• Validation of a novel particle isolation procedure using particle doped tissue samples

      Patel, J.; Lal, S.; Wilshaw, Stacy-Paul; Hall, R.M.; Tipper, J.L. (2018-06)
      A novel particle isolation method for tissue samples was developed and tested using particle-doped peri-articular tissues from ovine cadavers. This enabled sensitivity of the isolation technique to be established by doping tissue samples of 0.25 g with very low particle volumes of 2.5 µm3 per sample. Image analysis was used to verify that the method caused no changes to particle size or morphologies.
    • Validation of a voltage-sensitive dye (di-4-ANEPPS)-based method for assessing drug-induced delayed repolarisation in Beagle dog left ventricular midmyocardial myocytes

      Hardy, Matthew E.; Pollard, C.E.; Small, B.G.; Bridgland-Taylor, M.; Woods, A.J.; Valentin, J.-P.; Abi-Gerges, N. (2009)
      Evaluation of drug candidates in in-vitro assays of action potential duration (APD) is one component of preclinical safety assessment. Current assays are limited by technically-demanding, time-consuming electrophysiological methods. This study aimed to assess whether a voltage-sensitive dye-based assay could be used instead. Methods Optical APs were recorded using di-4-ANEPPS in electrically field stimulated Beagle left ventricular midmyocardial myocytes (LVMMs). Pharmacological properties of di-4-ANEPPS on the main cardiac ion channels that shape the ventricular AP were investigated using IonWorks™ and conventional electrophysiology. Effects of 9 reference drugs (dofetilide, E4031, d-sotalol, ATXII, cisapride, terfenadine, alfuzosin, diltiazem and pinacidil) with known APD-modulating effects were assessed on optically measured APD at 1 Hz. Results Under optimum conditions, 0.1 μM di-4-ANEPPS could be used to monitor APs paced at 1 Hz during nine, 5 s exposures without altering APD. di-4-ANEPPS had no effect on either hIERG, hINa, hIKs and hIto currents in transfected CHO cells (up to 10 µM) or ICa,L current in LVMMs (at 16 µM). di-4-ANEPPS had no effect on APs recorded with microelectrodes at 1 or 0.5 Hz over a period of 30 min di-4-ANEPPS displayed the sensitivity to record changes in optically measured APD in response to altered pacing frequencies and sequential vehicle additions did not affect the optically measured APD. APD data obtained with 9 reference drugs were as expected except (i) d-sotalol-induced increases in duration were smaller than those caused by other IKr blockers and (ii) increases in APD were not detected using low concentrations of terfenadine. Discussion Early in drug discovery, the di-4-ANEPPS-based method can reliably be used to assess drug effects on APD as part of a cardiac risk assessment strategy.
    • Validation of high-performance liquid chromatography assay for quantification of formoterol in urine samples after inhalation using UV detection technique.

      Nadarassan, D.K.; Chrystyn, Henry; Clark, Brian J.; Assi, Khaled H. (2007)
      A novel high-performance liquid chromatography (HPLC) assay for the estimation of formoterol in urine samples was developed and validated. A solid phase extraction (SPE) using Oasis HLB was optimised to isolate formoterol from a urine matrix followed by HPLC with UV detection. This extraction procedure concentrated the final analyte forty times so that UV detection can be used to determine even a low concentration of formoterol in urine samples. The urinary assay was performed in accordance with FDA and ICH regulations for the validation of bioanalytical samples. The samples were injected onto a C18 Spherisorb® (250 mm x 4.6 mm x 5 ¿m) analytical column maintained at 30 °C. The mobile phase consisted of 5 mM of potassium dihydrogen orthophosphate buffer (adjusted to pH 3 with ortho phosphoric acid):acetonitrile (ACN) (70:30, v/v), and the formoterol peak was detected at wavelength 214 nm. The extraction recovery of formoterol from the urine sample was >95%. The calibration curve was linear (r2=0.99) over formoterol concentrations ranging from 1.5 to 25 ng/mL (n=6). The method had an accuracy of >92% and intra and inter-day precision CV% of <3.9% and <2.2%, respectively, at three different concentrations low, medium and high (10, 15, 20 ng/mL). The limit of quantification (LOQ) for formoterol was found to be 1.50 ng/mL. The accuracy and precision at the LOQ level were 95% and %CV <3.7% (n = 10), respectively. The method reported is simple, reliable, precise, and accurate and has the capacity to be used for determination of formoterol in urine samples.
    • Vascular smooth muscle as a target for novel therapeutics

