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Biomedical subjects

R Griffiths

Publications and source records attributed to R Griffiths.

At least 73 records · Page 4Linked to original sources
PubMed1997

A CHD1 gene is Z chromosome linked in the chicken Gallus domesticus.

Chromo-helicase-DNA binding 1 (CHD1) is a conserved protein with a putative role in chromatin architecture. Single homologues have been found in mouse, Drosophila and yeast. In birds the situation is different as they possess two homologues. One is known to be W-linked, we show the second, closely related gene is linked to the Z sex chromosome. The basic structure of the Z-linked gene is similar to the homologous genes, however, it does possess an additional, internal 88 amino acid hydrophilic domain, rich in glutamic acid and lysine. Studies on pairs of genes sex-linked in mammals suggests rapid divergence of DNA sequence and function. We suggest the DNA sequences of CHD-W and CHD-Z do not follow this pattern.

Amino Acid Sequence↗
PubMed1997

Association of c-fos mRNA expression and excitotoxicity in primary cultures of mouse neocortical and cerebellar neurons.

The effect of excitatory amino acids (EAAs) on c-fos mRNA expression was studied in primary cultures of mouse cerebellar granule cells and in neocortical neurons after 2 and 7 days in vitro (div). In cultured granule cells at 2 and 7 div, and in cortical neurons at 2 div, exposure to low levels (< or = 10 microM) of a variety of EAAs (viz. glutamate [Glu], S-sulpho-L-cysteine [SC], N-methyl-D-aspartate [NMDA], alpha-amino-3-hydroxy-5-methyl-4-isoxazole [AMPA], and kainate [KA]) resulted in a transient increase in the level of c-fos mRNA which peaked at 30 min but returned to a basal level by 120 min. However, exposure of granule cells (7 div) to high levels (250 microM) of Glu, NMDA, KA, SC and of cortical neurons (7 div) to high levels (250 microM) of Glu, NMDA, KA, SC, or AMPA and to low levels (< or = 10 microM) of Glu and AMPA resulted in a delay in c-fos mRNA induction but a subsequent, progressive increase that was sustained for at least 240 min. Furthermore, this effect was accompanied by a dose-related increase in the release of the cytosolic enzyme, lactate dehydrogenase, used as an indicator of excitotoxicity. A ratio (Q240/30) for the steady-state levels of c-fos mRNA after 30 min and 240 min of exposure to EAAs was determined which showed that Q240/30 >2 correlated reproducibly with excitotoxic cell death, whereas a ratio of < or = 1 correlated with a nonexcitotoxic event. In both cell types at 7 div, coadministration of the selective NMDA receptor antagonist, DL(+/-)-2-amino-5-phosphonopentanoic acid (APV) with cytotoxic levels of Glu 1) protected against EAA-induced neurotoxicity and 2) exhibited a transient c-fos mRNA expression (Q240/30 values approximately 1). In contrast, the AMPA/KA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), provided no protection against excitotoxicity and had no significant effect on the Glu-induced delay in c-fos mRNA expression. These results suggest that the Q240/30 c-fos mRNA ratio may 1) be used as a predictive index for excitotoxic neuronal death, 2) provide information on the identity of the receptor subtype mediating excitotoxicity in different brain cell types, and 3) aid in establishing the role of excitotoxicity during the development of neurons in vitro.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1997

Thiamine supplementation mood and cognitive functioning.

One hundred and twenty young adult females took either a placebo or 50 mg thiamine, each day for 2 months. Before and after taking the tablets, mood, memory and reaction times were monitored. An improvement in thiamine status was associated with reports of being more clearheaded, composed and energetic. The taking of thiamine had no influence on memory but reaction times were faster following supplementation. These influences took place in subjects whose thiamine status, according to the traditional criterion, was adequate.

Adult↗
PubMed1997

Sulphur-containing amino acids modulate noradrenaline release from hippocampal slices.

