The neuroinflammatory response in humans after traumatic brain injury.

AIMS: Traumatic brain injury is a significant cause of morbidity and mortality worldwide. An epidemiological association between head injury and long-term cognitive decline has been described for many years and recent clinical studies have highlighted functional impairment within 12 months of a mild head injury. In addition chronic traumatic encephalopathy is a recently described condition in cases of repetitive head injury. There are shared mechanisms between traumatic brain injury and Alzheimer's disease, and it has been hypothesized that neuroinflammation, in the form of microglial activation, may be a mechanism underlying chronic neurodegenerative processes after traumatic brain injury. METHODS: This study assessed the microglial reaction after head injury in a range of ages and survival periods, from <24-h survival through to 47-year survival. Immunohistochemistry for reactive microglia (CD68 and CR3/43) was performed on human autopsy brain tissue and assessed 'blind' by quantitative image analysis. Head injury cases were compared with age matched controls, and within the traumatic brain injury group cases with diffuse traumatic axonal injury were compared with cases without diffuse traumatic axonal injury. RESULTS: A major finding was a neuroinflammatory response that develops within the first week and persists for several months after traumatic brain injury, but has returned to control levels after several years. In cases with diffuse traumatic axonal injury the microglial reaction is particularly pronounced in the white matter. CONCLUSIONS: These results demonstrate that prolonged microglial activation is a feature of traumatic brain injury, but that the neuroinflammatory response returns to control levels after several years.

Randomised comparison of uterine artery embolisation (UAE) with surgical treatment in patients with symptomatic uterine fibroids (REST trial): 5-year results.

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.

The effects of uterine artery embolisation and surgical treatment on ovarian function in women with uterine fibroids.

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.

Comparison of the efficacy of candesartan and losartan: a meta-analysis of trials in the treatment of hypertension.

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.

Are portable bladder scanning and real-time ultrasound accurate measures of bladder volume in postnatal women?

Real-time ultrasound and portable bladder scanners are commonly used instead of catheterisation to determine bladder volumes in postnatal women but it is not known whether these are accurate. Change in bladder volumes measured by ultrasound and portable scanners were compared with actual voided volume (VV) in 100 postnatal women. The VV was on average 41 ml (CI 29 - 54 ml) higher than that measured by ultrasound, and 33 ml (CI 17 - 48 ml) higher than that measured by portable scanners. Portable scanner volumes were 9 ml (CI -8 - 26 ml) higher than those measured by ultrasound. Neither method is an accurate tool for detecting bladder volume in postnatal women.

Association of APOE e4 and cerebrovascular pathology in traumatic brain 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.

Neuropathology of the vegetative state after head injury.

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.

Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score.

INTRODUCTION: 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. METHODS: 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. RESULTS: The GAHS was derived from five variables independently associated with outcome: age (p = 0.001) and, from day 1 results, serum bilirubin (p<0.001), blood urea (p = 0.019) and, from day 6-9 results, serum bilirubin (p<0.001), 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. CONCLUSIONS: 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.

Cerebral amyloid angiopathy in traumatic brain injury: association with apolipoprotein E genotype.

OBJECTIVE: In view of the association of the apolipoprotein E (APOE) epsilon 4 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-beta peptide (A beta) 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%) epsilon 4 carriers compared with 1/48 (2%) non-epsilon 4 carriers (p = 0.021, 95% confidence interval (CI) for difference in proportions with CAA 3% to 29%) with 6/40 (4 with CAA) epsilon 4 carriers being homozygotes. Thus the risk of having CAA for epsilon 4 carriers was 8.4 times that for the non-epsilon 4 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 epsilon 4 allele but not with the severity of contusions.

Tau immunohistochemistry in acute brain injury.

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 (<24 h, 24 h-1 week, 1 week-1 month) and were compared with age-matched controls. Subtle alterations in tau immunoreactivity, for example, in oligodendrocytes, were present in some head injury cases but not controls. However, neurofibrillary tangles did not appear more prevalent after traumatic brain injury (TBI) when compared with age-matched controls. Although alterations in tau immunoreactivity may occur which warrant further study, neurofibrillary tangles were not more prevalent after a single fatal episode of TBI.

Randomised trial of endoscopy with testing for Helicobacter pylori compared with non-invasive H pylori testing alone in the management of dyspepsia.

