Nitrogen fixation is an ecologically important microbial process that can contribute bioavailable combined N to habitats low in N. Shipworms, or wood-boring bivalves, host N2-fixing and cellulolytic symbiotic bacteria in gill bacteriocytes, which have been implicated as a necessary adaptation to an N-poor C-rich (wooden) diet. Shipworm symbionts are known to fix N within the gill habitat and newly fixed N is subsequently incorporated into non-symbiont containing host tissue. The presence of N2-fixation in gill bacteriocytes presents a conundrum because N2-fixation is tightly regulated by oxygen in most other diazotrophic microbes. Also, the direct evidence of new N being incorporated into the host tissue indicates that there are potentially complex nutrient cycles in this symbiosis, which have not been investigated. We used the cultivated symbiont Teredinibacter turnerae, which has been isolated from many shipworm species, as a model organism to elucidate controls on N2-fixation and N release in the shipworm symbiosis. Our results indicate that headspace oxygen concentration does not control biomass specific N2-fixation and respiration activity in T. turnerae, but it does influence the magnitude of the growth rate and timing of culture growth. Also, we examined the controls of oxygen on inorganic nutrient uptake rates, and documented a small amount of dissolved inorganic nitrogen release. While the N budget is only partially balanced, we provide indirect evidence for the allocation of fixed N to the excretion of exopolymeric substances and dissolved organic nitrogen; future studies that measure these additional N sinks are necessary to close the N budget. Although there are limitations of using pure cultures to investigate a complex symbiotic system, this study provides direct experimental evidence that T. turnerae has adaptations that are conducive to N2-fixation in gill bacteriocytes.

Fracture of polymer-metal interfaces is one of the main failure modes occurring in micro-electronic components. This phenomenon is particularly true when considering the delamination of several layers of an interconnect structure. In order to predict the failure nucleation and the crack propagation into the composite material, the finite element analysis is one of the key procedures. Even though simple linear models have been considered for years, we are now facing the necessity of using more complex models including non-linearity which can occur, in this case, with the presence of high local stresses near the crack front. However, the computational time can sometimes be incredibly long. Moreover, the fact that the considered materials are quasi-brittle brings some numerical difficulties such as sharp snap-back and snap-through. The actual challenge resides in obtaining a reliable result in a reasonable time of calculation. The present work considers the implementation of a new non-linear finite element solver, developed for the MSc. Marc/Mentat package software. It is based on a general arc-length constraint which considers the energy released during the propagation of the crack. This offers the advantage of being directly linked to the failure process, and no previous knowledge of the failure behavior is required. The models considered in this work represent the simulation of crack propagations in multilayer electronic systems, such as SIP devices, and are based on a cohesive zone approach. In order to clearly understand the issues of this problem, this work includes a brief description of the fracture mechanics and reviews the existing nonlinear finite element solvers. After explaining the principle of the energy release solver and the different issues due to its implementation, its efficiency is compared to pre-implemented solvers, such as the Crisfield method. The results show a significant improved robustness of the new energy released method compared to the previous arc-length methods.

<p>Remote Explosives Scent Tracing (REST) is the concept of bringing the mine field to Mine Detection Dogs or Rats, instead of vice versa. This is done by collecting air or dust from minefields, and taking these samples to a laboratory environment, where they are subsequently analysed by the detection animals.</p><p>REST has previously proven to be very fast and cost effective, but one of the issues facing the method is that there is yet no reliable tool for sampling dust. In earlier sampling units, air has been collected in filters. However, the concentration of scents related to mines has been seen to be a million times higher in dust particles than in air sampled from above the ground. The aim of this project was to evaluate and improve a dust sampling prototype constructed in the beginning of 2010. The project was initiated in cooperation with the GICHD (Geneva International Centre for Humanitarian demining), and carried out in cooperation with APOPO (Anti-Personnel Landmines Detection Product Development).</p><p>During this project, information was gathered on the samplers that have previously been used for REST. A new prototype was made in Trondheim in cooperation with NTNU (Norwegian University of Science and Technology). With this new sampler prototype, tests were made in a laboratory environment at NTNU as well as at APOPO’s test mine field in Morogoro, Tanzania. Several obstacles were faced, such as difficulties to test and evaluate the sampler during the rainy season, insufficient air supply for the prototype, and issues with the laboratory equipment in Morogoro. Due to this, the number of tests performed and the number of repetitions of each test was not as high as would have been desired.</p><p>The results of the information gathering and the tests are presented in this report, and the knowledge and experience gained resulted in several suggestions for improvements for the sampler prototype. A suggestion for a grid design that would cover the entire mouth piece, with a built-in distance to the suction inlet, in order to avoid both clogging of the grid and that too much dust is sucked in if the mouth piece touches the ground and a fully adjustable sampling unit. Several other recommendations are given that would reduce cross contamination risks and improve ergonomics and other aspects of the sampler prototype.</p>

