Showing papers by "Clinical Trial Service Unit published in 2000"

Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses

Abstract: Objective: To assess associations between baseline values of four different circulating markers of inflammation and future risk of coronary heart disease, potential triggers of systemic inflammation (such as persistent infection), and other markers of inflammation. Design: Nested case-control comparisons in a prospective, population based cohort. Setting: General practices in 18 towns in Britain. Participants: 506 men who died from coronary heart disease or had a non-fatal myocardial infarction and 1025 men who remained free of such disease until 1996 selected from 5661 men aged 40–59 years who provided blood samples in 1978-1980. Main outcome measures: Plasma concentrations of C reactive protein, serum amyloid A protein, and serum albumin and leucocyte count. Information on fatal and non-fatal coronary heart disease was obtained from medical records and death certificates. Results: Compared with men in the bottom third of baseline measurements of C reactive protein, men in the top third had an odds ratio for coronary heart disease of 2.13 (95% confidence interval 1.38 to 3.28) after age, town, smoking, vascular risk factors, and indicators of socioeconomic status were adjusted for. Similar adjusted odds ratios were 1.65 (1.07 to 2.55) for serum amyloid A protein; 1.12 (0.71 to 1.77) for leucocyte count; and 0.67 (0.43 to 1.04) for albumin. No strong associations were observed of these factors with Helicobacter pylori seropositivity, Chlamydia pneumoniae IgG titres, or plasma total homocysteine concentrations. Baseline values of the acute phase reactants were significantly associated with one another (P Conclusion: In the context of results from other relevant studies these findings suggest that some inflammatory processes, unrelated to the chronic infections studied here, are likely to be involved in coronary heart disease.

Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies

Abstract: Objective and design: To relate UK national trends since 1950 in smoking, in smoking cessation, and in lung cancer to the contrasting results from two large case-control studies centred around 1950 and 1990. Setting: United Kingdom. Participants: Hospital patients under 75 years of age with and without lung cancer in 1950 and 1990, plus, in 1990, a matched sample of the local population: 1465 case-control pairs in the 1950 study, and 982 cases plus 3185 controls in the 1990 study. Main outcome measures: Smoking prevalence and lung cancer. Results: For men in early middle age in the United Kingdom the prevalence of smoking halved between 1950 and 1990 but the death rate from lung cancer at ages 35–54 fell even more rapidly, indicating some reduction in the risk among continuing smokers. In contrast, women and older men who were still current smokers in 1990 were more likely than those in 1950 to have been persistent cigarette smokers throughout adult life and so had higher lung cancer rates than current smokers in 1950. The cumulative risk of death from lung cancer by age 75 (in the absence of other causes of death) rose from 6% at 1950 rates to 16% at 1990 rates in male cigarette smokers, and from 1% to 10% in female cigarette smokers. Among both men and women in 1990, however, the former smokers had only a fraction of the lung cancer rate of continuing smokers, and this fraction fell steeply with time since stopping. By 1990 cessation had almost halved the number of lung cancers that would have been expected if the former smokers had continued. For men who stopped at ages 60, 50, 40, and 30 the cumulative risks of lung cancer by age 75 were 10%, 6%, 3%, and 2%. Conclusions: People who stop smoking, even well into middle age, avoid most of their subsequent risk of lung cancer, and stopping before middle age avoids more than 90% of the risk attributable to tobacco. Mortality in the near future and throughout the first half of the 21st century could be substantially reduced by current smokers giving up the habit. In contrast, the extent to which young people henceforth become persistent smokers will affect mortality rates chiefly in the middle or second half of the 21st century.

Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies.

Abstract: Background—Studies of the association between the plasma concentration of lipoprotein(a) [Lp(a)] and coronary heart disease (CHD) have reported apparently conflicting findings. We report a meta-analysis of the prospective studies with at least 1 year of follow-up published before 2000. Methods and Results—The following information was abstracted for each study: geographical location of study, size, type of cohort (population-based or selected because of previous disease), mean age, follow-up duration, blood storage temperature and duration, assay methods, degree of adjustment for potential confounders, and relationship of baseline Lp(a) measurement with subsequent CHD risk. There were 5436 deaths from CHD or nonfatal myocardial infarctions during a weighted mean follow-up of 10 years in the 27 eligible studies. Comparison of individuals in the top third of baseline plasma Lp(a) measurements with those in the bottom third in each study yielded a combined risk ratio of 1.6 (95% CI 1.4 to 1.8, 2P<0.00001), w...

