Engineering Biomaterials to Direct Innate Immunity.

Small alterations during early stages of innate immune response can drive large changes in how adaptive immune cells develop and function during protective immunity or disease. Controlling these events creates exciting potential in development of immune engineered vaccines and therapeutics. This progress report discusses recent biomaterial technologies exploiting innate immunity to dissect immune function and to design new vaccines and immunotherapies for infectious diseases, cancer, and autoimmunity. Across these examples, an important idea is the possibility to co-opt innate immune mechanisms to enhance immunity during infection and cancer. During inflammatory or autoimmune disease, some of these same innate immune mechanisms can be manipulated in different ways to control excess inflammation by promotion of immunological tolerance.

WITHDRAWN: Eradication of Helicobacter pylori for non-ulcer dyspepsia.

BACKGROUND: Helicobacter pylori (H pylori) is the main cause of peptic ulcer disease. The role of H pylori in non-ulcer dyspepsia is less clear. OBJECTIVES: To determine the effect of H pylori eradication on dyspepsia symptoms in patients with non-ulcer dyspepsia. SEARCH STRATEGY: Trials were identified through electronic searches of the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, CINAHL and SIGLE, using appropriate subject headings and keywords, searching bibliographies of retrieved articles, and through contacts with experts in the fields of dyspepsia and with pharmaceutical companies. SELECTION CRITERIA: All parallel group randomised controlled trials (RCTs) comparing drugs to eradicate H pylori with placebo or other drugs known not to eradicate H pylori for patients with non-ulcer dyspepsia. DATA COLLECTION AND ANALYSIS: Data were collected on individual and global dyspeptic symptom scores, quality of life measures and adverse effects. Dyspepsia outcomes were dichotomised into minimal/resolved versus same/worse symptoms. MAIN RESULTS: Twenty one randomised controlled trials were included in the systematic review. Eighteen trials compared antisecretory dual or triple therapy with placebo antibiotics +/- antisecretory therapy, and evaluated dyspepsia at 3-12 months. Seventeen of these trials gave results as dichotomous outcomes evaluating 3566 patients and there was no significant heterogeneity between the studies. There was a 10% relative risk reduction in the H pylori eradication group (95% CI = 6% to 14%) compared to placebo. The number needed to treat to cure one case of dyspepsia = 14 (95% CI = 10 to 25). A further three trials compared Bismuth based H pylori eradication with an alternative pharmacological agent. These trials were smaller and had a shorter follow-up but suggested H pylori eradication was more effective than either H2 receptor antagonists or sucralfate in treating non-ulcer dyspepsia. AUTHORS' CONCLUSIONS: H pylori eradication therapy has a small but statistically significant effect in H pylori positive non-ulcer dyspepsia. An economic model suggests this modest benefit may still be cost-effective but more research is needed.

Injection therapy for the treatment of erectile dysfunction: a comparison between alprostadil and a combination of vasoactive intestinal polypeptide and phentolamine mesilate.

OBJECTIVE: To compare two injectable treatments, alprostadil 5-20 microg powder for injection and a combination of vasoactive intestinal polypeptide (VIP) and phentolamine in patients with erectile dysfunction (ED). DESIGN AND METHODS: This was an open multicentre, randomised crossover study comprising two phases. The first phase established the dose of each drug required to produce an erection suitable for sexual intercourse (grade 3 erection). In phase 2, responders to both drugs received, in random order, four doses of VIP/phentolamine, presented as ampoules, and four doses of alprostadil, presented as powder for injection. This was followed by four doses of VIP/phentolamine, presented in an autoinjector. In both phases, patient preference was assessed for each preparation. RESULTS: 187 patients were recruited. In the first phase, both treatments were effective, (83% alprostadil vs. 73% VIP/phentolamine, p = 0.002) but more patients preferred VIP/phentolamine (69 vs. 31%, p = 0.011). In phase 2 (n = 107), the proportion of injections that produced a grade 3 erection was similar for all three treatments (83-85%), but both presentations of VIP/phentolamine (ampoule and auto-injector) were preferred by significantly more patients (p < 0.001). Compared with both presentations of VIP/phentolamine, alprostadil produced a higher frequency of pain (28% of injections vs. 3% for each VIP/phentolamine presentation; p < 0.001) and a lower frequency of facial flushing (3 vs. 16-17%; p < 0.001). CONCLUSIONS: VIP/phentolamine and alprostadil were effective treatments for ED, however the VIP/phentolamine combination was preferred by more patients, which may be because it was much less likely to cause pain.