      Porter, K.E.; Riches-Suman, Kirsten (2015-10)
      Cardiovascular disease is the principal cause of death in patients with type 2 diabetes (T2DM). Exposure of the vasculature to metabolic disturbances leaves a persistent imprint on vascular walls, and specifically on smooth muscle cells (SMC) that favours their dysfunction and potentially underlies macrovascular complications of T2DM. Current diabetes therapies and continued development of newer treatments has led to the ability to achieve more efficient glycaemic control. There is also some evidence to suggest that some of these treatments may exert favourable pleiotropic effects, some of which may be at the level of SMC. However, emerging interest in epigenetic markers as determinants of vascular disease, and a putative link with diabetes, opens the possibility for new avenues to develop robust and specific new therapies. These will likely need to target cell-specific epigenetic changes such as effectors of DNA histone modifications that promote or inhibit gene transcription, and/or microRNAs capable of regulating entire cellular pathways through target gene repression. The growing epidemic of T2DM worldwide, and its attendant cardiovascular mortality, dictates a need for novel therapies and personalised approaches to ameliorate vascular complications in this vulnerable population.
    • Vegetation Changes on Ilkley Moor 1964-1984

      Cotton, David E.; Hale, William H.G. (1989)
      In 1970 a set of maps was published which summarized the results of an extensive survey of the vegetation of Ilkley Moor. This paper presents new maps showing the distribution of selected vegetation communities based on a detailed survey undertaken in 1983-84, and examines the changes which have occurred in the period 1964--1984. Comparison of the maps reveals that Calluna vulgaris and Pteridium aquilinum have increased their occupancy of the moor, whilst there has been a marked reduction in the abundance of Empetrum nigrum and Eriophorum spp. These changes indicate that the degradation of the moor which was recorded during the 1960s was reversed, at least partially, between 1964 and 1984.
    • Vegetation Changes on Ilkley Moor between 1964 and 1984, and Possible Environmental Causes

      Hale, William H.G.; Cotton, David E. (1993)
      In recent years there has been concern about the decrease in the quality and quantity of Britain's heaths and moorlands. This concern has prompted attempts to monitor change in moorland vegetation, and programmes of action designed to halt the decline, both nationally and locally (Bunce, 1989; Hudson & Newborn, 1989a). In northern England the decline has been brought about partly by a reduction in the areal extent of the moors but mainly by changes in their species composition, with Calluna vulgaris (L.) Hull (heather) declining and grasses, Empetrum nigrum L. (crowberry) and other species increasing. These changes have been attributed to changed management practices, such as less effective burning regimes and increased sheep grazing (Bunce, 1989). However, there are few detailed quantitative studies of long-term vegetation change. This paper draws upon historical records to determine the nature and extent of change in the vegetation of Ilkley Moor over a twenty-year interval.
    • The vesicular acetylcholine transporter is present in melanocytes and keratinocytes in the human epidermis

      Schallreuter, Karin U.; Chavan, Bhavan; Elwary, Souna M.A. (2006)
      The human epidermis holds the full machinery for cholinergic signal transduction. However, the presence of the vesicular transporter (vesicular acetylcholine (ACh) transporter (VAChT)) for both choline and ACh has never been shown in this compartment. The results of this study confirm the presence of VAChT in cutaneous nerves and in both epidermal melanocytes and keratinocytes as well as in their nuclei using immunofluorescence labelling in situ and in vitro, Western blot analysis of cellular and nuclear extracts and reverse transcription-PCR. These results underline that ACh/choline transport in the non-neuronal epidermis is no different from the neuronal pathway. However, the function of VAChT in the nucleus remains to be shown.
    • Vibrational spectroscopic characterisation of salmeterol xinafoate polymorphs and a preliminary investigation of their transformation using simultaneous in situ portable Raman spectroscopy and differential scanning calorimetry

