type theory by expressing a use case as a well-typed co-program over the program we verify. Thanks to this formalism, we can present a use case as a symbolic test program and symbolically debug it, step by step, using the interactive proof mode of Coq. To our knowledge, this is the first such adaptation of the use case specifications in type theory. We believe that the formal specification by use cases is one of the keys to verify effectful programs, as the method of use cases proved to be convenient to express (informal) specifications in the software industry. We extend our formalism to concurrent and potentially non-terminating programs with the language of concurrent computations. Apart from the use case method, we design a model-checker to verify the deadlock freedom of concurrent computations, by compiling the parallel composition to the non-deterministic choice operator using the language of blocking computations

Magister Curationis - MCur / There is a growing burden of disease associated with mental disorders especially in low and middle-income countries. This growing burden is accompanied by an increase in psychotic disorders and has increased the demand for antipsychotic medication. The increase in the use of antipsychotic medication has resulted in the increase in side-effects that have a detrimental effect on the health of the mental health care user. Antipsychotic medication side-effects have been classified as the primary indicator for medication non-adherence. There is a relationship between psychiatric nurses’ knowledge and attitudes towards the use and the non-adherence of antipsychotic medication.

>Magister Scientiae - MSc / Non-steroidal anti-inflammatory drugs (NSAIDs) are amongst the most commonly used medications globally, as they are highly effective and easily accessible. The NSAIDs are indicated for mild to moderate pain management. The increasing incidence of NSAID related side effects and hospitalisations has raised a concern about these medications’ safety. The prevalence of these side effects has drastic consequences to a challenged South Africanpublic healthcare system. The implications of not treating severe, potentially preventable upper gastrointestinal complications attributed to NSAIDs’ consumption continue to be a significant problem that healthcare professionals (HCP) face.

Dose tolerance and pharmacokinetic studies of pseudoephedrine sustained action capsules were performed in thirty-three adult male subjects who received either 120 mg or 150 mg capsules every twelve hours for seven consecutive days in a double-blind parallel design study. Although only one subject in the 150 mg group was discontinued prematurely from this study, a large number of side effects typical of CNS stimulation were seen. A placebo effect might account for a portion of these complaints, however symtoms evaluated as being due to drug were significantly more severe and persistent in the 150 mg group. Pulse rates showed a persistent and significant increase while systolic and diastolic blood pressure fell from the baseline values in both groups. A pharmacokinetic analysis of the pseudoephedrine plasma concentration-time data provided estimates of half-life and the volume of distribution/availability ratio. The values obtained were in good agreement with values reported by others. Half-life was not influenced by urine pH probably as a result of the narrow range of urine pHs observed in the subjects. Calculations of relative bioavailability suggest that the 120 mg capsule formulation has a 30% greater bioavailability compared to the 150 mg capsule.

Doxorubicin is one of the most effective anti-cancer agents; however its use is associated with adverse cardiac effects, including cardiomyopathy and progressive heart failure. Mitochondrial function and integrity are crucial for cellular processes in general and play an important role during diseased development. These characteristics of the mitochondria make them the prime target for treatments for majority of diseases and in particular of the cardiovascular system. The mitochondria are also considered to play an integral role in the manifestation of the cardiotoxic effects of compounds such as doxorubicin. The current project is designed to investigate the cardiotoxic effects of doxorubicin at tissue, cellular and protein level. In addition, it is investigated whether the inhibition of the mitochondrial permeability transition pore (mPTP) with cyclosporin A (CsA) or the inhibition of mitochondrial fission with the mitochondrial division inhibitor (mdivi-1) protects against the detrimental effects of doxorubicin on cardiac function. We also investigated whether co-treatment of doxorubicin with either CsA or mdivi-1 has any negative interaction with the cytotoxicity of doxorubicin against cancer cells. Langendorff results indicated that doxorubicin caused a time dependent reduction in the haemodynamic function of the heart as well as causing an increase in the infarct size to risk ratio in both naïve conditions and in conditions of ischaemia and reperfusion. Detrimental effects of doxorubicin on cardiac function were abrogated by co-treatment of doxorubicin with CsA or mdivi-1 in naïve conditions and in conditions of ischaemia and reperfusion. Cell viability data of isolated cardiac myocytes revealed that doxorubicin caused a concentration dependant decrease in the viability of neonatal cardiac myocytes as well as causing a reduction in the time taken to depolarisation and hypercontracture under sustained oxidative stress, all of which were prevented when co-treated with either CsA or mdivi-1. Doxorubicin significantly elevated the levels of p-Akt, p-Erk, p-Drp1 and p-p53. Co-treatment with CsA prevented the increase in the levels of p-Akt and p-Erk caused by doxorubicin in both naïve and IR condition whereas mdivi-1 prevented the increase in the levels of p-Erk, p-Drp1 and p-p53 and caused further increase in the levels of p-Akt. Using sinusoidal muscle length change during contraction and relaxation, it is demonstrated that doxorubicin caused a decrease in the power output, peak force and force during shorting. Detrimental effects of doxorubicin on work-loop contraction were abrogated when doxorubicin was co-administered with CsA. To conclude, results demonstrated that doxorubicin caused cardiotoxicity at tissue, cellular and protein level in both naïve conditions and in conditions of ischaemia and reperfusion injury. In addition, it is shown that the inhibition of mitochondrial permeability transition pore with CsA or the inhibition of the mitochondrial fission with mdivi-1 protect against doxorubicin-induced toxicity without affecting its anti-cancer properties.

