Dramatic increase in incidence of insulin-dependent diabetes mellitus in Western Australia.
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Adolescent↗
Biomedical subjects
R Griffiths
Publications and source records attributed to R Griffiths.
New drugs in phase I and beyond workshop.
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Animals↗
Depolarising levels of KCl inhibit endothelin-1-mediated release of arachidonic acid in rat C6 glioma cells.
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Animals↗
Modulation by ionotropic excitatory amino acids and potassium of (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid-stimulated phosphoinositide hydrolysis in mouse cerebellar granule cells.
The effect of ionotropic excitatory amino acids and potassium on the formation of inositol phosphates elicited by the metabotropic glutamate receptor agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD) was studied in mouse cerebellar granule cells. In Mg(2+)-containing buffers, NMDA (50-100 microM), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA; 10-1,000 microM), and high potassium (10-30 mM) enhanced synergistically the response to a maximally effective concentration of 500 microM trans-ACPD. Potentiation of the trans-ACPD response was blocked by higher concentrations of NMDA (> 500 microM) and potassium (> 35 mM) but not by AMPA (up to 1 mM). The potentiation by NMDA of the trans-ACPD-stimulated phosphoinositide hydrolysis was blocked by D,L-2-amino-5-phosphonopentanoic acid (APV), a competitive NMDA-receptor antagonist. Under Mg(2+)-free conditions, the accumulation of inositol phosphates in the presence of trans-ACPD alone was equal to that attained by trans-ACPD in Mg(2+)-containing buffers when costimulated with maximally enhancing concentrations of NMDA (50 microM). trans-ACPD potentiated synergistically the NMDA-evoked increases in cytosolic free-Ca2+ levels in Mg(2+)-containing but not in Mg(2+)-free solutions, and moreover did not enhance the AMPA-evoked increases in cytosolic free-Ca2+ levels. The calcium ionophore A23187 caused a dose-dependent increase in inositol phosphate accumulation but did not enhance the response stimulated by trans-ACPD alone. These results demonstrate the existence of cross talk between metabotropic and ionotropic glutamate receptors in cerebellar granule cells. The exact mechanism remains unclear but appears to involve interplay of G protein-coupled phospholipase C activation and regulated elevation of cytosolic free-Ca2+ levels. This study may provide a framework for future investigations at the cellular and molecular level that clarify the functional relevance and molecular mechanisms that are described.
Animals↗
Is there a seasonal variation in the incidence of gestational diabetes?
It has been suggested that the incidence of gestational diabetes (GDM) may vary with different seasons of the year. The fasting and 2 h glucose levels after a 75 g glucose tolerance test were therefore examined in 2749 women being tested for GDM and were correlated with the mean temperature at 0900 h by month and by season. The mean monthly temperature ranged from 22.3 degrees C in January to 13.6 degrees C in July. The monthly incidence of GDM ranged from 3.5% (95% CI, 0.7-6.3) in September to 8.7% (4.7-12.7) in November. The seasonal incidence of GDM ranged from 7.4% (5.6-9.2) in autumn to 5.5% (3.5-7.5) in winter. Chi-squared analysis did not suggest a significant association between the proportion of women diagnosed with GDM and either the month (p = 0.47) or the season (p = 0.39). Multiple regression analysis, after correction for maternal age, parity, BMI, and the week of testing revealed a non-significant association between fasting glucose and monthly temperature (p = 0.36) and an increase in the 2 h glucose of 0.026 mmol l-1 for each increase of 1 degree C in temperature (p = 0.011). In a temperate coastal area of Australia these differences do not appear clinically significant and have not caused a variation in the incidence of GDM with different seasons.
Adult↗
Inhibition by halothane of potassium-stimulated acetylcholine release from rat cortical slices.
1. Cholinergic neurones in the basal forebrain are linked to cortical activation and arousal. 2. The present study was designed to examine the hypothesis that clinically relevant doses of halothane (0.1 to 5%) would significantly reduce depolarization-evoked acetylcholine (ACh) release from rat cortical slices. 3. ACh release was measured from rat cortical slices by a chemiluminescent technique. 4. Depolarization-evoked ACh release was inhibited significantly by halothane with an IC50 of 0.38%. This value equates to 0.3 MAC (the minimum alveolar concentration at which no movement occurs to a standard surgical stimulus in 50% of subjects) for the rat. 5. The potent effect of halothane on ACh release suggests that this mechanism may be a target for the action of volatile anaesthetic agents. This in vitro effect on ACh release is consistent with effects of halothane reported in vivo.
Acetylcholine↗
Gestational diabetes: do all women need to be tested?
