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Biomedical subjects

R Deacon

Publications and source records attributed to R Deacon.

At least 19 recordsLinked to original sources
PubMed2004

Impaired motor coordination on static rods in BSE-infected mice.

Scrapie and bovine spongiform encephalopathy (BSE) are both progressive neurodegenerative diseases that are transmissible to mice. The onset of clinical symptoms is more subtle and variable in murine BSE than in murine scrapie. Assessment of behavioural changes that occur throughout disease would aid early diagnosis of disease so that more consistent end points could be made and potential therapies could be investigated. C57BL/6J mice inoculated via the intraperitoneal route with 301C BSE or control inoculum were monitored on a fortnightly basis. The end point was when a mouse showed clinical signs as opposed to behavioural signs of BSE for two consecutive observations. Significant loss of motor function, as assessed by mice balancing on a static rod, was observed consistently from approximately 40 days prior to death. No significant differences in home cage activity (locomotion, rearing) or cognitive function (T-maze alternation) were observed. However, there was an increase in digging by BSE-infected mice from an early stage. This data will aid the standardisation of behavioural tests to characterise and assess the onset of BSE.

Analysis of Variance↗
PubMed2004

Relationship between visceral adiposity and intramyocellular lipid content in two rat models of insulin resistance.

High visceral adiposity and intramyocellular lipid levels (IMCL) are both associated with the development of type 2 diabetes. The relationship between visceral adiposity and IMCL levels was explored in diet- and glucocorticoid-induced models of insulin resistance. In the diet-induced model, lean and fa/fa Zucker rats were fed either normal or high-fat (HF) chow over 4 wk. Fat distribution, IMCL content in the tibialis anterior (TA) muscle (IMCL(TA)), and whole body insulin resistance were measured before and after the 4-wk period. The HF diet-induced increase in IMCL(TA) was strongly correlated with visceral fat accumulation and greater glucose intolerance in both groups. The increase in IMCL(TA) to visceral fat accumulation was threefold greater for fa/fa rats. In the glucocorticoid-induced model, insulin sensitivity was impaired with dexamethasone. In vivo adiposity and IMCL(TA) content measurements were combined with ex vivo analysis of plasma and muscle tissue. Dexamethasone treatment had minimal effects on visceral fat accumulation while increasing IMCL(TA) levels approximately 30% (P < 0.05) compared with controls. Dexamethasone increased plasma glucose by twofold and increased the saturated fatty acid content of plasma lipids [fatty acid (CH2)n/omegaCH3 ratio +15%, P < 0.05]. The lipid composition of the TA muscle was unchanged by dexamethasone treatment, indicating that the relative increase in IMCL(TA) observed in vivo resulted from a decrease in lipid oxidation. Visceral adiposity may influence IMCL accumulation in the context of dietary manipulations; however, a "causal" relationship still remains to be determined. Dexamethasone-induced insulin resistance likely operates under a different mechanism, i.e., independently of visceral adiposity.

Adipose Tissue↗
PubMed2003

Synaptic changes characterize early behavioural signs in the ME7 model of murine prion disease.

Prion diseases are fatal, chronic neurodegenerative diseases of mammals, characterized by amyloid deposition, astrogliosis, microglial activation, tissue vacuolation and neuronal loss. In the ME7 model of prion disease in the C57BL/6 J mouse, we have shown previously that these animals display behavioural changes that indicate the onset of neuronal dysfunction. The current study examines the neuropathological correlates of these early behavioural changes. After injection of ME7-infected homogenate into the dorsal hippocampus, we found statistically significant impairment of burrowing, nesting and glucose consumption, and increased open field activity at 13 weeks. At this time, microglia activation and PrPSc deposition was visible selectively throughout the limbic system, including the hippocampus, entorhinal cortex, medial and lateral septum, mamillary bodies, dorsal thalamus and, to a lesser degree, in regions of the brainstem. No increase in apoptosis or neuronal cell loss was detectable at this time, while in animals at 19 weeks postinjection there was 40% neuronal loss from CA1. There was a statistically significant reduction in synaptophysin staining in the stratum radiatum of the CA1 at 13 weeks indicating loss of presynaptic terminals. Damage to the dorsal hippocampus is known to disrupt burrowing and nesting behaviour. We have demonstrated a neuropathological correlate of an early behavioural deficit in prion disease and suggest that this should allow insights into the first steps of the neuropathogenesis of prion diseases.