Eradication of Helicobacter pylori for non-ulcer dyspepsia.

BACKGROUND: Helicobacter pylori (H pylori) is the main cause of peptic ulcer disease. The role of H pylori in non-ulcer dyspepsia is less clear. OBJECTIVES: To determine the effect of H pylori eradication on dyspepsia symptoms in patients with non-ulcer dyspepsia. SEARCH STRATEGY: Trials were identified through electronic searches of the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, CINAHL and SIGLE, using appropriate subject headings and keywords, searching bibliographies of retrieved articles, and through contacts with experts in the fields of dyspepsia and with pharmaceutical companies. SELECTION CRITERIA: All parallel group randomised controlled trials (RCTs) comparing drugs to eradicate H pylori with placebo or other drugs known not to eradicate H pylori for patients with non-ulcer dyspepsia. DATA COLLECTION AND ANALYSIS: Data were collected on individual and global dyspeptic symptom scores, quality of life measures and adverse effects. Dyspepsia outcomes were dichotomised into minimal/resolved versus same/worse symptoms. MAIN RESULTS: Twenty one randomised controlled trials were included in the systematic review. Eighteen trials compared antisecretory dual or triple therapy with placebo antibiotics +/- antisecretory therapy, and evaluated dyspepsia at 3-12 months. Seventeen of these trials gave results as dichotomous outcomes evaluating 3566 patients and there was no significant heterogeneity between the studies. There was a 10% relative risk reduction in the H pylori eradication group (95% CI = 6% to 14%) compared to placebo. The number needed to treat to cure one case of dyspepsia = 14 (95% CI = 10 to 25). A further three trials compared Bismuth based H pylori eradication with an alternative pharmacological agent. These trials were smaller and had a shorter follow-up but suggested H pylori eradication was more effective than either H2 receptor antagonists or sucralfate in treating non-ulcer dyspepsia. AUTHORS' CONCLUSIONS: H pylori eradication therapy has a small but statistically significant effect in H pylori positive non-ulcer dyspepsia. An economic model suggests this modest benefit may still be cost-effective but more research is needed.

Targets and self monitoring in hypertension: randomised controlled trial and cost effectiveness analysis.

OBJECTIVES: To assess whether blood pressure control in primary care could be improved with the use of patient held targets and self monitoring in a practice setting, and to assess the impact of these on health behaviours, anxiety, prescribed antihypertensive drugs, patients' preferences, and costs. DESIGN: Randomised controlled trial. SETTING: Eight general practices in south Birmingham. PARTICIPANTS: 441 people receiving treatment in primary care for hypertension but not controlled below the target of < 140/85 mm Hg. INTERVENTIONS: Patients in the intervention group received treatment targets along with facilities to measure their own blood pressure at their general practice; they were also asked to visit their general practitioner or practice nurse if their blood pressure was repeatedly above the target level. Patients in the control group received usual care (blood pressure monitoring by their practice). PRIMARY OUTCOME: change in systolic blood pressure at six months and one year in both intervention and control groups. SECONDARY OUTCOMES: change in health behaviours, anxiety, prescribed antihypertensive drugs, patients' preferences of method of blood pressure monitoring, and costs. RESULTS: 400 (91%) patients attended follow up at one year. Systolic blood pressure in the intervention group had significantly reduced after six months (mean difference 4.3 mm Hg (95% confidence interval 0.8 mm Hg to 7.9 mm Hg)) but not after one year (mean difference 2.7 mm Hg (- 1.2 mm Hg to 6.6 mm Hg)). No overall difference was found in diastolic blood pressure, anxiety, health behaviours, or number of prescribed drugs. Patients who self monitored lost more weight than controls (as evidenced by a drop in body mass index), rated self monitoring above monitoring by a doctor or nurse, and consulted less often. Overall, self monitoring did not cost significantly more than usual care (251 pounds sterling (437 dollars; 364 euros) (95% confidence interval 233 pounds sterling to 275 pounds sterling) versus 240 pounds sterling (217 pounds sterling to 263 pounds sterling). CONCLUSIONS: Practice based self monitoring resulted in small but significant improvements of blood pressure at six months, which were not sustained after a year. Self monitoring was well received by patients, anxiety did not increase, and there was no appreciable additional cost. Practice based self monitoring is feasible and results in blood pressure control that is similar to that in usual care.

