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To report 5-year contrast-enhanced magnetic resonance imaging findings of the REST trial recruits who underwent either uterine artery embolization (UAE) or myomectomy. A total of 157 patients were randomized to UAE or surgery (hysterectomy or myomectomy). Ninety-nine patients who had UAE and eight patients who had myomectomy were analyzed. MRI scans at baseline, 6 months, and 5 years were independently interpreted by two radiologists. Dominant fibroid diameter, uterine volume, total fibroid infarction (complete 100 %, almost complete 90–99 %, partial

Please cite this paper as: Moss J, Cooper K, Khaund A, Murray L, Murray G, Wu O, Craig L, Lumsden M. Randomised comparison of uterine artery embolisation (UAE) with surgical treatment in patients with symptomatic uterine fibroids (REST trial): 5-year results. BJOG 2011;118:936–944. Objective To compare the long-term results of uterine artery embolisation (UAE) with surgery for women with symptomatic uterine fibroids. Design Pragmatic, open, multicentre, randomised trial. Setting Twenty-seven participating UK secondary care centres. Sample Women aged ≥18 years with symptomatic fibroids who were considered to justify surgical treatment. Methods In total, 157 women were randomised (in a 2:1 ratio): 106 to UAE and 51 to surgery (hysterectomy 42; myomectomy nine). Main outcome measures Quality of life at 5 years, as assessed by the Short Form General Health Survey (SF-36). Secondary measures included complications, adverse events and the need for further intervention. Results There were no significant differences between groups in any of the eight components of the SF-36 scores at 5 years (minimum P = 0.45). Symptom score reduction and patient satisfaction with either treatment was very high, with no group difference. Rates of adverse events were similar in both groups (19% embolization and 25% surgery; P = 0.40). The 5-year intervention rate for treatment failure or complications was 32% (UAE arm) and 4% (surgery arm), respectively. The initial cost benefit of UAE over surgery at 12 months was substantially reduced because of subsequent interventions, with treatments being cost neutral at 5 years. Conclusions We have found that UAE is a satisfactory alternative to surgery for fibroids. The less invasive nature of UAE needs to be balanced against the need for re-intervention in almost a third of patients. The choice should lie with the informed patient.

Summary Background Pathological waves of spreading mass neuronal depolarisation arise repeatedly in injured, but potentially salvageable, grey matter in 50–60% of patients after traumatic brain injury (TBI). We aimed to ascertain whether spreading depolarisations are independently associated with unfavourable neurological outcome. Methods We did a prospective, observational, multicentre study at seven neurological centres. We enrolled 109 adults who needed neurosurgery for acute TBI. Spreading depolarisations were monitored by electrocorticography during intensive care and were classified as cortical spreading depression (CSD) if they took place in spontaneously active cortex or as isoelectric spreading depolarisation (ISD) if they took place in isoelectric cortex. Investigators who treated patients and assessed outcome were masked to electrocorticographic results. Scores on the extended Glasgow outcome scale at 6 months were fitted to a multivariate model by ordinal regression. Prognostic score (based on variables at admission, as validated by the IMPACT studies) and spreading depolarisation category (none, CSD only, or at least one ISD) were assessed as outcome predictors. Findings Six individuals were excluded because of poor-quality electrocorticography. A total of 1328 spreading depolarisations arose in 58 (56%) patients. In 38 participants, all spreading depolarisations were classified as CSD; 20 patients had at least one ISD. By multivariate analysis, both prognostic score (p=0·0009) and spreading depolarisation category (p=0·0008) were significant predictors of neurological outcome. CSD and ISD were associated with an increased risk of unfavourable outcome (common odds ratios 1·56 [95% CI 0·72–3·37] and 7·58 [2·64–21·8], respectively). Addition of depolarisation category to the regression model increased the proportion of variance in outcome that could be attributed to predictors from 9% to 22%, compared with the prognostic score alone. Interpretation Spreading depolarisations were associated with unfavourable outcome, after controlling for conventional prognostic variables. The possibility that spreading depolarisations have adverse effects on the traumatically injured brain, and therefore might be a target in the treatment of TBI, deserves further research. Funding US Army CDMRP PH/TBI research programme.

Please cite this paper as: Rashid S, Khaund A, Murray L, Moss J, Cooper K, Lyons D, Murray G, Lumsden M. The effects of uterine artery embolisation and surgical treatment on ovarian function in women with uterine fibroids. BJOG 2010;117:985–989. Objective The aim of this study was to evaluate and compare both ovarian function and menstrual characteristics following uterine artery embolisation (UAE) and surgery. Design Subgroup of women from a randomised controlled trial. Setting Gynaecology and radiology units in Scotland, UK. Population Ninety-six women from the randomised controlled trial comparing embolisation with surgery as a treatment for fibroids (REST), which recruited 157 patients (106 UAE; 51 surgery). Methods Seventy-three women undergoing UAE and 23 women undergoing surgery (with ovarian conservation) had serum follicle-stimulating hormone (FSH) measurements taken on day 3 of the menstrual cycle prior to treatment, and at 6 and 12 months post-treatment. Data on menstrual cycle characteristics was also collected. Main outcome measures Ovarian failure, as defined by an FSH level of >40 iu/l, and change in duration of menses and length of menstrual cycle. Results There was no significant difference in the rate of ovarian failure at 12 months between UAE (11%) and surgical patients (18%) (P = 0.44). This finding was not influenced by age. The mean duration of menstrual flow decreased significantly, from baseline to 12 months, by 1.7 days (SD 3.8), (95% CI 0.8–2.6). There was no statistically significant change in mean cycle length at 12 months (0.7 days [SD 4.9]; 95% CI [−0.5, 1.9]). Conclusions There is no evidence for UAE accelerating a deterioration in ovarian function at 1 year, when compared with surgery. UAE is associated with a decrease in the duration of menstrual flow at 1 year.

Informed by the findings from prospective observational studies and randomized outcome trials, guidelines for the management of hypertension acknowledge that the benefit of treatment can be attributed largely to blood pressure (BP) reduction. Therefore, quantification of differential BP lowering of different agents within classes of anti-hypertensives is of practical importance. The objective of this analysis was to compare the efficacy of candesartan and losartan with respect to reduction in systolic and diastolic BP (SBP and DBP). A systematic literature search of databases from 1980 to 1 October 2008 identified 13 studies in which candesartan and losartan were compared in randomized trials in hypertensive patients. Data from 4066 patients were included in the analysis using a random effect model. Mean changes in SBP and DBP were compared for each drug alone and after stratification for dose and for combination with hydrochlorothiazide (HCTZ). On the basis of all the data, the weighted mean difference favoured candesartan-3.22 mm Hg (95% confidence interval (CI) 2.16, 4.29) for SBP and 2.21 mm Hg (95% CI 1.34, 3.07) for DBP. These findings were consistent when analyses according to dose and combination with HCTZ were carried out. Thus, it can be concluded that at currently recommended doses, candesartan is more effective than losartan in lowering BP.

