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Biomedical subjects

D M Jackson

Publications and source records attributed to D M Jackson.

At least 19 recordsLinked to original sources
PubMed2006

Mitochondrial involvement in transhemispheric diaschisis following hypoxia-ischemia: Clomethiazole-mediated amelioration.

Mitochondria play a central role in both the physiological and pathophysiological regulation of cell survival/death. Increasing evidence places mitochondrial dysfunction at the center of many neuropathological conditions. The present study investigates the extent of mitochondrial dysfunction in cortical, hippocampal and cerebellar tissues in a rat model of hypoxia-ischemia (HI). We hypothesized that; mitochondrial dysfunction in situ may be prevented by treatment with clomethiazole (CMZ), a GABA(A) receptor agonist. Assessment of mitochondrial FAD-linked respiration at both 1- and 3-day post-HI revealed a marked decrease in activity from ipsilateral cortical and hippocampal regions (P<0.001). In addition, small changes were seen in contralateral cortical and hippocampal tissues as well as in the cerebellum at 3-days (P<0.05). Assessment of the mitochondrial electron transport chain (complexes I-V), and mitochondrial markers of integrity (citrate synthase) and oxidative stress (aconitase) confirmed mitochondrial impairment in ipsilateral regions following HI. Complexes I, II-III, V and citrate synthase were also impaired in contralateral regions and cerebellum 3-days post-HI. Treatment with CMZ (414 mg/kg/day via minipumps) provided marked protection to all aspects of neuronal tissue assessed. Circulating cytokine (interleukin [IL]-1alpha, IL-1beta, tumor necrosis factor [TNF]-alpha, granulocyte macrophage colony-stimulating factor [GM-CSF], IL-4 and IL-10) levels were also assessed in these animals 3-days post-HI. Plasma IL-1alpha, IL-1beta, TNF-alpha and GM-CSF levels were significantly increased post-HI. Treatment with CMZ ameliorated the increases in IL-1alpha, IL-1beta, TNF-alpha and GM-CSF levels while increasing plasma IL-4 and IL-10 levels. This study provides evidence of the extent of mitochondrial damage following an HI-insult. In addition, we have shown that protection afforded by CMZ extends to preservation of mitochondrial function and integrity via anti-inflammatory mediated pathways.

Animals↗
PubMed2005

Associations between BMI, social strata and the estimated energy content of foods.

OBJECTIVE: Many studies have shown that the prevalence of obesity is greater in lower social classes. The reasons for this effect however are unclear. Since there is also a link between education and social class, and an association between education and prevalence of obesity, one hypothesis is that lack of education about energy contents of foods may contribute to the effects of social class on obesity. SUBJECTS: We tested the hypothesis that knowledge of food energy contents is associated with differences in body mass index (BMI) in a sample of 346 people of both genders, aged between 18 and 45 y, of variable body mass index and drawn from different social strata. RESULTS: Estimates of food energy contents were on average well correlated with the actual energy contents, but individual estimates were very poor in all subpopulations of this sample. We found that subjects of different BMIs did not differentially estimate the energy contents of foods high in carbohydrate, but low in fat and protein (fruit and bread). However, foods that contained high fat contents, independent of the other macronutrients present, were generally perceived to have significantly lower energy contents by obese people than nonobese subjects (although this was not observed for all high-fat foods). Overall, this difference interacted with social class, such that the difference between the BMI groups was exaggerated in the lower social stratum but abolished in the higher social class. Binary logistic regressions revealed that the probability of being obese (BMI>30 kg/m2) in the lower social class group was significantly negatively associated with the estimated food energy content of most high-fat foods. Such an association was not found in the higher social class group. In the lower social class group, overall food knowledge appeared superior in the leaner subject group (BMI<30 kg/m2), but obese subjects were actually better at estimating the energy contents of snacks and alcoholic beverages. The leaner group significantly overestimated the energy contents of these items. CONCLUSION: Differences between individuals in estimates of food energy contents may contribute to the development of obesity in lower social strata. Whether this is driven by a protective effect in lean subjects of overestimating the energy contents of certain foods (snacks and alcoholic beverages) or a susceptibility in the obese because they underestimate the energy contents of other foods is not certain. Knowing which of these alternatives is true is important and may help design public health education programmes directed at these people to help alleviate the obesity epidemic.

Adolescent↗
PubMed2004

Total energy expenditure and physical activity in young Scottish children: mixed longitudinal study.

