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Biomedical subjects

M H Roberts

Publications and source records attributed to M H Roberts.

At least 19 recordsLinked to original sources
PubMed2006

Upregulating promoter polymorphisms of RANTES relate to atopic dermatitis.

It has been reported that a functional polymorphism in the promoter of the RANTES gene (-403G/A) is associated with atopic dermatitis in a German population. Although there are several reports on the association of RANTES promoter polymorphisms (-403G/A and -28C/G) with asthma, the association of these polymorphisms with atopic dermatitis has not yet been confirmed in other populations. We therefore aimed to test whether the RANTES promoter polymorphisms relate to atopic dermatitis in a well-defined Japanese population. We conducted an association study of upregulating promoter polymorphisms of RANTES (-403G/A and -28C/G) in 389 patients with atopic dermatitis and 177 healthy control subjects. There was a significant association between the upregulating variant of RANTES -28G and atopic dermatitis, while -403A variant showed a significant association with atopic dermatitis with high IgE productivity. These results support a role for RANTES promoter polymorphisms in susceptibility to atopic dermatitis.

Adolescent↗
PubMed2001

CB1 receptor mediated analgesia from the Nucleus Reticularis Gigantocellularis pars alpha is activated in an animal model of neuropathic pain.

Cannabinoids are known to suppress responses to noxious stimulation in animals and man. Recent research has suggested a role for endogenous cannabinoids in the descending inhibition of dorsal horn cells via a supraspinal site of action. We have recently demonstrated [J. Physiol. 506(2) (1998) 459] that the nucleus reticularis gigantocellularis pars alpha (GiA) is a major source of such descending modulation, and importantly, that this system is activated in response to noxious stimulation. We have therefore investigated the role of CB1 receptor activation in mediating the antinociceptive effects of activation of GiA in models of acute and chronic pain. Microinjections (0.5 microl 60% DMSO) of either WIN 55,212-2 (5 microg, selective CB1 agonist), SR141716A (50 microg, competitive CB1 antagonist), both compounds together, or vehicle alone into GiA were performed prior to these tests in a randomised, blind manner. In control animals, WIN 55,212-2 markedly increased withdrawal latencies in the tail flick test and reduced responses to subcutaneous formalin. These effects were blocked by co-administration of SR141716A. These data suggest that activation of cannabinoid CB1 receptor subtypes in GiA leads to behavioural analgesia. In animals with partial sciatic nerve ligation, microinjection of drugs and injection of formalin were performed contralaterally to the site of ligation. Partial sciatic nerve ligation significantly reduced behavioural responses to contralaterally applied formalin. Microinjection of SR141716A to GiA reversed this inhibition of responses to formalin in animals with partial sciatic nerve ligation. These data provide evidence that endogenous CB1 receptor ligands are involved in GiA mediated antinociception, and that this system is important for the modulation of nociceptive transmission in an animal model of chronic neuropathic pain.

Analgesia↗
PubMed2001

Periaqueductal grey mediated inhibition of responses to noxious stimulation is dynamically activated in a rat model of neuropathic pain.

The periaqueductal grey (PAG) has been shown to be a major source of descending inhibition of dorsal horn cells (Textbook of Pain (1999) 309). However, few studies have demonstrated alterations in behavioural responses to noxious stimulation following inactivation of this nucleus. Many behavioural studies have looked for effects on nociceptive withdrawal thresholds in acute nociceptive tests. These tests would not reveal the presence of inhibition which is activated in response to noxious input. We have therefore investigated this possibility by studying behavioural responses to subcutaneous formalin injection in control animals, and in animals following partial sciatic nerve ligation (an animal model of neuropathic pain (Pain 43(2) (1990) 205). In control animals, microinjection of gamma-aminobutyric acid (GABA) to PAG did not significantly alter behavioural responses to formalin, while microinjection of D,L-homocysteic acid (DLH) reduced these responses. Responses to contralaterally applied formalin were significantly reduced in animals with partial sciatic ligation. Microinjection of GABA to PAG significantly increased these behavioural responses to formalin. We conclude that a component of PAG mediated inhibition of nociception is inactive under normal conditions. This inhibition may be activated by persistent nociceptive input, and possibly reflects long term changes in nociceptive circuitry which occur in neuropathic pain states.

Animals↗
PubMed2001

The behavioural importance of dynamically activated descending inhibition from the nucleus reticularis gigantocellularis pars alpha.