Indications for early aspirin use in acute ischemic stroke : A combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups.

Abstract: Background and Purpose—Long-term daily aspirin is of benefit in the years after ischemic stroke, and 2 large randomized trials (the Chinese Acute Stroke Trial [CAST] and the International Stroke Trial [IST]), with 20 000 patients in each, have shown that starting daily aspirin promptly in patients with suspected acute ischemic stroke also reduces the immediate risk of further stroke or death in hospital and the overall risk of death or dependency. However, some uncertainty remains about the effects of early aspirin in particular categories of patient with acute stroke. Methods—To assess the balance of benefits and risks of aspirin in particular categories of patient with acute stroke (eg, the elderly, those without a CT scan, or those with atrial fibrillation), a prospectively planned meta-analysis is presented of the data from 40 000 individual patients from both trials on events that occurred in the hospital during the scheduled treatment period (4 weeks in CAST, 2 weeks in IST), with 10 characteristics...

Chlamydia trachomatis infection as a risk factor for invasive cervical cancer

Abstract: Cervical carcinoma is a sexually transmitted disease most strongly linked with human-papillomavirus (HPV) infection. We conducted a prospective sero-epidemiologic study to evaluate the role of Chlamydia trachomatis infection in the development of cervical carcinoma, with invasive cancer as an end point. A nested case-control study within a cohort of 530000 Nordic women was performed. Linking data files of 3 Nordic serum banks and the cancer registries of Finland, Norway and Sweden identified 182 women with invasive cervical carcinoma diagnosed during a mean follow-up of 5 years after serum sampling. The serum samples of the cases and matched cancer-free controls were analyzed for IgG antibodies to C. trachomatis, C. pneumoniae (a control microbe) and HPV types 16, 18 and 33, as well as for serum cotinine (an indicator of tobacco smoking). Serum antibodies to C. trachomatis were associated with an increased risk for cervical squamous-cell carcinoma (HPV- and smoking-adjusted OR, 2.2; 95% CI, 1.3-3.5). The association remained also after adjustment for smoking both in HPV16-seronegative and -seropositive cases (OR, 3.0; 95% CI, 1.8-5.1; OR, 2.3, 95% CI, 0. 8-7.0 respectively). No such association was found for C. pneumoniae. Our prospective study provides sero-epidemiologic evidence that infection with C. trachomatis confers an increased risk for subsequent development of invasive squamous-cell carcinoma of the uterine cervix.

Chlamydia pneumoniae IgG titres and coronary heart disease: prospective study and meta-analysis.

Abstract: Objective: To examine the association between coronary heart disease and serum markers of chronic Chlamydia pneumoniae infection Design: “Nested” case-control analysis in a prospective cohort study and an updated meta-analysis of previous relevant studies Setting: General practices in 18 towns in Britain Participants: Of the 5661 men aged 40–59 who provided blood samples during 1978-80, 496 men who died from coronary heart disease or had non-fatal myocardial infarction and 989 men who had not developed coronary heart disease by 1996 were included Main outcome measures: IgG serum antibodies to C pneumoniae in baseline samples; details of fatal and non-fatal coronary heart disease from medical records and death certificates Results: 200 (40%) of the 496 men with coronary heart disease were in the top third of C pneumoniae titres compared with 329 (33%) of the 989 controls The corresponding odds ratio for coronary heart disease was 166 (95% confidence interval 125 to 221), which fell to 122 (082 to 182) after adjustment for smoking and indicators of socioeconomic status No strong associations were observed between C pneumoniae IgG titres and blood lipid concentrations, blood pressure, or plasma homocysteine concentration In aggregate, the present study and 14 other prospective studies of C pneumoniae IgG titres included 3169 cases, yielding a combined odds ratio of 115 (097 to 136), with no significant heterogeneity among the separate studies (χ2=105, df=14; P>01) Conclusion: This study, together with a meta-analysis of previous prospective studies, reliably excludes the existence of any strong association between C pneumoniae IgG titres and incident coronary heart disease Further studies are required, however, to confirm or refute any modest association that may exist, particularly at younger ages

Vitamin supplements and cardiovascular risk: review of the randomized trials of homocysteine-lowering vitamin supplements.