Childhood obesity has been attributed to a decline in total energy expenditure (TEE). We measured TEE, physical activity, and sedentary behaviour in a representative sample of young children from Glasgow, UK, at age 3 years (n=78), and we did a follow-up study at age 5 years (n=72). Mean physical activity level (TEE/resting energy expenditure) was 1.56 (SD 0.39) at age 3 years and 1.61 (0.22) at age 5 years. Median time in sedentary behaviour was 79% of monitored hours at age 3 years (IQR 74-84) and 76% (71-80) at age 5 years. Median time spent in moderate to vigorous physical activity represented only 2% of monitored hours at age 3 years (IQR 1-4) and 4% at age 5 years (2-6). Modern British children establish a sedentary lifestyle at an early age.

Age Factors↗
PubMed2004

Metabolic power of European starlings Sturnus vulgaris during flight in a wind tunnel, estimated from heat transfer modelling, doubly labelled water and mask respirometry.

It is technically demanding to measure the energetic cost of animal flight. Each of the previously available techniques has some disadvantage as well advantages. We compared measurements of the energetic cost of flight in a wind tunnel by four European starlings Sturnus vulgaris made using three independent techniques: heat transfer modelling, doubly labelled water (DLW) and mask respirometry. We based our heat transfer model on thermal images of the surface temperature of the birds and air flow past the body and wings calculated from wing beat kinematics. Metabolic power was not sensitive to uncertainty in the value of efficiency when estimated from heat transfer modelling. A change in the assumed value of whole animal efficiency from 0.19 to 0.07 (the range of estimates in previous studies) only altered metabolic power predicted from heat transfer modelling by 13%. The same change in the assumed value of efficiency would cause a 2.7-fold change in metabolic power if it were predicted from mechanical power. Metabolic power did not differ significantly between measurements made using the three techniques when we assumed an efficiency in the range 0.11-0.19, although the DLW results appeared to form a U-shaped power-speed curve while the heat transfer model and respirometry results increased linearly with speed. This is the first time that techniques for determining metabolic power have been compared using data from the same birds flying under the same conditions. Our data provide reassurance that all the techniques produce similar results and suggest that heat transfer modelling may be a useful method for estimating metabolic rate.

Analysis of Variance↗
PubMed2004

Bad attitudes.

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Adult↗
PubMed2003

Dual dopamine D2 receptor and beta2-adrenoceptor agonists for the treatment of chronic obstructive pulmonary disease: the pre-clinical rationale.

This paper describes the rationale for the development of dual dopamine D2-receptor and beta2-adrenoceptor agonists as potential treatments for the symptoms of chronic obstructive pulmonary disease (COPD). The putative involvement of pulmonary sensory afferent nerves in mediating the key COPD symptoms of breathlessness, cough and excess sputum production is outlined and the hypothesis that activation of D2-receptors on such nerves would modulate their activity is developed. This premise was tested, in a range of animal models, using the first of a novel class of dual dopamine D2-receptor and beta2-adrenoceptor agonists, sibenadet HCl (Viozan, AR-C68397AA). In the course of these studies it was demonstrated that sibenadet, through activation of D2-receptors, inhibited discharge of rapidly adapting receptors and was effective in reducing reflex-induced tachypnoea, mucus production and cough in the dog. Sibenadet, through its activation of beta2-adrenoceptors, was also shown to be an effective bronchodilator with a prolonged duration of action following topical administration to the lungs. These studies also indicated that sibenadet had a wide therapeutic ratio with respect to expected undesirable side-effects such as emesis and cardiovascular disturbances. These results provided a compelling rationale for the initiation of a clinical development programme with sibenadet for the treatment of COPD.

Adrenergic beta-2 Receptor Agonists↗
PubMed2002

Cardiac diastolic function and hypercapnic ventilatory responses in central sleep apnoea.

Hyperventilation is the key factor contributing to the development of idiopathic nonhypercapnic central sleep apnoea (ICSA), where left ventricular systolic function is normal. ICSA is reported to occur in 20% of patients with left ventricular diastolic dysfunction, in whom elevated pulmonary vascular pressures and resultant increased pulmonary vagal afferent traffic may contribute to hyperventilation. The contribution of the two potential mechanisms responsible for the hyperventilation seen in the following ICSA was measured: 1) left ventricular diastolic dysfunction-induced pulmonary hypertension; and 2) increased peripheral and central hypercapnic ventilatory responses (HCVR). The pulmonary artery pressure, left ventricular diastolic function and chemosensitivity to hypercapnia were measured during wakefulness in 16 subjects with ICSA. All subjects had systolic pulmonary artery pressures <3.99 kPa (<30 mmHg) and only four had diastolic dysfunction. All subjects had elevated peripheral and central HCVR compared with historical normal control subjects. Diastolic dysfunction correlated with increasing age but not with HCVR or markers of central sleep apnoea severity. Idiopathic nonhypercapnic central sleep apnoea is likely to be dependent upon raised hypercapnic ventilatory responses, and not pulmonary hypertension due to left ventricular diastolic dysfunction.