Objective To determine if the increased risk of cardiovascular disease in patients with lower socioeconomic status could be explained by higher prevalence of known risk factors including hypertension or whether there was an independent effect of deprivation. Methods A retrospective cohort study of mortality was carried out on 3360 patients who attended Glasgow Blood Pressure Unit between 1991 and 2000, followed for a mean period of 8.1 years. Cox proportional hazards models were used to adjust for the effects of age, sex, socioeconomic circumstances, systolic and diastolic blood pressures at baseline and on treatment, smoking, diabetes mellitus, history of angina and myocardial infarction, excessive alcohol consumption, BMI and serum cholesterol. Results Of 442 deaths, 244 (55%) were from cardiovascular diseases. After adjustment, residents of the most deprived areas had a hazard ratio for all cause mortality of 1.46 (95% confidence interval 1.04, 2.04). Adjusted hazard ratio for death from cardiovascular disease in the most deprived areas was 1.65 (1.04, 2.60) compared with those from the most affluent areas. Conclusion Socioeconomic deprivation appears to have a significant independent effect on risks of death from cardiovascular disease.

Purpose To prospectively compare contrast-enhanced (CE) magnetic resonance (MR) angiography against digital subtraction angiography (DSA) in patients with critical lower-limb ischemia. Materials and Methods Thirty patients with critical lower limb ischemia underwent both CE MR angiography and DSA. CE MR angiography commenced with a dedicated high-resolution study of the below-knee arteries followed by a three-station bolus-chase examination. Two blinded observers recorded the severity of the most significant stenosis within each arterial segment. Interobserver agreement was calculated and, with DSA as the reference standard, the sensitivity and specificity of CE MR angiography for the detection of significant stenosis (≥50% luminal narrowing) or occlusion was calculated. Results All 390 arterial segments were scored by both observers. Sensitivity was higher in the distal segments (92%–96%) compared with the proximal segments (69%–79%). Specificity was similar in distal (90%–91%) and more proximal segments (86%–96%). Overall, interobserver agreement was excellent (κ = 0.95 for CE MR angiography and DSA) and was superior within the distal segments. Twenty-eight segments that were considered occluded on DSA were shown to be patent on CE MR angiography and 16 segments that were considered occluded on CE MR angiography were shown to be patent on DSA. Conclusions In patients with critical lower-limb ischemia, CE MR angiography with high-resolution distal imaging is highly accurate for assessment of the below-knee arteries. Both DSA and CE MR angiography may identify patent vessels that are considered occluded based on the other modality.

The aim of the study was to compare the Glasgow Nutritional Screening Tool with the Malnutrition Universal Screening Tool (MUST) recently recommended for use by the British Association for Parenteral and Enteral Nutrition. Comparison-validation study. Four adult acute hospitals in Glasgow, UK. All 242 in-patients from a variety of specialties. Two investigators independently interviewed 202 in-patients for the comparison-validation study. Each used a single tool with each patient, using each tool in turn. Investigators were not aware of each other's assessments. Forty other patients were interviewed by both raters separately using the local tool to evaluate inter-rater reliability. When compared with MUST as a ‘gold standard’, the local tool had a sensitivity of 95.3% and a specificity of 64.9%, with moderate agreement between the two tools using kappa test (κ=0.57). Agreement between the raters was substantial (κ=0.69) with 85% of patients classified the same by both raters. The Glasgow Nutritional Screening Tool is a valid and reliable tool that can be used on admission for nutritional screening. University of Glasgow, Greek State Scholarship Foundation.

INTRODUCTION The objective of the study was to determine the effectiveness of endoscopy to detect curable upper gastrointestinal malignancy in patients older than 55 years presenting with uncomplicated dyspepsia. METHODS A cohort study was performed in North Glasgow Health Trust. One hundred and thirty-one patients older than 55 years of age, diagnosed to have upper gastrointestinal cancer within the North Glasgow Trust between January 1995 and December 1997, identified by the West of Scotland Cancer Registry were included. The main outcome measures were the proportion of upper gastrointestinal cancers that present in patients older than 55 years with uncomplicated dyspepsia, and the proportion of patients that presented with uncomplicated dyspepsia who have curable upper gastrointestinal cancer. RESULTS Of the 131 cancer cases identified, only 30 (23%) had dyspepsia (complicated or uncomplicated) as their predominant symptom and only eight (6%) patients presented with uncomplicated dyspepsia. Of those eight patients presenting with uncomplicated dyspepsia and found to have upper gastrointestinal cancer, six were found to have lymph node metastases and/or extensive metastases at the time of diagnosis. Each of these six patients died from their cancer within 39 months of diagnosis. Of the two patients presenting with uncomplicated dyspepsia without evidence of lymph node spread, one died 55 days after diagnosis. Only one patient presenting with uncomplicated dyspepsia and found to have cancer remains alive at 5-year follow-up. CONCLUSIONS Of the 131 patients diagnosed with upper gastrointestinal cancer, only eight presented with uncomplicated dyspepsia and only one of these was cured. Consequently a policy of endoscoping patients older than 55 years with uncomplicated dyspepsia will reduce death from upper gastrointestinal cancers by less than 1% in our population.

Alcoholic hepatitis is associated with a high short term mortality. We aimed to identify those factors associated with mortality and define a simple score which would predict outcome in our population.We identified 241 patients with alcoholic hepatitis. Clinical and laboratory data were recorded on the day of admission (day 1) and on days 6-9. Stepwise logistic regression was used to identify variables related to outcome at 28 days and 84 days after admission. These variables were included in the Glasgow alcoholic hepatitis score (GAHS) and its ability to predict outcome assessed. The GAHS was validated in a separate dataset of 195 patients.The GAHS was derived from five variables independently associated with outcome: age (p = 0.001) and, from day 1 results, serum bilirubin (p0.001), blood urea (p = 0.019) and, from day 6-9 results, serum bilirubin (p0.001), prothrombin time (p = 0.002), and peripheral blood white blood cell count (p = 0.001). The GAHS on day 1 had an overall accuracy of 81% when predicting 28 day outcome. In contrast, the modified discriminant function had an overall accuracy of 49%. Similar results were found using information at 6-9 days and when predicting 84 day outcome. The accuracy of the GAHS was confirmed by the validation study of 195 patients The GAHS was equally accurate irrespective of the use of the international normalised ratio or prothrombin time ratio, or if the diagnosis of alcoholic hepatitis was biopsy proven or on the basis of clinical assessment.Using variables associated with mortality we have derived and validated an accurate scoring system to assess outcome in alcoholic hepatitis. This score was able to identify patients at greatest risk of death throughout their admission.

A detailed neuropathological study of patients identified clinically after head injury as either severely disabled (SD, n = 30) or vegetative (VS, n = 35) has been carried out to determine the nature and frequency of the various pathologies that form the basis of these clinical states. Patients who were SD were older (SD median 49.5 yrs vs. VS median 38 yrs, p = .04), more likely to have a lucid interval (SD 31% vs. VS 9%, p = .03), and to have had an acute intracranial haematoma (SD 70% vs. VS 26%, p < .001). SD patients less often had severe, Grades (2 or 3) of traumatic diffuse axonal injury (SD 30% vs. VS 71%, p = .001) and less often had thalamic damage (SD 37% vs. VS 80%, p < .001). Similar features of both focal and diffuse damage were present in some SD and VS cases with both groups having considerable damage to white matter and to the thalamus. It is concluded that the principal structural basis of both SD and VS is diffuse traumatic axonal injury (DAI) with widespread damage to white matter and changes in the thalami. However, both ischaemic brain damage and the vascular complications of raised intracranial pressure contributed to the clinical signs and symptoms.