Eradication of Helicobacter pylori for non-ulcer dyspepsia.

BACKGROUND: Helicobacter pylori (H pylori) is the main cause of peptic ulcer disease. The role of H pylori in non-ulcer dyspepsia is less clear. OBJECTIVES: To determine the effect of H pylori eradication on dyspepsia symptoms in patients with non-ulcer dyspepsia. SEARCH STRATEGY: Trials were identified through electronic searches of the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, CINAHL and SIGLE, using appropriate subject headings and keywords, searching bibliographies of retrieved articles, and through contacts with experts in the fields of dyspepsia and with pharmaceutical companies. These searches were updated in October 2004. SELECTION CRITERIA: All parallel group randomised controlled trials (RCTs) comparing drugs to eradicate H pylori with placebo or other drugs known not to eradicate H pylori for patients with non-ulcer dyspepsia. DATA COLLECTION AND ANALYSIS: Data were collected on individual and global dyspeptic symptom scores, quality of life measures and adverse effects. Dyspepsia outcomes were dichotomised into minimal/resolved versus same/worse symptoms. MAIN RESULTS: Seventeen randomised controlled trials were included in the systematic review. Fourteen trials compared antisecretory dual or triple therapy with placebo antibiotics +/- antisecretory therapy, and evaluated dyspepsia at 3-12 months. Thirteen of these trials gave results as dichotomous outcomes evaluating 3186 patients and there was no significant heterogeneity between the studies. There was a 8% relative risk reduction in the H pylori eradication group (95% CI = 3% to 12%) compared to placebo. The number needed to treat to cure one case of dyspepsia = 18 (95% CI = 12 to 48). A further three trials compared Bismuth based H pylori eradication with an alternative pharmacological agent. These trials were smaller and had a shorter follow-up but suggested H pylori eradication was more effective than either H2 receptor antagonists or sucralfate in treating non-ulcer dyspepsia. AUTHORS' CONCLUSIONS: H pylori eradication therapy has a small but statistically significant effect in H pylori positive non-ulcer dyspepsia. An economic model suggests this modest benefit may still be cost-effective but more research is needed.

Systematic review and modelling of the investigation of acute and chronic chest pain presenting in primary care.

