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Biomedical subjects

S J Wilson

Publications and source records attributed to S J Wilson.

At least 19 recordsLinked to original sources

Quantification of the timing of continuous modulated muscle activity in a repetitive-movement task.

The timing of muscle activity is commonly measured in studies of motor control. In repetitive-movement tasks, muscle activity may be continuous, and no defined onset or offset of activity may be measured. This does not imply that no timing of muscle activity occurs. Where activity is continuous, this timing will typically be exhibited by modulation of the amplitude of the signal in specific movement phases. The existence of this electromyographic (EMG) timing is dependent upon the existence of EMG amplitude modulation. This paper investigates this relationship in developing a quantification algorithm of EMG timing in a repetitive-movement task. A frequency domain quantification algorithm involving EMG linear-envelope generation is used. An EMG simulation algorithm is used to test this algorithm and determine the minimal amplitude-modulation threshold for timing detection. At five repetitive-movement speeds (25, 50, 75, 100 and 125 cycles of movement per minute), thresholds between 1.558 and 2.326 times maximal to minimal linear-envelope amplitude are required for reliability of timing detection. Analysis of variance indicates that the robustness of the quantification algorithm was not significantly affected by burst width (F = 3.69, p = 0.055) or the underling input timing parameter (F = 0.52, p = 0.992). The phase-lead/lag quantification algorithm represents a useful tool for the analysis motor control via EMG during repetitive-movement tasks.

Algorithms↗

Expression of 5-lipoxygenase and cyclooxygenase pathway enzymes in nasal polyps of patients with aspirin-intolerant asthma.

In aspirin-intolerant subjects, adverse bronchial and nasal reactions to cyclooxygenase (COX) inhibitors are associated with over-production of cysteinyl-leukotrienes (cys-LTs) generated by the 5-lipoxygenase (5-LO) pathway. In the bronchi of patients with aspirin-intolerant asthma, we previously linked cys-LT over-production and aspirin hyper-reactivity with elevated immunoexpression in eosinophils of the terminal enzyme for cys-LT production, LTC4 synthase. We investigated whether this anomaly also occurs in the nasal airways of these patients. Immunohistochemical expression of 5-LO and COX pathway proteins was quantified in nasal polyps from 12 patients with aspirin-intolerant asthma and 13 with aspirin-tolerant asthma. In the mucosa of polyps from aspirin-intolerant asthmatic patients, cells immunopositive for LTC4 synthase were four-fold more numerous than in aspirin-tolerant asthmatic patients (p=0.04). There were also three-fold more cells expressing 5-LO (p=0.037), with no differences in 5-LO activating protein (FLAP), COX-1 or COX-2. LTC4 synthase-positive cell counts correlated exclusively with mucosal eosinophils (r=0.94, p<0.001, n=25). Co-localisation confirmed that five-fold higher eosinophil counts (p=0.007) accounted for the increased LTC4 synthase expression in polyps from aspirin-intolerant asthmatic patients, with no alterations in mast cells or macrophages. Within the epithelium, increased counts of eosinophils (p=0.006), macrophages (p=0.097), and mast cells (p=0.034) in aspirin-intolerant asthmatic polyps were associated only with 2.5-fold increased 5-LO-positive cells (p<0.05), while the other enzymes were not different. Our results indicate that a marked over-representation of LTC4 synthase in mucosal eosinophils is closely linked to aspirin intolerance in the nasal airway, as in the bronchial airways.

Adolescent↗

Reduced structural proteins in the conjunctival epithelium in allergic eye disease.

AIMS: Allergic eye disease affects up to 20% of the population with varying severity. The conjunctival epithelium plays a key role in allergic eye disease. The purpose of this study was to determine whether the conjunctival epithelium is abnormal in allergic eye disease. METHODS: Conjunctival biopsy samples were taken from patients with seasonal allergic conjunctivitis (SAC) 'in' and 'out of season' and nonatopic control subjects. Specimens were fixed in glycol methacrylate, 2 microm serial sections cut and Image-J used to assess the sites and areas of immuno-staining. RESULTS: E-cadherin, CD44, keratins K5/6, K8, K13, K14, K18 and pan-keratin immuno-staining were all significantly lower in patients 'out of season' compared with normal controls. No structural differences in the epithelium were observed between the two groups. The epithelium of patients 'in season' was thicker and immuno-staining of the above markers similar to controls. CONCLUSIONS: The expression of a wide spectrum of epithelial cell adhesion proteins and cytoskeletal elements is downregulated in the conjunctiva of SAC patients 'out of season' compared with normal controls. We suggest that this could have an important impact on the ability of the epithelium to protect itself against allergen penetration, potentially influencing the development and course of allergic eye disease and offering a novel area for therapeutic control.

