Effect of a protein and energy dense n-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia:A randomised double blind trial

Aim: N-3 fatty acids, especially eicosapentaenoic acid (EPA), may possess anticachectic properties. This trial compared a protein and energy dense supplement enriched with n-3 fatty acids and antioxidants (experimental: E) with an isocaloric isonitrogenous control supplement (C) for their effects on weight, lean body mass (LBM), dietary intake, and quality of life in cachectic patients with advanced pancreatic cancer. Methods: A total of 200 patients (95 E; 105 C) were randomised to consume two cans/day of the E or C supplement (480 ml, 620 kcal, 32 g protein ± 2.2 g EPA) for eight weeks in a multicentre, randomised, double blind trial. Results: At enrolment, patients' mean rate of weight loss was 3.3 kg/month. Intake of the supplements (E or C) was below the recommended dose (2 cans/day) and averaged 1.4 cans/day. Over eight weeks, patients in both groups stopped losing weight (Δweight E: -0.25 kg/month versus C: -0.37 kg/month; p=0.74) and LBM (ΔLBM E: +0.27 kg/month versus C: +0.12 kg/month; p=0.88) to an equal degree (change from baseline E and C, p<0.001). In view of evident non-compliance in both E and C groups, correlation analyses were undertaken to examine for potential dose-response relationships. E patients demonstrated significant correlations between their supplement intake and weight gain (r=0.50, p<0.001) and increase in LBM (r=0.33, p=0.036). Such correlations were not statistically significant in C patients. The relationship of supplement intake with change in LBM was significantly different between E and C patients (p=0.043). Increased plasma EPA levels in the E group were associated with weight and LBM gain (r=0.50, p<0.001; r=0.51, p=0.001). Weight gain was associated with improved quality of life (p<0.01) only in the E group. Conclusion: Intention to treat group comparisons indicated that at the mean dose taken, enrichment with n-3 fatty acids did not provide a therapeutic advantage and that both supplements were equally effective in arresting weight loss. Post hoc dose-response analysis suggests that if taken in sufficient quantity, only the n-3 fatty acid enriched energy and protein dense supplement results in net gain of weight, lean tissue, and improved quality of life. Further trials are required to examine the potential role of n-3 enriched supplements in the treatment of cancer cachexia.

A study of the effect of harmonics in the system on the performance of residual current-operated circuit-breakers and electromechanical overcurrent relays

Residual current-operated circuit-breakers (RCCBs) have proved useful devices for the protection of both human beings against ventricular fibrillation and installations against fire. Although they work well with sinusoidal waveforms, there is little published information on their characteristics. Due to shunt connected non-linear devices, not the least of which is the use of power electronic equipment, the supply is distorted. Consequently, RCCBs as well as other protection relays are subject to non-sinusoidal current waveforms. Recent studies showed that RCCBs are greatly affected by harmonics, however the reasons for this are not clear. A literature search has also shown that there are inconsistencies in the analysis of the effect of harmonics on protection relays. In this work, the way RCCBs operate is examined, then a model is built with the aim of assessing the effect of non-sinusoidal current on RCCBs. Tests are then carried out on a number of RCCBs and these, when compared with the results from the model showed good correlation. In addition, the model also enables us to explain the RCCBs characteristics for pure sinusoidal current. In the model developed, various parameters are evaluated but special attention is paid to the instantaneous value of the current and the tripping mechanism movement. A similar assessment method is then used to assess the effect of harmonics on two types of protection relay, the electromechanical instantaneous relay and time overcurrent relay. A model is built for each of them which is then simulated on the computer. Tests results compare well with the simulation results, and thus the model developed can be used to explain the relays behaviour in a harmonics environment. The author's models, analysis and tests show that RCCBs and protection relays are affected by harmonics in a way determined by the waveform and the relay constants. The method developed provides a useful tool and the basic methodology to analyse the behaviour of RCCBs and protection relays in a harmonics environment. These results have many implications, especially the way RCCBs and relays should be tested if harmonics are taken into account.

