Molecular and cellular effects of ultraviolet light-induced genotoxicity

Exposure to the solar ultraviolet spectrum that penetrates the Earth's stratosphere (UVA and UVB) causes cellular DNA damage within skin cells. This damage is elicited directly through absorption of energy (UVB), and indirectly through intermediates such as sensitizer radicals and reactive oxygen species (UVA). DNA damage is detected as strand breaks or as base lesions, the most common lesions being 8-hydroxydeoxyguanosine (8OHdG) from UVA exposure and cyclobutane pyrimidine dimers from UVB exposure. The presence of these products in the genome may cause misreading and misreplication. Cells are protected by free radical scavengers that remove potentially mutagenic radical intermediates. In addition, the glutathione-S-transferase family can catalyze the removal of epoxides and peroxides. An extensive repair capacity exists for removing (1) strand breaks, (2) small base modifications (8OHdG), and (3) bulky lesions (cyclobutane pyrimidine dimers). UV also stimulates the cell to produce early response genes that activate a cascade of signaling molecules (e.g., protein kinases) and protective enzymes (e.g., haem oxygenase). The cell cycle is restricted via p53-dependent and -independent pathways to facilitate repair processes prior to replication and division. Failure to rescue the cell from replication block will ultimately lead to cell death, and apoptosis may be induced. The implications for UV-induced genotoxicity in disease are considered.

Effects of yellow filters on visual acuity, contrast sensitivity and reading under conditions of forward light scatter

Background Yellow filters are sometimes recommended to people with low vision. Our aim was investigate the effects of three commercial yellow filters on visual acuity and contrast sensitivity (with and without glare) and reading (without glare) under conditions of forward light scatter (FLS). Method Fifty-five healthy subjects were assessed with Corning Photochromic Filters (CPFs) 450, 511 and 527 and a filter producing FLS. The effects on log MAR visual acuity, Pelli–Robson contrast sensitivity with and without glare, and reading (measured with MNRead charts) without glare were determined. Results Statistically significant differences were found between the overall effect of glare and between CPFs for visual acuity and contrast sensitivity. A gradual decline in visual acuity, contrast sensitivity and reading with increasing CPF absorption was noted. Conclusion Effects of CPF450, 511, 527 on visual acuity, contrast sensitivity and reading under conditions of FLS were negative but not clinically significant.

The effects of coloured light filter overlays on reading rates in age-related macular degeneration

Purpose: To determine the effect of coloured light filter overlays on reading rates for people with age-related macular degeneration (AMD). Method: Using a prospective clinical trial design, we examined the null hypothesis that coloured light filter overlays do not improve reading rates in AMD when compared to a clear filter. Reading rates for 12 subjects with non-exudative AMD, associated with a relative scotoma and central fixation (mean age 81 years, SD 5.07 years) were determined using the Rate of Reading Test® (printed, nonsense, lower case sans serif, stationary text) with 10 different, coloured light filter overlays (Intuitive Overlays®; figures in brackets are percentage transmission values); rose (78%), pink (78%), purple (67%), aqua (81%), blue (74%), lime-green (86%), mint-green (85%), yellow (93%), orange (83%) and grey (71%). A clear overlay (Roscolene # 00) (360 cdm-2) with 100% transmittance was used as a control. Results: ANOVA indicated that there was no statistically significant difference in reading rates with the coloured light filter overlays compared to the clear filter. Furthermore, chi-squared analysis indicated that the rose, purple and blue filters had a significantly poorer overall ranking in terms of reading rates compared to the other coloured and clear light filters. Conclusion: Coloured light filter overlays are unlikely to provide a clinically significant improvement in reading rates for people with non-exudative AMD associated with a relative scotoma and central fixation. Copyright © Acta Ophthalmol Scand 2004.

Finite-size effects in on-line learning of multilayer neural networks

We complement recent advances in thermodynamic limit analyses of mean on-line gradient descent learning dynamics in multi-layer networks by calculating fluctuations possessed by finite dimensional systems. Fluctuations from the mean dynamics are largest at the onset of specialisation as student hidden unit weight vectors begin to imitate specific teacher vectors, increasing with the degree of symmetry of the initial conditions. In light of this, we include a term to stimulate asymmetry in the learning process, which typically also leads to a significant decrease in training time.