      Ali, H.R.H.; Edwards, Howell G.M.; Hargreaves, Michael D.; Munshi, Tasnim; Scowen, Ian J.; Telford, Richard (2008-07)
      Knowledge and control of the polymorphic phases of chemical compounds are important aspects of drug development in the pharmaceutical industry. Salmeterol xinafoate, a long acting β-adrenergic receptor agonist, exists in two polymorphic Forms, I and II. Raman and near infrared spectra were obtained of these polymorphs at selected wavelengths in the range of 488–1064 nm; significant differences in the Raman and near-infrared spectra were apparent and key spectral marker bands have been identified for the vibrational spectro-scopic characterisation of the individual polymorphs which were also characterised with X ray diffractometry. The solid-state transition of salmeterol xinafoate polymorphs was studied using simultaneous in situ portable Raman spectroscopy and differential scanning calorimetry isothermally between transitions. This method assisted in the unambiguous characterisation of the two polymorphic forms by providing a simultaneous probe of both the thermal and vibrational data. The study demonstrates the value of a rapid in situ analysis of a drug polymorph which can be of potential value for at-line in-process control.
    • Vibrational spectroscopic study of budesonide

      Edwards, Howell G.M.; Ali, H.R.H.; Kendrick, John; Munshi, Tasnim; Scowen, Ian J. (2007)
      The Raman spectrum of budesonide is reported for the first time, and molecular assignments are proposed on the basis of ab initio BLYP DFT calculations with a 6-31 G* basis set and vibrational wavenumbers predicted on a quasi-harmonic approximation. Comparison with previously published infrared data has explained several spectral features, and the relative band intensities in the CO and CC stretching regions are interpreted. The results from this study provide data that can be used for the preparative process monitoring of budesonide, an important steroidal pharmaceutical in various dosage forms, and its interaction with excipients and other components.
    • Vibrational spectroscopic study of fluticasone propionate

      Ali, H.R.H.; Edwards, Howell G.M.; Kendrick, John; Scowen, Ian J. (Elsevier, 2009)
      Luticasone propionate is a synthetic glucocorticoid with potent anti-inflammatory activity that has been used effectively in the treatment of chronic asthma. The present work reports a vibrational spectroscopic study of fluticasone propionate and gives proposed molecular assignments on the basis of ab initio calculations using BLYP density functional theory with a 6-31G* basis set and vibrational frequencies predicted within the quasi-harmonic approximation. Several spectral features and band intensities are explained. This study generated a library of information that can be employed to aid the process monitoring of fluticasone propionate.
    • Vibrational spectroscopic study of salbutamol hemisulphate

      Ali, H.R.H.; Edwards, Howell G.M.; Kendrick, John; Scowen, Ian J. (Elsevier, 01/01/2009)
      Salbutamol hemisulphate is a relatively selective ß2-adrenergic agonist and is used as a bronchodilator. In this work, we present a detailed vibrational spectroscopic investigation of salbutamol hemisulphate using mid-infrared and near-infrared Fourier-transform (NIR-FT) Raman spectroscopies. These data are supported by quantum chemical calculations, which allow us to characterise the vibrational spectra of this compound reasonably. As such, this study could be viable for examining the way in which this drug interacts with its target molecules.
    • Vibrational spectroscopic study of terbutaline hemisulphate

      Ali, H.R.H.; Edwards, Howell G.M.; Kendrick, John; Scowen, Ian J. (01/05/2009)
      The Raman spectrum of terbutaline hemisulphate is reported for the first time, and molecular assignments are proposed on the basis of ab initio BLYP DFT calculations with a 6-31G* basis set and vibrational frequencies predicted within the quasi-harmonic approximation; these predictions compare favourably with the observed vibrational spectra. Comparison with previously published infrared data explains several spectral features. The results from this study provide data that can be used for the preparative process monitoring of terbutaline hemisulphate, an important ß2 agonist drug in various dosage forms and its interaction with excipients and other components.
    • Victims and survivors: stable isotopes used to identify migrants from the Great Irish Famine to 19th century London