Multiple dose regimens are frequently required to optimize therapy; however, such therapy is frequently undermined by poor patient adherence. In fact, patient adherence is inversely related to the number of doses a patient is asked to take each drug. Consequently, great efforts are under way to develop drug delivery systems that are able to release drugs over an extended time interval; this could offer considerable benefits including reducing administration frequency. This dissertation describes multiple dose platforms designed to deliver a variety of drugs as a single oral administration are described in this dissertation. We believe these drug delivery systems can be used to enhance patient compliance and achieve better therapeutic outcomes. We developed and tested a novel gastroretentive pulsatile drug delivery platform. This platform could deliver multiple unit doses of a drug in a pulsatile pattern and be controlled by dissolution/erosion of a lag-time interval layer. The platform was designed to be retained in the stomach whilst pulsing drug at various timed intervals. This would allow each dose of the drug to release above or within an optimized absorption window over an extended period of time. To assure the robustness and reproducibility of the platform, various in vitro dissolution studies and physical stability tests were performed and evaluated through drug release characteristics, buoyancy, and structural integrity evaluations. The applicability of the novel multiple dose platform was demonstrated by providing repeated release profiles of ciprofloxacin and verapamil in a single, once-daily delivery system. Ultimately, this dissertation demonstrates that a novel multiple dose platform could be a suitable alternative dosing strategy for a variety of drugs to improve patient adherence and treatment efficacy. / text

The Bio J-FIL process has been demonstrated to be a viable method for manufacturing nanoscale, polymeric drug carriers. The process allows for precise control of the size and shape of the drug carriers. While the original process is sufficient for research scale projects, reliability issues have prevented it from being scalable to levels that could potentially be used for mass-production of the drug carriers. In this thesis, a detailed root cause analysis has been conducted to determine the cause of the reliability issues limiting the Bio JFIL process. A series of experiments with varying substrate and imprint fluid combinations were conducted to pinpoint the cause of imprint failure in the Bio J-FIL process. Upon determining the cause of failure, an alternative imprint process was investigated that sought to increase the variety of materials used in the process by utilizing an intermediary layer. This process is referred to in this thesis as the Bio JFIL-I process. The results using Bio JFIL-I indicated increased reliability over the standard Bio J-FIL process. Further refinement of the Bio JFIL-I process could also address additional issues with the Bio J-FIL process unrelated to process reliability. The Bio JFIL-I approach presented in this thesis is complementary to other approaches that have been recently pursued in the literature which are discussed in the thesis. / text

The purpose of this study is to evaluate the association between sustained-release morphine (Avinza®), and performance on neuropsychological tests assessing short term memory, information processing, and motor skills in chronic pain patients, while controlling for stages of pain model variables and the effects of benzodiazepines. A convenience sampling procedure was utilized to enroll a sample of patients who had a trial of short-acting narcotic analgesics for their chronic non-malignant pain. Enrolled patients were treated with long-acting morphine Avinza.® Patient interviews were conducted at enrollment and one-month follow-up. A total of 129 patients were enrolled in the study. Mean pain intensity ratings at the highest, lowest, and average levels in the previous week were lower at follow-up (10.90, 4.56. 7.64) than at baseline (12.71, 6.76, 10.01) respectively. Reduction in pain levels was associated with a corresponding reduction in levels of pain unpleasantness, pain suffering, and pain behaviors. The models evaluating the associations between the stages of pain model variables, morphine dose, benzodiazepine dose, and digit span test (chi square = 147.79, p = 0.76), digit symbol test (chi square = 128.06, p = 0.5), and paced auditory serial attention test fit the data well (chi square = 160.39, p = 0.85). There was a statistically significant inverse association between frequency of pain behaviors and digit span test scores at baseline (-0.49, p = 0.01). Although the association between pain behaviors and digit symbol test scores (- 17. 0 %, p = 0.09) and paced auditory serial addition test scores (-4.0%, p = .28) at baseline were not statistically significant, a large negative effect was found. At follow-up, the association between pain behaviors and digit span test was positive and not significant. The negative association between frequency of pain behaviors and digit symbol test scores (-4.4%, p = 0.67 ) and paced auditory serial addition test scores (-2.8%, p = 0.21) at follow-up were considerably weaker. There were no significant association between opioid dose and cognitive function test scores. Opioid therapy, particularly, sustained release morphine therapy (Avinza) does not contribute to cognitive impairment in chronic pain patients. / text

