The teaching of drug development to medical students: collaboration between the pharmaceutical industry and medical school.

Collaboration between the medical school at Leicester and a local pharmaceutical company, AstraZeneca, led to the design and implementation of an optional third year special science skills module teaching medical students about drug discovery and development. The module includes didactic teaching about the complexities of the drug discovery process leading to development of candidate drugs for clinical investigation as well as practical experience of the processes involved in drug evaluation preclinically and clinically. It highlights the major ethical and regulatory issues concerned with the production and testing of novel therapies in industry and the NHS. In addition it helps to reinforce other areas of the medical school curriculum, particularly the understanding of clinical study design and critical appraisal. The module is assessed on the basis of a written dissertation and the critical appraisal of a drug advertisement. This paper describes the objectives of the module and its content. In addition we outline the results of an initial student evaluation of the module and an assessment of its impact on student knowledge and the opinion of the pharmaceutical industry partner. This module has proven to be popular with medical students, who acquire a greater understanding of the work required for drug development and therefore reflect more favourably on the role of pharmaceutical companies in the UK.

Delphi type methodology to develop consensus on the future design of EMS systems in the United Kingdom.

OBJECTIVE: To develop consensus opinion on future design characteristics of Emergency Medical Services (EMS) systems in the UK with particular regard to advanced life support skills (ALS). DESIGN: A Delphi questionnaire design with two rounds to gain a consensus of opinion. Investigation of four aspects of EMS design is reported-type of response to a priority based dispatch category, transportation options, enhancement of paramedic skills, and structure of a first responder system. SUBJECTS: Chief executives, directors of operations, and medical directors of Ambulance Trusts in the United Kingdom. OUTCOME MEASURES: Likert scales (0-9) to score opinion on a series of statements with achievement of inter-round consistency. A median score of 0-4 was classified as disagreement and 6-9 as agreement. RESULTS: A 65% response to the first questionnaire and with iteration, 52% response to the second questionnaire was attained. A tiered response (paramedics, technicians, and basic life support first responders) with technicians responding to selected category A and B calls and all category C calls (median score (MS) 7.5, interquartile range (IQR) 4), was recommended. Inter-unit handover of selected calls to maintain paramedic availablity ( MS 7.5, IQR 3.75) and enhancement of paramedic skills (MS 7.0, IQR 4.0) was also proposed. Finally, the development of a first responder system fully integrated into the EMS (MS 8.0, IQR 2.75) involving other agencies including the police force, fire service, and trained members of the local community was agreed. CONCLUSIONS: Senior expert staff from Ambulance Trusts in the UK achieved consensus on certain design characteristics of EMS systems. These are significantly different from the present EMS model.

A randomised trial to investigate the efficacy of magnesium sulphate for refractory ventricular fibrillation.

BACKGROUND: Ventricular fibrillation (VF) remains the most salvageable rhythm in patients suffering a cardiopulmonary arrest (CA). However, outcome remains poor if there is no response to initial defibrillation. Some evidence suggests that intravenous magnesium may prove to be an effective antiarrhythmic agent in such circumstances. STUDY HYPOTHESIS: Intravenous magnesium sulphate given early in the resuscitation phase for patients in refractory VF (VF after 3 DC shocks) or recurring VF will significantly improve their outcome, defined as a return of spontaneous circulation (ROSC) and discharge from hospital alive. DESIGN: A randomised, double blind, placebo controlled trial. Pre-defined primary and secondary endpoints were ROSC at the scene or in accident and emergency (A&E) and discharge from hospital alive respectively. SETTING, PARTICIPANTS, AND INTERVENTION: Patients in CA with refractory or recurrent VF treated in the prehospital phase by the county emergency medical services and/or in the A&E department. One hundred and five patients with refractory VF were recruited over a 15 month period and randomised to receive either 2-4 g of magnesium sulphate or placebo intravenously. RESULTS: Fifty two patients received magnesium treatment and 53 received placebo. The two groups were matched for most parameters including sex, response time for arrival at scene and airway interventions. There were no significant differences between magnesium and placebo for ROSC at the scene or A&E (17% v 13%). The 4% difference had 95% confidence intervals (CI) ranging from -10% to +18%. For patients being alive to discharge from hospital (4% v 2%) the difference was 2% (95% CI -7% to +11%). After adjustment for potential confounding variables (age, witnessed arrest, bystander cardiopulmonary resuscitation and system response time), the odds ratio (95% CI) for ROSC in patients treated with magnesium as compared with placebo was 1.69 (0.54 to 5.30). CONCLUSION: Intravenous magnesium given early in patients suffering CA with refractory or recurrent VF did not significantly improve the proportion with a ROSC or who were discharged from hospital alive.