Objective: In view of the association of the apolipoprotein E ( APOE ) e4 allele with poor outcome after traumatic brain injury we determined the frequency of cerebral amyloid angiopathy (CAA) and the extent of haemorrhagic pathology in relation to APOE genotype in an autopsy series of 88 head injured cases. Methods: Tissue sections from the frontal and temporal lobes were immunostained for amyloid-β peptide (Aβ) and stained for Congo red to identify vascular amyloid pathology. A semiquantitative assessment of contusions, the total contusion index, was used to estimate the severity of the haemorrhagic pathology. APOE genotypes were determined by polymerase chain reaction of genomic DNA extracted from paraffin embedded tissue sections. Results: CAA was present in 7/40 (18%) e4 carriers compared with 1/48 (2%) non-e4 carriers (p = 0.021, 95% confidence interval (CI) for difference in proportions with CAA 3% to 29%) with 6/40 (4 with CAA) e4 carriers being homozygotes. Thus the risk of having CAA for e4 carriers was 8.4 times that for the non-e4 carriers. However, there was no clear tendency for patients with CAA to have more severe or more numerous contusions (median contusion index 19 (CAA) v 14.5, p = 0.23, 95% CI for difference in medians −5 to 14). Conclusions: Presence of CAA in head injured cases was significantly associated with possession of an APOE e4 allele but not with the severity of contusions.

Traumatic brain injury (TBI) is an important cause of mortality and disability in children and teenagers. A particular feature of the neuropathology at post-mortem is brain swelling. The cause of the swelling in some cases is not known, while in others it is associated with traumatic axonal injury or hypoxia. Apolipoprotein E (APOE) 4 allele is known to be an important genetic determinant of outcome in children after TBI. We hypothesized a relationship between possession of APOE4 and diffuse traumatic brain swelling. A total of 165 cases aged between 2 and 19 years were identified from the department's tissue archive. APOE genotype was determined by polymerase chain reaction (PCR) in 106 cases. Bilateral swelling was present in 44 cases (11 with APOE4), unilateral swelling in 25 cases (7 with APOE4) and in 36 cases (9 with APOE4) there was no evidence of brain swelling. There was no significant relationship between possession of APOE4 and the presence of cerebral swelling (?2 = 0.09, df = 2, P = 0.96). The 95% confidence interval for difference in proportions with swelling in those with and without the APOE4 is ?19% to 22%. Thus, a significant relationship was not found between diffuse brain swelling and possession of APOE4, and in this cohort of patients there was an identifying cause of the brain swelling in all cases.

The new National Patient Safety Agency (NPSA) aims to facilitate the mandatory reporting of relevant significant events. A questionnaire survey of 617 general practitioners was undertaken and 466 responses were received (76 per cent). A minority (18 per cent) agreed the reporting of adverse incidents should be mandatory, while a majority (73 per cent) agreed that they would be selective in their reporting in a mandatory system. Most (75 per cent) favoured a local anonymised system of reporting. A difficulty in determining when an event is “significant” was acknowledged by 41 per cent of respondents and 30 per cent agreed significant events were often not acted on. Less experienced respondents were more likely to have difficulty in determining when an event is significant (p = 0.01). The success of the NPSA system may be obstructed by the mandatory requirement to participate and in the difficulty for some in determining when an event is “significant”.

Epidemiological studies have identified a history of head injury as a risk factor for Alzheimer's disease. However, the neuropathological mechanism underlying this relationship is as yet unclear. Neuronal cytoskeletal changes in the form of neurofibrillary tangles and neuropil threads have recently been demonstrated in young men who had sustained repetitive head injury and subsequently died in their 20s. In addition, recent experimental studies have found accumulation of tau within neuronal somata and damaged axons following diffuse brain injury. We hypothesized that tau-immunoreactive tangles may be present in the brains of patients who died after a single acute blunt head injury. A total of 45 cases of fatal head injury were immunostained for tau. They comprised nine groups (n=5 for each group) separated by age (0-19 years, 20-50 years, 50+ years) and survival time (

APOE polymorphism may influence risk for cold sores and, by interacting with latent HSV-1, risk for Alzheimer's disease (AD). APOE genotype also influences outcome after brain injury. We sought to determine whether APOE genotype influences risk for herpes simplex encephalitis (HSE), whether apoE is involved in the response to HSE and if APOE genotype influences outcome from HSE. There was increased immunoreactivity of neurons, neuropil and glia for apoE areas of brain damaged by HSE. APOE genotypes for cases of HSE (n = 57) were similar to those of controls (n = 41). APOE genotypes for survivors of HSE were similar to those of patients who died. We conclude that apoE is involved in the response to damage associated with HSE, as in other forms of brain injury. However, APOE genotype does not appear to influence either the risk of developing HSE or subsequent mortality.

Lipids are a major constituent of myelin and apolipoprotein E (apoE) plays a key role in lipid transport. We therefore hypothesized that apoE is involved in the processes of demyelination and remyelination. Furthermore as there is a biologically significant polymorphism in the APOE gene, the APOE genotype may influence the course of multiple sclerosis (MS). Specifically, as there is reduced affinity of the apoE E2 isoform for receptors on glial cells, we hypothesized that remyelination is impaired in individuals with the apoE epsilon2 allele. We determined the apoE genotypes of 71 archival cases of multiple sclerosis and 41 controls, reviewed the neurohistology, and performed apoE immunohistochemistry. ApoE immunoreactivity was increased in demyelinated areas compared with control white matter. ApoE immunostaining was markedly increased in areas of active demyelination, specifically in macrophages and astrocytes. The APOE allele frequencies of the cases of MS (epsilon2 = 0.06, epsilon3 = 0.8, epsilon4 = 0.13) resembled those of controls. Evidence of remyelination was identified in 25/ 71 MS cases (35%): in 25/64 patients (39%) without an epsilon2 allele and 0/7 (0%) patients with an epsilon2 allele (p < 0.05). In conclusion, we provide evidence that apoE is involved in the trafficking of lipid in MS and, although the number of cases with this allele was small, remyelination may be defective in patients with the APOE epsilon2 allele.