Adolescent↗
PubMed2001

Efficacy of disodium 4-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059), a free radical trapping agent, in a rat model of hemorrhagic stroke.

Because free radical mechanisms may contribute to brain injury in hemorrhagic stroke, the effect of the free radical trapping agent disodium 4-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059) was investigated on outcome following intracerebral hemorrhage (ICH) in rat. ICH was induced in 20 adult rats by infusion of collagenase into the caudate-putamen. Thirty minutes later rats were treated with NXY-059 (50 mg/kg subcutaneous plus 8.8 mg/kg/h for 3 days subcutaneous delivered via implanted osmotic pumps) or saline (equivalent volumes). Magnetic resonance imaging 24 h after ICH confirmed that the hemorrhage was uniform in the two groups, and subsequent imaging at 7 and 42 days post-ICH showed that the hematoma resolved similarly in the two groups. Behavioral testing on days 1, 3, 7, 14, and 21 after ICH showed that rats treated with NXY-059 had significantly decreased neurological impairment at all times. Deficits in skilled forelimb use 4-5 weeks post-ICH, and in striatal function 6 weeks post-ICH, were not reduced by treatment with NXY-059. Treatment with NXY-059 significantly reduced the neutrophil infiltrate observed 48 h post-hemorrhage in the vicinity of the hematoma, and the number of TUNEL-positive cells 48 h post-hemorrhage at the hematoma margin. However, by 6 weeks there were no differences in neuronal densities in treated and control rats.

Animals↗
PubMed2001

The interaction of AR-A008055 and its enantiomers with the GABA(A) receptor complex and their sedative, muscle relaxant and anticonvulsant activity.

AR-A008055 [(+/-)-1-(4-methyl-5-thiazolyl)-1-phenylmethylamine] is structurally related to clomethiazole and has been used to probe the mechanism of the neuroprotective effect of clomethiazole. Clomethiazole, (+/-)-AR-A008055 and (S)-(-)-AR-A008055 all displaced [35S]-t-butyl-bicyclophosphorothionate ([35S]TBPS) from rat cerebral cortex tissue (IC50 values: GABA, 8.1+/-0.04 microM; clomethiazole, 130+/-30 microM; (+/-)-AR-A008055, 494+/-7 microM; (S)-(-)-AR-A008055, 221+/-14 microM. (R)-(+)-AR-A008055 was without significant effect (IC50>1000 microM). None of the compounds interacted with NMDA or AMPA receptors or with sodium or calcium (N, P/Q) channels. Brain penetration of both enantiomers following their i.p. administration was excellent, with brain and plasma concentrations being similar. Clomethiazole dose-dependently inhibited spontaneous locomotor activity in rats and was approximately 10 times more sedative than either enantiomer of AR-A008055. Clomethiazole was more potent than (S)-(-)-AR-A008055 in the "pull-up" test (muscle relaxation) and in producing loss of righting reflex, while (R)-(+)-AR-A008055 had little effect. The time animals remained on a Rota-rod was of the order: clomethiazole<(S)-(-)-AR-A008055<(R)-(+)-AR-A008055. (S)-(-)-AR-A008055 (210 micromol/kg) raised seizure threshold to pentylenetetrazole (i.v.) by 119+/-21%. The (R)-(+)- enantiomer was not anticonvulsant. Overall, (S)-(-)-AR-A008055 exhibited a similar pharmacology to clomethiazole. However, its sedative and muscle relaxant effects were substantially less than clomethiazole, emphasising that these properties are not directly related to neuroprotective efficacy. The current data suggest that the proposed GABA uptake inhibitory property of (R)-(+)-AR-A008055 fails to produce significant sedative, myorelaxant or anticonvulsant activity.

Animals↗
PubMed2001

Metabolic power, mechanical power and efficiency during wind tunnel flight by the European starling Sturnus vulgaris.