Application of intrawell testing of RCRA groundwater monitoring data when no upgradient well exists.

A statistical quality control approach to detect changes in groundwater quality from a regulated waste unit is described. The approach applies the combined Shewhart-CUSUM control chart methodology for intrawell comparison of analyte concentrations over time and does not require an upgradient well. A case study from the U.S. Department of Energy's Hanford Site is used for illustration purposes. This method is broadly applicable in groundwater monitoring programs where there is no clearly defined upgradient location, the groundwater flow rate is exceptionally slow, or where a high degree of spatial variability exists in parameter concentrations. This study also indicates that the use of the Data Quality Objectives (DQO) process can assist in designing an efficient and cost-effective groundwater monitoring plan to achieve the optimum goal of both low false positive and low false negative rates (high power).

Plasma N-terminal pro BNP and cardiotrophin-1 are elevated in aortic stenosis.

BACKGROUND: Echocardiography with Doppler examination of the aortic valve provides a very accurate assessment of the transvalvular gradient and is used to monitor progression of aortic stenosis (AS). Plasma brain natriuretic peptide (BNP) has been shown to correlate with end-systolic wall stress in patients with AS. AIM: We hypothesized that plasma N-terminal proBNP (NT proBNP) and a newly identified cytokine cardiotrophin-1 (CT-1), which has been shown to stimulate BNP production at a transcriptional level are elevated in patients with AS and correlate to the maximum trans-valvular aortic pressure gradient (TVPG). METHOD: We compared plasma NT proBNP and CT-1 in 15 AS patients [five males, mean age 79 years [range 60-94], mean TPVG 39.3 mmHg (20-100)] with 10 controls (five male, mean age 68 years [56-79]). Results are expressed as mean [ranges] and comparisons were by the Mann-Whitney test. RESULTS: NT proBNP levels were elevated in AS patients [252.9 fmol/ml (79.2-541.8)] when compared with the controls (157.2 fmol/ml [104.7-236.9], P<0.005). Also CT-1 levels were elevated in AS patients (57.3 fmol/ml [33-86.3] when compared with the controls [28.3 fmol/ml (6.9-48.3), P<0.0005]. Both NT proBNP and CT-1 levels were correlated to the TVPG (r=0.53 and r=0.65, P<0.05 and P=0.009, respectively). On best subset analysis the strongest correlate with TVPG was CT-1 (R2=38%). The addition of NT proBNP did not improve diagnostic accuracy (R2=39%). CONCLUSION: These results suggest NT proBNP and CT-1 levels increase in proportion to the TVPG and could potentially be used to monitor progression of disease non-invasively. These markers may also be useful to identify the optimum time for surgery in AS.

Profile of plasma N-terminal proBNP following acute myocardial infarction; correlation with left ventricular systolic dysfunction.