Alzheimer’s disease (AD), the most common cause of dementia, is estimated to affect 5% of those more than 65 years of age and 40% of those more than 80 years of age, or a total of approximately 20 million people worldwide. The neuropathological characteristics of AD include (β-amyloid plaques that are diagnostic when associated with dystrophic neurites,1 neurofibrillary tangles, loss of neurons and synapses, and proliferation of glial cells. There has been substantial progress, in the last few years, in unraveling the genetic influences in AD. A small proportion of AD cases are inherited as an autosomal dominant trait and are attributable to point mutations in genes that encode the β-amyloid precursor protein (βAPP),2 presenilin 1,3 or presenilin 2.4 A major genetic risk factor for the much more common sporadic AD is possession of the apolipoprotein E (ApoE) e4 allele.5 However, possession of ApoE e4 is neither necessary nor sufficient for the development of AD, leaving scope for other potential genetic or environmental influences. Interleukin-1 (IL-1) is a potent proinflammatory cytokine that is markedly overexpressed in the brains of patients with AD, predominantly in microglia,6 which suggests a role for inflammatory processes in AD pathogenesis.7 This idea has received support from epidemiological studies that show that the use of anti-inflammatory agents, in particular nonsteroidal anti-inflammatory drugs, is associated with delayed onset or slowed progression of disease.8 IL-1 has two structurally distinct forms, IL-1α and IL-1β, encoded by separate genes (IL-1A and IL-1B, respectively) located in a cluster on the long arm of chromosome 2 that also includes the IL-1 receptor antagonist gene.9 Common polymorphisms have been described in both genes and there is evidence that they have functional significance. A polymorphism of the IL-1B gene (+3953), for instance, which introduces a TaqI restriction site, results in two alleles, designated allele 1 and allele 2.10 Homozygosity for allele 2 of IL-1B is associated with a fourfold increase in production of IL-1β compared with homozygosity for allele 1.10 A polymorphism in the 5′ regulatory region of the IL-1A gene (a C-to-T transition at position −889 relative to the start site of transcription) again results in two alleles, also designated allele 1 and allele 2.11 Both of these IL-1 polymorphisms have been associated with inflammatory diseases. For instance, IL-1A allele 2 has been associated with juvenile rheumatoid arthritis.11 In view of the evidence that suggests a role for inflammatory processes, and for IL-1 in particular in AD, we hypothesized that these IL-1 polymorphisms modulate susceptibility to AD.

Background & Aims: Helicobacter pylori is believed to predispose to gastric cancer by inducing gastric atrophy and hypochlorhydria. First-degree relatives of patients with gastric cancer have an increased risk of developing gastric cancer. The aim of this study was to determine the prevalence of atrophy and hypochlorhydria and their association with H. pylori infection in first-degree relatives of patients with gastric cancer. Methods: H. pylori status, gastric secretory function, and gastric histology were studied in 100 first-degree relatives of patients with noncardia gastric cancer and compared with those of controls with no family history of this cancer. Results: Compared with healthy controls, relatives of patients with gastric cancer had a higher prevalence of hypochlorhydria (27% vs. 3%) but a similar prevalence of H. pylori infection (63% vs. 64%). Relatives of cancer patients also had a higher prevalence of atrophy (34%) than patients with nonulcer dyspepsia (5%) matched for H. pylori prevalence. Among the relatives of cancer patients, the prevalence of atrophy and hypochlorhydria was increased only in those with evidence of H. pylori infection, was greater in relatives of patients with familial cancer than in relatives of sporadic cancer index patients, and increased with age. Eradication of H. pylori infection produced resolution of the gastric inflammation in each subject and resolution of hypochlorhydria and atrophy in 50% of the subjects. Conclusions: Relatives of patients with gastric cancer have an increased prevalence of precancerous gastric abnormalities, but this increase is confined to those with H. pylori infection. Consequently, prophylactic eradication of the infection should be offered to such subjects. GASTROENTEROLOGY 2000;118:22-30

Aims This study assessed the use of systolic time intervals (STI) as a potential noninvasive marker of the haemodynamic eVects of sumatriptan, a 5HT1 receptor agonist. Methods Twenty-six patients undergoing diagnostic cardiac catheterization participated. STIs were derived from haemodynamic pressure tracings at baseline, following placebo injection and following either subcutaneous (n=18) or intravenous injection (n=8) of sumatriptan. Results Sumatriptan (i.v. or s.c.) was associated with significant increases in mean arterial pressure (95% C.I. 9,14mmHg, P=0.0001), total electromechanical systole (95% C.I.8,36ms, P

Doxorubicin pharmacokinetics were determined in 33 patients with solid tumours who received intravenous doses of 20–320 mg m−2 HPMA copolymer bound doxorubicin (PK1) in a phase I study. Since assay constraints limited the data at lower doses, conventional analysis was not feasible and a ‘population approach’ was used. Bound concentrations were best described by a biexponential model and further analyses revealed a small influence of dose or weight on V1 but no identifiable effects of age, body surface area, renal or hepatic function. The final model was: clearance (Q) 0.194 l h−1; central compartment volume (V1) 4.48 × (1+0.00074 × dose (mg)) l; peripheral compartment volume (V2) 7.94 l; intercompartmental clearance 0.685 l h−1. Distribution and elimination half-lives had median estimates of 2.7 h and 49 h respectively. Free doxorubicin was present at most sampling times with concentrations around 1000 times lower than bound doxorubicin values. Data were best described using a biexponential model and the following parameters were estimated: apparent clearance 180 l h−1; apparent V1 (l) 1450 × (1+0.0013 × dose (mg)), apparent V2 (l) 21 300 × (1–0.0013 × dose (mg)) × (1+2.95 × height (m)) and apparent Q 6950 l h−1. Distribution and elimination half-lives were 0.13 h and 85 h respectively. © 1999 Cancer Research Campaign

Established in 1968 the Glasgow Blood Pressure Clinic has over 11,000 patients on its computer record. Up to 1980, mortality from all-causes and from cardiovascular causes was high: relative risks compared with two local control populations were greater than 2.0. Since 1980, all-cause mortality has decreased to 1.31 (859 deaths, CI 1.23-1.39). Lower mortality from cardiovascular causes, particularly coronary heart disease, contributes to the decrease. Reasons for the decrease are under investigation currently. Referral of patients with slightly lower blood pressure contributes, as may better blood pressure control with newer antihypertensive drugs. ACE inhibitors and calcium channel blockers were introduced in 1980 and during the 16-year period to 1995, all-cause mortality has decreased most in patients taking ACE inhibitor. A decrease also occurred in patients taking antihypertensive drugs other than ACE inhibitor.