published_or_final_version / Pathology / Master / Master of Philosophy

There is a significant current need to elucidate the molecular mechanisms of the side-effects caused by widely-used pharmaceuticals. Examples include the acute nephrotoxicity and irreversible ototoxicity promoted by the cationic drugs gentamicin and cisplatin. Gentamicin is an aminoglycoside antibiotic used for the prevention and treatment of life-threatening gram-negative bacterial infections, such as tuberculosis and meningitis. Cisplatin is used to treat a broad spectrum of cancers including head and neck, ovarian, cervical, stomach, bladder, sarcoma, lymphoma, testicular cancer and others. The objective of this study is to design and synthesize rhodamine derivatives that can be used for the construction of geometrically well-defined cationic drug conjugates. The long-term goal is to use the conjugates as tools to aid in elucidating the properties and identities of ion channels involved in the uptake of cationic pharmaceuticals into kidney and cochlear hair cells. This will shed light on the origin and potential prevention of unwanted side effects such as nephrotoxicity and ototoxicity associated with specific cationic drugs. A series of extended rhodamine analogs with reactive groups for biomolecule conjugation has been synthesized. These fluorophores show similar spectral properties to their prototype, Texas Red succinimidyl ester (TR-SE). However, they contain rigid linkers between the fluorophore and amine-reactive moiety. The resultant gentamicin conjugates of these materials are rigidified enabling one to assess channel pore dimensions without the confounding issue of conjugate folding. Preliminary cell studies are promising, as one observes reduced gentamicin uptake in both kidney and sensory hair cell upon systematically increasing the dimension of the fluorophore. This work has enabled us to tentatively assign the maximum dilated MET channel pore size as between 1.44 nm to 1.56 nm. However, this preliminary finding, though encouraging, needs further validation via ongoing studies with larger diameter fluorophore conjugates, A cisplatin-Texas Red conjugate has also been synthesized to enable studies of cellular uptake mechanisms. This conjugate preserves not only the spectral properties of Texas Red after conjugation, but also the cytotoxicity of cisplatin. This has been validated in zebrafish. The series of rhodamine probes that have been conjugated to gentamicin should be similarly useful for cisplatin studies. These studies are planned. Additional future work includes the synthesis of semi-flexible (glycol) and flexible (alkyl) linkers to evaluate structure-activity relationships.

Side effects of seizure medications in individuals with intellectual disabilities (ID) may affect speech and language development for this population. Research information about these effects may be useful for speech-language pathologist practitioners, since they will most likely work in environments that involve assessing and treating individuals with ID. In this meta-analysis, a total of 19 articles were reviewed to examine the side effects of AEDs in individuals with ID and seizure disorders. Side effects from AEDs were found; however, research regarding how AEDs and seizure disorders affected speech and language development was not available. Based on the findings, participants on AEDs regimens experienced a variety of side effects that included behavioral side effects, adverse cognitive side effects, and non-behavioral side effects. However, information regarding AEDs side effects and speech and language development was nonexistent. Based on the findings, further research in this is much needed for practicing speech-language pathologists in this topic. / text

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