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Cambridge, United Kingdom

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Cambridge, United Kingdom

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Cytlak U.M.,Madingley Road | Hannemann A.,Madingley Road | Rees D.C.,King's College London | Gibson J.S.,Madingley Road
Pflugers Archiv European Journal of Physiology | Year: 2013

Phosphatidylserine (PS) exposure in red blood cells (RBCs) from sickle cell disease (SCD) patients is increased compared to levels in normal individuals and may participate in the anaemic and ischaemic complications of SCD. Exposure is increased by deoxygenation and occurs with elevation of intracellular Ca 2+ to low micromolar levels. The Ca2+ entry step has not been defined but a role for the deoxygenation-induced pathway, P sickle, is postulated. Partial Psickle inhibitors 4-acetamido-4′-isothiocyanostilbene-2,2′-disulphonic acid (SITS), 4,4′-dithiocyano-2,2′-stilbene-disulphonic acid (DIDS) and dipyridamole inhibited deoxygenation-induced PS exposure (DIDS IC50, 118 nM). Inhibitors and activators of other pathways (including these stimulated by depolarisation, benzodiazepines, glutamate and stretch) were without effect. Zn2+ and Gd3+ stimulated PS exposure to high levels. In the case of Zn2+, this effect was independent of oxygen (and hence HbS polymerisation and RBC sickling) but required extracellular Ca2+. The effect was completely abolished when Zn2+ (100 μM) was added to RBCs suspended in autologous plasma, implying a requirement of high levels of free Zn2+. © 2013 The Author(s).


Williams D.L.,Madingley Road | Mann B.K.,SALt Inc | Mann B.K.,University of Utah
International Journal of Biomaterials | Year: 2013

Keratoconjunctivitis sicca, commonly referred to as dry eye or KCS, can affect both humans and dogs. The standard of care in treating KCS typically includes daily administration of eye drops to either stimulate tear production or to hydrate and lubricate the corneal surface. Lubricating eye drops are often applied four to six times daily for the life of the patient. In order to reduce this dosing regimen yet still provides sufficient hydration and lubrication, we have developed a crosslinked hydrogel based on a modified, thiolated hyaluronic acid (HA), xCMHA-S. This xCMHA-S gel was found to have different viscosity and rheologic behavior than solutions of noncrosslinked HA. The gel was also able to increase tear breakup time in rabbits, indicating a stabilization of the tear film. Further, in a preliminary clinical study of dogs with KCS, the gel significantly reduced the symptoms associated with KCS within two weeks while only being applied twice daily. The reduction of symptoms combined with the low dosing regimen indicates that this gel may lead to both improved patient health and owner compliance in applying the treatment. © 2013 David L. Williams and Brenda K. Mann.


PubMed | Islamic Azad University at Karaj, Madingley Road, Islamic Azad University at Tehran and Iranian pet hospital
Type: | Journal: Veterinary ophthalmology | Year: 2016

The purpose of this study was to establish a reference value of tear production and intraocular pressure in clinically normal ducks and geese.The study population consisted of forty-eight ducks (24 males and 24 females) and fifty-two geese (26 males and 26 females).Birds were gently physically restrained in dorsoventral position without any pressure to the head and neck. Tear secretion and intraocular pressure were measured using 5-mm-wide Schirmer tear test strips and TonoVetOverall mean 2SD STT and IOP values of all eyes were 6.2 2.2 mm/min and 10.2 2.2 mmHg, respectively, for the ducks; 5.5 2.6 mm/min and 9.1 2.0 mmHg, respectively, for the geese. There was no statistically significant difference in IOP between left eye and right eye or between males and females in ducks (P = 0.56, P = 0.63) and geese (P = 0.23, P = 0.22). Analysis of variance revealed that there were no significant differences in the STT and IOP between the breeds in ducks (P = 0.49, P = 0.68) and geese (P = 0.14, P = 0.26).Results of this study may be beneficial for the diagnosis and therapeutic monitoring of ducks and geese affected with Keratoconjunctivitis sicca, glaucoma, and uveitis.