AIMS: The aims of this study were to describe the temporal pattern of plasma N-terminal pro-brain natriuretic peptide, to examine the optimum time of sampling and to compare plasma N-terminal pro-brain natriuretic peptide to clinical criteria in terms of identification of impaired left ventricular systolic function following acute myocardial infarction. METHODS AND RESULTS: Measurements of N-terminal pro-brain natriuretic peptide were made in 60 patients at 14-48 h, 49-72 h, 73-120 h, 121-192 h following myocardial infarction and at 6 weeks in survivors. Left ventricular wall motion index was assessed during hospitalization (WMI-1) and at 6 weeks (WMI-2). N-terminal pro-brain natriuretic peptide levels were elevated at all time points, to a greater extent in anterior compared to inferior infarction (P < 0.05). A biphasic profile of plasma concentration was observed in anterior infarction with peaks at 14-48 h and 121-192 h. This was sustained at 6 weeks. N-terminal pro- brain natriuretic peptide at 73-120 h was the best independent predictor of WMI-1 (P < 0.005). N-terminal pro-brain natriuretic peptide was higher at all times in patients who received ACE inhibitor therapy compared to those who did not (P < 0.005). N-terminal pro-brain natriuretic peptide at 73-120 h (R(2) = 17.7%, P = 0.005) and previous myocardial infarction (R(2) = 5.3%, P < 0.05) were independent predictors of poor outcome (WMI-2 < or = 1.2 or death by 6 weeks). CONCLUSIONS: A biphasic pattern of plasma N-terminal pro-brain natriuretic peptide is seen after anterior myocardial infarction. Plasma level is strongly correlated to wall motion index soon after and remote from acute myocardial infarction. Plasma N-terminal pro-brain natriuretic peptide measured later in hospitalization better predicts poor outcome following myocardial infarction than when it is measured in the immediate post infarction period.

Increased risk of infection with Helicobacter pylori in spouses of infected subjects: observations in a general population sample from the UK.

BACKGROUND/AIMS: To investigate risk factors for infection with Helicobacter pylori in a general population sample who accepted an invitation to be screened. In particular, to determine whether being the spouse of an infected subject is an independent risk factor for infection after adjustment for other risks. METHODOLOGY: A serological screening test for Helicobacter pylori was offered to 4015 randomly selected subjects registered at a single general practice in Market Harborough, UK. Those invited were also asked to complete a questionnaire if attending for screening; this included information relating to possible risk factors for infection. Results were analyzed in the overall sample of attenders and a subset of married couples, using univariate and multivariate analyses. RESULTS: Complete results were obtained for 1431 (36%) subjects. Age, childhood social class and household crowding in childhood were independent risk factors after adjustment for other variables. Positive status of spouse was an independent risk factor in a subset of 389 married couples (P = 0.005, Odds Ratio: 2.65, 95% Confidence Interval: 1.34-5.25). CONCLUSIONS: Our study confirmed the correlation between childhood living conditions and infection with Helicobacter pylori. In the study population, having a Helicobacter pylori-positive spouse was associated with a significant increased risk of being infected.

The rational use of beta-adrenoceptor blockers in the treatment of heart failure. The changing face of an old therapy.

Heart failure is one of the commonest debilitating conditions of industrialized society, with mortality and morbidity comparable with that of the common neoplastic diseases. The role of antagonists of the adrenergic beta-receptor (beta-blockers) in heart failure has been the subject of debate for many years. Data from studies of the therapeutic use of beta-blockers in patients following acute myocardial infarction suggest that in this circumstance these agents confer at least as much benefit to patients with heart failure as they do to those without. Similarly retrospective analysis of a number of the studies of angiotensin converting enzyme (ACE) inhibitors in heart failure suggest a greater effect of the combination of beta-blocker with ACE inhibitor compared with ACE inhibitor alone. The results of recent prospective, placebo-controlled studies of the addition of beta-blocker to standard therapy in patients with chronic heart failure have confirmed a significant beneficial effect. beta-blocker therapy in these studies was well tolerated and in addition to improved mortality, beta-blocker therapy is associated with improved morbidity in terms of progressive heart failure and numbers of hospitalizations. Initiation of beta-blocker therapy in heart failure may be associated with deterioration of cardiac function in the short term. Treatment should be started at a low dose of beta-blocker with slow up-titration in a number of steps over several weeks. In spite of the established benefits of ACE inhibition in patients with heart failure, this treatment is under-utilized. Part of this shortfall is due to physicians' perceptions regarding potential unwanted effects of ACE inhibition. Perceptions regarding unwanted effects of beta-adrenoceptor blocker therapy are likely to be at least as great. While beta-blockade represents a welcome addition to the therapeutic armoury of physicians caring for patients with heart failure, initiation and stabilization of beta-adrenoceptor blocker therapy should be undertaken under specialist supervision.

Plasma N-terminal pro-brain natriuretic peptide and the ECG in the assessment of left-ventricular systolic dysfunction in a high risk population.

