Dissection of peripheral and central endogenous opioid modulation of systemic interleukin-1 beta responses using c-fos expression in the rat brain

In opiate addicts or patients receiving morphine treatment, it has been reported that the immune system is often compromised. The mechanisms responsible for the adverse effects of opioids on responses to infection are not clear but it is possible that central and/or peripheral opioid receptors may be important. We have utilised an experimental immune challenge model in rats, the systemic administration of the human pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) to study the effects of selectively blocking peripheral opioid receptors only (using naloxone methiodide) or after blocking both central and peripheral opioid receptors (using naloxone). Pre-treatment with naloxone methiodide decreased (15%) IL-1 beta-induced Fos-immunoreactivity (Fos-IR) in medial parvocellular paraventricular nucleus (mPVN) corticotropin-releasing hormone (CRH) neurons but increased responses in the ventrolateral medulla (VLM) C1 (65%) and nucleus tractus solitarius (NTS) A2 (110%) catecholamine cell groups and area postrema (136%). However no effect of blocking peripheral opioid receptors was detected in the central nucleus of the amygdala (CeA) or dorsal bed nucleus of the stria terminalis (BNST). We next determined the effect of blocking both central and peripheral opioid receptors with naloxone and, when compared to the naloxone methiodide pre-treated group, a further 60% decrease in Fos-IR mPVN CRH neurons induced by IL-1 beta was detected, which was attributed to block of central opioid receptors. Similar comparisons also detected decreases in Fos-IR neurons induced by IL-1 beta in the VLM A1, VLM C1 and NTS A2 catecholamine cell groups, area postrema, and parabrachial nucleus. In contrast, pre-treatment with naloxone increased Fos-IR neurons in CeA (98%) and dorsal BNST (72%). These results provide novel evidence that endogenous opioids can influence central neural responses to systemic IL-1 beta and also suggest that the differential patterns of activation may arise because of actions at central and/or peripheral opioid receptors that might be important in regulating behavioural, hypothalamic-pituitary-adrenal axis and sympathetic nervous system responses during an immune challenge. (c) 2005 Elsevier Ltd. All rights reserved.

Short-term effects of cycle and treadmill training on exercise tolerance in peripheral arterial disease

Background. To explore the efficacy of cycle training in the treatment of intermittent claudication, the present study compared performance and physiologic effects of cycle training with more conventional treadmill walking training in a group of patients with claudication. Method: Forty-two individuals with peripheral arterial disease and intermittent claudication (24 men, 18 women) were stratified by gender and the presence or absence of type 2 diabetes mellitus and then randomized to a treadmill (n = 13), cycle (n = 15), or control group (n = 14). Treadmill and cycle groups trained three times a week for 6 weeks, whereas the control group did not train during this period. Maximal and pain-free exercise times were measured on graded treadmill and cycle tests before and after training. Results. Treadmill training significantly improved maximal and pain-free treadmill walking times but did not improve cycle performance. Cycle training significantly improved maximal cycle time but did not improve treadmill performance. However, there was evidence of a stronger cross-transfer effect between the training modes for patients who reported a common limiting symptom during cycling and walking at baseline. There was also considerable variation in the training response to cycling, and a subgroup of responsive patients in the cycle group improved their walking performance by more than the average response observed in the treadmill group. Conclusion: These findings suggest that cycle exercise is not effective in improving walking performance in all claudication patients but might be an effective alternative to walking in those who exhibit similar limiting symptoms during both types of exercise.

Effect of training on the response of plasma vascular endothelial growth factor to exercise in patients with peripheral arterial disease

