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Biomedical subjects

R Griffiths

Publications and source records attributed to R Griffiths.

At least 91 records · Page 5Linked to original sources
PubMed1996

Endothelin-1 increases arachidonic acid release in C6 glioma cells through a potassium-modulated influx of calcium.

Endothelin-1 (Et-1) but not a range of other receptor agonists stimulated the release of arachidonic acid (AA) in C6 glioma. Et-1 activation was concentration dependent and was inhibited by chelation of extracellular calcium. The calcium ionophores A23187 and ionomycin could also stimulate release of AA. Et-1 caused an early increase in intracellular Ca2+ concentration ([Ca2+]i) followed by a sustained but lower plateau level. The sensitivity of the response to quinacrine, its dependence on Ca2+, and the demonstration of an increase in phospholipase A2 (PLA2) activity that was insensitive to dithiothreitol suggested that the release of AA was due to activation of cytosolic PLA2 in the cells. Staurosporine, a protein kinase C (PKC) inhibitor, had no effect on Et-1-induced AA release but abolished that by phorbol 12-myristate 13-acetate, demonstrating that the Et-1 response was PKC independent. Raised levels of extracellular KCl inhibited both AA release and the increase in [Ca2+]i triggered by Et-1, whereas valinomycin, which causes K+ efflux, not only caused a rapid rise in [Ca2+]i but also caused AA mobilisation. The results therefore suggest that Et-1 activation of PLA2 in this cell type requires calcium influx dependent on K+ efflux.

Animals↗
PubMed1996

Cost-effectiveness of directly observed versus self-administered therapy for tuberculosis.

Decision analysis was used to compare three alternative strategies for a 6-mo course of treatment for tuberculosis: directly observed drug therapy (DOT), self-administered fixed-dose combination drug therapy, and self-administered conventional individual drug therapy. Estimates of effectiveness were obtained from the published literature. Estimates of costs were obtained from the literature and the Baltimore City Health Department. Both DOT and fixed-dose combination therapy were less costly and more effective than conventional therapy, although DOT was most cost-effective. In total, the average cost per patient treated was $13,925 for DOT, $13,959 for fixed-dose combination therapy, and $15,003 for conventional therapy. Per 1,000 patients treated, 31 relapses and three deaths could be expected for DOT, 96 relapses and eight deaths for fixed-dose combination therapy, and 133 relapses and 13 deaths for conventional therapy. The marginal cost-effectiveness of DOT relative to fixed-dose combination therapy was most sensitive to variability in the direct cost of DOT and less sensitive to relapse rates for DOT and fixed-dose combination therapy. The inferior cost-effectiveness of conventional therapy was not sensitive to plausible variability in cost or effectiveness. Both DOT and fixed-dose combination therapy were cost-effective relative to conventional therapy, although DOT is probably most cost-effective.

Antitubercular Agents↗
PubMed1995

Excitatory amino acid-induced cytotoxicity in primary cultures of mouse cerebellar granule cells correlates with elevated, sustained c-fos proto-oncogene expression.

An elevated, sustained expression of c-fos mRNA was found in primary cultures of mouse cerebellar granule cells following exposure to toxic concentrations of the excitatory amino acids, L-glutamate, L-homocysteate, S-sulpho-L-cysteine and N-methyl-D-aspartate (NMDA), using leakage of lactate dehydrogenase (LDH) as an indicator of cytotoxicity. In contrast, when used at non-toxic concentrations these compounds induced a rapid and transient increase in c-fos mRNA levels. Both LDH release and elevated, sustained c-fos mRNA induction were blocked (in the case of L-homocysteate) or reduced (in the case of L-glutamate and S-sulpho-L-cysteine) by the selective NMDA receptor antagonist (DL(+/-)-2-amino- 5-phosphonopentanoic acid) whereas 6-cyano-7-nitroquinoxaline-2,3-dione (a selective antagonist at non-NMDA ionotropic receptors) had no effect. These data suggest a role for altered c-fos mRNA expression in excitotoxic mechanisms.

Animals↗
PubMed1995

Rejection of kidney allografts by MHC class I-deficient mice.

To evaluate the requirement for CD8+ T cells in kidney transplant rejection, we studied class I-deficient (class I-) mice that had received vascularized renal allografts. Because of the absence of MHC class I expression, these mice are grossly deficient in CD4-CD8+ alpha beta TCR+ cells. Despite the deficiency of CD8+ T cells in naive class I- mice, kidney allografts transplanted into class I- recipients developed significant reductions in renal blood flow and glomerular filtration rate to levels comparable to allograft controls. This functional deterioration was associated with histologic changes consistent with cellular rejection. There were no significant differences in the pattern, severity, or phenotypic character of the cellular infiltrate in allografts transplanted into class I- recipients compared to controls. In fact, substantial numbers of CD8+ T cells were present in these allografts, and the intensity and pattern of anti-CD8 staining was not different from controls. Virtually all of the CD8+ cells in the kidney grafts were class I- and CD4- and co-expressed CD8 alpha and beta chains; the majority were alpha beta TCR+. The CD8+ infiltrating cells were cytotoxic to donor targets but also exhibited activity against class I+ cells bearing self-MHC. Despite the marked CD8+ T cell infiltration of grafts, CD8+ T cells could not be detected by flow cytometry in freshly isolated splenocytes from the class I- recipients of allografts. High levels of circulating anti-class I antibodies were present in the serum of class I- recipients of kidney allografts, and these antibodies had unusual specificity in that they appeared to recognize framework epitopes of MHC class I. Thus, class I- mice readily reject kidney allografts. Although the number of CD8+ alloreactive precursors is substantially reduced in class mice, and their specificities are atypical, the pattern and character of the intra-graft CD8+ cellular response is not significantly altered. Thus, factors unrelated to precursor frequency determine the dimension of the intra-graft CD8+ response. Such factors might include cellular and/or biochemical properties of microenvironment within the graft.

Animals↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1994

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↗
PubMed1994

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↗
PubMed1994

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↗
PubMed1994

Acid aspiration prophylaxis in 202 obstetric anaesthetic units in the UK.

A postal survey of obstetric anaesthetic units in the UK was conducted by questionnaire to gain information about current acid aspiration prophylaxis. Information regarding the delivery rate and the caesarean section rate under regional techniques was also requested. Replies were received from 202 obstetric anaesthetic units in the UK, a 75% response rate. The results are compared to similar surveys carried out in 1984 and 1988. Sodium citrate and the H(2) antagonist ranitidine remain the drugs most commonly used for acid aspiration prophylaxis. However, the number of departments carrying out routine prophylaxis for patients in active labour has fallen from 75% in 1988 to 57% in the current survey.

Journal Article↗