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Biomedical subjects

G Edwards

Publications and source records attributed to G Edwards.

At least 91 records · Page 5Linked to original sources
PubMed1998

Tetanus--the silent killer: how safe are you?

Despite the fact that tetanus is entirely preventable, mortality and morbidity as a result of this disease remain significant. The tetanus toxoid is one of the most potent poisons known. While immunisation programs focus on children, the elderly remain at risk of contracting immunisable diseases. Tetanus often leads to prolonged hospital stays and requires emergency and intensive care intervention and management. This case study illustrates a number of important points concerning the recognition, treatment, management and prevention of tetanus poisoning, and highlights the importance of considering the immunisation status of our elderly patients.

Aged↗
PubMed1998

Assessment of the effect of malaria infection on hepatic clearance of dihydroartemisinin using rat liver perfusions and microsomes.

1. The clearance of dihydroartemisinin (DHA) in control and malaria-infected (MI) rats was investigated using the isolated perfused rat liver (IPRL) model and hepatic microsomal studies. 2. In the recirculating IPRL, clearance of DHA was reduced from a mean (s.d.) of 8.2+/-1.8 ml min(-1) in controls (n=8) to 6.0+/-1.0 ml min(-1) in MI (n=8; P<0.01). Clearance in control livers was similar to the perfusion flow rate, suggesting a high hepatic extraction ratio for DHA. 3. Single-pass IPRL studies in controls (n=8) showed that DHA bioavailability at 1.3, 8 and 38 microm was 0.026+/-0.020, 0.043+/-0.025 and 0.14+/-0.06, respectively (P<0.001 for 8 microM vs 38 microM). In MI livers (n=5), DHA bioavailability at 8 and 38 microM was 0.18+/-0.07 and 0.40+/-0.08, respectively (P=0.002). Bioavailability was higher in the MI group than in controls (P=0.01 at 8 microM and P<0.001 at 38 microM). DHA-glucuronide was the sole biliary metabolite. 4. Hepatic microsomal studies of DHA-glucuronide formation showed a significantly lower Vmax but no significant change in Km, in MI compared to control livers (n=6). Intrinsic metabolic clearance (Vmax/Km) was higher in control than in MI livers (5.2+/-1.3 and 2.5+/-1.4 microl min(-1) mg(-1), respectively; P=0.006). 5. These studies demonstrate that DHA has a high, concentration-dependent hepatic extraction ratio that is reduced by 20-30% in the P. berghei rodent malaria model. The impaired hepatic clearance of DHA in MI is attributable to a reduction in intrinsic metabolic clearance.

Animals↗
PubMed1998

Use of steroids, tocolytics and antibiotics in the management of preterm labour in Wales.

The management of preterm labour (PTL) remains contentious. Many regimes are used for the management of this common condition and in utero transfer of pregnant women to another unit is not unusual in British practice. Medical staff in the accepting unit may have little or no experience with one or more drug regimes used in this condition which used in isolation and in combination with others may have disastrous consequences for the mother. We have assessed the variation in practice for the management of preterm labour in all consultant-led obstetric units in Wales using a postal questionnaire. The percentage of units with written guidelines for the management of PTL was 40%. All units used corticosteroids although the regimes used varied. Fourteen of the 15 units used tocolytics. Ritodrine and nifedipine were the most frequently used tocolytics but there was much variation in practice. Only seven (46.7%) units used antibiotics and five of these were randomising women in PTL to the ORACLE study. Postal surveys may not reflect accurately what actually happens in clinical practice. These data demonstrate that there is no common policy for the management of PTL even in a relatively small region such as Wales. We would suggest that the development of a regional policy for the management of preterm labour would be a significant step forward in the management of this controversial, but important cause of neonatal morbidity and mortality.

Journal Article↗
PubMed1998

Morphological and immunocytochemical effects of dihydroartemisinin on differentiating NB2a neuroblastoma cells.

The toxicity caused by the artemisinin derivative dihydroartemisinin in differentiated NB2a neuroblastoma cells was studied by transmission and scanning electron microscopy, Western blotting and immunocytochemistry. Western blotting with monoclonal antibodies failed to detect any specific changes in the cell cytoskeleton, nor were any changes detected by immunocytochemistry. This was consistent with electron microscopy of surviving cell neurites. Transmission electron microscopy revealed that dihydroartemisinin damaged NB2a cell mitochondrial cristae and endoplasmic reticulum. Scanning electron microscopy revealed that dihydroartemisinin depleted the filopodia-like processes projecting from the surface of the cell body and neurites. Some, or all, of these drug-induced changes in differentiating NB2a cells may have a role in the neurotoxicity of artemisinin derivatives.

