PubMed Health⌕ Search

Biomedical subjects

M E Parsons

Publications and source records attributed to M E Parsons.

At least 19 recordsLinked to original sources

Neural correlates of lexical access during visual word recognition.

People can discriminate real words from nonwords even when the latter are orthographically and phonologically word-like, presumably because words activate specific lexical and/or semantic information. We investigated the neural correlates of this identification process using event-related functional magnetic resonance imaging (fMRI). Participants performed a visual lexical decision task under conditions that encouraged specific word identification: Nonwords were matched to words on orthographic and phonologic characteristics, and accuracy was emphasized over speed. To identify neural responses associated with activation of nonsemantic lexical information, processing of words and nonwords with many lexical neighbors was contrasted with processing of items with no neighbors. The fMRI data showed robust differences in activation by words and word-like nonwords, with stronger word activation occurring in a distributed, left hemisphere network previously associated with semantic processing, and stronger nonword activation occurring in a posterior inferior frontal area previously associated with grapheme-to-phoneme mapping. Contrary to lexicon-based models of word recognition, there were no brain areas in which activation increased with neighborhood size. For words, activation in the left prefrontal, angular gyrus, and ventrolateral temporal areas was stronger for items without neighbors, probably because accurate responses to these items were more dependent on activation of semantic information. The results show neural correlates of access to specific word information. The absence of facilitatory lexical neighborhood effects on activation in these brain regions argues for an interpretation in terms of semantic access. Because subjects performed the same task throughout, the results are unlikely to be due to task-specific attentional, strategic, or expectancy effects.

Adult↗

Modulation of the release of endogenous adenosine by cannabinoids in the myenteric plexus-longitudinal muscle preparation of the guinea-pig ileum.

1. Interactions between the cannabinoid system and the adenosine system were investigated in the myenteric plexus-longitudinal muscle (MPLM) of the guinea-pig ileum. 2. Electrically-evoked contractions of the MPLM were inhibited in a concentration dependent manner by exogenous adenosine and the adenosine receptor agonist 2-chloroadenosine. These inhibitory effects were reversed by the selective A(1) receptor antagonist DPCPX (20 nM). 3. Preincubation of the MPLM with the cannabinoid receptor agonist CP55,940 (1 nM) or the endogenous cannabinoid ligand anandamide caused a significant leftward shift in the concentration-effect curves to adenosine and 2-chloroadenosine. 4. Electrically-evoked contractions of the MPLM were inhibited in a concentration dependent manner by the adenosine uptake inhibitor dipyridamole. This inhibition was reversed by DPCPX (20 nM). 5. Pretreatment with CP55,940 (1 nM) or anandamide (10 microM) significantly reduced the inhibition produced by dipyridamole, an effect which was completely reversed by the selective CB(1) receptor ligand SR141716 (100 nM). 6. Electrically evoked adenosine release, measured in real time by means of adenosine-specific biosensors, was inhibited by CP55,940 (10 nM). This inhibition was blocked when CP55,940 was applied in the presence of SR141716 (100 nM). 7. These results confirm the presence of presynaptic CB(1) and A(1) receptors in the guinea-pig MPLM, and suggest that CB(1) receptor stimulation reduces electrically-evoked adenosine release. Overall the data raise the possibility that the cannabinoid system plays a role in the modulation of adenosine transmission in the MPLM.

Adenosine↗

GABA(B) receptor function in the ileum and urinary bladder of wildtype and GABA(B1) subunit null mice.