The results of glucose tolerance testing in 1,185 consecutive women were examined with respect to historical risk factors for gestational diabetes mellitus (GDM). GDM was present in 79 of 1,185 (6.7%) of the women. GDM was present in 8.5% of women aged > or = 30 years, in 12.3% of women with a preconception BMI > or = 30 and in 11.6% of women with a family history of diabetes in a first degree relation. A combination of one or all of these risk factors predicted GDM in only 48 of 79 (60.8%) cases. GDM was present in 4.8% of women without risk factors. Testing for GDM on the basis of these historical risk factors alone, and using the Australasian Diabetes in Pregnancy Society (ADIPS) criteria for diagnosis, would miss more than one-third of all cases. This study supports the ADIPS recommendation that there should be universal testing.
Adult↗
Job satisfaction and health of house officers in the West Midlands.
A postal questionnaire survey was conducted in 1993 to determine the job satisfaction and current state of health of British-trained pre-registration house officers (PRHOs) working in the West Midlands Regional Health Authority. The questionnaire included parts of the Occupational Stress Indicator looking at job satisfaction, and mental and physical ill-health (as manifestations of stress). Out of 234 eligible PRHOs 182 (78%) returned questionnaires: female PRHOs had significantly higher scores for physical and mental ill-health than male PRHOs; 14.2% of PRHOs had scores for mental ill-health, and 17.6% scores for physical ill-health that were higher than the average reported for patients with psycho-neurotic disorders. The PRHOs had significantly lower scores for all individual aspects of job satisfaction and total job satisfaction, and significantly higher scores for mental and physical ill-health than a comparative group of junior hospital doctors (all grades), and a large group of non-health-care white-collar workers. These results indicate that there is a need to raise awareness of stress and stress-related problems faced by junior doctors, and to provide adequate support.
Adult↗
Diabetic control and hypoglycaemia in the Illawarra area of NSW, Australia: a comparison with the DCCT.
The level of diabetic control and the number of hypoglycaemic episodes in the intensively treated insulin-dependent diabetes mellitus (IDDM) patients of the Diabetes Control and Complication Trial (DCCT) are a stimulus for other centres to critically examine their results. We examined diabetic control and the number of hypoglycaemic episodes in an unselected group of patients with IDDM diabetes from a population based diabetes register in the Illawarra area of Australia. Eligible patients were insulin dependent, aged 13-39 years, diagnosed for more than 1 year and had had a HbA1c test in the previous 6 months. Better diabetic control was achieved in patients with IDDM, without the need for intensive insulin therapy, than the intensively treated patients of the DCCT with fewer hypoglycaemic events. Before intensive insulin therapy for all patients with IDDM is considered, different models of diabetic healthcare delivery and medical treatment philosophies need to be examined.
Adolescent↗
Mixed actions of TMB-8 as a Ca2+ antagonist in cultured mouse cortical neurones.
The action of TMB-8 [8-N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate] on glutamate (Glu)- and 55 mM KCl (K+)-induced increases in intracellular free calcium levels ([Ca2+]i) was studied in cultured mouse cerebral cortical neurones. Glu-induced responses were mediated by two mechanisms, one independent of and the other dependent on extracellular Ca2+, both being inhibited by TMB-8 in a dose-dependent manner. TMB-8 had no effect on [3H]dizocilpine binding kinetics in cortical membrane preparations. The transient and sustained phases of K(+)-induced increases in [Ca2+]i were also inhibited by TMB-8 in a dose-dependent manner. The Ca2+ channel antagonist, verapamil, blocked K(+)-induced responses but had no effect on Glu-induced responses. Although TMB-8 displays multiple effects, its action at voltage-gated Ca2+ channels does not appear to contribute significantly to its inhibition of the Glu-induced increase in [Ca2+]i.
Animals↗
L-trans-pyrrolidine-2,4-dicarboxylate and cis-1-aminocyclobutane-1,3-dicarboxylate behave as transportable, competitive inhibitors of the high-affinity glutamate transporters.
