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Biomedical subjects

P M Smith

Publications and source records attributed to P M Smith.

At least 19 recordsLinked to original sources
PubMed2007

Cardiovascular actions of orexin-A in the rat subfornical organ.

Orexin-A is a neuropeptide, primarily produced in the lateral hypothalamic/perifornical hypothalamus. Orexin receptors and immunoreactive neuronal fibres are widely distributed throughout the brain, suggesting integrative neurotransmitter roles in a variety of physiological systems. Intracerebroventricular injections of orexin-A increase blood pressure and stimulate drinking, and the subfornical organ (SFO), a circumventricular structure implicated in autonomic control, is a potential site at which orexin may act to exert these effects. We have therefore used microinjection techniques to examine the effects of orexin-A administered directly into the SFO on blood pressure and heart rate in urethane anaesthetised male Sprague-Dawley rats. Orexin-A microinjection (50 fmol) into the SFO caused site-specific decreases in blood pressure (SFO: mean area under curve (AUC) = -681.7 +/- 46.8 mmHg*s, n = 22 versus non-SFO: 63.68 +/- 54.69 mmHg*s, n = 15, P < 0.001), and heart rate (SFO: mean AUC = -26.7 +/- 2.8 beats, n = 22, versus non-SFO: mean AUC = 1.62 +/- 2.1 beats, n = 15, P < 0.001). Vagotomy did not alter the hypotensive or bradycardic responses elicited by orexin-A microinjection. Prior alpha-adrenoceptor blockade with phenoxybenzamine (1 mg/kg, i.v.) masked the orexin-A induced blood pressure (mean AUC = -122.6 +/- 17.6 mmHg*s, n = 4, P < 0.01 paired t-test) and heart rate (mean AUC = -6.7 +/- 1.7 beats, n = 4, P < 0.05, paired test) response. The orexin-A induced heart rate response was attenuated when beta-adrenoceptors were blocked with propranolol (1 mg/kg, i.v.; mean AUC = 0.6 +/- 2.8 beats, n = 5, P < 0.01 paired t-test). These studies demonstrate that microinjection of orexin-A into the SFO causes site specific decreases in blood pressure and heart rate which is mediated by a reduction in sympathetic tone.

Animals↗
PubMed2006

Brain abscess in a dog immunosuppressed using cyclosporin.

This report describes a dog that developed brain abscesses following prolonged immunosuppression with cyclosporin. Bacteria within the abscess were most likely Nocardia, an organism well recognised in immunosuppressed humans, and probably reached the brain through haematogenous spread from a more long-standing abscess in the mediastinum. Bacterial brain abscesses developing in this manner are very rare in dogs and this case highlights the wider range of possible diagnoses that need to be considered in immunosuppressed patients and the care with which potent drugs such as cyclosporin should be used.

Animals↗
PubMed2006

Clinical canine spinal cord injury provides an opportunity to examine the issues in translating laboratory techniques into practical therapy.

STUDY DESIGN: Review. OBJECTIVES: To highlight the value of investigating the effects of putative therapeutic interventions in clinical spinal cord injury (SCI) in domestic dogs. SETTING: England, UK. METHODS: Many experimental interventions in laboratory rodents have been shown to ameliorate the functional deficits caused by SCI; the challenge now is to determine whether they can be translated into useful clinical techniques. Important differences between clinical SCI in human patients and that in laboratory rodents are in the size of the spinal cord and heterogeneity of injury severity. A further key issue is whether the statistical difference in outcome in the laboratory will translate into a useful difference in clinical outcome. Here, we stress the value of investigating the effects of putative therapies in clinical SCI in domestic dogs. The causes of injury, ability to categorise the severity and methods available to measure outcome are very similar between canine and human patients. Furthermore, postmortem tissue more rapidly becomes available from dogs because of their short lifespan than from human patients. RESULTS: The role that investigation of canine SCI might play is illustrated by our preliminary trials on intraspinal transplantation of olfactory glial cells for severe SCI. CONCLUSIONS: This canine translational model provides a means of 'filtering' putative treatments before human application.