1. GABA(B1) receptor subunit knockout mice were generated and the effects of the GABA(B) receptor agonist, baclofen, were evaluated within the peripheral nervous system (PNS) of wildtype (+/+), heterozygote (+/-) and knockout (-/-) animals. For this purpose, neuronally-mediated responses were evoked in both the isolated ileum and urinary bladder, using selective electrical field stimulation (EFS). 2. In ileum resected from 4-8-week-old-mice, low frequencies of EFS (0.5 Hz) evoked irregular muscle contractions which were prevented by atropine 1 microM and reduced by baclofen (33.4 +/- 5.6%, 100 microm). The latter effect was antagonized by the GABA(B) receptor antagonist CGP54626 0.2 microm. Baclofen 100 microm did not affect contractions of similar amplitude induced by carbachol, indicating that the ability of baclofen to inhibit cholinergic function in mouse ileum may be due to an action at prejunctional GABA(B) receptors. 3. To avoid the development of grand mal seizure by GABA(B1) (-/-) mice, a behaviour observed when the mice were greater than 3 weeks old, it was necessary to study the effects of this knockout in 1-3-week-old-animals. However, at this age, EFS at 0.5 Hz did not evoke robust muscle contractions. Consequently we used EFS at 5 Hz, which did evoke cholinergically mediated contractions, found to be of similar amplitude in (+/+) and (+/-) mice, of both 1-3 weeks and 4-8 weeks of age. At this frequency of EFS, baclofen reduced the amplitude of the evoked contractions [n = 6 (+/+) and n = 5 (+/-), IC50 19.2 +/- 4.8 microm) and this effect was greatly reduced in the presence of CGP54626 0.2 microm. 4. In urinary bladder from 1-3-week-old-mice, using higher frequencies of EFS to evoke clear, nerve-mediated contractions (10 Hz), baclofen 10-300 microm concentration-dependently inhibited contractions in (+/+) mice (IC50 9.6 +/- 3.8 microm). This effect was inhibited by CGP54626 (0.2 microm, 46.2 +/- 13.6% inhibition, 300 microm baclofen n = 7) a concentration which, by itself, had no effect on the EFS-evoked contractions. 5. The effects of baclofen in both ileum and urinary bladder were absent in the GABA(B1) receptor subunit (-/-) mice; however, responses to EFS were unaffected in (-/-) when compared to the (+/+) mice. 6. Our data suggest that, as in the central nervous system (CNS), the GABA(B1) receptor subunit is an essential requirement for GABA(B) receptor function in the enteric and PNS. As such, these data do not provide a structural explanation for the existence of putative subtypes of GABA(B) receptor, suggested by studies such as those in which different rank-orders of GABA(B) agonist affinity have been reported in different tissues.

Animals↗

Investigation of nicotine binding to THP-1 cells: evidence for a non-cholinergic binding site.

Nicotine is known to modulate immune function, but reports have produced conflicting evidence as to whether nicotinic acetylcholine (nACh) receptors are responsible for these effects. This study was designed to examine the identity of nicotine-binding sites on immune cells using a human leukaemic monocytic cell line, THP-1, that is known to have functions that are modulated by nicotine. Binding studies were performed on THP-1 whole cells using [3H]nicotine as a probe to analyse any possible nicotine-binding sites on these cells. Saturation analysis of THP-1 cells revealed the presence of 2 distinct binding sites; one with a K(d1) of 3.5 +/- 2.1 x 10(-9) M and a B(max1) of 4100 +/- 560 sites/cell (designated the high-affinity site) and the other with a K(d2) of 27 +/- 9.2 x 10(-9) M and a B(max2) of 11,600 +/- 630 sites/cell (low-affinity site). Competition analysis revealed that one site had an affinity to a range of cholinergic ligands including epibatidine and cytisine. When saturation analysis of [3H](-)-nicotine to THP-1 cells was performed in the presence of 1 x 10(-6) M epibatidine, only one binding site was detected. Comparisons of K(d) and B(max) values showed that the high-affinity site was not occluded by epibatidine. No drugs tested displayed any affinity for the high-affinity site except the two enantiomers of nicotine. The high-affinity site was shown to be stereoselective for the (+)-enantiomer of nicotine as shown by K(i) values produced by competition analysis in the presence of 1 x 10(-6) M epibatidine. These values were 5.7 +/- 0.32 x 10(-11) M and 1.9 +/- 4.9 x 10(-9) M for (+)-nicotine and (-)-nicotine, respectively. This study presents evidence for a possible non-cholinergic binding site that may play a role in the mechanism of immunomodulation by nicotine.

