Experimentally simulating high-rate behaviour: rate and temperature effects in polycarbonate and PMMA.

This paper presents results from applying a recently developed technique for experimentally simulating the high-rate deformation response of polymers. The technique, which uses low strain rate experiments with temperature profiles to replicate high-rate behaviour, is here applied to two amorphous polymers, polymethylmethacrylate (PMMA) and polycarbonate, thereby complementing previously obtained data from plasticized polyvinyl chloride. The paper presents comparisons of the mechanical data obtained in the simulation, as opposed to those observed under high-rate loading. Discussion of these data, and the temperature profile required to produce them, gives important information about yield and post-yield behaviour in these materials.

Mechanics of particulate composites with glassy polymer binders in compression.

Whether used as structural components in design or matrix materials for composites, the mechanical properties of polymers are increasingly important. The compressive response of extruded polymethyl methacrylate (PMMA) rod with aligned polymer chains and Al-Ni-PMMA particulate composites are investigated across a range of strain rates and temperatures. The particulate composites were prepared using an injection-moulding technique resulting in highly anisotropic microstructures. The mechanics of these materials are discussed in the light of theories of deformation for glassy polymers. The experimental data from this study are compared with PMMA results from the literature as well as epoxy-based composites with identical particulates. The PMMA exhibited the expected strain rate and temperature dependence and brittle failure was observed at the highest strain rates and lowest temperatures. The Al-Ni-PMMA composites were found to have similar stress-strain response to the PMMA with reduced strain softening after yield. Increasing volume fraction of particulates in the composite resulted in decreased strength.

The effects of head cooling on endurance and neuroendocrine responses to exercise in warm conditions.

The present study investigated the effects of head cooling during endurance cycling on performance and the serotonergic neuroendocrine response to exercise in the heat. Subjects exercised at 75 % VO(2max) to volitional fatigue on a cycle ergometer at an ambient temperature of 29+/-1.0 degrees C, with a relative humidity of approximately 50 %. Head cooling resulted in a 51 % (p<0.01) improvement in exercise time to fatigue and Borg Scale ratings of perceived exertion were significantly lower throughout the exercise period with cooling (p<0.01). There were no indications of peripheral mechanisms of fatigue either with, or without, head cooling, indicating the importance of central mechanisms. Exercise in the heat caused the release of prolactin in response to the rise in rectal temperature. Head cooling largely abolished the prolactin response while having no effect on rectal temperature. Tympanic temperature and sinus skin temperature were reduced by head cooling and remained low throughout the exercise. It is suggested that there is a co-ordinated response to exercise involving thermoregulation, neuroendocrine secretion and behavioural adaptations that may originate in the hypothalamus or associated areas of the brain. Our results are consistent with the effects of head cooling being mediated by both direct cooling of the brain and modified cerebral artery blood flow, but an action of peripheral thermoreceptors cannot be excluded.

The Northwick Park tragedy--protecting healthy volunteers in future first-in-man trials.

The development of potentially powerful drugs which may become effective in the treatment for disorders currently difficult to manage presents the pharmaceutical industry and the scientific community with a major challenge. Such drugs with novel modes of action and the capacity to modify the body's immune system could also be very toxic. The possibility became a tragic reality on March 13th 2006 when TGN1412 was given to six healthy volunteers at Northwick Park hospital. All six became seriously ill. Fortunately none died but some were left with serious residual defects. The British Secretary of State for Health set up an Expert Scientific Group to investigate this tragic event. The report had to make recommendations designed to prevent a recurrence whilst not unduly delaying or discouraging the development of new drugs designed to treat cancers and other serious disorders. They made 22 recommendations. The drug TGN1412 had been shown to be well tolerated by non-human primates. A recent report on non-human primates in research recommended their continued use in some forms of research, for example on brain disorders. However, they also recommended that non-human primates should be used sparingly and only when justified scientifically. Their treatment should be optimal and research on them should be restricted to selected centres of expertise. The tragedy at Northwick Park should encourage the Pharmaceutical Industry to rethink their use of non-human primates in drug toxicity testing and hopefully to reduce their use and treat them better.

Testing the practical aspects of therapeutics by objective structured clinical examination.

Medical students need to have a sound theoretical knowledge of pharmacology and a training in the practical aspects of therapeutics in order to prescribe effectively, safely and rationally when they qualify. Students have traditionally sat written exams and the practical aspects have been largely ignored. At the University of Birmingham we set up an objective structured clinical examination (OSCE) style examination to test the practical aspects of therapeutics. Over the last 2 years, 434 students have been examined in this way to determine competency in various clinical skills including, for example prescription writing, the drawing up and giving of injections, setting up nebulizers, and patient counselling about drug effects. Over that time we found the therapeutics OSCE to be feasible and useful. It has demonstrated serious practical deficiencies that were not apparent from written examinations in some students' ability to prescribe and administer drugs. Since its introduction, performance in the OSCE has improved. Whether this will result in safer and more effective prescribing in the preregistration house officer year has not been formally evaluated but it appears that they approach this aspect of patient care with greater confidence than graduates from other schools.

