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Biomedical subjects

Michael J Carr

Publications and source records attributed to Michael J Carr.

At least 19 recordsLinked to original sources
PubMed2006

Plasticity of the afferent innervation of the airways: the role of ion channels.

Neuronal pathways associated with cough exhibit remarkable plasticity that can result in a persistent and uncontrollable urge to cough during disease. Afferent neurones involved in detecting tussive stimuli are polymodal, i.e. they respond to several types of stimuli including acid, inflammatory mediators such as bradykinin and mechanical stimuli. The pattern of action potential discharge following the encounter of the nerve terminal with a tussive stimulus is likely to determine the magnitude of the urge to cough and cough itself. The discharge pattern in sensory neurones is determined by multiple distinct voltage-gated ion channels. The function of many of these channels can be modulated via several signal transduction pathways coupled to receptors for a variety of inflammatory mediators. In particular, a key role of voltage-gated Na(+) and K(+) channel subtypes in shaping action potential discharge patterns in sensory neurones seems apparent. This modulation of transduction pathways may be an underlying mechanism of cough reflex plasticity.

Action Potentials↗
PubMed2006

Poster discussion: summary.

The Fourth International Cough Symposium took place in London between the 29th of June and 1st of July 2006. There were overall 22 posters presented during the meeting. These posters were divided into the following sections: methods of cough investigations, definitions of cough, receptor mechanisms, neural pathways, animal experiments and clinical aspects of cough. This review will focus on the discussions related to the posters.

Adult↗
PubMed2006

Macropolyhedral boron-containing cluster chemistry. Cluster opening and B-frame rearrangement in the reaction of B(16)H(20) with [{(IrCl(2)(eta(5)-C(5)Me(5))}(2)]. Synchrotron X-ray structures of [(eta(5)-C(5)Me(5))(2)Ir(2)B(16)H(17)Cl] and [(eta(5)-C(5)Me(5))(2)Ir(2)B(16)H(15)Cl].

Products from the reaction of + nido ten-vertex : nido eight-vertex, B(16)H(20) with [{(IrCl(2)(eta(5)-C(5)Me(5))}(2)] and tmnd show unanticipated rearrangement of the starting {B(16)} skeleton, as exhibited by + nido ten-vertex : nido ten-vertex, [(eta(5)-C(5)Me(5))(2)Ir(2)B(16)H(17)Cl] which has a {B(2)} edge conjunction and by + nido ten-vertex : nido eleven-vertex, [(eta(5)-C(5)Me(5))(2)Ir(2)B(16)H(15)Cl] which has a {B(3)} face conjunction.

Journal Article↗
PubMed2006

Macropolyhedral boron-containing cluster chemistry. Metallathiaboranes from S2B17H17: isolation and characterisation of [(eta6-MeC6H4isoPr)RuS2B16H16] and [(eta6-MeC6H4isoPr)RuS2B15H15].

Deprotonation of [S2B17H17] with NaH and subsequent reaction with [{RuCl2(eta6-MeC6H4(iso)Pr)}2] gives new nineteen-vertex [(eta6-MeC6H4(iso)Pr)RuS2B16H16] , with a nido {SB9} unit and an arachno-type {RuSB9} unit conjoined with a B-B edge in common, and new eighteen-vertex [(eta6-MeC6H4(iso)Pr)RuS2B15H15] with a nido {RuSB9} subcluster fused via a common B-B edge to a nido {B8} subcluster that is additionally linked exo to the {RuSB9} unit by a bridging sulfur atom that is held endo to the {B8} unit.

Journal Article↗
PubMed2006

Unique BK virus non-coding control region (NCCR) variants in hematopoietic stem cell transplant recipients with and without hemorrhagic cystitis.

Hematopoietic stem cell transplant recipients frequently develop BK virus (BKV)-associated hemorrhagic cystitis, which coincides with BK viruria. However, the precise role of BKV in the etiology of hemorrhagic cystitis in hematopoietic stem cell transplant recipients remains unclear, since approximately 50% of all such adult transplant recipients excrete BKV, yet do not develop this clinical condition. In the present study, BKV were analyzed to determine if mutations in the non-coding control region (NCCR), and specific BKV sub-types defined by sequence analysis of major capsid protein VP1, were associated with development of hemorrhagic cystitis in hematopoietic stem cell transplant recipients. The regions encoding VP1 and NCCRs of BKV in urine samples collected from 15 hematopoietic stem cell transplant recipients with hemorrhagic cystitis and 20 without this illness were amplified and sequenced. Sequence variations in the NCCRs of BKV were identified in urine samples from those with and without hemorrhagic cystitis. Furthermore, five unique sequence variations within transcription factor binding sites in the canonical NCCR, O-P-Q-R-S, were identified, representing new BKV variants from a population of cloned quasi-species obtained from patients with and without hemorrhagic cystitis. Thirty-five BKV VP1 sequences were analyzed by phylogenetic analysis but no specific BKV sub-type was associated with hemorrhagic cystitis. Five previously unrecognized naturally occurring variants of the BKV are described which involve amplifications, deletions, and rearrangements of the archetypal BKV NCCRs in individuals with and without hemorrhagic cystitis. Architectural rearrangements in the NCCRs of BKV did not appear to be a prerequisite for development of hemorrhagic cystitis in hematopoietic stem cell transplant recipients.

