Electrophysiological studies of the visual pathways in Alzheimer's and Parkinson's disease

It is known that parallel pathways exist within the visual system. These have been described as magnocellular and parvocellular as a result of the layered organisation of the lateral geniculate nucleus and extend from the retina to the cortex. Dopamine (DA) and acetylcholine (ACH) are neurotransmitters that are present in the visual pathway. DA is present in the retina and is associated with the interplexiform cells and horizontal cells. ACH is also present in the retina and is associated with displaced amacrine cells; it is also present in the superior colliculus. DA is found to be significantly depleted in the brain of Parkinson's disease (PD) patients and ACH in Alzheimer's disease (AD) patients. For this reason these diseases were used to assess the function of DA and ACH in the electrophysiology of the visual pathway. Experiments were conducted on young normals to design stimuli that would preferentially activate the magnocellular or parvocellular pathway. These stimuli were then used to evoke visual evoked potentials (VEP) in patients with PD and AD, in order to assess the function of DA and ACH in the visual pathway. Electroretinograms (ERGs) were also measured in PD patients to assess the role of DA in the retina. In addition, peripheral ACH function was assessed by measuring VEPs, ERGs and contrast sensitivity (CS) in young normals following the topical instillation of hyoscine hydrobromide (an anticholinergic drug). The results indicate that the magnocellular pathway can be divided into two: a cholinergic tectal-association area pathway carrying luminance information, and a non-cholinergic geniculo-cortical pathway carrying spatial information. It was also found that depletion of DA had very little effect on the VEPs or ERGs, confirming a general regulatory function for this neurotransmitter.

Objective and psychophysical studies of infant visual development

Distortion or deprivation of vision during an early `critical' period of visual development can result in permanent visual impairment which indicates the need to identify and treat visually at-risk individuals early. A significant difficulty in this respect is that conventional, subjective methods of visual acuity determination are ineffective before approximately three years of age. In laboratory studies, infant visual function has been quantified precisely, using objective methods based on visual evoked potentials (VEP), preferential looking (PL) and optokinetic nystagmus (OKN) but clinical assessment of infant vision has presented a particular difficulty. An initial aim of this study was to evaluate the relative clinical merits of the three techniques. Clinical derivatives were devised, the OKN method proved unsuitable but the PL and VEP methods were evaluated in a pilot study. Most infants participating in the study had known ocular and/or neurological abnormalities but a few normals were included for comparison. The study suggested that the PL method was more clinically appropriate for the objective assessment of infant acuity. A study of normal visual development from birth to one year was subsequently conducted. Observations included cycloplegic refraction, ophthalmoscopy and preferential looking visual acuity assessment using horizontally and vertically oriented square wave gratings. The aims of the work were to investigate the efficiency and sensitivity of the technique and to study possible correlates of visual development. The success rate of the PL method varied with age; 87% of newborns and 98% of infants attending follow-up successfully completed at least one acuity test. Below two months monocular acuities were difficult to secure; infants were most testable around six months. The results produced were similar to published data using the acuity card procedure and slightly lower than, but comparable with acuity data derived using extended PL methods. Acuity development was not impaired in infants found to have retinal haemorrhages as newborns. A significant relationship was found between newborn binocular acuity and anisometropia but not with other refractive findings. No strong or consistent correlations between grating acuity and refraction were found for three, six or twelve months olds. Improvements in acuity and decreases in levels of hyperopia over the first week of life were suggestive of recovery from minor birth trauma. The refractive data was analysed separately to investigate the natural history of refraction in normal infants. Most newborns (80%) were hyperopic, significant astigmatism was found in 86% and significant anisometropia in 22%. No significant alteration in spherical equivalent refraction was noted between birth and three months, a significant reduction in hyperopia was evident by six months and this trend continued until one year. Observations on the astigmatic component of the refractive error revealed a rather erratic series of changes which would be worthy of further investigation since a repeat refraction study suggested difficulties in obtaining stable measurements in newborns. Astigmatism tended to decrease between birth and three months, increased significantly from three to six months and decreased significantly from six to twelve months. A constant decrease in the degree of anisometropia was evident throughout the first year. These findings have implications for the correction of infantile refractive error.