The eradication of Helicobacter pylori infection is beneficial in patients with gastric or duodenal ulcers. The value of eradicating the infection in patients with dyspepsia and no evidence of ulcer disease is not known.We performed a randomized, placebo-controlled trial comparing the efficacy of treatment for two weeks with 20 mg of omeprazole orally twice daily, 500 mg of amoxicillin three times daily (with 500 mg of tetracycline three times daily substituted for amoxicillin in patients allergic to penicillin), and 400 mg of metronidazole three times daily (160 patients) with that of omeprazole alone (158 patients) for resolving symptoms of dyspepsia in patients with H. pylori infection but no evidence of ulcer disease on upper gastrointestinal endoscopy. Symptoms were assessed with the Glasgow Dyspepsia Severity Score, with resolution of symptoms defined as a score of 0 or 1 in the preceding six months (maximal score, 20). One year later the patients were assessed to determine the frequency of the resolution of symptoms.One month after the completion of treatment, 132 of 150 patients (88 percent) in the group assigned to received omeprazole and antibiotics had a negative test for H. pylori, as compared with 7 of 152 (5 percent) in the group assigned to receive omeprazole alone. One year later, dyspepsia had resolved in 33 of 154 patients (21 percent) in the group given omeprazole and antibiotics, as compared with 11 of 154 (7 percent) in the group given omeprazole alone (95 percent confidence interval for the difference, 7 to 22 percent; P0.001). Among the patients in the group given omeprazole and antibiotics, the symptoms resolved in 26 of the 98 patients (27 percent) who had had symptoms for five years or less, as compared with 7 of the 56 patients (12 percent) who had had symptoms for more than five years (P=0.03).In patients with H. pylori infection and nonulcer, or functional, dyspepsia, treatment with omeprazole and antibiotics to eradicate the infection is more likely to resolve symptoms than treatment with omeprazole alone.

Summary Background Previous studies have reported an increased risk of cancer with calcium-channel blockers in man. Other work in animals suggests that inhibitors of angiotensin-l-converting enzyme (ACE) protect against cancer. We aimed to assess the risk of cancer in hypertensive patients receiving ACE inhibitors or other antihypertensive drugs. Methods Our retrospective cohort study was based on the records of 5207 patients who attended the Glasgow Blood Pressure Clinic between Jan 1, 1980, and Dec 31, 1995. The patients' records are linked with the Registrar General Scotland and the West of Scotland Cancer Registry. Findings Compared with the West of Scotland controls, the relative risks of incident and fatal cancer among the 1559 patients receiving ACE inhibitors were 0·72 (95% Cl 0·55–0·92) and 0·65 (0·44–0·93). Among the 3648 patients receiving antihypertensive drugs other than ACE inhibitors (calcium-channel blockers 1416, diuretics 2099, β-blockers 2681), the corresponding relative risks were 1·10 (0·97–1·22) and 1·03 (0·87–1·20). The relative risk of cancer was lowest in women on ACE inhibitors: 0·63 (0·41–0·93) for incident cancer; 0·48 (0·23–0·88) for fatal cancer; and 0·37 (0·12–0·87) for female-specific cancers. The reduced relative risk of cancer in patients on ACE inhibitors was greatest with follow-up of longer than 3 years. Calcium-channel blockers, diuretics, and β-blockers had no apparent effect on risk of cancer. Interpretation Long-term use of ACE inhibitors may protect against cancer. The status of this finding is more that of hypothesis generation than of hypothesis testing; randomised controlled trials are needed.

Aims To investigate the relationship in patients with heart failure between BP response to the first dose of ACE inhibitor and (1) plasma drug concentration and (2) baseline clinical and laboratory variables. Methods We studied individual placebo-corrected BP responses to initiation of treatment with one of a number ACE inhibitor preparations in 132 patients with mild to moderate CHF. Various pharmacokinetic/pharmacodynamic models were compared. We assessed the strength of association between baseline physiological and laboratory variables and the BP response as assessed directly from the AUC(0,10 h) and indirectly from the slope of the PK/PD relationship. Predictive models for response variables were developing using regression analysis. Results BP response was primarily related to plasma drug concentration. The association between the fall in BP and baseline variables was weak. The strongest single predictor of BP response was baseline mean arterial pressure (r2=5.8%, P=0.02). The best combinations of predictor variables contained mean arterial pressure, plasma renin activity, creatinine concentration and age (r2=14.4%, P=0.37). When the choice of ACE inhibitor was added, the predictive power of the model increased (r2=23.6%, P

In studies using strain-gauge forearm plethysmography to measure changes in forearm blood flow (FBF) during intra-arterial infusions of vasoactive substances, measurements are often made in both arms simultaneously and the change in ratio of the infused and control arms used to express responses. However, the reproducibility of bilateral plethysmography in this setting has not been addressed in published studies. The unilateral technique remains in use, and forearm vascular resistance (FVR), an alternative method of expressing responses, is used by some investigators. We have assessed: (a) the intra-subject variability of bilateral FBF measurements (FBF ratios) at rest, after unilateral forearm exercise, and during intra-arterial infusions of vasoconstrictor substances; (b) whether bilateral plethysmography is more reproducible than unilateral plethysmography; and (c) the reproducibility of FVR (unilateral and bilateral).Study 1 Nine healthy subjects attended 3 study days, 1 week apart. FBF was measured at rest and after 2 min of standardized unilateral forearm exercise; between-day intra-subject variability was expressed as coefficients of variation (CV) calculated using two-way analysis of variance (ANOVA). Study 2 Five healthy subjects attended 2 study days when FBF was measured during incremental infusions of noradrenaline (15, 30, 150, 300 pmol min[-1]) and angiotensin II (1, 5, 10, 50 pmol min[-1]); for each individual subject at each dose intra-subject variability was assessed using the difference between responses (percentage change from baseline) on days 1 and 2.Study 1 At rest, intra-subject variability (CV) of baseline FBF ratios was 19% compared with 31% (left) and 39% (right) for unilateral FBF measurements. After ipsilateral exercise, unilateral FBF measurements were more reproducible (32 vs 17%) than FBF ratios; by 20 min after exercise, the previous pattern had been re-established (19 vs 27%). Intra-subject variability (CV) of baseline FVR ratio and post-exercise FVR was 14%. Study 2 Inter-quartile ranges of the differences between responses on days 1 and 2 (FBF ratios vs FBF) were: angiotensin II 14 vs 18%; noradrenaline 16 vs 27%.FBF ratios are more reproducible than unilateral FBF measurements at rest (CV 19% vs 39%) and for measuring responses to intra-arterial infusions of vasoconstrictor substances. FVR may have a small reproducibility advantage. Non-experimental stimuli can cause significant and misleading changes in measured responses if unilateral measurements are used; it is therefore recommended that responses to intra-arterial infusions should be measured using bilateral forearm plethysmography with the results expressed as FBF ratios.

To measure rates of incident and fatal cancer in hypertensive patients taking calcium antagonists and to compare these with rates in three control groups.A retrospective analysis of cancer in patients of the Glasgow Blood Pressure Clinic prescribed either a calcium antagonist or other antihypertensive drugs (non-calcium antagonist group). Record linkage of the clinic with the West of Scotland Cancer Registry and with the Registrar General, Scotland provided information on incidence of cancer and on deaths and their causes.2297 patients were prescribed calcium antagonist and 2910 were prescribed antihypertensive drugs other than calcium antagonist.Relative risk of cancer, the ratio of observed to expected cancers in the calcium antagonist group, was estimated using expected values based on three control groups; namely the non-calcium antagonist group, a middle-aged population of Renfrew and Paisley and the West of Scotland population.There were 134 incident cancers in the calcium antagonist group, representing relative risks of 1.02 [95% confidence interval (CI) 0.82-1.271 compared with the non-calcium antagonist group, 1.01 (95% CI 0.84-1.18) compared with Renfrew-Paisley controls and 1.02 (95% CI 0.85-1.19) compared with West of Scotland controls. Findings for cancer mortality were similarly negative. Risks were no higher for older patients.Our study lends no support to the suggestion that calcium antagonists cause cancer.