Adolescent↗
PubMed2006

Identification of a genomic subgroup of BK polyomavirus spread in European populations.

BK polyomavirus (BKV) is highly prevalent in the human population, infecting children without obvious symptoms and persisting in the kidney in a latent state. In immunosuppressed patients, BKV is reactivated and excreted in urine. BKV isolates worldwide are classified into four serologically distinct subtypes, I-IV, with subtype I being the most frequently detected. Furthermore, subtype I is subdivided into subgroups based on genomic variations. In this study, the distribution patterns of the subtypes and subgroups of BKV were compared among four patient populations with various immunosuppressive states and of various ethnic backgrounds: (A) Finnish renal-transplant recipients; (B) Irish/English haematopoietic stem-cell transplant recipients with and without haemorrhagic cystitis; (C) Japanese renal-transplant recipients; and (D) Japanese bone-marrow transplant recipients. The typing sequences (287 bp) of BKV in population A were determined in this study; those in populations B-D have been reported previously. These sequences were subjected to phylogenetic and single nucleotide polymorphism analyses. Based on the results of these analyses, the BKV isolates in the four patient populations were classified into subtypes and subgroups. The incidence of subtype IV varied significantly among patient populations. Furthermore, the incidence of subgroup Ib-2 within subtype I was high in populations A and B, whereas that of Ic was high in populations C and D (P<0.01). These results suggest that subgroup Ib-2 is widespread among Europeans, whereas Ic is unique to north-east Asians. Furthermore, a phylogenetic analysis based on complete BKV DNA sequences supported the hypothesis that there is geographical separation of European and Asian BKV strains.

Asian People↗
PubMed2006

A consensus on fungal polymerase chain reaction diagnosis?: a United Kingdom-Ireland evaluation of polymerase chain reaction methods for detection of systemic fungal infections.

The limitations of classical diagnostic methods for invasive fungal infections (IFIs) have led to the development of molecular techniques to aid in the detection of IFIs. Despite good published performance, interlaboratory reproduction of these assays is variable, and no consensus has been reached for an optimal method. This publication describes the first multicenter study of polymerase chain reaction methods, for the detection of Aspergillus and Candida species, currently used in the UK and Ireland by distribution and analysis of multiple specimen control panels. All three Candida methods were comparable, achieving a satisfactory level of detection (10 cfu), and the method of preference was dependent on the requirements of the particular laboratory. The results for the five Aspergillus assays were more variable, but two methods (2Asp and 4Asp) were superior (10(1) conidia). Formally, the overall performances of the two Aspergillus assays were comparable (kappa statistic = 0.77). However, on the Roche LightCycler, there was a clear sample-type effect that greatly reduced the detection limit of the 4Asp method when testing whole blood samples. Therefore, the preferred Aspergillus method relied on the amplification platform available to the user. This study represents the initial process to achieve a consensus method for the diagnosis of IFIs.

Aspergillosis↗
PubMed2005

Plasticity of peripheral mechanisms of cough.

The cough reflex pathway is characterized by a remarkable plasticity often resulting in a persistent and uncontrollable urge to cough during airway inflammation. In many instances cough becomes up regulated to the extent that ceases to fulfill its defensive role in protecting the airways. The exact mechanisms underlying this plasticity are unknown and likely involves a variety of factors influencing the function of the peripheral and central nervous system. This review outlines the evidence of increased cough sensitivity during airway disease. This is followed by a discussion of the peripheral mechanisms involved including the potential role of inflammatory mediators, neutrophins and changes in the airway mucosal structure. A greater understanding of the mechanisms leading to enhanced cough should lead to the development of more effective therapeutic strategies.

Animals↗
PubMed2005

Effect of nociceptin in acid-evoked cough and airway sensory nerve activation in guinea pigs.