PubMed | Islamic Azad University at Karaj, Madingley Road and Science and Research Branch
Type: Journal Article | Journal: Journal of the American Association for Laboratory Animal Science : JAALAS | Year: 2016

The objective of this study was to measure intraocular pressure (IOP) in intact, healthy guinea pigs (15 male, 15 female) every 2 h for a 24-h period. First, IOP was measured by using rebound tonometry (RBT). After a 1-min rest period, 0.5% proparacaine ophthalmic solution, a topical anesthetic, was applied to both eyes; 4 min after anesthetic instillation, IOP was measured by using applanation tonometry (APT). The IOP was lower during the light period (0700 to 1900) than during the dark phase (2000 to 0600). The lowest IOP by both RBT and APT (3.68 and 13.37 mm Hg, respectively) occurred at 0700, whereas maximal IOP occurred at 2300 for RBT (8.12 mm Hg) but at 2100 for APT (20.62 mm Hg). No significant differences in IOP between the left and right eyes or between RBT and APT were noted. In addition, daily variations in the IOP of guinea pigs seem to be independent of sex and body weight. The results of this study may be beneficial in the diagnosis and observation of glaucoma in guinea pigs.


Ma Y.-L.,Oxford Genetics | Rees D.C.,King's College | Gibson J.S.,Madingley Road | Ellory J.C.,Oxford Genetics
Journal of Physiology | Year: 2012

The abnormally high cation permeability in red blood cells (RBCs) from patients with sickle cell disease (SCD) occupies a central role in pathogenesis. Sickle RBC properties are notably heterogeneous, however, thus limiting conventional flux techniques that necessarily average out the behaviour of millions of cells. Here we use the whole-cell patch configuration to characterise the permeability of single RBCs from patients with SCD in more detail. A non-specific cation conductance was reversibly induced upon deoxygenation and was permeable to both univalent (Na +, K +, Rb +) and also divalent (Ca 2+, Mg 2+) cations. It was sensitive to the tarantula spider toxin GsMTx-4. Mn 2+ caused partial, reversible inhibition. The aromatic aldehyde o-vanillin also irreversibly inhibited the deoxygenation-induced conductance, partially at 1 mm and almost completely at 5 mm. Nifedipine, amiloride and ethylisopropylamiloride were ineffective. In oxygenated RBCs, the current was pH sensitive showing a marked increase as pH fell from 7.4 to 6, with no change apparent when pH was raised from 7.4 to 8. The effects of acidification and deoxygenation together were not additive. Many features of this deoxygenation-induced conductance (non-specificity for cations, permeability to Ca 2+ and Mg 2+, pH sensitivity, reversibility, partial inhibition by DIDS and Mn 2+) are shared with the flux pathway sometimes referred to as P sickle. Sensitivity to GsMTx-4 indicates its possible identity as a stretch-activated channel. Sensitivity to o-vanillin implies that activation requires HbS polymerisation but since the conductance was observed in whole-cell patches, results suggest that bulk intracellular Hb is not involved; rather a membrane-bound subfraction is responsible for channel activation. The ability to record P sickle-like activity in single RBCs will facilitate further studies and eventual molecular identification of the pathway involved. © 2012 The Authors. The Journal of Physiology © 2012 The Physiological Society.


Corke M.J.,Madingley Road
Cattle Practice | Year: 2014

Ectoparasite control is an essential part of flock health planning in Britain. It is necessary in developing prevention and control strategies, to take into account the life cycles and epidemiology of ectoparasites that may cause disease in the flock, and the pharmacokinetics of any prophylactic or therapeutic treatments. Management strategies to minimise disease risk and reduce the use of drugs are essential for sustainable control of ectoparasites.


Milligan C.,Madingley Road | Rees D.C.,King's College | Ellory J.C.,Oxford Genetics | Osei A.,King's College | And 3 more authors.
Journal of Physiology | Year: 2013