Abstract: Epidemiological studies have shown that higher blood homocysteine levels appear to be associated with higher risks of coronary, cerebral, and peripheral vascular disease and are inversely related to blood levels of folate and of vitamin B12 and vitamin B6. However, observational studies cannot exclude the possibility that elevated homocysteine levels may be associated with some other factor, rather than being causally related to vascular disease. Large-scale clinical trials of sufficient dose and duration of treatment are required to test this hypothesis, but there was substantial uncertainty about the optimal vitamin regimen to test in such trials. A meta-analysis of 12 randomized trials of vitamin supplements to lower homocysteine levels was carried out to determine the optimal dose of folic acid required to lower homocysteine levels and to assess whether vitamin B12 or vitamin B6 had additive effects. This meta-analysis demonstrated that reductions in blood homocysteine levels were greater at higher pretreatment blood homocysteine levels and at lower pretreatment folate concentrations. After standardization for a pretreatment homocysteine concentration of 12 micromol/L and folate concentration of 12 nmol/L (approximate average concentrations for western populations), dietary folic acid reduced homocysteine levels by 25% (95% confidence interval [CI]: 23 to 28%) with similar effects in a daily dosage range of 0.5 to 5 mg. Vitamin B12 (mean 0.5 mg) produced an additional reduction in blood homocysteine of 7%, whereas vitamin B6 (mean 16.5 mg) did not have any significant effect. Hence, in typical populations, daily supplementation with both 0.5 to 5 mg folic acid and about 0.5 mg vitamin B12 would be expected to reduce homocysteine levels by one quarter to one third (from about 12 micromol/L to about 8 to 9 micromol/L). Large-scale randomized trials of such regimens are now required to determine whether lowering homocysteine levels by folic acid and vitamin B12, with or without added vitamin B6, reduces the risk of vascular disease.

Smoking and dementia in male British doctors: prospective study.

Abstract: Objective To assess the possible association between smoking and dementia. Design Prospective study. Setting Cohort of British male doctors followed up since 1951. Subjects 34 439 male British doctors, with 24 133 deaths recorded. Results For all types of dementia combined the relative risk was 0.96 (95% confidence interval 0.78 to 1.18), based on 473 deaths at a mean age of 81 years. For probable or definite Alzheimer's disease, the relative risk in continuing smokers was 0.99 (0.78 to 1.25), based on 370 deaths at a mean age of 82 years. In aggregate, however, the other prospective studies indicate a direct, although not clearly significant, association between smoking and the onset of dementia in general and of Alzheimer's disease in particular. Conclusions Contrary to previous suggestions persistent smoking does not substantially reduce the age specific onset rate of Alzheimer's disease or of dementia in general. If anything, it might increase rather than decrease the rate, but any net effect on severe dementia cannot be large in either direction.

Lowering blood homocysteine with folic acid-based supplements: meta-analysis of randomised trials.

Abstract: Objective: To determine the size of reduction in homocysteine concentrations produced by dietary supplementation with folic acid and with vitamins B-12 or B-6. Design: Meta-analysis of randomised controlled trials that assessed the effects of folic acid based supplements on blood homocysteine concentrations. Multivariate regression analysis was used to determine the effects on homocysteine concentrations of different doses of folic acid and of the addition of vitamin B-12 or B-6. Subjects: Individual data on 1114 people included in 12 trials. Findings: The proportional and absolute reductions in blood homocysteine produced by folic acid supplements were greater at higher pretreatment blood homocysteine concentrations (P < 0.001) and at lower pretreament blood folate concentrations (P < 0.001). After standardisation to pretreatment blood concentrations of homocysteine of 12 mu mol/l and of folate of 12 nmol/l (approximate average concentrations for Western populations), dietary folic acid reduced blood homocysteine concentrations by 25% (95% confidence interval 23% to 28%; P < 0.001), with similar effects in the range of 0.5-5 mg folic acid daily, Vitamin B-12 (mean 0.5 mg daily) produced an additional 7% (3% to 10%) reduction in blood homocysteine, Vitamin B-6 (mean 16.5 mg daily) did not have a significant additional effect. Conclusions: Typically in Western populations, daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B-12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 mu mol/l to 8-9 mu mol/l). Large scale randomised trials of such regimens in high risk populations are now needed to determine whether lowering blood homocysteine concentrations reduces the risk of vascular disease.

