Šiame darbe pristatomi mechanistiniai kiekybinio struktūros ir aktyvumo ryšio modeliai, skirti vaistinių junginių savybių, charakterizuojančių jų absorbciją ir pasiskirstymą organizme prognozavimui. Nagrinėjama keletas parametrų, apibūdinančių paprastos difuzijos per biologines membranas greitį, taip pat termodinaminės konstantos, aprašančios vaistų pasiskirstymą tarp kraujo plazmos ir audinių. Ląstelinių pernašos barjerų pralaidumas buvo modeliuojamas netiesinėmis lygtimis, siejančiomis paprastos difuzijos greitį su vaistų fizikocheminėmis savybėmis, tokiomis kaip lipofiliškumas, jonizacija, vandenilinių ryšių sudarymo potencialas ir molekulių dydis. Nustatyta, kad smegenų endotelyje ir žarnyno epitelyje stebima panašaus pobūdžio difuzijos greičio priklausomybė nuo jonizacijos – katijonai ir anijonai difunduoja atitinkamai 2 ir 3 eilėmis lėčiau už neutralias molekules. Pademonstruota, kad analizuojant vaistų pasiskirstymo tarp audinių ir kraujo duomenis, būtina paversti pradines eksperimentines vertes kitais dydžiais, atspindinčiais vaistų jungimosi prie plazmos ir audinių komponentų stiprumą. Vaistų giminingumas audiniams gali būti aprašytas jų lipofiliškumu, o neigiama jonizacijos įtaka stebima tik rūgštiniams junginiams. Taip pat parodyta, kad vaistų pernašos per hematoencefalinę užtvarą kiekybinių parametrų tiesinė kombinacija leidžia 94% tikslumu klasifikuoti vaistus pagal jų prieinamumą centrinei nervų sistemai. / The objective of this work was to develop mechanistic quantitative structure activity relationship models that would facilitate the assessment of drug properties related to their absorption and distribution in the body. The analysis involved several parameters reflecting the rate of passive diffusion across brain endothelium and intestinal epithelium, and thermodynamic constants related to drug distribution between plasma and tissues. Permeation through cellular transport barriers was modeled by nonlinear equations relating the passive diffusion rate to physicochemical properties of drugs: lipophilicity, ionization, hydrogen bonding potential and molecular size. It was demonstrated that brain endothelium and intestinal epithelium exhibit a quantitatively similar pattern of permeability-ionization dependence – ionized species permeate 2-3 orders of magnitude slower than neutral molecules. Analysis of tissue to plasma partitioning data revealed the necessity to split original experimental values into separate terms reflecting plasma and tissue binding strength. Drugs’ affinity to tissues could then be described by their lipophilicity, whereas detrimental effect of ionization was only observed for acidic drugs. Finally, it was shown that a linear combination of quantitative blood-brain barrier transport parameters allows classifying drugs according to their access to central nervous system with 94% overall accuracy.

The objective of this work was to develop mechanistic quantitative structure activity relationship models that would facilitate the assessment of drug properties related to their absorption and distribution in the body. The analysis involved several parameters reflecting the rate of passive diffusion across brain endothelium and intestinal epithelium, and thermodynamic constants related to drug distribution between plasma and tissues. Permeation through cellular transport barriers was modeled by nonlinear equations relating the passive diffusion rate to physicochemical properties of drugs: lipophilicity, ionization, hydrogen bonding potential and molecular size. It was demonstrated that brain endothelium and intestinal epithelium exhibit a quantitatively similar pattern of permeability-ionization dependence – ionized species permeate 2-3 orders of magnitude slower than neutral molecules. Analysis of tissue to plasma partitioning data revealed the necessity to split original experimental values into separate terms reflecting plasma and tissue binding strength. Drugs’ affinity to tissues could then be described by their lipophilicity, whereas detrimental effect of ionization was only observed for acidic drugs. Finally, it was shown that a linear combination of quantitative blood-brain barrier transport parameters allows classifying drugs according to their access to central nervous system with 94% overall accuracy. / Šiame darbe pristatomi mechanistiniai kiekybinio struktūros ir aktyvumo ryšio modeliai, skirti vaistinių junginių savybių, charakterizuojančių jų absorbciją ir pasiskirstymą organizme prognozavimui. Nagrinėjama keletas parametrų, apibūdinančių paprastos difuzijos per biologines membranas greitį, taip pat termodinaminės konstantos, aprašančios vaistų pasiskirstymą tarp kraujo plazmos ir audinių. Ląstelinių pernašos barjerų pralaidumas buvo modeliuojamas netiesinėmis lygtimis, siejančiomis paprastos difuzijos greitį su vaistų fizikocheminėmis savybėmis, tokiomis kaip lipofiliškumas, jonizacija, vandenilinių ryšių sudarymo potencialas ir molekulių dydis. Nustatyta, kad smegenų endotelyje ir žarnyno epitelyje stebima panašaus pobūdžio difuzijos greičio priklausomybė nuo jonizacijos – katijonai ir anijonai difunduoja atitinkamai 2 ir 3 eilėmis lėčiau už neutralias molekules. Pademonstruota, kad analizuojant vaistų pasiskirstymo tarp audinių ir kraujo duomenis, būtina paversti pradines eksperimentines vertes kitais dydžiais, atspindinčiais vaistų jungimosi prie plazmos ir audinių komponentų stiprumą. Vaistų giminingumas audiniams gali būti aprašytas jų lipofiliškumu, o neigiama jonizacijos įtaka stebima tik rūgštiniams junginiams. Taip pat parodyta, kad vaistų pernašos per hematoencefalinę užtvarą kiekybinių parametrų tiesinė kombinacija leidžia 94% tikslumu klasifikuoti vaistus pagal jų prieinamumą centrinei nervų sistemai.