Effect of light filters on reading speed in normal and low vision due to age-related macular degeneration

Purpose: To investigate the effects of light filters on reading speed in normal and low vision due to age-related macular degeneration (AMD). Methods: Reading speed was determined for 12 subjects with normal vision and 12 subjects with non-exudative AMD using stationary lowercase nonsensical print in Times Roman font and four light filters; a yellow Corning Photochromic Filter (CPF) 450, a grey neural density (ND) filter, an individual filter obtained using the Intuitive Colorimeter® and a clear filter. Results: There was no statistically significant light filter effect on reading speed for the normal subjects. The AMD group demonstrated a statistically significant 5% average improvement in reading speed with the CPF450 compared with the other filters although some AMD subjects had improvements of 10-15%. Conclusions: Light filters obtained using the Intuitive Colorimeter® performed poorly when compared with the CPF450, ND and clear filters for both the study groups. For the AMD group, average reading speed was statistically greater with the CPF450 than the other filters, however it is questionable whether the improvement (5%) would be clinically significant. As some of the subjects with AMD had greater improvements with the CPF450 we advocate clinical assessment of light filters using existing protocols on an individual basis. © 2004 The College of Optometrists.

What are the practical implications for treating diabetes in light of recent evidence? Updated recommendations from the Global Partnership for Effective Diabetes Management

The Global Partnership for Effective Diabetes Management was established in 2004 to provide practical guidance to improving glycaemic control for people with type 2 diabetes. Those recommendations have been updated to take account of recent trials assessing the effects of intensive glucose control. We continue to emphasis the importance of early and sustained glycaemic control, aiming for HbA( 1c) 6.5-7% wherever safe and appropriate. Individualisation of targets and the management process is strongly encouraged to accommodate patient circumstances and to avoid hypoglycaemia. Prompt introduction of combinations of agents is suggested when monotherapy is inadequate.Treatments will preferably address the underlying pathophysiology of type 2 diabetes and integrate within a wider programme of care which also aims to reduce modifiable cardiovascular risk factors and better equip patients in the self-management of their condition.

Raman amplification and performance altering effects

This thesis presents an experimental investigation into several applications of the Raman scattering effect in communication optical fibres as well as how some of these applications can be modified to enhance the resulting performance. The majority of the work contained within is based on laboratory results using many commercially available components. The results can be divided into and presented in three main parts: Firstly, a novel application of a known effect is used to broaden Raman pump light in order to achieve a more continuous distribution of gain with respect to wavelength. Multiple experimental results are presented, all based around the prior spreading of the pump spectrum before being used in the desired transmission fibre. Gathered results show that a notable improvement can be obtained from applying such a technique along with the scope for further optimisation work. Secondly, an investigation into the interaction between the well known effect of Four Wave Mixing (FWM) and Raman scattering is provided. The work provides an introduction to the effect as well commenting on previous literature regarding the effect and its mitigation. In response to existing research experimental results are provided detailing some limitations of proposed schemes along with concepts of how further alleviation from the deleterious effects maybe obtained. Lastly, the distributed nature of the Raman gain process is explored. A novel technique on how a near constant distribution of gain can be employed is implemented practically. The application of distributed gain is then applied to the generation of optical pulses with special mathematical properties within a laboratory setting and finally the effect of pump noise upon distributed gain techniques is acknowledged.

An experimental study of the effects of noise upon short term memory

The overall aim of this study was to examine experimentally the effects of noise upon short-term memory tasks in the hope of shedding further light upon the apparently inconsistent results of previous research in the area. Seven experiments are presented. The first chapter of the thesis comprised a comprehensive review of the literature on noise and human performance while in the second chapter some theoretical questions concerning the effects of noise were considered in more detail follovred by a more detailed examination of the effects of noise upon memory. Chapter 3 described an experiment which examined the effects of noise on attention allocation in short-term memory as a function of list length. The results provided only weak evidence of increased selectivity in noise. In further chapters no~effects Here investigated in conjunction vrith various parameters of short-term memory tasks e.g. the retention interval, presentation rate. The results suggested that noise effects were significantly affected by the length of the retention interval but not by the rate of presentation. Later chapters examined the possibility of differential noise effects on the mode of recall (recall v. recognition) and the type of presentation (sequential v. simultaneous) as well as an investigation of the effect of varying the point of introduction of the noise and the importance of individual differences in noise research. The results of this study were consistent with the hypothesis that noise at presentation facilitates phonemic coding. However, noise during recall appeared to affect the retrieval strategy adopted by the subject.