AIMS: To examine the value of N-terminal pro-brain natriuretic peptide, abnormal electrocardiogram and other baseline clinical and laboratory variables in identifying patients with left ventricular systolic dysfunction in a high risk population. METHODS AND RESULTS: We studied 243 patients (129 male, median age 73 years, range 20-94) referred for echocardiography. The relationship between left ventricular wall motion index and log N-terminal pro-brain natriuretic peptide, log creatinine, electrocardiogram, age, history of hypertension, history of ischaemic heart disease, gender, valvular disease and current drug therapy was examined using regression analysis. There was a strong correlation between N-terminal pro-brain natriuretic peptide and left ventricular wall motion index for the whole population (r=-0.624, P<0.001) and in those receiving diuretic +/- angiotensin converting enzyme inhibitor (r= -0.661, P<0.005) and in those receiving neither (r=-0.584, P<0. 005). On multiple regression analysis, log N-terminal pro-brain natriuretic peptide (P<0.001), age (P=0.015), current diuretic (P=0. 002) or angiotensin converting enzyme inhibitor use (P=0.001) and male gender (P=0.026) were independently associated with a low left ventricular wall motion index. Log N-terminal pro-brain natriuretic peptide alone (R(2)=39%) was a better predictor of left ventricular wall motion index than any other single or combination of factors. Plasma N-terminal pro-brain natriuretic peptide>275 pmol l(-1)predicted left ventricular wall motion index < or =1.2 with a sensitivity of 93.8%, a specificity of 55% and a negative predictive value of 93%. Left ventricular function was impaired in 18/36 patients with a normal electrocardiogram, in all of whom N-terminal pro-brain natriuretic peptide was >275 fmol ml(-1). CONCLUSION: Of the variables studies, N-terminal pro-brain natriuretic peptide had the strongest correlation with reduced left ventricular wall motion index. The electrocardiogram had a poor predictive value for left ventricular systolic dysfunction in this population. Plasma N-terminal pro-brain natriuretic peptide can usefully predict patients with a reduced left ventricular wall motion index in whom echocardiographic examination may be appropriate.

Assessment of the stability of N-terminal pro-brain natriuretic peptide in vitro: implications for assessment of left ventricular dysfunction.

Plasma concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) are raised in patients with left ventricular dysfunction. Measurement of this peptide has a potential diagnostic role in the identification and assessment of patients with heart failure. The stability of this peptide over time periods and conditions pertaining to routine clinical practice has not been reported previously. Blood samples were obtained from 15 subjects. One aliquot was processed immediately, and the remaining portions of the blood samples were stored for 24 h or 48 h at room temperature or on ice prior to processing. Plasma concentrations of NT-proBNP were measured with a novel immunoluminometric assay developed within our laboratory. Mean plasma concentrations of NT-proBNP were not significantly different whether blood samples were centrifuged immediately and stored at -70 degrees C or kept at room temperature or on ice for 24 h or 48 h. The mean percentage differences from baseline (reference standard) were +5.2% (95% confidence interval +18.2 to -7.8%) and +0.8% (+15.2 to -13.7%) after storage for 24 h at room temperature or on ice respectively, and +8.9% (+24.2 to -6. 5%) and +3.2% (+15.1 to -0.9%) for storage for 48 h at room temperature or on ice respectively. Pearson correlation coefficients for baseline NT-proBNP concentrations compared with levels at 48 h at room temperature or on ice were r=0.89 and r=0.83 respectively (both P<0.0001). Thus NT-proBNP extracted from plasma samples treated with EDTA and aprotinin is stable under conditions relevant to clinical practice.

An immunoluminometric assay for cardiotrophin-1: a newly identified cytokine is present in normal human plasma and is increased in heart failure.

Cardiotrophin-1, a member of the interleukin-6 related cytokine family which acts via the glycoprotein 130 signalling pathway, may be involved in the process of ventricular remodelling. Its presence in human plasma has never been reported. We have devised a non-radioactive immunoluminometric sensitive and specific assay for CT-1 based on a competitive ligand binding principle. The chemiluminescent label 4-(2-succinimidyl-oxycarbonylethyl)phenyl-10-methylacridinium 9-carboxylate fluorosulfonate was used to label a peptide representing a domain in the middle section of CT-1. Assay of this domain of CT-1 (amino acids 105-120) in patients with heart failure revealed elevated CT-1 values median 87 [range 74.3-182.8] fmol/ml) compared to normal controls (CT-1 median 29.55 [range 6.9-48.3] fmol/ml, P<0.0005). The molecular weight of human CT-1 was estimated to be 26.7 kD from sodium dodecyl sulphate polyacrylamide gel electrophoresis. This is the first quantitative assessment of CT-1 in humans. Furthermore, this is the first demonstration of significant elevation of plasma CT-1 in patients with heart failure.