We have recently demonstrated (J Physiol 506 (1998) 459) that the dynamic activation of descending inhibition of the nociceptive response of spinal multireceptive cells occurs in the nucleus reticularis gigantocellularis pars alpha (GiA). In the same paper we have shown that Lamina I dorsal horn cells are responsible for activating this inhibition via a pathway which runs in the contralateral dorsolateral funiculus. The effects of dynamically activating this system by noxious stimulation on behavioural responses to noxious stimuli have not been established. Here we demonstrate the effects of GiA on the behavioural response during application of standardized noxious stimuli. As this system is activated in response to noxious stimulation (J Physiol 506 (1998) 459), it is possible that chronic pain states may also activate GiA. We have therefore investigated this possibility in animals following partial sciatic nerve ligation (an animal model of chronic pain; Pain 43 (1990) 205). Male Wistar rats (280-310 g) were anaesthetized with halothane (0.5-2% in O(2)). Guide cannulae for microinjections were stereotaxically placed above GiA. In one group of animals the sciatic nerve was partially ligated. Animals were allowed to recover for 4-6 days. The responses of each animal during the formalin test (Pain 4 (1977) 161) and the tail flick test (Pain 12 (1982) 229) were recorded on different days. Microinjections (0.5 microl) of either gamma-aminobutyric acid (GABA, 200 mM), D-L homocysteic acid (DLH, 25 mM) or 0.9% saline (as control) into GiA were performed during these tests in a randomized, blind manner. In animals without sciatic nerve ligation, microinjection of GABA to GiA did not significantly affect the animal's response during the tail flick test. However microinjection of DLH significantly increased the latency of tail flick from 6.2 +/- 0.8 to 8.4 +/- 0.5 s for up to 15 min (n = 7, P < 0.01, Mann-Whitney U-test). Microinjection of GABA to GiA increased the behavioural response to formalin between 10 and 20 min post-injection, while microinjection of DLH reduced this response at all time points except 10 min post-injection (n = 8, P < 0.05, Mann-Whitney U-test). In animals with sciatic nerve ligation, microinjections (0.5 microl) of either GABA (200 mM), or saline (as control) into GiA contralateral to the partial sciatic ligation were performed during these tests in a randomized, blind manner. Partial sciatic ligation significantly reduced the behavioural response to contralaterally applied formalin from 15 min post-injection onwards, compared to controls without sciatic nerve ligation. Microinjection of GABA to GiA significantly increased the behavioural response to formalin from 20 to 50 min post-injection. The inactivation of GiA only causes behavioural effects in nociceptive tests of a long enough duration to activate the system (i.e. the formalin test but not the tail flick test). Chemical activation of the system affects both tests. These data strongly support the concept of an important analgesic system which is activated in response to noxious stimulation, and subsequently acts to reduce behavioural responses to noxious stimuli.

Animals↗
PubMed2001

Genetic polymorphisms of CC chemokine receptor 3 in Japanese and British asthmatics.

Whole genome scan analyses have revealed that chromosomal region 3p21-24, which contains a gene cluster of CC chemokine receptors such as CCR3, is possibly linked to asthma. Because CCR3 ligands play a pivotal role in the selective recruitment and activation of inflammatory cells in the asthmatic airway, the authors examined whether there is any association between asthma and the CCR3 gene polymorphisms. Three polymorphisms were identified using the single stranded conformational polymorphism method in Japanese (Asian) and British (Caucasian) subjects; one silent mutation T51C and two missense mutations G824A and T971C. These polymorphisms were examined in 391 Japanese subjects (210 asthmatics and 181 nonasthmatic controls) and 234 British subjects (142 asthmatics and 92 nonasthmatic controls). Asthma diagnosis was based on episodic symptoms, documented wheeze, and the presence of reversible airflow limitation. CCR3 T51C demonstrated a significant association with the diagnosis of asthma in the British population (odds ratio 2.35, p<0.01), but not in the Japanese population. Multiple logistic regression analysis also showed that CCR3 T51C was associated with asthma (odds ratio 2.83, p < 0.02), independent of atopic phenotypes such as high levels of total or house dust mite-specific immunoglobulin-E in serum. In conclusion, a significant association between asthma and CCR3 T51C polymorphism localized on chromosome 3p21 was found.

Alleles↗
PubMed2000

The Ile198Thr and Ala379Val variants of plasmatic PAF-acetylhydrolase impair catalytical activities and are associated with atopy and asthma.