The L- and D-enantiomers of the sulphur-containing amino acids (SAAs)-homocysteate, homocysteine sulphinate, cysteate, cysteine sulphinate, and S-sulphocysteine-stimulated [3H] noradrenaline release from rat hippocampal slices in a concentration-dependent manner. The relative potencies of the L-isomers (EC50 values of 1.05-1.96 mM) were of similar order to that of glutamate (1.56 mM), which was 10-fold lower than that of NMDA (0.15 mM), whereas the D-isomers exhibited a wider range of potencies (0.75 to > 5 mM). All stimulatory effects of the SAAs were significantly inhibited by the voltage-sensitive Na+ channel blocker tetrodotoxin (55-71%) and completely blocked by addition of Mg2+ or Co2- to the incubation medium. All SAA-evoked responses were concentration-dependently antagonized by the selective NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid (IC50 values of 3.2 - 49.5 microM). 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA receptor antagonist, at 100 microM inhibited the [3H]noradrenaline release induced by glutamate and NMDA (65 and 76%, respectively) and by all SAAs studied (65-85%), whereas 10 microM CNQX only inhibited the effects of S-sulpho-L-cysteine and L- and D-homocysteate (33, 32, and 44%, respectively). However, the more selective AMPA/kainic acid receptor antagonist 6-nitro-7-sulphamoylbenzo (f) quinoxaline-2,3-dione (100 microM), which did not antagonize the [3H]noradrenaline release induced by glutamate and NMDA, reduced only the S-sulpho-L-cysteine-evoked response (25%). Thus, the stimulation of Ca2(+)-dependent [3H]noradrenaline release from hippocampal slices elicited by the majority of the SAAs appears to be mediated by the NMDA receptor.

2-Amino-5-phosphonovalerate↗
PubMed1997

Anaesthetic potency of inhalation agents is independent of membrane microviscosity.

The decrease in membrane microviscosity of erythrocyte ghosts in the presence of clinically relevant concentrations of seven inhalation anaesthetic agents was studied using fluorescence polarization anisotropy of the membrane incorporated fluorescent probes 1,6-diphenyl-1,3,5-hexatriene and 1-[4-trimethylammoniumphenyl]-6-phenyl-1,3,5-hexatriene. All anaesthetic agents produced a dose-dependent decrease in anisotropy of both probes, indicating decreased membrane microviscosity. The reduction in anisotropy measured at the minimum alveolar concentration (ED50) for anaesthesia was related inversely to the anaesthetic potency of the agent and was directly proportional to the hypothetical concentration of agent in the membrane calculated from lipid-water partition coefficients. These findings do not support the hypothesis that volatile anaesthetic agents act by increasing membrane microviscosity of the bulk lipid bilayer to produce anaesthesia.

Anesthetics, Inhalation↗
PubMed1997

Enhanced choline acetyltransferase activity does not explain the action of inhaled convulsants.

Enhancement of choline acetyltransferase (ChAT) activity and increased intraneuronal acetylcholine (ACh) may explain the convulsant activity of some inhaled compounds. Enflurane, for example, enhances such activity. Accordingly, we measured choline acetyltransferase (ChAT) activity in rat cortical synaptosomes in the presence of two inhaled convulsants, flurothyl (CF3CH2OCH2CF3) and 1,2-dichlorohexafluorocyclobutane at partial pressures below and greatly exceeding those which produce convulsions in vivo. Neither agent changed the kinetic parameters, maximum velocity (vmax) or Michaelis constant (Km). The vmax for controls in the flurothyl series was 016 (0.06) nmol mg-1 min-1 and the Km was 0.23 (0.11) mmol litre-1. For the 1,2-dichlorohexafluorocyclobutane series of experiments the results for the controls were vmax 0.23 (0.10) nmol mg-1 min-1 and Km 0.20 (0.08) mmol litre-1. Modification of ChAT activity did not contribute to the excitatory effects of these agents.

Administration, Inhalation↗
PubMed1997

Comparison of the cardiovascular effects of the novel 5-HT(1B/1D) receptor agonist, SB 209509 (VML251), and sumatriptan in dogs.

The systemic cardiovascular effects of a novel 5-hydroxtryptamine (5-HT)(1B/1D)-receptor agonist were investigated in the anaesthetised dog. SB 209509 (VML 251) was more potent than sumatriptan in producing increases in carotid vascular resistance after intravenous administration and was similar in potency to sumatriptan after sequential intraduodenal administration at 30-min intervals. In open-chest dogs, sequential intravenous administration of SB 209509 or sumatriptan produced marked increases in carotid vascular resistance without changing coronary vascular resistance. In contrast to sumatriptan, after administration of high doses of SB 209509 (>790 nmol/kg), a reduction in coronary vascular resistance was observed. After a single bolus intraduodenal dose of SB 209509 (260, 520, or 790 nmol/kg), increases in carotid vascular resistance could be detected over a 5-h period. Sumatriptan (i.d.), 2.4 micromol/kg but not 700 nmol/kg, produced a sustained effect similar to the effects of SB 209509 (790 nmol/kg). In all experiments, SB 209509 and sumatriptan had minimal effects on arterial blood pressure or heart rate but produced marked changes in carotid vascular resistance over the same concentration range. SB 209509 was rapidly absorbed after intraduodenal administration in conscious dogs and had good bioavailability. These data indicate that SB 209509 is a potent 5-HT(1B/1D)-receptor agonist that is rapidly absorbed from the duodenum. The effects of SB 209509 are long lasting and selective for the carotid vascular bed.

