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Biomedical subjects

P S Thomas

Publications and source records attributed to P S Thomas.

At least 19 recordsLinked to original sources
PubMed2006

AMP challenge induces a decrease in FE(NO) in asthmatic subjects modulated by nedocromil.

BACKGROUND: Allergen challenge results in an immediate reduction in exhaled nitric oxide (FE(NO)) followed by a long-term increase. To study mast cell activation in relation to nitric oxide (NO), the study investigated the effect of inhaled adenosine monophosphate (AMP) as a mast cell activator and mast cell stabilizer - nedocromil sodium - on FE(NO). The NO synthase (NOS) iso-enzyme involved was studied by the NOS inhibitor aminoguanidine. MATERIALS AND METHODS: A double-blind, placebo-controlled, cross-over study was performed in two parts. Part I: eight atopic asthmatic subjects inhaled nedocromil or placebo before the AMP challenge. Spirometry and FE(NO) were measured at intervals over a 24-h period. Part II: seven subjects inhaled aminoguanidine before an identical protocol was used, as in Part I. RESULTS: Part I: AMP challenge caused a significant decrease from baseline FE(NO)[placebo, 28.9 (20.3-37.4)%, P < 0.002 and nedocromil, 20.9 (8.2-33.6)%, P < 0.01]. Nedocromil gave partial protection against this decrease in FE(NO). The time-FE(NO) curve (AUC(0-24)) differed significantly between nedocromil and placebo: 2.7% (-3.6 to -9) vs. -6.6% (-12 to -1.3) FE(NO) changes h(-1), P < 0.002, respectively. Nedocromil protected against AMP-induced bronchoconstriction (AMP PC(20)) [nedocromil 182 (72.5-291) mg mL(-1) vs. placebo 21.7 (10.7-33) mg mL(-1), P < 0.002]. Part II: nebulized aminoguanidine resulted in a significant reduction in FE(NO) from baseline and was greater than after AMP alone (P = 0.006). Nedocromil increased AMP PC(20), but no longer protected against the late decrease in FE(NO). CONCLUSIONS: The AMP challenge caused a reduction in FE(NO) as a result of prior treatment with nedocromil. Aminoguanidine abolished the nedocromil-induced protection on the late reduction in FE(NO), but not on AMP PC(20). Inducible NOS was implicated in the late FE(NO) decrease after the AMP challenge.

Adenosine Monophosphate↗
PubMed2005

Exhaled nitric oxide in paediatric asthma.

Assessment of airway function is difficult in young children with asthma, and in addition, only reflects the status of the disease at the time of the measurement. Thus, there is increasing interest in monitoring airway inflammation in asthma, which may provide a longer term assessment of disease activity. Most methods of assessing asthmatic inflammation are invasive, and are not feasible in the paediatric population. This review discusses exhaled nitric oxide as a marker of asthmatic inflammation, and compares it with other recognized markers. Exhaled nitric oxide has the potential to become a noninvasive method of assessing asthma control in the paediatric population.

Asthma↗
PubMed2004

Laughter-associated asthma.

This study was conducted to assess the prevalence of laughter-induced asthma, and to study any associations with asthma-related triggers and measures of disease activity, using a questionnaire-based survey of asthma subjects in both the community and on presentation to hospital. A total of 105 subjects participated, and 44 (41.9%) reported laughter-associated asthma. Exercise and laughter were strongly associated as triggers (p < 0.006), as well as molds and grass pollen (p = 0.03). It seems to be associated with poor asthma control as well, since hospital admissions are also more frequent in this group (p = 0.043). Laughter-induced asthma is strongly associated with exercise as a trigger; the mechanism remains uncertain, but better understanding of this problem may assist in controlling difficult asthma.

Adult↗
PubMed2003

Error reduction: academic detailing as a method to reduce incorrect prescriptions.