OBJECTIVES: To ascertain the value of a range of methods - including clinical features, resting and exercise electrocardiography, and rapid access chest pain clinics (RACPCs) - used in the diagnosis and early management of acute coronary syndrome (ACS), suspected acute myocardial infarction (MI), and exertional angina. DATA SOURCES: MEDLINE, EMBASE, CINAHL, the Cochrane Library and electronic abstracts of recent cardiological conferences. REVIEW METHODS: Searches identified studies that considered patients with acute chest pain with data on the diagnostic value of clinical features or an electrocardiogram (ECG); patients with chronic chest pain with data on the diagnostic value of resting or exercise ECG or the effect of a RACPC. Likelihood ratios (LRs) were calculated for each study, and pooled LRs were generated with 95% confidence intervals. A Monte Carlo simulation was performed evaluating different assessment strategies for suspected ACS, and a discrete event simulation evaluated models for the assessment of suspected exertional angina. RESULTS: For acute chest pain, no clinical features in isolation were useful in ruling in or excluding an ACS, although the most helpful clinical features were pleuritic pain (LR+ 0.19) and pain on palpation (LR+ 0.23). ST elevation was the most effective ECG feature for determining MI (with LR+ 13.1) and a completely normal ECG was reasonably useful at ruling this out (LR+ 0.14). Results from 'black box' studies of clinical interpretation of ECGs found very high specificity, but low sensitivity. In the simulation exercise of management strategies for suspected ACS, the point of care testing with troponins was cost-effective. Pre-hospital thrombolysis on the basis of ambulance telemetry was more effective but more costly than if performed in hospital. In cases of chronic chest pain, resting ECG features were not found to be very useful (presence of Q-waves had LR+ 2.56). For an exercise ECG, ST depression performed only moderately well (LR+ 2.79 for a 1 mm cutoff), although this did improve for a 2 mm cutoff (LR+ 3.85). Other methods of interpreting the exercise ECG did not result in dramatic improvements in these results. Weak evidence was found to suggest that RACPCs may be associated with reduced admission to hospital of patients with non-cardiac pain, better recognition of ACS, earlier specialist assessment of exertional angina and earlier diagnosis of non-cardiac chest pain. In a simulation exercise of models of care for investigation of suspected exertional angina, RACPCs were predicted to result in earlier diagnosis of both confirmed coronary heart disease (CHD) and non-cardiac chest pain than models of care based around open access exercise tests or routine cardiology outpatients, but they were more expensive. The benefits of RACPCs disappeared if waiting times for further investigation (e.g. angiography) were long (6 months). CONCLUSIONS: Where an ACS is suspected, emergency referral is justified. ECG interpretation in acute chest pain can be highly specific for diagnosing MI. Point of care testing with troponins is cost-effective in the triaging of patients with suspected ACS. Resting ECG and exercise ECG are of only limited value in the diagnosis of CHD. The potential advantages of RACPCs are lost if there are long waiting times for further investigation. Recommendations for further research include the following: determining the most appropriate model of care to ensure accurate triaging of patients with suspected ACS; establishing the cost-effectiveness of pre-hospital thrombolysis in rural areas; determining the relative cost-effectiveness of rapid access chest pain clinics compared with other innovative models of care; investigating how rapid access chest pain clinics should be managed; and establishing the long-term outcome of patients discharged from RACPCs.

A determination of tumor necrosis factor expression in TMJ inflammation with the use of microarray analysis.

Many different factors can lead to inflammatory changes within temporomandibular joint tissues. This investigation examined if the expression of TNF-alpha and its receptors was altered in TMJ tissues during inflammation. Adult male rats were injected bilaterally with complete Freund's adjuvant (CFA) into the TMJ or served as uninjected controls and were killed two days after CFA treatment. TMJ tissues were removed, and expression of TNF-alpha and its receptors was examined via gene microarray analysis, RT-PCR, Western blot, and ELISA. Gene microarray analysis provided evidence for changes in gene expression, notably that TNF-alpha and TNF-R1, but not TNF-R2, were significantly elevated in CFA-treated TMJ tissues. However, protein levels of TNF-alpha, TNF-R1, and TNF-R2 were all significantly increased in CFA-treated TMJ tissues. These results indicate that the pro-inflammatory cytokine TNF-alpha may play a significant role in the onset of inflammatory conditions associated with adjuvant-induced arthritis of the TMJ.

Eradication of Helicobacter pylori for non-ulcer dyspepsia.