Expansion of the capillary network, or angiogenesis, occurs following endurance training. This process, which is reliant on the presence of VEGF (vascular endothelial growth factor), is an adaptation to a chronic mismatch between oxygen demand and supply. Patients with IC (intermittent claudication) experience pain during exercise associated with an inadequate oxygen delivery to the muscles. Therefore the aims of the present study were to examine the plasma VEGF response to acute exercise, and to establish whether exercise training alters this response in patients with IC. In Part A, blood was collected from patients with IC (n = 18) before and after (+ 20 and + 60 min post-exercise) a maximal walking test to determine the plasma VEGF response to acute exercise. VEGF was present in the plasma of patients (45.11 +/- 29.96 pg/ml) and was unchanged in response to acute exercise. Part B was a training study to determine whether exercise training altered the VEGF response to acute exercise. Patients were randomly assigned to a treatment group (TMT; n = 7) that completed 6 weeks of high-intensity treadmill training, or to a control group (CON; n = 6). All patients completed a maximal walking test before and after the intervention, with blood samples drawn as for Part A. Training had no effect on plasma VEGF at rest or in response to acute exercise, despite a significant increase in maximal walking time in the TMT group (915 + 533 to 1206 + 500 s; P = 0.009) following the intervention. The absence of a change in plasma VEGF may reflect altered VEGF binding at the endothelium, although this cannot be confirmed by the present data.

Use of regression equation of peripheral pulse timing characteristics to predict hypertension in children

Studies have shown that an increase in arterial stiffening can indicate the presence of cardiovascular diseases like hypertension. Current gold standard in clinical practice is by measuring the blood pressure of patients using a mercury sphygmomanometer. However, the nature of this technique is not suitable for prolonged monitoring. It has been established that pulse wave velocity is a direct measure of arterial stiffening. However, its usefulness is hampered by the absence of techniques to estimate it non-invasively. Pulse transit time (PTT) is a simple and non-intrusive method derived from pulse wave velocity. It has shown its capability in childhood respiratory sleep studies. Recently, regression equations that can predict PTT values for healthy Caucasian children were formulated. However, its usefulness to identify hypertensive children based on mean PTT values has not been investigated. This was a continual study where 3 more Caucasian male children with known clinical hypertension were recruited. Results indicated that the PTT predictive equations are able to identify hypertensive children from their normal counterparts in a significant manner (p < 0.05). Hence, PTT can be a useful diagnostic tool in identifying hypertension in children and shows potential to be a non-invasive continual monitor for arterial stiffening.

In vivo vitamin C supplementation increases phosphoinositol transfer protein expression in peripheral blood mononuclear cells from healthy individuals

Ascorbate can act as both a reducing and oxidising agent in vitro depending on its environment. It can modulate the intracellular redox environment of cells and therefore is predicted to modulate thiol-dependent cell signalling and gene expression pathways. Using proteomic analysis of vitamin C-treated T cells in vitro, we have previously reported changes in expression of five functional protein groups associated with signalling, carbohydrate metabolism, apoptosis, transcription and immune function. The increased expression of the signalling molecule phosphatidylinositol transfer protein (PITP) was also confirmed using Western blotting. Herein, we have compared protein changes elicited by ascorbate in vitro, with the effect of ascorbate on plasma potassium levels, on peripheral blood mononuclear cell (PBMC) apoptosis and PITP expression, in patients supplemented with vitamin C (0-2 g/d) for up to 10 weeks to investigate whether in vitro model systems are predictive of in vivo effects. PITP varied in expression widely between subjects at all time-points analysed but was increased by supplementation with 2 g ascorbate/d after 5 and 10 weeks. No effects on plasma potassium levels were observed in supplemented subjects despite a reduction of K+ channel proteins in ascorbate-treated T cells in vitro. Similarly, no effect of vitamin C supplementation on PBMC apoptosis was observed, whilst ascorbate decreased expression of caspase 3 recruitment domain protein in vitro. These data provide one of the first demonstrations that proteomics may be valuable in developing predictive markers of nutrient effects in vivo and may identify novel pathways for studying mechanisms of action in vivo.