OBJECTIVES: Clinical decision making can be influenced by academic detailing, and it was hypothesised that this technique may be used to reduce simple errors when prescribing drugs of addiction. These prescriptions require specific details to be included, otherwise the prescription has to be returned to the prescriber and re-written, wasting the time of the dispenser and prescriber alike. METHODS: The legal requirements for the prescription of addictive drugs were used to define prescription errors. Prescription error rates at six hospitals were assessed, including a control and an intervention hospital where academic detailing was carried out. Prescription error rates were documented before and after an academic detailing visit to junior doctors, including the provision of a bookmark containing the requirements for these drugs. These errors were expressed as a percentage of the total written for a 4-week period. RESULTS: At the intervention hospital, there was a significant decrease in error rate (from 41% to 24%, P<0.0001) with an improvement in all the requirements stated on the bookmark. At this hospital, the confidence of the junior doctors on a self-rating 5-point scale in writing prescriptions for these drugs increased from a mean of 3.25 (95% CI 2.92-3.58) to 4.14 (95%CI 3.90-4.38) after the intervention (P=0.03). The baseline error rates at the other hospitals ranged from 25% to 46%, but the control hospital did not show a significant change in error rate over the same study period ( P=0.66). A post-hoc review suggested that liquid preparations were more difficult to prescribe correctly, which in part accounted for the differences in error rate between hospitals. CONCLUSIONS: Academic detailing appears to be a useful method of reducing erroneous hospital prescriptions; and, to our knowledge, this is a novel finding.

Analgesics, Opioid↗
PubMed2003

Association between dorsolateral prefrontal N-acetyl aspartate and depression in chronic back pain: an in vivo proton magnetic resonance spectroscopy study.

Most studies of pain, including chronic pain, agree that depression and pain are interrelated, although the neurobiology of this relationship remains unknown. Neuroimaging studies suggest a specific role of the prefrontal brain regions in the mechanisms of mood disorders and chronic pain. The present study examines the interrelationships between regional brain N-Acetyl aspartate (NAA) levels (as identified by in vivo proton magnetic resonance spectroscopy in the right and left dorsolateral prefrontal cortex [DLPFC], orbitofrontal cortex, cingulate and thalamus), depression (as measured by the Beck Depression Inventory), and pain (as measured by short form of the McGill Pain Questionnaire) in 10 chronic back pain (CBP) patients with depression, and compared to the relationship between regional brain NAA levels and depression in 10 normal subjects (sex and age-matched). Reduction of NAA levels was demonstrated in the right DLPFC of CBP patients with depression, as compared to the normal controls (p < 0.02, two-tailed t-test). The depression levels in CBP patients were highly correlated with NAA levels in the right DLPFC (r = -0.99, p < 0.0001), and were unrelated to the other studied regional NAA in both groups, including the right DLPFC in normal subjects (p < 10(-6); comparing the difference between r values in the right DLPFC between the two groups). The pain levels in CBP patients were also associated with the right DLPFC (r = -0.62, p < 0.05), although these relationships were much weaker as compared to depression-NAA correlations (p < 0.0001; comparing the difference between r values). The interrelationships between NAA across brain regions were examined using correlation analysis, which detected different connectivity patterns between CBP patients with depression and normal subjects. These findings provide evidence for a stronger association of prefrontal NAA to depression than to pain in CBP, which may reflect the common neurobiological substrate underlying these conditions in CBP patients. Spectroscopic brain mapping of NAA, the marker of neuronal density and function, to the depression and pain measures might be used for segregation of their circuitries in the chronic pain brain.

Adult↗
PubMed2003

Nicorandil inhibits the release of TNFalpha from a lymphocyte cell line and peripheral blood lymphocytes.

Modulation of cytokine release may be of interest in modulating inflammatory diseases. This study determined whether nicorandil, a potassium channel opener, and nitric oxide (NO) donor could inhibit the release of tumour necrosis factor alpha (TNFalpha) from lymphocytes. Nicorandil significantly and dose-dependently inhibited the TNFalpha release from a human Epstein Barr virus-transformed B lymphocyte cell line (EBV-B) and peripheral blood B and T lymphocytes. The inhibition was reversed by the addition of both potassium channel inhibitor glibenclamide and the guanylyl cyclase inhibitor 1H-(1,2,4) oxadiazolo (4,3) quinoxalin-1-one (ODQ). Other potassium channel openers, pinacidil, or the nicorandil analogue SG-209, however, failed to demonstrate inhibition of TNFalpha release. The NO scavenger haemoglobin was unable to reverse the nicorandil-induced TNFalpha inhibition, but in contrast to this, sodium nitroprusside (SNP) partially inhibited the release, which was reversed by haemoglobin. Nicorandil is able to inhibit TNFalpha release from lymphocytes, which requires the dual modes of both potassium channel opening and the nitrate moiety. Moreover, NO donation mechanism appears to be more dominant in the nicorandil inhibitory activity in lymphocytes.The dual mechanism involved in the inhibition of this cytokines may represent a novel therapeutical approach in the modulation of inflammatory disease.

B-Lymphocytes↗
PubMed2003

Health and stress in Australian interns.