Binding, Competitive↗

Signal transduction of cannabinoid CB1 receptors in a smooth muscle cell line.

1. The effects of cannabinoid (CB) receptor stimulation on membrane currents in single cells from the Syrian hamster vas deferens cell line DDT1MF-2 were investigated using the whole cell patch clamp technique. 2. The CB receptor agonist CP55,940 evoked a concentration-dependent transient outward current. The selective CB1 receptor ligand SR141716 (1 microM), but not the selective CB2 receptor ligand SR144528 (1 microM), inhibited the outward current. Pertussis toxin (100 ng ml-1 for 20 h) completely abolished the outward current. 3. Western blotting with an antibody against the rat (r)CB1 receptor showed a band characteristic for the CB1 receptor around 63 kDa in DDT1MF-2 cells. 4. The reversal potential for the outward current measured using a voltage ramp protocol was -84 +/- 5 mV. The current was inhibited by the Ca2+-dependent K+ channel blockers iberiotoxin (10 nM) and charybdotoxin (10 nM). 5. Removal of Ca2+ from the bathing solution, or the addition of 0.1 mM Cd2+ completely abolished the outward current evoked by 10 microM CP55,940. 6. The sarcoplasmic Ca2+ pump inhibitor thapsigargin reduced the outward current evoked by 10 microM CP55,940 in a concentration-dependent manner. 7. The mitogen-activating protein kinase (MAP kinase) inhibitor PD98059, but not the phospholipase C inhibitor U73122, inhibited the outward current evoked by 10 microM CP55,940. 8. The adenylyl cyclase inhibitor SQ22,536 (100 microM) and 8-Br-cyclic AMP (10 microM) significantly reduced the outward current evoked by 10 microM CP55,940. 9. Our data suggest that CB1 receptor stimulation in DDT1MF-2 cells leads to activation of a large conductance Ca2+-dependent K+ channel through a Gi/Go protein-mediated rise in [Ca2+]i, for which both inhibition of adenylyl cyclase and activation of MAP kinase are required. In addition, the cannabinoid-induced increase in [Ca2+]i is likely to arise from capacitive Ca2+ entry.

8-Bromo Cyclic Adenosine Monophosphate↗

Activation of presynaptic A1-receptors by endogenous adenosine inhibits acetylcholine release in the guinea-pig ileum.

1. It is well established that presynaptic adenosine A1-receptor activation inhibits acetylcholine (ACh) release in the guinea-pig ileum. The present study extends this observation and examines a possible role for endogenous adenosine in modulating cholinergic nerve function. 2. The actions of the adenosine uptake blocker, dipyridamole, the adenosine deaminase inhibitor, erythro-9(2-hydroxy-3-nonyl)adenine (EHNA) and the A1-receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) were examined on electrically evoked neurogenic, cholinergic twitch contractions of the guinea-pig ileum. Some additional studies measuring [3H]-ACh release were also performed. 3. Adenosine and the selective A1-receptor agonist, 2-chloroadenosine (2-CA), inhibited electrically evoked contractions and, in the case of 2-CA, [3H]-ACh release. The actions were antagonized by DPCPX. At low concentrations, dipyridamole and EHNA enhanced the effect of adenosine causing a leftward shift of the concentration-response curve. In contrast, inhibition induced by 2-CA was unaffected by either dipyridamole or EHNA. 4. When applied alone at higher concentrations, EHNA and dipyridamole produced a concentration-dependent suppression of cholinergic neurotransmission. In both cases, the effect could be reversed by DPCPX. At the same concentration, DPCPX alone produced a small but consistent increase in twitch height and [3H]-ACh release. 5. The data confirm the existence of inhibitory presynaptic adenosine A1-receptors modulating cholinergic nerve function in the guinea-pig ileum and suggests that these receptors can be activated by endogenous adenosine released either as adenosine itself or as an ATP metabolite.