Formulation intervention, through the application of processing technologies, is a requirement for enabling therapy for the vast majority of drugs. Without these enabling technologies, poorly soluble drugs may not achieve therapeutic concentrations in the blood or tissue of interest. Conversely, freely soluble and/or rapidly cleared drugs may require frequent dosing resulting in highly cyclic tissue concentrations. During the last several years, thermal processing techniques, such as melt mixing, spray congealing, sintering, and hot-melt extrusion (HME), have evolved rapidly. Several new technologies, specifically dry powder coating, injection molding, and KinetiSol® dispersing (KSD), have been adapted to the pharmaceutical arena. Co-rotating twin screw extrusion is routinely applied for the purposes of dissolving poorly soluble drugs into glassy polymers to prepare amorphous solid dispersions, which create supersaturated drug concentrations in the gastro-intestinal tract. A potentially more advantageous alternate geometry, counter-rotating twin screw extrusion was evaluated for preparation of model amorphous solid dispersion and was observed to be more efficient in forming a solid solution and reduced the thermal stress on the drug. HME and KSD processes were utilized to prepare two phase systems consisting of a lipid, glyceryl behenate, and a polymeric amorphous solid dispersion intended to provide both controlled release of drug and supersaturated drug concentrations in the release medium. Such systems are challenging due to the potential for crystallization of the drug within the dosage form during release, which was observed to be influenced by lipophilicity and porosity of the formulation, as well as the surface area to volume ratio of the system. High molecular weight cellulose based glassy dispersions were prepared using a weakly basic model drug by KSD, which when formulated into tablets were optimized to provide either immediate or approximately 2 hours of controlled release under the pH conditions simulating the environment of the stomach. Without formulation intervention in the external phase of the tablet, these compositions gel, muting drug release and missing the drug absorption window. Compositions optimized by an in vitro dissolution test were compared to a lower molecular weight HME prepared commercial product in a beagle dog model and observed to have statistically similar bioavailability, and in one case improved variability. A modified twin screw extrusion machine was utilized to develop a continuous granulation process capable of producing granules that do not require subsequent grinding or sizing. This novel process, which employs previously un-reported temperature profiles, produces lipid based granules that when compressed into tablets produce a controlled release of tramadol hydrochloride, which were not susceptible to alcohol induced dose dumping. / text

Predictive models for diffusion-controlled particle dissolution are important for designing advanced and efficient solid products for controlled release applications. A computer-aided modeling framework was developed to derive the effective dissolution rates of multiple particles as the solid surface material eroded gradually into the surrounding liquid phase. The mathematical models were solved with numerical methods using the computational software MATLAB. Results from the models were imported into COMSOL Script to create three-dimensional plots of the particle size data as a function of time. The release model found for the monodispersed particles was manipulated to incorporate polydisperse solids, as these are found more frequently in chemical processes. The program was further developed to calculate the particle size as a function of time for particles encapsulated for use in controlled release. The parameters, such as radius size, coating material and encapsulation thickness, can be altered in the computer models to aid in the design of particles for different desired applications. Simulations produced conversion profiles and three-dimensional visualizations for the dissolution processes. Experiments for the dissolution of citric acid in water were performed using a reaction microcalorimeter to verify results found from the computer models.

The influence of water soluble and insoluble stabilizing excipients on the physical stability of coated dosage forms was investigated in this study. The effect of the excipients on the thermal and physico-mechanical properties, and water vapor permeability of free films was studied, as was the influence of these excipients on the physical stability and release kinetics of coated pellets. The effect of water-soluble proteins, bovine serum albumin (BSA) and Type B gelatin, on the physical aging of Eudragit[trademark] RS/RL 30 D films was investigated. It was found that ionic interactions occurred above the isoelectric point of BSA and caused unstable films which showed accelerated decreases in drug release rate. The adjustment of the pH of the dispersion below the isoelectric point of BSA resulted in electrostatic repulsive charges that stabilized the drug release rate from coated dosage forms at both ambient and accelerated conditions. The addition of gelatin to the coating dispersion increased the drug release rate due to the formation of gel-domains through which the drug was able to easily diffuse. The influence of silicon dioxide on the stability of Eudragit[trademark] RS/RL 30 D films was investigated. Colloidal grades showed enhanced incorporation in the acrylic matrix; however, unstable films were formed. The addition of silicon dioxide with a larger particle size increased the permeability of the film and stabilization in drug release rate was attributed to constant water vapor permeability values of free films. The influence of ethylcellulose on the physical aging of Eudragit[trademark] NE 30 D coated pellets was studied. The two polymers were found to be substantially immiscible and the drug release rate of coated pellets was constant at both ambient and accelerated conditions which correlated to stabilizations in both the physico-mechanical properties and water vapor permeability of free films. Blending both Eudragit[trademark] NE 30 D and RS 30 D resulted in the formation of coherent films without the need of plasticizer. The two polymers were found to be miscible and both films and coated dosage forms were stable when stored below the glass transition temperature of the polymer blend. When films were stored above this temperature, instabilities occurred as a result of the further coalescence and densification of the polymer blend.

Thesis (MTech. degree in Pharmaceutical Sciences)--Tshwane University of Technology, 2010. / Investigates the absorption enchancing properties of N-trimethyl chitosan chloride (TMC) and monocaprin (MC), individually and in combination, on the permeability of insulin across the Caco-2 intestinal epothelial cell line.