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.

Studies on the luminance-related characteristics of the transient pattern reversal electroretinogram

The electroretinogram evoked by reversal pattern stimulation (rPERG) is known to contain both pattern contrast and luminance related components. The retinal mechanisms of the transient rPERGs subserving these functional characteristics are the main concern in the present studies. Considerable attention has been paid to the luminance-related characteristics of the response. The transient PERGs were found to consist of two subsequent processes using low frequency attenuation analysis. The processes overlapped and the individual difference in each process timings formed the major cause for the variations of the negative potential waveform of the transient rPERGs. Attention has been paid to those having ‘notch’ type of variation. Under different contrast levels, the amplitudes of the positive and negative potentials were linearly increased with higher contrast level and the negative potential showed a higher sensitivity to contrast changes and higher contrast gain. Under lower contrast levels, the decreased amplitudes made the difference in the timing course of the positive and negative processes evident, interpreting the appearance of the notch in some cases. Visual adaptation conditions for recording the transient rPERG were discussed. Another effort was to study the large variation of the transient rPERGs (especially the positive potential, P50) in the elderly who’s distant and near visual acuity were normal. It was found that reduction of retinal illumination contributed mostly to the P50 amplitude loss and contrast loss mostly to the negative potential (N95) amplitude loss. Senile miosis was thought to have little effect on the reduction of the retinal illumination, while the changes in the optics of the eye was probably the major cause for it, which interpreted the larger individual variation of the P50 amplitude of the elderly PERGs. Convex defocus affected the transient rPERGs more effectively than concave lenses, especially the N95 amplitude in the elderly. The disability of accommodation and the type and the degree of subjects’ ametropia should be taken into consideration when the elderly rPERGs were analysed.

Studies on the antiobesity effect of zinc-α2-glycoprotein in the ob/ob mouse

OBJECTIVE: To investigate the mechanism of the lipid depletion by zinc-a(2)-glycoprotein (ZAG). DESIGN: Studies were conducted in the ob/ob mouse, or on isolated adipocytes from these animals or their lean counterparts. RESULTS: Treatment of these animals for 15 days with ZAG (100? µg, intravenously, daily) resulted in a reduction of body weight of 6.55? g compared with phosphate-buffered saline-treated controls, without a change in food or water intake, but with a 0.4?°C rise in rectal temperature. ZAG-treated mice had a 30% reduction in carcass fat mass and a twofold increase in weight of brown adipose tissue. Epididymal adipocytes from ZAG-treated mice showed an increased expression of ZAG and hormone-sensitive lipase (HSL), and this was maintained for a further 3 days in the absence of ZAG. There was an increased lipolytic response to isoproterenol, which was retained for 3 days in vitro in the absence of ZAG. Expression of HSL was also increased in subcutaneous and visceral adipose tissue, as was also adipose triglyceride lipase (ATGL). There was a rapid loss of labelled lipid from epididymal adipose tissue of ZAG-treated mice, but not from the other depots, reflecting the difference in sensitivity to lipolytic stimuli. The increased expression of HSL and ATGL may involve the extracellular signal-regulated kinase (ERK) pathway, as the active (phospho) form was upregulated in all adipose depots after ZAG administration, whereas in vitro studies showed induction of HSL and ATGL by ZAG to be attenuated by PD98059, an inhibitor of the ERK pathway. CONCLUSION: These results suggest that ZAG not only induces direct lipolysis, but also sensitizes adipose tissue to other lipolytic stimuli.