Animals↗
PubMed2006

Acquired idiopathic laryngeal paralysis as a prominent feature of generalised neuromuscular disease in 39 dogs.

A retrospective evaluation of 17 dogs treated surgically for idiopathic acquired laryngeal paralysis demonstrated a marked variability in outcome, with many dogs continuing to exhibit weakness and exercise tolerance. In a subsequent prospective study, 22 consecutive affected dogs were tested for neurological deficits by neurological examination, electrodiagnostic evaluation, and blood analysis to measure thyroxine and thyroid-stimulating hormone and to detect any evidence of myasthenia gravis. Clinical neurological deficits and/or electrodiagnostic abnormalities were found in each case. There was limited evidence that specific neurological deficits were associated with a poor prognosis for full recovery of exercise tolerance. None of the dogs was positive for anti-acetylcholine receptor antibodies, and only three showed evidence of thyroid dysfunction.

Animals↗
PubMed2006

Antimuscarinic antibodies in primary Sjögren's syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells.

OBJECTIVE: Sjögren's syndrome (SS) is an autoimmune condition affecting salivary glands, for which a clearly defined pathogenic autoantibody has yet to be identified. Autoantibodies that bind to the muscarinic M3 receptors (M3R), which regulate fluid secretion in salivary glands, have been proposed in this context. However, there are no previous data that directly show antisecretory activity. This study was undertaken to investigate and characterize the antisecretory activity of anti-M3R. METHODS: Microfluorimetric Ca2+ imaging and patch clamp electrophysiologic techniques were used to measure the secretagogue-evoked increase in [Ca2+]i and consequent activation of Ca2+-dependent ion channels in individual mouse and human submandibular acinar cells. Together, these techniques form a sensitive bioassay that was used to determine whether IgG isolated from patients with primary SS and from control subjects has antisecretory activity. RESULTS: IgG (2 mg/ml) from patients with primary SS reduced the carbachol-evoked increase in [Ca2+]i in both mouse and human acinar cells by approximately 50%. IgG from control subjects had no effect on the Ca2+ signal. Furthermore, the inhibitory action of primary SS patient IgG on the Ca2+ signal was acutely reversible. We repeated our observations using rabbit serum containing antibodies raised against the second extracellular loop of M3R and found an identical pattern of acutely reversible inhibition. Anti-M3R-positive serum had no effect on Ca2+-dependent ion channel activation evoked by the direct intracellular infusion of inositol 1,4,5-triphosphate. CONCLUSION: These observations show for the first time that IgG from patients with primary SS contains autoantibodies capable of damaging saliva production and contributing to xerostomia. The unusual but not unprecedented acute reversibility of the effects of anti-M3 autoantibodies is the subject of further research.

Animals↗
PubMed2006

The effect of crank rate on physiological responses and exercise efficiency using a range of submaximal workloads during arm crank ergometry.

This study examined the effects of variations in crank rate on physiological responses during submaximal arm ergometry. Fifteen non-specifically trained male subjects volunteered to participate in this study. Each subject undertook a discontinuous arm crank ergometry test (30, 50, 70, 90 W) on three separate occasions using crank rates of 50, 70, and 90 rev.min(-1). Respiratory parameters and heart rate were continuously monitored. An 80-microL capillary blood sample was obtained immediately following each exercise bout for the determination of whole blood lactate. Measures of efficiency were calculated using specific caloric equivalents of oxygen consumption (V(O2)). Heart rate was lowest (p < 0.05) at 30, 50, and 70 W using 50 rev.min(-1). Values of gross and net efficiency tended to be higher (p < 0.05) using 50 rev.min (-1) at the lower absolute workloads, but no differences (p > 0.05) were observed between the three crank rates at 90 W. No differences (p > 0.05) were observed between crank rates for delta efficiency. This study confirms that variations in crank rate can influence gross and net values of V(O2) and exercise efficiency at low absolute workloads, but crank rate ceases to be an influential factor at moderate workloads. Further research is required to identify the specific mechanisms underpinning the observations reported in the present study relating to the interaction between crank rate, workload, and exercise efficiency during arm crank ergometry.