Acetylcholine↗

An investigation into the effect and mechanisms of action of nicotine in inflammatory bowel disease.

OBJECTIVE AND DESIGN: To determine the effect of nicotine on colonic inflammation in the trinitrobenzenesulphonic acid (TNBS) model of inflammatory bowel disease in comparison with sulphasalazine. MATERIALS: Male Wistar rats were used for the in-vivo and ex-vivo studies. In-vitro studies were performed using human leukemia peripheral blood monocyte cells (THP-1 cells) grown in continuous culture. TREATMENT: Rats were given access to either nicotine (5 or 100 microg/mL) or sulphasalazine (375 microg/mL) in their drinking water for 10 or 2 days respectively before and 3 days after TNBS administration. THP-1 cells were treated with nicotine (10(-14) to 10(-11) M) for 2 h before and after stimulation with 3 microg/mL lipopolysaccharide (LPS). METHODS: Inflammation in the TNBS model was assessed by measuring the tissue myeloperoxidase activity, leukotriene B4 concentration, inducible nitric oxide protein expression, the ex-vivo production of tumour necrosis factor alpha (TNFalpha), macroscopic damage score, plasma corticosterone levels and by a qualitative histological evolution. The effect of nicotine on TNFalpha production in LPS stimulated THP-1 monocyte cells in-vitro was also determined. Statistical comparisons were made using the Mann-Whitney U-test for the macroscopic damage score and an ANOVA for all other parameters. RESULTS: TNBS treated rats given access to 100 microg/mL nicotine in their drinking water had a marked reduction in several of the markers of inflammation compared to control TNBS treated rats, but a greater reduction was found at 5 microg/mL nicotine or 375 microg/mL sulphasalazine, the latter producing comparable reductions in inflammation to the low dose nicotine. Nicotine also caused a significant reduction in TNFalpha release from THP-1 cells. CONCLUSIONS: Nicotine reduced inflammation in the TNBS model of colonic damage confirming the use of nicotine in IBD although the choice of dose requires further investigation. The mechanism of action of nicotine does not involve increased corticosterone levels, but may be a consequence of a reduction in TNFalpha or leukotriene B4 production.

Animals↗

Topical and intravenous administration of trefoil factors protect the gastric mucosa from ethanol-induced injury in the rat.

BACKGROUND: hTFF2 and pTFF2 (formerly PSP and hSP, respectively) are members of the trefoil factor family (TFF) and are distributed throughout the gastrointestinal tract in both normal and diseased tissue. Trefoil factors have been shown to exert a mucosal protectant and/or healing role in a number of animal models but controversy exists surrounding this property in relation to their dose and route of administration. AIM: To investigate the effects of topically applied and intravenously infused trefoil factors (hTFF2 and pTFF2) and prostaglandin E2 on ethanol-induced gastric mucosal damage in rats. METHOD: A gastric chamber preparation in the anaesthetized rat was used. Injury was caused by exposing the gastric mucosa to absolute ethanol for 1 min. Trefoil factors or prostaglandin E2 were administered either intravenously or topically before and after the introduction of absolute ethanol onto the gastric mucosa. Damage was assessed by measurement of gastric mucosal Na+ leakage and area of macroscopic injury. RESULTS: Like prostaglandin E2, intravenous administration of hTFF2 and pTFF2 reduced both the gastric mucosal Na+ leakage and the mean area of damage caused by ethanol. Similarly, treatment of the gastric mucosa with topical application of hTFF2 at doses of 120 microg/kg and above reduced the Na+ leakage and the area of damage. pTFF2 at 120 microg/kg and 1.2 mg/kg applied topically produced a marked reduction in total area of damage. CONCLUSION: Intravenously infused hTFF2 and pTFF2 protect the gastric mucosa from ethanol-induced damage in the anaesthetized rat. In addition, topical application of trefoil factors also was effective at protecting the gastric mucosa from injury at doses lower than previously reported.