Animals↗
PubMed1997

Gestational diabetes mellitus; resource utilization and costs of diagnosis and treatment.

The recommendation to test every woman for gestational diabetes mellitus (GDM) has a defined cost. The management of women diagnosed with GDM will use additional health resources. This examines the cost and resource utilization of a consecutive group of women diagnosed over a 1-year period. The cost of testing a woman for GDM is around $10.00 with slight variations depending on the testing procedure. The annual cost of testing in NSW would be less than 1 million dollars. Women diagnosed with GDM used the resources of a diabetes education centre for an average of 2.8 hours and attended for 3.4 (2.3) medical visits. Insulin was required by 18.7% of the women for 9.7 (4.7) weeks using 47.7 (21.2) units each day. Testing women for GDM is a low-cost item. Managing a woman diagnosed with GDM may cost several hundred dollars. Cost reductions could be made by reducing the amount of insulin used and by avoiding hospitalization.

Costs and Cost Analysis↗
PubMed1997

Predominance of a maternal history of diabetes for patients with non-insulin-dependent diabetes mellitus. Implications for the intrauterine transmission of diabetes.

In Europid populations, patients with non-insulin-dependent diabetes mellitus (NIDDM) are more than twice as likely to have a mother than a father with diabetes. We have examined this aspect in an Australian population. For this purpose records of 1,000 consecutive patients with NIDDM were reviewed. A history of diabetes was present in 193 mothers (19.3%) and in only 86 fathers (8.6%) (p < 0.0001). The predominance of maternal history of diabetes in patients with NIDDM is suggestive of a maternal transmission of this disorder. This metabolic tendency may develop due to an adverse intrauterine environment in women with undiagnosed gestational diabetes mellitus.

Adult↗
PubMed1996

Sex identification in birds using two CHD genes.

In theory, birds should control the sex ratio of the offspring they produce. In practice, we have very limited evidence to support this idea because of our difficulty in sexing nestling birds. In addition, extinction is facing an increasing number of birds. Our ability to help includes captive breeding which, again, is difficult if male and female adults cannot be recognized. Here we describe the discovery of a W-linked gene in the Great tit (Parus major). It is named CHD-W (chromodomain-helicase-DNA-binding protein W-linked), it is highly conserved and it is W-chromosome linked in a range of bird species. These birds also possess a second, non-W-linked CHD gene (CHD-NW). A single, simple polymerase chain reaction technique based on both genes can be used to identify the sex in a wide variety of birds.

Animals↗
PubMed1996

NMDA receptor-mediated cGMP synthesis in primary cultures of mouse cerebellar granule cells appears to involve neuron-astrocyte communication with NO operating as the intercellular messenger.

The possibility that neuron-astrocyte communication may be responsible for glutamate (Glu)-stimulated cGMP formation even in relatively homogeneous primary cultures of mouse cerebellar granule cells (7 days in vitro) was investigated. Pharmacological analysis using selective excitatory amino acid (EAA) receptor antagonists showed that cGMP production, stimulated in these cultures by Glu and a variety of endogenous EAAs structurally-related to Glu (namely, L-aspartate, L-cysteine sulphinate, L-homocysteate, S-sulpho-L-cysteine), was mediated wholly by N-methyl-D-aspartate (NMDA) receptor activation. Moreover, EAA-induced responses were dependent on the presence of extracellular calcium but unaffected by addition of the L-type voltage-sensitive calcium channel blockers nifedipine (10 microM) or verapamil (5 microM). The mode of calcium entry was also shown to be important since the calcium ionophore, A23187 (10 microM), was unable to stimulate cGMP levels above basal. cGMP formation was blocked by the competitive nitric oxide synthase inhibitor, L-NG-nitroarginine (100 microM), consistent with a role of nitric oxide (NO) in this signalling pathway. In the presence of added haemoglobin (1 microM), acting as a membrane-impermeable NO scavenger, Glu-stimulated cGMP formation was abolished implying that NO must act as an intercellular messenger. When the neuronal population was destroyed following a 24 hr exposure to the excitotoxin, S-sulpho-L-cysteine (200 microM), Glu-stimulated cGMP formation was abolished; whereas responses to the NO donor, sodium nitroprusside (SNP), although markedly reduced were still double that stimulated by Glu in the absence of the excitotoxin, suggesting the presence of non-neuronal cells that can generate cGMP if supplied directly with NO. Consistent with this suggestion, low levels of the glial specific enzyme, glutamine synthetase, were detected in granule cell cultures. Furthermore, omission or delayed addition of the antimitotic agent, cytosine arabinoside (20 microM), to the growth medium caused a significant increase in the level of Glu-stimulated cGMP formation.