      Beaumont, Julia; Geber, J.; Powers, N.; Wilson, Andrew S.; Lee-Thorp, Julia A.; Montgomery, Janet (2013)
      Historical evidence documents mass migration from Ireland to London during the period of the Great Irish Famine of 1845-52. The rural Irish were reliant on a restricted diet based on potatoes but maize, a C(4) plant, was imported from the United States of America in 1846-47 to mitigate against Famine. In London, Irish migrants joined a population with a more varied diet. To investigate and characterize their diet, carbon and nitrogen isotope ratios were obtained from bone collagen of 119 and hair keratin of six individuals from Lukin Street cemetery, Tower Hamlets (1843-54), and bone collagen of 20 individuals from the cemetery at Kilkenny Union Workhouse in Ireland (1847-51). A comparison of the results with other contemporaneous English populations suggests that Londoners may have elevated delta(15) N compared with their contemporaries in other cities. In comparison, the Irish group have lower delta(15) N. Hair analysis combined with bone collagen allows the reconstruction of perimortem dietary changes. Three children aged 5-15 years from Kilkenny have bone collagen delta(13) C values that indicate consumption of maize (C(4)). As maize was only imported into Ireland in quantity from late 1846 and 1847, these results demonstrate relatively rapid bone collagen turnover in children and highlight the importance of age-related bone turnover rates, and the impact the age of the individual can have on studies of short-term dietary change or recent migration. Stable light isotope data in this study are consistent with the epigraphic and documentary evidence for the presence of migrants within the London cemetery.
    • Vikings, peat formation and settlement abandonment: multi-method chronological approach from Shetland

      Swindles, G.T.; Outram, Z.; Batt, Catherine M.; Hamilton, W.D.; Church, M.J.; Bond, Julie M.; Watson, E.J.; Cook, G.T.; Sim, T.G.; Newton, A.J.; et al. (2019-04-15)
      Understanding the chronology of Norse settlement is crucial for deciphering the archaeology of many sites across the North Atlantic region and developing a timeline of human-environment interactions. There is ambiguity in the chronology of settlements in areas such as the Northern Isles of Scotland, arising from the lack of published sites that have been scientifically dated, the presence of plateaus in the radiocarbon calibration curve, and the use of inappropriate samples for dating. This novel study uses four absolute dating techniques (AMS radiocarbon, tephrochronology, spheroidal carbonaceous particles and archaeomagnetism) to date a Norse house (the “Upper House”), Underhoull, Unst, Shetland Isles and to interpret the chronology of settlement and peat which envelops the site. Dates were produced from hearths, activity surfaces within the structure, and peat accumulations adjacent to and above the structure. Stratigraphic evidence was used to assess sequences of dates within a Bayesian framework, constraining the chronology for the site as well as providing modelled estimates for key events in its life, namely the use, modification and abandonment of the settlement. The majority of the absolute dating methods produced consistent and coherent datasets. The overall results show that occupation at the site was not a short, single phase, as suggested initially from the excavated remains, but instead a settlement that continued throughout the Norse period. The occupants of the site built the longhouse in a location adjacent to an active peatland, and continued to live there despite the encroachment of peat onto its margins. We estimate that the Underhoull longhouse was constructed in the period cal. AD 805–1050 (95% probability), and probably in cal. AD 880–1000 (68% probability). Activity within the house ceased in the period cal. AD 1230–1495 (95% probability), and most probably in cal. AD 1260–1380 (68% probability). The Upper House at Underhoull provides important context to the expansion and abandonment of Norse settlement across the wider North Atlantic region.
    • Visibility and Invisibility: Some Thoughts on Neolithic and Bronze Age Sites, Monuments and Rituals.

      Gibson, Alex M. (2009-11-16)
      This volume represents the publication of a highly successful conference held in 2003 to celebrate the contribution to Neolithic and Early Bronze Age studies of one of archaeology's finest synthesisers, Professor Stuart Piggott. The title is a reference to his famous work, Ancient Europe from the beginnings of agriculture to Classical Antiquity, itself a publication of his Society of Antiquaries of Scotland's Rhind Lectures of 1962. The scope of the volume spans the three crucial millennia, from the beginning of the fourth to the mid second, that saw major impacts on the area we now call Scotland. There was transformation of the landscape through the introduction and development of farming, the creation of many striking monuments and the spread of important ideas and technologies, of which metalworking, particularly in Aberdeenshire, was one of the most significant. The contributions cover major advances in research in the period which demonstrate the interplay of the key factors of climate, culture, and resources, where the theme of exchange of information, objects and materials played a vital role. Individual chapters range from chambered tombs to climate change, from dietary choices to faience beads, from timber enclosures to bronze hoards. Together these present a valuable and up-to-the-minute overview of Scotland in ancient Europe and a fine tribute to a past-master of the subject.
    • Vision and visual history in elite/near-elite level cricketers and rugby-league players