Effect of a liposomal spray on the pre-ocular tear film

Purpose: With the potential to address evaporative dry eye, a novel spray has been developed in which phospholipid liposomes are delivered to the tear film via the surface of the closed eyelid. This study evaluated the short-term effects of liposomal spray application on the lipid and stability characteristics of the pre-ocular tear film in normal eyes. Methods: Twenty-two subjects (12M, 10F) aged 35.1 ± 7.1 years participated in this prospective, randomised, double-masked investigation in which the liposomal spray was applied to one eye, and an equal volume of saline spray (control) applied to the contralateral eye. Lipid layer grade (LLG), non-invasive tear film stability (NIBUT) and tear meniscus height (TMH) were evaluated at baseline, and at 30, 60, 90 and 135 minutes post-application. Subjective reports of comfort were also compared. Results: Treated and control eyes were not significantly different at baseline (p>0.05). Post-application, LLG increased significantly, at 30 and 60 minutes, only in the treated eyes (p=0.005). NIBUT also increased significantly in the treated eyes only (p<0.001), at 30, 60 and 90 minutes. TMH did not alter significantly (p>0.05). Comfort improved relative to baseline in 46% of treated and 18% of control eyes, respectively, at 30 minutes post-application. Of those expressing a preference in comfort between the eyes, 68% preferred the liposomal spray. Conclusions: Consistent with subjective reports of improved comfort, statistically and clinically significant improvements in lipid layer thickness and tear film stability are observed in normal eyes for at least an hour after a single application of a phospholipid liposomal spray.

Frequency selectivity and dopamine-dependence of plasticity at glutamatergic synapses in the subthalamic nucleus

In Parkinson's disease, subthalamic nucleus (STN) neurons burst fire with increased periodicity and synchrony. This may entail abnormal release of glutamate, the major source of which in STN is cortical afferents. Indeed, the cortico-subthalamic pathway is implicated in the emergence of excessive oscillations, which are reduced, as are symptoms, by dopamine-replacement therapy or deep brain stimulation (DBS) targeted to STN. Here we hypothesize that glutamatergic synapses in the STN may be differentially modulated by low-frequency stimulation (LFS) and high-frequency stimulation (HFS), the latter mimicking deep brain stimulation. Recordings of evoked and spontaneous excitatory post synaptic currents (EPSCs) were made from STN neurons in brain slices obtained from dopamine-intact and chronically dopamine-depleted adult rats. HFS had no significant effect on evoked (e) EPSC amplitude in dopamine-intact slices (104.4±8.0%) but depressed eEPSCs in dopamine-depleted slices (67.8±6.2%). Conversely, LFS potentiated eEPSCs in dopamine-intact slices (126.4±8.1%) but not in dopamine-depleted slices (106.7±10.0%). Analyses of paired-pulse ratio, coefficient of variation, and spontaneous EPSCs suggest that the depression and potentiation have a presynaptic locus of expression. These results indicate that the synaptic efficacy in dopamine-intact tissue is enhanced by LFS. Furthermore, the synaptic efficacy in dopamine-depleted tissue is depressed by HFS. Therefore the therapeutic effects of DBS in Parkinson's disease appear mediated, in part, by glutamatergic cortico-subthalamic synaptic depression and implicate dopamine-dependent increases in the weight of glutamate synapses, which would facilitate the transfer of pathological oscillations from the cortex.

Effect of dopamine on synchronous neuronal oscillations in the globus pallidus-subthalamic nucleus network