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<p>The number of children with disabilities under the age of 18 years around the world varies from 120 to 150 million. In many countries, throughout the world, the majority of children with disabilities either do not receive any form of education or, if they receive any, it is often inappropriate. UNESCO estimates that more than 90% of children with disabilities in developing countries do not attend schools. Rwanda has recently started inclusive education in a number of schools around the country for ensuring that children with disabilities have access to education. Despite this, in Rwanda, many children with disabilities do not attend school and this number is not known. This study aimed to identify the barriers to school attendance by children with disabilities in Rwanda.</p>

The purpose of this research document is to understand the social issues that are generated from a globally ageing demographic, which relate to the aged identity and the current care environments available to them. Research will be conducted under the hypothesis that the design of a strategically sited care facility which, grouped with facilities that pertain to the care of the aged, could improve the quality of life for the elderly whilst promoting intergenerational connectivity. It is also hoped that ageist stereotypes could be abridged by lowering the dependency of the elderly on care providers by providing preventative and post operative rehabilitative care. The scope of the work is limited to the urban context of South Africa's ageing population primarily based on the current trend of mass urbanisation, after the abolition of the Apartheid government, which is creating a new family dynamic within South Africa where the care of the elderly is shifting onto medical institutions and care facilities. The demand for aged care facilities and the lack of resources in the field of aged care potentially create a situation where medical facilities are unnecessarily overburdened. An architectural response was generated through an investigation of current literature, case studies, precedent studies and personally conducted interviews with a number of aged care professionals. The research was conducted from a global standpoint and then focused towards issues that affect the aged individuals identity and care. The goal of this research was ultimately to inform the design of a care facility within Pietermaritzburg that is responsive to the needs of the elderly whilst being innovative towards its approach of aged care within a community. / Thesis (M.Arch.)-University of KwaZulu-Natal, Durban, 2010.

INTRODUCTION: The blood brain barrier (BBB), formed by the brain capillary endothelial cells separating the blood from the brain. Furthermore, the brain endothelial cells also express numerous transporter systems which help regulate and maintain the brain microenvironment. The protective function of the BBB and their transporter systems under pathological disease states, including brain tumor, can be an obstacle for the entry of therapeutic agents to the brain. OBJECTIVES: The current study set out to characterize brain tumor-induced alterations of the BBB of a mouse brain tumor model. Studies were performed to address changes in BBB permeability to P-gp dependent solutes using Rhodamine (R800). Furthermore, the use of lysophosphatidic acid (LPA) to modulate BBB permeability was also examined in healthy mice and tumor-bearing mice. METHODS: Tumors were induced by injecting Lewis Lung carcinoma (3LL) cells into the right hemisphere of female Balb/c mice. Changes in BBB permeability were assessed at various stages of tumor development, using both gadolinium contrast-enhanced agent (Gad) and 3H-mannitol. Functional activity of P-gp in the BBB was examined in adult mice following i.v. injection of R800 in the presence and absence of GF120918 (a P-gp inhibitor). Alterations in BBB permeability were characterized in healthy and tumor-bearing mice using a small (Gad) and large (IRdye800cw PEG) vascular permeability agent as well as R800 (changes in P-gp mediated permeability). RESULTS: Median mouse survival following 3LL injection was 17 days. The BBB was largely intact during tumor development with disruptions observed at the later stages of tumor development as indicated by Gad permeability. By inhibiting the function of P-gp with GF120918, the distribution of R800 in the brain increased by 4-fold. The enhancement effect of LPA on BBB permeability occurs within 3-6 minutes of injection with the barrier being restored back to its normal function within 20 minutes. Furthermore, an increased in brain penetration of IRdye800ce PEG and R800 were observed following LPA injection in both healthy and tumo-bearing mice. CONCLUSION: These studies provide the initial proof of concept for the use of BBB modulators including LPA and GF120918 to enhance drug delivery to the brain and the tumor sites.