The platelet-activating factor (PAF) represents a phospholipid with complex biological functions, including involvement in inflammatory processes. The degrading enzyme PAF acetylhydrolase (PAFAH) represents a candidate for asthma and other atopic diseases. Two loss-of-function mutations of PAFAH are associated with severe asthma in Japanese individuals. Our aim was to look for further PAFAH variants in white populations, their possible association with atopic and asthmatic phenotypes, and their functional importance. We picked up three common variants in the PAFAH gene: Arg92His (exon 4), Ile198Thr (exon 7), and Ala379Val (exon 11). The known loss-of-function mutations were not seen. The variant allele Thr198 was found to be highly associated with total IgE concentrations in an atopic population (P=.009) and with "atopic asthma" in an asthmatic population (P=.008). The variant allele Val379 was found to be highly associated with "specific sensitization" in the atopic population (P=.002) and with "asthma" in the asthmatic population (P=.003). By use of recombinant PAFAH enzymes, the variant Val379 showed increased (14 microM) and Thr198 markedly increased (42 microM) KM values compared to the wild type (7 microM); furthermore, Vmax of Val379 was highly increased (132%). Thr198 and Val379 influence plasmatic PAFAH toward lower substrate affinities and therefore are very likely to prolong the activities of PAF. At the same time, they are associated with an increased risk to develop asthma and atopy. Thus, two PAFAH variants seem to play a key role in atopic and asthmatic processes in Caucasian populations.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2000

Genetic variants of IL-13 signalling and human asthma and atopy.

Asthma and atopy show epidemiological association and are biologically linked by T-helper type 2 (T(h)2) cytokine-driven inflammatory mechanisms. IL-4 operates through the IL-4 receptor (IL-4R, a heterodimer of IL-4Ralpha and either gammac or IL-13Ralpha1) and IL-13 operates through IL-13R (a heterodimer of IL-4Ralpha and IL-13Ralpha1) to promote IgE synthesis and IgE-based mucosal inflammation which typify atopy. Recent animal model data suggest that IL-13 is a central cytokine in promoting asthma, through the stimulation of bronchial epithelial mucus secretion and smooth muscle hyper-reactivity. We investigated the role of common genetic variants of IL-13 and IL-13Ralpha1 in human asthma, considering IgE levels. A novel variant of human IL-13, Gln110Arg, on chromosome 5q31, associated with asthma rather than IgE levels in case-control populations from Britain and Japan [peak odds ratio (OR) = 2.31, 95% CI 1.33-4.00]; the variant also predicted asthma and higher serum IL-13 levels in a general, Japanese paediatric population. Immunohistochemistry demonstrated that both subunits of IL-13R are prominently expressed in bronchial epithelium and smooth muscle from asthmatic subjects. Detailed molecular modelling analyses indicate that residue 110 of IL-13, the site of the charge-modifying variants Arg and Gln, is important in the internal constitution of the ligand and crucial in ligand-receptor interaction. A non-coding variant of IL-13Ralpha1, A1398G, on chromosome Xq13, associated primarily with high IgE levels (OR = 3. 38 in males, 1.10 in females) rather than asthma. Thus, certain variants of IL-13 signalling are likely to be important promoters of human asthma; detailed functional analysis of their actions is needed.

Adult↗
PubMed2000

Variants of NOS1, NOS2, and NOS3 genes in asthmatics.

Nitric oxide (NO) gas concentrations are higher in expired air in asthmatics. NO is synthesized by three isoforms of NO synthase (NOS) encoded by three distinct genes, NOS1, NOS2, and NOS3. Genome-wide searches have identified linkages to asthma on chromosomes 7, 12, and 17 where these three genes are localized. No association study, however, has been reported to date. To test whether variants of NOS1, NOS2, and NOS3 relate to asthma, a genetic association study was conducted in a British population (n = 300). Intragenic microsatellite variants of NOS1 were significantly associated with asthma [odds ratio (OR) = 2.08, 95% CI: 1.20-3.57 (95% CI), P = 0.008 (Pc = 0.048)], but not with IgE levels. Neither NOS2 nor NOS3 variants showed any association with asthma nor IgE levels. These findings suggest that NOS1 variants may be a significant contributor to asthma in a British population.

Alleles↗
PubMed1999

Nonpathogenic common variants of IFNGR1 and IFNGR2 in association with total serum IgE levels.