Changes in plasma lipids and markers of oxidative stress in normal pregnancy and pregnancies complicated by diabetes.

The purpose of the present study was to determine changes in plasma lipids and markers of oxidative stress longitudinally in pregnancy complicated by diabetes compared with non-diabetic pregnancy. This was carried out by following a group of normal pregnant women (n=17) and groups of pregnant women with Type I diabetes (n=19), Type II diabetes (n=12) and gestational diabetes mellitus (n=12) throughout pregnancy, with sampling carried out at the end of each trimester. Serum total cholesterol and triacylglycerols (triglycerides) were determined using standard colorimetric techniques and low-density lipoprotein (LDL) subfraction profile by disc PAGE. Total antioxidant capacity (TAC) was determined by enhanced chemiluminescence and lipid hydroperoxides by the ferrous oxidation of Xylenol Orange method. Total cholesterol and triacylglycerols increased significantly throughout pregnancy in all groups, but there were no significant differences between normal and diabetic women with respect to either. The LDL score was significantly higher (P<0.001) in diabetic women compared with normal women at each point throughout pregnancy, although there were no significant differences between the diabetic groups. There was evidence of greater oxidative stress in diabetic compared with normal women throughout. Corrected TAC was significantly lower (P<0.001) in all diabetic women throughout pregnancy. In addition, lipid hydroperoxides were higher in all diabetic compared with normal women, particularly so in those with Type II diabetes (P<0.05). These changes may have important implications for diabetic women during pregnancy, as an elevated risk of pre-eclampsia is thought to reflect an oxidative stress-related mechanism. In addition, these changes may have important implications for the development of atherosclerosis and the long-term cardiovascular health of women with diabetes.

The impact of therapeutic doses of paracetamol on serum total antioxidant capacity.

INTRODUCTION: A link between regular paracetamol intake and asthma in adults has recently been postulated. Detoxification of paracetamol may deplete stores of glutathione, which is one of the major antioxidants present in the lung. A reduced source of glutathione in the lung may lead to increased oxidative damage to the epithelium and hence increased frequency and severity of asthma attacks in susceptible individuals. AIM OF STUDY: This study aimed to determine whether regular intake of maximum therapeutic doses of paracetamol reduced serum antioxidant capacity in healthy volunteers. METHODS: Fifteen young healthy volunteers (nine men, six women, mean age 21.3 years, range 19-32) took maximum therapeutic doses of paracetamol (1 g four times a day) for 14 days. On days 0 and 14 blood samples were taken at baseline and hourly for a period of 4 h following ingestion of 1 g paracetamol. Single venous blood samples were collected 1 h after ingestion of 1 g paracetamol on days 4, 7 and 10. Blood samples were analysed for serum paracetamol concentration and total antioxidant capacity. RESULTS: Mean total antioxidant capacity was significantly reduced over the 3-h post-dosing on both days 0 and 14 (P < 0.01). The results from days 4, 7 and 10 showed a trend towards reduced antioxidant activity over time. On day 14 values were consistently lower compared with the corresponding times on day 0 (P < 0.01 at 0, 1, 3 and 4 h, P < 0.05 at 2 h). CONCLUSIONS: Chronic ingestion of maximum therapeutic doses of paracetamol depletes serum antioxidant capacity in healthy volunteers in as few as 14 days, possibly by a reduction in glutathione. This may have implications for analgesic use in asthmatic individuals. Further studies are now required to assess the impact of paracetamol on antioxidant defences in the lung.

Insulin resistance--the new goal!

Diabetes mellitus is a well-recognized risk-factor for coronary artery disease (CAD). Epidemiological studies have shown that the risk of CAD increases two to sixfold in patients with type 2 diabetes compared with those without the disease. Furthermore the prevalence of diabetes in the UK has increased by 30% since 1991 and the world population of people with diabetes in 2010 is expected to be twice that of 1990. In addition whilst the mortality from CAD in patients without diabetes has declined over the past 20 years the mortality in men with type 2 diabetes has not changed and in women may have increased. UKPDS and other studies have shown a significant improvement in the onset and course of microvascular complications with good diabetic control. However the same is not true for macrovascular complications for which there is no good evidence of improvement with better diabetic control. This apparent lack of benefit from improved care of diabetic patients has led to many different approaches. These include attempts to achieve even better glycaemic control, greater emphasis on other risk factors particularly hypertension and interestingly attention to the prediabetic state characterized by insulin resistance (IR). The latter is associated with a number of abnormalities which could play a causative role in the development of cardiovascular disease. This article will review the concept of IR and the possible interventions available to tackle it.

A comparison of the beta1-selectivity of three beta1-selective beta-blockers.