The work presented here report findings in (1) infrared detectors based on p-GaAs/AlGaAs heterojunctions, (2) J and H aggregate sensitized heterojunctions for solar cell and photon detection applications, (3) heterojunctions sensitized with quantum dots as low cost solar energy conversion devices and near infrared photodetectors. (1)A GaAs/AlGaAs based structure with a graded AlGaAs barrier is found to demonstrate a photovoltaic responsivity of ~ 30mA/W (~ 450mV/W) at the wavelength of 1.8 mm at 300K. Additionally the graded barrier has enhanced the photoconductive response at 78 K, showing a responsivity of ~ 80mA/W with a D*=1.4×108 Jones under 1V bias at 2.7 mm wavelength. This is an approximately 25 times improvement compared to the flat barrier detector structure, probably due to the improved carrier transport, and low recapture rate in the graded barrier structure. However, these graded barrier devices did not indicate a photoresponse with photoconductive mode at 300K due to high shot noise. Additionally, two generation-recombination noise components and a 1/f noise component were identified. A series of GaAs/AlGaAs multilayer hetero-junction structures were tested as thermal detectors. A superlattice structure containing 57% Al fraction in the barrier and 3 × 1018 cm-3 p-doped GaAs emitter showed the highest responsivity as a thermal detector with a TCR of ~ 4% K-1, at 300K. (2)The photovoltaic properties of heterojunctions with J-/ H- aggregated dye films sandwiched between n– and p-type semiconductors were investigated for potential application as solar cells and IR detectors. Films of cationic dye Rhodamine-B-thiocyanate adsorbed on Cu2O substrate are found to form organized dye layers by self-assembled J- aggregation, resulting in large red-shifts in the photo -response. Additionally, cells sensitized with a pentamethine cyanine dye exhibited a broad spectral response originating from J- and H-aggregates. The photocurrent is produced by exciton transport over relatively long distances with significant hole-mobility as well as direct sensitized injection at the first interface. (3) A ZnO/PbS-QD/Dye heterostructure had enhanced efficiency compared to ZnO/Dye heterostructure as a solar cell. Furthermore, a ZnO/PbS-QD structure has demonstrated UV and NIR responses with 4×105V/W (390 nm) and 5.5×105 V/W (750 nm) under 1V bias at 300K.

Focused ultrasound combined with intravenously injected microbubbles is a promising non-invasive therapy capable of temporarily disrupting the blood-brain barrier for targeted drug delivery. Established in vivo experiments on rodent models combine focused ultrasound treatment with two-photon microscopy imaging to improve understanding of microvasculature response. A phased array, an advanced ultrasound therapy device, was successfully developed to improve pressure transmission in these experiments. An investigation of transducer sensitivity to setup equipment suggested modifications to setup procedures, for example recording objective position, may improve in situ pressure estimates. A ring array composed of 50 lateral mode elements, geometry determined by pressure field simulations, was successfully fabricated. Fibre optic hydrophone pressure field measurements confirmed the device had an appropriate focal size (0.7mm diameter x 4mm axial length) and reached therapeutic pressure levels (>0.5MPa). Ex vivo transcranial measurements demonstrated moderate focal correction and off-axis steering capabilities that may improve experimental throughput and target alignment.

Focused ultrasound combined with intravenously injected microbubbles is a promising non-invasive therapy capable of temporarily disrupting the blood-brain barrier for targeted drug delivery. Established in vivo experiments on rodent models combine focused ultrasound treatment with two-photon microscopy imaging to improve understanding of microvasculature response. A phased array, an advanced ultrasound therapy device, was successfully developed to improve pressure transmission in these experiments. An investigation of transducer sensitivity to setup equipment suggested modifications to setup procedures, for example recording objective position, may improve in situ pressure estimates. A ring array composed of 50 lateral mode elements, geometry determined by pressure field simulations, was successfully fabricated. Fibre optic hydrophone pressure field measurements confirmed the device had an appropriate focal size (0.7mm diameter x 4mm axial length) and reached therapeutic pressure levels (>0.5MPa). Ex vivo transcranial measurements demonstrated moderate focal correction and off-axis steering capabilities that may improve experimental throughput and target alignment.