Reduced transferrin binding in Down syndrome:a route to senile plaque formation and dementia

Plasma transferrin binding in Down syndrome and Alzheimer's disease is significantly reduced compared with age matched controls and it was thought this may help elucidate a pathological time sequence for the onset of dementia in Down syndrome. In Down syndrome, there was a reduction in gallium and aluminium transferrin binding both with age and the onset of dementia. Non-transferrin bound gallium species were identified as non-transportable phosphate or silicate. Thus, the route of entry of metals into the brain must be via a transferrin mediated complex only. A clear sequence of pathological events has been demonstrated in Down syndrome which shows the pathway to development of plaques and dementia and this is believed to have an immunological origin.

Lobe formation and division in the foliose lichen Xanthoparmelia conspersa

New lobe development and lobe division was studied in the foliose lichen Xanthoparmelia conspersa (Ehrh. ex. Ach.) Hale. In thalli with either the centre or margin removed, the inside edge of the perimeter, the outer edge of the reproductive centre, and fragments derived from the thallus perimeter all regenerated growing points (‘lobe primordia’) within a year. Thalli possessing isidia had the greatest ability to regenerate growing points. In reproductive thalli, there was a positive correlation between the density of new growing points and thallus size. When fragments were cut from the perimeters of mature X. conspersa thalli and glued to pieces of slate, the ratio of growing points to mature lobes increased over 54 months. Lobes within a thallus exhibited different degrees of bifurcation. In some bifurcating lobes, the point of origin of the bifurcation advanced at the same rate as the lobe tips over 4 months but in most lobes, the bifurcation point either advanced less rapidly than the lobe tips or retreated from its original location. Removing adjacent lobes had no significant effect on the radial growth of a lobe over 4 months or on the location of the bifurcation point but it increased the number of growing points. These results suggest that for X. conspersa: 1) all portions of of thalli can regenerate growing points, 2) few growing points actually develop into mature lobes, 3) individual lobes within a thallus grow and divide differently, and 4) adjacent lobes inhibit the development of growing points on their neighbours.

Transducer diffraction theory and development of an ultrasonic tomogram

The work described in this thesis is the development of an ultrasonic tomogram to provide outlines of cross-sections of the ulna in vivo. This instrument, used in conjunction with X-ray densitometry previously developed in this department, would provide actual bone mineral density to a high resolution. It was hoped that the accuracy of the plot obtained from the tomogram would exceed that of existing ultrasonic techniques by about five times. Repeat measurements with these instruments to follow bone mineral changes would involve very low X-ray doses. A theoretical study has been made of acoustic diffraction, using a geometrical transform applicable to the integration of three different Green's functions, for axisymmetric systems. This has involved the derivation of one of these in a form amenable to computation. It is considered that this function fits the boundary conditions occurring in medical ultrasonography more closely than those used previously. A three dimensional plot of the pressure field using this function has been made for a ring transducer, in addition to that for disc transducers using all three functions. It has been shown how the theory may be extended to investigate the nature and magnitude of the particle velocity, at any point in the field, for the three functions mentioned. From this study. a concept of diffraction fronts has been developed, which has made it possible to determine energy flow also in a diffracting system. Intensity has been displayed in a manner similar to that used for pressure. Plots have been made of diffraction fronts and energy flow direction lines.

The formation and impact of hazard control policy:a study of the regulation of white lead paint in Britain