Adult↗

Airway antioxidant and inflammatory responses to diesel exhaust exposure in healthy humans.

Pulmonary cells exposed to diesel exhaust (DE) particles in vitro respond in a hierarchical fashion with protective antioxidant responses predominating at low doses and inflammation and injury only occurring at higher concentrations. In the present study, the authors examined whether similar responses occurred in vivo, specifically whether antioxidants were upregulated following a low-dose DE challenge and investigated how these responses related to the development of airway inflammation at different levels of the respiratory tract where particle dose varies markedly. A total of 15 volunteers were exposed to DE (100 microg x m(-3) airborne particulate matter with a diameter of <10 microm for 2 h) and air in a double-blinded, randomised fashion. At 18 h post-exposure, bronchoscopy was performed with lavage and mucosal biopsies taken to assess airway redox and inflammatory status. Following DE exposure, the current authors observed an increase in bronchial mucosa neutrophil and mast cell numbers, as well as increased neutrophil numbers, interleukin-8 and myeloperoxidase concentrations in bronchial lavage. No inflammatory responses were seen in the alveolar compartment, but both reduced glutathione and urate concentrations were increased following diesel exposure. In conclusion, the lung inflammatory response to diesel exhaust is compartmentalised, related to differing antioxidant responses in the conducting airway and alveolar regions.

Adult↗

Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma.

BACKGROUND: Tumour necrosis factor alpha (TNFalpha) is a major therapeutic target in a range of chronic inflammatory disorders characterised by a Th1 type immune response in which TNFalpha is generated in excess. By contrast, asthma is regarded as a Th2 type disorder, especially when associated with atopy. However, as asthma becomes more severe and chronic, it adopts additional characteristics including corticosteroid refractoriness and involvement of neutrophils suggestive of an altered inflammatory profile towards a Th1 type response, incriminating cytokines such as TNFalpha. METHODS: TNFalpha levels in bronchoalveolar lavage (BAL) fluid of 26 healthy controls, 42 subjects with mild asthma and 20 with severe asthma were measured by immunoassay, and TNFalpha gene expression was determined in endobronchial biopsy specimens from 14 patients with mild asthma and 14 with severe asthma. The cellular localisation of TNFalpha was assessed by immunohistochemistry. An open label uncontrolled clinical study was then undertaken in 17 subjects with severe asthma to evaluate the effect of 12 weeks of treatment with the soluble TNFalpha receptor-IgG1Fc fusion protein, etanercept. RESULTS: TNFalpha levels in BAL fluid, TNFalpha gene expression and TNFalpha immunoreative cells were increased in subjects with severe corticosteroid dependent asthma. Etanercept treatment was associated with improvement in asthma symptoms, lung function, and bronchial hyperresponsiveness. CONCLUSIONS: These findings may be of clinical significance in identifying TNFalpha as a new therapeutic target in subjects with severe asthma. The effects of anti-TNF treatment now require confirmation in placebo controlled studies.

Adult↗

GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic study.

RATIONALE: Gamma-aminobutyric acid (GABA)-benzodiazepine receptor function is hypothesised to be reduced in alcohol dependence. OBJECTIVES: We used positron emission tomography (PET) with [11C]flumazenil, a non-selective tracer for brain GABA-benzodiazepine (GABA-BDZ) receptor binding, to determine in vivo the relationship between BDZ receptor occupancy by an agonist, midazolam, and its functional effects. METHODS: Abstinent male alcohol dependent subjects underwent [11C]flumazenil PET to measure occupancy of BDZ receptors by midazolam whilst recording its pharmacodynamic effects on behavioural and physiological measures. Rate constants describing the exchange of [11C]flumazenil between the plasma and brain compartments were derived from time activity curves. RESULTS: A 50% reduction in electroencephalography (EEG)-measured sleep time was seen in the alcohol dependent group despite the same degree of occupancy by midazolam as seen in the control group. The effects of midazolam on other measures of benzodiazepine receptor function, increasing EEG beta1 power and slowing of saccadic eye movements, were similar in the two groups. No differences in midazolam or flumazenil metabolism were found between the groups. CONCLUSIONS: In summary, our study suggests that alcohol dependence in man is associated with a reduced EEG sleep response to the benzodiazepine agonist, midazolam, which is not explained by reduced BDZ receptor occupancy, and is consistent with reduced sensitivity in this measure of GABA-BDZ receptor function in alcohol dependence. The lack of change in other functional measures may reflect a differential involvement of particular subtypes of the GABA-BDZ receptor.