We trained two starlings (Sturnus vulgaris) to fly in a wind tunnel whilst wearing respirometry masks. We measured the metabolic power (P(met)) from the rates of oxygen consumption and carbon dioxide production and calculated the mechanical power (P(mech)) from two aerodynamic models using wingbeat kinematics measured by high-speed cinematography. P(met) increased from 10.4 to 14.9 W as flight speed was increased from 6.3 to 14.4 m s(-1) and was compatible with the U-shaped power/speed curve predicted by the aerodynamic models. Flight muscle efficiency varied between 0.13 and 0.23 depending upon the bird, the flight speed and the aerodynamic model used to calculate P(mech). P(met) during flight is often estimated by extrapolation from the mechanical power predicted by aerodynamic models by dividing P(mech) by a flight muscle efficiency of 0.23 and adding the costs of basal metabolism, circulation and respiration. This method would underestimate measured P(met) by 15-25 % in our birds. The mean discrepancy between measured and predicted P(met) could be reduced to 0.1+/-1.5 % if flight muscle efficiency was altered to a value of 0.18. A flight muscle efficiency of 0.18 rather than 0.23 should be used to calculate the flight costs of birds in the size range of starlings (approximately 0.1 kg) if P(met) is calculated from P(mech) derived from aerodynamic models.

Animals↗
PubMed2000

GABA potentiation: a logical pharmacological approach for the treatment of acute ischaemic stroke.

It has been shown that enhancing the function of the major inhibitory neurotransmitter GABA decreases glutamatergic activity in the brain. Since increased glutamatergic activity is the major primary event that results in cell death following an acute hypoxic-ischaemic stroke, GABAmimetic drugs might therefore be expected to be neuroprotective. This review examines the evidence that GABAergic function is acutely depressed following an ischaemic insult, and also reviews the data that suggest that increasing cerebral GABA concentration has a neuroprotective effect, as does the administration of some (but not all) GABAmimetic agents. The GABA uptake inhibitor CI-966, the GABA(A) agonist muscimol and the GABA(A)mimetic clomethiazole have all been shown to be neuroprotective in animal models of stroke when given after the ischaemic insult. In contrast, benzodiazepines and particularly barbiturates, although potent GABA(A) potentiators, have shown little promise as neuroprotectants. The diversity of GABA(A) receptor subtypes and the in vivo efficacy of certain GABA(A) receptor ligands in animal models of stroke suggests that GABAmimetic drugs are an undervalued approach to stroke therapy.

Acute Disease↗
PubMed2000

Clomethiazole protects against hemineglect in a primate model of stroke.

Permanent occlusion of the M1 segment of the middle cerebral artery (pMCAO) in the marmoset, a New World species of monkey, produces unilateral functional deficits, including motor neglect with the contralesional arm and contralesional spatial hemineglect. In this study we examined whether clomethiazole, a drug which modulates the gamma-aminobutyric acid(A) receptor, reduced the severity of the hemineglect and other deficits in this primate model of stroke. Nine monkeys received pMCAO; 1 h later four of the nine were administered clomethiazole by intraperitoneal injection and subcutaneous implantation of osmotic mini-pumps, which released clomethiazole for 48 h. The monkeys had been trained and tested on a number of behavioral tasks prior to surgery and were re-tested 3 and 10 weeks later. Three weeks after pMCAO, monkeys treated with clomethiazole had a significantly reduced degree of spatial neglect compared to untreated controls. Clomethiazole was not effective against the severe contralesional motor impairment in the current study, although it ameliorated a somewhat less severe motor deficit in a previous study in which the more distal, M2 segment of the middle cerebral artery had been occluded. Postmortem analysis of the brains showed that clomethiazole treatment had significantly reduced the area of damage in part of the parietal cortex. These data suggest that clomethiazole may reduce the neglect that can be a debilitating consequence of right-sided stroke in man.

Animals↗
PubMed2000

The effect of dopamine on the rapidly adapting receptors in the dog lung.

The effect of an infusion of dopamine (50 microg/kg per min) on both resting and histamine-stimulated discharge of rapidly adapting receptors has been studied in the dog lung. In dogs pretreated with propranolol and phentolamine (1 mg/kg) dopamine inhibited the ability of histamine to stimulate the rapidly adapting receptors. This inhibition was attenuated by sulpiride, a selective D(2)antagonist, (0.5 mg/kg i.v.). Dopamine did not affect the increases in R(L)or the falls in C(dyn)produced by histamine. It is suggested that dopamine may play a role in the control of lung function by reducing the ability of sensory nerves to produce harmful reflex activity.