Red blood cells (RBCs) from patients with sickle cell disease (SCD) lyse in deoxygenated isosmotic non-electrolyte solutions. Haemolysis has features which suggest that it is linked to activation of the pathway termed Psickle. This pathway is usually described as a non-specific cationic conductance activated by deoxygenation, HbS polymerisation and RBC sickling. The current work addresses the hypothesis that this haemolysis will provide a novel diagnostic and prognostic test for SCD, dependent on the altered properties of the RBC membrane resulting from HbS polymerisation. A simple test represented by this haemolysis assay would be useful especially in less affluent deprived areas of the world where SCD is most prevalent. RBCs from HbSS and most HbSC individuals showed progressive lysis in deoxygenated isosmotic sucrose solution at pH 7.4 to a level greater than that observed with RBCs from HbAS or HbAA individuals. Cytochalasin B prevented haemolysis. Haemolysis was temperature- and pH-dependent. It required near physiological temperatures to occur in deoxygenated sucrose solutions at pH 7.4. At pH 6, haemolysis occurred even in oxygenated samples. Haemolysis was reduced in patients on long-term (>5 months) hydroxyurea treatment. Several manoeuvres which stabilise soluble HbS (aromatic aldehydes o-vanillin or 5-hydroxymethyl, and urea) reduced haemolysis, an effect not due to increased oxygen affinity. Conditions designed to elicit HbS polymerisation in cells from sickle trait patients (deoxygenated hyperosmotic sucrose solutions at pH 6) supported their haemolysis. These findings are consistent with haemolysis requiring HbS polymerisation and support the hypothesis that this may be used as a test for SCD. © 2013 The Authors. The Journal of Physiology. © 2013 The Physiological Society.


Dalibalta S.,Oxford Genetics | Ellory J.C.,Oxford Genetics | Browning J.A.,Oxford Genetics | Wilkins R.J.,Oxford Genetics | And 2 more authors.
Blood Cells, Molecules, and Diseases | Year: 2010

Individuals heterozygous for HbS and HbC (HbSC) represent about 1/3rd of sickle cell disease (SCD) patients. Whilst HbSC disease is generally milder, there is considerable overlap in symptoms with HbSS disease. HbSC patients, as well as HbSS ones, present with the chronic anaemia and panoply of acute vaso-occlusive complications that characterize SCD. However, there are important clinical and haematological differences. Certain complications occur with greater frequency in HbSC patients (like proliferative retinopathy and osteonecrosis) whilst intravascular haemolysis is reduced. Patients with HbSC disease can be considered as a discrete subset of SCD cases. Although much work has been carried out on understanding the pathogenesis of SCD in HbSS homozygotes, including the contribution of altered red blood cell permeability, relatively little pertains directly to HbSC individuals. Results reported in the literature suggest that HbSC cells, and particularly certain subpopulations, present with similar permeability to HbSS cells but there are also important differences - these have not been well characterized. We hypothesise that their unique cell transport properties accounts for the different pattern of disease in HbSC patients and represents a potential chemotherapeutic target not shared in red blood cells from HbSS patients. The distinct pattern of clinical haematology in HbSC disease is emphasised here. We analyse some of the electrophysiological properties of single red blood cells from HbSC patients, comparing them with those from HbSS patients and normal HbAA individuals. We also use the isosmotic haemolysis technique to investigate the behaviour of total red blood cell populations. Whilst both HbSS and HbSC cells show increased monovalent and divalent (Ca2+) cation conductance further elevated upon deoxygenation, the distribution of current magnitudes differs, and outward rectification is greatest for HbSC cells. In addition, although Gd3+ largely abolishes the cation conductance of both HbSS and HbSC cells, only in HbSS ones are currents inhibited by the aminoglycosides like streptomycin. This distinction is retained in isosmotic lysis experiments where both HbSS and HbSC cells undergo haemolysis in sucrose solutions but streptomycin significantly inhibits lysis only in HbSS cells. These findings emphasise similarities but also differences in the permeability properties of HbSS and HbSC cells, which may be important in pathogenesis. © 2010 Elsevier Inc.


Corke M.J.,Madingley Road
Cattle Practice | Year: 2010

Adequate ingestion of colostrum is essential for the survival of neonatal calves. Changes in husbandry practices and in dairy cow milk yields have led to the marketing of colostrum supplements to ensure adequate passive transfer of immunity to calves. This paper reviews current knowledge about maternal and neonatal factors affecting passive transfer, managed delivery of colostrum and factors affecting immunoglobulin availability in colostrum supplements.


A high incidence of failure of passive transfer of immunoglobulins in modern dairy herds has led to the marketing of colostrum supplements for calves. The concentration of immunoglobulin G (IgG) in a number of colostrum supplements was measured by radial immuno-diffusion assay using a commercially available kit. The IgG concentrations ranged from 6 to 52 grams per litre. If fed at the manufacturers' recommended rates in the first feed, the colostrum supplements would provide 30 grams or less of IgG.

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