Retinal and systemic vascular function in health and disease: the effect of smoking and coronary artery disease

The purpose of the following studies was to explore the effect of systemic vascular and endothelial dysfunction upon the ocular circulation and functionality of the retina. There are 6 principal sections to the present work. Retinal vessel activity in smokers and non-smokers: the principal findings of this work were: chronic smoking affects retinal vessel motion at baseline and during stimulation with flickering light; chronic smoking leads to a vaso-constrictory shift in retinal arteriolar reactivity to flicker; retinal arteriolar elasticity is decreased in chronic smokers. The effect of acute smoking on retinal vessel dynamics in smokers and non-smokers: the principal finding of this work was that retinal reactivity in chronic smokers is blunted when exposed to clicker light provocation immediately after smoking one cigarette. Ocular blood flow in coronary artery disease: The principal findings of this work were: retrobulbar and retinal blood flow is preserved in CAD patients, despite a change pulse wave transmission; arterial retinal response to flickering light provocation is significantly delayed in CAD patients; retinal venular diameters are significantly dilated in CAD patients. Autonomic nervous system function and peripheral circulation in CAD: The principal findings in this work were: CAD patients demonstrate a sympathetic overdrive during a 24 period; a delay in peripheral vascular reactivity (nail-fold capillaries) as observed in patients suffering from CAD could be caused by either arteriosclerotic changes of the vascular walls or due to systemic haemodynamic changes. Visual function in CAD: The principal findings in this work were: overall visual function in CAD patients is preserved, despite a decrease in contrast sensitivity; applying a filtering technique selecting those with greater coefficient of variance which in turn represents a decrease in reliability, some patients appear to have an impaired visual function as assessed using FDT visual field evaluation. Multiple functional, structural and biochemical vascular endothelial dysfunctions in patients suffering from CAD: relationships and possible implications: The principal findings of this work were: BMI significantly correlated with vWF (a marker of endothelial function) in CAD patients. Retinal vascular reactivity showed a significant correlation with peripheral reactivity parameters in controls which lacked in the CAD group and could reflect a loss in vascular endothelial integrity; visual field parameters as assessed by frequency doubling technology were strongly related with systemic vascular elasticity (ambulatory arterial stiffness index) in controls but not CAD patients.

Origin of the ESR spectrum in the Prussian Blue analogue RbMn[Fe(CN)6]*H2O

We present an ESR study at excitation frequencies of 9.4 GHz and 222.4 GHz of powders and single crystals of a Prussian Blue analogue (PBA), RbMn[Fe(CN)6]*H2O in which Fe and Mn undergoes a charge transfer transition between 175 and 300 K. The ESR of PBA powders, also reported by Pregelj et al. (JMMM, 316, E680 (2007)) is assigned to cubic magnetic clusters of Mn2+ ions surrounding Fe(CN)6 vacancies. The clusters are well isolated from the bulk and are superparamagnetic below 50 K. In single crystals various defects with lower symmetry are also observed. Spin-lattice relaxation broadens the bulk ESR beyond observability. This strong spin relaxation is unexpected above the charge transfer transition and is attributed to a mixing of the Mn3+ - Fe2+ state into the prevalent Mn2+ - Fe3+ state.

Activation of the left inferior frontal gyrus in the first 200 ms of reading:evidence from magnetoencephalography (MEG)

Background - It is well established that the left inferior frontal gyrus plays a key role in the cerebral cortical network that supports reading and visual word recognition. Less clear is when in time this contribution begins. We used magnetoencephalography (MEG), which has both good spatial and excellent temporal resolution, to address this question. Methodology/Principal Findings - MEG data were recorded during a passive viewing paradigm, chosen to emphasize the stimulus-driven component of the cortical response, in which right-handed participants were presented words, consonant strings, and unfamiliar faces to central vision. Time-frequency analyses showed a left-lateralized inferior frontal gyrus (pars opercularis) response to words between 100–250 ms in the beta frequency band that was significantly stronger than the response to consonant strings or faces. The left inferior frontal gyrus response to words peaked at ~130 ms. This response was significantly later in time than the left middle occipital gyrus, which peaked at ~115 ms, but not significantly different from the peak response in the left mid fusiform gyrus, which peaked at ~140 ms, at a location coincident with the fMRI–defined visual word form area (VWFA). Significant responses were also detected to words in other parts of the reading network, including the anterior middle temporal gyrus, the left posterior middle temporal gyrus, the angular and supramarginal gyri, and the left superior temporal gyrus. Conclusions/Significance - These findings suggest very early interactions between the vision and language domains during visual word recognition, with speech motor areas being activated at the same time as the orthographic word-form is being resolved within the fusiform gyrus. This challenges the conventional view of a temporally serial processing sequence for visual word recognition in which letter forms are initially decoded, interact with their phonological and semantic representations, and only then gain access to a speech code.