Animals↗
PubMed1996

Does behavior reflect phylogeny in swiftlets (Aves: Apodidae)? A test using cytochrome b mitochondrial DNA sequences.

Swiftlets are small insectivorous birds, many of which nest in caves and are known to echolocate. Due to a lack of distinguishing morphological characters, the taxonomy of swiftlets is primarily based on the presence or absence of echolocating ability, together with nest characters. To test the reliability of these behavioral characters, we constructed an independent phylogeny using cytochrome b mitochondrial DNA sequences from swiftlets and their relatives. This phylogeny is broadly consistent with the higher classification of swifts but does not support the monophyly of swiftlets. Echolocating swiftlets (Aerodramus) and the nonecholocating "giant swiftlet" (Hydrochous gigas) group together, but the remaining nonecholocating swiftlets belonging to Collocalia are not sister taxa to these swiftlets. While echolocation may be a synapomorphy of Aerodramus (perhaps secondarily lost in Hydrochous), no character of Aerodramus nests showed a statistically significant fit to the molecular phylogeny, indicating that nest characters are not phylogenetically reliable in this group.

Animals↗
PubMed1996

Glutamate toxicity in primary cerebellar cultures from mouse brain is unaffected by changes in cGMP levels.

During evaluation of potential end-points for in vitro neurotoxicity screening we investigated what influence changes in cyclic GMP (cGMP) levels might exert on the degree of glutamate (Glu)-induced neurotoxicity in primary cultures of mouse cerebellar granule cells. Depletion of Glu-stimulated cGMP levels by N-methyl-D-aspartate receptor antagonists fully protected against Glu-induced toxicity. However, when Glu-stimulated cGMP levels were either depleted or elevated by the use of a variety of pharmacological agents acting intracellularly at various points of the NO/cGMP signalling pathway the degree of cytotoxicity exerted by Glu was unaltered. These results imply that cGMP and NO do not modulate the toxic effects of Glu and are therefore unsuitable as biomarkers of excitotoxicity in these cells.

Animals↗
PubMed1996

Delivering cancer care: a model from the West Midlands.

It would seem that time, tide and wind are favourably set for a shift in the organisation of cancer services. Let us test the hypotheses outlined in this brief paper and see if these changes will bring about demonstrable benefit.

Delivery of Health Care↗
PubMed1996

A prototypic intracellular calcium antagonist, TMB-8, protects cultured cerebellar granule cells against the delayed, calcium-dependent component of glutamate neurotoxicity.

The effect(s) of a prototypic intracellular Ca2+ antagonist, 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8), on glutamate-induced neurotoxicity was investigated in primary cultures of mouse cerebellar granule cells. Glutamate evoked an increase in cytosolic free-Ca2+ levels ([Ca2+]i) that was dependent on the extracellular concentration of Ca2+ ([Ca2+]o). In addition, this increase in [Ca2+]i correlated with a decrease in cell viability that was also dependent on [Ca2+]o. Glutamate-induced toxicity, quantified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) staining, was shown to comprise two distinct components, an "early" Na+/Cl(-)-dependent component observed within minutes of glutamate exposure, and a "delayed" Ca(2+)-dependent component (ED50 approximately 50 microM) that coincided with progressive degeneration of granule cells 4-24 h after a brief (5-15 min) exposure to 100 microM glutamate. Quantitative analysis of cell viability and morphological observations identify a "window" in which TMB-8 (at > 100 microM) protects granule cells from the Ca(2+)-dependent, but not the Na+/Cl(-) -dependent, component of glutamate-induced neurotoxic damage, and furthermore, where TMB-8 inhibits glutamate-evoked increases in [Ca2+]i. These findings suggest that Ca2+ release from a TMB-8-sensitive intracellular store may be a necessary step in the onset of glutamate-induced excitotoxicity in granule cells. However, these conclusions are compromised by additional observations that show that TMB-8 (1) exhibits intrinsic toxicity and (2) is able to reverse its initial inhibitory action on glutamate-evoked increases in [Ca2+]i and subsequently effect a pronounced time-dependent potentiation of glutamate responses. Dantrolene, another putative intracellular Ca2+ antagonist, was completely without effect in this system with regard to both glutamate-evoked increases in [Ca2+]i and glutamate-induced neurotoxicity.

Animals↗