RATIONALE: Nociceptin/orphanin FQ has been reported to inhibit capsaicin- and mechanically provoked cough in animal models, but the mechanism of this effect has not been elucidated. OBJECTIVES: The objectives of this study were to determine whether nociceptin inhibits acid-evoked cough in conscious animals and to evaluate the mechanism of this effect. METHODS: We tested the effect of nociceptin on acid-induced cough in conscious guinea pigs and acid-induced nerve activation in airway-specific vagal sensory neurons using calcium imaging techniques and the gramicidin-perforated patch clamp technique. MEASUREMENTS AND MAIN RESULTS: Nociceptin (3 mg/kg, intraperitoneal) effectively inhibited acid-evoked cough in guinea pigs by nearly 70%. Acid (pH 5) increased intracellular free calcium in acutely dissociated vagal jugular ganglionic neurons. The acid-induced increase in intracellular calcium was inhibited by a selective transient receptor potential vanilloid-1 antagonist, 5-iodo-resiniferatoxin (1 microM, approximately 80% reduction). The inhibitory effect of 5-iodo-resiniferatoxin on acid-induced increases in calcium was mimicked by nociceptin (0.1 microM). In gramicidin-perforated patch clamp recordings on airway-specific capsaicin-sensitive jugular ganglion neurons, acid (pH 5) induced two distinct inward currents. A transient current was evoked that was inhibited by amiloride and a sustained current was evoked that was inhibited by 5-iodo-resiniferatoxin. Nociceptin selectively inhibited only the sustained component of acid-induced inward current. CONCLUSION: These results indicate that the inhibitory effect of nociceptin on acid-induced cough may result from a direct inhibitory effect on peripheral C-fiber activity caused by the selective inhibition of acid-induced transient receptor potential vanilloid-1 activation.

Animals↗
PubMed2005

Influence of mexiletine on action potential discharge and conduction in nodose Adelta afferent neurons innervating guinea pig isolated trachea.

Local anesthetics are among the most effective peripherally acting antitussives. A complete understanding of their pharmacological properties in airway afferent neurons associated with the cough reflex has been hampered by an incomplete understanding of the contribution of various classes of afferent neuron to cough. The aim of this study was to evaluate the influence of the antitussive local anesthetic mexiletine on nodose ganglion-derived vagal afferent Adelta-fibers innervating guinea pig trachea. This distinct subtype of airway sensory neuron was recently shown to be involved in evoking cough in anaesthetized guinea pigs. The current findings demonstrate that a concentration of mexiletine sufficient to inhibit citric acid- or mechanically-induced action potential initiation at the nerve ending did not block action potential conduction along axons. These findings are indicative of differences in sensitivity to local anesthetics of highly specialized regions of afferent neurons involved in initiation or conduction of impulses.

Action Potentials↗
PubMed2005

Carboranethiol-modified gold surfaces. A study and comparison of modified cluster and flat surfaces.

Four different carboranethiol derivatives were used to modify the surfaces of gold nanoparticles and flat gold films. The novel materials engendered from these modifications are extraordinarily stable species with surfaces that support self-assembled monolayers of 1-(HS)-1,2-C2B10H11, 1,2-(HS)2-1,2-C2B10H10, 1,12-(HS)2-1,12-C2B10H10, and 9,12-(HS)2-1,2-C2B10H10, respectively. Surprisingly, characterization of these materials revealed that a number of molecules of the carboranethiol derivatives are incorporated inside the nanoparticles. This structural feature was studied using a number of techniques, including X-ray photoelectron spectroscopy (XPS), UV-vis, and IR spectroscopies. Thermal desorption experiments show that carborane molecules detach and leave the nanoparticle surface mostly as 1,2-C2B10H10 isotopic clusters, leaving sulfur atoms bound to the gold surface. The surfaces of both the gold nanoparticles and the flat gold films are densely packed with carboranethiolate units. One carborane cluster molecule occupies an area of six to seven surface gold atoms of the nanoparticle and eight surface gold atoms of the flat film. XPS data showed that molecules of 1,12-(HS)2-1,12-C2B10H10 bind to the flat gold surface with only half of the thiol groups due to the steric demands of the icosahedral carborane skeleton. Electrochemical measurements indicate complete coverage of the modified gold surfaces with the carboranethiol molecules.

Boron Compounds↗
PubMed2005

Diphosphacarborane analogues of ferrocene: the synthesis of two isomeric twelve-vertex closo-[(eta5-C5H5)FeP2CB8H9] complexes.

The reaction of the Tl+ salt of the [nido-7,8,9-P2CB8H9]- anion (1-) with [CpFe(CO)2I](Cp =eta(5)-C5H5) in refluxing mesitylene for 12 h gives mixed-sandwich [1-Cp-closo-1,2,3,4-FeP2CB8H9] (2) (yield 63%). Reaction of the PPh4+ salt of the isomeric [nido-7,8,10-P2CB8H9]- anion 3- with [CpFe(CO)2I] in refluxing mesitylene gives [1-Cp-closo-1,2,3,5-FeP2CB8H9]4 (yield 56%), isomeric with 2. Compound 4 also results (yield 92%) from the sublimation of 2 under argon at ca. 350 degrees C. The constitution of all compounds is established by mass spectrometry, IR spectroscopy and multinuclear NMR spectroscopy (1H, 11B, 31P, and 13C; two-dimensional [11B-11B]-COSY, and 1H- 11B(selective)), further confirmed in the case of 4 by a single-crystal X-ray diffraction analysis.