The Medical Research Council trials in adult acute lymphocytic leukemia.

Abstract: Overall, the MRC Adult Leukaemia Trials have been successful, in that since the 1970s they have demonstrated a stepwise improvement in outcome. Examination of the survival curves shows the DFS rate at 5 years in UKALL Trial 1 of 5% rising to 38% in UKALL Trial XII (year 2000). Unfortunately, compared with children with ALL, these results in adults must be regarded as poor, because in the UKALL children's trials the EFS rate at 5 years for a child entered in the year 2000 is expected to be above 80%. With a low proportion of all adults entered into randomized trials, one cannot be certain that improvements result from treatment rather than patient selection. Only recently have randomized trials in adults become large enough to detect plausible treatment effects. The authors believe that the main contribution of these trials so far, confirmed by other groups, is in examining prognostic features in al patients and finding that age and the presence of the Ph chromosome, independent of WBC count, gender, and cell type, is the main feature for predicting outcome. The UKALL XII trial will provide valuable information on the relative merits of transplantation and molecular studies of MRD. An in-depth study of a large number of Ph chromosome-positive ALL leukemias will also provide information on which to base future studies. Preliminary data suggest that all Ph-positive patients should undergo some sort of allograft early after CR is achieved, because these patients are not rescued by BMT after relapse. At the time of the publication of this article, preliminary studies suggest that STIs may not be as effective in Ph-positive ALL as in chronic granulocytic leukemia. The challenge for the future is to understand the biologic role of age and its impact on outcome so as to overcome "ageism" in adult ALL.

Leukoaraiosis at Presentation and Disease Progression during Follow-up in Histologically Confirmed Cases of Dementia

Abstract: While Alzheimer’s disease and vascular dementia have distinct histopathological features, the combination of both may result in more severe symptoms of dementia.1,2 The effect of concomitant cerebrovascular disease or cerebrovascular risk factors on the clinical course of Alzheimer’s disease is uncertain. Leukoaraiosis, the bilateral symmetrical white matter lucencies visible on computed tomography (CT), is common in very elderly people and in patients with vascular dementia and Alzheimer’s disease.3 Leukoaraiosis is more common among individuals with a prior history of stroke, or cardiovascular risk factors,3 which has prompted many to consider that leukoaraioisis is a radiological correlate of small vessel disease. There is little histopathological evidence to substantiate this and, indeed, the pathological correlates of leukoaraiosis are by no means clear and may well reflect several different processes.4,5 The aim of this longitudinal clinicopathological study was to examine the prevalence of leukoaraiosis on CT at presentation among histological subtypes of dementia and assess their relevance to clinical progression of dementia.

The contribution of bacterial hypermutators to mutation in stationary phase.

Abstract: IN their discussion of mutation in stationary populations of Escherichia coli , Bull et al. ([2000][1]) conclude that all the mutations are arising in a small fraction of the population. They give as their reason the fact that they could fit the data of Torkelson et al. ([1997][2]) on multiple

High prevalence of potentially virulent strains of Helicobacter pylori in the general male British population

Abstract: BACKGROUND Strains of Helicobacter pylori that express the cytotoxin associated gene product A (CagA) may be more strongly associated with serious gastric diseases, such as gastric cancer and peptic ulceration, than other strains. Data, however, are sparse on the prevalence, risk factors, and other correlates of these strains in the general popu- lation. AIM To characterise aspects of the seroepidemiology of CagA + strains of H pylori in the general British population. METHODS We measured serum IgG antibodies to mixed H pylori antigens and separately to CagA in 1025 men aged 40–59 years who were randomly selected from a larger group of participants in a community based survey conducted in 18 different British towns. RESULTS Overall, 44% (95% confidence interval 41–47%) of the men were seropositive to CagA antibodies, representing about 61% (57–65%) of the men seropositive to mixed antigen H pylori . The risk factors for seropositivity to CagA antibodies were similar to those for seropositivity to mixed antigen H pylori , apart from an increased prevalence of reported bedroom sharing in childhood (p CONCLUSION In a nationwide study of potentially virulent H pylori strains, there was a high prevalence of the infection, with some evidence that acquisition of such strains might occur earlier in life than other strains.