A model for the modular evolution of rna addressing open questions on the origin of life

A main unsolved problem in the RNA world scenario for the origin of life is how a template-dependent RNA polymerase ribozyme emerged from short RNA oligomers generated by random polymerization of ribonucleotides (Joyce and Orgel 2006). Current estimates establish a minimum size about 165 nt long for such a ribozyme (Johnston et al. 2001), a length three to four times that of the longest RNA oligomers obtained by random polymerization on clay mineral surfaces (Huang and Ferris 2003, 2006). To overcome this gap, we have developed a stepwise model of ligation-based, modular evolution of RNA (Briones et al. 2009) whose main conceptual steps are summarized in Figure 1. This scenario has two main advantages with respect to previous hypotheses put forward for the origin of the RNA world: i) short RNA....

Spatial patterns of the pathological changes in neuronal intermediate filament inclusion disease (NIFID):an α-internexin immunohistochemical study

Neuronal intermediate filament inclusion disease (NIFID) is characterized by α-internexin positive neuronal cytoplasmic inclusions (NCI), swollen achromatic neurons (SN), neuronal loss, and gliosis. This study tested: 1) whether the spatial patterns of the lesions was topographically organized in areas of the frontal and temporal lobe and 2) whether a spatial relationship exists between the NCI and SN. The NCI were distributed in regular clusters and in a quarter of these areas, the clusters were 400-800 μm in diameter approximating to the size of the cells of origin of the cortico-cortical pathways. Variations in the density of the NCI were positively correlated with the SN. Hence, cortical degeneration in NIFID appears to be topographically organized and may affect the cortico-cortical projections, the clusters of NCI and SN developing within the same vertical columns of cells. © 2007 Springer-Verlag.

Topography of the visual evoked magnetic response and hemispherical specialization

The visual evoked magnetic response CIIm component to a pattern onset stimulus presented half field produced a consistent scalp topography in 15 normal subjects. The major response was seen over the contralateral hemisphere, suggesting a dipole with current flowing away from the medial surface of the brain. Full field responses were more unpredictable. The reponses of five subjects were studied to the onset of a full, left half and right half checkerboard stimuli of 38 x 27 min arc checks appearing for 200 ms. In two subjects the full field CIIm topography was consistent with that of the mathematical summation of their relevant half field distribution. The remaining subjects had unpredictable full field topographies, showing little or no relationship to their half or summated half fields. In each of these subjects, a distribution matching that of the summated half field CIIm distribution appears at an earlier latency than that of the predominant full field waveform peak. By examining the topography of the full and half field responses at 5 ms intervals along the waveform for one such subject, the CIIm topography of the right hemisphere develops 10 ms before that of the left hemisphere, and is replaced by the following CIIIm component 20 ms earlier. Hence, the large peak seen in full field results from a combination of the CIIm component of the left hemisphere plus that of the CIIIm from the right. The earlier peak results from the CIIm generated in both hemispheres, at a latency where both show similar amplitudes. As the relative amplitudes of these two peaks alter with check and field size, topographic studies would be required for accurate CIIm identification. In addition. the CIIm-CIIIm complex lasts for 80 ms in the right hemisphere and 135 ms in the left, suggesting hemispherical apecialization in the visual processing of the pattern onset response.