Adult↗
PubMed2006

The influence of ramp rate on VO2peak and "excess" VO2 during arm crank ergometry.

The principal aim of this study was to examine how different ramp rates influenced the attainment of peak physiological responses during incremental arm crank ergometry (ACE). Additionally, the study examined whether there was any evidence for the development of an "excess" VO (2) during ACE due to upward curvi-linearity in the VO (2)-work rate relationship, and whether this was influenced by the ramp rate. Sixteen physically active, though non-specifically trained, men (mean +/- S age 30 +/- 8 years; height 1.79 +/- 0.07 m; body mass 84.7 +/- 13.2 kg) volunteered to participate. Having completed a familiarisation test, all subjects returned to the laboratory to complete two ramp tests on an electrically-braked ergometer in a counter-balanced order. Both ramp tests started at 60 W with work rate subsequently incremented by either 6 or 12 W . min (-1). Pulmonary gas exchange was measured breath-by-breath throughout the tests. Subjects achieved a greater final work rate during the 12 W . min (-1) test compared to the 6 W . min (-1) test (168 +/- 28 vs. 149 +/- 26 W; p < 0.001). The VO (2peak) (3.06 +/- 0.65 vs. 2.96 +/- 0.48 L . min (-1); p = 0.27), HR (peak) (179 +/- 15 vs. 177 +/- 16 b . min (-1); p = 0.17) and V.E (peak) (112 +/- 22 vs. 105 +/- 16 L . min (-1); p = 0.09) were not different between the tests, but VCO (2peak) (3.54 +/- 0.64 vs. 3.27 +/- 0.46 L . min (-1); p = 0.01) RER (peak) (1.17 +/- 0.07 vs. 1.11 +/- 0.06; p < 0.001), and end-exercise blood (lactate) (11.9 +/- 2.1 vs. 10.8 +/- 2.6 mmol . L (-1); p = 0.005) were all higher in the 12 W . min (-1) test. An "excess" VO (2) was observed in 13 out of 16 tests at 12 W . min (-1) and in 15 out of 16 tests at 6 W . min (-1). Neither the magnitude of the "excess" VO (2) (0.42 +/- 0.41 vs. 0.37 +/- 0.18 L . min (-1); p = 0.66) nor the VO (2) at which the V.O (2)-work rate relationship departed from linearity (2.17 +/- 0.34 vs. 2.18 +/- 0.32 L . min (-1); p = 0.94) were significantly different between the two ramp tests. These data indicate that differences in ramp rate within the range of 6 - 12 W . min (-1) influence the peak values of work rate, VCO (2) and RER, but do not influence peak values of VO (2) or HR during ACE. The development of an "excess" VO (2) appears to be a common feature of ramp exercise in ACE, although the mechanistic basis for this effect is presently unclear.

Adult↗
PubMed2005

Effects of caffeine ingestion on rating of perceived exertion during and after exercise: a meta-analysis.

The purpose of this study was to use the meta-analytic approach to examine the effects of caffeine ingestion on ratings of perceived exertion (RPE). Twenty-one studies with 109 effect sizes (ESs) met the inclusion criteria. Coding incorporated RPE scores obtained both during constant load exercise (n=89) and upon termination of exhausting exercise (n=20). In addition, when reported, the exercise performance ES was also computed (n=16). In comparison to placebo, caffeine reduced RPE during exercise by 5.6% (95% CI (confidence interval), -4.5% to -6.7%), with an equivalent RPE ES of -0.47 (95% CI, -0.35 to -0.59). These values were significantly greater (P<0.05) than RPE obtained at the end of exercise (RPE % change, 0.01%; 95% CI, -1.9 to 2.0%; RPE ES, 0.00, 95% CI, -0.17 to 0.17). In addition, caffeine improved exercise performance by 11.2% (95% CI; 4.6-17.8%). Regression analysis revealed that RPE obtained during exercise could account for approximately 29% of the variance in the improvement in exercise performance. The results demonstrate that caffeine reduces RPE during exercise and this may partly explain the subsequent ergogenic effects of caffeine on performance.