Administration, Topical↗

Signaling mechanisms coupled to presynaptic A(1)- and H(3)-receptors in the inhibition of cholinergic contractile responses of the guinea pig ileum.

The mechanisms coupled to adenosine A(1)- and histamine H(3)-receptors have been examined in the presynaptic inhibition of acetylcholine (ACh) release from the guinea pig ileum. Electrically evoked twitch contractions were used as a measure of neuronal ACh release. A(1)- and H(3)-receptors were activated by adenosine and R-(alpha)-methylhistamine (RAMH), respectively. The neuroinhibitory effect of adenosine and RAMH was augmented in the presence of the N-type Ca(2+) channel blocker, omega-conotoxin GVIA but unaffected by the L-type Ca(2+) channel blocker, nifedipine. The irreversible adenylyl cyclase inhibitor, MDL-12330A, potentiated the action of both adenosine and RAMH. Conversely, neither agonist was affected by the cAMP phosphodiesterase III and IV inhibitors, SKF-95654 and Ro-20-1724, respectively, or the cAMP antagonist, (R(p))-adenosine 3',5'-cyclic monophosphorothioate triethylamine. The neuromodulatory effect of adenosine, only, was potentiated by the cGMP phosphodiesterase V inhibitors, SKF-96231 and 1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)- pyrazolo[3, 4-d]pyrimidin-4-(5H)-one but was unmodified by the cGMP analog, 8-bromo-cGMP or the guanylyl cyclase inhibitors, N-methylhydroxylamine and 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxaline-1-one (ODQ). N-Methylhydroxylamine reduced, and ODQ potentiated, the inhibitory action of H(3)-receptor activation, but 8-bromo-cGMP was without effect. The study suggests that presynaptic A(1)- and H(3)-receptors inhibit cholinergic neurotransmission in the guinea pig ileum by limiting the availability of intraneuronal Ca(2+) via inhibition of N-type Ca(2+) channels. The balance of evidence does not support the involvement of the adenylyl cyclase/cAMP or guanylyl cyclase/cGMP systems.

Acetylcholine↗

The effect of an inhibitor of matrix metalloproteinases on colonic inflammation in a trinitrobenzenesulphonic acid rat model of inflammatory bowel disease.

BACKGROUND: Recent publications have reported that matrix metalloproteinases (MMPs) are expressed in colonic tissue taken from ulcerative colitis and Crohn's disease patients. AIM: To evaluate the effects of a matrix metalloproteinase inhibitor, marimastat, on colonic inflammation in experimental colitis induced by trinitrobenzenesulphonic acid (TNBS)-ethanol in the rat. METHODS: Rats were dosed (by mouth) for 7 days (b.d.) with either sulphasalazine (50 mg/kg), marimastat (40 mg/kg) or vehicle. TNBS-ethanol was administered rectally on the 4th day of dosing. On the last day of dosing, colons were removed and assessed for inflammation using myeloperoxidase activity, production of soluble TNFalpha (tumour necrosis factor alpha), clinical score and histological assessment. In addition, the bioavailability and effect of marimastat on a range of MMPs were assessed in-vitro. RESULTS: In this study we have confirmed that marimastat is a broad spectrum MMPI with a bioavailability of 5%. TNBS rats dosed with sulphasalazine had a significantly lower (P < 0.05) myeloperoxidase activity, TNFalpha production and a markedly lower clinical score. Similarly, rats dosed with marimastat had a significantly lower (P < 0.05) myeloperoxidase activity and clinical score, but the TNFalpha production was not significantly reduced. CONCLUSIONS: Dosing rats with TNBS-induced colitis using sulphasalazine or marimastat produced a significant reduction in tissue injury and inflammation.

Animals↗

Evidence for a role for nitric oxide in relation of the frog oesophageal body to electrical field stimulation.