      Barrett, Brendan T.; Flavell, Jonathan C.; Bennett, S.J.; Cruickshank, Alice G.; Mankowska, Aleksandra M.; Harris, J.M.; Buckley, John G. (2017-11)
      Background: The importance of optimal and/or superior vision for participation in high-level sport remains the subject of considerable clinical research interest. Here we examine the vision and visual history of elite/near-elite cricketers and rugby-league players. Methods: Stereoacuity (TNO), colour vision, and distance (with/without pinhole) and near visual acuity (VA) were measured in two cricket squads (elite/international-level, female, n=16; near-elite, male, n=23) and one professional rugby-league squad (male, n=20). Refractive error was determined, and details of any correction worn and visual history were recorded. Results: Overall, 63% had their last eye-examination within 2 years. However, some had not had an eye examination for 5 years, or had never had one (near-elite-cricketers: 30%; rugby-league players: 15%; elite-cricketers: 6%). Comparing our results for all participants to published data for young, optimally-corrected, non-sporting adults, distance VA was ~1 line of letters worse than expected. Adopting α=0.01, the deficit in distance-VA deficit was significant, but only for elite-cricketers (p<0.001) (near-elite cricketers, p=0.02; rugby-league players, p=0.03). Near-VA did not differ between subgroups or relative to published norms for young adults (p>0.02 for all comparisons). On average, stereoacuity was better than in young adults, but only in elite-cricketers (p<0.001; p=0.03, near-elite-cricketers; p=0.47, rugby-league -players). On-field visual issues were present in 27% of participants, and mostly (in 75% of cases) comprised uncorrected ametropia. Some cricketers (near-elite: 17.4%; elite: 38%) wore refractive correction during play but no rugby-league player did. Some individuals with prescribed correction choose not to wear it when playing. Conclusion: Aside from near stereoacuity in elite-cricketers, these basic visual abilities were not better than equivalent, published data for optimally-corrected adults. 20-25% exhibited sub-optimal vision, suggesting that the clearest possible vision might not be critical for participation at the highest levels in the sports of cricket or rugby-league. Although vision could be improved in a sizeable proportion of our sample, the impact of correcting these, mostly subtle, refractive anomalies on playing performance is unknown.
    • Vision in high-level football officials

      Baptista, A.M.G.; Serra, P.M.; McAlinden, C.; Barrett, Brendan T. (2017-11)
      Officiating in football depends, at least to some extent, upon adequate visual function. However, there is no vision standard for football officiating and the nature of the relationship between officiating performance and level of vision is unknown. As a first step in characterising this relationship, we report on the clinically-measured vision and on the perceived level of vision in elite-level, Portuguese football officials. Seventy-one referees (R) and assistant referees (AR) participated in the study, representing 92% of the total population of elite level football officials in Portugal in the 2013/2014 season. Nine of the 22 Rs (40.9%) and ten of the 49 ARs (20.4%) were international-level. Information about visual history was also gathered. Perceived vision was assessed using the preference-values-assigned-to-global-visual-status (PVVS) and the Quality-of-Vision (QoV) questionnaire. Standard clinical vision measures (including visual acuity, contrast sensitivity and stereopsis) were gathered in a subset (n = 44, 62%) of the participants. Data were analysed according to the type (R/AR) and level (international/national) of official, and Bonferroni corrections were applied to reduce the risk of type I errors. Adopting criterion for statistical significance of p<0.01, PVVS scores did not differ between R and AR (p = 0.88), or between national- and international-level officials (p = 0.66). Similarly, QoV scores did not differ between R and AR in frequency (p = 0.50), severity (p = 0.71) or bothersomeness (p = 0.81) of symptoms, or between international-level vs national-level officials for frequency (p = 0.03) or bothersomeness (p = 0.07) of symptoms. However, international-level officials reported less severe symptoms than their national-level counterparts (p<0.01). Overall, 18.3% of officials had either never had an eye examination or if they had, it was more than 3 years previously. Regarding refractive correction, 4.2% had undergone refractive surgery and 23.9% wear contact lenses when officiating. Clinical vision measures in the football officials were similar to published normative values for young, adult populations and similar between R and AR. Clinically-measured vision did not differ according to officiating level. Visual acuity measured with and without a pinhole disc indicated that around one quarter of participants may be capable of better vision when officiating, as evidenced by better acuity (≥1 line of letters) using the pinhole. Amongst the clinical visual tests we used, we did not find evidence for above-average performance in elite-level football officials. Although the impact of uncorrected mild to moderate refractive error upon officiating performance is unknown, with a greater uptake of eye examinations, visual acuity may be improved in around a quarter of officials.