Changes in the pattern of activity of neurones within the basal ganglia are relevant in the pathophysiology and symptoms of Parkinson’s disease. The globus pallidus (GP) – subthalamic nucleus (STN) network has been proposed to form a pacemaker driving regenerative synchronous bursting activity. In order to test whether this activity can be sustained in vitro a 20o parasagittal slice of mouse midbrain was developed which preserved functional connectivity between the STN and GP. Mouse STN and GP cells were characterised electrophysiologically by the presence or absence of a voltage sag in response to hyperpolarising current steps indicative of Ih and the presence of rebound depolarisations. The presence of evoked and spontaneous post-synaptic GABA and glutamatergic currents indicated functional connectivity between the STN and GP. In control slices, STN cells fired action potentials at a regular rate, activity which was unaffected by bath application of the GABAA receptor antagonist picrotoxin (50 μM) or the glutamate receptor antagonist CNQX (10 μM). Paired extracellular recordings of STN cells showed uncorrelated firing. Oscillatory burst activity was induced pharmacologically using the glutamate receptor agonist, NMDA (20 μM), in combination with the potassium channel blocker apamin (50 -100 nM). The burst activity was unaffected by bath application of picrotoxin or CNQX while paired STN recordings showed uncorrelated activity indicating that the activity is not produced by the neuronal network. Thus, no regenerative activity is evident in this mouse brain preparation, either in control slices or when bursting is pharmacologically induced, suggesting the requirement of other afferent inputs that are not present in the slice. Using single-unit extracellular recording, dopamine (30 μM) produced an excitation of STN cells. This excitation was independent of synaptic transmission and was mimicked by both the Dl-like receptor agonist SKF38393 (10 μM) and the D2-like receptor agonist quinpirole (10 μM). However, the excitation was partially reduced by the D1-like antagonist SCH23390 (2 μM) but not by the D2-like antagonists sulpiride (10 μM) and eticlopride (10 μM). Using whole-recordings, dopamine was shown to induce membrane depolarisation. This depolarisation was caused either by a D1-like receptor mediated increase in a conductance which reversed at -34 mV, consistent with a non-specific cation conductance, or a D2-like receptor mediated decrease in conductance which reversed around -100 mV, consistent with a potassium conductance. Bath application of dopamine altered the pattern of the burst-firing produced by NMDA an apamin towards a more regular pattern. This effect was associated with a decrease in amplitude and ll1crease in frequency of TTX-resistant plateau potentials which underlie the burst activity.

Parametric study of the behaviour of reinforced concrete columns in fire

The research is concerned with the application of the computer simulation technique to study the performance of reinforced concrete columns in a fire environment. The effect of three different concrete constitutive models incorporated in the computer simulation on the structural response of reinforced concrete columns exposed to fire is investigated. The material models differed mainly in respect to the formulation of the mechanical properties of concrete. The results from the simulation have clearly illustrated that a more realistic response of a reinforced concrete column exposed to fire is given by a constitutive model with transient creep or appropriate strain effect The assessment of the relative effect of the three concrete material models is considered from the analysis by adopting the approach of a parametric study, carried out using the results from a series of analyses on columns heated on three sides which produce substantial thermal gradients. Three different loading conditions were used on the column; axial loading and eccentric loading both to induce moments in the same sense and opposite sense to those induced by the thermal gradient. An axially loaded column heated on four sides was also considered. The computer modelling technique adopted separated the thermal and structural responses into two distinct computer programs. A finite element heat transfer analysis was used to determine the thermal response of the reinforced concrete columns when exposed to the ISO 834 furnace environment. The temperature distribution histories obtained were then used in conjunction with a structural response program. The effect of the occurrence of spalling on the structural behaviour of reinforced concrete column is also investigated. There is general recognition of the potential problems of spalling but no real investigation into what effect spalling has on the fire resistance of reinforced concrete members. In an attempt to address the situation, a method has been developed to model concrete columns exposed to fire which incorporates the effect of spalling. A total of 224 computer simulations were undertaken by varying the amounts of concrete lost during a specified period of exposure to fire. An array of six percentages of spalling were chosen for one range of simulation while a two stage progressive spalling regime was used for a second range. The quantification of the reduction in fire resistance of the columns against the amount of spalling, heating and loading patterns, and the time at which the concrete spalls appears to indicate that it is the amount of spalling which is the most significant variable in the reduction of fire resistance.