Investigating the effects of antiepileptic drugs on the electrophysiology of vision

The principal aim of this work was to examine the effects of antiepileptic drugs (AEDs) on vision. Vigabatrin acts by increasing GABA at brain inhibitory synapses by irreversibly binding to GABA-transaminase. Remacemide is a novel non-competitive NMDA receptor antagonist and fast sodium channel inhibitor that results in the inhibition of the NMDA receptors located in the neuronal membrane calcium channels increasing glutamate in the brain. Vigabatrin has been shown to cause a specific pattern of visual field loss, as one in three adults taking vigabatrin have shown a bilateral concentric constriction. Remacemide has unknown effects on vision. The majority of studies of the effects of AEDs on vision have not included the paediatric population due to difficulties assessing visual field function using standard perimetry testing. Evidently an alternative test is required to establish and monitor visual field problems associated with AEDs both in children and in adults who cannot comply with perimetry. In order to test paediatric patients exposed to vigabatrin, a field-specific visual evoked potential was developed. Other tests performed on patients taking either vigabatrin or remacemide were electroretinograms, electro-oculograms, multifocal VEPs and perimetry. Comparing these tests to perimetry results from vigabatrin patients the field specific VEP was found to have a high sensitivity and specificity, as did the 30Hz flicker amplitude. The modified VEP was also found to provide useful results in vigabatrin patients. Remacemide did not produce a similar visual field loss to vigabatrin although macular vision was affected. The field specific VEP is a useful method for detecting vigabatrin associated visual field loss that is well tolerated by young children. This technique combined with the ERG under light adapted (30Hz flicker) condition is presently the superior method for detecting vigabatrin-attributed peripheral field defects present in children below the developmental age of 9. The effects of AEDs on vision should be monitored carefully and the use of multifocal stimulation allows for specific areas of the retina and visual pathway to be monitored.

The toxic effects of anticholinesterases on muscle

It has been shown that acute administration of ecothiopate iodine in vivo caused an approximate 80% depression of acetylcholinesterase activity in the diaphragms of mice. Inhibition of acetylcholinesterase was accompanied by an influx of calcium at the junctional region of the diaphragm, which continued during subsequent progressive development of a severe myopathy located in the same region. Myopathy was accompanied by loss of creatine kinase from the muscle and was represented, at the light microscope level, by hypercontraction, Procion Yellow staining and loss of cross striations within the muscle fibres. It appeared to reach a point of maximum severity approximately 3-6 hours after ecothiopate administration and then, by means of some repair/regeneration process, regained an apparently normal morphology within 72 hours of the intoxication. At the ultrastructural level, ecothiopate-induced myopathy was recognised by loss of Z-lines, swelling and vacuolation of mitochondria and sarcoplasmic reticulum, dissarray of myofilaments, crystal formation, and sometimes, by the complete obliteration of sarcomeric structure. The development of myopathy in vitro was shown to be nerve-mediated and to require a functional acetylcholine receptor for its development It was successfully treated therapeutically in vivo by pyridine-2-aldoxime methiodide and prophylactically by pyridostigmine bromide. However, the use of a range of membrane-on channel blockers, and of leupeptin, an inhibitor of calcium-activated-neutral-protease, have been unsuccessful in the prevention of ecothiopate-induced myopathy.