Government regulation of industrial hazards is examined in the context of the economic and technical processes of industrial development. Technical problems and costs of control are considered as factors in both the formation and impact of regulation. This thesis focuses on an historical case-study of the regulation of the hazard to painting workers from the use of lead pigments in paint. A regulatory strategy based on the prohibition of lead paints gained initial acceptance within the British state in 1911, but was subsequently rejected in favour of a strategy that allowed continued use of lead paint subject to hygiene precautions. The development of paint technology and its determinants, including concern about health hazards, are analysed, focusing on the innovation and diffusion into the paint industry of the major white pigments: white lead (PbC03 .PB(OH)2)and its substitutes. The process of regulatory development is examined, and the protracted and polarised regulatory d~bate contrasted to the prevailing 'consensual' methods of workplace regulation. The rejection of prohibition is analysed in terms of the different political and technical resources of those groups in conflict over this policy. This highlights the problems of consensus formation around such a strategy, and demonstrates certain constraints on state regulatory activity, particularly regarding industrial development. Member-states of the International Labour Organisation agreed to introduce partial prohibition of lead paint in 1921. Whether this was implemented is related to the economic importance of lead and non-lead metal and pigment industries to a nation. An analysis is made of the control of lead poisoning. The rate of control is related to the economic and technological trajectory of the regulated industry. Technical and organisational characteristics are considered as well as regulatory factors which range from voluntary compliance and informal pressures to direct legal requirements. The implications of this case-study for the analysis of the development and impacts of regulation are assessed.

Flt1 acts as a negative regulator of tip cell formation and branching morphogenesis in the zebrafish embryo

Endothelial tip cells guide angiogenic sprouts by exploring the local environment for guidance cues such as vascular endothelial growth factor (VegfA). Here we present Flt1 (Vegf receptor 1) loss- and gain-of-function data in zebrafish showing that Flt1 regulates tip cell formation and arterial branching morphogenesis. Zebrafish embryos expressed soluble Flt1 (sFlt1) and membrane-bound Flt1 (mFlt1). In Tg(flt1(BAC):yfp) × Tg(kdrl:ras-cherry)(s916) embryos, flt1:yfp was expressed in tip, stalk and base cells of segmental artery sprouts and overlapped with kdrl:cherry expression in these domains. flt1 morphants showed increased tip cell numbers, enhanced angiogenic behavior and hyperbranching of segmental artery sprouts. The additional arterial branches developed into functional vessels carrying blood flow. In support of a functional role for the extracellular VEGF-binding domain of Flt1, overexpression of sflt1 or mflt1 rescued aberrant branching in flt1 morphants, and overexpression of sflt1 or mflt1 in controls resulted in short arterial sprouts with reduced numbers of filopodia. flt1 morphants showed reduced expression of Notch receptors and of the Notch downstream target efnb2a, and ectopic expression of flt4 in arteries, consistent with loss of Notch signaling. Conditional overexpression of the notch1a intracellular cleaved domain in flt1 morphants restored segmental artery patterning. The developing nervous system of the trunk contributed to the distribution of Flt1, and the loss of flt1 affected neurons. Thus, Flt1 acts in a Notch-dependent manner as a negative regulator of tip cell differentiation and branching. Flt1 distribution may be fine-tuned, involving interactions with the developing nervous system.

Design of experiments to study the impact of process parameters on droplet size and development of non-invasive imaging techniques in tablet coating

Atomisation of an aqueous solution for tablet film coating is a complex process with multiple factors determining droplet formation and properties. The importance of droplet size for an efficient process and a high quality final product has been noted in the literature, with smaller droplets reported to produce smoother, more homogenous coatings whilst simultaneously avoiding the risk of damage through over-wetting of the tablet core. In this work the effect of droplet size on tablet film coat characteristics was investigated using X-ray microcomputed tomography (XμCT) and confocal laser scanning microscopy (CLSM). A quality by design approach utilising design of experiments (DOE) was used to optimise the conditions necessary for production of droplets at a small (20 μm) and large (70 μm) droplet size. Droplet size distribution was measured using real-time laser diffraction and the volume median diameter taken as a response. DOE yielded information on the relationship three critical process parameters: pump rate, atomisation pressure and coating-polymer concentration, had upon droplet size. The model generated was robust, scoring highly for model fit (R2 = 0.977), predictability (Q2 = 0.837), validity and reproducibility. Modelling confirmed that all parameters had either a linear or quadratic effect on droplet size and revealed an interaction between pump rate and atomisation pressure. Fluidised bed coating of tablet cores was performed with either small or large droplets followed by CLSM and XμCT imaging. Addition of commonly used contrast materials to the coating solution improved visualisation of the coating by XμCT, showing the coat as a discrete section of the overall tablet. Imaging provided qualitative and quantitative evidence revealing that smaller droplets formed thinner, more uniform and less porous film coats.