Adult↗
PubMed2004

Hydroxychloroquine therapy in patients with primary Sjögren's syndrome may improve salivary gland hypofunction by inhibition of glandular cholinesterase.

OBJECTIVE: To determine whether (i) cholinesterase activity is increased in the saliva of patients with primary Sjogren's syndrome (pSS), (ii) increased levels of cholinesterase of lymphocyte origin could interfere with the secretory activity of submandibular acinar cells, and (iii) hydroxychloroquine at therapeutic doses could interfere with cholinesterase activity. METHODS: The Ellman method was used to determine the levels of salivary cholinesterase activity and the K(i) of both chloroquine and hydroxychloroquine for serum cholinesterase. The ability of lymphocyte cholinesterase to inhibit the acetylcholine (ACh)-evoked rise in [Ca(2+)](i) in mouse submandibular acinar cells was determined using fura-2 microfluorimetry. RESULTS: Patients with pSS had significantly higher levels of cholinesterase activity in both their unstimulated (P < 0.05) and stimulated saliva (P < 0.0001) compared with control subjects. Lymphocyte cholinesterase was capable of inhibiting the ACh-evoked rise in [Ca(2+)](i). The in vitro K(i) for hydroxychloroquine inhibition of cholinesterase was 0.38 +/- 1.4 microM. CONCLUSION: These data suggest that increased levels of cholinesterase present in the salivary glands of patients with pSS may contribute to glandular hypofunction and provide evidence that the therapeutic enhancement of salivary secretion in patients with pSS by hydroxychloroquine may be mediated by inhibition of glandular cholinesterase activity, although further in vivo investigation is needed.

Animals↗
PubMed2004

Putative anti-muscarinic antibodies cannot be detected in patients with primary Sjogren's syndrome using conventional immunological approaches.

OBJECTIVE: To determine whether autoantibodies directed against muscarinic M3 receptors are present in the serum of patients with primary Sjogren's syndrome (pSS), and if so whether these autoantibodies inhibit secretion by intact salivary acinar cells. METHODS: IgG was purified by affinity chromatography using protein G from sera collected from 15 patients with pSS. Antibody detection was by Western blotting, whole-cell enzyme-linked immunosorbent assay (ELISA) and immunoblotting. The antisecretory activity of the IgG faction was determined using fura-2 microfluorimetry to measure changes in intracellular Ca(2+) activity ([Ca(2+)](i)) in human and mouse salivary gland acinar cells and in Chinese hamster ovary (CHO) cells transfected with human M3 receptors (CHO-M3). RESULTS: We found no specific M3 receptor recognition by the IgG fraction obtained from pSS patients using either Western blotting or ELISA or immunoblot techniques in which epitope conformation were preserved. Chronic exposure to pSS IgG had no effect on agonist-evoked Ca(2+) signals measured in human or mouse submandibular acinar cells or in CHO-M3 cells. However, acute application of IgG from Sjogren's syndrome patients produced a rapidly reversible reduction in the agonist-stimulated elevation in [Ca(2+)](i). CONCLUSION: These data represent the first demonstration of salivary acinar cell inhibition by pSS IgG; however, this inhibition was found to be reversible. Our data also show that pSS IgG binding to M3R cannot be visualized by conventional immunological approaches.

Animals↗
PubMed2004

Local and global calcium signals and fluid and electrolyte secretion in mouse submandibular acinar cells.