Adult↗

Age-related factors that confound peripheral pulse timing characteristics in Caucasian children.

Characteristics obtained from peripheral pulses can be used to assess the status of cardiovascular system of subjects. However, nonintrusive techniques are preferred when prolonged monitoring is required for their comfort. Pulse transit time (PTT) measurement has showed its potentials to monitor timing changes in peripheral pulse in cardiovascular and respiratory studies. In children, the common peripheries used for these studies are fingers or toes. Presently, there is no known study conducted on children to investigate the possible physiologic parameters that can confound PTT measure at these sites. In this study, PTT values from both peripheral sites were recorded from 55 healthy Caucasian children (39 male) with mean age of 8.4+/-2.3 years (range 5-12 years). Peripheries' path length, heart rate, systolic blood pressure, diastolic blood pressure (DBP) and mean arterial pressure (MAP) were measured to investigate their contributions to PTT measurement. The results reveal that PTT is significantly related to all parameters (P<0.05), except for DBP and MAP. Age is observed to be the dominant factor that affects PTT at both peripheries in a child. Regression equations for PTT were derived for measuring from a finger and toe, (6.09 age+189.2) ms and (6.70 age+243.0) ms, respectively.

Aging↗

Pulse transit time as a derived noninvasive mean to monitor arterial distensibility changes in children.

Changes in arterial distensibility have been widely used to identify the presence of cardiovascular abnormalities like hypertension. Pulse wave velocity (PWV) has shown to be related to arterial distensibility. However, the lack of suitable techniques to measure PWV nonintrusively has impeded its clinical usefulness. Pulse transit time (PTT) is a noninvasive technique derived from the principle of PWV. PTT has shown its capabilities in cardiovascular and cardiorespiratory studies in adults. However, no known study has been conducted to understand the suitability and utility of PTT to estimate PWV in children. Two computational methods to derive PWV from PTT values obtained from 23 normotensive Caucasian children (19 males, aged 5-12 years old) from their finger and toe were conducted. Furthermore, the effects of adopting different postures on the PWV derivations were investigated. Statistical analyses were performed in comparison with two previous PWV studies conducted on children. Results revealed that PWV derived from the upper limb correlated significantly (P<0.05) regardless of computing methods or postures adopted. The findings here suggest that PTT measurement can be used as a convenient and noninvasive surrogate measure of derived PWV in prolonged clinical studies, especially on younger or less cooperative children. Furthermore, the simple set-up and noninvasive nature of PTT can promote its usefulness in ambulatory monitoring.

Arteries↗

Epithelial stress and structural remodelling in childhood asthma.

BACKGROUND: In adult asthma the bronchial epithelium shows high expression of the epidermal growth factor receptor (EGFR) and the cyclin dependent kinase inhibitor, p21waf, linked to ongoing stress and injury. METHODS: To determine if these are early markers of disease, sections of bronchial specimens obtained post mortem or by bronchoscopy from non-asthmatic (n = 7), moderate (n = 7), or severe (n = 9) asthmatic children aged 5-15 years were examined immunohistochemically. All severe and one moderately asthmatic children were receiving inhaled corticosteroids. RESULTS: The lamina reticularis of the asthmatic biopsy sections was found to be thicker (p = 0.01) than normal with increased deposition of collagen III (p = 0.007); submucosal eosinophil numbers did not differ between groups. As in adults, there was an asthma-related increase in epithelial EGFR (p<0.002) but there was no evidence of proliferation, with Ki67 being reduced (p = 0.001) and p21waf increased (p<0.004). The thickness of the lamina reticularis was significantly correlated with epithelial EGFR (rho = 0.77, p<0.001). CONCLUSIONS: These data provide evidence that, in asthmatic children, the epithelium is stressed or injured without significant eosinophilic inflammation. This change in the epithelial phenotype is associated with collagen deposition in the lamina reticularis, suggesting that the epithelial mesenchymal trophic unit is active early in, and may contribute to, the pathogenesis of asthma.