Behaviour of concrete frame structures under localised fire scenarios

This thesis encompasses an investigation of the behaviour of concrete frame structure under localised fire scenarios by implementing a constitutive model using finite-element computer program. The investigation phase included properties of material at elevated temperature, description of computer program, thermal and structural analyses. Transient thermal properties of material have been employed in this study to achieve reasonable results. The finite-element computer package of ANSYS is utilized in the present analyses to examine the effect of fire on the concrete frame under five various fire scenarios. In addition, a report of full-scale BRE Cardington concrete building designed to Eurocode2 and BS8110 subjected to realistic compartment fire is also presented. The transient analyses of present model included additional specific heat to the base value of dry concrete at temperature 100°C and 200°C. The combined convective-radiation heat transfer coefficient and transient thermal expansion have also been considered in the analyses. For the analyses with the transient strains included, the constitutive model based on empirical formula in a full thermal strain-stress model proposed by Li and Purkiss (2005) is employed. Comparisons between the models with and without transient strains included are also discussed. Results of present study indicate that the behaviour of complete structure is significantly different from the behaviour of individual isolated members based on current design methods. Although the current tabulated design procedures are conservative when the entire building performance is considered, it should be noted that the beneficial and detrimental effects of thermal expansion in complete structures should be taken into account. Therefore, developing new fire engineering methods from the study of complete structures rather than from individual isolated member behaviour is essential.

Development of a neurotoxicity test-system, using human post-mitotic, astrocytic and neuronal cell lines in co-culture

Astrocytes are essential for neuronal function and survival, so both cell types were included in a human neurotoxicity test-system to assess the protective effects of astrocytes on neurons, compared with a culture of neurons alone. The human NT2.D1 cell line was differentiated to form either a co-culture of post-mitotic NT2.N neuronal (TUJ1, NF68 and NSE positive) and NT2.A astrocytic (GFAP positive) cells (∼2:1 NT2.A:NT2.N), or an NT2.N mono-culture. Cultures were exposed to human toxins, for 4 h at sub-cytotoxic concentrations, in order to compare levels of compromised cell function and thus evidence of an astrocytic protective effect. Functional endpoints examined included assays for cellular energy (ATP) and glutathione (GSH) levels, generation of hydrogen peroxide (H2O2) and caspase-3 activation. Generally, the NT2.N/A co-culture was more resistant to toxicity, maintaining superior ATP and GSH levels and sustaining smaller significant increases in H2O2 levels compared with neurons alone. However, the pure neuronal culture showed a significantly lower level of caspase activation. These data suggest that besides their support for neurons through maintenance of ATP and GSH and control of H2O2 levels, following exposure to some substances, astrocytes may promote an apoptotic mode of cell death. Thus, it appears the use of astrocytes in an in vitro predictive neurotoxicity test-system may be more relevant to human CNS structure and function than neuronal cells alone. © 2007 Elsevier Ltd. All rights reserved.

The effect of contact lens wear on dynamic ocular surface temperature

Aim: To determine the dynamic emitted temperature changes of the anterior eye during and immediately after wearing different materials and modalities of soft contact lenses. Method: A dynamic, non-contact infrared camera (Thermo-Tracer TH7102MX, NEC San-ei) was used to record the ocular surface temperature (OST) in 48 subjects (mean age 21.7 ± 1.9 years) wearing: lotrafilcon-A contact lenses on a daily wear (LDW; n = 8) or continuous wear (LCW; n = 8) basis; balafilcon-A contact lenses on a daily wear (BDW; n = 8) or continuous wear (BCW; n = 8) basis; etafilcon-A contact lenses on a daily disposable regimen (EDW; n = 8); and no lenses (controls; n = 8). OST was measured continuously five times, for 8 s after a blink, following a minimum of 2 h wear and immediately following lens removal. Absolute temperature, changes in temperature post-blink and the dynamics of temperature changes were calculated. Results: OST immediately following contact lens wear was significantly greater compared to non-lens wearers (37.1 ± 1.7 °C versus 35.0 ± 1.1 °C; p < 0.005), predominantly in the LCW group (38.6 ± 1.0 °C; p < 0.0001). Lens surface temperature was highly correlated (r = 0.97) to, but lower than OST (by -0.62 ± 0.3 °C). There was no difference with modality of wear (DW 37.5 ± 1.6 °C versus CW 37.8 ± 1.9 °C; p = 0.63), but significant differences were found between etafilcon A and silicone hydrogel lens materials (35.3 ± 1.1 °C versus 37.5 ± 1.5 °C; p < 0.0005). Ocular surface cooling following a blink was not significantly affected by contact lens wear with (p = 0.07) or without (p = 0.47) lenses in situ. Conclusions: Ocular surface temperature is greater with hydrogel and greater still with silicone hydrogel contact lenses in situ, regardless of modality of wear. The effect is likely to be due to the thermal transmission properties of a contact lens. © 2004 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Higher-order aberrations in amblyopia:an analysis of pre- and post-wavefront-guided laser refractive correction