Over a 3-year period, interns completed questionnaires on self-reported health and stress during their orientation week at the beginning of the year, during mid year, and at the end of the first year. Interns experienced increased levels of stress and ill health in the middle of the year as compared with the start and end of the year (chi2=11.9, P=0.003 and chi2=20.4, P<0.001, respectively). Despite workplace reform for junior doctors, this study suggests that interns still feel overburdened with work expectations and this is having a negative effect on their health.

Adult↗
PubMed2002

Nicorandil inhibits degranulation and TNF-alpha release from RBL-2H3 cells.

OBJECTIVE: Nicorandil is a potassium channel opener and nitric oxide (NO) donor, and the hypothesis was tested that these modes of action may inhibit cellular degranulation and release of tumour necrosis factor-alpha (TNF-alpha). MATERIALS AND METHODS: TNF-alpha and beta-hexosaminidase secretion were measured from rat basophilic leukemia cells (RBL-2H3) activated via the high affinity IgE receptor with dinitrophenyl-albumin (DNP-A) challenge in the presence of nicorandil. Inhibitors of K+ openers and NO were pre-incubated with the RBL-2H3 cells to determine the principal mode of action. RESULTS: Nicorandil significantly inhibited the release of TNF-alpha in a dose-dependent manner (p < 0.001, ANOVA) reaching a maximum inhibition of DNP-A 74.1% at 10(-3) M, (p < 0.001). Similarly it inhibited beta-hexosaminidase release (p < 0.001, ANOVA) with maximal inhibition at 10(-3) M (p < 0.001). Other K+ openers did not show this effect. Neither the potassium channel blocker glibenclamide nor the guanylyl cyclase inhibitor, ODQ, could reverse this inhibition, but when added in combination reduced the effect by 47%. CONCLUSIONS: Nicorandil is able to inhibit degranulation and TNF-alpha release of RBL cells stimulated through the IgE receptor, and requires both the K+ opening and nitric oxide donor activity, which may represent a novel method for inhibiting cytokine release.

Animals↗
PubMed2002

Caffeine decreases exhaled nitric oxide.

BACKGROUND: Caffeine is known to inhibit phosphodiesterases, to mobilise intracellular calcium, and to act as an antagonist at adenosine receptors, all of which can potentially alter nitric oxide (NO) production. It was therefore hypothesised that caffeine may alter exhaled NO (eNO) levels. METHODS: In a randomised, single blind, crossover manner, 12 normal subjects consumed either (1) coffee and a placebo capsule, (2) decaffeinated coffee and a capsule of 200 mg caffeine, or (3) decaffeinated coffee and a placebo capsule. Serum caffeine levels were measured at baseline and 1 hour later. Exhaled NO levels were also measured at baseline and each hour for 4 hours. RESULTS: A significant percentage fall in mean (SE) eNO from baseline was seen 1 hour after either caffeinated coffee or a caffeine capsule when compared with placebo (13.5 (4.0)%, p=0.009 and 19.0 (3.8)%, p=0.001, respectively). CONCLUSION: Caffeine causes a significant decrease in eNO which will need to be considered when designing trials to measure eNO levels. The mechanism may be via adenosine receptor antagonism or by altering levels of cGMP.

Adult↗
PubMed2002

Effects of inhaled tumour necrosis factor alpha in subjects with mild asthma.

BACKGROUND: Inhaled tumour necrosis factor alpha (TNF alpha) has previously been shown to induce airway neutrophilia and increased airway reactivity in normal subjects. It was hypothesised that a similar challenge would increase airway reactivity in those with mild asthma, but that the inflammatory profile may differ. METHODS: Ten mild asthmatic subjects were recruited on the basis of clinical asthma and either a sensitivity to methacholine within the range defined for asthma or a 20% improvement in forced expiratory volume (FEV(1)) after 200 micro g salbutamol. Subjects inhaled either vehicle control or 60 ng recombinant human (rh)TNF alpha and were studied at baseline, 6, 24, and 48 hours later. Variables included spirometric parameters, methacholine provocative concentration causing a 20% fall in FEV(1) (PC(20)), induced sputum differential cell count, relative sputum level of mRNA of interleukins (IL)-4, IL-5, IL-9, IL-14, IL-15 and TNF alpha, and the exhaled gaseous markers of inflammation, nitric oxide and carbon monoxide. RESULTS: PC(20) showed an increase in sensitivity after TNF alpha compared with control (p<0.01). The mean percentage of neutrophils increased at 24-48 hours (24 hour control: 1.1 (95% CI 0.4 to 2.7) v 9.2 (95% CI 3.5 to 14.9), p<0.05), and there was also a rise in eosinophils (p=0.05). Relative levels of sputum mRNA suggested a rise in expression of TNF alpha, IL-14, and IL-15, but no change in IL-4 and IL-5. Spirometric parameters and exhaled gases showed no significant change. CONCLUSION: The increase in airway responsiveness and sputum inflammatory cell influx in response to rhTNF alpha indicates that TNF alpha may contribute to the airway inflammation that characterises asthma.