Animals↗
PubMed1998

Binding of dihydroartemisinin to differentiating neuroblastoma cells and rat cortical homogenate.

The binding characteristics of dihydroartemisinin to neural tissues and cells in culture were studied by incubating differentiating C6 and NB2a cells and rat cerebral cortex homogenate with 1 to 200 microM 14C-labelled dihydroartemisinin with or without 2 microM haemin for 24 h. The role of protein thiol and amine groups in dihydroartemisinin binding was assessed by pre-incubation of the cortex homogenate with sodium cyanate and/or iodoacetamide. Rosenthal plots of binding data demonstrated that there were two discrete phases of dihydroartemisinin binding. Haemin increased the total binding of dihydroartemisinin to both cortex and cell proteins. In each preparation, haemin increased Bmax of the high affinity binding sites and also increased kD of NB2a high affinity binding sites and decreased kD of cortex low affinity binding sites. The effects of haemin on the binding parameters of cortex resembled its effects on C6 cells rather than NB2a cells. NB2a high and low affinity binding sites had a greater affinity for dihydroartemisinin than those of either rat cortex or C6 cells. Iodoacetamide and sodium cyanate reduced binding to cortex proteins by approximately 70%. Co-incubation of 14C-dihydroartemisinin with arteether reduced binding of dihydroartemisinin but co-incubation with desoxyartemisinin did not. These studies demonstrate that the known haemin-induced increase in toxicity of dihydroartemisinin to differentiating neuroblastoma cells is accompanied by a corresponding increase in dihydroartemisinin binding to cell proteins, that protein thiol and amine groups react with the products of the reaction between dihydroartemisinin and haemin and point to a relationship between the toxicity of artemisinin derivatives and protein binding.

Animals↗
PubMed1997

Model-based interpretation of complex and variable images.

The ultimate goal of machine vision is image understanding-the ability not only to recover image structure but also to know what it represents. By definition, this involves the use of models which describe and label the expected structure of the world. Over the past decade, model-based vision has been applied successfully to images of man-made objects. It has proved much more difficult to develop model-based approaches to the interpretation of images of complex and variable structures such as faces or the internal organs of the human body (as visualized in medical images). In such cases it has been problematic even to recover image structure reliably, without a model to organize the often noisy and incomplete image evidence. The key problem is that of variability. To be useful, a model needs to be specific-that is, to be capable of representing only 'legal' examples of the modelled object(s). It has proved difficult to achieve this whilst allowing for natural variability. Recent developments have overcome this problem; it has been shown that specific patterns of variability in shape and grey-level appearance can be captured by statistical models that can be used directly in image interpretation. The details of the approach are outlined and practical examples from medical image interpretation and face recognition are used to illustrate how previously intractable problems can now be tackled successfully. It is also interesting to ask whether these results provide any possible insights into natural vision; for example, we show that the apparent changes in shape which result from viewing three-dimensional objects from different viewpoints can be modelled quite well in two dimensions; this may lend some support to the 'characteristic views' model of natural vision.

Form Perception↗
PubMed1997

Division of labor of Schwann cell integrins during migration on peripheral nerve extracellular matrix ligands.

Myelination of the peripheral nervous system (PNS) requires the migration of Schwann cells during both development and regeneration. We have characterized the expression pattern of Schwann cell integrins and analyzed their role in migration on different ECM substrates known to be present within the PNS. We found that Schwann cells in cell culture express four beta1 integrins, alpha1 beta1, alpha2 beta1, alpha6 beta1, and another unidentified beta1 integrin, as well as two alpha v integrins, alpha v beta3 and alpha v beta8. Using the Varani migration assay, we found that laminin-1, laminin-2 (merosin), and fibronectin increased Schwann cell migration, while vitronectin and collagen did not increase migration compared to an uncoated plastic substrate. Schwann cell migration on laminin-1 and laminin-2 (merosin) was blocked by antibodies against beta1 integrins, but not affected by RGD peptides or antibodies against beta3 integrins. In contrast, migration on fibronectin was unaffected by antibodies against beta1 and beta3 integrins but was blocked by RGD peptides. This in vitro study shows that there is a division of labor of Schwann cell integrins in the regulation of migration on peripheral nerve ECM components; beta1 integrins mediate migration on laminin-1 and laminin-2 (merosin), while alpha v integrins mediate migration on fibronectin. Taken together, these results suggest that multiple interactions between Schwann cell integrins and ECM within the PNS will contribute to Schwann cell migration during myelination of the PNS.