BACKGROUND: Helicobacter pylori (H pylori) is the main cause of peptic ulcer disease. The role of H pylori in non-ulcer dyspepsia is less clear. OBJECTIVES: To determine the effect of H pylori eradication on dyspepsia symptoms and quality of life scores in patients with non-ulcer dyspepsia. SEARCH STRATEGY: Trials were identified through electronic searches of the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, CINAHL and SIGLE, using appropriate subject headings and keywords, searching bibliographies of retrieved articles, and through contacts with experts in the fields of dyspepsia and with pharmaceutical companies. SELECTION CRITERIA: All parallel group randomised controlled trials (RCTs) comparing drugs to eradicate H pylori with placebo or other drugs known not to eradicate H pylori for patients with non-ulcer dyspepsia. DATA COLLECTION AND ANALYSIS: Data were collected on individual and global dyspeptic symptom scores, quality of life measures and adverse effects. Dyspepsia outcomes were dichotomised into minimal/resolved versus same/worse symptoms. MAIN RESULTS: Fifteen randomised controlled trials were included in the systematic review. Thirteen trials compared antisecretory dual or triple therapy with placebo antibiotics +/- antisecretory therapy, and evaluated dyspepsia at 3-12 months. Twelve of these trials gave results as dichotomous outcomes evaluating 2,903 patients and there was no significant heterogeneity between the studies. There was a 9% relative risk reduction in the H pylori eradication group (95% CI = 5% to 14%) compared to placebo. The number needed to treat to cure one case of dyspepsia = 15 (95% CI = 10 to 28). A further two trials compared Bismuth based H pylori eradication with an alternative pharmacological agent. These trials were smaller and had a shorter follow-up but suggested H pylori eradication was more effective than either H2 receptor antagonists or sucralfate in treating non-ulcer dyspepsia. REVIEWER'S CONCLUSIONS: H pylori eradication therapy has a small but statistically significant effect in H pylori positive non-ulcer dyspepsia. An economic model suggests this modest benefit may still be cost-effective but more research is needed.

A systematic review of the evidence for rapid access chest pain clinics.

To determine the impact of rapid access chest pain clinics (RACPC) on patient management, a systematic search (1966-2000) was performed of electronic databases, recent conference abstracts, citations of all identified studies, and by contact with other researchers. Studies of any design were included. Assessment of eligibility, methodological quality of studies and data abstraction was conducted independently by two reviewers. Outcome measures were sought in terms of admission rate of patients without acute coronary syndrome detection rate of acute coronary syndrome unrecognised by the GP, timing of specialist assessment of patients with stable angina and speed and accuracy of detection of those with non-cardiac chest pain. Nine relevant studies were found, but all had methodological flaws when considered as evaluative studies. All clinics described reviewed patients within 24 hours of referral. Only three studies made comparisons with control groups, none of which were randomised, and a further three provided follow-up data only. Limited data were found for all four outcome measures, indicating possible benefits of RACPCs. However, all findings could be explained by potential biases in the original studies. In conclusion, the evidence base for the introduction of rapid access chest pain clinics is poor. The introduction of these clinics should include a randomised prospective evaluation of their worth.

Initial management strategies for dyspepsia.

