Abstract Bipolar disorder is a complex illness. It is a life long episodic disorder very disruptive for the patient and family. Repeated episodes lead to progressively deteriorating level of functioning and poor response to the treatment. Suicide attempts and completed suicide has been a frequent complication. The complexity and difficulties involved in treating this mental condition are well recognised .The pharmacological options include lithium, valproate, carbamazepine, lamotrigine, topiramate, benzodiazepines. The use of neuroleptics in bipolar disorder remain controversial because of the increased susceptibility of this group of patients to side effects of neuroleptics. Objectives: The aim of this research is to investigate in a population of patients with bipolar disorder who are having treatment with combination of a mood stabilizer and antipsychotics: 1) The number of prescriptions of antipsychotics, in bipolar patients in a community clinic 2) The rationale of such combination 3) Whether correlates exist between variables such as substance abuse and noncompliance and the prescription of antipsychotics Method: This retrospective, descriptive, analytic study was conducted at Voslooros Psychiatric Clinic, which is situated in the south of Johannesburg. The clinical records of all adult patients with an initial diagnosis of bipolar disorder as at December 2004 were examined Particular note was taken of demographic data, diagnosis, age of onset of psychiatric illness, V duration of illness, treatment prescribed, reasons for prescribing this medication, response to the treatment, social circumstances of each patient, substances use and compliance. Results: 74.1% of the patients were maintained on a combination of mood stabilizer with antipsychotic. Combination treatment was used in an attempt to improve the psychotic symptoms and dangerous behaviour in 48% of the patients, noncompliance in 38% of the cases and 14% patients were in transitional phase to stop antipsychotics. 80.65% of the patients were on treatment with antipsychotics for longer than 6 months. Use of atypical antipsychotics is associated with a better outcome than the conventional agents. In this study only a small percentage (10 %) of patients received atypical antipsychotics. 19.4 % patients reported side effects of the medication. The lower figures in our study can be due to underreporting and inadequate documentation. . 38.7% of the patients reported substance misuse. Our finding were much lower compared with the literature, probably due to underreporting. Alcohol was the most common substance. This study show that the need for more medication was increased 6.6 fold in patients with polysubstance abuse compared with the patients not abusing any substance. Noncompliance in the maintenance phase of the treatment is a important issue in the management of the patients with bipolar disorder. This study found that the majority of the patients (59.7%) were noncompliant with their treatment. Those findings were in line with studies done by Keck PE who reported rates of noncompliance from 51% to 64%. Our study show that 63% of the patients had a level of VI education less than matric and this may be a contributing factor to noncompliance. Conclusions: The results of the study suggest that a large number of bipolar patients are only partially responsive to mood stabilizers alone and the maintenance treatment with antipsychotics for longer than 6 months are needed because of persistence of the symptoms. More efficient strategies are necessary to educate the people, to improve the compliance and to decreased the use of substances.

Current pharmaceutical engineering for the manufacture of binary and combined dry powder inhaler (DPI) dosage forms relies on destructive strategies such as micronisation to generate respirable drug particles. Such processes are inefficient and difficult to control to produce particles of defined quality and functionality for inhaled drug delivery, which can affect drug product performance throughout the shelf-life of the product. Furthermore, owing to current pharmaceutical manufacturing practises of combined inhalation products, these products are subject to greater variability in dose delivery of each active, which may be perpetuated as a function of product storage conditions and limit clinical efficacy of the drug product. Hence, there is a requirement of processes that may enable production of binary and combination DPI products that will allow actives to be delivered more efficiently and independently of dose variations. The aim, therefore, of this study was to develop the solution atomisation and crystallisation by sonication (SAX) process for engineering of single and combination drug particles with suitable physicochemical properties for delivery to the lungs. The SAX process consists of key stages, which include, solution atomisation to produce aerosol droplets, generation of highly supersaturated droplets by evaporation of carrier solvent from aerosol droplet, collection of droplets in a crystallisation vessel containing appropriate non-solvent and the application of ultrasonic waves to the crystallisation vessel. Atomisation of a 1.5% w/v solution of budesonide in dichloromethane resulted in particles with defined surface geometry, which were formulated in binary dry powder inhaler (DPI) formulations and assessed using the next generation impactor.