A myocardial perfusion reserve index in humans using first-pass contrast-enhanced magnetic resonance imaging.

OBJECTIVES: The purpose of this study was to evaluate a myocardial perfusion reserve index (MPRI) derived from a quantitative magnetic resonance imaging (MRI) technique in normal human volunteers and patients with coronary artery disease and to relate MPRI to coronary artery stenosis severity measured with quantitative arteriography. BACKGROUND: Magnetic resonance imaging could be a useful noninvasive tool in the investigation of ischemic heart disease. However, there have been few studies in humans to quantify myocardial perfusion and myocardial perfusion reserve using MRI and none in patients with coronary disease. METHODS: Twenty patients with angiographically proven coronary artery disease and five normal volunteers underwent both resting and stress (adenosine 140 microg/kg(-1)/min(-1)) first-pass contrast-enhanced MRI examinations (using 0.05 mmol/kg 1 of gadopentetate dimeglumine. Using a tracer kinetic model, the unidirectional transfer constant (K(i)), a perfusion marker for the myocardial uptake of contrast, was computed in each coronary arterial territory. The ratio of K(i) for the rest and stress scans was used to calculate the MPRI. Percent reduction in luminal diameter of coronary lesions was measured using an automated edge-detection algorithm. RESULTS: Myocardial perfusion reserve index was significantly reduced in patients compared with normal subjects (2.02+/-0.7 vs. 4.21+/-1.16, p < 0.02). For regions supplied by individual vessels, there was a significant negative correlation of MPRI with percent diameter stenosis (r = -0.81, p < 0.01). Importantly, regions supplied by vessels with <40% diameter stenosis (non-flow limiting) had a significantly higher MPRI than regions supplied by stenoses of "intermediate" severity, that is, >40% to 59% diameter stenosis (2.80+/-0.77 and 1.93+/-0.38, respectively, p < 0.02). However, even regions supplied by vessels with <40% diameter stenosis had a significantly lower MPRI than volunteers (p < 0.01). CONCLUSIONS: A myocardial perfusion reserve index derived from first-pass MRI studies can distinguish between normal subjects and patients with coronary artery disease. Furthermore, it provides useful functional information on coronary lesions, particularly where the physiologic significance cannot be predicted accurately from the angiogram.

Mechanism and clinical significance of precordial ST depression in inferior myocardial infarction: evaluation by contrast-enhanced dynamic myocardial perfusion magnetic resonance imaging.

We elucidated the mechanism and clinical significance of precordial ST depression in patients with an inferior myocardial infarction using first-pass, contrast-enhanced, myocardial perfusion magnetic resonance imaging (MRI). Forty-seven patients with acute inferior myocardial infarction underwent first-pass contrast-enhanced MR studies within 2-6 days postinfarction. Patients were followed-up for a minimum of 1 year after infarct (range, 12-32 months). Total perfusion deficit scores derived qualitatively from MRIs were compared in patients with (group 1, n = 30) and without (group 2, n = 17) ST depression precordially. Perfusion remote from the infarct zone was also compared. The combined end points of adverse clinical events and/or the need for further intervention were assessed for each group. Total perfusion deficit scores were significantly higher in group 1 than group 2 (medians 9.7 versus 4.5, p < 0.005). Posterolateral basal extension of hypoperfusion was greater in group 1 versus group 2 (1.23 versus 0.42, p < 0.02), with no evidence of remote anterior perfusion abnormalities. There were more patients with an adverse clinical end point in group 1 versus group 2 (18 versus 1, p < 0.01). Furthermore, in patients with ST depression (group 1), there was a significant increase in number of adverse clinical end points in patients with a global deficit score > 15 versus 0-5 (7/7 versus 1/7, p < 0.01). MRI shows that precordial ST depression in inferior myocardial infarction is a marker for a larger global perfusion abnormality with posterolateral basal extension and an increase in adverse clinical end points. Furthermore, the magnitude of the perfusion deficit correlates with an increase in the number of adverse clinical end points, highlighting the potential of MRI perfusion studies as a research and clinical tool in myocardial infarction.

