Publications by authors named "Conor McCloskey"

9 Publications

  • Page 1 of 1

Burden of selected infectious diseases covered by UK childhood vaccinations: systematic literature review.

Future Microbiol 2020 11 19;15:1679-1688. Epub 2020 Nov 19.

Sanofi Pasteur UK & Ireland, Reading, UK.

An overview of recent epidemiology and disease burden, independent of patient age, of diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and invasive disease in the UK. A systematic review was undertaken. Outcomes included incidence, prevalence, risk factors and cost burden. 39 publications were included. Hepatitis B prevalence is high among certain risk groups. A small pertussis risk remains in pregnancy and for infants, which led to the introduction of maternal vaccination. invasive disease cases are limited to rare serotypes. Polio, tetanus and diphtheria are well controlled. The evaluated diseases are currently well controlled, thanks to a comprehensive vaccination program, with a generally low clinical and cost burden.
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http://dx.doi.org/10.2217/fmb-2020-0170DOI Listing
November 2020

The clinical and humanistic burden of cutaneous T-cell lymphomas and response to conventional and novel therapies: results of a systematic review.

Expert Rev Hematol 2020 04 31;13(4):405-419. Epub 2020 Jan 31.

Global Outcomes Research, Millennium Pharmaceuticals, Inc., A Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.

: To summarize the impact of relapsed/refractory primary cutaneous T-cell lymphomas (CTCL) on quality of life (QoL) and the efficacy of available treatments in two systematic reviews (SRs).: Searches were performed on 16 January 2018 and 23 January 2018, respectively, in Medline, Medline in process, the Cochrane database, and EconLit. Studies reporting QoL outcomes in adults with CTCL or treatment efficacy in relapsed/refractory CTCL were included.: Based on 15 QoL studies, CTCL symptoms/complications negatively affect patients' physical, emotional, and social functioning. Skin problems pose considerable symptom burden, while advanced disease stage is associated with poorer QoL. CTCL negatively affects caregivers, primarily through family dynamics and relationships. The clinical efficacy SR included 72 publications covering 23 therapies. Overall response rate (ORR) ranged from 14% (belinostat) to 95% (total skin electron beam therapy). ORRs >50% were reported for several therapies including brentuximab vedotin (50-78%) and bexarotene (39-86%). Over half (13 of 23 therapies) had ORRs <30%. Median progression-free survival varied between treatments (3.5-116.4 months) and was >20 months for brentuximab vedotin and alemtuzumab.: CTCL negatively affects patients' and caregivers' QoL. A considerable proportion of patients have no response or no sustainable response to current treatments.
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http://dx.doi.org/10.1080/17474086.2020.1717945DOI Listing
April 2020

Reconstruction of Cell Surface Densities of Ion Pumps, Exchangers, and Channels from mRNA Expression, Conductance Kinetics, Whole-Cell Calcium, and Current-Clamp Voltage Recordings, with an Application to Human Uterine Smooth Muscle Cells.

PLoS Comput Biol 2016 Apr 22;12(4):e1004828. Epub 2016 Apr 22.

Division of Reproductive Health, Warwick Medical School, University of Warwick, Coventry, United Kingdom.

Uterine smooth muscle cells remain quiescent throughout most of gestation, only generating spontaneous action potentials immediately prior to, and during, labor. This study presents a method that combines transcriptomics with biophysical recordings to characterise the conductance repertoire of these cells, the 'conductance repertoire' being the total complement of ion channels and transporters expressed by an electrically active cell. Transcriptomic analysis provides a set of potential electrogenic entities, of which the conductance repertoire is a subset. Each entity within the conductance repertoire was modeled independently and its gating parameter values were fixed using the available biophysical data. The only remaining free parameters were the surface densities for each entity. We characterise the space of combinations of surface densities (density vectors) consistent with experimentally observed membrane potential and calcium waveforms. This yields insights on the functional redundancy of the system as well as its behavioral versatility. Our approach couples high-throughput transcriptomic data with physiological behaviors in health and disease, and provides a formal method to link genotype to phenotype in excitable systems. We accurately predict current densities and chart functional redundancy. For example, we find that to evoke the observed voltage waveform, the BK channel is functionally redundant whereas hERG is essential. Furthermore, our analysis suggests that activation of calcium-activated chloride conductances by intracellular calcium release is the key factor underlying spontaneous depolarisations.
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http://dx.doi.org/10.1371/journal.pcbi.1004828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841602PMC
April 2016

A High-Throughput Electrophysiology Assay Identifies Inhibitors of the Inwardly Rectifying Potassium Channel Kir7.1.

J Biomol Screen 2015 Jul 5;20(6):739-47. Epub 2015 Feb 5.

MRC Technology, Center for Therapeutics Discovery, London, UK.