The use of drug combinations (DCs) in cancer therapy can prevent the development of drug resistance and decrease the severity and number of side effects. Synthetic lethality (SL), a genetic interaction wherein two nonessential genes cause cell death when knocked out simultaneously, has been suggested as a method of identifying novel DCs. A combination of two drugs that mimic genetic knockout may cause cellular death through a synthetic lethal pathway. Because SL can be context-specific, it may be possible to find DCs that target SL pairs in tumours while leaving healthy cells unscathed. However, elucidating all synthetic lethal pairs in humans would take more than 200 million experiments in a single biological context – an unmanageably large search space. It is thus necessary to develop computational methods to predict human SL. In this thesis, we develop connectivity homology, a novel measure of network similarity that allows for the comparison of interspecies protein-protein interaction networks. We then use this principle to develop Species-INdependent TRAnslation (SINaTRA), an algorithm that allows us to predict SL between species using protein-protein interaction networks. We validate it by predicting SL in S. pombe from S. cerevisiae, then generate over 100 million SINaTRA scores for putative human SL pairs. We use these data to predict new areas of cancer combination therapy, and then test fifteen of these predictions across several cell lines. Finally, in order to better understand synergy, we develop DAVISS (Data-driven Assessment of Variability In Synergy Scores), a novel way to statistically evaluate the significance of a drug interaction.

This thesis gives a comprehensive view of the scope of formulations and<br />related solution approaches for the cutting stock problem (CSP) and its<br />variants. The focus is on branch-and-price approaches. Specialized<br />algorithms are developed for knapsack subproblems that arise in the<br />course of the algorithm. Thorough numerical tests are used to identify good strategies<br />for initialization, stabilization, branching, and producing<br />primal solutions. Industrial variants of the <br />problem are shown to be tractable for a branch-and-price approach.<br /><br /><br />The models studied are the following: the standard cutting stock and<br />bin packing problems, a variant in which the production levels lie in<br />a prescribed interval of tolerance, the multiple width cutting stock<br />problem in which stock pieces are of different size, a variant with<br />additional technical constraints that arise typically in industrial<br />applications, and a variant where the number of distinct cutting<br />patterns used is minimized given a waste threshold. <br /><br /><br />First, we consider various formulation of the Cutting Stock Problem<br />(CSP): different models of the knapsack subproblem can be exploited to<br />reformulate the CSP. Moreover, we introduce different ways of<br />modeling local exchanges in the solution (primal exchanges imply dual<br />constraints that stabilize the column generation procedure). Some<br />models are shown to be valid integer programming (IP) reformulations while others define<br />relaxations. The dual bounds defined by their LP solution are compared<br />theoretically.<br /><br />Then, we study the variants of the knapsack subproblem that arise<br />in a column generation approach to the CSP. The branching constraints<br />used in the branch-and-price algorithm can result in class bound and<br />setup cost or the need for a binary decomposition in the subproblem. <br />We show how standard knapsack solvers (dynamic programming approach and specialized<br />branch-and-bound algorithm) can be extended to these variants of the<br />knapsack problem.<br /><br />Next, we discuss some branch-and-price implementation strategies. We compare <br />different modes of initialization of the column generation procedure, we present our numerical study of various stabilization<br />strategies to accelerate convergence of the procedure. We compare in particular the impact of the various ways of introducing<br />local exchanges in our primal model and other stabilization techniques<br />such as dual solution smoothing techniques or penalization from a<br />stability center that prevent the fluctuation of the dual variables. <br />To generate the columns we study different strategies based on the use of heuristic columns or on a multiple generation of columns.<br />We also consider the use of heuristics based on column generation to find a primal bound. These are compared to a classic constructive heuristic. Then, we compare the different branching rules that are used in the branch-and-price procedure. <br /><br />Finally, we present numerical results on two industrial applications that<br />correspond to the variant with technical restrictions for which we<br />minimize first the waste and then the number of setups.