Molecular basis for reduced estrone sulfate transport and altered modulator sensitivity of transmembrane helix (TM) 6 and TM17 mutants of multidrug resistance protein 1 (ABCC1)

Multidrug resistance protein 1 (MRP1) confers drug resistance and also mediates cellular efflux of many organic anions. MRP1 also transports glutathione (GSH); furthermore, this tripeptide stimulates transport of several substrates, including estrone 3-sulfate. We have previously shown that mutations of Lys(332) in transmembrane helix (TM) 6 and Trp(1246) in TM17 cause different substrate-selective losses in MRP1 transport activity. Here we have extended our characterization of mutants K332L and W1246C to further define the different roles these two residues play in determining the substrate and inhibitor specificity of MRP1. Thus, we have shown that TM17-Trp(1246) is crucial for conferring drug resistance and for binding and transport of methotrexate, estradiol glucuronide, and estrone 3-sulfate, as well as for binding of the tricyclic isoxazole inhibitor N-[3-(9-chloro-3-methyl-4-oxo-4H-isoxazolo-[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-benzamide (LY465803). In contrast, TM6-Lys(332) is important for enabling GSH and GSH-containing compounds to serve as substrates (e.g., leukotriene C(4)) or modulators (e.g., S-decyl-GSH, GSH disulfide) of MRP1 and, further, for enabling GSH (or S-methyl-GSH) to enhance the transport of estrone 3-sulfate and increase the inhibitory potency of LY465803. On the other hand, both mutants are as sensitive as wild-type MRP1 to the non-GSH-containing inhibitors (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl][[3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid (MK571), 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl]-ethanone (LY171883), and highly potent 6-[4'-carboxyphenylthio]-5[S]-hydroxy-7[E], 11[Z]14[Z]-eicosatetrenoic acid (BAY u9773). Finally, the differing abilities of the cysteinyl leukotriene derivatives leukotriene C(4), D(4), and F(4) to inhibit estradiol glucuronide transport by wild-type and K332L mutant MRP1 provide further evidence that TM6-Lys(332) is involved in the recognition of the gamma-Glu portion of substrates and modulators containing GSH or GSH-like moieties.

Synthetic studies of thymosin alpha-1 fragments

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25-hydroxycholesterol, 7β-hydroxycholesterol and 7-ketocholesterol upregulate interleukin-8 expression independently of Toll-like receptor 1, 2, 4 or 6 signalling in human macrophages

Recent studies have shown that Toll-like receptor (TLR)- signalling contributes significantly to the inflammatory events of atherosclerosis. As products of cholesterol oxidation (oxysterols) accumulate within atherosclerotic plaque and have been proposed to contribute to inflammatory signalling in the diseased artery, we investigated the potential of 7-ketocholesterol (7-KC), 7β-hydroxycholesterol (7β-HC) and 25-hydroxycholesterol (25-HC) to stimulate inflammatory signalling via the lipid-recognising TLRs 1, 2, 4 and 6. Each oxysterol stimulated secretion of the inflammatory chemokine interleukin-8 (IL-8), but not I?B degradation or tumour necrosis factor- release from monocytic THP-1 cells. Transfection of TLR-deficient HEK-293 cells with TLRs 1, 2, 4 or 6 did not increase sensitivity to the tested oxysterols. Moreover, blockade of TLR2 or TLR4 with specific inhibitors did not reduce 25-hydroxycholesterol (25-HC) induced IL-8 release from THP-1 cells. We conclude that although the oxysterols examined in this study may contribute to increased expression of certain inflammatory genes, this occurs by mechanisms independent of TLR signalling.

How are task reflexivity and intercultural sensitivity related to the academic performance of MBA students?

Higher education in business school environments is increasingly focused on how to best equip students with the skills necessary for leadership in the global workplace. This paper examines the impact of two particularly important cognitive capabilities - task reflexivity and intercultural sensitivity, on academic performance in an MBA programme. It was hypothesised that in an intercultural learning environment, task reflexivity would be associated with higher academic performance, and that this relationship would be mediated via intercultural sensitivity. Questionnaire data from 77 MBA students was analysed alongside academic performance. Results demonstrated that task reflexivity was indirectly related to academic performance through intercultural sensitivity. These findings suggest that engagement in task reflexivity enables students to develop greater levels of intercultural sensitivity, allowing them to reap the positive effects of diversity in their peer group for their own learning and performance. Limitations and practical implications of the research for professional practice are discussed. © 2014 © 2014 Society for Research into Higher Education.