Technical entrepreneurship in the UK:an examination of the relationship between the previous occupational background of the technical entrepreneur and the management of the small technology-based venture

With the growing appreciation of the contribution of small technology-based ventures to a healthy economy, an analysis of the individual who initiates and manages such ventures - the technical entrepreneur - is highly desirable, predominantly because of the influence of such an individual on the management and future strategy of the venture. An examination of recent research has indicated that a study of the previous experience and expertise of the entrepreneur, gained in previous occupations, may be highly relevant in determining the possible success of a new venture. This is particularly true where the specific expertise of the entrepreneur forms the main strategic advantage of the business, as in the case of small technology-based firms. Despite this, there has been very little research which has attempted to examine the relationship between the previous occupational background of the technical entrepreneur, and the management of the small technology-based firm. This thesis will examine this relationship, as well as providing an original contribution to the study of technical entrepreneurship in the UK. Consequently, the exploratory nature of the research prompted an inductive qualitative approach being adopted for the thesis. Through a two stage, multiple-site research approach, an examination was made of technical entrepreneurs heading award-winning technology-based small firms in the UK. The main research questions focused on management within the firm, the novelty and origin of the technology adopted, and the personal characteristics of the entrepreneur under study. The results of this study led to the creation of a specific typology for technical entrepreneurs, based on the individual's role in the development of technology within his previous occupation.

A study of the scattering of fast neutrons in large samples

In the present work, the elastic scattering of fast neutrons from iron and concrete samples were studied at incident neutron energies of 14.0 and 14.4 Mev, using a neutron spectrometer based on the associated particle time-of-flight technique. These samples were chosen because of their importance in the design of fusion reactor shielding and construction. Using the S.A.M.E.S. accelerator and the 3 M v Dynamitron accelerator at the Radiation Centre, 14.0 and 14.4 Mev neutrons were produced by the T(d, n)4He reaction at incident deuteron energies of 140 keV and 900 keV mass III ions respectively. The time of origin of the neutron was determined by detecting the associated alpha particles. The samples used were extended flat plates of thicknesses up to 1.73 mean free paths for iron and 2.3 mean free paths for concrete. The associated alpha particles and fast neutrons were detected by means of a plastic scintillator mounted on a fast focused photomultiplier tube. The differential neutron elastic scattering cross-sections were measured for 14 Mev neutrons in various thicknesses of iron and concrete in the angular range from zero to 90°. In addition, the angular distributions of 14.4 Mev neutrons after passing through extended samples of iron were measured at several scattering angles in the same angular range. The measurements obtained for the thin sample of iron were compared with the results of Coon et al. The differential cross-sections for the thin iron sample were also analyzed on the optical model using the computer code RAROMP. For the concrete sample, the angular distribution of the thin sample was compared with the cross-sections calculated from the major constituent elements of concrete, and with the predicted values of the optical model for those elements. No published data could be found to compare with the results of the concrete differential cross-sections. In the case of thick samples of iron and concrete, the number of scattered neutrons were compared with a phenomological calculation based on the continuous slowing down model. The variation of measured cross-sections with sample thickness were found to follow the empirical relation σ = σ0 eαx. By using the universal constant "K", good fits were obtained to the experimental data. In parallel with the work at 14.0 and 14.4 Mev, an associated particle time-of-flight spectrometer was investigated which used the 2H(d,n)3He reaction for 3.02 Mev neutron energy at the incident deuteron energy of 1 Mev.

Further studies of the visually evoked subcortical potential in man

The Visually Evoked Subcortical Potential, a far-field signal, was originally defined to flash stimulation as a triphasic positive-negative-positive complex with mean latencies of P21 N26.2 P33.6 (Harding and Rubinstein 1980). Inconsistent with its subcortical source however, the signal was found to be tightly localised to the mastoid. This thesis re-examines the earlier protocols using flash stimulation and with auditory masking establishes by topographic studies that the VESP has a widespread scalp distribution, consistent with a far-field source of the signal, and is not a volume-conducted electroretinogram (ERG). Furthermore, mastoid localisation indicates auditory contamination from the click, on discharge of the photostimulator. The use of flash stimulation could not precisely identify the origin of the response. Possible sources of the VESP are the lateral geniculate body (LGB) and the superior colliculus. The LGB received 80% of the nerve fibres from the retina, and responds to high contrast achromatic stimulation in the form of drifting gratings of high spatial frequencies. At low spatial frequencies, it is more sensitive to colour. The superior colliculus is insensitive to colour and suppressed by contrast and responds to transitory rapid movements, and receives about 20% of the optic nerve fibres. A pattern VESP was obtained to black and white checks as a P23.5 N29.2 P34 complex in 93% of normal subjects at an optimal check size of 12'. It was also present as a P23.0 N28.29 P32.23 complex to red and green luminance balanced checks at 2o check size in 73% of subjects. These results were not volume-conducted pattern electroretinogram responses. These findings are consistent with the spatial frequency properties of the lateral geniculate body which is the considered source of the signal. With further work, the VESP may supplement electrodiagnosis of post-chiasmal lesions.