Adrenergic beta-Agonists↗
PubMed2000

Expression of the circadian clock genes clock and period1 in human skin.

The circadian clock is a cellular machine composed of proteins with regulated expression that gives rise to circadian rhythms. Two main new concepts have arisen from recent research in the field in the last few years: (i) at least three to five key genes are involved in maintaining the basic circadian cellular rhythms, and (ii) their expression is fairly ubiquitous, extending beyond the traditionally considered pacemaker in mammals, the suprachiasmatic nucleus. We have demonstrated the expression of two circadian clock genes, clock and period1, in human skin cells. Reverse transcriptase polymerase chain reaction revealed the presence of clock and period1 mRNA in cultured human keratinocytes, melanocytes, and dermal fibroblasts, as well as in the human keratinocyte cell line HaCaT and the human melanoma line A375. In addition, antibodies to these two proteins produced immuno-positive staining in these cell types. Our investigations demonstrate for the first time that skin cells express circadian clock proteins constitutively although regulation of their expression and activity has not been elucidated. These proteins may have a role in cutaneous and/or systemic circadian biology and the skin and skin cells may provide an attractive model for the study of circadian rhythms.

CLOCK Proteins↗
PubMed2000

Sublethal effects of resin glycosides from the periderm of sweetpotato storage roots on Plutella xylostella (Lepidoptera: Plutellidae).

Resin glycoside material extracted from the periderm tissue of storage roots from sweetpotato, Ipomoea batatas (L.) Lam., was bioassayed for effects on survival, development, and fecundity of the diamondback moth, Plutella xylostella (L.). The resin glycoside was incorporated into an artificial diet and fed to P. xylostella larvae. First instars were placed individually into snap-top centrifuge vials containing artificial diet with one of six concentrations of resin glycoside material (0.00, 0.25, 0.50, 1.00, 1.50, and 2.00 mg/ml). Each replication consisted of 10 individuals per concentration, and the experiment was repeated 13 times. Vials were incubated at 25 degrees C and a photoperiod of 14:10 (L:D) h in a growth chamber. After 6 d, surviving larvae were weighted and their sex determined, then returned to their vials. Later, surviving pupae were weighed and incubated at 25 degrees C until moths emerged. Females were fed, mated with males from the laboratory colony, and allowed to lay eggs on aluminum foil strips. Lifetime fecundity (eggs/female) was measured. There were highly significant negative correlations between resin glycoside levels and survival, and between glycoside levels and larval weight after 6 d of feeding. For larvae that lived at least 6 d, there was no additional mortality that could be attributed to the resin glycoside material. However, there was a significant positive correlation between glycoside dosages and developmental time of larvae (measured as days until pupation). Lifetime fecundity also was negatively affected at sublethal doses. Resin glycosides may contribute to the resistance in sweetpotato breeding lines to soil insect pests.

Animals↗
PubMed2000

Effects of planting pattern of collards on resistance to whiteflies (Homoptera: Aleyrodidae) and on parasitoid abundance.

Fourteen collard entries, Brassica oleraceae L., Acephala group, were evaluated for resistance to natural populations of Bemisia argentifolii Bellows & Perring in replicated field plots in Charleston, SC. Glossy-leaf phenotypes ('SC Glaze', 'SC Landrace,' 'Green Glaze') were the most resistant collard entries and had fewer whiteflies than the nonglossy, open-pollinated cultivars. Also, two F1 hybrid cultivars with normal, nonglossy leaves ('Blue Max' and 'Top Bunch') were resistant. In laboratory experiments, there were no differences in the intrinsic rate of growth (rs) of B. argentifolii populations on either glossy or nonglossy collard phenotypes. Over a 2-yr period, there were no differences in the abundance of whiteflies on the glossy phenotype of Green Glaze when it was planted in solid 20-plant plots or when it was alternated (every other plant) with the nonglossy phenotype of Green Glaze. In a similarly designed experiment, there was no difference in the resistance of Blue Max in either solid or mixed planting scheme compared with the susceptible 'Morris Heading'. Higher numbers of whiteflies and parasitoids (primarily Eretmocerus spp.) were collected on yellow sticky cards in the solid plantings of the nonglossy phenotype of Green Glaze than were collected in the solid plantings of the glossy Green Glaze phenotype. Counts on sticky cards in the mixed plots were intermediate. These data show that planting pattern of collard entries is relatively unimportant in the deployment of these sources of host plant resistance. The data also suggest that nonpreference is the primary mode of resistance to whiteflies for certain collard entries.

Agriculture↗