In situ X-ray studies of crotyl alcohol selective oxidation over Au/Pd(1 1 1) surface alloys

The selective oxidation of crotyl alcohol to crotonaldehyde over ultrathin Au overlayers on Pd(1 1 1) and Au/Pd(1 1 1) surface alloys has been investigated by time-resolved X-ray photoelectron spectroscopy (XPS) and mass spectrometry. Pure gold is catalytically inert towards crotyl alcohol which undergoes reversible adsorption. In contrast, thermal processing of a 3.9 monolayer (ML) gold overlayer allows access to a range of AuPd surface alloy compositions, which are extremely selective towards crotonaldehyde production, and greatly reduce the extent of hydrocarbon decomposition and eventual carbon laydown compared with base Pd(1 1 1). XPS and CO titrations suggest that palladium-rich surface alloys offer the optimal balance between alcohol oxidative dehydrogenation activity while minimising competitive decomposition pathways, and that Pd monomers are not the active surface ensemble for such selox chemistry over AuPd alloys. Crown Copyright © 2008.

X-ray crystallographic and theoretical studies of an anticonvulsant enaminone:methyl 4-(4'-bromophenyl)amino-6-methyl-2-oxocyclohex-3-en-1-oate

Objective: The aims of this study were to establish the structure of the potent anticonvulsant enaminone methyl 4-(4′-bromophenyl)amino-6-methyl-2- oxocyclohex-3-en-1-oate (E139), and to determine the energetically preferred conformation of the molecule, which is responsible for the biological activity. Materials and Methods: The structure of the molecule was determined by X-ray crystallography. Theoretical ab initio calculations with different basis sets were used to compare the energies of the different enantiomers and to other structurally related compounds. Results: The X-ray crystal structure revealed two independent molecules of E139, both with absolute configuration C11(S), C12(R), and their inverse. Ab initio calculations with the 6-31G, 3-21G and STO-3G basis sets confirmed that the C11(S), C12(R) enantiomer with both substituents equatorial had the lowest energy. Compared to relevant crystal structures, the geometry of the theoretical structures shows a longer C-N and shorter C=O distance with more cyclohexene ring puckering in the isolated molecule. Conclusion: Based on a pharmacophoric model it is suggested that the enaminone system HN-C=C-C=O and the 4-bromophenyl group in E139 are necessary to confer anticonvulsant property that could lead to the design of new and improved anticonvulsant agents. Copyright © 2003 S. Karger AG, Basel.

Lessening sensitivity:student experiences of teaching and learning sensitive issues

Despite growing interest in learning and teaching as emotional activities, there is still very little research on experiences of sensitive issues. Using qualitative data from students from a range of social science disciplines, this study investigates student's experiences. The paper highlights how, although they found it difficult and distressing at times, the students all valued being able to explore sensitive issues during their studies. The paper argues that it is though repeated exposure to sensitive issues within the classroom that the students became more comfortable with the issues. This process of lessening sensitivity is an important part of the emotional journey through higher education. It will argue that good student experiences need not always be positive emotions and that sensitive issues should be seen as an important part of transformational education.