<p>The intention of the study is to evaluate the risk of artemisinin in early pregnancy through the use of a qualitative research approach, with a focus on rural women in Babati District, Manyara Region, Tanzania.</p><p>Artemisinin-Based Combination Therapy (ACT) is the most effective and recommended antimalarial treatment at the present. Artemisinin compounds are extracted from <em>Artemisia annua</em><em>, </em>a plant which has been used as an herbal medical treatment in China for 2000 years.</p><p>Except few side-effects, there have not been any reports on medical problems due to artemisinin intake during pregnancy. On the other hand, artemisinin tested on animals have revealed that complications such as death of embryos are possible during pregnancy, why more research is needed concerning artemisinin safety in first trimester of pregnancy.</p><p>However, evaluating the risk of artemisinin in pregnancy is referred as complex, when numerous factors could contribute to e.g. fetal loss, abnormalities, or wrong medication. Cultural and economical aspects have to be considered when designing a monitoring system, to enable effective registration of drug quality and drug intake, and follow-up study of mother and child. Accessibility, affordability, possibility and knowledge, are other significant related aspects that have to be managed to eliminate the risk of artemisinin in early pregnancy.</p><p> </p><p><strong></strong></p><p> </p><p> </p>

The intention of the study is to evaluate the risk of artemisinin in early pregnancy through the use of a qualitative research approach, with a focus on rural women in Babati District, Manyara Region, Tanzania. Artemisinin-Based Combination Therapy (ACT) is the most effective and recommended antimalarial treatment at the present. Artemisinin compounds are extracted from Artemisia annua, a plant which has been used as an herbal medical treatment in China for 2000 years. Except few side-effects, there have not been any reports on medical problems due to artemisinin intake during pregnancy. On the other hand, artemisinin tested on animals have revealed that complications such as death of embryos are possible during pregnancy, why more research is needed concerning artemisinin safety in first trimester of pregnancy. However, evaluating the risk of artemisinin in pregnancy is referred as complex, when numerous factors could contribute to e.g. fetal loss, abnormalities, or wrong medication. Cultural and economical aspects have to be considered when designing a monitoring system, to enable effective registration of drug quality and drug intake, and follow-up study of mother and child. Accessibility, affordability, possibility and knowledge, are other significant related aspects that have to be managed to eliminate the risk of artemisinin in early pregnancy.

This thesis proposes a theoretical framework explaining cognitive processes of meaning construction through conceptual interactions. It was noted that while the nine models or theories (Fuzzy Sets, Selective Modification model, Amalgam theory, Concept Specialization model, Composite Prototype Model, Dual-Process model, Constraint model, CARIN model, and Coherence Theory) in literature on conceptual combination offered insights on the problem of how people understand conceptual combinations, most of them assumed a schematic representation of our knowledge of concepts. However, it is possible that our minds represent knowledge in less structured ways and that schematic structure may not necessarily play a role in making sense of conceptual combinations. In this thesis, I attempted to make fewer assumptions about how knowledge is represented to explain the cognitive processes of conceptual combinations. I assume that concepts are related to other concepts, and knowledge can be represented by associations among concepts. Based on this assumption, the meaning of a conceptual combination is constructed through interactions between these associated concepts. It is proposed that the cognitive processes involved in meaning construction start from a distinction between different roles each component concept plays (head or modifier), and then a system of associations are activated contingently, prototypically, and efficiently with the goal of forming a cognitive field (analytically represented as a closed cycle) to connect head and modifier in a balanced way. The balanced system of concepts is strengthened further by reconciling remaining tensions in the field. Experimental results confirmed that component concepts in a combination activate associations contingently, and prototypicality and balance are major factors influencing whether an association will be activated by the combination to construct the meaning. Head / Modifier and Novelty were also studied as moderating variables. The experimental results indicated that head is a stronger moderator for association activation than modifier, and novelty was not found to be a significant moderator in association activation. Implications of these findings are discussed and future research is identified.

This thesis proposes a theoretical framework explaining cognitive processes of meaning construction through conceptual interactions. It was noted that while the nine models or theories (Fuzzy Sets, Selective Modification model, Amalgam theory, Concept Specialization model, Composite Prototype Model, Dual-Process model, Constraint model, CARIN model, and Coherence Theory) in literature on conceptual combination offered insights on the problem of how people understand conceptual combinations, most of them assumed a schematic representation of our knowledge of concepts. However, it is possible that our minds represent knowledge in less structured ways and that schematic structure may not necessarily play a role in making sense of conceptual combinations. In this thesis, I attempted to make fewer assumptions about how knowledge is represented to explain the cognitive processes of conceptual combinations. I assume that concepts are related to other concepts, and knowledge can be represented by associations among concepts. Based on this assumption, the meaning of a conceptual combination is constructed through interactions between these associated concepts. It is proposed that the cognitive processes involved in meaning construction start from a distinction between different roles each component concept plays (head or modifier), and then a system of associations are activated contingently, prototypically, and efficiently with the goal of forming a cognitive field (analytically represented as a closed cycle) to connect head and modifier in a balanced way. The balanced system of concepts is strengthened further by reconciling remaining tensions in the field. Experimental results confirmed that component concepts in a combination activate associations contingently, and prototypicality and balance are major factors influencing whether an association will be activated by the combination to construct the meaning. Head / Modifier and Novelty were also studied as moderating variables. The experimental results indicated that head is a stronger moderator for association activation than modifier, and novelty was not found to be a significant moderator in association activation. Implications of these findings are discussed and future research is identified.