BACKGROUND: There is interest in noninvasive H pylori testing as a means of predicting diagnosis and determining management in dyspeptic patients. AIMS: To assess the value of the 14C urea breath test as a predictor of peptic ulcer disease in patients presenting with dyspepsia. PATIENTS AND METHODS: 327 consecutive patients referred for investigation of dyspepsia had a 14C urea breath test performed before endoscopy. Patients were not included if they had previously confirmed ulcer disease, previous gastric surgery, or were taking non-steroidal anti-inflammatory drugs. RESULTS: Of the 182 patients with a positive 14C urea breath test, duodenal and/or gastric ulcers were present in 45% and erosive duodenitis in a further 2%. Oesophagitis was present in 12% of the breath test positive patients with two thirds of the oesophagitis patients having co-existent ulcer disease. The prevalence of ulcer disease in the H pylori positive dyspeptic patients was independently related to smoking and previous investigation status. If previously uninvestigated, the prevalence of ulcers was 67% in smokers and 46% in non-smokers. If previous upper gastrointestinal investigations were negative, the prevalence of ulcers was 53% in smokers and 28% in non-smokers. Of the 136 patients with a negative breath test, only 5% had peptic ulcers. The most frequent endoscopic finding in these H pylori negative subjects was oesophagitis, being present in 17%. CONCLUSIONS: This study demonstrates that a positive H pylori test is a powerful predictor of the presence of underlying ulcer disease in dyspeptic patients, especially if smokers, and that a negative H pylori test is a powerful predictor of the absence of ulcer disease. It also indicates that a negative upper gastrointestinal investigation does not preclude subsequent presentation with ulcer disease.

Aims: This study assessed the patterns of weight change in response to surgical treatment for obesity. Methods: Vertical Banded Gastroplication (VBG) was performed during the period 1994–2000. Patients were required to follow a liquid diet (8oo kcals) for 12 weeks before surgery. The same diet plus a multivitamin capsule (Forceval) was followed for 12 weeks postoperatively, after which normal foods were introduced. Data from 23 patients, 16 women and 7 men, aged 33–63 years (mean, SD; 42±8yrs), with BMI from 38 to 69 kg/m2 (52.5 ± 8.1 kg/m2) at the time of the surgery were available for analysis. Follow up was 3 to 7 years (mean 4 years). Results: An initial weight loss of 44.4 ± 24.3 kg (min 11.5, max 110.5 kg) was reached during the first two years (mean BMI decrease 15.8 kg/m2). However a regain in weight (36% of the initial weight loss = 5.6 kg/m2) up to 3 to 7 years after surgery was usual. Average annual regain was 13.6 kg (n=17), 9.45 kg (n=11) and 0.8 kg (n=8) during the 3rd, 4th and 5th year after surgery). Five participants reached a BMI below 30 but only one, BMI

Bolus/infusional 5-fluorouracil (5-FU) and folinic acid (FA) is reported to be highly active [partial response (PR) = 54%, median survival 18 months] in patients with metastatic colorectal carcinoma (MCCa). To confirm this level of activity, we conducted a retrospective analysis of 95 previously untreated patients with MCCa treated with FA by 2 h i.v. infusion (200 mg m-2) followed by 5-FU bolus/22 h i.v. infusion (300-500 mg m-2) on days 1 and 2 every 2 weeks. Thirty patients also received N-(phosphonacetyl)-L-aspartate (PALA), 250 mg m-2, 24 h prior to 5-FU/FA. In 81 evaluable patients, the response rate was low: PR = 11%, stable disease (SD) = 36% and median survival = 8 months. There was an improvement in survival with increased 5-FU dosage (500 mg m-2) [relative hazard (RH) = 0.38, 95% CI 0.21-0.70], controlled for age, primary site, PALA, liver function and performance status. Good performance status (PS 0 or 1) was also associated with improved survival (RH = 0.21, 95% CI 0.10-0.46). Response, survival and toxicity were not altered by the co-administration of PALA. Bolus/infusional 5-FU (500 mg m-2) and FA was well tolerated. WHO toxicities (grade 3) were: mucositis, 2%; diarrhoea, 14%; nausea and vomiting, 5%. In light of the apparent dose effect, poor response and low toxicity, we recommend that regimes incorporating higher 5-FU dosages are explored and prospectively validated before bolus/infusional 5-FU becomes accepted standard practice.

We investigated how the occurrence and severity of the main neuropathological types of traumatic brain injury (TBI) influenced the severity of disability after a head injury. Eighty-five victims, each of whom had lived at least a month after a head injury but then died, were studied. Judged by the Glasgow Outcome Scale (GOS), before death 35 were vegetative, 30 were severely and 20 were moderately disabled. Neuropathological assessment showed that 71 (84%) victims had sustained cerebral contusions, 49 (58%) had diffuse axonal injury (DAI), 57 (67%), had ischemic brain damage (IBD), 58 (68%) had symmetrical ventricular enlargement, and in 47 (55%) intracranial pressure (ICP) had been increased. Thirty-five (41%) had undergone evacuation of an intracranial hematoma. Brainstem damage was seen in only 11 (13%). Analysis (χ(2) test for trends) of the relationship between these features and outcome showed that findings of DAI, raised ICP, thalamic damage, or ventricular enlargement (all p0.005), and IBD (p=0.04) were associated with an increasingly worse outcome. Conversely, moderate or severe contusions (p=0.001) were increasingly associated with better outcomes, and evacuation of a hematoma was associated (p=0.001) with outcomes likely to be better than vegetative. We conclude that diffuse or multifocal neuropathological patterns of TBI from primary axonal injury or secondary ischemic damage are most likely to be associated with the most severely impaired outcomes after a head injury.

Rationale, aims and objectives Clinical audit informs general practitioner (GP) appraisal and will provide evidence of performance for revalidation in the UK. However, objective evidence is now required. An established peer assessment system may offer an educational solution for making objective judgements on clinical audit quality. National Health Service (NHS) clinical audit specialists could potentially support this system if their audit assessments were comparable with established medical peer assessors. The study aimed to quantify differences between clinical audit specialists and medical peer assessors in their assessments of clinical audit projects. Methods A comparison study of the assessment outcomes of clinical audit reports by two groups using appropriate assessment instruments was conducted. Mean scores were compared and 95% confidence intervals (CIs) and limits of agreement calculated. A two-point mean difference would be relevant. Results Twelve significant event analysis (SEA) reports and 12 criterion audit projects were assessed by 11 experienced GP assessors and 10 NHS audit specialist novice assessors. For SEA, the mean score difference between groups was