Adolescent↗

A long-term study of the effects of diazinon on sleep, the electrocorticogram and cognitive behaviour in common marmosets.

The long-term sequelae of exposure to low doses of organophosphate compounds are ill defined, with effects variously reported on a range of indices of central nervous system functions such as sleep, cognitive performance and electroencephalogram (EEG). These indices were examined in common marmosets exposed to a range of doses of the organophosphorous sheep dip, diazinon. Cognitive performance was assessed by means of elements from the Cambridge Neuropsychological Test Automated Battery (CANTAB), and radiotelemetry techniques were employed to monitor the electrocorticogram and sleep patterns. Data were collected for 12 months following intramuscular administration of a single dose of diazinon (10, 90 or 130 mg.kg (-1)) or vehicle. Although high levels of erythrocyte acetylcholinesterase (AChE) inhibition (up to 82%) and short-term changes in sleep patterns were seen, there was no evidence of biologically significant long-term changes in any measures. The effects of multiple exposures, impurities or mixtures of OP compounds remain to be investigated.

Acetylcholinesterase↗

Altered protein tyrosine phosphorylation in asthmatic bronchial epithelium.

A disease-related, corticosteroid-insensitive increase in the expression of epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase in asthmatic bronchial epithelium has been shown previously by the current authors. To determine whether this is associated with enhanced intracellular signalling, the aim of this study was to evaluate epithelial tyrosine phosphorylation. Bronchial biopsies were analysed for the presence of phosphotyrosine by immunohistochemistry. Bronchial epithelial cells were exposed to EGF, hydrogen peroxide or tumour necrosis factor-alpha in vitro for measurement of tyrosine phosphorylated signalling intermediates and interleukin (IL)-8 release. Phosphotyrosine was increased significantly in the epithelium of severe asthmatics when compared with controls or mild asthmatics; however, in mild asthma, phosphotyrosine levels were significantly decreased when compared with controls. There was no significant difference between phosphotyrosine levels before or after 8 weeks of treatment with budesonide. Stimulation of bronchial epithelial cells resulted in tyrosine phosphorylation of several proteins, including EGFR, Shc and p42/p44 mitogen-activated protein kinase. In the presence of salbutamol, a transient partial suppression of EGFR phosphorylation occurred, whereas dexamethasone was without effect. Neither salbutamol nor dexamethasone inhibited EGF-stimulated IL-8 release. These data indicate that regulation of protein tyrosine kinase activity is abnormal in severe asthma. The epidermal growth factor receptor and/or other tyrosine kinase pathways may contribute to persistent, corticosteroid-unresponsive inflammation in severe asthma.

Administration, Inhalation↗

Acute wake-promoting actions of JNJ-5207852, a novel, diamine-based H3 antagonist.

1 1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidine (JNJ-5207852) is a novel, non-imidazole histamine H3 receptor antagonist, with high affinity at the rat (pKi=8.9) and human (pKi=9.24) H3 receptor. JNJ-5207852 is selective for the H3 receptor, with negligible binding to other receptors, transporters and ion channels at 1 microm. 2 JNJ-5207852 readily penetrates the brain tissue after subcutaneous (s.c.) administration, as determined by ex vivo autoradiography (ED50 of 0.13 mg kg(-1) in mice). In vitro autoradiography with 3H-JNJ-5207852 in mouse brain slices shows a binding pattern identical to that of 3H-R-alpha-methylhistamine, with high specific binding in the cortex, striatum and hypothalamus. No specific binding of 3H-JNJ-5207852 was observed in brains of H3 receptor knockout mice. 3 In mice and rats, JNJ-5207852 (1-10 mg kg(-1) s.c.) increases time spent awake and decreases REM sleep and slow-wave sleep, but fails to have an effect on wakefulness or sleep in H3 receptor knockout mice. No rebound hypersomnolence, as measured by slow-wave delta power, is observed. The wake-promoting effects of this H3 receptor antagonist are not associated with hypermotility. 4 A 4-week daily treatment of mice with JNJ-5207852 (10 mg kg(-1) i.p.) did not lead to a change in body weight, possibly due to the compound being a neutral antagonist at the H3 receptor. 5 JNJ-5207852 is extensively absorbed after oral administration and reaches high brain levels. 6 The data indicate that JNJ-5207852 is a novel, potent and selective H3 antagonist with good in vitro and in vivo efficacy, and confirm the wake-promoting effects of H3 receptor antagonists.