Polarized Ca(2+) signals that originate at and spread from the apical pole have been shown to occur in acinar cells from lacrimal, parotid, and pancreatic glands. However, "local" Ca(2+) signals, that are restricted to the apical pole of the cell, have been previously demonstrated only in pancreatic acinar cells in which the primary function of the Ca(2+) signal is to regulate exocytosis. We show that submandibular acinar cells, in which the primary function of the Ca(2+) signal is to drive fluid and electrolyte secretion, are capable of both Ca(2+) waves and local Ca(2+) signals. The generally accepted model for fluid and electrolyte secretion requires simultaneous Ca(2+)-activation of basally located K(+) channels and apically located Cl(-) channels. Whereas a propagated cell-wide Ca(2+) signal is clearly consistent with this model, a local Ca(2+) signal is not, because there is no increase in intracellular Ca(2+) concentration at the basal pole of the cell. Our data provide the first direct demonstration, in submandibular acinar cells, of the apical and basal location of the Cl(-) and K(+) channels, respectively, and confirm that local Ca(2+) signals do not Ca(2+)-activate K(+) channels. We reevaluate the model for fluid and electrolyte secretion and demonstrate that Ca(2+)-activation of the Cl(-) channels is sufficient to voltage-activate the K(+) channels and thus demonstrate that local Ca(2+) signals are sufficient to support fluid secretion.

Animals↗
PubMed2004

The influence of step and ramp type protocols on the attainment of peak physiological responses during arm crank ergometry.

The present study examined the impact of two exercise protocols on the attainment of peak physiological responses during arm crank ergometry (ACE). Fourteen physically active, although non-specifically trained male subjects completed two V.O (2) peak tests using an electrically braked arm ergometer (Lode Angio, Groningen, Netherlands). The tests consisted of a stepwise or rampwise increase in external workload. The order of tests was randomised and each test was separated by at least two days. Respiratory data were collected continuously using an on-line gas analysis system with sample time set at 30 s. Fingertip capillary blood samples ( approximately 20 microL) were collected at volitional exhaustion and at minute intervals for 7 min of passive recovery for the determination of peak whole blood lactate concentration. Time on the test (T (lim); s), peak minute power (PMP; W), and total work done (TWD; kJ) were also recorded. In addition to determining systematic bias using separate independent t-tests, the level of agreement was also examined by way of calculating the 95 % limits of agreement. Sub-maximal values of V.O (2), V.E, and HR were similar (p > 0.05) between test when the amount of external work completed was taken into consideration. There was no systematic bias (p > 0.05) for mean (+/- s) peak values of V.O (2) (3.12 [0.37] vs. 3.04 [0.38] L . min (-1)) or any other parameter between the step and ramp tests, respectively. Mean values of T (lim), PMP, and TWD were also similar (p > 0.05) between tests. However, the level of agreement for peak values of all test parameters was low. It is therefore concluded that while either test can be considered as being suitable for the purpose of eliciting V.O (2) peak and other physiological responses using ACE, they should not be used interchangeably for the purpose of assessing parameters linked to the aerobic capacity of the upper-body.

Adult↗
PubMed2004

Effects of the rotor pedalling system on the performance of trained cyclists during incremental and constant-load cycle-ergometer tests.