It is the goal of this body of work to research an assortment of different photoacid generators (PAGs) and quantify their ability to perform the decomposition of poly(propylene carbonate) (PPC). Adding PAGs to PPC allows for a decreased polymer decomposition temperature, which can in turn be used as a sacrificial polymer for the fabrication of various microelectromechanical and microfluidic devices. A focus will be placed on relating the properties of the PAG such as acid strength, acid volatility, and PAG activation to processing issues like percentage of total film decomposition, amount and composition of film residue, decomposition rate, decomposition temperature, and environmental dependencies. This research discovered that the use of superacid triflic and nonaflic based PAGs were not adequate for the decomposition of PPC due to the high vapor pressure of the acid. Furthermore, the non-fluorinated sulfonic acid based PAGs do not posses the super-acid level acidity needed to sufficiently decompose PPC. Conversely, a perfluorinated methide and a tetrakis(pentafluoropheyl)borate based PAG both demonstrated the capability for high level PPC decomposition. Building on the knowledge gained through experimentation with these individual PAGs, the creation of a novel Combination PAG was accomplished. The Combination PAG uses acid groups with different physical properties collectively working to achieve what neither could complete individually.

Listeria monocytogenes is a foodborne pathogenic bacterium responsible for ~500 deaths and a financial burden of ~$2.3 billion each year in the United States. Though a zero tolerance policy is enforced with regard to its detection in cooked ready-to-eat foods, additional preemptive control alternatives are required for certain products. Among these alternatives are strategies permitting the usage of food antimicrobial combinations to control the pathogen. Research on antimicrobial combinations can provide insight into more efficient control of the pathogen, but is currently lacking. The purpose of this study was to evaluate the in vitro inhibition of L. monocytogenes exposed to the antimicrobials e-Poly-L-Lysine (EPL), lauric arginate ester (LAE), and sodium lactate (SL) at pH 7.3, octanoic acid (OCT) at pH 5.0, and nisin (NIS) and acidic calcium sulfate (ACS) at both pH 5.0 and 7.3. A broth dilution assay was used to determine single antimicrobial minimum inhibitory and bactericidal concentrations for L. monocytogenes Scott A, 310, NADC 2783, and NADC 2045. Optical density differences (delta<0.05 at 630 nm) were used to denote inhibition. Concentrations producing population decreases of greater than or equal to 3.0 log10 CFU/ml after incubation were considered bactericidal. Inhibition resulting from combinations of antimicrobials (NIS+ACS, EPL+ACS, SL+ACS, NIS+LAE, OCT+ACS, and OCT+NIS) was assessed using a checkerboard assay, and fractional inhibitory concentrations (FIC) were determined. FIC values were plotted on isobolograms and were used to create FIC indices (FICI). Isobologram curvature was used to classify combinations as synergistic, additive, or antagonistic. From FIC indices, interactions were defined as antagonistic (FICI >1.0), additive (FICI =1.0), or synergistic (FICI &lt;1.0). Strain-dependent factors had a bearing on MIC and MBC values for NIS and EPL. At pH 7.3, NIS+ACS displayed synergistic inhibition, NIS+LAE and EPL+ACS demonstrated additive-type interactions, and the SL+ACS pairing was unable to be defined. At pH 5.0, interpretation of the OCT+NIS interaction also presented challenges, while the OCT+ACS combination resulted in synergistic behavior. Additional studies are needed to validate in vitro findings on surfaces of ready-to-eat meats. Future in vivo studies should investigate the ability of synergistic combinations (NIS+ACS and OCT+ACS) to control the pathogen. Better characterizations of inhibitory mechanisms should also be performed.