OBJECTIVE: To determine the relative beta1-selectivity of three beta-blockers (nebivolol, bisoprolol and atenolol), administered orally at normal therapeutic doses, by assessing their impact on the beta2-mediated, haemodynamic and biochemical responses to a terbutaline infusion, which decreases serum potassium and increases serum glucose and insulin. METHODS: Twenty-four healthy volunteers (14 men, 10 women), with no history of respiratory disease, attended on five separate occasions; beta-blockers (nebivolol 5 mg, bisoprolol 10 mg, atenolol 50 and 100 mg) or placebo were supplied in random order. Three baseline blood samples were collected at 65-85 min post-beta-blocker. A 60-min terbutaline infusion was started 90 min after taking the beta-blocker. Blood samples were taken and blood pressure and heart rate recorded at 15 min intervals up to 30-min post-infusion. Blood samples were analysed for serum potassium, glucose and insulin concentrations. RESULTS: Terbutaline increased heart rate. Pretreatment with nebivolol caused a modest and non-significant reduction in terbutaline-induced tachycardia whilst bisoprolol produced a more marked effect. Atenolol at both 50 and 100 mg doses caused a highly significant reduction in terbutaline-induced tachycardia. All active preparations had a comparable impact on the terbutaline-induced increase in systolic blood pressure, but the drugs had no impact on the changes produced in diastolic blood pressure. After pretreatment with placebo, the terbutaline infusion caused a significant decrease in serum potassium and increases in serum glucose and insulin. Pretreatment with nebivolol had no discernible effect on potassium compared with placebo. In contrast, when compared with either placebo or nebivolol, bisoprolol (P < 0.01) and both doses of atenolol (P < 0.001) significantly attenuated the hypokalaemic effect of terbutaline. Treatment with nebivolol and bisoprolol modestly but significantly reduced the terbutaline-induced increases in glucose (P < 0.05). The blocking effects of both doses of atenolol were highly significant (P < 0.001) when compared with placebo and also significant (P < 0.05 and P < 0.01, respectively) when compared with nebivolol and bisoprolol. A similar pattern of responses with the different beta-blocker treatments was observed for the effects on insulin concentrations during the terbutaline infusion. CONCLUSION: The beta1-selectivity of three different beta1-blockers has been demonstrated in healthy volunteers using the blocking of biochemical and haemodynamic responses to a beta2 stimulus. Terbutaline alone caused an increase in heart rate, a rise in systolic blood pressure, a fall in serum potassium and a rise in both serum glucose and insulin. In this study, for both haemodynamic and biochemical responses, atenolol 100 mg had the greatest beta2-blocking effect, nebivolol 5 mg the least. Bisoprolol 10 mg and atenolol 50 mg had intermediate effects; bisoprolol was the more beta1-selective of these two.

Review article: esomeprazole--the first proton pump inhibitor to be developed as an isomer.

Omeprazole is a racemate, from which the R- and S-isomers can be isolated. At the cellular level, both of these isomers convert to the same inhibitor of the H+,K+-ATPase and produce the same reduction in gastric acid secretion. However, the S-isomer, esomeprazole, is metabolized more slowly and reproducibly than the R-isomer and omeprazole, and therefore produces higher plasma concentrations for longer and, as a result, inhibits gastric acid production more effectively and for longer. Thus, esomeprazole has the pharmacological properties of a more effective form of treatment for disorders related to gastric acid secretion. Clinical studies have confirmed the anticipated increased efficacy, but have shown no evidence of impaired tolerability or increased toxicity when compared with omeprazole.

Oxidative stress and normal pregnancy.

OBJECTIVE: To determine whether, in normal pregnancies, there is evidence of oxidative stress that is related to the lipid changes observed in pregnancy. DESIGN: Longitudinal study of healthy women having a normal pregnancy. Samples were obtained towards the end of each trimester and after 8 weeks postpartum. PATIENTS: Seventeen healthy women during a normal singleton pregnancy were compared with 12 healthy, non-pregnant women. MEASUREMENTS: Oxidative stress was determined by measuring total antioxidant capacity (TAC), uric acid and lipid hydroperoxides (LHP). Lipid status was evaluated by measuring total and high-density lipoprotein cholesterol, triglycerides and low-density lipoprotein (LDL) subfractions. RESULTS: Pregnancy was associated with decreased TAC and uric acid in the first trimester, which gradually increased during pregnancy, reaching normal values during the postpartum period. LHP significantly increased towards the end of pregnancy. The changes observed in LHP were significantly correlated with increases in LDL subfraction profile. CONCLUSIONS: Late pregnancy was associated with the formation of susceptible, oxidisable particles (high LDL score) and an increase in oxidative damage. These biochemical changes may be relevant for the long-term cardiovascular health of women, especially those of high parity or those who are at high risk for cardiovascular disease (e.g. women with diabetes).

The cardioprotective role of beta-blockers in patients with diabetes mellitus.

This paper reviews the role of beta-blockers in the prevention of cardiovascular morbidity and mortality in patients with diabetes mellitus. There is good evidence from randomized controlled trials that beta-blockers, in particular the lipophilic agents, substantially reduce cardiovascular mortality and morbidity. However, hitherto beta-blockers have been underused in diabetic patients, perhaps because of perceived risks of beta-blocker therapy. Reappraisal of the evidence suggests that the traditional reluctance to use beta-blockers in this group is based on fears of adverse effects that are largely unfounded.