BACKGROUND: This review considers management strategies (combinations of initial investigation and empirical treatments) for dyspeptic patients. Dyspepsia was defined to include both epigastric pain and heartburn. OBJECTIVES: To determine the effectiveness, acceptability, and cost effectiveness of the following initial management strategies for patients presenting with dyspepsia (a) initial pharmacological therapy (including endoscopy for treatment failures) (b) early endoscopy (c) testing for Helicobacter pylori and endoscope only those positive (d) H.pylori eradication therapy with or without prior testing. SEARCH STRATEGY: Trials were located through electronic searches and extensive contact with trialists. SELECTION CRITERIA: All randomised controlled trials of dyspeptic patients presenting in primary care. DATA COLLECTION AND ANALYSIS: Data was collected on dyspeptic symptoms, quality of life and use of resources. MAIN RESULTS: Eighteen papers reporting 20 comparisons were found. Trials comparing proton pump inhibitors (PPI) with antacids (two trials) and H2 receptor antagonists (three trials), early endoscopy with initial acid suppression (five trials), H.pylori 'test and scope' v usual management (three trials) and H.pylori test and treat v. endoscopy (three trials) were pooled. PPIs were significantly more effective than both H2RA s and antacids. Relative risks (RR) and 95% CI were, for PPI: antacid 0.72 (0.64-0.80), PPI: H2RA 0.63 (0.47-0.85). Results for other drug comparisons were either absent or inconclusive. Initial endoscopy was associated with a small reduction in the risk of recurrent dyspepstic symptoms compared with initial prescribing (RR 0.89 (0.77-1.02). H.pylori test and endoscopy increases costs in primary care, but does not improve symptoms. H.pylori test and eradicate may be as effective as endoscopy- based management and reduces costs, by decreasing the proportion of patients that are endoscoped. Further primary care-based trials are needed to compare 'test and treat' with empirical acid suppression. REVIEWER'S CONCLUSIONS: PPIs are effective in the treatment of dyspepsia in these trials which may not adequately exclude patients with gastro-oesophageal reflux disease. The relative efficacy of H2RA and PPI is uncertain. Early investigation by endoscopy or H.pylori testing may benefit some patients with dyspepsia. The review will be updated in 2002 with an individual patient data meta-analysis of the economic data, and a subgroup analysis by age and predominant dyspeptic symptom.

Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial.

OBJECTIVE: To compare paroxetine with placebo and imipramine with placebo for the treatment of adolescent depression. METHOD: After a 7- to 14-day screening period, 275 adolescents with major depression began 8 weeks of double-blind paroxetine (20-40 mg), imipramine (gradual upward titration to 200-300 mg), or placebo. The two primary outcome measures were endpoint response (Hamilton Rating Scale for Depression [HAM-D] score < or = 8 or > or = 50% reduction in baseline HAM-D) and change from baseline HAM-D score. Other depression-related variables were (1) HAM-D depressed mood item; (2) depression item of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version (K-SADS-L); (3) Clinical Global Impression (CGI) improvement scores of 1 or 2; (4) nine-item depression subscale of K-SADS-L; and (5) mean CGI improvement scores. RESULTS: Paroxetine demonstrated significantly greater improvement compared with placebo in HAM-D total score < or = 8, HAM-D depressed mood item, K-SADS-L depressed mood item, and CGI score of 1 or 2. The response to imipramine was not significantly different from placebo for any measure. Neither paroxetine nor imipramine differed significantly from placebo on parent- or self-rating measures. Withdrawal rates for adverse effects were 9.7% and 6.9% for paroxetine and placebo, respectively. Of 31.5% of subjects stopping imipramine therapy because of adverse effects, nearly one third did so because of adverse cardiovascular effects. CONCLUSIONS: Paroxetine is generally well tolerated and effective for major depression in adolescents.

Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression.

OBJECTIVE: This study compared the efficacy and safety of paroxetine and imipramine with that of placebo in the treatment of bipolar depression in adult outpatients stabilized on a regimen of lithium. METHOD: In a double-blind, placebo-controlled study, 117 outpatients with DSM-III-R bipolar disorder, depressive phase, were randomly assigned to treatment with paroxetine (N=35), imipramine (N=39), or placebo (N=43) for 10 weeks. In addition to lithium monotherapy, patients may have received either carbamazepine or valproate in combination with lithium for control of manic symptoms. Patients were stratified on the basis of trough serum lithium levels determined at the screening visit (high: >0.8 meq/liter; low:

Eradication of Helicobacter pylori for non-ulcer dyspepsia.