Re-survey of the Whitehall Study of London Civil Servants: Changes in Risk Factors for Cardiovascular Disease during 29 Years of Follow-up:

Abstract: Background Substantial uncertainty persists about the relevance of blood pressure and cholesterol to the risk of cardiovascular disease in the elderly.Objective To investigate the determinants of cardiovascular risk in old age, and the relevance of such risk factors when recorded in middle and old age.Methods A re-survey in 1997 of 8537 survivors of a cohort of men who were originally examined in 1967-1970 when aged 40-69 years.Results Completed questionnaires were received from 7050 (82%) of the survivors, and blood pressure and blood samples from 5427 (64%), The response rate declined with increasing age, was inversely related to markers of socioeconomic status in 1967-70 and in 1997, and was lower in those who had been current smokers or had a higher blood pressure level in 1967-70, After excluding those with reported cardiovascular disease (25% of respondents), the mean levels of total cholesterol and apolipoprotein B were lower in older age groups, whereas apolipoprotein A, levels did not vary much with age. Among those with risk factors recorded both in 1967-70 and 1997, the prevalence of smoking had declined by two-thirds (32% in 1970 and 12% in 1997), the prevalence of diabetes had increased (0.3% versus 4.5%), and the mean systolic blood pressure had increased by 16 mmHg (130 versus 146 mmHg), but the diastolic blood pressure had not changed materially (80 versus 81 mmHg), and the measured levels of total cholesterol had increased by 0.5 mmol/l (although that change may be artefactual),Conclusion Follow-up of vital status in this cohort should permit an assessment of the relevance of risk factors recorded in middle and old age to cardiovascular disease in old age. (C) 2000 Lippincott Williams & Wilkins.

Re-survey of the whitehall study of London civil servants: Changes in risk factors for cardiovascular disease during 29 years of follow-up

Abstract: Background Substantial uncertainty persists about the relevance of blood pressure and cholesterol to the risk of cardiovascular disease in the elderly.Objective To investigate the determinants of cardiovascular risk in old age, and the relevance of such risk factors when recorded in middle and old age.Methods A re-survey in 1997 of 8537 survivors of a cohort of men who were originally examined in 1967-1970 when aged 40-69 years.Results Completed questionnaires were received from 7050 (82%) of the survivors, and blood pressure and blood samples from 5427 (64%), The response rate declined with increasing age, was inversely related to markers of socioeconomic status in 1967-70 and in 1997, and was lower in those who had been current smokers or had a higher blood pressure level in 1967-70, After excluding those with reported cardiovascular disease (25% of respondents), the mean levels of total cholesterol and apolipoprotein B were lower in older age groups, whereas apolipoprotein A, levels did not vary much with age. Among those with risk factors recorded both in 1967-70 and 1997, the prevalence of smoking had declined by two-thirds (32% in 1970 and 12% in 1997), the prevalence of diabetes had increased (0.3% versus 4.5%), and the mean systolic blood pressure had increased by 16 mmHg (130 versus 146 mmHg), but the diastolic blood pressure had not changed materially (80 versus 81 mmHg), and the measured levels of total cholesterol had increased by 0.5 mmol/l (although that change may be artefactual),Conclusion Follow-up of vital status in this cohort should permit an assessment of the relevance of risk factors recorded in middle and old age to cardiovascular disease in old age. (C) 2000 Lippincott Williams & Wilkins.