Spatial tuning studies of the pattern evoked electroretinogram

The locus of origin of the pattern evoked electroretinogram, (PERG), has been the subject of considerable discussion. A novel approach was adopted in this study to further elaborate the nature of the PERG evoked by pattern onset/offset presentation. The PERG was found to be linearly related to stimulus contrast and in particular was linearly related to the temporal contrast of the retinal image, when elicited by patterns of low spatial frequency. At high spatial frequencies the retinal image contrast is significantly reduced because of optical degradation. This is described by the eye's modulation transfer function (MTF). The retinal contrast of square wave grating and chequerboard patterns of increasing spatial frequency were found by filtering their Fourier transforms by the MTF. The filtered pattern harmonics were then resynthesised to constitute a profile of retinal image illuminance from which the temporal and spatial contrast of the image could be calculated. If the PERG is a pure illuminance response it should be spatially insensitive and dependent upon the temporal contrast of stimulation. The calculated loss of temporal contrast for finer patterns was expressed as a space-averaged temporal contrast attentuation factor. This factor, applied to PERGs evoked by low spatial frequency patterns, was used to predict the retinal illuminance response elicited by a finer pattern. The predicted response was subtracted from the recorded signal and residual waveform was proposed to represent specific activity. An additional correction for the attenuation of spatial contrast was applied to the extracted pattern specific response. Pattern specific responses computed for different spatial frequency patterns in this way are the predicted result of iso-contrast pattern stimulation. The pattern specific responses demonstrate a striking bandpass spatial selectivity which peaks at higher spatial frequencies in the more central retina. The variation of spatial sensitivity with eccentricity corresponds closely with estimated ganglion receptive field centre separation and psychophysical data. The variation of retinal structure with eccentricity, in the form of the volumes of the nuclear layers, was compared with the amplitudes of the computed retinal illuminance and pattern specific responses. The retinal illuminance response corresponds more closely to the outer and inner nuclear layers whilst the pattern specific response appears more closely related to the ganglion cell layer. In general the negative response transients correspond to the more proximal retinal layers. This thesis therefore supports the proposed contribution of proximal retinal cell activity to the PERG and describes techniques which may be further elaborated for more detailed studies of retinal receptive field dimensions.

Atomic structure of the two intermediate phase glasses SiSe4 and GeSe4

The microscopic origin of the intermediate phase in two prototypical covalently bonded AxB1-x network glass forming systems, where A=Ge or Si, B=Se, and 0=x=1, was investigated by combining neutron diffraction with first-principles molecular-dynamics methods. Specifically, the structure of glassy GeSe4 and SiSe4 was examined, and the calculated total structure factor and total pair-correlation function for both materials are in good agreement with experiment. The structure of both glasses differs markedly from a simple model comprising undefective AB4 corner-sharing tetrahedra in which all A atoms are linked by B2 dimers. Instead, edge-sharing tetrahedra occur and the twofold coordinated Se atoms form three distinct structural motifs, namely, Se-Se2, Se-SeGe (or Se-SeSi), and Se-Ge2 (or Se-Si2). This identifies several of the conformations that are responsible for the structural variability in GexSe1-x and SixSe1-x glasses, a quantity that is linked to the finite width of the intermediate phase window.