The aim of this study was to determine the effects of Rotor, a new cycle crank configuration that effectively allows the pedals to move independently throughout the duty cycle, on indices of endurance cycling performance in trained cyclists. Ten cyclists (5 Rotor users and 5 non-users; age (mean +/- SD): 22 +/- 5 y; VO(2)max: 69.5 +/- 5.1 mL. kg(-1).min(-1)) volunteered to participate in the study. On four separate days, the subjects performed four cycle-ergometer tests, i.e. two incremental tests and two 20-min tests. An imposed crank rate of 75 rev.min(-1) was used during all tests. The incremental protocol started at 112.5 W, and the power output was increased by 37.5 W every 3 min until volitional exhaustion. The 20-min tests were performed at a fixed power output equivalent to 80 % of the highest power output that the cyclists maintained for a complete 3-min period during incremental tests. Both types of tests were performed with the conventional crank system and the Rotor following a counter-balanced, cross-over design. Gas exchange parameters were measured in all the tests and blood lactate was determined at the end of each 3-min period (incremental tests) and at the end of the 20-min tests. A three factor (pedalling system used during the tests x habitual pedalling system x power output [incremental tests] or time [20-min tests]) ANOVA with repeated measures on power output (incremental tests) or time (20-min tests) was used to analyse several indices of performance, e.g. peak power output, VO(2)max, lactate threshold, onset of blood lactate accumulation, economy, delta, and gross efficiency. No differences (p > 0.05) were found between the Rotor and conventional systems for any of the aforementioned variables. It seems that the theoretical advantage brought about by the Rotor system, i.e. improved contra-lateral cooperation of both legs, would be minimized in trained cyclists. Although field studies are needed to assess the possible implications, in terms of actual racing, of the new system, commonly used indicators of endurance cycling performance do not seem to be improved with the Rotor in trained cyclists.

Adult↗
PubMed2004

Examining the associations between physical work demands and work injury rates between men and women in Ontario, 1990-2000.

AIMS: To describe the decline in injury rates between 1990 and 2000 within occupations stratified across three levels of physical demands and gender, adjusting for industry, in Canada's largest province. METHODS: Records of injury compensation claims were obtained from the Ontario Workplace Safety & Insurance Board. The population likely to be insured by the Ontario Workplace Safety & Insurance Board was estimated from Statistics Canada's Labour Force Survey. Injury rates were calculated by three broad levels of physical demands, separately for men and women. RESULTS: Injury rates decreased across each grouping of lower physical demands at work for both men and women, with the largest absolute differences in manual occupational groups (high physical demands). Occupations classified as manual (high physical demands) and mixed (moderate physical demands) showed larger differences in injury rates between genders than did non-manual (low physical demands), although the directions of these differences were not always consistent across different natures of injury classification. CONCLUSIONS: The absolute reduction in injury rates in Ontario between 1990 and 2000 was dominated by the reduction in injury rates for men and women in manual and mixed occupations. However, not all types of injury have declined to the same extent. A large proportion of differences in injury rates between men and women can be attributed to the differential labour force participation across occupations and industries, as well as the differential tasks within occupational groups.

Accidents, Occupational↗
PubMed2003

Odontoblast transport of sulphate--the in vitro influence of fluoride.

The present study reports the development of a culture system for the analysis of 35S-sulphate release from odontoblasts in vitro. Pulpless longitudinally split rat incisors were cultured in supplemented minimum essential medium (alphaMEM) with 20 microCi 35S-sulphate per ml, 20 microCi 3H-mannitol per ml for 1h. Teeth were then transferred to fresh unlabelled media and aliquots of media were removed and the level of 35S-sulphate 3H-mannitol determined. Results indicated a two phase release of 35S-sulphate into the media, and comparison with pulp tissue indicated a specific release pattern. Transport of sulphate is essential for correct synthesis and glycosylation of macromolecules such as proteoglycans (PG). Previous studies have shown that post-translational modifications of these proteins can be influenced by excess fluoride, resulting in decreased sulphation and elongation of glycosaminoglycan (GAG) chains. Therefore the influence of fluoride on sulphate transport, using the optimised culture system was also investigated. Inclusion of 6mM fluoride during pulse labelling caused a significant decrease of 35S-sulphate (P<0.0001) during the initial release phase. Inclusion of 3 and 6mM fluoride only in the post-labelling incubation media resulted in a significant decrease in the release of 35S-sulphate (P<0.0001), during the total time course. The influence of fluoride was not dose dependent. Inclusion of a specific chloride channel blocker SITS, into the culture system indicated that 35S-sulphate transport may in part be via this route. Fluoride would therefore appear to influence the transport of 35S-sulphate across the odontoblast membrane, potentially via a chloride channel.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