Zidovudine (AZT) versus AZT plus didanosine (ddI) versus AZT plus zalcitabine (ddC) in HIV infected adults

Abstract: BACKGROUND: Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. The next two drugs to be developed were didanosine (ddI) and zalcitabine (ddC). OBJECTIVES: To assess the effects of zidovudine (AZT), zidovudine plus didanosine (ddI) and zidovudine plus zalcitabine (ddC) on HIV disease progression and survival. SEARCH STRATEGY: Investigators and pharmaceutical companies were contacted, and MEDLINE searches were supplemented by searching conference abstracts. SELECTION CRITERIA: Randomised controlled trials comparing any two of AZT plus ddI, AZT plus ddC or AZT alone in participants with or without AIDS which collected information on deaths and new AIDS events. DATA COLLECTION AND ANALYSIS: Individual patient data with, wherever possible, follow-up obtained beyond that previously published were obtained and checked for internal consistency and consistency with any published reports; any apparent discrepancies were resolved with the trialists. Time to death and to disease progression (defined as a new AIDS-defining event or prior death) were analysed on an intention to treat basis, stratified to avoid direct comparisons between participants in different trials. MAIN RESULTS: Six trials were included in the meta-analysis. During a median follow-up of 29 months, 2904 individuals progressed, of whom 1850 died. The addition of ddI to AZT delayed both progression (RR 0.74; 95% CI 0.67 to 0.82, P<0.0001) and death (RR 0.72; 95% CI 0.64 to 0.82, P<0.0001). Likewise, the addition of ddC to AZT also delayed progression (RR 0. 86; 95% CI 0.78 to 0.94, P=0.001) and death (RR 0.87; 95% CI 0.77 to 0.98, P=0.02). After 3 years the estimated percentages alive and without a new AIDS event were 53% for AZT+ddI, 49% for AZT+ddC and 44% for AZT alone; the percentages alive were 68%, 63% and 59% respectively. Five of the six trials involved randomised comparisons of AZT+ddI versus AZT+ddC: in these, the AZT+ddI regimen had greater effects on disease progression (P=0.004) and death (P=0.009). REVIEWER'S CONCLUSIONS: The use of ddI and, to a lesser extent, ddC delayed both HIV disease progression and death, at least when added to AZT.

Immediate versus deferred zidovudine (AZT) in asymptomatic or mildly symptomatic HIV infected adults.

Abstract: BACKGROUND: Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. Subsequent trials in asymptomatic or early symptomatic HIV infection indicated short-term delays in disease progression with AZT, but not improved survival. OBJECTIVES: To assess the effects of immediate versus deferred zidovudine (AZT) on HIV disease progression and survival. SEARCH STRATEGY: Investigators and pharmaceutical companies were contacted, and MEDLINE searches were supplemented by searching conference abstracts. SELECTION CRITERIA: Randomised controlled trials comparing immediate versus deferred AZT in participants without AIDS which prospectively collected deaths and new AIDS events. DATA COLLECTION AND ANALYSIS: Individual patient data with, wherever possible, follow-up obtained beyond that previously published was obtained and checked for internal consistency and consistency with any published reports; any apparent discrepancies were resolved with the trialists. Time to death and to disease progression (defined as a new AIDS-defining event or prior death) were analysed on an intention to treat basis, stratified to avoid direct comparisons between participants in different trials. MAIN RESULTS: Nine trials were included in the meta-analysis. During a median follow-up of 50 months, 1908 individuals developed disease progression, of whom 1351 died. In the deferred group, 61% started antiretroviral therapy (median time to therapy 28 months, which was AZT monotherapy in 94%). During the first year of follow-up immediate AZT halved the rate of disease progression (P<0.0001), increasing the probability of AIDS-free survival at one year from 96% to 98%, but this early benefit did not persist: after 6 years AIDS-free survival was 54% in both groups, and at no time was there any difference in overall survival, which at 6 years was 64% with immediate and 65% with deferred AZT (rate ratio [RR] 1.04, 95% confidence interval [CI] 0. 94 to 1.15). REVIEWER'S CONCLUSIONS: Although immediate use of AZT halved disease progression during the first year, this effect was not sustained, and there was no improvement in survival in the short or long term.

Zidovudine (AZT) versus AZT plus didanosine (ddI) versus AZT plus zalcitabine (ddC) in HIV infected adults.