Dietary supplementation with vitamin C but not vitamin E reduces constitutive expression of ICAM-1 in peripheral blood monocytes of normal subjects with low plasma vitamin C levels

Monocytes play a central role in inflammatory responses through systemic antigen presentation and cytokine secretion. Regulation of monocyte adhesion molecule and inflammatory gene expression is via redox sensitive transcription factors. Therefore we have investigated the hypothesis that dietary antioxidant supplementation with vitamins C (250mg/d) or E (400iU/d) for six weeks can modulate monocyte ICAM-1 expression in healthy male subjects with low plasma vitamin C at baseline. In a randomised, double-blind, crossover study, ICAM-1 mRNA and protein was analysed using quantitative RTPCR with ELISA measurement of PCR products and by flow cytometry and ELISA respectively. Monocyte numbers were unaltered by supplementation. Subjects with low plasma vitamin C (<50uM) prior to supplementation expressed higher levels of monocyte ICAM-1 mRNA, and showed a significant (50%) reduction in ICAM-1 mRNA expression after 6 weeks of 250mg/d vitamin C supplementation compared to subjects with normal plasma vitamin C. This was paralleled by a reduction in plasma sICAM-1. Vitamin E supplementation had no effect on ICAM-1 expression. For the first time, these results show that dietary vitamin C can modulate monocyte ICAM-1 gene expression in vivo, where regulation of gene expression represents a novel mechanism for benefit from dietary antioxidants.

The relative contributions of colour and luminance signals towards the visuomotor localisation of targets in human peripheral vision

We sought to determine the extent to which colour (and luminance) signals contribute towards the visuomotor localization of targets. To do so we exploited the movement-related illusory displacement a small stationary window undergoes when it has a continuously moving carrier grating behind it. We used drifting (1.0-4.2 Hz) red/green-modulated isoluminant gratings or yellow/black luminance-modulated gratings as carriers, each curtailed in space by a stationary, two-dimensional window. After each trial, the perceived location of the window was recorded with reference to an on-screen ruler (perceptual task) or the on-screen touch of a ballistic pointing movement made without visual feedback (visuomotor task). Our results showed that the perceptual displacement measures were similar for each stimulus type and weakly dependent on stimulus drift rate. However, while the visuomotor displacement measures were similar for each stimulus type at low drift rates (<4 Hz), they were significantly larger for luminance than colour stimuli at high drift rates (>4 Hz). We show that the latter cannot be attributed to differences in perceived speed between stimulus types. We assume, therefore, that our visuomotor localization judgements were more susceptible to the (carrier) motion of luminance patterns than colour patterns. We suggest that, far from being detrimental, this susceptibility may indicate the operation of mechanisms designed to counter the temporal asynchrony between perceptual experiences and the physical changes in the environment that give rise to them. We propose that perceptual localisation is equally supported by both colour and luminance signals but that visuomotor localisation is predominantly supported by luminance signals. We discuss the neural pathways that may be involved with visuomotor localization. © 2007 Springer-Verlag.

Languaging the worker:globalized governmentalities in/of language in peripheral spaces

In the introduction to the special issue “Languaging the worker: globalized governmentalities in/of language in peripheral spaces”, we take up the notion of governmentality as a means to interrogate the complex relationship between language, labor, power and subjectivity in peripheral multilingual spaces. Our aim here is to argue for the study of governmentality as a viable and growing approach in critical sociolinguistic research. As such, in this introduction, we first discuss key concepts germane to our interrogations, including the notions of governmentality, languaging, peripherality and language worker. We proceed to map out five ethnographically and discourse-analytically informed case studies. These examine diverse actors in different settings pertaining to the domain of work. Finally we chart how the case studies construe the issue of languaging the worker through a governmentality frame.

Influence of accommodation and refractive status on the peripheral refractive profile