Adult↗
PubMed2001

Prefrontal cortical hyperactivity in patients with sympathetically mediated chronic pain.

Chronic pain continues to impose a large burden of suffering, yet its neural correlates remain poorly understood. In sympathetically mediated chronic pain (SMP), peripheral sympathetic blockade temporarily relieves this pain, so that related neural activity can be studied without perturbing sensory inputs. We used functional magnetic resonance imaging and thermal painful stimuli applied to the chronically painful body site, before and after sympathetic blockade, to examine the cortical network of chronic pain. The chronic SMP state was associated with a widely spread prefrontal hyperactivity, increased anterior cingulate activity and decreased activity in the thalamus contralateral to the body side suffering from SMP, but was unrelated to sensorimotor activity. Ineffective sympathetic blocks, i.e. blocks that did not diminish the SMP pain, did not change the cortical responses to the painful thermal stimulus; while effective placebo resulted in similar responses to those of effective blocks. These findings provide evidence for abnormal brain responses to pain in patients with chronic SMP, which engages prefrontal/limbic networks more extensively than in acute pain-states.

Adult↗
PubMed2001

Passive smoke inhalation decreases exhaled nitric oxide in normal subjects.

Environmental tobacco smoke (ETS) exposure is one of the commonest pollutants in modern society. Despite documented clinical adverse effects of ETS on the lungs, objective methods of assessing airway damage have been lacking. Exhaled nitric oxide (eNO) is a rapid, sensitive method of assessing airway inflammation, and could be useful in this regard. Active smoking decreases eNO in normal subjects and eNO levels are low in habitual smokers, but the effect of ETS exposure on eNO has not previously been examined. In a single-blinded, placebo-controlled cross-over study, we examined the effect of ETS, sham and active smoke inhalation on eNO in non-smoking normal volunteers. Subjects were exposed to smoke over a period of 1 hour in a separately ventilated chamber, and eNO was measured at baseline, 15, 30, 45 and 60 minutes. With sham inhalation (n = 15), eNO levels did not change significantly from baseline, although a small decrease occurred. ETS exposure (n = 15) resulted in a rapid fall in eNO from mean (SE) 134 (29) ppb to 102 (22) ppb, or by 23.6% (p < 0.05), and remained low for 60 minutes. With active smoking (n = 7), levels fell acutely from baseline within the same time interval (71 [16] to 49 [11] ppb, or by 30.3%), and remained low. These changes were significant compared with sham exposure for both ETS (p < 0.05) and active smoke inhalation (p <.01). This suggests that eNO can be used for the investigation of the mechanisms of cigarette-induced lung damage in the experimental setting, and may potentially be useful also for environmental assessment of ETS effects.

Adult↗
PubMed2001

Elevated expression of Nkx-2.5 in developing myocardial conduction cells.

A number of different phenotypes emerge from the mesoderm-derived cardiomyogenic cells of the embryonic tubular heart, including those comprising the cardiac conduction system. The transcriptional regulation of this phenotypic divergence within the cardiomyogenic lineage remains poorly characterized. A relationship between expression of the transcription factor Nkx-2.5 and patterning to form cardiogenic mesoderm subsequent to gastrulation is well established. Nkx-2.5 mRNA continues to be expressed in myocardium beyond the looped, tubular heart stage. To investigate the role of Nkx-2.5 in later development, we have determined the expression pattern of Nkx-2.5 mRNA by in situ hybridization in embryonic chick, fetal mouse, and human hearts, and of Nkx-2.5 protein by immunolocalization in the embryonic chick heart. As development progresses, significant nonuniformities emerge in Nkx-2.5 expression levels. Relative to surrounding force-generating ("working") myocardium, elevated Nkx-2.5 mRNA signal becomes apparent in the specialized cells of the conduction system. Similar differences are found in developing chick, human, and mouse fetal hearts, and nuclear-localized Nkx-2.5 protein is prominently expressed in differentiating chick conduction cells relative to adjacent working myocytes. This tissue-restricted expression of Nkx-2.5 is transient and correlates with the timing of spatio-temporal recruitment of cells to the central and the peripheral conduction system. Our data represent the first report of a transcription factor showing a stage-dependent restriction to different parts of the developing conduction system, and suggest some commonality in this development between birds and mammals. This dynamic pattern of expression is consistent with the hypothesis that Nkx-2.5, and its level of expression, have a role in regulation and/or maintenance of specialized fate selection by embryonic myocardial cells.