1. Electrical field stimulation (EFS) (1-10 Hz, 30 V, 2 ms) of frog oesophageal body strips resulted in frequency-dependent non-adrenergic, non-cholinergic (NANC) relaxations. 2. Tetrodotoxin (TTX) (10(-6)-10(-5) M) had no effect on EFS evoked relaxations with a 2 ms pulse width. At a pulse width of 0.5 ms only the responses to the highest frequency (10 Hz) were significantly inhibited by TTX at 10(-5) M. Relaxation at 2 ms pulse width were unaffected by omega-conotoxin (10(-6) M), nifedipine (10(-6) M) or cobalt (5 x 10(-4) M). 3. NG-nitro-L-arginine (L-NOARG) (10(-6)-10(-4) M), a nitric oxide synthase (NOS) inhibitor, caused a concentration-dependent inhibition of the EFS-induced NANC relaxant responses. The inhibitory effect of L-NOARG was both prevented and reversed by L-arginine but not D-arginine (5 x 10(-3) M). 4. The phosphodiester type V inhibitor (PDE V), SK&F 96231 (10(-7)-10(-4) M), caused a concentration-dependent potentiation of both the percentage relaxation and the duration of the relaxant responses to EFS. 5. ODQ (10(-7)-10(-5) M), a guanylate cyclase inhibitor, produced a concentration-dependent inhibition of EFS-evoked NANC relaxations. 6. Oxyhaemoglobin (10(-6) M), which binds nitric oxide (NO), inhibited NANC relaxations to EFS. 7. The NO donor sodium nitroprusside (SNP) (10(-8)-10(-4) M) produced a concentration-dependent inhibition of evoked tone. L-NOARG (10(-4) M) had no effect on the SNP evoked relaxations. Preincubation with oxyhaemoglobin (10(-6) M) caused a reduction in the SNP (10(-6)-10(-5) M) induced relaxations. 8. These results suggest NO is the relaxant transmitter of the frog oesophageal body and the source of NO may be non-neuronal.

Adrenergic Agents↗

Pancreatic spasmolytic polypeptide protects the gastric mucosa but does not inhibit acid secretion or motility.

The objectives of these studies were to examine whether the trefoil peptide porcine pancreatic spasmolytic polypeptide (PSP) had gastric mucosal protectant properties similar to its human equivalent human spasmolytic polypeptide (hSP) and to confirm the antisecretory and antimotility action of the peptide. PSP and recombinant hSP reduced gastric mucosal damage caused by a combination of subcutaneous indomethacin and restraint stress in the conscious rat. At a dose of 500 micrograms/kg bolus plus 500 micrograms.kg-1.h-1 sc, PSP significantly reduced the total area of damage by 58%. PSP at a dose of 150 micrograms/kg iv had no inhibitory effect on pentagastrin-stimulated gastric acid secretion in the perfused stomachs of anesthetized rats. This lack of antisecretory activity was confirmed in vitro using an isolated stomach preparation from the immature rat. PSP and hSP at concentrations up to 800 nM did not inhibit electrically or chemically evoked contractions of the guinea pig ileum and duodenum in vitro. Thus antisecretory and antimotility actions do not underlie the mucosal protectant properties of PSP. PSP did, however, stimulate cell migration, and this may, at least in part, account for its protectant properties.

Animals↗

Moral orientation of elderly persons: considering ethical dilemmas in health care.

Knowledge about moral development and elderly persons is very limited. A hermeneutical interpretative study was conducted with healthy elderly persons (n = 20) in order to explore and describe their moral orientation based on the paradigms of justice (Kohlberg) and care (Gilligan). The types of moral reasoning, dominance, alignment and orientation were determined. All but one participant included both types of reasoning when discussing an ethical conflict. None of the men's moral reasoning was dominated by caring, but justice dominated the reasoning of four women. The implications for ethical decision-making and future research are discussed.

Aged↗