Kir7.1 is an inwardly rectifying potassium channel that has been implicated in controlling the resting membrane potential of the myometrium. Abnormal uterine activity in pregnancy plays an important role in postpartum hemorrhage, and novel therapies for this condition may lie in manipulation of membrane potential. This work presents an assay development and screening strategy for identifying novel inhibitors of Kir7.1. A cell-based automated patch-clamp electrophysiology assay was developed using the IonWorks Quattro (Molecular Devices, Sunnyvale, CA) system, and the iterative optimization is described. In total, 7087 compounds were tested, with a hit rate (>40% inhibition) of 3.09%. During screening, average Z' values of 0.63 ± 0.09 were observed. After chemistry triage, lead compounds were resynthesized and activity confirmed by IC50 determinations. The most potent compound identified (MRT00200769) gave rise to an IC50 of 1.3 µM at Kir7.1. Compounds were assessed for selectivity using the inwardly rectifying potassium channel Kir1.1 (ROMK) and hERG (human Ether-à-go-go Related Gene). Pharmacological characterization of known Kir7.1 inhibitors was also carried out and analogues of VU590 tested to assess selectivity at Kir7.1.
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http://dx.doi.org/10.1177/1087057115569156DOI Listing
July 2015

The inwardly rectifying K+ channel KIR7.1 controls uterine excitability throughout pregnancy.

EMBO Mol Med 2014 Sep;6(9):1161-74

Division of Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School University of Warwick, Coventry, UK

Abnormal uterine activity in pregnancy causes a range of important clinical disorders, including preterm birth, dysfunctional labour and post-partum haemorrhage. Uterine contractile patterns are controlled by the generation of complex electrical signals at the myometrial smooth muscle plasma membrane. To identify novel targets to treat conditions associated with uterine dysfunction, we undertook a genome-wide screen of potassium channels that are enriched in myometrial smooth muscle. Computational modelling identified Kir7.1 as potentially important in regulating uterine excitability during pregnancy. We demonstrate Kir7.1 current hyper-polarizes uterine myocytes and promotes quiescence during gestation. Labour is associated with a decline, but not loss, of Kir7.1 expression. Knockdown of Kir7.1 by lentiviral expression of miRNA was sufficient to increase uterine contractile force and duration significantly. Conversely, overexpression of Kir7.1 inhibited uterine contractility. Finally, we demonstrate that the Kir7.1 inhibitor VU590 as well as novel derivative compounds induces profound, long-lasting contractions in mouse and human myometrium; the activity of these inhibitors exceeds that of other uterotonic drugs. We conclude Kir7.1 regulates the transition from quiescence to contractions in the pregnant uterus and may be a target for therapies to control uterine contractility.
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http://dx.doi.org/10.15252/emmm.201403944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197863PMC
September 2014

Spatial heterogeneity enhances and modulates excitability in a mathematical model of the myometrium.

J R Soc Interface 2013 Sep 10;10(86):20130458. Epub 2013 Jul 10.

MOAC Doctoral Training Centre, University of Warwick, Coventry CV4 7AL, UK.

The muscular layer of the uterus (myometrium) undergoes profound changes in global excitability prior to parturition. Here, a mathematical model of the myocyte network is developed to investigate the hypothesis that spatial heterogeneity is essential to the transition from local to global excitation which the myometrium undergoes just prior to birth. Each myometrial smooth muscle cell is represented by an element with FitzHugh-Nagumo dynamics. The cells are coupled through resistors that represent gap junctions. Spatial heterogeneity is introduced by means of stochastic variation in coupling strengths, with parameters derived from physiological data. Numerical simulations indicate that even modest increases in the heterogeneity of the system can amplify the ability of locally applied stimuli to elicit global excitation. Moreover, in networks driven by a pacemaker cell, global oscillations of excitation are impeded in fully connected and strongly coupled networks. The ability of a locally stimulated cell or pacemaker cell to excite the network is shown to be strongly dependent on the local spatial correlation structure of the couplings. In summary, spatial heterogeneity is a key factor in enhancing and modulating global excitability.
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http://dx.doi.org/10.1098/rsif.2013.0458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3730699PMC
September 2013

Kv1.3 is the exclusive voltage-gated K+ channel of platelets and megakaryocytes: roles in membrane potential, Ca2+ signalling and platelet count.

J Physiol 2010 May 22;588(Pt 9):1399-406. Epub 2010 Mar 22.

Department of Cell Physiology & Pharmacology, University of Leicester, Medical Sciences Building, University Road, LE1 9HN, UK.