Atopy is an immune disorder in which a Th2 dominant mechanism leads to high IgE levels and the clinical disorder asthma. It has been postulated that the Th1 cytokine IFNgamma, acting through its heterodimeric receptors, IFNgammaR1 and IFNgammaR2, in the induction/proliferation of Th1 cells, might suppress the Th2 responses that may underlie atopic asthma. However, neither murine nor human variants of IFNgamma associate with atopy. Several dysfunctional mutations have been identified in IFNgamma receptor genes (IFNGR1 and IFNGR2) in relation to severe and selective infections with poorly pathogenic organisms. However, little is known about common polymorphisms and their functional role in atopy. To test whether such variants of IFNGR1 and IFNGR2 relate to atopic asthma, we conducted a genetic association study in both British (n = 300) and Japanese (n = 200) populations. An intronic variant of IFNGR1 showed marginal association with total serum IgE levels in the British population compared with those with total IgE levels <30 IU/ml and those with >120-500 IU/ml [odds ratio = 2.00 (95% CI 1. 00-4.07), P = 0.048]. A coding variant, Gln64Arg of the IFNGR2, also associated with total serum IgE levels in the British population [chi(2) = 5.08, P = 0.024]. Further genetic and functional analyses are needed to clarify the role of variants of IFNgamma receptor genes in atopic immune disorder among different ethnic groups.

Asthma↗
PubMed1999

Variants of endothelin-1 and its receptors in atopic asthma.

Endothelin-1 (ET-1) is a 21 amino acid peptide released from several types of bronchial cells. It operates through two types of receptors, type A(ET-RA) and type B(ET-RB) and has various activities in the pathophysiology of atopic asthma. These genes are localised on different chromosomes where genome-wide searches have identified linkage for atopic asthma, thus supporting the candidacy of ET-1 and its receptors for atopic asthma. A genetic association study was performed with variants of these three genes in both British (n = 300) and Japanese populations (n = 200). No significant association was found between variants of EDN1 and EDNRB genes, and atopic asthma in either population. However, variants of EDNRA gene showed a marginal association with atopy [odds = 0.39(95% CI: 0.17-0.89), p = 0.022, Pc = 0.066], especially with antigen specific IgE levels [odds = 0.31 (95% CI: 0.20-0.77), p = 0.006, Pc = 0.018] in the British population. These findings suggest that EDNRA is a major candidate locus for atopy on chromosome 4.

Antibody Specificity↗
PubMed1999

Toxicity of creosote water-soluble fractions generated from contaminated sediments to the bay mysid.

Creosote, a globally used wood preservative, is a complex mixture consisting primarily of aromatic organic compounds (ACs). Creosote-derived ACs can persist for decades in aquatic sediments. Natural and anthropogenic activities may result in dissolution and resuspension of sediment-associated ACs. These processes were mimicked by generating a water-soluble fraction (WSF) from creosote-contaminated sediment (ERS) collected from a polluted site. The epibenthic mysid Mysidopsis bahia was exposed to five sublethal concentrations of WSF for 7 days. The WSF significantly decreased dry weight gain and proportion of gravid females (EC50=15 microgram/liter total identified ACs). Chemical analysis indicated that high-molecular-weight ACs (more than three aromatic rings) dominated the ERS, but were undetected in the WSF. Low-molecular-weight ACs (fewer than three aromatic rings) dominated the WSF. Compositional differences can thus result from fractionation processes and affect environmental fate and toxicity of the mixture.

Animals↗
PubMed1998

Supraspinal inhibition of nociceptive dorsal horn neurones in the anaesthetized rat: tonic or dynamic?

1. Tonic inhibition of sensory spinal neurones is well known to descend from the rostroventral medulla. It is not clear if this inhibition is dynamically activated by peripheral noxious stimuli. 2. Transection of the ipsilateral dorsolateral funiculus (DLF) removed a descending inhibition of multireceptive spinal neurones and disproportionally prolonged the after-discharge component of their response to a noxious cutaneous stimulus. 3. Microinjection of GABA or tetracaine into the medullary nucleus gigantocellularis pars alpha (GiA) similarly prolonged the after-discharge in response to noxious stimuli. 4. Recordings of GiA cells, initially using minimal surgery, revealed that many had low levels of spontaneous activity and responded vigorously to noxious stimuli applied to any part of the body surface. One hour after the surgery necessary to expose the spinal cord, GiA cells had a high firing rate but responded weakly to noxious stimuli. 5. The response of GiA cells to noxious stimuli was abolished by transection of only the DLF contralateral to the stimulus. 6. It is concluded that the inhibition of multireceptive dorsal horn neurones from GiA is dynamically activated by noxious cutaneous stimuli via a projection in the contralateral DLF. Surgical exposure of the spinal cord tonically activates this inhibition and masks the dynamic component.