Animals↗
PubMed2002

Pharmacologic restoration of the early insulin response in pre-diabetic monkeys controls mealtime glucose excursions without peripheral hyperinsulinaemia.

AIMS/HYPOTHESIS: This study sought first to compare the pharmacodynamics and pharmocokinetics of two rapid-onset, rapidly-reversible insulinotropic agents, nateglinide and repaglinide, in pre-diabetic Cynomolgus monkeys and second to use these agents to assess the metabolic effects of early insulin secretion on prandial glucose control. METHODS: First, equipotent doses of nateglinide (20 mg/kg) and repaglinide (0.1 mg/kg) or vehicle were given intragastrically to overnight-fasted ketamine-anesthetized pre-diabetic Cynomolgus monkeys and samples were obtained for measurement of plasma glucose, insulin, glucagon, NEFA and drug concentrations. Second, nateglinide, repaglinide or vehicle were administered 10 min before a glucose-supplemented liquid meal and prandial glucose and insulin profiles were compared. RESULTS: Although oral administration of nateglinide and repaglinide elicited similar maximum increments of plasma insulin (+403 and +448 pmol/l, respectively), the effects of nateglinide were more rapidly manifest and less prolonged. With nateglinide, insulin increased within 10 min and returned to baseline within 50 min. After repaglinide, the first increase occurred at 30 min and insulin concentrations remained increased for 3.5 h post-dose. When given 10 min before a meal, nateglinide increased early, but not total insulin release (AUC(0-210)=108 vs 150 nmol/l min for nateglinide and vehicle, respectively) and reduced prandial glucose excursions by 78%. Repaglinide increased total insulin release (AUC(0-210)=298 nmol/l min) and reduced glucose excursions by 53%. CONCLUSION/INTERPRETATION: Nateglinide is more rapid-acting and rapidly-reversible than is repaglinide. By restoring a more physiologic insulin profile, nateglinide is more effective than repaglinide in controlling prandial glucose excursions with less hyperinsulinaemia.

Animals↗
PubMed1994

Sweeping changes for Welsh Health Authorities.

Despite the fact that Welsh Secretary John Redwood has stated he would like to see Welsh health authorities (HAs) administration cut by around 50% he has provided no indication as to whether or not his local government reforms will alter the HA's geographical or structural basis. This may mean that not only is there the possibility of moves towards 'commissioning authorities' and increases in the number of HAs and FHSAs merging, in addition Wales will have to contend with the unknown effect of local authority boundary changes. This is a concept which England and Scotland will also have to deal with. Russell Deacon and Tracey Deacon explore.

Catchment Area, Health↗
PubMed1993

Invalidity from nonparallelism in a radioimmunoassay for erythropoietin accounted for by human serum antibodies to rabbit IgG.

An immunologic crossreactant of erythropoietin seemed to develop and persist in serum samples from a patient during treatment and remission of idiopathic aplastic anemia. It had a steeper slope to radioimmunoassay log-dose response lines and a larger molecular size than erythropoietin. On fractionation of serum, the apparent crossreactant was bound by staphylococcal Protein A at pH 7.5 and recovered by elution from it at pH 3.0. Adsorption of serum from the patient, and from one of two similarly affected children, with rabbit IgG linked to agarose appeared to remove completely the apparent crossreactant. These treated sera gave radioimmunoassay log-dose response lines essentially parallel to that given by the International Reference Preparation (IRP) for erythropoietin and estimates of immunoreactive erythropoietin appropriate to the normal hemoglobin concentrations. The apparent crossreactant of erythropoietin is thus accounted for by heterophilic antibodies to rabbit IgG. These developed in the patient following treatment with rabbit antilymphocyte globulin but seem to have arisen spontaneously in the children. Thus iatrogenic and idiopathic antibodies to rabbit IgG interfered in a radioimmunoassay for erythropoietin in serum through their ability to react with the radioimmunoassay anti-erythropoietin antiserum raised in rabbits.