OBJECTIVE: To compare the efficacy of non-invasive testing for Helicobacter pylori with that of endoscopy (plus H pylori testing) in the management of patients referred for endoscopic investigation of upper gastrointestinal symptoms. DESIGN: Randomised controlled trial with follow up at 12 months. SETTING: Hospital gastroenterology unit. PARTICIPANTS: 708 patients aged under 55 referred for endoscopic investigation of dyspepsia, randomised to non-invasive breath test for H pylori or endoscopy plus H pylori testing. MAIN OUTCOME MEASURE: Glasgow dyspepsia severity score at one year. Use of medical resources, patient oriented outcomes, and safety were also assessed. RESULTS: In 586 patients followed up at 12 months the mean change in dyspepsia score was 4.8 in the non-invasive H pylori test group and 4.6 in the endoscopy group (95% confidence interval for difference -0.7 to 0.5, P=0.69). Only 8.2% of patients followed up who were randomised to breath test alone were referred for subsequent endoscopy. The use of non-endoscopic resources was similar in the two groups. Reassurance value, concern about missed pathology, overall patient satisfaction, and quality of life were similar in the two groups. The patients found the non-invasive breath test procedure less uncomfortable and distressing than endoscopy with or without sedation. No potentially serious pathology requiring treatment other than eradication of H pylori was missed. CONCLUSION: In this patient group, non-invasive testing for H pylori is as effective and safe as endoscopy and less uncomfortable and distressing for the patient. Non-invasive H pylori testing should be the preferred mode of investigation.

Involvement of apolipoprotein E in herpes simplex encephalitis.

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.

Neuropathology in vegetative and severely disabled patients after head injury.

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.

Association of interleukin-1 gene polymorphisms with Alzheimer's disease.

Interleukin-1 (IL-1) is markedly overexpressed in Alzheimer's disease. We found the IL-1A 2,2 genotype in 12.9% of 232 neuropathologically confirmed Alzheimer's disease patients and 6.6% of 167 controls from four centers in the United Kingdom and United States (odds ratio, 3.0; controlled for age and for ApoE [apolipoprotein E] genotype). Homozygosity for both allele 2 of IL-1A and allele 2 of IL-1B conferred even greater risk (odds ratio, 10.8). IL-1 genotypes may confer risk for Alzheimer's disease through IL-1 overexpression and IL-1-driven neurodegenerative cascades.

Increased prevalence of precancerous changes in relatives of gastric cancer patients: critical role of H. pylori.

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.

Glasgow head injury outcome prediction program: an independent assessment.

Using an independent data set, the utility of the Glasgow Head Injury Outcome Prediction Program was investigated in terms of possible frequency of use and reliability of outcome prediction in patients with severe head injury, or haematoma requiring evacuation, or coma lasting 6 hours or more, in whom outcome had been reliably assessed at 6 to 24 months after injury. Predictions were calculated on admission, before evacuation of a haematoma, or 24 hours, 3 days, and 7 days after onset of coma lasting 6 hours or more. Three hundred and twenty four patients provided 426 predictions which were possible in 76%, 97%, 19%, 34%, and 53% of patients on admission, before operation, 24 hours, 3 days, and 7 days respectively. Major reasons for non-feasible predictions were that patients were paralysed/ventilated as part of resuscitation or management. Overall, 75.8% of predictions were correct, 14.6% were pessimistic (outcome better than predicted), and 9.6% optimistic (outcome worse than predicted). Of 197 patients (267 predictions) whose eventual outcome was good or moderate, 84.3% of predictions were correct. For death or vegetative survival (96 patients with 110 predictions), 83.6% of predictions were correct but for severe disability (31 patients with 49 predictions), only 12.2% were correctly predicted. The utility of the Glasgow Head Injury Outcome Prediction Program compares favourably with other outcome prediction algorithms for patients with head injury.

Changes in systolic time intervals-a non-invasive marker for the haemodynamic effects of sumatriptan.

AIMS: This study assessed the use of systolic time intervals (STI) as a potential non-invasive marker of the haemodynamic effects 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<0.0001), pre-ejection period (95%C.I. 8,21ms, P=0.0001) and left ventricular ejection time (95% C.I. 2,12ms, P=0.004). Conclusion STI responses were consistent with sumatriptan-induced changes in afterload. In summary, the measurement of STIs is a potential non-invasive method of investigating the influence of serotonergic compounds on the cardiovascular system.