A delayed rectifier voltage-gated K(+) channel (Kv) represents the largest ionic conductance of platelets and megakaryocytes, but is undefined at the molecular level. Quantitative RT-PCR of all known Kv alpha and ancillary subunits showed that only Kv1.3 (KCNA3) is substantially expressed in human platelets. Furthermore, megakaryocytes from Kv1.3(/) mice or from wild-type mice exposed to the Kv1.3 blocker margatoxin completely lacked Kv currents and displayed substantially depolarised resting membrane potentials. In human platelets, margatoxin reduced the P2X(1)- and thromboxaneA(2) receptor-evoked [Ca(2+)](i) increases and delayed the onset of store-operated Ca(2+) influx. Megakaryocyte development was normal in Kv1.3(/) mice, but the platelet count was increased, consistent with a role of Kv1.3 in apoptosis or decreased platelet activation. We conclude that Kv1.3 forms the Kv channel of the platelet and megakaryocyte, which sets the resting membrane potential, regulates agonist-evoked Ca(2+) increases and influences circulating platelet numbers.
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http://dx.doi.org/10.1113/jphysiol.2010.188136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876798PMC
May 2010

Voltage-dependent Ca2+ currents contribute to spontaneous Ca2+ waves in rabbit corpus cavernosum myocytes.

J Sex Med 2009 Nov 17;6(11):3019-31. Epub 2009 Aug 17.

University of Leicester-Department of Cell Physiology Pharmacology, Leicester, UK.

Introduction: Corpus cavernosum myocytes generate spontaneous tone that contributes to penile detumescence. It is essential to elucidate how tone is generated to fully understand the processes involved in erection. Tissue experiments have shown that blockers of voltage-dependent Ca2+ channels (VDCCs) reduce tone. However, there is also a widespread belief that these channels are poorly expressed in this tissue. Furthermore, it is unclear how VDCC would interact with recently described intracellular Ca2+ waves, which initiate contractions.

Aims: (i) To directly examine VDCC currents in freshly isolated corpus cavernosum myocytes; and (ii) to study the relationship between VDCC and intracellular Ca2+ waves.

Main Outcome Measures: VDCC and cytosolic Ca2+ were measured using patch clamp and confocal microscopy. Methods. Male New Zealand white rabbits were euthanized and corpus cavernosum myocytes dispersed enzymatically for patch clamp recording and confocal Ca2+ imaging (using fluo-4AM).

Results: Isolated myocytes developed robust VDCC that could be separated into two components. One activated at -45 mV, reversed at +40 mV, inactivated with a V(1/2) of -27 mV and was enhanced by Ba2+. This component was blocked with nifedipine, but not Ni2+ or mibefradil. The other component inactivated with a V(1/2) of -87 mV, was unchanged in Ba2+, and was blocked by Ni2+ or mibefradil, but not nifedipine. Even though Ni2+ had no effect on intracellular Ca2+ waves, nifedipine blocked them, although localized Ca2+ events remained.

Conclusions: At least two VDCC are expressed in rabbit corpus cavernousum myocytes. One may be designated L-type Ca2+ current, whereas the other is a putative T-type current. The L-current facilitates conversion of local Ca2+ events into global Ca2+ waves, whereas the putative T-current plays little part in this process. These results provide a new basis for understanding the role of L-type Ca2+ current in generating detumescent tone in the corpus cavernosum.
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http://dx.doi.org/10.1111/j.1743-6109.2009.01451.xDOI Listing
November 2009

Effects of female steroid hormones on A-type K+ currents in murine colon.

J Physiol 2006 Jun 31;573(Pt 2):453-68. Epub 2006 Mar 31.

Department of Physiology and Cell Biology, University of Nevada School of Medicine, MS 352, Reno, NV 89557, USA.

Idiopathic constipation is higher in women of reproductive age than postmenopausal women or men, suggesting that female steroid hormones influence gastrointestinal motility. How female hormones affect motility is unclear. Colonic motility is regulated by ion channels in colonic myocytes. Voltage-dependent K(+) channels serve to set the excitability of colonic muscles. We investigated regulation of Kv 4.3 channel expression in response to acute or chronic changes in female hormones. Patch clamp experiments and quantitative PCR were used to compare outward currents and transcript expression in colonic myocytes from male, non-pregnant, pregnant and ovariectomized mice. Groups of ovariectomized mice received injections of oestrogen or progesterone to investigate the effects of hormone replacement. The capacitance of colonic myocytes from non-pregnant females was larger than in males. Net outward current density in male and ovariectomized mice was higher than in non-pregnant females and oestrogen-treated ovariectomized mice. Current densities in late pregnancy were lower than in female controls. Progesterone had no effect on outward currents. A-type currents were decreased in non-pregnant females compared with ovariectomized mice, and were further decreased by pregnancy or oestrogen replacement. Kv 4.3 transcripts did not differ significantly between groups; however, expression of the potassium channel interacting protein KChIP1 was elevated in ovariectomized mice compared with female controls and oestrogen-treated ovariectomized mice. Delayed rectifier currents were not affected by oestrogen. In the mouse colon, oestrogen suppresses A-type currents, which are important for regulating excitability. These observations suggest a possible link between female hormones and altered colonic motility associated with menses, pregnancy and menopause.
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http://dx.doi.org/10.1113/jphysiol.2006.107375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1779718PMC
June 2006