Abstract: BACKGROUND: Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. The next two drugs to be developed were didanosine (ddI) and zalcitabine (ddC). OBJECTIVES: To assess the effects of zidovudine (AZT), zidovudine plus didanosine (ddI) and zidovudine plus zalcitabine (ddC) on HIV disease progression and survival. SEARCH STRATEGY: Investigators and pharmaceutical companies were contacted, and MEDLINE searches were supplemented by searching conference abstracts. SELECTION CRITERIA: Randomised controlled trials comparing any two of AZT plus ddI, AZT plus ddC or AZT alone in participants with or without AIDS which collected information on deaths and new AIDS events. DATA COLLECTION AND ANALYSIS: Individual patient data with, wherever possible, follow-up obtained beyond that previously published were obtained and checked for internal consistency and consistency with any published reports; any apparent discrepancies were resolved with the trialists. Time to death and to disease progression (defined as a new AIDS-defining event or prior death) were analysed on an intention to treat basis, stratified to avoid direct comparisons between participants in different trials. MAIN RESULTS: Six trials were included in the meta-analysis. During a median follow-up of 29 months, 2904 individuals progressed, of whom 1850 died. The addition of ddI to AZT delayed both progression (RR 0.74; 95% CI 0.67 to 0.82, P<0.0001) and death (RR 0.72; 95% CI 0.64 to 0.82, P<0.0001). Likewise, the addition of ddC to AZT also delayed progression (RR 0. 86; 95% CI 0.78 to 0.94, P=0.001) and death (RR 0.87; 95% CI 0.77 to 0.98, P=0.02). After 3 years the estimated percentages alive and without a new AIDS event were 53% for AZT+ddI, 49% for AZT+ddC and 44% for AZT alone; the percentages alive were 68%, 63% and 59% respectively. Five of the six trials involved randomised comparisons of AZT+ddI versus AZT+ddC: in these, the AZT+ddI regimen had greater effects on disease progression (P=0.004) and death (P=0.009). REVIEWER'S CONCLUSIONS: The use of ddI and, to a lesser extent, ddC delayed both HIV disease progression and death, at least when added to AZT.

The interface between molecular biology and cancer research.

Abstract: During the last thirty years, cancer research has been a remarkably fruitful resource for molecular biologists. Numerous fundamental discoveries in basic biology have come out of research into the properties of cancer cells; for example, the discovery of reverse transcriptase, RNA splicing and the protein kinases. Recently, information has started to flow in the other direction, and we are at last beginning to see molecular biology yielding discoveries of practical importance in the management and control of human cancer. Some of the past and possible future interactions of molecular biology and cancer research are discussed in this paper.

Estimating the contribution of Helicobacter pylori to gastric cancer.

Abstract: A synthesis of available prospective epidemiological studies i cates that chronic infection with Helicobacter pyloriis about two or three times as common in people with gastric cancer tha others (risk ratio 2.5, 95% confidence interval 1.9–3.4) (Dan 1999a). As stated previously (Danesh, 1999b), some pote biases in published studies may have exaggerated this es (such as the preferential publication of more striking findin and/or inadequate adjustment for possible confounders, smoking); by contrast, other possible biases may have result some underestimation (such as the use of serological assa developing countries based on bacterial antigens found in d oped countries and/or failure of studies to exclude from anal the first few years of follow-up to minimize any effects of ea gastric cancer on H. pylori serostatus) (Danesh, 1999b). Su factors cannot, however, plausibly account for much of the ov association observed between H. pylori infection and gastric cancer (although more appropriate allowances for such bias future studies might somewhat change the present estimate magnitude of risk). Ponce-de-Leon and colleagues discuss another possible that might overestimate the association between H. pylori infection and gastric cancer. They suggest that, in comparison with infected people, H. pylori seropositive individuals might receiv additional gastroenterological investigation (such as up

Cancer Research by Way of Metaphor

Abstract: Cancer The Evolutionary Legacy. Mel Greaves. Oxford University Press, Oxford, 2000. 288 pp. $27.50, £19.99. ISBN 0-19-262835-6. Writing for non-scientists, Greaves offers a perspective that emphasizes the evolutionary context of the diverse illnesses we call cancer.