Animals↗
PubMed2001

Nasal and exhaled nitric oxide in response to occupational latex exposure.

BACKGROUND: Latex sensitivity is an increasing problem among health-care workers. Allergic responses are associated with changes in nitric oxide (NO) generation and the changes secondary to latex have not been described. METHODS: A total of 22 subjects comprising equal numbers of control volunteers and subjects with self-reported latex sensitivity were recruited to undergo latex skin prick testing. Symptom scores, exhaled nitric oxide (eNO), and nasal nitric oxide (nNO) were studied 1) before and after a controlled latex challenge (n=16), and 2) at the beginning and end of the working week, during exposure to latex (n=18). RESULTS: Latex challenge caused a significant fall in nNO levels in latex-sensitive subjects, compared to normal control subjects (P=0.04). eNO levels also decreased in the latex-sensitive subjects after latex challenge, but to a lesser degree. There were no significant differences between the beginning and end of the working week in terms of eNO or nNO in either group, although symptom scores showed a nonsignificant increase in latex-sensitive subjects. CONCLUSION: Fall in nasal NO after latex challenge is associated with reported symptomatic latex sensitivity, and this corresponds to latex skin prick test positivity. Neither nNO nor eNO showed a clear relationship to routine workplace exposure.

Adult↗
PubMed2001

Tumour necrosis factor-alpha: the role of this multifunctional cytokine in asthma.

Tumour necrosis factor-alpha (TNF-alpha) is recognized as an important mediator in many cytokine- dependent inflammatory events. It is known that TNF-alpha is released in allergic responses from both mast cells and macrophages via IgE-dependent mechanisms, and elevated levels have been demonstrated in the bronchoalveolar fluid (BALF) of asthmatic subjects undergoing allergen challenge. Inhaled TNF-alpha increases airway responsiveness to methacholine in normal and asthmatic subjects associated with a sputum neutrophilia. Additional data indicate that TNF-alpha can upregulate adhesion molecules, facilitate the immigration of inflammatory cells into the airway wall and activate pro-fibrotic mechanisms in the subepithelium. These data suggest that TNF-alpha plays a role in the initiation of allergic asthmatic airway inflammation and the generation of airway hyper-reactivity. In addition, polymorphisms of the TNF-alpha gene 5' untranslated region, particularly at -308 bp, have been described as being associated with asthma. This polymorphism is associated with increased levels of TNF-alpha, but as yet, no asthma studies have demonstrated a phenotypic difference between those individuals with the polymorphism and those with the wild type gene. The TNF receptors (TNF-R p55 and p75), also known as CD120a and b, have also been shown to be present in the lung, but their functional importance is only just emerging. In asthma, TNF may function as a pro-inflammatory cytokine that causes the recruitment of neutrophils and eosinophils. Treatment directed specifically at a reduction in TNF-alpha activity may conceivably be useful as a glucocorticosteroid-sparing asthma therapy.

Animals↗
PubMed2001

Subcutaneous emphysema associated with chest tube drainage.

BACKGROUND: Subcutaneous emphysema may complicate a pneumothorax, but may also occur as a consequence of its treatment by chest tube drainage. The aim of this study was to evaluate the factors involved in the association between subcutaneous emphysema and chest tube drainage, and the clinical outcomes in these cases. METHODOLOGY: One hundred and sixty-seven patients undergoing chest tube drainage within a 12-month period were evaluated retrospectively. There were 30 reported cases of subcutaneous emphysema (SE). Comparisons were made between those with subcutaneous emphysema and those who did not develop this complication. RESULTS: A total of 134 patient notes were evaluated (25 SE and 109 non-SE). Subcutaneous emphysema was more commonly associated with trauma, bronchopleural fistulae, large and bilateral pneumothoraces, and mechanical ventilation. Subcutaneous emphysema was also associated with prolonged drainage, poor tube placement, tube blockage, side-port migration, and a greater number of chest tubes. Importantly, those with SE had a longer length of stay and increased mortality. CONCLUSION: Subcutaneous emphysema can be spontaneous or traumatic, but is associated with avoidable causes such as inadequate chest tube drainage, particularly due to poor tube placement, anchorage and blockage, and also with side-port migration into the subcutaneous tissue. It is associated with an increased morbidity and mortality, and may indicate the need for urgent chest tube replacement.

Adolescent↗