Animals↗
PubMed1997

Enhanced in vitro neurotoxicity of artemisinin derivatives in the presence of haemin.

The role of haem in the neurotoxicity of artemisinin derivatives has been studied in vitro by examining neurite outgrowth measured by image analysis and cellular metabolism of the tetrazolium salt MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) measured spectrophotometrically in the neuroblastoma cell line NB2a, and by examining binding of radiolabelled dihydroartemisinin to NB2a cell and rat brain proteins. In the cases of artemether, dihydroartemisinin, and arteether, haemin (ferriprotoporphyrin IX) significantly increased the dose-related inhibition of neurite outgrowth from differentiating NB2a cells and significantly increased the dose-dependent inhibition of MTT metabolism. Inhibition of neurite outgrowth and metabolism of MTT in the presence or absence of haemin ranged from 72% to 93% and from 27% to 49% at a drug concentration of 300 nM. Haemin also significantly increased the dose-related binding of radiolabelled dihydroartemisinin to proteins from NB2a cells approximately twofold and to rat brain between three- and sixfold. Haemin did not enhance the neurotoxicity of desoxyarteether, a structural analogue of arteether with an ether linkage in the place of the endoperoxide bridge. It is suggested that haemin may catalyse the transformation of these derivatives via an interaction with the endoperoxide bridge of the artemisinin derivative to produce free radicals or electrophilic intermediates that are toxic to neuronal cells.

Animals↗
PubMed1997

Analytical Debye-Huckel model for electrostatic potentials around dissolved DNA.

We present an analytical, Green-function-based model for the electric potential of DNA in solution, treating the surrounding solvent with the Debye-Huckel approximation. The partial charge of each atom is accounted for by modeling DNA as linear distributions of atoms on concentric cylindrical surfaces. The condensed ions of the solvent are treated with the Debye-Huckel approximation. The resultant leading term of the potential is that of a continuous shielded line charge, and the higher order terms account for the helical structure. Within several angstroms of the surface there is sufficient information in the electric potential to distinguish features and symmetries of DNA. Plots of the potential and equipotential surfaces, dominated by the phosphate charges, reflect the structural differences between the A, B, and Z conformations and, to a smaller extent, the difference between base sequences. As the distances from the helices increase, the magnitudes of the potentials decrease. However, the bases and sugars account for a larger fraction of the double helix potential with increasing distance. We have found that when the solvent is treated with the Debye-Huckel approximation, the potential decays more rapidly in every direction from the surface than it did in the concentric dielectric cylinder approximation.

DNA↗
PubMed1997

Adolescents' ideas about the health of the fetus.

OBJECTIVE: To determine the preponderance of ideas in adolescents about the relationship between maternal habits and the health of the fetus. DESIGN: Quantitative survey using a precoded questionnaire, the content of which was derived from the transcripts of interviews and the responses to open-form questionnaires. SETTING: North West Region Health Authority area, UK. PARTICIPANTS: 674 adolescents in British National Curriculum Year 10 (age 14/15) from 6 Community Comprehensive Schools. FINDINGS: Most of the adolescents were aware of the dangers to the fetus of alcohol and smoking, including passive smoking. However, they were less aware of the potential hazards during pregnancy of eggs (Salmonella), soft cheeses (Listeria), liver (Vitamin A excess) or handling cats (Toxoplasmosis). Most of the respondents thought that the optimum time to initiate actions for a healthy pregnancy was when pregnancy had been confirmed, suggesting that the benefits of preconceptual care are not well known. KEY CONCLUSIONS: Adolescents lack knowledge about some of the specific hazards to the fetus of maternal diet and behaviour during pregnancy and are unaware of the importance of the early stages of pregnancy in this context. IMPLICATIONS: There is a need for the provision of education about the importance of a healthy maternal lifestyle before conception and during early pregnancy for adolescents. Midwives may have a proactive role in such education, but should be aware that young people may have specific areas of ignorance and misconceptions which will need addressing.

Adolescent↗
PubMed1997

Involvement of voltage-dependent potassium channels in the EDHF-mediated relaxation of rat hepatic artery.