Administration, Oral↗

Motion artefact reduction of the photoplethysmographic signal in pulse transit time measurement.

Motion artefact is a common occurrence that contaminates photoplethysmographic (PPG) measurements. To extract timing information from signals during artefact is challenging. PPG signal is very sensitive to artefacts and can be used in applications like, pulse transit time (PTT) as part of the polysomnographic studies. A correlation cancellation or signal processing approach is implemented with the adaptive cancelling filter concept and a triaxial accelerometry. PPG signals obtained from a Masimo (Reference) pulse oximeter is used as reference to compare with the reconstructed PPG signals. Different hands are used for each PPG source, one stationary while the other involves typical movements during sleep. A second Masimo pulse oximeter is used to register intensity of timing errors on commercial PPG signals. 108 PTT measurements are recorded in three different movements with PTT estimates from unprocessed PPG signals showing 35.51+/-27.42%, Masimo 50.02+/-29.40% and reconstructed 4.32+/-3.59% difference against those from the Reference PPG. The triaxial accelerometry can be used to detect the presence of artefact on PPG signals. This is useful in PTT measurements when signal contaminated with artefacts are required for further analysis, especially after and during arousals in sleep. The suggested filtering model can then reconstruct these corrupted PPG signals.

Acceleration↗

Using sleep to evaluate comparative serotonergic effects of paroxetine and citalopram.

BACKGROUND: SSRIs suppress rapid eye movement (REM) sleep, probably by increasing serotonin in the brainstem, and also increase sleep fragmentation. Although in the UK, paroxetine (PAR) and citalopram (CIT) have recommended doses of 20 mg/day for the treatment of depression, the recommended dose of CIT in USA is higher (40 mg). If similar doses of PAR and CIT have similar effects on central serotonin then they should have similar effects on sleep measures in volunteers. METHOD: This was a randomised, double blind placebo controlled crossover study in 12 healthy volunteers. Subjects took PAR 20 mg mane, CIT 20 mg mane or placebo mane for 3 days and sleep was recorded overnight at home on the third night. Standard measures of sleep were derived. RESULTS: REM sleep was significantly suppressed and sleep fragmentation increased by both drugs. Measures of REM sleep and sleep continuity previously found to be altered by SSRIs were considered together and compared with placebo as a 'serotonin response'; this was significantly greater in the PAR group. CONCLUSIONS: Sleep effects typical of SSRIs were greater with PAR 20 mg/day than CIT 20 mg/day, suggesting greater effects on 5HT uptake blockade.

Adult↗

Evaluation of actigraphy and automated telephoned questionnaires to assess hypnotic effects in insomnia.

This study aimed to explore new methodologies in insomnia research, namely whether actigraphy was suitable to show hypnotic effects over weeks in insomnia, and to compare an automated method of questionnaire data collection with traditional methods. Thirty-eight insomniacs took part in a 5-week, double-blind, placebo-controlled study of the effects of 2 weeks of administration of temazepam 20 mg on sleep. Outcome measures were actigraphy and daily St Mary's Hospital Sleep Questionnaires (SMHSQ). Actigraphy was performed using Actiwatch (CNT) and analysed using both the automated Actiwatch sleep analysis software and non-parametric analysis of rest-activity rhythms. The questionnaires were administered as straightforward pencil-and-paper for half of the time and an automated telephoned system for the other half. The experimental paradigm allowed within-subject comparison of traditional and automated data collection, both on and off drug. Actigraphy showed a high degree of inter-subject variability but, nevertheless, some sleep variables (Fragmentation Index, Actual Sleep Time %) showed significant improvement during drug treatment, and Sleep Efficiency and Actual Sleep Time were significantly worsened during the first post-drug week. Nonparametric circadian rhythm analysis showed no significant effect. Subjective data from the SMHSQ showed significant drug effects and there was no significant difference in scores between the automated and pencil-and-paper methods; automated data collection was slightly more acceptable to patients and minimized data entry and management. Effect sizes using within-subject and between-subject comparisons were calculated for the subjective and objective measures to inform future studies

Adolescent↗