Adult↗
PubMed1990

Methylthioadenosine serves as a single carbon source to the folate co-enzyme pool in rat bone marrow cells.

[ribose-U-14C]Methylthioadenosine (MTA) was prepared by incubating methionine with [14C-U]ATP in the presence of methionine adenosyltransferase and the resulting S-adenosylmethionine was heated to release MTA. Labelled [14C]MTA, when incubated with rat bone marrow cells, yielded [14C]formate which was used in the synthesis of adenine and guanine. Unlike 14C from sodium, formate, serine and glycine, there was no decline in 14C utilization from MTA with bone marrow cells from rats in which cobalamin had been inactivated by exposure to nitrous oxide. It was concluded that methionine via MTA is a significant contributor of single-carbon units at the formate level of oxidation and that this pathway is maintained in cobalamin 'deficiency'.

Adenine↗
PubMed1990

Cobalamin inactivation induces formyltetrahydrofolate synthetase.

Loss of cobalamin function produces profound changes in the metabolism of formate. There is impaired synthesis of formyltetrahydropteroylglutamate synthetase (CHO-H4PteGlu), accumulation of endogenous formate and impaired utilization of [14C]formate. There are contradictory reports on the effect of cobalamin inactivation on CHO-H4PteGlu synthetase. This study confirms a significant increase in synthetase activity following cobalamin inactivation.

Analysis of Variance↗
PubMed1990

Formate metabolism in the cobalamin-inactivated rat.

Endogenous formate levels in blood and liver were assayed in rats both after inactivation of cobalamin (Cbl) by exposure to N2O as well as in air-breathing controls. The uptake of [14C]formate by tetrahydrofolate (H4folate) in bone marrow cells and liver homogenate and the incorporation of [14C]formate into purine, pyrimidine, methionine, serine and choline, was measured. There was a significant accumulation of endogenous formate following Cbl inactivation. There was impaired utilization of [14C]formate for single unit carbon (C1 unit) transfers mediated by folate in Cbl-inactivated tissues, other than for synthesis of adenine. The impairment was not accompanied by any accumulation of labelled methylH4folate indicating that methylfolate trapping played no part in impaired single carbon unit transfer. The effect of Cbl lack was a failure to form formylH4folate so that formate accumulated. The reason for this is not known.

Animals↗
PubMed1990

Methylation of DNA in megaloblastic anaemia.

Methylation of cytosine residues in DNA samples, collected before and serially after cobalamin treatment from patients with cobalamin deficiency, was studied using restriction endonucleases Hpa II and Msp I and an epsilon globin gene probe. There was no evidence of hypomethylation in any of the samples. It was concluded that although hypomethylation of metabolites such as choline occurs, that of DNA is preserved in megaloblastic anaemia.

Anemia, Macrocytic↗
PubMed1989

Oxidation of 5-methyltetrahydrofolate in cobalamin-inactivated rats.

Rats were exposed to nitrous oxide, which inactivates cob(I)alamin (Cbl). As in air-breathing rats methionine administration led to the conversion of hepatic 5-methyltetrahydrofolate (MeH4 folate) into formyltetrahydrofolate. The recovery of MeH4 folate levels in liver after its oxidation initiated by methionine was noted and the rate compared with that for air-breathing rats. Oxidation of MeH4 folate was less complete and occurred more slowly in Cbl-inactivated rats as compared with controls. However, recovery of MeH4 folate levels was more rapid in Cbl inactivation. S-Adenosylmethionine did not produce a significant change in MeH4 folate levels in Cbl-inactivated rats, whereas it did so in air-breathing animals.

Animals↗
PubMed1989

Regulation of 5-methyltetrahydrofolate synthesis.

After an intraperitoneal injection of 100 mumol of methionine to rats, there is rapid oxidation of the methyl group of hepatic 5-methyltetrahydrofolate to formate and CO2. Recovery of the methylfolate level starts 2.5 h after the methionine injection, when the hepatic methionine level and the S-adenosylmethionine/S-adenosylhomocysteine ratio have returned to baseline values. S-Adenosylmethionine concentration is still elevated at this time.

Animals↗
PubMed1989

Cobalamin-folate interrelations.