Lack of correlation between self-reported symptoms of dyspepsia and infection with Helicobacter pylori, in a general population sample.

OBJECTIVE: To investigate any correlation between infection with Helicobacter pylori (H. pylori) and overall symptoms of dyspepsia, in a general population sample. DESIGN: Analysis of test results and questionnaire replies from a population screening study involving subjects registered at a single general practice in Market Harborough, UK. METHODS: H. pylori status was established using a commercial enzyme-linked immunosorbent assay (ELISA), and frequent dyspepsia was assessed using a previously validated self-completion symptom questionnaire. RESULTS: Complete results for dyspepsia and H. pylori status were obtained and analysed for 1524 men and women aged 21-55 years at the start of the study. In those who attended for screening, the prevalence of dyspepsia was 39%, with a 15% prevalence of infection with H. pylori. No significant correlation was found between H. pylori status and frequent dyspepsia, upper abdominal pain or reflux-like symptoms. Adjustment for age, gender, smoking and alcohol consumption did not alter these findings. CONCLUSION: The analysis suggested that H. pylori infection does not play an important role in overall symptoms of non-ulcer dyspepsia in the community, nor is it important in protecting against acid reflux in patients without duodenal ulcer.

General population screening for infection with Helicobacter pylori: a realistic option?

OBJECTIVES: To consider the effectiveness of a community programme of Helicobacter pylori (H pylori) screening and eradication run in collaboration with general practitioners. Specifically, to assess numbers successfully eradicating H pylori and consequently reducing the prevalence of infection, and to identify and consider areas of poor compliance. SETTING: A large general practice in Market Harborough, Leicestershire, UK. METHODS: A general population sample of 4015 subjects aged 21-55 was offered a serological screening test for H pylori through their general practitioners. Those testing positive were offered a prescription for eradication treatment and an information pack designed to encourage good compliance. Successful eradication was assessed by a urea breath test. RESULTS: The screening test was accepted by 1566 (39%) of those invited, with men and younger people least likely to attend. Of the 235 (15%) subjects who tested positive, 186 (79%) were treated and eradication was confirmed in 170 (95%) of the 179 subjects who had a urea breath test. Overall, eradication was confirmed in 4% (170/4015) of those offered screening. Assuming a 15% overall prevalence of H pylori infection, it is estimated that H pylori was eradicated in 29% of those infected in the target group. CONCLUSIONS: When an intervention was used to encourage good compliance, the eradication rate was high. Effectiveness was limited most strongly by the acceptance rate for the screening test, but also by the rate of uptake of eradication treatment. If benefits of population screening can be shown, appropriate interventions to improve compliance in these areas would need consideration.

Reasons for non-compliance with screening for infection with Helicobacter pylori, in a multi-ethnic community in Leicester, UK.

In this study, we aimed to identify reasons for non-compliance with a screening programme for Helicobacter pylori (H pylori), in a multi-ethnic community and to assess the effectiveness of Asian language materials towards increasing compliance. A serological screening test for infection with H pylori was offered to 200 Asians and 200 non-Asians (mainly Europeans), aged 21-55 y, registered at a single general practice. Reasons for non-attendance for screening were identified by reply slip or interview. A second group of 200 Asians who were offered screening were sent information in Gujarati as well as English. When information was mailed in English only, 30% Asians and 22% non-Asians attended (P = 0.09, ns). Stated reasons for non-attendance in the Asian group were not generally language related; reasons were similar in the Asian and non-Asian groups and were most frequently related to other commitments. The use of materials in Gujarati did not improve compliance. Language problems should not be assumed to dominate reasons for non-compliance with screening in ethnic minority groups. In common with those of UK origin, subjects from ethnic minority groups may more generally have insufficient interest in preventive medicine for them to prioritise health screening above other commitments.