AIM: The aim of the study was to determine, objectively and non-invasively, whether changes in accommodative demand modify differentially the peripheral refraction in emmetropic and myopic human eyes. METHODS: Forty subjects (19 male, 21 female) aged 20-30 years (mean 22.7 (SD 2.8) years), 21 emmetropes (mean spherical equivalent refractive error (MSE) -0.13 (SD 0.29) D) and 19 myopes (MSE -2.95 (SD 1.76) D) participated in the study. Ametropia was corrected with soft contact lenses (etafilcon A, 58% water content). Subjects viewed monocularly a stationary, high contrast (85%) Maltese cross at 0.0, 1.0, 2.0 and 3.0 D of accommodative demand and at 0, 10, 20 and 30 degrees field angle (nasal and temporal) through a +3.0 D Badal optical system. Static recordings of the accommodation response were obtained for each accommodative level, at each field angle, with an objective, open-view, infrared optometer. RESULTS: Peripheral mean spherical equivalent (M) data showed that the emmetropic cohort exhibited relative myopic shifts into the periphery, while the myopic group showed hypermetropic shifts. Increasing accommodative demand did not alter the peripheral refractive profile in either the temporal (p = 0.25) or nasal (p = 0.07) periphery with no differential accommodative effect between refractive groups in either the temporal (p = 0.77) or nasal (p = 0.73) field. Significant shifts in the J(0) astigmatic component were seen in the temporal (p<0.0005) and nasal (p<0.0005) fields with increasing eccentricity. Interaction effects between eccentricity and accommodative demand illustrated that increasing accommodative demand significantly altered the peripheral refractive profile in the temporal J(0) astigmatic component (p<0.0005). The nasal periphery, however, failed to show such an effect (p = 0.65). CONCLUSIONS: Alterations in peripheral refraction augmented by changes in ocular accommodation are relatively unaffected by refractive error for young, healthy human eyes.

The neurotoxicity of acrylamide

The experiments described in this thesis compared conventional methods of screening for neurotoxins with potential electrophysiological and pharmacological tests in an attempt to improve the sensitivity of detection of progressive distal neuropathy. Adult male albino mice were dosed orally with the neurotoxicant acylamide and subjected to a test of limb strength and co-ordination and a functional observational battery. These methods established a no observable effect level of 10 mg/kg. A dose of 200 mg/kg resulted in abnormalities of gait and reduced limb strength and/or co-ordination. Analysis of the in vitro 'jitter' of the latency of trains of action potentials evoked at a frequency of 30 Hz in the mouse phrenic nerve/hemidiaphragm preparation showed this technique to be unsuitable for detection of the early phases of acrylamide induced peripheral neuropathy (l00 mg/kg). The evoked and spontaneous twitch responses of the hemidiaphragm preparation following in vitro exposure to the organophosphorous anticholinesterase compound ecothiopate were altered by in vivo pre treatment with acrylamide. Acrylamide caused an increase in the time course of the potentiation of stimulated twitches and a decrease in the maximum potentiation. Spontaneous twitches were reduced in amplitude and frequency. These effects occurred at an acrylamide dose level insufficient to cause clinical signs of neuropathy. Investigations into the mechanisms underlying these observations yielded the following observations. Analysis of miniature endplate potentials at this dose level indicated prolongation of the life of acetylcholine in the synaptic cleft but the implied decrease in cholinesterase activity could not be demonstrated biochemically or histologically. The electrical excitability of the nerve terminal region of phrenic motor nerves was reduced following acrylamide although a possible compromise of antidromic action potential conduction could not be confirmed. There was no histopathological evidence of neuropathy at this dose level. Further exploration of this phenomenon is desirable in order to ascertain whether the effect is specific to acrylamide and/or ecothiopate and to elucidate the mechanisms behind these novel observations.

Psychophysical investigations of human peripheral vision

This thesis investigates various aspects of peripheral vision, which is known not to be as acute as vision at the point of fixation. Differences between foveal and peripheral vision are generally thought to be of a quantitative rather than a qualitative nature. However, the rate of decline in sensitivity between foveal and peripheral vision is known to be task dependent and the mechanisms underlying the differences are not yet well understood. Several experiments described here have employed a psychophysical technique referred to as 'spatial scaling'. Thresholds are determined at several eccentricities for ranges of stimuli which are magnified versions of one another. Using this methodology a parameter called the E2 value is determined, which defines the eccentricity at which stimulus size must double in order to maintain performance equivalent to that at the fovea. Experiments of this type have evaluated the eccentricity dependencies of detection tasks (kinetic and static presentation of a differential light stimulus), resolution tasks (bar orientation discrimination in the presence of flanking stimuli, word recognition and reading performance), and relative localisation tasks (curvature detection and discrimination). Most tasks could be made equal across the visual field by appropriate magnification. E2 values are found to vary widely dependent on the task, and possible reasons for such variations are discussed. The dependence of positional acuity thresholds on stimulus eccentricity, separation and spatial scale parameters is also examined. The relevance of each factor in producing 'Weber's law' for position can be determined from the results.