Fourth-root summation of contrast over area:no end in sight when spatially inhomogeneous sensitivity is compensated by a witch's hat

Measurements of area summation for luminance-modulated stimuli are typically confounded by variations in sensitivity across the retina. Recently we conducted a detailed analysis of sensitivity across the visual field (Baldwin et al, 2012) and found it to be well-described by a bilinear “witch’s hat” function: sensitivity declines rapidly over the first 8 cycles or so, more gently thereafter. Here we multiplied luminance-modulated stimuli (4 c/deg gratings and “Swiss cheeses”) by the inverse of the witch’s hat function to compensate for the inhomogeneity. This revealed summation functions that were straight lines (on double log axes) with a slope of -1/4 extending to ≥33 cycles, demonstrating fourth-root summation of contrast over a wider area than has previously been reported for the central retina. Fourth-root summation is typically attributed to probability summation, but recent studies have rejected that interpretation in favour of a noisy energy model that performs local square-law transduction of the signal, adds noise at each location of the target and then sums over signal area. Modelling shows our results to be consistent with a wide field application of such a contrast integrator. We reject a probability summation model, a quadratic model and a matched template model of our results under the assumptions of signal detection theory. We also reject the high threshold theory of contrast detection under the assumption of probability summation over area.

Catalyst studies on the ring opening of tetrahydrofuran-dimethanol to 1,2,6-hexanetriol

The metal catalyzed hydrogenolysis of the biomass-derived THF-dimethanol to 1,2,6-hexanetriol using heterogeneous catalysts was investigated. Bimetallic Rh-Re catalysts (4 wt% Rh and a Re/Rh (mol. ratio of 0.5) on a silica support gave the best performance and 1,2,6-hexanetriol was obtained in 84% selectivity at 31% conversion (120 C, 80 bar, 4 h); the selectivity reaches a maximum of 92% at 80 C. The product distribution at prolonged reaction times or higher temperatures or both shows the formation of diols and mono-alcohols, indicating that the 1,2,6-hexanetriol is prone to subsequent hydrodeoxygenation reactions. Different silica supports were investigated and optimal results were obtained with an amorphous silica featuring an intermediate surface area and an average mesopore size of about 6 nm. TPR and XPS surface analysis support the presence of mixed Rh and Re particles. The redox Reδ+/ReTotal surface ratio correlates with the conversion in a volcano type dependency. Both gas phase as well as Rh200Re1OH cluster DFT calculations support an acid-metal bifunctional mechanism and explain the products distribution. © 2013 Elsevier B.V. All rights reserved.

Perceptions and experiences of the implementation, management, use and optimisation of electronic prescribing systems in hospital settings:protocol for a systematic review of qualitative studies

Introduction: There is increasing evidence that electronic prescribing (ePrescribing) or computerised provider/physician order entry (CPOE) systems can improve the quality and safety of healthcare services. However, it has also become clear that their implementation is not straightforward and may create unintended or undesired consequences once in use. In this context, qualitative approaches have been particularly useful and their interpretative synthesis could make an important and timely contribution to the field. This review will aim to identify, appraise and synthesise qualitative studies on ePrescribing/CPOE in hospital settings, with or without clinical decision support. Methods and analysis: Data sources will include the following bibliographic databases: MEDLINE, MEDLINE In Process, EMBASE, PsycINFO, Social Policy and Practice via Ovid, CINAHL via EBSCO, The Cochrane Library (CDSR, DARE and CENTRAL databases), Nursing and Allied Health Sources, Applied Social Sciences Index and Abstracts via ProQuest and SCOPUS. In addition, other sources will be searched for ongoing studies (ClinicalTrials.gov) and grey literature: Healthcare Management Information Consortium, Conference Proceedings Citation Index (Web of Science) and Sociological abstracts. Studies will be independently screened for eligibility by 2 reviewers. Qualitative studies, either standalone or in the context of mixed-methods designs, reporting the perspectives of any actors involved in the implementation, management and use of ePrescribing/CPOE systems in hospital-based care settings will be included. Data extraction will be conducted by 2 reviewers using a piloted form. Quality appraisal will be based on criteria from the Critical Appraisal Skills Programme checklist and Standards for Reporting Qualitative Research. Studies will not be excluded based on quality assessment. A postsynthesis sensitivity analysis will be undertaken. Data analysis will follow the thematic synthesis method. Ethics and dissemination: The study does not require ethical approval as primary data will not be collected. The results of the study will be published in a peer-reviewed journal and presented at relevant conferences.