Anesthesia↗
PubMed1997

The cyclin-dependent kinase (cdk) inhibitors, olomoucine and roscovitine, alter the expression of a molluscan circadian pacemaker.

1. In this study, we determined the effects of the cyclin-dependent kinase (cdk) inhibitors, olomoucine and roscovitine, on the circadian rhythm of optic nerve impulse activity recorded from the eye of the marine snail Bulla gouldiana. 2. We found that olomoucine lengthened period and altered circadian phase in a dose-dependent manner without appreciably affecting gene transcription or translation. We also found that the more specific cdk inhibitor, roscovitine, was approximately 10-fold more effective in lengthening circadian period, while the inactive analogue, iso-olomoucine, was ineffective. 3. The current results, along with previous results from our laboratory, are consistent with the hypothesis that the biochemical mechanism responsible for generating the ocular circadian rhythm in B. gouldiana is related to the biochemical mechanism that regulates the eukaryotic cell division cycle, i.e., by modulation of the activity of protein kinases belonging to the cdk family.

Animals↗
PubMed1995

Efferent connections from the anterior pretectal nucleus to the diencephalon and mesencephalon in the rat.

The anterior pretectal nucleus has been described as part of the visual pretectal complex. However, several electrophysiological and behavioural studies showed that this area is involved in somatosensory modulation, more specifically, antinociception. The efferents of the anterior pretectal nucleus have not been identified taking into account the different function of this nucleus in relation to the rest of the pretectal complex. In the study herein described, a sensitive anterograde tracer Phaseolus vulgaris leucoagglutinin was used to trace the mesencephalic and diencephalic efferents of the anterior pretectal nucleus in the rat. The majority of the connections were ipsilateral. Fibres with varicosities were observed in discrete areas of the thalamus (central lateral, posterior complex), hypothalamus (lateral, posterior and ventromedial), zona incerta, parvocellular red nucleus, intermediate and deep layers of the superior colliculus, central grey, deep mesencephalon, pontine parabrachial region, and pontine nuclei. Fibres en passant were detected in the medial lemniscus, from the level of the injection site to rostral medullary levels. Some labelled axons were seen coursing to the contralateral side through the posterior commissure and the decussation of the superior cerebellar peduncle. These results show that the anterior pretectal nucleus projects principally to areas involved in somatosensory and motor control in a manner that permits sensory modulation at higher and lower levels of the brain. These connections may explain the antinociceptive and antiaversive effects of stimulating the anterior pretectal nucleus in freely moving animals.

Animals↗
PubMed1995

Anterior pretectal nucleus facilitation of superficial dorsal horn neurones and modulation of deafferentation pain in the rat.

1. Functional relationships between the anterior pretectal nucleus (APTN) and nociceptive dorsal horn neurones were investigated electrophysiologically in the anaesthetized rat. The effects of APTN lesions were assessed behaviourally in a model of deafferentation pain. 2. Cells in the dorsal and rostral parts of the APTN were excited orthodromically by electrical stimulation of the ipsilateral dorsolateral funiculus or the contralateral dorsal columns, and by noxious and innocuous cutaneous stimuli. 3. Electrical stimulation of the APTN excited nociceptive lamina I spinal neurones. These cells all projected rostrally in the contralateral dorsolateral funiculus. Identical APTN stimulation also inhibited multireceptive spinal neurones which lay deep in the dorsal horn. These particular cells were shown to project to the brain in the ventrolateral funiculus. 4. It is proposed that noxious stimuli excite spinal lamina I projection neurones which send excitatory axons to the brain, including the APTN. The APTN inhibits deep multireceptive neurones, to reduce the perception of noxious stimuli. The discharge of spinal lamina I neurones, however, will be sustained by the noxious stimulus and by facilitation from the APTN. A sustained descending inhibition of this nature would reduce responses to prolonged injury. 5. The involvement of the APTN in responses to a chronic pain state was examined by comparing the behaviour of animals with bilateral lesions of the APTN with normal controls. Lesions of the APTN strongly enhanced the autotomy behaviour triggered by sectioning of the dorsal roots. 6. These observations support the suggestion that the APTN reduces the debilitating effects of prolonged injury.

Afferent Pathways↗