The ability of two conformationally restricted analogues of L-glutamate to function as non-transportable inhibitors of plasma membrane L-glutamate transport was investigated in primary cultures of cerebellar granule cells and cortical astrocytes. L-trans-Pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC) and cis-1-aminocyclobutane-1,3-dicarboxylic acid (cis-ACBD) behaved as linear competitive inhibitors of the uptake of D-[3H]aspartate (used as a non-metabolizable analogue of L-glutamate) exhibiting Ki values between 40 and 145 microM; L-trans-PDC being the more potent inhibitor in each preparation. However, both L-trans-PDC and cis-ACBD, over a concentration range of 1 microM-5 mM, dose-dependently stimulated the release of exogenously supplied D-[3H]aspartate from granule cells maintained in a continuous superfusion system. The stimulated release was independent of extracellular calcium ions; essentially superimposable dose-response profiles being obtained in the absence and presence of 1.3 mM CaCl2 and yielding EC50 values of 16-25 microM and 180-220 microM for L-trans-PDC and cis-ACBD, respectively. Stimulated release of D-[3H]aspartate was unaffected by either 300 microM D-(-)-2-amino-5-phosphonopentanoic acid [D-APV; a selective antagonist of the N-methyl-D-aspartate (NMDA) receptor] or by 25 microM 6-cyano-7-nitroquinoxaline-2,3-dione [CNQX; a selective antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor]. The release of D-[3H]-aspartate following stimulation by either L-trans-PDC or cis-ACBD was however markedly attenuated following substitution in the superfusion medium of sodium ions by choline ions. Taken together, these results support an action of L-trans-PDC and cis-ACBD consistent with that of being competitive substrates rather than non-transportable blockers of the plasma membrane L-glutamate uptake system.
Amino Acid Transport System X-AG↗
Sulphur-containing excitatory amino acid-stimulated inositol phosphate formation in primary cultures of cerebellar granule cells is mediated predominantly by N-methyl-D-aspartate receptors.
The stimulatory effect of excitatory sulphur-containing amino acids on inositol phosphate formation was investigated in primary cultures of cerebellar granule cells. L-Cysteine sulphinate (CSA), L-cysteate (CA), L-homocysteine sulphinate (HCSA), L-homocysteate (HCA) and S-sulpho-L-cysteine (SSC) dose-dependently stimulated the formation of [3H]inositol phosphates exhibiting EC50 values in the range 60-200 microM and maximal effects of six- to 17-fold that of basal [3H]inositol phosphate levels. Endogenous L-glutamate spontaneously released into the extracellular medium or following exposure of cells to HCSA, HCA or SSC did not contribute significantly to formation of [3H]inositol phosphates, whereas 10% of the total [3H]inositol phosphates accumulated following exposure to CSA and CA was due to released L-glutamate. The selective N-methyl-D-aspartate receptor antagonist, D,L-2-amino-5-phosphonopentanoic acid (APV, 500 microM) attenuated by 20% (HCSA) to between 80 and 100% (CSA, CA, SSC, HCA) the formation of [3H]inositol phosphates induced by 1 mM sulphur-containing amino acids. When, however, HCSA was used at 100 microM (a concentration near to its EC50 for phosphoinositide hydrolysis), APV inhibited induced responses by 70%. Sulphur-containing amino acid-stimulated [3H]inositol phosphate formation was unaffected by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM). Inhibition of sulphur-containing amino acid-stimulated [3H]inositol phosphate formation by co-administration of APV and CNQX was similar to that obtained in the presence of APV alone. CSA-, CA-, SSC- and HCA-stimulated [3H]inositol phosphate formation was markedly reduced by removal of Ca2+ from the extracellular medium whereas that stimulated by HCSA was less affected. A similar inhibitory profile was observed when the levels of sulphur-containing amino acid-induced increases in intracellular free calcium ([Ca2+]i) were measured in the presence of 500 microM APV; 1 mM HCSA-induced responses being inhibited by only 30% whereas responses to the remaining sulphur-containing amino acid (also at 1 mM) were inhibited by > 45%. When the sulphur-containing amino acids were used at concentrations approximating their EC50 values for phosphoinositide hydrolysis, APV inhibited the induced increases in [Ca2+]i by 70-100%. HCA and SSC co-administered with the less efficacious but selective metabotropic glutamate receptor agonist, (+-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD) at maximally effective concentrations (1 mM) of each agonist stimulated [3H]inositol phosphate formation in an additive manner.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Day surgery--how much is possible? A Delphi consensus among surgeons.
Although day surgery (DS) has been performed for many years, it has only relatively recently become a popular and acceptable method of treating many common surgical conditions. With considerable pressure to maximise resource usage DS has been seized upon as a way of stretching scarce resources further. A review of the amount of DS undertaken within the West Midlands region revealed that the current workload showed considerable variation both between districts and between consultants. In an effort to gain clinical commitment to increasing generally the amount of DS undertaken, and obtaining more uniform coverage of DS across the region, a consensus conference was held. The two aims of the conference were to set targets as to the amount of DS considered feasible at a procedural level, and to seek clinicians' views as to the obstacles to developing the service. Targets for 43 procedures at one and/or five years were obtained by the use of a modified Delphi consensus. The groups showed a high level of consensus in the targets reached. A variety of obstacles were discussed. We have shown that it is possible to involve a large number of doctors in the decision-making/target-setting process by using a modified Delphi technique. It remains to be seen whether those targets are met in clinical practice. Surprisingly, obstacles to development were mainly concerned with management and personnel issues rather than capital investment.