BACKGROUND: Helicobacter pylori (H pylori) is the main cause of peptic ulcer disease. The role of H pylori in non-ulcer dyspepsia is less clear. OBJECTIVES: To determine the effect of H pylori eradication on dyspepsia symptoms and quality of life scores in patients with non-ulcer dyspepsia. SEARCH STRATEGY: Trials were identified through electronic searches of the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, CINAHL and SIGLE, using appropriate subject headings and keywords, searching bibliographies of retrieved articles, and through contacts with experts in the fields of dyspepsia and with pharmaceutical companies. SELECTION CRITERIA: All parallel group randomised controlled trials (RCTs) comparing drugs to eradicate H pylori with placebo or other drugs known not to eradicate H pylori for patients with non-ulcer dyspepsia. DATA COLLECTION AND ANALYSIS: Data were collected on individual and global dyspeptic symptom scores, quality of life measures and adverse effects. Dyspepsia outcomes were dichotomised into minimal/resolved versus same/worse symptoms. MAIN RESULTS: Twelve randomised controlled trials were included in the systematic review. Ten trials compared antisecretory dual or triple therapy with placebo antibiotics +/- antisecretory therapy, and evaluated dyspepsia at 3-12 months. Nine of these trials gave results as dichotomous outcomes evaluating 2,541 patients and there was no significant heterogeneity between the studies. There was a 9% relative risk reduction in the H pylori eradication group (95% CI = 4% to 14%) compared to placebo. The number needed to treat to cure one case of dyspepsia = 15 (95% CI = 10 to 31). A further two trials compared Bismuth based H pylori eradication with an alternative pharmacological agent. These trials were smaller and had a shorter follow-up but suggested H pylori eradication was more effective than either H2 receptor antagonists or sucralfate in treating non-ulcer dyspepsia. REVIEWER'S CONCLUSIONS: H pylori eradication therapy has a small but statistically significant effect in H pylori positive non-ulcer dyspepsia. An economic model suggests this modest benefit may still be cost-effective but more research is needed.

Low dose fractionated radiation enhances the radiosensitization effect of paclitaxel in colorectal tumor cells with mutant p53.

BACKGROUND: The current study was undertaken to investigate the influence of wild-type or mutant p53 status on the radiosensitizing effect of paclitaxel in colorectal tumor cell lines. METHODS: HCT-116 (contains wild-type p53) and HT-29 (contains mutant p53) established from moderately differentiated colorectal carcinomas were used in this study. Colony-forming assay was performed after exposure to either different radiation doses (0.5-6 gray [Gy]) or paclitaxel (1-10 nM) or in combination. Induction of p53 and p21(waf1/cip1) by these treatments were determined by immunocytochemistry and Western blot analysis. RESULTS: Radiation caused an increase in nuclear p53 and p21(waf1/cip1) proteins in HCT-116 cells, indicating that p53 functionally induced p21(waf1/cip1). However, induction of nuclear p53 and p21(waf1/cip1) protein was not evident in HT-29 cells, suggesting that p53 was not functional in these cells. Survival data showed that the HCT-116 cells (survival fraction of exponentially growing cells that were irradiated at the clinically relevant dose of 2 Gy [SF(2)] = 0.383; dose required to reduce the fraction of cells to 37% [D(0)] = 223 centigray [cGy]) were significantly sensitive to ionizing radiation (P < 0.008) when compared with the HT-29 cells (SF(2) = 0.614; D(0) = 351 cGy). Paclitaxel caused a higher degree of clonogenic inhibition in HCT-116 (D(0) = 0.7 nM) than HT-29 (D(0) = 1.11 nM) cells (P < 0.06). When paclitaxel and radiation were combined, an enhanced radiosensitizing effect (P < 0.05) was observed in HCT-116 cells (SF(2) = 0.138; D(0) = 103 cGy), whereas in HT-29 cells no significant radiosensitization of paclitaxel was observed (SF(2) = 0.608; D(0) = 306 cGy). However, pretreatment with paclitaxel followed by multifractionated low dose radiation (0.5- or 1-Gy fractions for a total dose of 2 Gy) significantly enhanced the radiosensitizing effect in both HCT-116 and HT-29 cells. CONCLUSIONS: The results of the current study suggested that multifractionated radiation given at very low doses after exposure of cells to paclitaxel conferred a potent radiation sensitizing effect irrespective of p53 status.

Initial management strategies for dyspepsia.