For more than a century it has been known that the eye is not a perfect optical system, but rather a system that suffers from aberrations beyond conventional prescriptive descriptions of defocus and astigmatism. Whereas traditional refraction attempts to describe the error of the eye with only two parameters, namely sphere and cylinder, measurements of wavefront aberrations depict the optical error with many more parameters. What remains questionable is the impact these additional parameters have on visual function. Some authors have argued that higher-order aberrations have a considerable effect on visual function and in certain cases this effect is significant enough to induce amblyopia. This has been referred to as ‘higher-order aberration-associated amblyopia’. In such cases, correction of higher-order aberrations would not restore visual function. Others have reported that patients with binocular asymmetric aberrations display an associated unilateral decrease in visual acuity and, if the decline in acuity results from the aberrations alone, such subjects may have been erroneously diagnosed as amblyopes. In these cases, correction of higher-order aberrations would restore visual function. This refractive entity has been termed ‘aberropia’. In order to investigate these hypotheses, the distribution of higher-order aberrations in strabismic, anisometropic and idiopathic amblyopes, and in a group of visual normals, was analysed both before and after wavefront-guided laser refractive correction. The results show: (i) there is no significant asymmetry in higher-order aberrations between amblyopic and fixing eyes prior to laser refractive treatment; (ii) the mean magnitude of higher-order aberrations is similar within the amblyopic and visually normal populations; (iii) a significant improvement in visual acuity can be realised for adult amblyopic patients utilising wavefront-guided laser refractive surgery and a modest increase in contrast sensitivity was observed for the amblyopic eye of anisometropes following treatment (iv) an overall trend towards increased higher-order aberrations following wavefront-guided laser refractive treatment was observed for both visually normal and amblyopic eyes. In conclusion, while the data do not provide any direct evidence for the concepts of either ‘aberropia’ or ‘higher-order aberration-associated amblyopia’, it is clear that gains in visual acuity and contrast sensitivity may be realised following laser refractive treatment of the amblyopic adult eye. Possible mechanisms by which these gains are realised are discussed.

In vitro protective effect and antioxidant mechanism of Resveratrol induced by Dapsone Hydroxylamine in human cells

Dapsone (DDS) hydroxylamine metabolites cause oxidative stress- linked adverse effects in patients, such as methemoglobin formation and DNA damage. This study evaluated the ameliorating effect of the antioxidant resveratrol (RSV) on DDS hydroxylamine (DDSNHOH) mediated toxicity in vitro using human erythrocytes and lymphocytes. The antioxidant mechanism was also studied using in-silico methods. In addition, RSV provided intracellular protection by inhibiting DNA damage in human lymphocytes induced by DDS-NHOH. However, whilst pretreatment with RSV (10-1000 μM significantly attenuated DDS-NHOH-induced methemoglobinemia, but it was not only significantly less effective than methylene blue (MET), but also post-treatment with RSV did not reverse methemoglobin formation, contrarily to that observed with MET. DDS-NHOH inhibited catalase (CAT) activity and reactive oxygen species (ROS) generation, but did not alter superoxide dismutase (SOD) activity in erythrocytes. Pretreatment with RSV did not alter these antioxidant enzymes activities in erythrocytes treated with DDS-NHOH. Theoretical calculations using density functional theory methods showed that DDS-NHOH has a pro-oxidant effect, whereas RSV and MET have antioxidant effect on ROS. The effect on methemoglobinemia reversion for MET was significantly higher than that of RSV. These data suggest that the pretreatment with resveratrol may decrease heme-iron oxidation and DNA damage through reduction of ROS generated in cells during DDS therapy.