Quasi-separation of the biharmonic partial differential equation

In this paper, we consider analytical and numerical solutions to the Dirichlet boundary-value problem for the biharmonic partial differential equation on a disc of finite radius in the plane. The physical interpretation of these solutions is that of the harmonic oscillations of a thin, clamped plate. For the linear, fourth-order, biharmonic partial differential equation in the plane, it is well known that the solution method of separation in polar coordinates is not possible, in general. However, in this paper, for circular domains in the plane, it is shown that a method, here called quasi-separation of variables, does lead to solutions of the partial differential equation. These solutions are products of solutions of two ordinary linear differential equations: a fourth-order radial equation and a second-order angular differential equation. To be expected, without complete separation of the polar variables, there is some restriction on the range of these solutions in comparison with the corresponding separated solutions of the second-order harmonic differential equation in the plane. Notwithstanding these restrictions, the quasi-separation method leads to solutions of the Dirichlet boundary-value problem on a disc with centre at the origin, with boundary conditions determined by the solution and its inward drawn normal taking the value 0 on the edge of the disc. One significant feature for these biharmonic boundary-value problems, in general, follows from the form of the biharmonic differential expression when represented in polar coordinates. In this form, the differential expression has a singularity at the origin, in the radial variable. This singularity translates to a singularity at the origin of the fourth-order radial separated equation; this singularity necessitates the application of a third boundary condition in order to determine a self-adjoint solution to the Dirichlet boundary-value problem. The penultimate section of the paper reports on numerical solutions to the Dirichlet boundary-value problem; these results are also presented graphically. Two specific cases are studied in detail and numerical values of the eigenvalues are compared with the results obtained in earlier studies.

Differential effects of chlorinated and oxidized phospholipids in vascular tissue:implications for neointima formation

The presence of inflammatory cells and MPO (myeloperoxidase) in the arterial wall after vascular injury could increase neointima formation by modification of phospholipids. The present study investigates how these phospholipids, in particular oxidized and chlorinated species, are altered within injured vessels and how they affect VSMC (vascular smooth muscle cell) remodelling processes. Vascular injury was induced in C57BL/6 mice and high fat-fed ApoE-/- (apolipoprotein E) mice by wire denudation and ligation of the left carotid artery (LCA). Neointimal and medial composition was assessed using immunohistochemistry and ESI-MS. Primary rabbit aortic SMCs (smooth muscle cells) were utilized to examine the effects of modified lipids on VSMC proliferation, viability and migration at a cellular level. Neointimal area, measured as intima-to-media ratio, was significantly larger in wire-injured ApoE-/- mice (3.62±0.49 compared with 0.83±0.25 in C57BL/6 mice, n=3) and there was increased oxidized low-density lipoprotein (oxLDL) infiltration and elevated plasma MPO levels. Relative increases in lysophosphatidylcholines and unsaturated phosphatidylcholines (PCs) were also observed in wire-injured ApoE-/- carotid arteries. Chlorinated lipids had no effect on VSMC proliferation, viability or migration whereas chronic incubation with oxidized phospholipids stimulated proliferation in the presence of fetal calf serum [154.8±14.2% of viable cells at 1 μM PGPC (1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine) compared with control, n=6]. In conclusion, ApoE-/- mice with an inflammatory phenotype develop more neointima in wire-injured arteries and accumulation of oxidized lipids in the vessel wall may propagate this effect.

The role of monocytes in atherosclerotic coronary artery disease

Inflammation plays a key role in the pathogenesis of atherosclerosis. The more we discover about the molecular pathways involved in atherosclerosis, the more we perceive the importance of monocytes in this process. Circulating monocytes are components of innate immunity, and many pro-inflammatory cytokines and adhesion molecules facilitate their adhesion and migration to the vascular endothelial wall. In addition to the accumulation of lipids and formation of atherogenic 'foam' cells, monocytes may promote atherosclerotic plaque growth by production of inflammatory cytokines, matrix metalloproteinases, and reactive oxidative species. However, the contribution of monocytes to atherogenesis is not only limited to tissue destruction. Monocyte subsets are also involved in intraplaque angiogenesis and tissue reparative processes. The aim of this overview is to discuss the mechanisms of monocyte activation, the pivotal role and importance of activated monocytes in atherosclerotic coronary artery disease, their implication in the development of acute coronary events, and their potential in cardiovascular reparative processes such angiogenesis.