BACKGROUND: This review considers management strategies (combinations of initial investigation and empirical treatments) for dyspeptic patients. OBJECTIVES: To determine the effectiveness, acceptability, and cost effectiveness of the following initial management strategies for patients presenting with dyspepsia (a) initial pharmacological therapy (including endoscopy for treatment failures) (b) early endoscopy (c) testing for Helicobacter pylori and endoscope only those positive (d) H.pylori eradication therapy with or without prior testing. SEARCH STRATEGY: Trials were located through electronic searches and extensive contact with trialists. SELECTION CRITERIA: All randomised controlled trials of dyspeptic patients presenting in primary care. DATA COLLECTION AND ANALYSIS: Data was collected on dyspeptic symptoms, quality of life and use of resources. MAIN RESULTS: Ten papers reporting 12 comparisons were found. Trials comparing proton pump inhibitors (PPI) with antacids (2 trials) and H2 receptor antagonists (3 trials), and of early endoscopy compared with initial acid suppression (3 trials) were pooled. PPIs were significantly more effective than both H2RA s and antacids. Relative risks (RR) and 95% CI were, for PPI: antacid 0.72 (0.64-0.80), PPI: H2RA 0.63 (0.47-0.85). Results for other drug comparisons were either absent or inconclusive. Early endoscopy was not more effective than initial prescribing (RR 0.90 (0.77-1.04), but current studies lack power. No eligible trials of H.pylori test and endoscopy or test and eradicate were found. REVIEWER'S CONCLUSIONS: PPIs are effective in the treatment of dyspepsia in these trials which may not adequately exclude patients with gastro-oesophageal reflux disease. The relative efficacy of H2RA and PPI is uncertain. Early investigation may benefit some patients with dyspepsia. The review will be updated shortly with several large trials that have recently been completed.

Eradication of helicobacter pylori for non-ulcer dyspepsia.

BACKGROUND: Helicobacter pylori (H pylori) is the main cause of peptic ulcer disease. The role of H pylori in non-ulcer dyspepsia is less clear. OBJECTIVES: To determine the effect of H pylori eradication on dyspepsia symptoms and quality of life scores in patients with non-ulcer dyspepsia. SEARCH STRATEGY: Trials were identified through electronic searches of the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, CINAHL and SIGLE, using appropriate subject headings and keywords, searching bibliographies of retrieved articles, and through contacts with experts in the fields of dyspepsia and with pharmaceutical companies. SELECTION CRITERIA: All parallel group randomised controlled trials (RCTs) comparing drugs to eradicate H pylori with placebo or other drugs known not to eradicate H pylori for patients with non-ulcer dyspepsia. DATA COLLECTION AND ANALYSIS: Data were collected on individual and global dyspeptic symptom scores, quality of life measures and adverse effects. Dyspepsia outcomes were dichotomised into minimal/resolved versus same/worse symptoms. MAIN RESULTS: Seven randomised controlled trials were included in the systematic review. Five trials compared proton pump inhibitor dual or triple therapy with a proton pump inhibitor + placebo antibiotics, and evaluated dyspepsia at 6-12 months in 1,385 patients. H pylori eradication was significantly superior to placebo in treating non ulcer dyspepsia (relative risk reduction = 7%; 95% CI = 1% to 12%; p=0.02) and there was no significant heterogeneity between the studies. The number needed to treat to cure one case of dyspepsia = 19 (95% CI = 11 to 132). A further two trials compared Bismuth based H pylori eradication with an alternative pharmacological agent. These trials were smaller and had a shorter follow-up but suggested H pylori eradication was more effective than either H2 receptor antagonists or sucralfate in treating non-ulcer dyspepsia. REVIEWER'S CONCLUSIONS: H pylori eradication may be an effective therapy for H pylori positive non-ulcer dyspepsia. This result is not robust and further evidence on the efficacy of H pylori eradication in non ulcer dyspepsia would be helpful. The effect is modest and economic models would help establish whether this approach is cost-effective. This review will be updated as results from other ongoing trials (Malfertheiner 2000) are made available.