Transforming the relationship between staff and students to effect change

This opinion piece argues for the necessity of student-staff partnerships that go beyond the common rhetoric of ‘student engagement’, achieving a richer student and staff dialogue which results in more meaningful change in policy and practice. In particular, attention is drawn to the need for such partnerships when determining technology applications that are often missed out from, or treated in isolation from, the curriculum design process. This piece cites, as an example, a student-led taught day on the Post Graduate Diploma in Learning and Teaching at Aston University in July 2015. There was clear evidence that the staff participants designed their assessments with student partners in mind. It is therefore proposed that a partnership relationship offers an effective means of moving forward from common practices where technology simply replicates, or supplements, traditional activities.

An analysis of penalty kicks in elite football post 1997

The penalty kick in football is a seemingly simplistic play; however, it has increased in complexity since 1997 when the rules changed allowing goalkeepers to move laterally along their goal line before the ball was kicked. Prior to 1997 goalkeepers were required to remain still until the ball was struck. The objective of this study was to determine the importance of the penalty kick in the modern game of football. A retrospective study of the 2002, 2006 and 2010 World Cup and the 2000, 2004 and 2008 European Championship tournaments was carried out, assessing the importance of the penalty kick in match play and shootouts and the effect of the time of the game on the shooter's success rate. This study demonstrated the conversion rate of penalties was 73% in shootouts and 68% in match play. Significantly more penalties were awarded late in the game: twice as many penalties in the second half than the first and close to four times as many in the fourth quarter vs. the first. Teams awarded penalty kicks during match play won 52%, drew 30% and lost 18% of the time; chances of winning increased to 61% if the penalty was scored, but decreased to 29% if missed. Teams participating in either the World Cup or European Championship final match had roughly a 50% chance of being involved in a penalty shootout during the tournament. Penalty shots and their outcome significantly impact match results in post 1997 football.

The redoxomics of PTEN: walking a fine line between damage and signaling:mass spectrometry-based approaches to study the effect of oxidation on PTEN function, structure, and protein-protein interactions

The research described in this PhD thesis focuses on proteomics approaches to study the effect of oxidation on the modification status and protein-protein interactions of PTEN, a redox-sensitive phosphatase involved in a number of cellular processes including metabolism, apoptosis, cell proliferation, and survival. While direct evidence of a redox regulation of PTEN and its downstream signaling has been reported, the effect of cellular oxidative stress or direct PTEN oxidation on PTEN structure and interactome is still poorly defined. In a first study, GST-tagged PTEN was directly oxidized over a range of hypochlorous acid (HOCl) concentration, assayed for phosphatase activity, and oxidative post-translational modifications (oxPTMs) were quantified using LC-MS/MS-based label-free methods. In a second study, GSTtagged PTEN was prepared in a reduced and reversibly H2O2-oxidized form, immobilized on a resin support and incubated with HCT116 cell lysate to capture PTEN interacting proteins, which were analyzed by LC-MS/MS and comparatively quantified using label-free methods. In parallel experiments, HCT116 cells transfected with a GFP-tagged PTEN were treated with H2O2 and PTENinteracting proteins immunoprecipitated using standard methods. Several high abundance HOCl-induced oxPTMs were mapped, including those taking place at amino acids known to be important for PTEN phosphatase activity and protein-protein interactions, such as Met35, Tyr155, Tyr240 and Tyr315. A PTEN redox interactome was also characterized, which identified a number of PTEN-interacting proteins that vary with the reversible inactivation of PTEN caused by H2O2 oxidation. These included new PTEN interactors as well as the redox proteins peroxiredoxin-1 (Prdx1) and thioredoxin (Trx), which are known to be involved in the recycling of PTEN active site following H2O2-induced reversible inactivation. The results suggest that the oxidative modification of PTEN causes functional alterations in PTEN structure and interactome, with fundamental implications for the PTEN signaling role in many cellular processes, such as those involved in the pathophysiology of disease and ageing.

On the peculiar relevance of a fundamental dilemma of minimum-wage regulation in post-socialism – apropos of an international investigation

To the extent minimum-wage regulation is effective in fighting against excessive earnings handicaps of those at the lower end-tail of earnings distribution, it may have the side-effect of worsening their employment prospects. A demand-and-supply interpretation of data on the relative employment rate and earnings position of the least educated in the EU27 suggests that the resulting dilemma might be particularly relevant for minimum-wage policies in post-socialist countries.