1. In the rat hepatic artery, the acetylcholine-induced relaxation mediated by endothelium-derived hyperpolarizing factor (EDHF) is abolished by a combination of apamin and charybdotoxin, inhibitors of small (SKCa) and large (BKCa) conductance calcium-sensitive potassium (K)-channels, respectively, but not by each toxin alone. The selective BKCa inhibitor iberiotoxin cannot replace charybdotoxin in this combination. Since delayed rectifier K-channels (KV) represent another target for charybdotoxin, we explored the possible involvement of KV in EDHF-mediated relaxation in this artery. 2. The KV inhibitors, agitoxin-2 (0.3 microM), kaliotoxin (0.3 microM), beta-dendrotoxin (0.3 microM), dofetilide (1 microM) and terikalant (10 microM), each in combination with apamin (0.3 microM) had no effect on the EDHF-mediated relaxation induced by acetylcholine in the presence of N omega-nitro-L-arginine (0.3 mM) and indomethacin (10 microM), inhibitors of nitric oxide (NO) synthase and cyclo-oxygenase, respectively (n = 2-3). Although the KV inhibitor margatoxin (0.3 microM) was also without effect (n = 5), the combination of margatoxin and apamin produced a small inhibition of the response (pEC50 and Emax values were 7.5 +/- 0.0 and 95 +/- 1% in the absence and 7.0 +/- 0.1 and 81 +/- 6% in the presence of margatoxin plus apamin, respectively; n = 6; P < 0.05). 3. Ciclazindol (10 microM) partially inhibited the EDHF-mediated relaxation by shifting the acetylcholine-concentration-response curve 12 fold to the right (n = 6; P < 0.05) and abolished the response when combined with apamin (0.3 microM; n = 6). This combination did not inhibit acetylcholine-induced relaxations mediated by endothelium-derived NO (n = 5). 4. A 4-aminopyridine-sensitive delayed rectifier current (IK(V)) was identified in freshly-isolated single smooth muscle cells from rat hepatic artery. None of the cells displayed a rapidly-activating and -inactivating A-type current. Neither charybdotoxin (0.3 microM; n = 3) nor ciclazindol (10 microM; n = 5), alone or in combination with apamin (0.3 microM; n = 4-5), had an effect on IK(V). A tenfold higher concentration of ciclazindol (0.1 mM, n = 4) markedly inhibited IK(V), but this effect was not increased in the additional presence of apamin (0.3 microM; n = 2). 5. By use of membranes prepared from rat brain cortex. [125I]-charybdotoxin binding was consistent with an interaction at a single site with a KD of approximately 25 pM. [125I]-charybdotoxin binding was unaffected by iberiotoxin (0.1 microM, n = 6), but was increased by apamin in a concentration-dependent manner (Emax 43 +/- 10%, P < 0.05 and pEC50 7.1 +/- 0.2; n = 7-8). Agitoxin-2 (10 nM) displaced [125I]-charybdotoxin binding by 91 +/- 3% (n = 6) and prevented the effect of apamin (1 microM; n = 6). 6. It is concluded that the EDHF-mediated relaxation in the rat hepatic artery is not mediated by the opening of either KV or BKCa. Instead, the target K-channels for EDHF seem to be structurally related to both KV and BKCa. The possibility that a subtype of SKCa may be the target for EDHF is discussed.

4-Aminopyridine↗
PubMed1997

Comparison of the acute cardiotoxicity of the antimalarial drug halofantrine in vitro and in vivo in anaesthetized guinea-pigs.

1. Several unrelated drugs have pro-arrhythmic activity associated with an ability to prolong the QT interval of the ECG. The aim of this work was to examine the effects of the antimalarial drug halofantrine in vivo and in vitro. 2. In anaesthetized guinea-pigs consecutive bolus doses of halofantrine (0.3, 1, 3, 10 and 30 mg kg(-1), i.v.) at 25 min intervals caused dose-dependent prolongation of the rate corrected QTc interval and bradycardia. The change in heart rate became significant after administration of 10 mg kg(-1) halofantrine (-23+/-9 beats min[-1]) whereas the increase in QTc was significant with only 1 mg kg(-1) halofantrine (22+/-10 ms). It was only with the highest dose of halofantrine that the PR interval was increased (from 52+/-3 to 67+/-4 ms) and second degree atrioventricular (AV) block (type 1 Mobitz) occurred in all animals. No changes were observed in any parameters in a separate group of guinea-pigs which received vehicle (dimethylacetamide 60% propylene glycol 40%) at equivalent time points. 3. The blood concentrations of halofantrine ranged from 0.26+/-0.17 microM after administration of 0.3 mg kg(-1) to 2.79+/-0.87 microM after 30 mg kg(-1), i.v. There was a significant correlation between the blood concentrations of halofantrine and the changes in QTc interval. 4 In guinea-pig left papillary muscles the effective refractory period was increased significantly 60 min after addition of halofantrine; from 161+/-4 to 173+/-6 ms with 10 microM, 156+/-8 to 174+/-6 ms with 30 microM and 165+/-6 to 179+/-5 ms with 100 microM halofantrine. However, the vehicle (0.1% Tween 80 in DMSO; final concentration of vehicle in Krebs, 1%) also increased the effective refractory period from 164+/-5 to 173+/-6 ms. Similar results were obtained in right ventricular strips but left atrial effective refractory periods were not altered by either the vehicle or halofantrine. 5. The results of these experiments suggest that any direct effects that halofantrine may have had on the effective refractory period of cardiac muscle cannot be separated from those of the vehicle. The prolongation of QTc and consistent observation of AV block with halofantrine in anaesthetized guinea-pigs suggest that in vivo models may be more useful for further studies investigating the mechanisms underlying the cardiotoxicity of halofantrine.