Oxidation effects on tetrahydropterin metabolism

The susceptibility of tetrahydropterins to oxidation was investigated in vitro and related to in vivo metabolism. At physiological pH, tetrahydrobiopterin (BH4) was oxidized, with considerable loss of the biopterin skeleton, by molecular oxygen. The hydroxyl radical (.OH) was found to increase this oxidation and degradation, whilst physiological concentrations of glutathione (GSH) retarded both the dioxygen and .OH mediated oxidation. Nitrite, at acid pH, oxidized BH4 to biopterin and tetrahydrofolates to products devoid of folate structure. Loss of dietary folates, from the stomach, due to nitrite mediated catabolism is suggested. The in vivo response of BH4 metabolism to oxidising conditions was examined in the rat brain and liver. Acute starvation depressed brain biopterins and transiently BH4 biosynthetic and salvage (dihydropteridine reductase, DHPR) pathways. Loss of biopterins, in starvation, is suggested to arise primarily from catabolism, due to oxygen radical formation and GSH depletion. L-cysteine administration to starving rats was found to elevate tissue biopterins, whilst depletion of GSH in feeding rats, by L-buthionine sulfoximine, decreased biopterins. An in vivo role for GSH to protect tetrahydropterins from oxidation is suggested. The in vivo effect of phenelzine dosing was investigated. Administration lowered brain biopterins, in the presence of dietary tyrosine. This loss is considered to arise from p-tyramine generation and subsequent DHPR inhibition. Observed elevations in plasma biopterins were in line with this mechanism. In conditions other than gross inhibition of DHPR or BH4 biosynthesis, plasma total biopterins were seen to be poor indicators of tissue BH4 metabolism. Evidence is presented indicating that the pterin formed in tissue samples by acid iodine oxidation originates from the tetrahydrofolate pool and 7,8-dihydropterin derived from BH4 oxidation. The observed reduction in this pterin by prior in vivo nitrous oxide exposure and elevation by starvation and phenelzine administration is discussed in this light. The biochemical importance of the changes in tetrahydropterin metabolism observed in this thesis are discussed with extrapolation to the situation in man, where appropriate. An additional role for BH4 as a tissue antioxidant and reductant is also considered.

On the modulation of the effects of some 5 - HT - related agents in axiety models

The results of an investigation into how stressors interact with the action of serotonergic agents in animal models of anxiety are presented. Water deprivation and restraint both increased plasma corticosterone concentrations and elevated 5-HT turnover. In the elevated X-maze, water deprivation had a duration-dependent "anxiolytic" effect. The effect of restraint was dependent on the duration of restraint and was to inhibit maze exploration. Water-deprivation did not influence the action of diazepam or any 5-HT1A ligand in the X-maze. Restraint switched the "anxiogenic" effect of 8-0H-DPAT to either "anxiolytic" or inactive, depending on the time after the restraint when testing was performed. The Vogel conflict test detected an "anxiolytic" "anxiolytic"V"anxiolytic""anxiolytic" effect of buspirone which was additive with "anxiolytic" effects of pindolol and propranolol. Diazepam and fluoxetine were also active, but 8-0H-DPAT, ipsapirone, gepirone and yohimbine were inactive. In the elevated X-maze, "anxiogenic" responses to picrotoxin, flumazenil, RU 24969, CGS 12066B, fluoxetine and 8-0H-DPAT were detected. Other 5-HT1A ligands were inactive. Diazepam and corticosterone had "anxiolytic" effects. Increasing light intensity did not change behaviour on the elevated X-maze, but was able to reverse the effect of 8- OH-DPAT to an "anxiolytic" action. This effect was attributed to a presynaptic mechanism, because it was abolished by pCPA. The occurence of different behaviours in different reglons of the maze was shown to be susceptible to modulation by "anxiolytic" and "anxiogenic" drugs. These results are discussed in the context of there being at least two separate 5-HT mechanisms which are involved in the control of anxiety.

Observations of diffraction and self diffraction effects during two wave mixing in a nematic liquid crystal

We report observations of the diffraction pattern resulting when a nematic liquid crystal is illuminated with two equal power, high intensity beams of light from an Ar+ laser. The time evolution of the pattern is followed from the initial production of higher diffraction orders to a final striking display arising as a result of the self-diffraction of the two incident beams. The experimental results are described with good approximation by a model assuming a phase distribution at the output plane of the liquid crystal in the form of the sum of a gaussian and a sinusoid.

Too old to choose? The effects of age and age related constructs on consumer decision making

Ageing of societies is a major challenge to academic research as well as to management. The unstoppable trend of an aging society in most western societies offers opportunities and challenges at the same time. This paper sheds light on the impact of age as well as age-related constructs on relevant consumer attitudes and behavior. More precisely, the empirical study, conducted in the market for cars, examining the relationships between four distinct age constructs and assesses the impact of these age constructs on information gathering, a consumer’s evoked set, and on rand loyalty.