Cobalamin deficiency leads to impaired folate function as demonstrated by markedly impaired single-carbon unit transfer into purine, thymidine and methionine. This occurs in the total absence of 'methylH4folate trapping'. In cobalamin deficiency there is impaired synthesis of formylH4folate and raised levels of endogenous formate in blood and liver. FormylH4folate and methionine reverse the effects of cobalamin deficiency. Methionine provides formate via its metabolism to methylthioribose. Recently it has been suggested that the neuropathy of cobalamin deficiency is due to impaired methylation but this was not confirmed. It is likely that defects demonstrated in marrow and liver are also the explanation for the effects of cobalamin deficiency in the CNS.

Anemia, Megaloblastic↗
PubMed1988

In vivo oxidation of the methyl group of hepatic 5-methyltetrahydrofolate.

Methionine given parenterally to rats caused rapid disappearance of methyltetrahydrofolate from the liver and a corresponding rise in tetrahydrofolate and formyl-tetrahydrofolate concentrations. When [14C]H3--H4folate was given, methionine caused an increased [14C]0(2) excretion, indicating that oxidation of the methyl group had occurred. Methionine was more effective than S-adenosylmethionine at causing oxidation, but serine was ineffective. The lowest dose of methionine to produce an effect was 0.5 mumol, which is less than the daily dietary intake in a rat. The data suggest that the concentration of methylfolate in rat livers is controlled by the concentrations of methionine.

Adenosine↗
PubMed1987

Agonist and antagonist activities at benzodiazepine receptors of a novel series of quinoline derivatives.

Five members of a novel series of quinoline derivatives which all have similar activities on benzodiazepine receptor binding in vitro were compared in a food-motivated conflict and stress-induced ultrasounds models of anxiety and on suprahyoid muscle twitching in urethane-anaesthetised rats. RU 42382, RU 43028 and RU 39419 showed anxiolytic activity in both tests and RU 40410 was an antagonist. RU 40744 inhibited stress-induced ultrasounds but had little activity in the conflict test. Amphetamine-induced suprahyoid muscle twitching was only weakly inhibited by RU 42382 and RU 43028 in comparison with a classical benzodiazepine agonist. Ro15-1788 antagonised RU 42382 indicating that a major component of its action was agonism at benzodiazepine receptors. RU 39419 had no effect, RU 40744 tended to increase and RU 40410 evoked a small but statistically significant increase in twitching. The same rank order was observed in antagonism of a benzodiazepine in the muscle twitching model. RU 42382 was least effective as an antagonist and RU 40410 most effective. RU 39419 had no effect alone but antagonised the decrease of firing rate of cerebellar Purkinje cells induced by a benzodiazepine in urethane-anaesthetised rats. Comparison of in vivo occupancy of benzodiazepine receptors and efficacy in the conflict test in rats suggests a ranking of agonist intrinsic activity: RU 42382 greater than RU 43028 greater than RU 39419. A simple relationship between intrinsic activity at benzodiazepine receptors and structure of the compounds is proposed.

Action Potentials↗
PubMed1987

Impaired formylation and uptake of tetrahydrofolate by rat small gut following cobalamin inactivation.

The effect of inactivation of cobalamin by N2O on the intestinal absorption of folate was studied using rat everted gut sacs. Further, in view of uncertainties about the presence of methionine synthetase in gut [1], this enzyme was measured. Everted gut sacs were incubated with [2-14C]tetrahydrofolate, and the subsequent appearance of labelled formyl- and methyl [14C] tetrahydrofolate in everted segments of small intestine of rats was studied. Considerable methionine synthetase activity was present in washed everted gut sacs but not in gut segments in the absence of such treatment. Methionine synthetase activity declined after exposure to N2O, which oxidizes and inactivates cob(I)alamin. Folate uptake by gut sacs was not affected by 24 h exposure of the animals to N2O but fell significantly after 7 days exposure. There was a significant fall in the amount of formyltetrahydrofolate formed after cobalamin inactivation and this was reversed by supplying either methionine, methylthioadenosine or sodium formate. Serine had no effect. The data support the hypothesis that methionine and methylthioadenosine act by supplying single carbon units at the formate level of oxidation.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