Background and aims: There is variation in the identification, analysis and reporting of significant events in general practice. Consistency is desired to optimise learning from, and reporting of, patient safety incidents. We examined levels of agreement among different groups of general practitioners (GPs) on the grading, analysis and reporting of selected significant event scenarios. Method: Cross-sectional postal questionnaire survey of 162 GPs split into five professional groups in the west of Scotland. Differences in grading severity and willingness to formally analyse and report seven significant event scenarios were examined using analysis of variance (ANOVA). Differences in proportions were calculated together with 95% confidence intervals. Results: 122 GPs responded (77%). No difference was found in the grading severity of significant events by GP groups. Increased grading severity was linked to the willingness of GP groups to analyse and report that event (p

We have analyzed features of patients who had what appeared initially to be a minor head injury but who developed an acute traumatic intracranial hematoma. Over a 10-year period, 183 patients who were able to open their eyes spontaneously, were oriented to person, place, and time, and who obeyed commands when they were first seen at a hospital subsequently underwent operation for an acute intracranial hematoma. The hematoma was extradural in 54% of these patients. A history of altered consciousness or symptoms of headache and vomiting were present in 61% of the patients; 33% had a focal neurological deficit, and 43% had either focal deficit or signs of a basal skull fracture. A skull fracture was shown radiologically in 60% of patients, including 52% of those not clinically suspected of having an intracranial lesion. Six months after injury, 77% of the patients had made a moderate or good recovery. The possibility that a patient who has recently sustained a head injury might develop an acute intracranial hematoma can never be completely discounted, even when there are no abnormal clinical signs, and a skull x-ray retains a useful place in the investigation of selected patients with a minor head injury.

Background: Previous studies have found the e4 allele of the apolipoprotein E gene ( APOE e4) is associated with an unfavourable outcome after head injury, but this has not been related to specific pathological features. Objectives: This study tested the postulate that head injured patients with APOE e4, amounting to approximately a third of the population, are selectively predisposed to one or more of the different pathological features that constitute the response to traumatic brain injury (TBI), and that this underlies the association of APOE e4 with poor clinical outcome. Methods: Included in the study were 239 fatal cases of TBI (1987–1999) for which APOE genotypes were determined from archival tissue. For each case, specific pathological features of trauma were recorded by researchers blinded to the APOE e4 status. Of the 239 cases examined, 83 (35%) were APOE e4 carriers and 156 (65%) were non-carriers. Results: Possession of APOE e4 was associated with a greater incidence of moderate or severe contusions (42% v 30% for carriers versus e4 non-carriers; p = 0.05) and there was a trend towards a greater incidence of severe ischaemic brain damage (54% v 42%; p = 0.08). Significant differences were not noted between the other pathological features examined. Conclusions: Possession of APOE e4 is associated with a greater incidence of moderate/severe contusional injury and severe ischaemic brain damage in fatal cases of TBI. This may be relevant to the relatively poor outcome from traumatic brain injury in patients with APOE e4 identified in clinical studies.

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial and the Study on Cognition and Prognosis in the Elderly (SCOPE) superficially produced comparable outcomes, with effects on stroke greater than those anticipated from blood pressure (BP) lowering alone. This, however, ignores important features of both studies. It ignores firstly the disparate comparator agents — atenolol in LIFE and predominantly hydrochlorthiazide in SCOPE, secondly the small, but potentially important BP differential between the treatment arms in SCOPE and finally the small, statistically non-significant increase in coronary heart disease (CHD) in both trials. This analysis compares the major cardiovascular outcomes in these trials with reference to placebo. Two alternative reference populations were employed to calculate the imputed placebo, firstly the MRC Trial in Elderly Hypertensives and secondly a meta-analysis of trials in the elderly, which included comparisons between diuretic- and β-blocker-based regimens. Overall, the choice of `comparator placebo' did not substantially influence the derived results. Accounting for BP difference and based on the meta-analysis, both trials demonstrated statistically significant reductions in fatal/non-fatal stroke compared with placebo — relative risks (95% confidence intervals [CI]) of 0.53 (0.39, 0.73) and 0.56 (0.41, 0.76) for SCOPE and LIFE, respectively. For fatal/non-fatal MI, there were greater discrepancies between the studies, but with neither achieving statistical significance compared with placebo — relative risks of 0.85 (0.59, 1.24) and 1.08 (0.80, 1.46) for SCOPE and LIFE, respectively. This analysis clearly demonstrates that both candesartan in SCOPE and losartan in LIFE are associated with reductions in stroke events compared with placebo, greater than that observed in the well-established meta-analysis of placebo-controlled hypertensive trials. However, the CIs are such that it is not possible to suggest definitively that this is a benefit beyond BP reduction alone. Neither trial is sufficiently `powered' to demonstrate a benefit in CHD outcomes, but with SCOPE there was a trend towards benefit with a point estimate compatible with the major meta-analysis.

We hypothesised that apolipoprotein E (apoE) influences brain tumours by delivery of lipids to tumour cells and by analogy with other brain insults. APOE gene analysis was performed for 126 glioblastomas, the commonest primary brain tumour. Neither APOE epsilon2 nor epsilon4 alleles were significantly associated with differences in post-operative survival. However, there was apoE immunoreactivity of tumour cells, macrophages in areas of necrosis and astrocytes nearby. The immunohistochemistry findings support the hypothesis that apoE is involved in the delivery of lipids to tumour cells and in the recycling of lipids by macrophages in necrotic areas, raising the possibility that apoE-mediated lipid transport may represent a new therapeutic target in brain tumours.

Objective: To discover if the neuropathology differs in head-injured patients who were in a vegetative state (VS) or were severely disabled at time of death. Methods: Review of 35 VS cases and 30 severely disabled cases treated in this institute in the acute stage, surviving at least a month; all brains were fixed for 3 weeks before full neuropathologic examination. Results: The severely disabled cases were older, had a higher incidence of skull fracture and of evacuated intracranial hematoma, and they had more cortical contusions. Diffuse axonal injury (DAI) was less common in the severely disabled cases, particularly its most severe grade. Structural damage in the thalamus was much less common in severely disabled cases. Half of the severely disabled patients had neither grade 2 or 3 DAI nor thalamic damage and 10 of these 15 cases did not have ischemic brain damage either. These combinations did not occur in a single VS case. However, some severely disabled cases had similar lesions to VS cases, and this included some patients who were in a minimally conscious state as well as some who were out of bed and mobile. Conclusions: Half the severely disabled cases had only focal brain damage, a feature not found in any VS cases. In the severely disabled patients with lesions similar to those of VS cases it is likely that a greater quantitative amount of damage occurred in the VS cases.