Ambulatory Surgical Procedures↗
Choline acetyltransferase activity of rat synaptosomes is sensitive to enflurane, but not halothane or isoflurane.
We have examined the activity of choline acetyltransferase (ChAT) in rat cortical synaptosomes in the presence of three volatile anaesthetic agents: enflurane, halothane and isoflurane. The Michaelis constant Km, for choline was reduced significantly (P = 0.012) in the presence of 6.5% enflurane (3 rat MAC) compared with control samples exposed to carrier air only, while maximum reaction velocity (Vmax) remained unaltered. The reduction in Km was also significant at enflurane concentrations of 4.4% (2 rat MAC) (P = 0.043) and 2.2% (1 rat MAC) (P = 0.043). Halothane 3% (2.5 rat MAC) and 4.5% isoflurane (3 rat MAC) had no effect on either kinetic property. If present in vivo, an enflurane-induced alteration in acetylcholine metabolism, through modified ChAT, may contribute to the convulsive properties of this anaesthetic.
Anesthetics↗
Volatile anesthetic agents inhibit choline uptake into rat synaptosomes.
BACKGROUND: Acetylcholine is an excitatory neurotransmitter associated with the maintenance of consciousness. Choline uptake is the rate-limiting step in acetylcholine synthesis and may be a target for the action of volatile anesthetic agents. METHODS: [Methyl-3H]choline uptake was investigated using rat cortical synaptosomes. The preparation was exposed to air, as control, or equipotent partial pressures (2.4 rat MAC) of enflurane, halothane or isoflurane. In addition, the dose-response relation for halothane on [methyl-3H]choline uptake was studied. RESULTS: The maximum rate of uptake was reduced significantly by 24% in the presence of enflurane (5.5%, 2.4 rat MAC) and isoflurane (3.5%, 2.4 rat MAC) and by 38% in the presence of halothane (3%, 2.4 rat MAC) with no change in Michaelis constant in the presence of each agent. A linear relation between the inhibition of [methyl-3H]choline uptake and the concentration of halothane was observed up to 3% halothane above which there was no further inhibition. The concentration of halothane resulting in half-maximum inhibition of total choline uptake was 1.5%. CONCLUSIONS: Noncompetitive inhibition of [methyl-3H]choline uptake by volatile anesthetic agents has been demonstrated in the in vitro synaptosome preparation. If present in vivo reduction in anesthetic-sensitive choline uptake may reduce the presynaptic availability of acetylcholine and hence contribute to the process of anesthesia.
Anesthetics↗
Full circle. Interview by Annabelle May.
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Health Resources↗
The isolation of molecular genetic markers for the identification of sex.
It is difficult to identify sex in many species of eukaryotic organism. This can considerably impede research into their biology. Fortunately, one sex often possesses a unique chromosome termed Y or W. When DNA markers are available for these chromosomes, then sex identification becomes straightforward. We describe a technique that facilitates the isolation of such markers. The procedure makes use of low-stringency PCR to screen randomly selected primers for their ability to amplify sex-specific loci.
Animals↗
Improved renal function in mouse kidney allografts lacking MHC class I antigens.
The immunological responses that lead to rejection of organ and tissue transplants are triggered by the recognition of proteins encoded within the MHC. The relative contributions of responses directed toward MHC class I compared with class II in the loss of functional integrity of vascularized organ grafts have been difficult to define. The recent development of technologies which allow the generation of mice in which specific genes have been altered by gene targeting offers a new approach to addressing this question. We examine here the rejection of kidney allografts from mice lacking native MHC class I Ag. These mice were obtained from embryonic stem cells in which the beta 2 microglobulin (beta 2m) gene had been disrupted by homologous recombination. We found a significant improvement in function of renal allografts from MHC class I-deficient donors compared with allografts from donors with normal MHC class I expression. Surprisingly, the improved function of the MHC class I-deficient grafts was not associated with differences in mononuclear inflammatory cell infiltration of these grafts nor in differences in alloreactive proliferative or cytotoxic T cell responses. However, we did find differences in alloantibody response between the groups. Recipients of control allografts produced antibodies against both donor MHC class I and II, whereas recipients of MHC class I-deficient grafts formed alloantibodies primarily against donor MHC class II Ag. These studies confirm that immune responses directed toward donor MHC class I alloantigens contribute to kidney transplant dysfunction in this model. Also, these findings suggest that, at least for renal transplants, genetic manipulations which reduce MHC class I expression may be effective in overcoming some of the effects of MHC incompatibility.
Animals↗