Journal Article↗
PubMed2005

First reported case of endocarditis caused by Candida dubliniensis.

Candida dubliniensis is an uncommon cause of bloodstream infection. We describe the first reported case of endocarditis caused by C. dubliniensis and the use of a rapid and novel real-time PCR assay based on the internal transcribed spacer 2 variable region of the rRNA operon that was used to identify this organism.

Adult↗
PubMed2004

Monocarbaborane anion chemistry. [COOH], [CH2OH] and [CHO] units as functional groups on ten-vertex monocarbaborane anionic compounds.

B(10)H(14) reacts with para-C(6)H(4)(CHO)(COOH) in aqueous KOH solution to give the [nido-6-CB(9)H(11)-6-(C(6)H(4)-para-COOH)](-) anion 1, which undergoes cage closure with iodine in alkaline solution to give the [closo-2-CB(9)H(9)-2-(C(6)H(4)-para-COOH)](-) anion 2. Upon heating, anion 2 rearranges to form the [closo-1-CB(9)H(9)-1-(C(6)H(4)-para-COOH)](-) anion 3. Similarly, B(10)H(14) with glyoxylic acid OHCCOOH in aqueous KOH gives the [arachno-6-CB(9)H(13)-6-(COOH)](-) anion 4, which undergoes cage closure with iodine in alkaline solution to give the [closo-2-CB(9)H(9)-2-(COOH)](-) anion 5. Upon heating, anion 5 rearranges to give the [closo-1-CB(9)H(9)-1-(COOH)](-) anion 6. Reduction of the [COOH] anions 3 and 6 with diisobutylaluminium hydride gives the [CH(2)OH] hydroxy anions [closo-1-CB(9)H(9)-1-(C(6)H(4)-para-CH(2)OH)](-) and [closo-1-CB(9)H(9)-1-(CH(2)OH)](-) 8 respectively. The [closo-1-CB(9)H(9)-1-(C(6)H(4)-para-CH(2)OH)](-) anion 7 can also be made via isomerisation of the [closo-2-CB(9)H(9)-2-(C(6)H(4)-para-CH(2)OH)](-) anion 9, in turn obtained from the [nido-6-CB(9)H(11)-6-(C(6)H(4)-para-CH(2)OH)](-) anion 10, which is obtained from the reaction of B(10)H(14) with terephthaldicarboxaldehyde, C(6)H(4)-para-(CHO)(2), in aqueous KOH solution. Oxidation of the hydroxy anions 7 and 8 with pyridinium dichromate gives the aldehydic [closo-1-CB(9)H(9)-1-(C(6)H(4)-para-CHO)](-) anion 11 and the aldehydic [closo-1-CB(9)H(9)-1-(CHO)](-) anion 12 respectively, characterised as their 2,4-dinitrophenylhydrazone derivatives, the [closo-1-CB(9)H(9)-1-C(6)H(4)-para-CH=N-NHC(6)H(3)(NO(2))(2)](-) anion 13 and the [closo-1-CB(9)H(9)-1-CH=N-NHC(6)H(3)(NO(2))(2)](-) anion respectively.

Journal Article↗
PubMed2004

Genetic variation in clinical varicella-zoster virus isolates collected in Ireland between 2002 and 2003.

Analysis of genetic variation in 16 varicella-zoster virus (VZV) isolates selected at random and circulating in the Irish population between March 2002 and February 2003 was carried out. A 919 bp fragment of the glycoprotein E gene (open reading frame 68) encompassing codon 150, at which a non-synonymous mutation defines the escape mutant VZV-MSP, and including two other epitope regions e1 and c1, was sequenced. No new single nucleotide polymorphisms (SNPs) were detected, indicating stability of these epitopes in clinical isolates of VZV. However, when four informative polymorphic markers consisting of defined regions from genes 1, 21, 50, and 54 were sequenced 14 variable nucleotide positions were identified. Phylogenetic analysis showed the presence of three highly supported clades A, B, and C circulating in the Irish population. Approximately one third (6/16; 37.5%) of the Irish VZV isolates in this study belonged to genotype C, 4/16 (25%) to genotype A, and 4/16 (25%) to genotype B. A smaller number 2/16 (12.5%) belonged to genotype J1. This indicates remarkable heterogeneity in the Irish population given the small sample size. No evidence was found to suggest any of the 16 isolates was a recombinant. These findings have implications for the model of geographic isolation of VZV clades to certain regions as the circulating Irish VZV population appears to comprise approximately equal numbers of each of the main genotypes. This data is inconsistent with a model of strict geographical separation of VZV genotypes and suggests that VZV diversity is more pronounced in certain areas than had been thought previously.

Adult↗