The pharmacokinetics of a drug in individual patients can be estimated using plasma samples collected at a limited number of time points. However, different methods for a limited-sampling strategy (LSS) design exist and the optimal method has not yet been defined. Plasma concentration data were available from 27 of 74 courses in a phase I study (dose range, 5-55 mg m-2) of the novel anthrapyrazole DuP-941. Three approaches to LSS development were compared. Firstly, forward stepwise regression (FSR) was used to derive equations to predict the DuP-941 area under the concentration-time curve (AUC) based on plasma concentrations measured at specified times. LSSs were developed using 14 randomly chosen data sets and were validated using the remaining 13 data sets. Secondly, "all subsets" regression (ASR) was used to develop LSSs. A jack-knife technique was also used to allow model development utilising 26 data sets and validation on the 27th data set. Thirdly, an LSS was developed using optimal sampling theory (OST), and the LSS was used in conjunction with a Bavesian algorithm. Selected sampling times for four-point LSSs were 10, 65, 185 and 485 min (FSR) and 10, 45, 200 and 480 min (OST). Ten candidate LSSs were developed using the ASR approach. ASR- and OST/Bayesian-derived four-point LSSs gave more precise (P0.05) estimates of AUC [mean absolute percentage of difference (MAD%) +/- SD: ASR, 6.4 +/- 3.7%; OST/Bayesian, 6.8 +/- 4.6%] than did FSR (MAD% = 15.1 +/- 9.9%). The OST/Bayesian approach is recommended because it allows estimation of all model parameters and is more flexible with regard to sample collection time and design variables.

Introduction: Previous studies have found that polymorphisms of the apolipoprotein E gene (APOE) influences the outcome from head injury, with possession of APOE e4 being associated with an unfavourable outcome (Teasdale et al. Lancet 1997; 350: 1069–1071). In this study we correlated the pathological features of traumatic brain injury with the presence or absence of APOE e4. Materials and methods: During the 13-year period 1987–99, 238 brains were examined from cases of traumatic brain injury (TBI) in the Department of Neuropathology, Glasgow. APOE genotype was determined by PCR. For each case a number of pathological features were recorded ‘blind’ to the APOE e4 status. Results: Of the 238 cases examined, 83 (35%) had the APOE e4 allele, while 155 (65%) did not. Possession of APOE e4 was associated with a greater incidence of severe hypoxic brain damage (e4+ 54%, e4– 42%) and with a greater incidence of moderate or severe contusion index (e4+ 42%, e4– 30%). No significant differences were noted between the other pathological features examined. Conclusions: Possession of APOE e4 is associated with a greater incidence of moderate/severe contusional injury and severe hypoxic brain damage in fatal cases of TBI. This may be relevant to the relatively poor outcome from TBI in patients with an APOE e4 allele identified in clinical studies.

Background: Most patients with upper gastrointestinal symptoms are now H. pylori negative and no abnormalities are seen at endoscopy. Proton pump inhibitors (PPIs) are usually prescribed to these patients, though only a proportion benefit. Aim: To identify factors predicting response to PPI therapy in patients with upper GI symptoms and normal endoscopy. Methods: 105 patients with upper gastrointestinal symptoms of >3 months, normal endoscopy and HP-ve tests were prospectively recruited. Patients with hiatus hernia or taking NSAIDs were excluded. Character of symptoms and lifestyle factors were assessed by validated questionnaires and baseline severity over 7 days. The predominant symptom was retrosternal discomfort in 43, epigastric discomfort in 42, nausea/vomiting in 10, fullness/satiety in 1 and other symptoms in 6. Their median BMI was 26 (range 17.6-40.4) with 39% overweight and 20% obese. 24h esophageal pH monitoring and manometry of the lower esophageal sphincter (LES) by perfusion pull through technique (1cm every minute) was performed. Patients were then randomised in double-blind fashion to two weeks daily treatment with 2/3 receiving lansoprazole 30mg/day and 1/3 placebo. Symptomswere re-assessed throughout the second week of treatment, with the primary outcome being absolute change in symptom severity score (Glasgow Dyspepsia Score). Results: 102 individuals were treated (69 randomised to Lansoprazole, 33 to placebo). The mean pre-treatment symptom score in the active treatment group was 10.4 (SD 2.2) and in placebo 10.9 (SD2.7). The mean reduction in score following active treatment was 3.8 (SD 3.8) vs 0.6 (SD 2.1) following placebo (p

Introduction Western populations have recently experienced a substantial rise in both obesity and gastro-oesophageal reflux disease (GORD). There is growing evidence of a link between both conditions with higher BMI associated with greater prevalence of GORD symptoms, Barrett9s oesophagus and oesophageal adenocarcinoma. Currently, the most common dyspeptic patients seen in clinical practice are H pylori negative with a normal endoscopy. It is unclear if BMI has any effect on oesophageal physiology in these patients. Aims To examine the association between BMI and the function of the lower oesophageal sphincter (LOS) in dyspeptic patients with a normal endoscopy. Methods Patients with dyspepsia, a normal endoscopy and negative for H pylori had their BMI measured followed by assessment with water perfused oesophageal manometry and 24-h oesophageal pH monitoring. The LOS pressure, LOS length and LOS intra-abdominal length (high pressure zone distal to respiratory inversion point) were measured by station pull through. This involved withdrawing the catheter at 1 cm increments every minute with the patients sitting. Pressures were expressed using intragastric pressure as baseline. 24-h oesophageal acid exposure was measured as the per cent time pH Results 105 patients (46 males) were studied (mean age 44 years range 20–74). The median BMI was 26 (range 17.6–40.4) with 39% overweight and 20% obese. Higher BMI was associated with higher oesophageal per cent time pH Conclusion In patients with normal endoscopy there is a strong association between BMI and impaired function of the gastro-oesophageal barrier. The mechanism of this association requires to be investigated.

Introduction Most patients with upper gastrointestinal symptoms are now H pylori negative and no abnormalities are seen at endoscopy. Proton pump inhibitors (PPIs) are usually prescribed to these patients, though only a proportion benefit. Aim To identify factors predicting response to PPI therapy in patients with upper GI symptoms and normal endoscopy. Methods 105 patients with upper gastrointestinal symptoms of >3 months, normal endoscopy and HP-ve tests were prospectively recruited. Patients with hiatus hernia or taking NSAIDs were excluded. Character of symptoms and lifestyle factors were assessed by validated questionnaires and baseline severity over 7 days. The predominant symptom was retrosternal discomfort in 43, epigastric discomfort in 42, nausea/vomiting in 10, fullness/satiety in 1 and other symptoms in 6. Their median BMI was 26 (range 17.6–40.4) with 39% overweight and 20% obese. 24 h oesophageal pH monitoring and manometry of the lower oesophageal sphincter (LOS) by perfusion pull through technique (1 cm every minute) was performed. Patients were then randomised in double-blind fashion to 2 weeks daily treatment with 2/3 receiving lansoprazole 30 mg/day and 1/3 placebo. Symptoms were re-assessed throughout the second week of treatment, with the primary outcome being absolute change in symptom severity score (Glasgow Dyspepsia Score). Results 102 individuals were treated (69 randomised to Lansoprazole, 33 to placebo). The mean pre-treatment symptom score in the active treatment group was 10.4 (SD 2.2) and in placebo 10.9 (SD2.7). The mean reduction in score following active treatment was 3.8 (SD 3.8) vs 0.6 (SD 2.1) following placebo (p 2 =19.4%). Neither predominant symptom nor any other symptom characteristic predicted response. Conclusion This study indicates the lack of value of detailed symptom assessment in predicting response to PPI therapy. The strong predictive value of BMI is likely to be due to its association with gastro-oesophageal reflux which will respond to PPI therapy and highlights the important role of BMI in reflux disease.