Animals↗
PubMed1997

Studies on the effects of anandamide in rat hepatic artery.

1. The effects of anandamide on K+ currents and membrane potential have been examined in freshly-isolated smooth muscle cells from rat hepatic artery and the results compared with the effects of this arachidonic acid derivative on tension and membrane potential changes in segments of whole artery. 2. In the presence of 0.3 mM L-NOARG and 10 microM indomethacin, anandamide (0.1-100 microM) and endothelium-derived hyperpolarizing factor (EDHF; liberated by acetylcholine, 0.01-10 microM) each relaxed endothelium-intact segments of hepatic artery precontracted with phenylephrine. These effects of anandamide, but not those of EDHF, were antagonized by the cannabinoid receptor antagonist, SR141716A (3 microM). 3. The relaxant effects of anandamide were unaffected by a toxin combination (apamin plus charybdotoxin, each 0.3 microM) which abolishes EDHF relaxations and were essentially unchanged in endothelium-denuded arteries. The relaxant effects of anandamide in endothelium-intact arteries were significantly reduced in a physiological salt solution containing 30 mM KCl and abolished when the K+ concentration was raised to 60 mM. 4. Anandamide (10 microM), acetylcholine (1 microM, via release of EDHF) and levcromakalim (10 microM) each markedly hyperpolarized the membrane potential of the smooth muscle cells of endothelium-intact arteries. However, when the endothelium was removed, the hyperpolarizing effects of both anandamide (10 microM) and acetylcholine were essentially abolished whereas those of levcromakalim (10 microM) were unaffected. 5. Under voltage-clamp conditions, anandamide (10 microM) abolished spontaneous transient outward currents (STOCs) in freshly-isolated single hepatic artery cells held at 0 mV but had no effect on the holding current at this potential. In current-clamp mode, the spontaneous hyperpolarizing potentials which corresponded to the STOCs were abolished with no significant change in basal membrane potential. 6. Anandamide (10 microM) abolished the iberiotoxin-sensitive K+ current (IBK(Ca)) produced by caffeine and the corresponding hyperpolarizations generated by this xanthine derivative in current-clamp mode. In contrast, anandamide had no effect on IBK(Ca) generated on exposure to NS1619 (30 microM). 7. It was concluded that anandamide is not EDHF in the rat hepatic artery. Anandamide-induced hyperpolarization is exerted indirectly and requires the presence of the endothelium. Anandamide also acts on the smooth muscle cells to inhibit processes which require functional intracellular calcium stores. This direct action seems more important than membrane hyperpolarization in relaxing phenylephrine-contracted vessels.

Animals↗
PubMed1997

Ventilator management of infants before extracorporeal membrane oxygenation.

The aim of this project was to review the course of infants referred for consideration of extracorporeal membrane oxygenation (ECMO) to identify maximal ventilator settings that, when exceeded, did not provide clinical benefit to the patient. These settings might then be used in defining failure of conventional mechanical ventilation. We reviewed referral records and hospital charts of all infants treated for severe respiratory failure due to meconium aspiration syndrome during the 52.5 month period from March 15, 1985, to August 1, 1989. At an inspiratory pressure > 35 cm H2O, 75% (43/57) of patients eventually required ECMO, and 28% (4/14) of the infants who did not receive ECMO died. When the inspiratory pressure was > or = 40 cm H2O, 39/49 patients required ECMO, and 30% (3/10) of those not treated with ECMO died. Once the inspiratory pressure was > 45 cm H2O, 91% (29/32) of patients required ECMO, and only one third of those not treated with ECMO survived. Although the limitations for conventional therapy suggested in this paper may be helpful to clinicians, each center needs to establish guidelines for maximal conventional ventilator support. If these guidelines are clearly defined, alternative methods of therapy can be used once these criteria are achieved.

Apgar Score↗